Chapter75_Drug Reactions

75.1

C HA PT E R 75

Drug Reactions S.M. Breathnach St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK

Incidence of drug reactions, 75.3

Eczematous eruptions, 75.35

Drugs acting on the cardiovascular system, 75.89

Classification and mechanisms of drug reactions,

Bullous eruptions, 75.37

Drugs acting on the respiratory system, 75.98

Vasculitis, 75.40

Drugs acting on the renal system, 75.99

Histopathology of drug reactions, 75.21

Lupus erythematosus-like syndrome, 75.41

Drugs acting on the skeletal system, 75.99

Types of clinical reaction, 75.22

Dermatomyositis reactions, 75.42

Drugs for erectile dysfunction, 75.99

Exanthematic (maculopapular) reactions, 75.22

Scleroderma-like reactions, 75.42

Metals and metal antagonists, 75.99

Purpura, 75.23

Erythema nodosum, 75.43

Anticoagulants, fibrinolytic agents and antiplatelet

Annular erythema, 75.23

Pseudolymphomatous drug hypersensitivity syndrome,

75.9

Pityriasis rosea-like reactions, 75.24 Psoriasiform eruptions, 75.24 Exfoliative dermatitis, 75.24

75.44

drugs, 75.104 Vitamins including retinoids, 75.108

Acanthosis nigricans-like and ichthyosiform eruptions, 75.44

Hormones and related compounds, 75.114 Chemotherapeutic (cytotoxic) agents, 75.121

Anaphylaxis and anaphylactoid reactions, 75.25

Erythromelalgia, 75.44

Drugs affecting the immune response, 75.136

Urticaria, 75.26

Hair changes, 75.45

Injections, infusions and procedures, 75.150

Drug rash with eosinophilia and systemic symptoms

Nail changes, 75.46

Drugs affecting metabolism or gastrointestinal

(DRESS) syndrome, 75.26 Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis, 75.27

Oral conditions, 75.46

function, 75.156

Important or widely prescribed drugs, 75.47

Miscellaneous drugs, 75.158

Antibacterial agents, 75.47

Herbal remedies, homeopathy and naturopathy

Serum sickness, 75.27

Antileprotic drugs, 75.62

Fixed eruptions, 75.28

Antifungal drugs, 75.64

Industrial and other exposure to chemicals, 75.162

Lichenoid eruptions, 75.30

Antiviral agents, 75.66

Local and systemic effects of topical applications,

Photosensitivity, 75.30

Antimalarials, 75.69

Pigmentation reactions, 75.32

Anthelmintics, 75.71

Management of drug reactions, 75.167

Acneiform and pustular eruptions, 75.34

Drugs for Pneumocystis, 75.72

Diagnosis, 75.167

Acute generalized exanthematous pustulosis (toxic

Non-steroidal anti-inflammatory drugs, 75.72

Treatment, 75.175

pustuloderma), 75.34

(alternative therapy), 75.160

75.163

Drugs acting on the central nervous system, 75.78

Introduction [1–4] A drug may be defined as a chemical substance, or combination of substances, administered for the investigation, prevention or treatment of diseases or symptoms, real or imagined. The distinction between drugs and ‘other chemicals’ is not always easily made, as chemicals of very diverse structure are increasingly added to foods and beverages as dyes, flavours or preservatives. Such chemicals may cause harmful side effects. Moreover, chemicals used in agriculture or in veterinary medicine may contaminate human food. In addition, with the advent of therapeutic agents that may be useful for improving the appearance, as with

Rook’s Textbook of Dermatology, Volume 1, Eighth Edition Edited by Tony Burns, Stephen Breathnach, Neil Cox and Christopher Griffiths © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-16169-5

minoxidil for androgenetic alopecia and tretinoin for photo-aged skin, the distinction between drugs and cosmetics has become blurred [5]. An adverse drug reaction (ADR) may be defined as an undesirable clinical manifestation resulting from administration of a particular drug; this includes reactions due to overdose, predictable side effects and unanticipated adverse manifestations. Another definition is that of ‘an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product’ [6]. It has been proposed that therapeutic ineffectiveness should also be regarded as an ADR [7]. ADRs may be said to be the inevitable price we pay for the benefits of modern drug therapy [8]. They are costly

75.2

Chapter 75: Drug Reactions

both in terms of the human illness caused and in economic terms, and can undermine the doctor–patient relationship. Sometimes, ADRs result from human error [9]. In one study, 0.9% of 530 medication errors resulted in ADRs [10]; these usually involved errors at the ordering stage, but also occurred at the administration stage [11]. In hospitals, medication errors occur at a rate of about one per patient per day; dispensing errors made by pharmacy staff range from 0.87 to 2.9% [12]. ADRs are underreported and are an underestimated cause of morbidity and mortality; it has been estimated that ADRs represent the fourth to the sixth leading cause of death [13]. The actual frequency of fatal adverse drug events is unknown; estimates in the USA are as high as 140 000/year, although this number is heavily disputed [14]. In one study, 68% of fatal ADRs were judged to have been preventable; of these, a pharmacist could have prevented 57% [15]. Approximately 1 in 2000 of all deaths for which there were records of coroners’ inquests in one district were related to drugs; of these, 20% were due to errors [16]. During 1995, 206 deaths were attributed to ADRs on death certificates in the USA, but the spontaneous post-marketing surveillance system (MedWatch) of the Food and Drug Administration (FDA) tabulated 6894 fatalities. The numbers of deaths in these datasets varied 34-fold and were up to several 100-fold less than values based on extrapolations of surveillance programmes [17]. Confusion may occur between drugs with similar spelling of their brand names [18,19]. It has been proposed that licensing authorities should exercise more control over the naming of new proprietary formulations, that non-proprietary and new proprietary names should be internationalized, and that doctors should issue printed prescriptions if possible [20]. The average extra length of stay for patients with an adverse drug event in one study in the USA was 1.9 days, and the average extra cost of hospitalization was $1939 [21]. In another study, at a university-affiliated hospital, the mean cost of an ADR or medication error varied from $95 for additional laboratory tests to $2640 for intensive care; the estimated total cost for the medicationrelated problems reported in 1994 was almost $1.5 million [22]. In a European study, ADRs occurred at 10.1 per 1000 patient-days, and the cost of ADRs leading to hospitalization was estimated at €11 357 per hospital bed per year [23]. Litigation was reported for 14% of fatal ADR cases at one centre; judgements and settlements averaged $1.1 million [15]. Drug reactions, principally to corticosteroids and methotrexate, accounted for 32% of claims and 26% of dollar losses in dermatology malpractice suits in the USA from 1963 to 1973 inclusive [24]. Medication side effects, most frequently to corticosteroids, antibiotics and chemotherapeutic agents, represented 26% of lawsuits in a study of dermatology residency programmes in the USA between 1964 and 1988 [25]. If legal consequences are to be avoided, consistent care is needed at every stage from drug manufacture to administration [26]. It is in everyone’s interests to minimize the chances of ADR occurrence, and to this end government regulatory bodies and the pharmaceutical industry collaborate to ensure adequate screening of new products. In addition to extensive in vitro and animal testing, prolonged and strictly controlled clinical trials are essential. Even so, hazards cannot be completely eliminated, because a serious reaction of low incidence may not be suspected until a

very large number of patients have been treated with a new drug. Pre-marketing clinical trials conducted before a new drug is licensed may have involved less than 5000 patients, with exclusion of women of childbearing potential, the elderly and children, and those with coexistent disease and using a number of common drug treatments [27]. They will not identify adverse reactions occurring in less than 0.1–1% of patients, or those occurring only after prolonged administration, or with a long latency period, or only in susceptible patients, or when the drug is combined with some other factor, such as another drug [28,29]. Participation in post-marketing pharmacosurveillance by clinicians is generally voluntary, and underreporting is widespread [27]. Another problem is that only a very small fraction of all adverse reactions are ever reported to monitoring agencies, and first warning is still often given by anecdotal reports published in medical journals [30,31]. Many of these reports are subsequently validated, but a substantial proportion of poorly documented reports are not [31,32]. In an analysis of 5737 articles from 80 countries between 1972 and 1979, only half the reports contained enough information for the calculation of the frequency of a particular reaction [32]. The usefulness of anecdotal case reports has been called into question, as suspicions are seldom subjected to confirmatory investigation, and such alerts are not systematically incorporated into drug reference sources [33,34]. As incorrect reports may have serious legal and other consequences, a heavy responsibility rests with medical editors; a chance association or coincidental reaction should not be allowed to enter the literature. Criteria for assessment of potential drug reactions have been promulgated, and include: recurrence on challenge; existence of a pharmacological basis for the reactions; the occurrence of immediate acute or local reactions at the time of administration, of previously known reactions with a new route of administration, or of repeated rare reactions; and the presence of immunological abnormalities [31,35]. In the assessment of an unrecorded new reaction, the existence of similar but unpublished reports to the manufacturer or to surveillance bodies is of particular importance. References 1 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 2 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 3 Zürcher L, Krebs A. Cutaneous Drug Reactions. Basel: Karger, 1992. 4 Litt JZ, Pawlak WA Jr. Drug Eruption Reference Manual. New York: Parthenon, 1997. 5 Lavrijsen APM, Vermeer BJ. Cosmetics and drugs. Is there a need for a third group: cosmeceutics? Br J Dermatol 1991; 124: 503–4. 6 Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255–9. 7 Meyboom RH, Lindquist M, Flygare AK et al. The value of reporting therapeutic ineffectiveness as an adverse drug reaction. Drug Saf 2000; 23: 95–9. 8 Nolan L, O’Malley K. Adverse drug reactions in the elderly. Br J Hosp Med 1989; 41: 446–57. 9 Wright D, Mackenzie SJ, Buchan I et al. Critical events in the intensive therapy unit. Lancet 1991; 338: 676–8. 10 Bates DW, Boyle DL, Vander Vliet MB et al. Relationship between medication errors and adverse drug events. J Gen Intern Med 1995; 10: 199–205. 11 Bates DW, Cullen DJ, Laird N et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA 1995; 274: 29–34. 12 Allan EL, Barker KN. Fundamentals of medication error research. Am J Hosp Pharm 1990; 47: 555–71.

Drug reactions 13 Brown SD Jr, Landry FJ. Recognizing, reporting, and reducing adverse drug reactions. South Med J 2001; 94: 370–3. 14 Kelly WN. Can the frequency and risks of fatal adverse drug events be determined? Pharmacotherapy 2001; 21: 521–7. 15 Kelly WN. Potential risks and prevention. Part 1: fatal adverse drug events. Am J Health Syst Pharm 2001; 58: 1317–24. 16 Ferner RE, Whittington RM. Coroner’s cases of death due to errors in prescribing or giving medicines or to adverse drug reactions: Birmingham 1986–1991. J R Soc Med 1994; 87: 145–8. 17 Chyka PA. How many deaths occur annually from adverse drug reactions in the United States? Am J Med 2000; 109: 122–30. 18 Fine SN, Eisdorfer RM, Miskovitz PF, Jacobson IM. Losec or Lasix? N Engl J Med 1990; 322: 1674. 19 Faber J, Azzugnuni M, Di Romana S, Vanhaeverbeek M. Fatal confusion between ‘Losec’ and ‘Lasix’. Lancet 1991; 337: 1286–7. 20 Aronson JK. Confusion over similar drug names. Problems and solutions. Drug Saf 1995; 12: 55–60. 21 Evans RS, Classen DC, Stevens LE et al. Using a hospital information system to assess the effects of adverse drug events. In: Proceedings of the Ann Symp Comp Appl Medical Care. 1993: 161–5. 22 Schneider PJ, Gift MG, Lee YP et al. Cost of medication-related problems at a university hospital. Am J Health System Pharm 1995; 52: 2415–8. 23 Lagnaoui R, Moore N, Fach J et al. Adverse drug reactions in a department of systemic diseases-oriented internal medicine: prevalence, incidence, direct costs and avoidability. Eur J Clin Pharmacol 2000; 56: 181–6. 24 Altman J. Survey of malpractice claims in dermatology. Arch Dermatol 1975; 111: 641–4. 25 Hollabaugh ES, Wagner RF Jr, Weedon VW, Smith EB. Patient personal injury litigation against dermatology residency programs in the United States 1964– 1988. Arch Dermatol 1990; 126: 618–22. 26 Day AT. Adverse drug reactions and medical negligence. Adverse Drug React Bull 1995; 172: 651–4. 27 Gough S. Post-marketing surveillance: a UK/European perspective. Curr Med Res Opin 2005; 21: 565–70. 28 Bruinsma W. Drug monitoring in dermatology. Int J Dermatol 1986; 25: 166–7. 29 Committee of Management Prescribers’ Journal. Adverse drug reactions. Prescribers J 1991; 31: 1–3. 30 Anonymous. Crying wolf on drug safety. BMJ 1982; 284: 219–20. 31 Venning GR. Validity of anecdotal reports of suspected adverse drug reactions: the problem of false alarms. BMJ 1982; 284: 249–52. 32 Venulet J, Blattner R, von Bülow J, Berneker GC. How good are articles on adverse drug reactions? BMJ 1982; 284: 252–4. 33 Stern RS, Chan H-L. Usefulness of case report literature in determining drugs responsible for toxic epidermal necrolysis. J Am Acad Dermatol 1989; 21: 317–22. 34 Loke YK, Price D, Derry S, Aronson JK. Case reports of suspected adverse drug reactions—systematic literature survey of follow-up. BMJ 2006; 332: 335–9. 35 Stern RS, Wintroub BU. Adverse drug reactions: reporting and evaluating cutaneous reactions. Adv Dermatol 1987; 2: 3–18.

Incidence of drug reactions [1,2] Data collection It is difficult to obtain reliable information on the incidence of drug reactions, despite attempts at monitoring by government and the pharmaceutical industry. One problem is the lack of standardized coding for drug reactions [3]. Moreover, the information that is available must be interpreted with considerable care, because data will be biased, depending on the method of collection [1,2]. Thus, data on medical in-patients, especially from acute care facilities, may indicate a relatively high incidence, because these patients are generally sicker and receive more intensive drug treatment. In contrast, spontaneous reporting may underestimate the true incidence [4–7]. National schemes for collating reported ADRs exist

75.3

in many countries, and the World Health Organization’s Adverse Reaction Collaborating Centre, in Uppsala, provides a very large database [2], as does the Adverse Event Reporting System of the US Food and Drug Administration [6–8]. For the 33-year period from 1969 to 2002, about 2.3 million case reports of adverse events for the cumulative number of approximately 6000 marketed drugs were entered in the FDA database [8]. During this period, numerous drug reactions were identified, over 75 drugs/drug products were removed from the market, and 11 drugs were restricted; drugs withdrawn or restricted represent about 1% of marketed drugs. The UK’s ‘yellow card’ reporting scheme solicits ADR reports from doctors, dentists, coroners and drug manufacturers; the wide availability of reporting forms is important in encouraging reporting [2]. The scheme has recently encouraged reporting by nursing staff, midwives and health visitors [9]. Yellow reporting cards may be obtained electronically on http://yellowcard. mhra.gov.uk/. Pharmacists also play an important role in reporting ADRs [10]. The advisability of direct reporting of ADRs by patients is becoming an increasingly important topic for discussion in the world of pharmacovigilance [11–13]. Patient reports identified possible new ADRs not previously reported by health professionals [12], and were judged to contribute significantly to pharmacovigilance [13]. However, 94% of claimed ADRs in children were not confirmed following complete evaluation [14]. ‘Pharmacovigilence’ in France, which involves reporting to regional centres, along with most other national schemes, also relies entirely on spontaneous reporting [15,16]. Institution of an ADR reporting project in Rhode Island in the USA increased the rate of reporting of such reactions more than 17-fold over a 2-year period [17]. The quality of ADR reporting to the FDA improved following introduction of the MedWatch scheme [18]. Specialitybased systems for spontaneous reporting of ADRs (e.g. the Adverse Drug Reaction Reporting System of the American Academy of Dermatology [19] and the Gruppo Italiano Studi Epidemiologici in Dermatologia [20]) have been introduced. In the UK, in contrast, the specialty-based Cutaneous Reactions Database established at the Institute of Dermatology in 1988 was unfortunately closed in 1990 because of a meagre response [21]. Reporting of ADRs in clinical trials is neglected, compared with efficacy outcomes; of 192 randomized trials analysed, only 46% specified reasons for withdrawals due to toxicity, and only 39% of clinical adverse effects and 29% of laboratory-determined toxicity were adequately documented [22]. Inherent difficulties with spontaneous reporting are that reactions associated with newly marketed drugs, those of unusual morphology and reactions starting soon after initiation of therapy are more likely to be notified; at best only a crude estimate of true incidence is provided [23–25]. Thus, drugs with a high potential for eliciting clinically significant ADRs are usually detected and either withdrawn from the market or placed on restricted use within the first year or two of marketing [26]. In contrast, spontaneous reports do not reliably detect ADRs widely separated in time from the original use of the drug, or that occur more commonly in populations not usually exposed to the drug [27]. They are an unreliable measure of risk, and may simply provide evidence of the relative awareness among physicians of specific toxic effects [28], or of variation in prescribing practice [29].

75.4

Chapter 75: Drug Reactions

All national spontaneous reporting systems are compromised by underreporting [2,4,5]; in the UK, past surveys suggested that only around 10% of serious reactions were notified to the Committee on Safety of Medicines [30,31]. A survey of 44 000 patients receiving one or other of seven new drugs suggested that underreporting by the spontaneous system may be as high as 98% when compared with information collected by the more objective ‘event monitoring’ system [15]. A recent report emphasizes that most UK doctors do not report adverse drug reactions [32]. This is a worldwide phenomenon. The Global Advisory Committee on Vaccine Safety of the WHO Adverse Reactions Database determined that, in 2005, three countries contributed 82% of vaccine-related reports, the mean time lag being 2.4 years [33]; concern was expressed that many member countries did not forward all or even any reports of adverse events, and that poor timeliness and regularity of reporting jeopardized timely generation of safety signals. Heavy prescribing by a minority of doctors immediately following licensing may place patients at unnecessary risk, and affects safety monitoring of new drugs; the 10% of doctors who prescribed most heavily accounted for 42% of total prescribing in a survey of 28 402 general practitioners asked to supply post-marketing data on 27 new drugs dispensed in England between September 1984 and June 1991, but returned proportionately far fewer questionnaires [34]. Reasons for underreporting include lack of time, lack of report forms and the misconception that absolute confidence in the diagnosis of an adverse reaction was important [35]; workload may affect reporting [36]. Another factor is the perceived deterrent to reporting ADRs caused by fear of involvement in litigation [37]; reporting of errors should be free of recrimination [38]. The offer of a small fee increased the rate of reporting in one hospital study almost 50-fold [39]. Pharmacoepidemiology, the epidemiological assessment of adverse drug effects, and pharmacovigilance, the process of identifying and responding to safety issues about marketed drugs, necessitate making use of information from clinical trials, spontaneous reporting systems, speciality-based reporting systems, case reports, prescription monitoring, case series, cohort studies, case– control studies, population-based registries using computerized material, and special surveillance programmes (e.g. Boston Collaborative Drug Surveillance Program in the USA) [40–42]. Crude inspection of lists of spontaneously reported drug-event combinations can be supplemented by quantitative and automated numerator-based methods such as Bayesian data mining; pharmacovigilance specialists should not be intimidated by the mathematics [43]. Computerized detection of adverse events may soon be practical on a widespread basis [44]. This is just as well, as it has been estimated that the top 20 drug companies will each need to launch four to six times the number of drugs they currently produce merely to maintain shareholder returns, with more trials, and more safety reports for evaluation [45]. References 1 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 2 Rawlins MD, Breckenridge AM, Wood SM. National adverse drug reaction reporting: a silver jubilee. Adverse Drug React Bull 1989; 138: 516–9. 3 Bonnetblanc JM, Roujeau JC, Benichou C. Standardized coding is needed for reports of adverse drug reactions. BMJ 1996; 312: 776–7.

4 Edwards IR. The management of adverse drug reactions: from diagnosis to signal. Therapie 2001; 56: 727–33. 5 Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006; 29: 385–96. 6 Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf 2001; 10: 407–10. 7 Ahmad SR. Adverse drug event monitoring at the Food and Drug Administration. J Gen Intern Med 2003; 18: 57–60. 8 Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Arch Intern Med 2005; 165: 1363–9. 9 Morrison-Griffiths S, Walley TJ, Park BK et al. Reporting of adverse drug reactions by nurses. Lancet 2003; 361: 1347–8. 10 van Grootheest AC, van Puijenbroek EP, de Jong-van den Berg LT. Contribution of pharmacists to the reporting of adverse drug reactions. Pharmacoepidemiol Drug Saf 2002; 11: 205–10. 11 van Grootheest K, de Graaf L, de Jong-van den Berg LT. Consumer adverse drug reaction reporting: a new step in pharmacovigilance? Drug Saf 2003; 26: 211–7. 12 Blenkinsopp A, Wilkie P, Wang M, Routledge PA. Patient reporting of suspected adverse drug reactions: a review of published literature and international experience. Br J Clin Pharmacol 2007; 63: 148–56. 13 de Langen J, van Hunsel F, Passier A et al. Adverse drug reaction reporting by patients in the Netherlands: three years of experience. Drug Saf 2008; 3: 515–24. 14 Rebelo Gomes E, Fonseca J, Araujo L, Demoly P. Drug allergy claims in children: from self-reporting to confirmed diagnosis. Clin Exp Allergy 2008; 38: 191–8. 15 Fletcher AP. Spontaneous adverse drug reaction reporting vs event monitoring: a comparison. J R Soc Med 1991; 84: 341–4. 16 Moore N, Paux G, Begaud B et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; ii: 1056–8. 17 Scott HD, Thacher-Renshaw A, Rosenbaum SE et al. Physician reporting of adverse drug reactions. Results of the Rhode Island Adverse Drug Reaction Reporting Project. JAMA 1990; 263: 1785–8. 18 Piazza-Hepp TD, Kennedy DL. Reporting of adverse events to MedWatch. Am J Health Syst Pharm 1995; 52: 1436–9. 19 Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroid anti-inflammatory drugs. Reports to a specialty-based system for spontaneous reporting of adverse reactions to drugs. JAMA 1984; 252: 1433–7. 20 Gruppo Italiano Studi Epidemiologici in Dermatologia. Spontaneous monitoring of adverse reactions to drugs by Italian dermatologists: a pilot study. Dermatologica 1991; 182: 12–7. 21 Kobza Black A, Greaves MM. Cutaneous reactions database closure. Br J Dermatol 1990; 123: 277. 22 Ioannidis JP, Lau J. Improving safety reporting from randomised trials. Drug Saf 2002; 25: 77–84. 23 Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting: Part I. Adverse Drug React Acute Poisoning Rev 1985; 4: 213–30. 24 Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting: Part II. Adverse Drug React Acute Poisoning Rev 1986; 5: 23–55. 25 Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting: Part III. Adverse Drug React Acute Poisoning Rev 1989; 8: 203–15. 26 Ajayi FO, Sun H, Perry J. Adverse drug reactions: a review of relevant factors. J Clin Pharmacol 2000; 40: 1093–101. 27 Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999; 281: 824–9. 28 Miwa LJ, Jones JK, Pathiyal A, Hatoum H. Value of epidemiologic studies in determining the true incidence of adverse events. The nonsteroidal anti-inflammatory drug story. Arch Intern Med 1997; 157: 2129–36. 29 Clark RC, Maxwell SR, Kerr S et al. The influence of primary care prescribing rates for new drugs on spontaneous reporting of adverse drug reactions. Drug Saf 2007; 30: 357–66. 30 Rawlins MD. Spontaneous reporting of adverse drug reactions I: the data. Br J Clin Pharmacol 1988; 26: 1–5. 31 Bem JL, Mann RD, Rawlins MD. Review of yellow cards 1986 and 1987. BMJ 1988; 296: 1319. 32 Hitchen L. Most doctors still don’t report adverse reactions to drugs. BMJ 2008; 336: 299.

Drug reactions 33 Letourneau M, Wells G, Walop W, Duclos P. Improving global monitoring of vaccine safety: a quantitative analysis of adverse event reports in the WHO Adverse Reactions Database. Vaccine 2008; 26: 1185–94. 34 Inman W, Pearce G. Prescriber profile and post-marketing surveillance. Lancet 1993; 342: 658–61. 35 Belton KJ, Lewis SC, Payne S et al. Attitudinal survey of adverse drug reaction reporting by medical practitioners in the United Kingdom. Br J Clin Pharmacol 1995; 39: 223–6. 36 Bateman DN, Sanders GL, Rawlins MD. Attitudes to adverse drug reaction reporting in the Northern Region. Br J Clin Pharmacol 1992; 34: 421–6. 37 Kaufman MB, Stoukides CA, Campbell NA. Physicians’ liability for adverse drug reactions. South Med J 1994; 87: 780–4. 38 Upton DR, Cousins DH. Avoiding drug errors. Reporting of errors should be free of recrimination. BMJ 1995; 311: 1367. 39 Feely J, Moriarty S, O’Connor P. Stimulating reporting of adverse drug reactions by using a fee. BMJ 1990; 300: 22–3. 40 Stern RS, Wintroub BU. Adverse drug reactions: reporting and evaluating cutaneous reactions. Adv Dermatol 1987; 2: 3–18. 41 Stern RS. Epidemiologic assessment of adverse drug effects. Semin Dermatol 1989; 8: 136–40. 42 Rawlins MD. Pharmacovigilance: paradise lost, regained or postponed? J R Coll Physicians Lond 1995; 29: 41–5. 43 Hauben M, Zhou X. Quantitative methods in pharmacovigilance: focus on signal detection. Drug Saf 2003; 26: 159–86. 44 Bates DW, Evans RS, Murff H et al. Detecting adverse events using information technology. J Am Med Inform Assoc 2003; 10: 115–28. 45 Peachey J. From pharmacovigilance to pharmacoperformance. Drug Saf 2002; 25: 399–405.

General incidence of adverse drug reactions The incidence of ADRs varies from 6% [1] to 30% [2], with an estimated at least 90 million courses of drug treatment given yearly in the USA, as recorded in 1984 [3]. A report in 2006 estimated that adverse drug reactions resulted in 250 000 UK admissions a year [4]. The reported percentage of patients who develop an ADR during hospitalization varies markedly in different studies from 1.4 to 44%, although in most studies the incidence is about 10–20% [5–7], of which about one-third are allergic or pseudoallergic [7]. In one study, 0.23% of a total of 90 910 admissions had drug allergy; antimicrobials and antiepileptic drugs comprised 75% of the drug allergies reported [8]. The incidence of drug allergy in hospitalized patients was 4.2 per 1000; drug allergy developed during in-patient treatment in 2.07 per 1000 hospitalizations [8]. About 3–8% of hospital admissions are a consequence of ADRs [9–11]. A survey of 30 195 randomly selected hospital records in 51 hospitals in the state of New York found that 19% of adverse events caused by medical treatment were the result of drug complications; the most frequently implicated classes of drugs were antibiotics, antitumour agents and anticoagulants [12]. Negligence accounted for 18% of ADRs, and allergic/cutaneous complications constituted 14% of all drugrelated complications. Less information is available about the incidence among outpatients. It has been estimated that about 1 in 40 consultations in general practice are the result of ADRs [13], and eventually 41% of patients develop a reaction [14]. In one multicentre general practice study in the UK, the percentage of consultations involving an ADR increased from 0.6% for patients aged 0–20 years to 2.7% for patients aged over 50 years [15]; in another study, 2.5% of consultations were the result of iatrogenic illness [16]. It was estimated that more than 1 in 9 emergency department visits were

75.5

due to drug-related adverse events, a potentially preventable problem [17]. Fatal reactions to drugs are more common than is generally realized. It was previously estimated that penicillin caused 300 deaths each year in the USA alone [18]. Anaphylactic reactions to penicillin were reported, in 1968, to occur in about 0.015%, and fatal reactions in up to 0.002% (i.e. 1 per 50 000), of treatment courses [19]. These figures may be somewhat lower today, with use of newer beta-lactam antibiotics. The risk of fatal aplastic anaemia with chloramphenicol therapy was reported as at least 1 in 60 000 [20], and the risk of a fatal outcome from treatment with monoamine oxidase inhibitors may be of the same order. It has been estimated that the incidence of fatality as a result of a drug reaction among in-patients is between 0.1 and 0.3% [6,21,22]; fatality due to allergy occurs at a rate of 0.09 per 1000 cases [8]. References 1 Deswarte RD. Drug allergy: problems and strategies. J Allergy Clin Immunol 1984; 74: 209–21. 2 Jick H. Adverse drug reactions: the magnitude of the problem. J Allergy Clin Immunol 1984; 74: 555–7. 3 Goldstein RA. Foreword. Symposium proceedings on drug allergy: prevention, diagnosis, treatment. J Allergy Clin Immunol 1984; 74: 549–50. 4 Hitchen L. Adverse drug reactions result in 250,000 UK admissions a year. BMJ 2006; 332: 1109. 5 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 6 Gruchalla R. Understanding drug allergies. J Allergy Clin Immunol 2000; 105: S637–44. 7 Demoly P, Bousquet J. Epidemiology of drug allergy. Curr Opin Allergy Clin Immunol 2001; 1: 305–10. 8 Thong BY, Leong KP, Tang CY, Chung HH. Drug allergy in a general hospital: results of a novel prospective inpatient reporting system. Ann Allergy Asthma Immunol 2003; 90: 342–7. 9 McKenney JM, Harrison WL. Drug-related hospital admissions. Am J Hosp Pharm 1976; 33: 792–5. 10 Levy M, Kewitz H, Altwein W et al. Hospital admissions due to adverse drug reactions: a comparative study from Jerusalem and Berlin. Eur J Clin Pharmacol 1980; 17: 25–31. 11 Black AJ, Somers K. Drug-related illness resulting in hospital admission. J R Coll Physicians Lond 1984; 18: 40–1. 12 Leape LL, Brennan TA, Laird N et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324: 377–84. 13 Kellaway GSM, McCrae E. Intensive monitoring of adverse drug effects in patients discharged from acute medical wards. NZ Med J 1973; 78: 525–8. 14 Martys CR. Adverse reactions to drugs in general practice. BMJ 1979; ii: 1194–7. 15 Lumley LE, Walker SR, Hall CG et al. The under-reporting of adverse drug reactions seen in general practice. Pharm Med 1986; 1: 205–12. 16 Mulroy R. Iatrogenic disease in general practice: its incidence and effects. BMJ 1973; ii: 407–10. 17 Zed PJ, Abu-Laban RB, Balen RM et al. Incidence, severity and preventability of medication-related visits to the emergency department: a prospective study. Can Med Assoc J 2008; 178: 1563–9. 18 Parker CW. Allergic reactions in man. Pharmacol Rev 1983; 34: 85–104. 19 Idsøe O, Guthe T, Willcox RR, De Weck AL. Nature and extent of penicillin side reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968; 38: 159–88. 20 Witts LJ. Adverse reactions to drugs. BMJ 1965; ii: 1081–6. 21 Davies DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 1–11. 22 Caranasos GJ, May FE, Stewart RB, Cluff LE. Drug-associated deaths of medical inpatients. Arch Intern Med 1976; 136: 872–5.

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Chapter 75: Drug Reactions

Risk of adverse drug reactions among different patient groups Certain patient groups are at increased risk of developing an ADR. Women are more likely than men to develop ADRs [1]. The incidence of such reactions increases with the number of drugs taken in both hospital in-patients [2–4] and out-patients [5,6]. Although data are somewhat conflicting [7], the burden of evidence suggests that the incidence of adverse reactions increases with patient age [1,8,9]. Although those over 65 years of age comprise only 12% of the population in the USA, 33% of all drugs are prescribed for this age group, and the elderly have a significantly higher incidence of ADRs, related to decreased organ reserve capacity, altered pharmacokinetics and pharmacodynamics, and polypharmacy [10]. Similarly, in the UK, the elderly are dispensed twice as many prescriptions as the national average [11]. Potential adverse drug interactions are more common in elderly patients because of the higher number of concurrent medications, rather than age-based factors [12]. ADRs contribute to the need for hospitalization in 6–17% of elderly in-patients [13–16]. Inappropriate medication is a major cause of ADRs in elderly patients [16,17]; 27% of elderly patients on medication who were admitted to a teaching hospital experienced ADRs, of which almost 50% were due to drugs with absolute contraindications and/or that were unnecessary [18]. ADRs occur in 6–17% of children admitted to specialist paediatric hospitals [19]. Immunosuppressed patients are most frequently affected, such as those with connective tissue diseases, including systemic lupus erythematosus (SLE) (relative risk 4.68 higher) and autoimmune hepatitis, AIDS patients (relative risk 8.68), and non-Hodgkin’s lymphoma [20,21]. Patients with Sjögren’s syndrome (SS) have also been reported to have a high frequency of drug allergy. In different series, drug allergy has been reported in 43% of SS patients compared with 9% of patients with SLE without SS [22], in 62% of SS patients [23], and in 41% of rheumatoid arthritis patients with SS compared with 17% of those without SS [24]. Antibiotic allergy is increased in SLE [25]. References 1 Davies DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 1–11. 2 Vakil BJ, Kulkarni RD, Chabria NL et al. Intense surveillance of adverse drug reactions. An analysis of 338 patients. J Clin Pharmacol 1975; 15: 435–41. 3 May FE, Stewart RB, Cluff LE. Drug interactions and multiple drug administration. Clin Pharmacol Ther 1977; 22: 322–8. 4 Steel K, Gertman PM, Crescenzi C, Anderson J. Iatrogenic illness on a general medical service at a university hospital. N Engl J Med 1981; 304: 638–42. 5 Kellaway GSM, McCrae E. Intensive monitoring of adverse drug effects in patients discharged from acute medical wards. NZ Med J 1973; 78: 525–8. 6 Hutchinson TA, Flegel KM, Kramer MS et al. Frequency, severity, and risk factors for adverse reactions in adult outpatients: a prospective study. J Chron Dis 1986; 39: 533–42. 7 Gurwitz JH, Avorn J. The ambiguous relation between aging and adverse drug reactions. Ann Intern Med 1991; 114: 956–66. 8 Nolan L, O’Malley K. Adverse drug reactions in the elderly. Br J Hosp Med 1989; 41: 446–57. 9 Sullivan JR, Shear NH. Drug eruptions and other adverse drug effects in aged skin. Clin Geriatr Med 2002; 18: 21–42. 10 Sloan RW. Principles of drug therapy in geriatric patients. Am Fam Physician 1992; 45: 2709–18.

11 Black D, Denham MJ, Acheson RM et al. Medication for the elderly. A report of the Royal College of Physicians. J R Coll Physicians Lond 1984; 18: 7–17. 12 Heininger-Rothbucher D, Bischinger S, Ulmer H et al. Incidence and risk of potential adverse drug interactions in the emergency room. Resuscitation 2001; 49: 283–8. 13 Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990; 150: 841–5. 14 Levy M, Kewitz H, Altwein W et al. Hospital admissions due to adverse drug reactions: a comparative study from Jerusalem and Berlin. Eur J Clin Pharmacol 1980; 17: 25–31. 15 Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the elderly: a multicentre investigation. Age Ageing 1980; 9: 73–80. 16 Franceschi M, Scarcelli C, Niro V et al. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf 2008; 31: 545–56. 17 Passarelli MC, Jacob-Filho W, Figueras A. Adverse drug reactions in an elderly hospitalised population: inappropriate prescription is a leading cause. Drugs Aging 2005; 22: 767–77. 18 Lindley CM, Tully MP, Paramsothy V, Tallis RC. Inappropriate medication is a major cause of adverse drug reactions in elderly patients. Age Ageing 1992; 21: 294–300. 19 Rylance G, Armstron D. Adverse drug events in children. Adverse Drug React Bull 1997; 184: 689–702. 20 Hernández-Salazar A, Rosales SP, Rangel-Frausto S et al. Epidemiology of adverse cutaneous drug reactions. A prospective study in hospitalized patients. Arch Med Res 2006; 37: 899–902. 21 Fiszenson-Albala F, Auzerie V, Mahe E et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol 2003; 149: 1018–22. 22 Katz J, Marmary Y, Livneh A, Danon Y. Drug allergy in Sjögren’s syndrome. Lancet 1991; 337: 239. 23 Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjögrens’s syndrome: a clinical, pathological and serological study of 62 cases. Medicine (Baltimore) 1965; 44: 187–231. 24 Williams BO, Onge RAST, Young A et al. Penicillin allergy in rheumatoid arthritis with special reference to Sjögren’s syndrome. Ann Rheum Dis 1969; 28: 607–11. 25 Petri M, Allbritton J. Antibiotic allergy in systemic lupus erythematosus: a case– control study. J Rheumatol 1992; 19: 265–9.

Acquired immune deficiency syndrome Patients with acquired immune deficiency syndrome (AIDS) appear to be at increased risk for ADRs [1–7], up to 100-fold by some estimates [6,7]. The reasons are likely to be multifactorial, and include changes in drug metabolism, oxidative stress, cytokine profiles and immune hyperactivation. Human immunodeficiency virus (HIV)-positive individuals have been postulated to have a systemic glutathione deficiency, resulting in a decreased capacity to scavenge reactive hydroxylamine derivatives of sulphonamides, although this has been disputed (see section on pharmacogenetic mechanisms, p. 75.12). In the past, drugs especially implicated included sulphonamides such as co-trimoxazole (trimethoprim–sulfamethoxazole) [8–14], other sulphur congeners, for example dapsone [15], pentamidine, antituberculosis regimens containing thioacetazone (thiacetazone) [16,17] or isoniazid and rifampicin, amoxicillin–clavulanate [18,19], clindamycin, pyrimethamine [20] and thalidomide. Patients with AIDS are more likely to have particularly severe reactions, ranging from erythema multiforme to toxic epidermal necrolysis (TEN) (especially with sulphonamides, clindamycin, phenobarbital (phenobarbitone) and chlormezanone) [21,22], and to demonstrate multiple cutaneous drug reactions [2] (see Chapter 76). Drugs that are implicated in hypersensitivity have changed since the advent of highly active

Drug reactions

antiretroviral therapy, including abacavir, non-nucleoside reverse transcriptase inhibitors such as nevirapine, and protease inhibitors such as amprenavir [6]. There has been a decrease in the use of antimicrobials such as co-trimoxazole, and in Europe nevirapine has replaced sulphonamides as the leading cause of Stevens–Johnson syndrome and TEN related to AIDS [23] (see also Chapter 76). References 1 Bayard PJ, Berger TG, Jacobson MA. Drug hypersensitivity reactions and human immunodeficiency virus disease. J Acquir Immune Defic Syndr 1992; 5: 1237–57. 2 Carr A, Tindall B, Penny R, Cooper DA. Patterns of multiple-drug hypersensitivities in HIV-infected patients. AIDS 1993; 7: 1532–3. 3 Sadick NS, McNutt NS. Cutaneous hypersensitivity reactions in patients with AIDS. Int J Dermatol 1993; 32: 621–7. 4 Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993; 328: 1670–4. 5 Heller HM. Adverse cutaneous drug reactions in patients with human immunodeficiency virus-1 infection. Clin Dermatol 2000; 18: 485–9. 6 Pirmohamed M, Park BK. HIV and drug allergy. Curr Opin Allergy Clin Immunol 2001; 1: 311–6. 7 Phillips E, Mallal S. Drug hypersensitivity in HIV. Curr Opin Allergy Clin Immunol 2007; 7: 324–30. 8 Kletzel M, Beck S, Elser J et al. Trimethoprim–sulfamethoxazole oral desensitization in hemophiliacs infected with human immunodeficiency virus with a history of hypersensitivity reactions. Am J Dis Child 1991; 145: 1428–9. 9 Carr A, Swanson C, Penny R, Cooper DA. Clinical and laboratory markers of hypersensitivity to trimethoprim–sulfamethoxazole in patients with Pneumocystis carinii pneumonia and AIDS. J Infect Dis 1993; 167: 180–5. 10 Mathelier-Fusade P, Leynadier F. Intolerance aux sulfamides chez les sujets infectés par le VIH. Origine toxique et allergique. Presse Med 1993; 22: 1363–5. 11 Chanock SJ, Luginbuhl LM, McIntosh K, Lipshultz SE. Life-threatening reaction to trimethoprim/sulfamethoxazole in pediatric human immunodeficiency virus infection. Pediatrics 1994; 93: 519–21. 12 Roudier C, Caumes E, Rogeaux O et al. Adverse cutaneous reactions to trimethoprim–sulfamethoxazole in patients with the acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Arch Dermatol 1994; 130: 1383–6. 13 Rabaud C, Charreau I, Izard S et al. Adverse reactions to cotrimoxazole in HIVinfected patients: predictive factors and subsequent HIV disease progression. Scand J Infect Dis 2001; 33: 759–64. 14 Eliaszewicz M, Flahault A, Roujeau JC et al. Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS. J Am Acad Dermatol 2002; 47: 40–6. 15 Jorde UP, Horowitz HW, Wormser GP. Utility of dapsone for prophylaxis of Pneumocystis carinii pneumonia in trimethoprim–sulfamethoxazole-intolerant, HIV-infected individuals. AIDS 1993; 7: 355–9. 16 Nunn P, Kibuga D, Gathua S et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991; 337: 627–30. 17 Pozniak AL, MacLeod GA, Mahari M et al. The influence of HIV status on single and multiple drug reactions to antituberculous therapy in Africa. AIDS 1992; 6: 809–14. 18 Battegay M, Opravil M, Wütrich B, Lüthy R. Rash with amoxycillin–clavulanate therapy in HIV-infected patients. Lancet 1989; ii: 1100. 19 Paparello SF, Davis CE, Malone JL. Cutaneous reactions to amoxicillin–clavulanate among Haitians. AIDS 1994; 8: 276–7. 20 Piketty C, Weiss L, Picard-Dahan C et al. Toxidermies à la pyrimethamine chez les patients infectés par le virus de l’immunodeficience acquise. Presse Med 1995; 24: 1710. 21 Porteous DM, Berger TG. Severe cutaneous drug reactions (Stevens–Johnson syndrome and toxic epidermal necrolysis) in human immunodeficiency virus infection. Arch Dermatol 1991; 127: 740–1. 22 Saiag P, Caumes E, Chosidow O et al. Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. J Am Acad Dermatol 1992; 26: 567–74.

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23 Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN et al. Nevirapine and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. AIDS 2001; 15: 1843–8.

Drug reaction frequency in relation to types of medication The incidence of reactions to a particular drug must obviously be related to the quantity prescribed [1]. Nearly one in every 10 prescriptions in the USA in 1981 contained either hydrochlorothiazide or codeine [2]. One in every five prescriptions was for a diuretic or other cardiovascular drug; analgesics and antiarthritics constituted 13%, anti-infectives 13%, and sedatives and other psychotropics 11% of prescriptions. Of the 10 drugs most frequently reported by the yellow-card system to the UK Committee on Safety of Medicines in the first 6 months of 1986, seven were nonsteroidal anti-inflammatory drugs (NSAIDs) (accounting for 74% of serious adverse reactions); the remaining drugs were the angiotensin-converting enzyme (ACE) inhibitors enalapril and captopril (accounting for 19% of serious reactions) and co-trimoxazole (accounting for 7% of serious adverse reactions) [3]. In another study, anti-inflammatory agents were the drugs responsible for almost 50% of the reactions necessitating admission to a general medical ward; most of the drug-related admissions to the hospital as a whole were caused by digoxin, phenytoin, tranquillizers, antihypertensives, cardiac depressants and antineoplastic agents [4]. ADRs accounted for 8% of 1999 consecutive admissions to medical wards in yet another study [5]; the drugs most frequently involved were antirheumatics and analgesics (27%), cardiovascular drugs (23%), psychotropic drugs (14%), antidiabetics (12%), antibiotics (7%) and corticosteroids (5%). Nitrofurantoin and insulin were associated with admission rates of 617 and 182 per million daily doses, compared with 10 for diuretics and seven for benzodiazepines. ADRs were responsible for the admission of 2% of 5227 consecutive patients to the University Hospital Centre in Zagreb [6]; drugs incriminated included acetylsalicylic acid (aspirin) (38%), other NSAIDs (23%), cardiovascular agents (20%) and antimicrobials (3%). References 1 Committee on Safety of Medicines. CSM update: non-steroidal anti-inflammatory drugs and serious gastrointestinal reactions-2. BMJ 1986; 292: 1190–1. 2 Baum C, Kennedy DL, Forbes MB, Jones JK. Drug use in the United States in 1981. JAMA 1984; 251: 1293–7. 3 Mann RD. The yellow card data: the nature and scale of the adverse drug reactions problem. In: Mann RD, ed. Adverse Drug Reactions. Carnforth: Parthenon, 1987: 5–66. 4 Black AJ, Somers K. Drug-related illness resulting in hospital admission. J R Coll Physicians Lond 1984; 18: 40–1. 5 Hallas J, Gram LF, Grodum E et al. Drug related admissions to medical wards: a population based survey. Br J Clin Pharmacol 1992; 33: 61–8. 6 Huic M, Mucolic V, Vrhovac B et al. Adverse drug reactions resulting in hospital admission. Int J Clin Pharmacol Ther 1994; 32: 675–82.

Incidence of drug eruptions (adverse cutaneous drug reactions (ACDRs)) Drug eruptions are probably the most frequent of all manifestations of drug sensitivity—24% of all ADRs in one study [1] and 29% in another [2]—although their incidence is difficult to determine. Even where the eruption is apparently the only

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Chapter 75: Drug Reactions

manifestation, death can result from exfoliative dermatitis, erythema multiforme or TEN. For information on the incidence of drug-induced erythema multiforme, Stevens–Johnson syndrome and TEN, the reader is referred to Chapter 76. Epidemiological data suggest that a relatively small number of drugs are most frequently responsible for the most serious reactions [3]. Cutaneous reactions to common drugs such as digoxin, antacids, paracetamol (acetaminophen), glyceryl trinitrate, spironolactone, meperidine, aminophylline, propranolol, prednisone, salbutamol and diazepam are very rare. The baseline rate of rash development, reflecting a variety of different causes, was similar for 36 marketed drugs in the UK, at around 1 per 1000 patients per month from the second to the sixth month of one study; however, the rate for rash in the first month after prescription varied substantially from 0.9 to 6.4 per 1000 patients per month, and was highest for diltiazem [4]. Most estimates of the incidence of drug eruptions are inaccurate, because many mild and transitory eruptions are not recorded, and because skin disorders are sometimes falsely attributed to drugs. There have been several studies of the incidence of drug eruptions [4–15]. The reaction rate has been reported as about 2% [7,10], or 5.5 adverse skin reactions per 100 000 of the population in four Italian regions [11]. The prevalence of drug reactions in 4785 hospitalized patients was 0.7% in another series, the most commonly seen dermatoses being a morbilliform rash (51.2%), urticaria (12.2%) and erythema multiforme (4.9%), and drugs most frequently associated with ACDRs were amoxicillin clavulanate, amphotericin B and metamizole [16]. In yet another series of hospitalized patients, cutaneous drug reactions occurred at a prevalence of 3.6/1000, were principally exanthematous (56%), and were severe in 34% of cases and life-threatening in 2%; imputable drugs were mainly antibiotics, especially penicillins [17]. There is reportedly a relatively low incidence of severe ACDRs in China; antibiotics, anticonvulsants and traditional Chinese medicines are the most common causative drugs [18]. A survey [8] of ACDRs among in-patients found that one-third were fixed drug reactions, one-third were exanthematous and 20% were urticaria or angio-oedema; the high frequency of fixed drug reactions in this series reflects the fact that patients under study had been admitted to hospital. Antimicrobial agents were most frequently incriminated (42%), then antipyretic/antiinflammatory analgesics (27%), with drugs acting on the central nervous system accounting for 10% of reactions. A few drugs gave specific reactions (e.g. phenazone salicylate caused a fixed eruption, and penicillin and salicylates caused urticaria); however, most were capable of causing several types of eruption. Morbilliform exanthematous eruptions, urticaria and generalized pruritus were the commonest reactions in other large series [10,15]. The average patient had received eight different medications, which contributed considerably to the difficulties in identifying the causative drugs [10]. Antibiotics, blood products and inhaled mucolytics together caused 75% of the eruptions; amoxicillin (51 cases/ 1000 exposed), trimethoprim–sulfamethoxazole (33 cases/1000 exposed) and ampicillin (33 cases/1000 exposed) caused the most reactions. Reaction rates varied in the range of 1–8% for several classes of antibiotic [15]. In a study of ACDRs among children and adolescents in northern India, antibiotics were responsible for

most eruptions, followed by antiepileptics; co-trimoxazole was the commonest antibacterial culprit, followed by penicillin and its semi-synthetic derivatives, and then sulphonamides, with antiepileptics being the most frequently incriminated drugs in erythema multiforme, Stevens–Johnson syndrome and TEN [12]. More recent studies from India found that the drugs most often incriminated included antimicrobials (especially sulphonamides, including co-trimoxazole), anticonvulsants and NSAIDs (especially ibuprofen) [13,14]. Antimicrobials, NSAIDs, analgesics and radiological contrast media were the most frequent culprits in a study from Italy [11], and the most common drug classes involved in yet another study were cardiovascular agents (36%), contrast media (20%), drugs affecting blood clotting (13%) and anti-infectives (14%) [1]. Desensitizing vaccines, muscle relaxants, intravenous anaesthetics and radiological contrast media were the most frequent causes of anaphylaxis or anaphylactoid reactions reported to the UK Committee on Safety of Medicines in 1986/1987 [19]. The chairman of the Committee accordingly advised, in 1986, that desensitizing vaccines only be given where full cardiorespiratory resuscitation facilities are available. Quinidine, cimetidine, phenylbutazone, hydrochlorothiazide (especially in combination with amiloride) and furosemide (frusemide) have also been frequently implicated in drug eruptions [20,21]. In the USA and the UK, antibiotics, hypnotics and tranquillizers are the most frequent offenders; on a reaction per dose basis, penicillin, warfarin and imipramine are the three drugs most frequently incriminated [22]. The prevalence of a history of penicillin allergy in the US population has been estimated to be between 5 and 10% [23]. An international study of 1790 patients from 11 countries documented the frequency of allergic reactions to long-term benzathine benzylpenicillin (benzathine penicillin) prophylaxis for rheumatic fever at 3.2%; anaphylaxis occurred in 0.2% (1.2/10 000 injections) and the fatality rate was 0.05% (0.31/10 000 injections) [24]. Reactions to sulphonamides may affect up to 5% of those treated [25]. Rashes occurred in 7.3% of children given commonly used oral antibiotics [26]. Based on the number of patients treated, the frequency of rash with cefaclor was 12.3%, with penicillins 7.4%, with sulphonamides 8.5%, and with other cephalosporins 2.6%. References 1 Bordet R, Gautier S, Le Louet H et al. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin Pharmacol 2001; 56: 935– 41. 2 Thiessard F, Roux E, Miremont-Salamé G et al. Trends in spontaneous adverse drug reaction reports to the French pharmacovigilance system (1986–2001). Drug Saf 2005; 28: 731–40. 3 Stern RS, Steinberg LA. Epidemiology of adverse cutaneous reactions to drugs. Dermatol Clin 1995; 13: 681–8. 4 Kubota K, Kubota N, Pearce GL et al. Signalling drug-induced rash with 36 drugs recently marketed in the United Kingdom and studied by Prescription-Event Monitoring. Int J Clin Pharmacol Ther 1995; 33: 219–25. 5 Kaplan AP. Drug-induced skin disease. J Allergy Clin Immunol 1984; 74: 573–9. 6 Kauppinen K. Cutaneous reactions to drugs. With special reference to severe mucocutaneous bullous eruptions and sulphonamides. Acta Derm Venereol Suppl (Stockh) 1972; 68: 1–89. 7 Arndt KA, Jick H. Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1976; 235: 918– 22.

Drug reactions 8 Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. A series of inpatients during a 10-year period. Acta Derm Venereol (Stockh) 1984; 64: 320–4. 9 Alanko K, Stubb S, Kauppinen K. Cutaneous drug reactions: clinical types and causative agents. A five year survey of in-patients (1981–1985). Acta Derm Venereol (Stockh) 1989; 69: 223–6. 10 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63. 11 Naldi L, Conforti A, Venegoni M et al. Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999; 48: 839–46. 12 Sharma VK, Dhar S. Clinical pattern of cutaneous drug eruption among children and adolescents in north India. Pediatr Dermatol 1995; 12: 178–83. 13 Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: clinical pattern and causative agents. A 6 year series from Chandigarh, India. J Postgrad Med 2001; 47: 95–9. 14 Raksha MP, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol 2008; 74: 80. 15 Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001; 137: 765–70. 16 Hernández-Salazar A, Rosales SP, Rangel-Frausto S et al. Epidemiology of adverse cutaneous drug reactions. A prospective study in hospitalized patients. Arch Med Res 2006; 37: 899–902. 17 Fiszenson-Albala F, Auzerie V, Mahe E et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol 2003; 149: 1018–22. 18 Li LF, Ma C. Epidemiological study of severe cutaneous adverse drug reactions in a city district of China. Clin Exp Dermatol 2006; 31: 642–7. 19 Bem JL, Mann RD, Rawlins MD. Review of yellow cards 1986 and 1987. BMJ 1988; 296: 1319. 20 Kalish RS. Drug eruptions: a review of clinical and immunological features. Adv Dermatol 1991; 6: 221–37. 21 Thestrup-Pedersen K. Adverse reactions in the skin from antihypertensive drugs. Dan Med Bull 1987; 34: 3–5. 22 Davies DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 1–11. 23 Green CR, Rosenblum A. Report of the Penicillin Study Group: American Academy of Allergy. J Allergy Clin Immunol 1971; 48: 331–43. 24 International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. Lancet 1991; 337: 1308–10. 25 Anonymous. Hypersensitivity to sulphonamides: a clue? Lancet 1986; ii: 958–9. 26 Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: a survey in a private practice setting. Arch Dermatol 2000; 136: 849–54.

Classification and mechanisms of drug reactions [1–11] Drug reactions may arise as a result of immunological allergy directed against the drug itself, a reactive metabolite or some contaminant of the drug or, more commonly, by non-immunological mechanisms, such as pseudoallergic reactions caused by nonimmune-mediated degranulation of mast cells and basophils. Autoimmune reactions, in which the drug elicits an immune reaction to autologous structures, may also occur. Drug reactions may be predictable (type A) or unpredictable (type B) (Table 75.1). About 80% of drug reactions are predictable, usually dose-related, are a function of the known pharmacological actions of the drug and occur in otherwise normal individuals. Side effects are unavoidable at the regular prescribed dose. Unpredictable reactions are dose-independent, are not related to the pharmacological action of the drug, and may have a basis in pharmacogenetic variation in drug bioactivation and drug or metabolite detoxification or clearance. Intolerance refers to an expected drug reaction occurring at a lower dose, and idiosyncratic and hypersensitivity

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Table 75.1 Classification of adverse drug reactions. Non-immunological Predictable Overdosage Side effects Cumulation Delayed toxicity Facultative effects Drug interactions Metabolic alterations Teratogenicity Non-immunological activation of effector pathways Exacerbation of disease Drug-induced chromosomal damage Unpredictable Intolerance Idiosyncrasy Immunological (unpredictable) IgE-dependent drug reactions Immune complex-dependent drug reactions Cytotoxic drug-induced reactions Cell-mediated reactions Miscellaneous Jarisch–Herxheimer reactions Infectious mononucleosis–ampicillin reaction

reactions are qualitatively abnormal, unexpected responses. Type C reactions include those associated with prolonged therapy (e.g. analgesic nephropathy), and type D reactions consist of delayed reactions (e.g. carcinogenesis and teratogenicity). The skin has a limited repertoire of morphological reaction patterns in response to a wide variety of stimuli, and it is therefore often impossible to identify an offending drug, or the pathological mechanism involved, on the basis of clinical appearances alone. We therefore remain relatively ignorant about the mechanisms underlying many clinical drug eruptions. References 1 Rawlins MD, Thompson JW. Mechanisms of adverse drug reactions. In: Davies DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 12–38. 2 Wintroub BU, Stern R. Cutaneous drug reactions: pathogenesis and clinical classification. J Am Acad Dermatol 1985; 13: 833–45. 3 Stern RS, Wintroub BU, Arndt KA. Drug reactions. J Am Acad Dermatol 1986; 15: 1282–8. 4 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 5 Weiss ME. Drug allergy. Med Clin North Am 1992; 76: 857–82. 6 Gibaldi M. Adverse drug effect-reactive metabolites and idiosyncratic drug reactions: Part I. Ann Pharmacother 1992; 26: 416–21. 7 Anderson JA. Allergic reactions to drugs and biological agents. JAMA 1992; 268: 2844–57. 8 Pichler WJ. Medikamentenallergien. Ther Umsch 1994; 51: 55–60. 9 Rieder MJ. Mechanisms of unpredictable adverse drug reactions. Drug Saf 1994; 11: 196–212. 10 Breathnach SM. Mechanisms of drug eruptions: Part I. Australas J Dermatol 1995; 36: 121–7. 11 Bonnetblanc JM, Vaillant L, Wolkenstein P. Facteurs predisposants des reactions cutanées aux medicaments. Ann Dermatol Vénéréol 1995; 122: 484–6.

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Non-immunological drug reactions Overdosage The manifestations are a predictable exaggeration of the desired pharmacological actions of the drug, and are directly related to the total amount of drug in the body. Overdosage may be absolute, as a result of a prescribing or dispensing error or due to deliberate excess intake by the patient. It may also occur despite standard dosage, due to varying individual rates of absorption, metabolism or excretion (see below). An inappropriately large dose may be given to an infant or very old person or to one with renal impairment. Drug interaction (see below) may also cause drug overdosage.

Side effects These include unwanted or toxic effects, which are not separable from the desired pharmacological action of the drug. Examples are: the drowsiness induced by antihistamines; the atropine-like anticholinergic properties of some phenothiazines, many antihistamines, and tricyclic antidepressants; and the anagen alopecia caused by cytotoxic drugs. Cumulative toxicity Prolonged exposure may lead to cumulative toxicity. Accumulation of drugs in the skin may lead to colour disturbance, as a result of either deposition within phagocytic cells or mucous membranes (e.g. prolonged administration of gold, silver, bismuth or mercury) or binding of the drug or a metabolite to a skin component (e.g. high-dose chlorpromazine therapy). Delayed toxicity Examples are the keratoses and skin tumours that appear many years after inorganic arsenic, and the delayed hepatotoxicity associated with methotrexate therapy. Facultative effects These include the consequences of drug-induced alterations in skin or mucous membrane flora. Antibiotics that destroy Grampositive bacteria may allow the multiplication of resistant Gramnegative species. Broad-spectrum antibiotics, corticosteroids and immunosuppressive drugs may promote multiplication of Candida albicans and favour its transition from saprophytism to pathogenicity. Corticosteroids promote the spread of tinea and erythrasma. Antibiotics such as clindamycin and tetracycline may be associated with pseudomembranous enterocolitis following bowel superinfection with Clostridium difficile. Drug interactions Interactions between two or more drugs administered simultaneously may occur before entry into the body (in an intravenous drip), in the intestine, in the blood and/or at tissue receptor sites; interaction may also occur indirectly as a result of acceleration or slowing in the rate of drug metabolism or excretion. It should be remembered that the adverse consequences of drug interactions may occur not only on introduction of a drug but also on removal of a drug that causes acceleration of drug metabolism, as this may result in effective overdosage of the remaining drug. The subject of drug interactions has been extensively reviewed [1,2].

Combinations of drugs with potential adverse interactions continue to be prescribed [3]. Intestinal drug interactions. Examples include inhibition of griseofulvin absorption by phenobarbital [1], inhibition of tetracycline absorption by antacids [4] and decreased absorption of the oral contraceptive by tetracycline [5]. Whether the last-mentioned is of real significance is a matter of debate [6]. Displacement from carrier or receptor sites. Most drugs are reversibly bound to carrier proteins in plasma or extracellular fluid; bound drug acts as a reservoir, preventing excessive fluctuation in the level of the active, unbound fraction. Displacement from a carrier protein augments drug activity, whereas displacement from a receptor site diminishes it. Many acidic drugs such as salicylates, coumarins, sulphonamides and phenylbutazone are bound to plasma albumin, and compete for binding sites. Thus, a sulphonamide may displace tolbutamide from albumin, leading to hypoglycaemia; or aspirin, sulphonamides, clofibrate or phenylbutazone may displace warfarin from albumin, causing bleeding and ecchymoses. Similarly, sulphonamides and aspirin may increase methotrexate toxicity. Ciprofloxacin increases plasma levels of theophylline. Enzyme stimulation or inhibition [2]. A drug may either stimulate or inhibit metabolic enzymes important to its own degradation or that of another agent, with significant clinical consequences. Thus, some drugs induce synthesis of drug-metabolizing enzymes in liver microsomes. The liver microsomal hydroxylating system (which mediates metabolism of phenytoin and debrisoquine) is based on cytochrome P-450, and appears to be a family of enzymes capable of acting on different substrates including barbiturates, fatty acids and endogenous steroids. The cytochrome P-450-dependent system also catalyses deamination (e.g. amfetamine (amphetamine)), dealkylation (e.g. morphine, azathioprine), sulphoxidation (e.g. chlorpromazine, phenylbutazone), desulphuration (thiopental (thiopentone)) and dehalogenation (e.g. halogenated anaesthetics). This lack of specificity accounts for the ability of an inducing agent to stimulate metabolism of many other drugs, and of one drug to inhibit metabolism of a structurally unrelated drug. Antibiotics, if administered over a period of time (e.g. rifampicin for tuberculosis), can be enzyme inducers. Barbiturates stimulate metabolism of griseofulvin, phenytoin and coumarin anticoagulants, and griseofulvin induces increased metabolism of coumarins. Similarly, rifampicin, phenytoin and carbamazepine increase the metabolism of ciclosporin [7]. Drugs causing enzyme inhibition include chloramphenicol, cimetidine, monoamine oxidase inhibitors, p-aminosalicylic acid, pethidine and morphine. Dicoumarol, chloramphenicol and phenylbutazone inhibit metabolic inactivation of tolbutamide. Allopurinol inhibits metabolism of azathioprine and mercaptopurine by xanthine oxidase. Cimetidine inhibits liver enzymes and decreases hepatic blood flow, thereby potentiating the action of some β-blockers (propranolol) and benzodiazepines, carbamazepine, warfarin, morphine, phenytoin and theophylline. Ketoconazole may potentiate oral anticoagulants [8] and erythromycin may potentiate carbamazepine [9]; both may potentiate ciclosporin. Nifedipine and ciclosporin

Drug reactions

are both metabolized by the same cytochrome P-450 enzyme, P450cpn; ciclosporin potentiates the action of nifedipine, phenytoin and to a lesser extent valproate, by decreasing P-450cpn availability by competitive inhibition [10]. Altered drug excretion. Examples include the well-known probenecid-induced reduction in the renal excretion of penicillin, and aspirin-induced reduction in renal clearance of methotrexate. References 1 Griffin JP, D’Arcy PF, Speirs CJ. A Manual of Adverse Drug Interactions, 4th edn. London: Wright (Butterworth), 1988. 2 Shapiro LE, Shear NH. Drug interactions: proteins, pumps, and P-450s. J Am Acad Dermatol 2002; 47: 467–84. 3 Beers MH, Storrie MS, Lee G. Potential adverse drug interactions in the emergency room. An issue in the quality of care. Ann Intern Med 1990; 112: 61–4. 4 Garty M, Hurwitz A. Effect of cimetidine and antacids on gastrointestinal absorption of tetracycline. Clin Pharmacol Ther 1980; 28: 203–7. 5 Bacon JF, Shenfield GM. Pregnancy attributable to interaction between tetracycline and oral contraceptives. BMJ 1980; 280: 293. 6 Fleischer AB, Resnick SD. The effect of antibiotics on the efficacy of oral contraceptives. Arch Dermatol 1989; 125: 1562–4. 7 Schofield OMV, Camp RDR, Levene GM. Cyclosporin A in psoriasis: interaction with carbamazepine. Br J Dermatol 1990; 122: 425–6. 8 Smith AG. Potentiation of oral anticoagulants by ketoconazole. BMJ 1984; 288: 188–9. 9 Wroblewski BA, Singer WD, Whyte J. Carbamazepine–erythromycin interaction: case studies and clinical significance. JAMA 1986; 255: 1165–7. 10 McFadden JP, Pontin JE, Powles AV et al. Cyclosporin decreases nifedipine metabolism. BMJ 1989; 299: 1224.

Metabolic changes Drugs may induce cutaneous changes by their effects on nutritional or metabolic status. Thus, drugs such as phenytoin that interfere with folate absorption or metabolism increase the risk of aphthous stomatitis, and isotretinoin may cause xanthomas by elevation of very low-density lipoproteins [1]. Reference 1 Dicken CH. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 1980; 116: 951–2.

Teratogenicity and other effects on the fetus [1–6] The advent of isotretinoin has focused the attention of dermatologists considerably on the problem of teratogenicity in general [5]. The fetus is particularly at risk from drug-induced developmental malformations during the period of organogenesis, which lasts from about the third to the tenth week of gestation. Thalidomide, retinoids and cytotoxic drugs are proven teratogens. Heavy alcohol intake (which produces fetal alcohol syndrome), smoking, anticonvulsants (especially phenytoin and trimethadione (troxidone)), warfarin and antiplatelet drugs, inhalational anaesthetics, lithium, quinine, ACE inhibitors, misoprostol, certain antimicrobials (e.g. trimethoprim, aminoglycosides, 4-quinolones and itraconazole) and cocaine are probably teratogenic. High-dose corticosteroids have been linked to cleft palate. A major correlation has been found between the incidence of glucocorticoid-induced cleft palate and the chromosome 8 segment identified by N-acetyltransferase in mice [7]. 6-Aminonicotinamide-induced cleft palate and phenytoin-induced cleft lip with or without cleft palate are also

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influenced by this genetic region, but not as strongly. Sex hormones, psychotropic drugs, benzodiazepines, tetracycline, rifampicin, penicillamine and the folate antagonist pyrimethamine are possibly teratogenic and should be avoided in the first trimester of pregnancy. Chlorpheniramine appears safe to use. The potential adverse effects on the fetus and on the breastfed infant of a number of drugs not infrequently used by the dermatologist have been reviewed [4]. Drugs may also cause fetal damage later in pregnancy. Warfarin may cause haemorrhage, and phenytoin near to term produces a coagulation defect in the neonate, which is correctable by vitamin K. Antithyroid drugs and iodides may cause neonatal goitre and hypothyroidism. Fetal adrenal atrophy may follow high-dose maternal corticosteroid therapy. NSAIDs have various ill effects, although aspirin has been advocated in pregnancy for the prevention of fetal growth retardation. Tetracyclines are deposited in developing bones and cause discoloration and enamel hypoplasia of teeth [8]. Aminoglycoside antibiotics are ototoxic, and chloroquine has caused a neonatal chorioretinitis. Androgens and progestogens may virilize the fetus. Diethylstilbestrol (stilboestrol) administered from early pregnancy for several months has been associated with female and male genital tract abnormalities, and carcinoma of the vagina 20 years later in the offspring. References 1 Ellis C, Fidler J. Drugs in pregnancy: adverse reactions. Br J Hosp Med 1982; 28: 575–84. 2 Kalter H, Warkany J. Congenital malformations: etiologic factors and their role in prevention. N Engl J Med 1983; 308: 424–31, 491–7. 3 Ashton CH. Disorders of the fetus and infant. In: Davis DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 77–127. 4 Stockton DL, Paller AS. Drug administration to the pregnant or lactating woman: a reference guide for dermatologists. J Am Acad Dermatol 1990; 23: 87–103. 5 Mitchell AA. Teratogens and the dermatologist. New knowledge, responsibilities, and opportunities. Arch Dermatol 1991; 127: 399–401. 6 Ferner RE. Teratogenic drugs: an update. Adverse Drug React Bull 1993; 161: 607–10. 7 Karolyi J, Erickson RP, Liu S, Killewald L. Major effects on teratogen-induced facial clefting in mice determined by a single genetic region. Genetics 1990; 126: 201–5. 8 Witkop CJ, Wolf RO. Hypoplasia and intrinsic staining of enamel following tetracycline therapy. JAMA 1963; 185: 1008–11.

Effects on spermatogenesis Most chemotherapeutic agents potentially damage sperm; conception should also be avoided for 3 months after griseofulvin. A number of drugs cause oligospermia [1], which may come to light only as a result of infertility investigations; oestrogens, androgens, cyproterone acetate, cytotoxic drugs, including methotrexate given for psoriasis [2], colchicine, most monoamine oxidase inhibitors, ketoconazole and sulfasalazine (sulphasalazine) have all been incriminated. The synthetic retinoids isotretinoin and etretinate do not seem to affect the numbers of sperm [3,4]. References 1 Drife JO. Drugs and sperm. BMJ 1982; 284: 844–5. 2 Sussman A, Leonard J. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980; 116: 215–7. 3 Schill W-B, Wagner A, Nikolowski JM, Plewig G. Aromatic retinoid and 13-cisretinoic acid: spermatological investigations. In: Orfanos CE, Braun-Falco O,

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Farber EM et al., eds. Retinoids, Advances in Basic Research and Therapy. Berlin: Springer, 1981: 389–95. 4 Töröck L, Kása M. Spermatological and endocrinological examinations connected with isotretinoin treatment. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 407–10.

Non-immunological activation of effector pathways (anaphylactoid reactions) Certain drugs, such as opiates, codeine, amfetamine, polymyxin B, d-tubocurarine, atropine, hydralazine, pentamidine, quinine and radiocontrast media, may release mast cell mediators directly to produce urticaria or angio-oedema [1–7]. Some drugs, such as radiocontrast media, may activate complement by an antibodyindependent method [8]. Anaphylaxis-like responses to cyclooxygenase inhibitors such as aspirin and other NSAIDs may lead to amplified mast cell degranulation and enhanced biosynthesis of lipoxygenase products of arachidonic acid, which cause vasodilatation and oedema [9,10]. ACE inhibitors, which cause or exacerbate angio-oedema, may potentiate bradykinin activity; they have been reported to enhance bradykinin-induced cutaneous weals in normal individuals [11,12].

References 1 Schoenfeld MR. Acute allergic reactions to morphine, codeine, meperidine hydrochloride and opium alkaloids. NY State J Med 1960; 60: 2591–3. 2 Comroe JH, Dripps RD. Histamine-like action of curare and tubocurarine injected intracutaneously and intra-arterially in man. Anesthesiology 1946; 7: 260–2. 3 Greenberger PA. Contrast media reactions. J Allergy Clin Immunol 1984; 74: 600–5. 4 Assem ESK, Bray K, Dawson P. The release of histamine from human basophils by radiological contrast agents. Br J Radiol 1983; 56: 647–52. 5 Rice MC, Lieberman P, Siegle RL, Mason J. In vitro histamine release induced by radiocontrast media and various chemical analogs in reactor and control subjects. J Allergy Clin Immunol 1983; 72: 180–6. 6 Watkins J. Markers and mechanisms of anaphylactoid reactions. Monogr Allergy 1992; 30: 108–29. 7 Bircher AJ. Drug-induced urticaria and angioedema caused by non-IgE mediated pathomechanisms. Eur J Dermatol 1999; 9: 657–63. 8 Arroyave CM, Bhatt KN, Crown NR. Activation of the alternative pathway of the complement system by radiographic contrast media. J Immunol 1976; 117: 1866–9. 9 Stevenson DD, Lewis RA. Proposed mechanisms of aspirin sensitivity reactions. J Allergy Clin Immunol 1987; 80: 788–90. 10 Morassut P, Yang W, Karsh J. Aspirin intolerance. Semin Arthritis Rheum 1989; 19: 22–30. 11 Wood SM, Mann RD, Rawlins MD. Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. BMJ 1987; 294: 91–2. 12 Ferner RE. Effects of intradermal bradykinin after inhibition of angiotensin converting enzyme. BMJ 1987; 294: 1119–20.

Exacerbation of disease Examples of adverse drug effects on pre-existing skin conditions include lithium exacerbation of acne and psoriasis, β-blocker induction of a psoriasiform dermatitis [1] and corticosteroid withdrawal resulting in exacerbation of psoriasis; cimetidine, penicillin or sulphonamide exacerbation of lupus erythematosus (LE); and vasodilator exacerbation of rosacea. Sometimes, a drug may unmask a latent condition, as when barbiturates precipitate symptoms of porphyria.

Reference 1 Abel EA, Dicicco LM, Orenberg EK et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007–22.

Intolerance The characteristic effects of the drug are produced to an exaggerated extent by an abnormally small dose. This may simply represent an extreme within normal biological variation. Alternatively, the intolerance may be contributed to by delayed metabolism or excretion due to impaired hepatic or renal function, or by genetic variation in the rate of drug metabolism (see below). Idiosyncrasy This describes an uncharacteristic response, not predictable from animal experiments, and not mediated by an immunological mechanism. The cause is often unknown, but genetic variation in metabolic pathways may be involved. Such genetic abnormalities include glucose-6-phosphate dehydrogenase deficiency, hereditary methaemoglobinaemia, porphyria, glucocorticoid glaucoma and malignant hyperthermia of anaesthesia, all of which are characterized by unusual pharmacological responses to various drugs. Pharmacogenetic mechanisms and genetic influences underlying intolerance and idiosyncratic reactions [1–5] The pharmacokinetics of drugs, including their absorption, plasma protein binding, distribution, transportation and metabolism, and elimination, may be influenced by genetic factors. Oxidation, hydrolysis and acetylation are the three metabolic pathways most subject to genetic influence. Variation in the regulation and expression of the human cytochrome P-450 enzyme system may play a key role in both interindividual variation in sensitivity to drug toxicity and tissue-specific damage [4]. Polymorphisms in drugmetabolizing enzymes, including: cytochrome P450 (CYP) 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5; dihydropyrimidine dehydrogenase; uridine diphosphate glucuronosyltransferase (UGT) 1A1; glutathione S-transferase, sulfotransferase 1A1; N-acetyltransferase, and thiopurine methyltransferase (TPMT), and in drug transporters including: P-glycoprotein (multidrug resistance 1), multidrug resistance protein 2 (MRP2), and breast cancer resistance protein (BCRP), may influence efficacy and toxicity of chemotherapy agents [5]. Thus, polymorphisms in UGT1A1*28 are associated with an increase in toxicity with irinotecan [5]. Other polymorphisms are associated with docetaxelinduced leukopenia [6]. Genetic variation in thiopurine methyltransferase activity may be linked to the side effects of azathioprine therapy, as homozygotes for the low-activity allele are at risk of myelosuppression, whereas homozygotes for high activity are inadequately immunosuppressed with conventional doses of azathioprine [5,7]. Genetic factors also influence pharmacodynamics, that is tissue or organ responsiveness. Thus, genetic variations in all these areas may underlie both intolerance and idiosyncrasy. Pharmacogenetic variability probably underlies reactions such as TEN (see Influence of human leukocyte antigen (HLA) types, below, p. 75.14). It has been proposed that most patients who have a severe ACDR have an abnormal metabolism of the offending drug [8].

Drug reactions

Examples of genetically-mediated intolerance include pupil size responses to phenylephrine and parasympatholytics, and the very rare, dominantly-inherited, familial resistance to coumarin anticoagulants, the result of mutation in the receptor for vitamin K and anticoagulants. Low levels of red cell glucose-6-phosphate dehydrogenase, inherited as a sex-linked dominant trait, are common in black people, certain Levantine peoples and Filipinos, and result in a chronic deficit of reduced glutathione sulphydryl (SH) groups. Affected individuals are at risk of acute haemolysis on exposure to antimalarials, sulphonamides, dapsone, nitrofurantoin, phenacetin, aspirin and chloramphenicol, all of which may oxidize the few reduced SH groups in older red cells. Increased susceptibility to aminoglycoside-induced deafness in two Japanese pedigrees was associated with a particular mitochondrial DNA polymorphism [9]. References 1 Shear NH, Bhimji S. Pharmacogenetics and cutaneous drug reactions. Semin Dermatol 1989; 8: 219–26. 2 Lennard MS, Tucker GT, Woods HF. Inborn ‘errors’ of drug metabolism. Pharmacokinetic and clinical implications. Clin Pharmacokinet 1990; 19: 257–63. 3 Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 2000; 356: 1587–91. 4 Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther 1995; 68: 385–424. 5 Bosch TM, Meijerman I, Beijnen JH, Schellens JH. Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin Pharmacokinet 2006; 45: 253–85. 6 Kiyotani K, Mushiroda T, Kubo M et al. Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci 2008; 99: 967–72. 7 Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1995; 131: 193–7. 8 Chosidow O, Bourgault L, Roujeau JC. Drug rashes. What are the targets of cellmediated cytotoxicity? Arch Dermatol 1994; 130: 627–9. 9 Hutchin T, Haworth I, Higashi K et al. A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Res 1993; 21: 4174–9.

Oxidation. Anticonvulsants, many hypnotics, tricyclic antidepressants, anticoagulants and various anti-inflammatory and anxiolytic agents are eliminated by oxidation. For many drugs, oxidation rates vary as a continuous spectrum within the population. Genetic differences in metabolism of sulphonamides may underlie idiosyncratic toxicity [1–6]. Oxidative metabolism of sulphonamides by cytochrome P-450 enzymes and N-acetylation yields a reactive hydroxylamine intermediate [7], which is inactivated by glutathione conjugation. The hydroxylamine metabolite is toxic to lymphocytes, and the lymphocyte toxicity is markedly increased in patients with a history of hypersensitivity or with glutathione synthetase deficiency. HIV-positive individuals have been reported in some studies to have a systemic glutathione deficiency, resulting in a decreased capacity to scavenge hydroxylamine derivatives of sulphonamides, which may partially explain the increased frequency of sulphonamide reactions [8–10]. However, other studies have not been able to confirm intracellular glutathione deficiency in peripheral blood cells of HIV-infected patients [11,12]. Phenytoin, phenobarbital and carbamazepine are oxidized by the cytochrome P-450 enzyme system into potentially reactive

75.13

arene oxide intermediates; liver microsomal epoxide hydrolase converts such reactive intermediates to non-toxic dihydrodiols [13–17]. Phenytoin hypersensitivity syndrome appears to be associated with an inherited deficiency of epoxide hydrolase, which is primarily responsible for detoxifying the toxic arene-oxide intermediate [13–16]. Activated phenytoin has been shown to be toxic to lymphocytes from patients with phenytoin reactions and, to a lesser degree, to lymphocytes from their parents [15]. However, in another study a genetic defect altering the structure and function of the microsomal epoxide hydrolase protein was thought unlikely to be responsible for predisposing patients to anticonvulsant adverse reactions [17]. Culprit drug-reactive metabolites, generated by a microsomal oxidation system, had increased toxic effects on lymphoid cells from patients with TEN (13 each with sulphonamide and anticonvulsant reactions) and on those from first-degree relatives, whereas oxygen free radical and/or aldehyde detoxification pathways were normal [18]. Impaired metabolism of phenacetin and phenformin, inherited as a result of genetic polymorphism in liver microsomal oxidation, may result in adverse reactions [19,20]. The induction of liver enzymes responsible for drug oxidation may itself be under genetic control [21]. There is a fourfold increase in toxicity to penicillamine in patients with rheumatoid arthritis with a genetically determined poor capacity to sulphoxidate the structurally related mucolytic agent, carbocysteine [22]. References 1 Shear NH, Spielberg SP. In vitro evaluation of a toxic metabolite of sulfadiazide. Can J Physiol Pharmacol 1985; 63: 1370–2. 2 Shear NH, Spielberg SP. An in vitro lymphocytotoxicity assay for studying adverse reactions to sulphonamides. Br J Dermatol 1985; 113: 112–3. 3 Shear N, Spielberg S, Grant D et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105: 179–84. 4 Anonymous. Hypersensitivity to sulphonamides: a clue? Lancet 1986; ii: 958–9. 5 Rieder MJ, Uetrecht J, Shear NH et al. Synthesis and in vitro toxicity of hydroxylamine metabolites of sulphonamides. J Pharmacol Exp Ther 1988; 244: 724–8. 6 Rieder MJ, Uetrecht J, Shear NH et al. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9. 7 Meekins CV, Sullivan TJ, Gruchalla RS. Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins. J Allergy Clin Immunol 1994; 94: 1017–24. 8 Buhl R, Jaffe HA, Holroyd KJ et al. Systemic glutathione deficiency in symptomfree HIV-seropositive individuals. Lancet 1989; 334: 1294–8. 9 van der Ven AJAM, Koopmans PP, Vree TB, van der Meer JWM. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; 338: 431–3. 10 Koopmans PP, van der Ven AJ, Vree TB, van der Meer JWM. Pathogenesis of hypersensitivity reactions to drugs in patients with HIV infection: allergic or toxic? AIDS 1995; 9: 217–22. 11 Aukrust P, Svardal AM, Muller F et al. Increased levels of oxidized glutathione in CD4+ lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency type 1 infection. Blood 1995; 86: 258–67. 12 Pirmohamed M, Williams D, Tingle MD et al. Intracellular glutathione in the peripheral blood cells of HIV-infected patients: failure to show a deficiency. AIDS 1996; 10: 501–7. 13 Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988; 82: 1826–32. 14 Spielberg SP, Gordon GB, Blake DA et al. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981; 305: 722–7.

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15 Spielberg SP. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc 1984; 43: 2308–13. 16 Yoo JH, Kang DS, Chun WH et al. Anticonvulsant hypersensitivity syndrome with an epoxide hydrolase defect. Br J Dermatol 1999; 140: 181–3. 17 Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics 1994; 4: 142–53. 18 Wolkenstein P, Charue D, Laurent P et al. Metabolic predisposition to cutaneous adverse drug reactions. Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants. Arch Dermatol 1995; 131: 544–51. 19 Shahidi NT. Acetophenetidin sensitivity. Am J Dis Child 1967; 113: 81–2. 20 Eichelbaum M. Defective oxidation of drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet 1982; 7: 1–22. 21 Vessell ES, Passananti T, Greene FE, Page JG. Genetic control of drug levels and of the induction of drug-metabolizing enzymes in man: individual variability in the extent of allopurinol and nortriptyline inhibition of drug metabolism. Ann NY Acad Sci 1971; 179: 752–3. 22 Dasgupta B. Adverse reactions profile: 2. Penicillamine. Prescribers J 1991; 31: 72–7.

Hydrolysis. Genetic influence on drug hydrolysis is well illustrated in the case of suxamethonium, which normally results in only very brief neuromuscular blockade due to rapid hydrolysis by plasma pseudocholinesterase. Genetically determined atypical cholinesterases cannot hydrolyse the drug, leading to prolonged apnoea in affected individuals; conversely, dominantly inherited resistance to suxamethonium, mediated by a highly active cholinesterase, has been reported. Acetylation. Isoniazid, many sulphonamides, hydralazine, dapsone, procainamide, etc. are inactivated by conversion to acetyl conjugates. Acetylation rates vary greatly, with a bimodal frequency distribution, and there is marked ethnic variation. Rapid inactivation is dominantly inherited, and is commonest among Eskimos and Japanese and least common among certain Mediterranean Jews. The LE-like syndrome due to procainamide may occur more in fast acetylators, implying that a conjugate and not the parent compound is responsible [1]. Slow acetylators, in whom higher and more persistent drug levels occur, are more liable to develop adverse reactions to isoniazid (pellagra-like syndrome and peripheral neuritis), dapsone (haemolysis) [2] and hydralazine (LE-like syndrome) [3,4]. A slow acetylation phenotype is a risk factor for hypersensitivity to trimethoprim–sulfamethoxazole in HIV-infected subjects [5,6], and for sulphonamide-induced TEN and Stevens–Johnson syndrome independent of HIV infection [7,8]. References 1 Davies DM, Beedie MA, Rawlins MD. Antinuclear antibodies during procainamide treatment and drug acetylation. BMJ 1975; iii: 682–4. 2 Ellard GA, Gammon PT, Savin LA, Tan RSH. Dapsone acetylation in dermatitis herpetiformis. Br J Dermatol 1974; 90: 441–4. 3 Perry HM Jr, Sakamoto A, Tan EM. Relationship of acetylating enzyme to hydralazine toxicity. J Lab Clin Med 1967; 70: 1020–1. 4 Russell GI, Bing RF, Jones JA et al. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. QJM 1987; 65: 845–52. 5 Carr A, Gross AS, Hoskins JM et al. Acetylation phenotype and cutaneous hypersensitivity to trimethoprim–sulphamethoxazole in HIV-infected patients. AIDS 1994; 8: 333–7. 6 Delomenie C, Grant DM, Mathelier-Fusade P et al. N-Acetylation genotype and risk of severe reactions to sulphonamides in AIDS patients. Br J Clin Pharmacol 1994; 38: 581–2.

7 Wolkenstein P, Carriere V, Charue D et al. A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens–Johnson syndrome. Pharmacogenetics 1995; 5: 255–8. 8 Dietrich A, Kawakubo Y, Rzany B et al. Low N-acetylating capacity in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol 1995; 4: 313–6.

Influence of human leukocyte antigen (HLA) types. An association between HLA types and susceptibility to drug eruptions has been previously reported [1], particularly in relation to gold (HLADRw3, HLA-DR5 and HLA-B8) and penicillamine toxicity [2–7]. Penicillamine toxicity is associated with HLA phenotypes as follows [2]: HLA-DR3 and HLA-B8 with renal toxicity; HLA-DR3, HLA-B7 and HLA-DR2 with haematological toxicity; HLA-A1 and HLA-DR4 with thrombocytopenia; and HLA-DRw6 with cutaneous adverse reactions. DR1/DR4 heterozygosity, or the DR5 subtypes DRB1*1102 or DRB1*1201, have been found in 61% of patients with intolerance to tiopronin given for rheumatoid arthritis [8]. A positive association with HLA-Aw33 and HLA-B17/Bw58 haplotypes, and a negative association with the HLA-A2 haplotype, was reported some time ago in southern Chinese patients with drug eruptions after exposure to allopurinol [9]. Several more recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity [10–15]. The genetic associations can be drug specific. HLA-B*5701 has been linked with abacavir hypersensitivity, such that prospective HLA typing has dramatically reduced the risk of abacavir hypersensitivity [10–13]. Significant predisposition to nevirapine hypersensitivity has been reported in Caucasian Australians with HLA-DRB1*0101 and high CD4+ T-cell counts, and Sardinians and Japanese with HLA-Cw8 [13]. Most Han Chinese individuals with allopurinol-induced severe cutaneous adverse reactions are positive for HLA-B*5801 [13,14]. HLA-B*1502 is associated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), but not with carbamazepineinduced maculopapular eruption or carbamazepine hypersensitivity syndrome; thus, a genetic association can be phenotype specific [12]. Moreover, a genetic association can also be ethnicity specific, as carbamazepine-SJS/TEN associated with B*1502 is seen in Han Chinese from Taiwan and other Asian countries but not in whites, which may be explained by the different allele frequencies [12,13,15]. Even when HLA-B alleles behave as strong risk factors, they are neither sufficient nor necessary to explain the disease. The high sensitivity/specificity of some markers provides a basis for developing tests to identify individuals at risk for drug hypersensitivity, and allows personalized treatment [13]. As with HLA-B*5701 and abacavir hypersensitivity, HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be valuable in preventing carbamazepine-induced SJS/TEN in southeast Asian countries. Aspirin-sensitive asthma is associated with HLA-DQw2 [16]. HLA-linkage associations with certain bullous disorders have been reported [17,18]. Hydralazine-induced LE is commonest in female patients with the HLA-DRw4 haplotype [19,20]. Fixed drug eruptions to feprazone and trimethoprim–sulfamethoxazole are linked, respectively, to HLA-B22 and HLA-A30 B13 Cw6 [21,22].

Drug reactions References 1 Ingelman-Sundberg M. Pharmacogenomic biomarkers for prediction of severe adverse drug reactions. N Engl J Med 2008; 358: 637–9. 2 Dasgupta B. Adverse reactions profile: 2. Penicillamine. Prescribers J 1991; 31: 72–7. 3 Wooley PH, Griffin J, Payani GS et al. HLA-DR antigens and toxic reaction to sodium aurothiomalate and d-penicillamine in patients with rheumatoid arthritis. N Engl J Med 1980; 303: 300–2. 4 Latts JR, Antel JP, Levinson DJ et al. Histocompatibility antigens and gold toxicity: a preliminary report. J Clin Pharmacol 1980; 20: 206–9. 5 Bardin T, Dryll A, Debeyre N et al. HLA system and side effects of gold salts and d-penicillamine treatment of rheumatoid arthritis. Ann Rheum Dis 1982; 41: 599–601. 6 Emery P, Panayi GS, Huston G et al. D-penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3. J Rheumatol 1984; 11: 626–32. 7 Rodriguez-Perez M, Gonzalez-Dominguez J, Mataran L et al. Association of HLA-DR5 with mucocutaneous lesions in patients with rheumatoid arthritis receiving gold sodium thiomalate. J Rheumatol 1994; 21: 41–3. 8 Ju LY, Paolozzi L, Delecoeuillerie G et al. A possible linkage of HLA-DRB haplotypes with tiopronin intolerance in rheumatoid arthritis. Clin Exp Rheumatol 1994; 12: 249–54. 9 Chan SH, Tan T. HLA and allopurinol drug eruption. Dermatologica 1989; 179: 32–3. 10 Waters LJ, Mandalia S, Gazzard B, Nelson M. Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience. AIDS 2007; 21: 2533–4. 11 Phillips E, Mallal S. Drug hypersensitivity in HIV. Curr Opin Allergy Clin Immunol 2007; 7: 324–30. 12 Chung WH, Hung SI, Chen YT. Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007; 7: 317–23. 13 Gatanaga H, Honda H, Oka S. Pharmacogenetic information derived from analysis of HLA alleles. Pharmacogenomics 2008; 9: 207–14. 14 Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens– Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 2008; 18: 99–107. 15 Lonjou C, Thomas L, Borot N et al. A marker for Stevens–Johnson syndrome: ethnicity matters. Pharmacogenomics J 2006; 6: 265–8. 16 Mullarkey MF, Thomas PS, Hansen JA et al. Association of aspirin-sensitive asthma with HLA-DQw2. Am Rev Respir Dis 1986; 133: 261–3. 17 Roujeau J-C, Bracq C, Huyn NT et al. HLA phenotypes and bullous cutaneous reactions to drugs. Tissue Antigens 1986; 28: 251–4. 18 Mobini N, Ahmed AR. Immunogenetics of drug-induced bullous diseases. Clin Dermatol 1993; 11: 449–60. 19 Batchelor JR, Welsh KI, Mansilla Tinoco R et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980; i: 1107–9. 20 Russell GI, Bing RF, Jones JA et al. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. QJM 1987; 65: 845–52. 21 Pellicano R, Lomuto M, Ciavarella G et al. Fixed drug eruptions with feprazone are linked to HLA-B22. J Am Acad Dermatol 1997; 36: 782–4. 22 Özkaya-Bayazit E, Akar U. Fixed drug eruption induced by trimethoprim– sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol 2001; 45: 712–7.

Drug-induced chromosomal damage [1–3] This may be studied by examining the chromosomes of patients or animals exposed to drugs, or in vitro by the addition of drugs to cell cultures; substances capable of inducing chromosomal damage are termed clastogens. Effects may be dose related, but in vitro results may not be representative of the in vivo situation. Antimitotic and antibiotic agents have been the most studied, although psychotropics, anticonvulsants, hallucinogens, immunosuppressants and oral contraceptives have also been investigated and shown to cause, in varying degree, chromosomal damage. Damage ranges from staining variations through ‘gaps’ in stain-

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ing, chromosome breaks, gross aberrations (such as deletions, fragments, translocations and inversions) to polyploidy. Such damage may be stable and retained over a succession of cell divisions, or transient. References 1 Shaw MW. Human chromosome damage by chemical agents. Annu Rev Med 1970; 21: 409–32. 2 Bender MA, Griggs HG, Bedford JS. Mechanisms of chromosomal aberration production. III. Chemicals and ionizing radiation. Mutat Res 1974; 23: 197–212. 3 Rawlins MD, Thompson JW. Mechanisms of adverse drug reactions. In: Davies DM, ed. Textbook of Adverse Drug Reactions, 3rd edn. Oxford: Oxford University Press, 1985: 12–38.

Miscellaneous Jarisch–Herxheimer reaction. This is the focal exacerbation of lesions of infective origin when potent antimicrobial therapy is initiated, and is classically observed in the treatment of early syphilis with penicillin; it may also occur 3 days after starting griseofulvin therapy, during therapy with diethylcarbamazine for onchocerciasis and tiabendazole (thiabendazole) for strongyloidiasis, and with penicillin or minocycline for erythema chronicum migrans due to Borrelia burgdorferi infection [1]. The reaction has been attributed to sudden release of pharmacologically and/or immunologically active substances from killed microorganisms or damaged tissues. However, there is little evidence that it is an allergic reaction [2]. Clinically, there may be fever, rigors, lymphadenopathy, arthralgia and transient macular urticarial eruptions; a vesicular eruption has also been described [3]. References 1 Weber K. Jarisch–Herxheimer-Reaktion bei Erythema-migrans-Krankheit. Hautarzt 1984; 35: 588–90. 2 Skog E, Gudjónsson H. On the allergic origin of the Jarisch–Herxheimer reaction. Acta Derm Venereol (Stockh) 1966; 46: 136–43. 3 Rosen T, Rubin H, Ellner K et al. Vesicular Jarisch–Herxheimer reaction. Arch Dermatol 1989; 125: 77–81.

Infectious mononucleosis–ampicillin reaction. Ampicillin almost always causes a severe morbilliform eruption when given to a patient with infectious mononucleosis or lymphatic leukaemia (see later). The reaction occurs much less frequently with amoxicillin. The exact mechanism is not known, although one report suggests that real sensitization to ampicillin and amoxicillin occurs, and is detectable in vivo and in vitro by skin tests and the lymphocyte transformation test [1]. Reference 1 Renn CN, Straff W, Dorfmüller A et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol 2003; 147: 1166–7.

Immunological drug reactions Allergic hypersensitivity reactions are usually caused by immunological sensitization to a drug, as a result of previous exposure to that drug or to a chemically related cross-reacting substance [1–5]. It has been estimated that only about 6–10% of ADRs are immunologically mediated [6]. Although drugs frequently elicit an immune response, clinically evident hypersensitivity reactions

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Chapter 75: Drug Reactions

are manifest only in a small proportion of exposed individuals. Thus, using highly sensitive passive haemagglutination assays, IgM class antibodies to the penicilloyl group (the major hapten determinant derived from penicillin) are detectable in almost 100% of normal individuals, even in the absence of a history of penicillin therapy; 40% of patients receiving more than 2 g of penicillin for more than 10 days develop IgG class antibodies [7]. Macromolecular drugs such as protein or peptide hormones, insulin or dextran are antigenic in their own right. In contrast, most drugs are small organic molecules with a molecular mass of less than 1 kDa. In the past, it had been understood, according to the classical ‘hapten hypothesis’, that conjugation of free drug, reactive drug metabolites, or minor contaminants such as haptens with a macromolecular self protein, was required to initiate an immune response [8], and that, fortunately, many drugs have only a limited capacity to form covalent bonds with tissue proteins. This historical view is being challenged by new findings that drugspecific clones are stimulated by the parent drug much more often than by reactive metabolites [9]. Instead, it seems that medications usually stimulate specific T-cells after non-covalent binding to major histocompatibility (MHC) molecules on antigen-presenting cells. Drugs may be immunogenic not only because of their chemical reactivity, but also because they bind in a labile way to available T-cell receptors and possibly MHC molecules. In some patients with drug hypersensitivity this occurs within hours, even upon first exposure to the drug. The T-cell reaction to the drug might thus not be due to a classical primary response, but to peptidespecific T-cells which happen to be stimulated by the drug [10]. Clinical features distinguishing allergic from non-allergic drug reactions. Prior exposure before sensitization should have been without adverse effect. If there has been no previous exposure, there should usually be a latent period of several days of uneventful therapy before the reaction supervenes, during which primary sensitization occurs. Thereafter, reactions may develop within minutes (or even seconds) and certainly within 24 h. However, as stated above, occasionally reactions can occur without prior exposure. Allergic reactions do not resemble the pharmacological action of the drug, may follow exposure to doses far below the therapeutic level, and are reproducible on readministration (if judged safe). Factors concerned in the development of hypersensitivity. The route of administration of a drug may affect its immunogenicity and the nature of any allergy. Topical drug exposure is more likely to result in sensitization than oral administration, and favours development of contact dermatitis; thus, poison ivy is a potent contact sensitizer but oral ingestion may promote tolerance. Anaphylaxis is more likely to be associated with intravenous drug administration. However, anaphylaxis may sometimes occur as quickly after oral penicillin administration [11]. Whether allergy develops may also depend on the antigenic load in terms of degree of drug exposure, and individual genetic variation in drug absorption and metabolism. Thus, an LE-like syndrome with antinuclear antibody formation following hydralazine therapy occurs more frequently in slow acetylators of the drug [12]. Hydralazine-related SLE is 10 times more frequent in HLA-DR4-positive patients than

in the population at large, and is commoner in females. Allergic drug reactions are less common in childhood and possibly in the aged; in the latter, this may be related to impaired immunological responsiveness. Immunosuppression may increase the risk by inhibiting the regulatory function of suppressor T cells [13]. Environmental factors may also affect susceptibility to drug hypersensitivity, as for example the well-recognized increase in ampicillin-induced morbilliform eruptions associated with infectious mononucleosis, and photoallergic reactions to drugs such as thiazide diuretics or phenothiazines. Duration of hypersensitivity. The duration of allergic sensitivity is unpredictable. Although there is a general tendency for immunological responses to a drug to fall off with time, provided the patient is not re-exposed to the drug or a related substance, this can never be relied on; where necessary, safe confirmatory procedures (if available) should be carried out. Drug-reactive peripheral blood T cells were detectable at a significant level as long as 12 years later in a patient, even after strict drug avoidance [14]. References 1 Wintroub BU, Stern R. Cutaneous drug reactions: pathogenesis and clinical classification. J Am Acad Dermatol 1985; 13: 833–45. 2 De Swarte RD. Drug allergy: an overview. Clin Rev Allergy 1986; 4: 143–69. 3 Stern RS, Wintroub BU, Arndt KA. Drug reactions. J Am Acad Dermatol 1986; 15: 1282–8. 4 Blaiss MS, de Shazo RD. Drug allergy. Pediatr Clin North Am 1988; 35: 1131– 47. 5 Kalish RS. Drug eruptions: a review of clinical and immunological features. Adv Dermatol 1991; 6: 221–37. 6 Gruchalla RS. Drug allergy. J Allergy Clin Immunol 2003; 111 (Suppl. 2): S548–59. 7 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 8 Park BK, Naisbitt DJ, Gordon SF et al. Metabolic activation in drug allergies. Toxicology 2001; 158: 11–23. 9 Roujeau JC. Immune mechanisms in drug allergy. Allergol Int 2006; 55: 27–33. 10 Posadas SJ, Pichler WJ. Delayed drug hypersensitivity reactions—new concepts. Clin Exp Allergy 2007; 37: 989–99. 11 Simmonds J, Hodges S, Nicol F, Barnett D. Anaphylaxis after oral penicillin. BMJ 1978; ii: 1404. 12 Perry HM Jr, Sakamoto A, Tan EM. Relationship of acetylating enzyme to hydralazine toxicity. J Lab Clin Med 1967; 70: 1020–1. 13 Lakin JD, Grace WR, Sell KW. IgE antipolymyxin B antibody formation in a T-cell depleted bone marrow transplant patient. J Allergy Clin Immunol 1975; 56: 94–103. 14 Beeler A, Engler O, Gerber BO, Pichler WJ. Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions. J Allergy Clin Immunol 2006; 117: 455–62.

Drug eruptions may occur as a result of a variety of different immunological mechanisms as described below.

IgE-dependent (type I) drug reactions: urticaria and anaphylaxis [1] In vivo cross-linkage by polyvalent drug–protein conjugates of two or more specific IgE molecules, fixed to sensitized tissue mast cells or circulating basophil leukocytes, triggers the cell to release a variety of chemical mediators, including histamine, peptides such as eosinophil chemotactic factor of anaphylaxis, lipids such as leukotriene C4 or prostaglandin D2, and a variety of pro-

Drug reactions

inflammatory cytokines [2]. Interleukin-5 (IL-5) and eotaxin play a role in activating and recruiting eosinophils in drug-induced cutaneous eruptions [3]. Such cytokines in turn have effects on a variety of target tissues including skin, respiratory, gastrointestinal and/or cardiovascular systems. Eosinophil degranulation may also result in release of pro-inflammatory mediators [4]. Dilatation and increased permeability of small blood vessels with resultant oedema and hypotension, contraction of bronchiolar smooth muscle and excessive mucus secretion, and chemotaxis of inflammatory cells, including polymorphs and eosinophils, occurs. Clinically, this may produce pruritus, urticaria, bronchospasm and laryngeal oedema, and in severe cases anaphylactic shock with hypotension and possibly death. Immediate reactions occur within minutes of drug administration; accelerated reactions may occur within hours or days, and are generally urticarial but may involve laryngeal oedema. Penicillins are the commonest cause of IgEdependent drug eruptions. References 1 Champion RH, Greaves MW, Kobza Black A, eds. The Urticarias. Edinburgh: Churchill Livingstone, 1985. 2 Schwartz LB. Mast cells and their role in urticaria. J Am Acad Dermatol 1991; 25: 190–204. 3 Yawalkar N, Shrikhande M, Hari Y et al. Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions. J Allergy Clin Immunol 2000; 106: 1171–6. 4 Leiferman KM. A current perspective on the role of eosinophils in dermatologic diseases. J Am Acad Dermatol 1991; 24: 1101–12.

Antibody-mediated (type II) drug reactions Binding of antibody to cells may lead to cell damage following complement-mediated cytolysis. The classical example of immune complex formation between a drug (as hapten) bound to the surface of a cell (in this case, platelets) and IgG-class antibody, with subsequent complement fixation, was the purpura caused by apronalide (Sedormid). A further example is the thrombocytopenic purpura that may result from antibodies to quinidine–platelet conjugates [1,2]. A number of drugs, including penicillin, quinine and sulphonamides, may rarely produce a haemolytic anaemia via this mechanism. Methyldopa very occasionally induces a haemolytic anaemia mediated by autoantibodies directed against red cell antigens. References 1 Christie DJ, Weber RW, Mullen PC et al. Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets. J Lab Clin Med 1984; 104: 730–40. 2 Garty M, Ilfeld D, Kelton JG. Correlation of a quinidine-induced platelet-specific antibody with development of thrombocytopenia. Am J Med 1985; 79: 253–5.

Immune complex-dependent (type III) drug reactions Urticaria and anaphylaxis. Immune complexes may activate the complement cascade, with resultant formation of anaphylatoxins such as the complement protein fragments C3a and C5a, which trigger release of mediators from mast cells and basophils directly, resulting in urticaria or anaphylaxis. Serum sickness. Serum sickness-like reactions and other immune complex-mediated conditions necessitate persistence of a drug

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antigen in the circulation for long enough to enable antibody, largely of IgG or IgM class, to be synthesized and to combine with it to form circulating antibody–antigen immune complexes. They therefore develop about 6 days or more after drug administration. Serum sickness occurs when antibody combines with antigen in antigen excess, leading to slow removal of persistent complexes by the mononuclear phagocyte system. It was usually seen in the context of serum therapy with large doses of heterologous antibody, as with horse antiserum for the treatment of diphtheria. It has been reported more recently with antilymphocyte globulin therapy [1]. Clinical manifestations of serum sickness include fever, arthritis, nephritis, neuritis, oedema, and an urticarial or papular rash. Vasculitis [2–4]. Drug-induced immune complexes play a part in the pathogenesis of cutaneous necrotizing vasculitis. Deposition of immune complexes on vascular endothelium results in activation of the complement cascade, with generation of the anaphylatoxins C3a and C5a, which have chemotactic properties. Vasoactive amines and pro-inflammatory cytokines are released from basophils and mast cells, with resultant increased vascular permeability and attraction of polymorphonuclear neutrophil cells. Immune complex interaction with platelets via their Fc receptors causes platelet aggregation and microthrombus formation. Release of lysosomal enzymes by neutrophils contributes further to local inflammation. These events lead to the histological appearance of leukocytoclastic vasculitis. Deposition of immunoglobulins and complement in and around blood vessel walls is detectable by direct immunofluorescence staining of skin biopsies. Hydralazine and the hydroxylamine metabolite of procainamide bind to complement component C4 and inhibit its function; this may impair clearance of immune complexes, and predispose to development of an LE syndrome [4]. Arthus reaction. The Arthus reaction is a localized form of immune complex vasculitis. Intradermal or subcutaneous injection of antigen such as a vaccine into a sensitized individual with circulating precipitating antibodies, usually of IgG1 class, leads to local immune complex formation and the cascade of events described above. Clinically, there is erythema and oedema, haemorrhage and occasionally necrosis at the injection site, which reaches a peak at 4–10 h, and then gradually wanes. References 1 Lawley TJ, Bielory L, Gascon P et al. A prospective clinical and immunologic analysis of patients with serum sickness. N Engl J Med 1984; 311: 1407–13. 2 Mackel SE, Jordon RE. Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease. Arch Dermatol 1983; 118: 296–301. 3 Sams WM. Hypersensitivity angiitis. J Invest Dermatol 1989; 93: 78S–81S. 4 Sim E. Drug-induced immune complex disease. Complement Inflamm 1989; 6: 119–26.

Cell-mediated (type IV) reactions The role of delayed-type cell-mediated immune reactions in contact drug hypersensitivity, as with penicillin [1], is well established, but the importance of such mechanisms involving specific effector lymphocytes in other varieties of cutaneous drug allergy has only recently been elucidated [2–7]. A number of ACDRs,

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Chapter 75: Drug Reactions

including some morbilliform and bullous ACDRs, fixed drug reactions, lichenoid reactions, LE-like reactions, dress syndrome and erythema multiforme, Stevens–Johnson syndrome and TEN, involve T-lymphocyte responses to altered self. The involvement of the skin immune system in cell-mediated drug eruptions, and graft-versus-host disease as a model for cutaneous drug eruptions, have been reviewed [2,8,9]. Patients with acute drug allergy to carbamazepine, phenytoin, sulfamethoxazole, allopurinol or paracetamol had activated drug-specific CD4+ or CD8+ T cells in the circulation [10]. Sulfamethoxazole-reactive lymphocytes were detected in peripheral blood of patients with drug-induced eruptions, at a frequency of 1/172 000, within the frequency range of urushiol-reactive T cells in patients with urushiol (poison ivy) dermatitis [11]. In another study, about 1 : 250 to 1 : 10 000 of all the T cells in patients following a severe systemic drug hypersensitivity reaction were reactive to the relevant drugs, a frequency of drug-reactive T cells higher than the frequency of T cells able to recognize recall antigens such as tetanus toxoid in the same subjects [12]. Moreover, drug-reactive T cells were detectable at a significant level for as long as 12 years later in one patient, despite strict drug avoidance. In one study, predominant CD8+ T-cell activation was associated with more severe (bullous) skin lesions or liver involvement, whereas predominant activation of CD4+ cells elicited mainly maculopapular reactions [13]. Drug-specific T-cell clones from drug-induced exanthems contained heterogeneous T-cell subsets with distinct phenotypes (CD4+ > CD8+ perforin and granzyme B positive) and cell functions (strong IL-5 production, moderate interferon-γ (IFN-γ) production and cytotoxic potential) [14,15]. Perivascular predominantly CD4+ T cells, with 30% CD8+ cells, basal keratinocyte HLA-DR and intercellular adhesion molecule (ICAM)-1 expression, and E selectin expression by endothelial cells, were seen in maculopapular or exfoliative antibiotic-induced ACDRs [16,17]. However, in other studies, CD8+ T cells predominated in the epidermis in drug-induced maculopapular and bullous eruptions and patch-test reactions to beta-lactam antibiotics [18,19]. β-lactam-specific peripheral and epidermal T lymphocytes from bullous exanthems were predominantly CD8+CD4−, displayed a Th1-like cytokine pattern, proliferated in an antigen- and major histocompatibility complex (MHC)-specific manner, and were cytotoxic against epidermal keratinocytes in lectin-induced cytotoxicity assays. In contrast, T-cell lines from patients with penicillin-induced urticarial exanthems were predominantly CD4+CD8−, with a Th2-like cytokine pattern. Drugspecific T-cell clones and cell lines from a phenobarbital-induced eruption were heterogeneous with regard to CD4/CD8 phenotype, T-cell receptor Vβ repertoire, antigen recognition pattern and cytokine production [20]. Epicutaneous test reactions to antibiotics contained a heterogeneous population of drug-specific T cells [21]; it has been proposed that T cells producing IL-5 might contribute to eosinophilia, whereas cytotoxic CD4+ T cells might account for tissue damage [21–23]. Drug-specific T cells also contribute to the neutrophil infiltration in drug-induced acute generalized exanthematous pustulosis, by secreting the chemokine IL-8 [24–26]. Proliferation of CD8+ dermal T cells, from a sulfamethoxazoleinduced bullous exanthem, to sulfamethoxazole was significantly increased in the presence of liver microsomes, suggesting that microsomal enzymes, such as the cytochrome P-450 system, gen-

erate highly reactive metabolites, which are the nominal antigens for T-cell activation [27,28]. The expression of ICAM-1 by target keratinocytes plays an important role in the cytotoxicity of epidermal T cells in bullous drug eruptions [29]. Penicilloyl-modified MHC-associated peptides may act as T-cell epitopes; T cells may have specificity for both the backbone and the side-chain of penicillin [30]. Penicillin G may also stimulate T cells directly by binding to MHC molecules on the cell surface. Alternatively, it may bind to soluble proteins such as human serum albumin, which require processing for presentation in an immunogenic form. These different modes of presentation, which elicit a variety of immunological reactivities, may explain the heterogeneity of clinical pictures seen in penicillin allergy [31]. Morbilliform drug hypersensitivity reactions in HIV-infected subjects showed spongiosis, hydropic generation of the basal layer, Civatte bodies, an epidermal lymphocytic infiltrate, and perivascular lymphocytes and macrophages [32]. Immunohistochemistry demonstrated CD8+ HLA-DR-positive T lymphocytes, marked depletion of epidermal Langerhans’ cells and strong keratinocyte IL-6, tumour necrosis factor-α (TNF-α) and, to a lesser degree, IFN-γ expression. The above data have established the importance of T-cellmediated immunity in delayed-type hypersensitivity-mediated drug eruptions. In delayed reactions, drug-specific CD4+ and CD8(+) T cells recognize drugs through their T-cell receptors (TCRs) in an MHC-dependent way. MHC restriction could explain the key role of HLA genes as factors predisposing to severe drug reactions (see section on Pharmacogenetic mechanisms and genetic influences, pp. 75.12–15). Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthems revealed that distinct T cell functions lead to different clinical phenotypes. Thus, delayed hypersensitivity reactions (type IV) may be subclassified according to which cytokines and chemokines are released [4,7]. Maculopapular exanthema may be either Th1 or Th2 in nature, depending on whether they are interferon-γ/tumour necrosis factor-α or interleukin-4, 5 and 13 driven. Bullous reactions to drugs (i.e. Stevens–Johnson syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthematic reactions to medications are stimulated via the T-cell release of IL-8 and granulocyte–monocyte colony-stimulating factor (GM-CSF). Delayed-type IV hypersensitivity reactions have therefore been re-classified into four main subtypes: IVa (Th1/monocyte directed), IVb (Th2/eosinophil directed), IVc (CD8+/Fas/perforin/granzyme B directed) and IVd (IL-8/GM-CSF/neutrophil directed). In practice, delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture. An intercurrent infectious disease (especially respiratory tract and urinary tract infections in the case of maculopapular eruptions) was documented in 58.5% of patients with ACDRs, compared with 7.5% of a control group [33]. It has been proposed that viruses may non-specifically stimulate cytotoxicity in general, which spills over to affect target cells altered by drug antigen [34]. Viruses incriminated, especially in the dress (drug hypersensitiv-

Drug reactions

ity) syndrome, include human herpesvirus 6 and 7, Epstein–Barr virus, cytomegalovirus and hepatitis C virus [35–43]. The sequential reactivation of these viruses may be responsible for the delayed onset, paradoxical worsening of clinical symptoms after discontinuation of the causative drugs, and a step-wise development of several organ system failures, including encephalitis and type 1 diabetes mellitus, long after discontinuation of the causative drug [37,40,43]. In conclusion, dress is a complex disease composed of drug allergy and viral reactivation, with similarities to graftversus-host disease. References 1 Stejskal VDM, Forsbeck M, Olin R. Side chain-specific lymphocyte responses in workers with occupational allergy induced by penicillins. Int Arch Allergy Appl Immunol 1987; 82: 461–4. 2 Roujeau JC. Immune mechanisms in drug allergy. Allergol Int 2006; 55: 27– 33. 3 Schmid DA, Depta JP, Pichler WJ. T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity. Clin Exp Allergy 2006; 36: 59– 69. 4 Meth MJ, Sperber KE. Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation. Mt Sinai J Med 2006; 73: 769–76. 5 Rodriguez-Pena R, Lopez S, Mayorga C et al. Potential involvement of dendritic cells in delayed-type hypersensitivity reactions to beta-lactams. J Allergy Clin Immunol 2006; 118: 949–56. 6 Nishio D, Izu K, Kabashima K, Tokura Y. T cell populations propagating in the peripheral blood of patients with drug eruptions. J Dermatol Sci 2007; 48: 25–33. 7 Posadas SJ, Pichler WJ. Delayed drug hypersensitivity reactions—new concepts. Clin Exp Allergy 2007; 37: 989–99. 8 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 9 Breathnach SM. Mechanisms of drug eruptions: Part I. Australas J Dermatol 1995; 36: 121–7. 10 Mauri-Hellweg D, Bettens F, Mauri D. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995; 155: 462–72. 11 Kalish RS, Laporte A, Wood JA, Johnson KL. Sulfonamide-reactive lymphocytes detected at very low frequency in the peripheral blood of patients with druginduced eruptions. J Allergy Clin Immunol 1994; 94: 465–72. 12 Beeler A, Engler O, Gerber BO, Pichler WJ. Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions. J Allergy Clin Immunol 2006; 117: 455–62. 13 Hari Y, Frutig-Schnyder K, Hurni M et al. T cell involvement in cutaneous drug eruptions. Clin Exp Allergy 2001; 31: 1398–408. 14 Yawalkar N, Egli F, Hari Y et al. Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions. Clin Exp Allergy 2000; 30: 847–55. 15 Yawalkar N, Pichler WJ. Pathogenesis of drug-induced exanthema. Int Arch Allergy Immunol 2001; 124: 336–8. 16 Barbaud AM, Béné M-C, Schmutz J-L et al. Role of delayed cellular hypersensitivity and adhesion molecules in amoxicillin-induced morbilliform rashes. Arch Dermatol 1997; 133: 481–6. 17 Barbaud AM, Béné MC, Reichert-Penetrat S et al. Immunocompetent cells and adhesion molecules in 14 cases of cutaneous drug reactions induced with antibiotics. Arch Dermatol 1998; 134: 1040–1. 18 Hertl M, Geisel J, Boecker C, Merk HF. Selective generation of CD8+ T-cell clones from the peripheral blood of patients with cutaneous reactions to beta-lactam antibiotics. Br J Dermatol 1993; 128: 619–26. 19 Hertl M, Bohlen H, Jugert F et al. Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by β-lactam antibiotics. J Invest Dermatol 1993; 101: 794–9. 20 Hashizume H, Takigawa M, Tokura Y. Characterization of drug-specific T cells in phenobarbital-induced eruption. J Immunol 2002; 168: 5359–68. 21 Yawalkar N, Hari Y, Frutig K et al. T cells isolated from positive epicutaneous test reactions to amoxicillin and ceftriaxone are drug specific and cytotoxic. J Invest Dermatol 2000; 115: 647–52.

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22 Choquet-Kastylevsky G, Intrator L, Chenal C et al. Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome. Br J Dermatol 1998; 139: 1026–32. 23 Mikami C, Ochiai K, Umemiya K et al. Eosinophil activation and in situ interleukin-5 production by mononuclear cells in skin lesions of patients with drug hypersensitivity. J Dermatol 1999; 26: 633–9. 24 Britschgi M, Steiner UC, Schmid S et al. T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest 2001; 107: 1433–41. 25 Schmid S, Kuechler PC, Britschgi M et al. Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation. Am J Pathol 2002; 161: 2079–86. 26 Britschgi M, Pichler WJ. Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inflammatory processes orchestrated by T cells. Curr Opin Allergy Clin Immunol 2002; 2: 325–31. 27 Hertl M, Merk HF. Lymphocyte activation in cutaneous drug reactions. J Invest Dermatol 1995; 105 (Suppl.): S95–8. 28 Hertl M, Jugert F, Merk HF. CD8+ dermal T cells from a sulphamethoxazoleinduced bullous exanthem proliferate in response to drug-modified liver microsomes. Br J Dermatol 1995; 132: 215–20. 29 Hertl M, Rönnau A, Bohlen H et al. The cytotoxicity of epidermal T lymphocytes in bullous drug reactions is strongly but not completely abrogated by inhibition of ICAM-1 on target cells (abstract). Arch Dermatol Res 1993; 285: 63. 30 Weltzien HU, Padovan E. Molecular features of penicillin allergy. J Invest Dermatol 1998; 110: 203–6. 31 Brander C, Mauri-Hellweg D, Bettens F et al. Heterogeneous T cell responses to beta-lactam-modified self-structures are observed in penicillin-allergic individuals. J Immunol 1995; 155: 2670–8. 32 Carr A, Vasak E, Munro V et al. Immunohistological assessment of cutaneous drug hypersensitivity in patients with HIV infection. Clin Exp Immunol 1994; 97: 260–5. 33 Cohen AD, Friger M, Sarov B, Halevy S. Which intercurrent infections are associated with maculopapular cutaneous drug reactions? A case–control study. Int J Dermatol 2001; 40: 41–4. 34 Chosidow O, Bourgault L, Roujeau JC. Drug rashes. What are the targets of cellmediated cytotoxicity? Arch Dermatol 1994; 130: 627–9. 35 Mizukawa Y, Shiohara T. Virus-induced immune dysregulation as a triggering factor for the development of drug rashes and autoimmune diseases: with emphasis on EB virus, human herpesvirus 6 and hepatitis C virus. J Dermatol Sci 2000; 22: 169–80. 36 Aihara M, Sugita Y, Takahashi S et al. Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus. Br J Dermatol 2001; 144: 1231–4. 37 Hashimoto K, Yasukawa M, Tohyama M. Human herpesvirus 6 and drug allergy. Curr Opin Allergy Clin Immunol 2003; 3: 255–60. 38 Kano Y, Inaoka M, Sakuma K, Shiohara T. Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome. Toxicology 2005; 209: 165–7. 39 Seishima M, Yamanaka S, Fujisawa T et al. Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome. Br J Dermatol 2006; 155: 344–9. 40 Kano Y, Hiraharas K, Sakuma K, Shiohara T. Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in graft-versus-host disease. Br J Dermatol 2006; 155: 301–6. 41 Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 2006; 55: 1–8. 42 Tohyama M, Hashimoto K, Yasukawa M et al. Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol 2007; 157: 934–40. 43 Shiohara T, Kano Y. A complex interaction between drug allergy and viral infection. Clin Rev Allergy Immunol 2007; 33: 124–33.

Erythema multiforme, Stevens–Johnson syndrome and TEN. The reader is referred to Chapter 76. Lichenoid drug eruptions. The mechanisms underlying lichenoid drug eruptions are essentially unknown, but they may develop as

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Chapter 75: Drug Reactions

a result of autoreactive cytotoxic T-cell clones directed against a drug–class II MHC antigen complex, such that keratinocytes and Langerhans’ cells are viewed by the immune system as ‘non-self’. Cloned murine autoreactive T cells produce a lichenoid reaction in recipient animals following injection [1]. The presence of epidermotropic T cells correlates with that of class II MHC (HLADR)-expressing keratinocytes and Langerhans’ cells in lichenoid eruptions [2]. References 1 Shiohara T. The lichenoid tissue reaction. An immunological perspective. Am J Dermatopathol 1988; 10: 252–6. 2 Shiohara T, Moriya N, Tanaka Y et al. Immunopathological study of lichenoid skin diseases: correlation between HLA-DR-positive keratinocytes or Langerhans cells and epidermotropic T cells. J Am Acad Dermatol 1988; 18: 67–74.

LE-like syndrome induced by drugs. Drug-induced LE, with production of antihistone antibodies, may result from interaction between the drug and nuclear material to produce a drug–nucleoprotein complex that is immunogenic. Alternatively, drugs may alter immunoregulation in such a way that autoantibody production is favoured; procainamide and hydralazine modulate lymphocyte function directly and induce autoreactivity. Thus, drugs may cause an SLE-like condition by a mechanism analogous to that in immunostimulatory graft-versus-host disease [1]. Hydralazine, isoniazid and the hydroxylamine metabolites of procainamide and practolol may also predispose to the development of an LE-like syndrome by inhibiting binding of C4 and in turn of C3 to immune complexes, thus preventing complement-mediated clearance of immune complexes by solubilization and opsonization [2]. References 1 Gleichman E, Pals ST, Rolinck AG et al. Graft-versus-host reactions: clues to the etiopathogenesis of a spectrum of immunological diseases. Immunol Today 1984; 5: 324–32. 2 Sim E. Drug-induced immune complex disease. Complement Inflamm 1989; 6: 119–26.

Drug-induced pemphigus. Immunoprecipitation studies have shown that patients with drug-induced pemphigus foliaceus and pemphigus vulgaris often have circulating autoantibodies with the same antigenic specificity at a molecular level as autoantibodies from patients with idiopathic pemphigus [1]. Binding of an active thiol group in a drug to the pemphigus antigen complex might result in autoantibody production, or culprit drugs may result in immune dysregulation. In addition, drugs with thiol groups in their molecule, such as penicillamine, captopril and thiopronine, and piroxicam can cause acantholysis directly in vitro in the absence of autoantibody [2]. References 1 Korman NJ, Eyre RW, Stanley JR. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol 1991; 96: 273–6. 2 Ruocco V, Pisani M, de Angelis E, Lombardi ML. Biochemical acantholysis provoked by thiol drugs. Arch Dermatol 1990; 126: 965–6.

Fixed drug eruptions. Graft autotransplantation investigations carried out in the 1930s demonstrated cutaneous memory in involved skin in fixed drug eruption [1]. Serum factors from patients with fixed drug eruption have been reported to cause inflammation on injection into a previously involved site, but not when injected into normal skin [2], and to induce lymphocyte blast transformation [3,4]. However, cell-mediated rather than humoral immunity is thought to play the major role in the development of lesions in this condition. Lesional skin contains increased numbers of both helper and suppressor T lymphocytes [5–8], and T suppressor/cytotoxic T cells may be seen adjacent to necrotic keratinocytes in the epidermis in the acute phase [6]. CD8+ cytotoxic T cells persist within lesional skin and contribute to immunological memory [5,7,9]. Intraepidermal CD8+ memory T cells phenotypically resembling effector memory T cells are greatly enriched in resting lesional skin of fixed drug eruption; upon activation, they can rapidly produce large amounts of IFN-γ, transiently acquire a natural killer-like phenotype, and express cytotoxic granules, followed by localized epidermal injury [10,11]. T cells from lesional epidermis in two patients with fixed drug eruption utilized a very limited range of Vα and Vβ genes compared with peripheral blood T cells, indicating expansion of T cells recognizing a restricted set of antigens [12]. Interleukin-15 derived from lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells, even in the absence of antigenic stimulus, over a prolonged period of time [13]. The influx into the epidermis of IL-10-producing CD4+ T cells and CD8+ T cells, including Foxp3+ regulatory T cells, during the evolution of an acute attack serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells and promotes resolution [13,14]. Successful desensitization to allopurinol-induced fixed drug eruption was associated with a significant increase in CD25+CD4+ T cells in lesional epidermis [15]. Keratinocytes in lesional skin express ICAM-1 [16], which is involved in interaction between keratinocytes and lymphocytes, HLA-DR [6] and the chemotactic protein IP-10 [8], findings that suggest a role for cytokines in the evolution of the histological changes [8,17]. ICAM-1 was noted to be induced on endothelium and keratinocytes 1.5 h after drug challenge, and there was increased reactivity in lesional skin in vitro to TNF-α and IFN-γ, as well as to the causative drug [17]; drug-induced, TNF-αdependent keratinocyte ICAM-1 expression in lesional skin may provide a localized initiating stimulus for epidermal T-cell activation. Early release of histamine from mast cells or basophils has been reported in fixed drug eruption, based on suction blister fluid levels [18]. Significantly higher frequencies of HLAB22 and HLA-Cw1 antigens were found in 36 patients with fixed drug eruption, and familial cases occur, suggesting a genetic predisposition [19]. References 1 Korkij W, Soltani K. Fixed drug eruption. A brief review. Arch Dermatol 1984; 120: 520–4. 2 Wyatt E, Greaves M, Søndergaard J. Fixed drug eruption (phenolphthalein). Arch Dermatol 1972; 106: 671–3. 3 Gimenez-Camarasa JM, Garcia-Calderon P, De Moragas JM. Lymphocyte transformation test in fixed drug eruption. N Engl J Med 1975; 292: 819–21.

Drug reactions 4 Suzuki S, Asai Y, Toshio H et al. Drug-induced lymphocyte transformation in peripheral lymphocytes from patients with drug eruption. Dermatologica 1978; 157: 146–53. 5 Hindsén M, Christensen OB, Gruic V, Löfberg H. Fixed drug eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol 1987; 116: 351–6. 6 Murphy GF, Guillén FJ, Flynn TC. Cytotoxic T lymphocytes and phenotypically abnormal epidermal dendritic cells in fixed cutaneous eruption. Hum Pathol 1985; 16: 1264–71. 7 Visa K, Käyhkö K, Stubb S, Reitamo S. Immunocompetent cells of fixed drug eruption. Acta Derm Venereol (Stockh) 1987; 67: 30–5. 8 Smoller BR, Luster AD, Krane JF et al. Fixed drug eruptions: evidence for a cytokine-mediated process. J Cutan Pathol 1991; 18: 13–9. 9 Scheper RJ, Von Blomberg M, Boerrigter GH et al. Induction of immunological memory in the skin. Role of local T cell retention. Clin Exp Immunol 1983; 51: 141–8. 10 Shiohara T, Mizukawa Y, Teraki Y. Pathophysiology of fixed drug eruption: the role of skin-resident T cells. Curr Opin Allergy Clin Immunol 2002; 2: 317–23. 11 Teraki Y, Shiohara T. IFN-gamma-producing effector CD8+ T cells and IL-10producing regulatory CD4+ T cells in fixed drug eruption. J Allergy Clin Immunol 2003; 112: 609–15. 12 Komatsu T, Moriya N, Shiohara T. T cell receptor (TCR) repertoire and function of human epidermal T cells: restricted TCR V alpha-V beta genes are utilized by T cells residing in the lesional epidermis in fixed drug eruption. Clin Exp Immunol 1996; 104: 343–50. 13 Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol 2008; 158: 1230–8. 14 Teraki Y, Kokaji T, Shiohara T. Expansion of IL-10-producing CD4+ and CD8+ T cells in fixed drug eruption. Dermatology 2006; 213: 83–7. 15 Teraki Y, Shiohara T. Successful desensitization to fixed drug eruption: the presence of CD25+CD4+ T cells in the epidermis of fixed drug eruption lesions may be involved in the induction of desensitization. Dermatology 2004; 209: 29–32. 16 Shiohara T, Nickoloff BJ, Sagawa Y et al. Fixed drug eruption. Expression of epidermal keratinocyte intercellular adhesion molecule-1 (ICAM-1). Arch Dermatol 1989; 125: 1371–6. 17 Teraki Y, Moriya N, Shiohara T. Drug-induced expression of intercellular adhesion molecule-1 on lesional keratinocytes in fixed drug eruption. Am J Pathol 1994; 145: 550–60. 18 Alanko K, Stubb S, Salo OP, Reitamo S. Suction blister fluid histamine in fixed drug eruption. Acta Derm Venereol (Stockh) 1992; 72: 89–91. 19 Pellicano R, Ciavarella G, Lomuto M, Di Giorgio G. Genetic susceptibility to fixed drug eruption: evidence for a link with HLA-B22. J Am Acad Dermatol 1994; 30: 52–4.

Histopathology of drug reactions [1] In most patterns of reaction to drugs, the histological changes are no more distinctive than are the clinical features. For example, urticaria, erythema multiforme, TEN and exfoliative dermatitis provoked by drugs cannot be differentiated from the same reactions resulting from other causes. Graft-versus-host disease-type drug eruptions in the acute phase show a predominance of epidermal CD8+ T cells, reduced epidermal OKT6-positive Langerhans’ cells, and increased keratinocyte expression of HLA-DR and ICAM-1 [2]. In contrast, in one study [3], Langerhans’ cells from lesional maculopapular drug eruptions reportedly increased in number by 66% and displayed more intense staining and more prominent dendrites. No single or combined histological feature, including tissue eosinophilia, is useful in differentiating graftversus-host disease from drug eruptions in bone marrow recipients; the cause of a new-onset, blanchable, erythematous rash in a bone marrow transplant recipient is most accurately determined by close clinical examination and follow-up [4].

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The histological changes in the vegetating iododermas and bromodermas, certain lichenoid eruptions and fixed drug eruptions are not pathognomonic, but are sufficiently characteristic to be of importance in differential diagnosis. The histology of a number of other drug eruptions has been reviewed [5]. Amiodarone-induced hyperpigmentation shows a lymphocytic dermatitis and yellowish-brown granules within several cell types; the drug or a metabolite forms at least a portion of the deposits. Clofazimine-induced hyperpigmentation involves accumulation of a ceroid lipofuscin within lipid-laden macrophages. The cutaneous eruption of lymphocyte recovery after chemotherapeutic agents is a maculopapular eruption with a non-specific, superficial perivascular dermatitis. Chemotherapy-induced acral erythema reveals a non-specific interface dermatitis. Specific reactions occur with etoposide (starburst cells) and busulfan (busulphan) (large atypical keratinocytes), and other chemotherapeutic agents may involve sweat glands: neutrophilic eccrine hidradenitis is characterized by neutrophil infiltration and by necrosis; syringosquamous metaplasia involves squamous metaplasia of the sweat duct. Drug-induced, generalized, pustular toxic erythema is characterized by subcorneal pustules and occasional eosinophils. Cephalosporins may produce a syndrome clinically and histologically like pemphigus, and naproxen produces one like porphyria cutanea tarda. The photosensitive dermatitis associated with quinine and piroxicam is histologically a non-specific spongiotic dermatitis. A lichenoid giant cell dermatitis may be caused by methyldopa or chlorothiazide, and phenytoin and carbamazepine dermatitis histologically imitates mycosis fungoides.

Bromodermas and iododermas In bromoderma, verrucous pseudoepitheliomatous hyperplasia is associated with abscesses containing neutrophils and eosinophils in the epidermis, and a dense dermal infiltrate initially consisting mainly of neutrophils and eosinophils and later containing many lymphocytes, plasma cells and histiocytes. The abundant dilated blood vessels may show endothelial proliferation. In iododermas, ulceration is more marked, but there is usually less epithelial hyperplasia. Both conditions must be differentiated from blastomycosis and coccidioidomycosis, and from pemphigus vegetans.

Fixed eruptions In the acute stage, the epidermal changes may be indistinguishable from erythema multiforme, with loss of cell outlines and necrosis of the lower epidermis. In less acute lesions, the epidermis may show little abnormality, but the dermis is oedematous and there is a conspicuous perivascular lymphocytic infiltrate. Later, there is increased melanin in the epidermis and within melanophages in the dermis.

Lichenoid eruptions The changes may be non-specific or may resemble idiopathic lichen planus, although the cellular infiltrate tends to be more pleomorphic and less dense, and the presence of focal parakeratosis, focal interruption of the granular layer, and cytoid bodies in the cornified and granular layers suggest a drug cause [6]. Later, there may be scarring, with destruction of the sweat glands.

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Chapter 75: Drug Reactions

References 1 Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever’s Histopathology of the Skin, 8th edn. Philadelphia: Lippincott, 1997. 2 Osawa J, Kitamura K, Saito S et al. Immunohistochemical study of graft-versushost reaction (GVHR)-type drug eruptions. J Dermatol 1994; 21: 25–30. 3 Dascalu DI, Kletter Y, Baratz M, Brenner S. Langerhans’ cell distribution in drug eruption. Acta Derm Venereol (Stockh) 1992; 72: 175–7. 4 Marra DE, McKee PH, Nghiem P. Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease. J Am Acad Dermatol 2004; 51: 543–6. 5 Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin 1992; 10: 19–36. 6 Van den Haute V, Antoine JL, Lachapelle JM. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica 1989; 179: 10–3.

Types of clinical reaction [1–13] The mucocutaneous reactions that may result from ADRs have been the subject of extensive reviews, to which the reader is referred for further information. The following section details a number of different drug-induced reaction patterns; see also the discussion of adverse effects of individual drugs later. The clinical presentation of drug eruptions is highly variable, in part explicable by involvement of a variety of cytokines, inflammatory cells and regulatory mechanisms, and ranges from common transient and benign erythema occurring 6–9 days after the introduction of a new drug in up to 3% of users, to the most severe forms which affect fewer than 1/10 000 users. It is important for clinicians to recognize these severe cutaneous adverse reactions: anaphylaxis; drug reaction with eosinophilia and systemic symptoms (dress) syndrome (previously termed drug hypersensitivity syndrome) (mortality 10%); acute generalized exanthematous pustulosis (AGEP) (mortality 5%); bullous fixed drug eruptions; serum sickness syndrome; vasculitis; Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN) (mortality 25 to 30%). It is clearly critical to realize as rapidly as possible that an unusual, acute eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection, and to look for relevant internal involvement. Chronic-onset drug-induced disorders may mimic dermatological diseases; these include pigmentary changes, drug-induced autoimmune bullous diseases, lichenoid eruptions, lupus erythematosus, pseudolymphoma and acneiform eruptions. It is unfortunate that although certain drugs are commonly associated with a specific reaction pattern (e.g. pristinamycin, hydroxychloroquine, and diltiazem for AGEP; minocycline for dress; anti-infectious sulfonamides and allopurinol for TEN), most drugs are capable of causing several different types of eruption. References 1 Stern RS, Wintroub BU. Adverse drug reactions: reporting and evaluating cutaneous reactions. Adv Dermatol 1987; 2: 3–18. 2 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 3 Alanko K, Stubbs S, Kauppinen K. Cutaneous drug reactions: clinical types and causative agents. A five year survey of in-patients (1981–1985). Acta Derm Venereol (Stockh) 1989; 69: 223–6. 4 Shear NH, ed. Adverse reactions to drugs. Semin Dermatol 1989; 8: 135–226. 5 Kalish RS. Drug eruptions: a review of clinical and immunological features. Adv Dermatol 1991; 6: 221–37.

Fig. 75.1 Maculopapular erythema caused by ampicillin.

6 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 7 Zürcher L, Krebs A. Cutaneous Drug Reactions. Basel: Karger, 1992. 8 Bruinsma WA. A Guide to Drug Eruptions: File of Side Effects in Dermatology, 6th edn. Oosthuizen, The Netherlands: File of Medicines, 1996. 9 Litt JZ, Pawlak WA Jr. Drug Eruption Reference Manual. New York: Parthenon, 1997. 10 Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol 2005; 23: 171–81. 11 Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology 2005; 209: 123–9. 12 Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail and hair disorders. Drug Saf 2007; 30: 1011–30. 13 Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics 2007; 120: e1082–96.

Exanthematic (maculopapular) reactions [1] These are the most frequent of all cutaneous reactions to drugs, and can occur after almost any drug at any time up to 3 (but usually 2) weeks after administration; they may be accompanied by fever, pruritus and eosinophilia. It is not possible to identify the offending drug by the nature of the eruption. The clinical features are variable; the lesions may be scarlatiniform, rubelliform or morbilliform, or may consist of a profuse eruption of small papules showing no close resemblance to any infective exanthem (Fig. 75.1). Less common are eruptions with large macules, polycylic and gyrate erythema, reticular eruptions and sheet-like erythema. The distribution is also variable but is generally symmetrical. The trunk and extremities are usually involved, and not uncommonly intertriginous areas may be favoured, but the face may be spared. Palmar and plantar lesions may occur, and sometimes the eruption is generalized. Purpuric lesions, especially on the legs,

Types of clinical reaction Table 75.2 Drugs causing exanthematic reactions. Most common

Less common

Ampicillin and penicillin Phenylbutazone and other pyrazolones Sulphonamides Phenytoin Carbamazepine Gold Gentamicin

Cephalosporins Barbiturates Thiazides Naproxen Isoniazid Phenothiazines Quinidine Meprobamate Atropine

and erosive stomatitis may develop. There may be relative sparing of pressure areas. If the administration of the drug is continued, an exfoliative dermatitis may develop, although occasionally the eruption subsides despite continuation of the medication. Morbilliform drug eruptions usually, but not always, recur on rechallenge. The main differential diagnosis is from viral rashes. In a recent series of atypical exanthems, morphology and laboratory investigations led to an aetiological diagnosis in about 70% of cases [2]. It is useful, in differentiating exanthematic drug eruptions from viral exanthems, to remember that viral rashes may start on the face and progress to involve the trunk, and are more often accompanied by conjunctivitis, lymphadenopathy and fever. Maculopapular drug eruptions usually fade with desquamation, sometimes with post-inflammatory hyperpigmentation. Commoner causes are listed in Table 75.2. References 1 Yawalkar N. Drug-induced exanthems. Toxicology 2005; 209: 131–4. 2 Drago F, Rampini PR, Rampini E, Rebora A. Atypical exanthems: morphology and laboratory investigations may lead to an aetiological diagnosis in about 70% of cases. Br J Dermatol 2002; 147: 255–60.

Purpura A purpuric element to a drug eruption is not uncommon, but primarily purpuric drug-induced rashes also occur. Many drugs may interfere with platelet aggregation [1] but, with the exception of aspirin, this does not usually result in bleeding. A number of drugs have been implicated in the development of drug-induced purpura [2–4]. Several mechanisms may be involved. These include altered coagulation after anticoagulants or some cephalosporins, allergic and non-allergic thrombocytopenia, altered platelet function (as after valproic acid) or vascular causes, including steroid-induced fragility and loss of support. Cytotoxic drug therapy may result in non-allergic purpura due to bone marrow depression, with a platelet count of less than 30 000/mm3. Bleomycin may induce thrombocytopenia by causing endothelial damage and consequent platelet aggregation [5]. A large number of drugs have been reported to cause allergic thrombocytopenia [2–4]. Heparin may cause purpura with overdosage or due to an allergic thrombocytopenia [6]. The classical example of complement-mediated destruction of platelets, following immune complex formation between a drug (as hapten) bound to the platelet surface and IgG class antibody, was the purpura caused by apronalide (Sedormid). Quinine, quinidine [7,8] and chlorothiazide may also cause aller-

75.23

gic purpura. Tissue plasminogen activator (alteplase) has been associated with painful purpura [9]. A purpuric vasculitis-like rash followed secondary spread of a contact dermatitis to balsam of Peru [10]. Capillaritis (pigmented purpuric eruption) may be due to aspirin, carbromal or more rarely to thiamine or meprobamate [11], carbamazepine, phenacetin, as well as glipizide, pefloxacin, lorazepam, aspirin, paracetamol (acetuminophen), polyvinyl pyrrolidone plasma expander, ciclosporin and griseofulvin [12–16]; it may be due to formation of antibody to a drug–capillary endothelial cell complex [12]. Chronic pigmented purpura is recorded with thiamine propyldisulphide and chlordiazepoxide [13], and aminoglutethimide [17]. NSAIDs, diuretics, meprobamate and ampicillin were the commonest drug cause of pigmented purpuric eruptions in one study [18]. References 1 George JN, Shattil SJ. The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324: 27–39. 2 Miescher PA, Graf J. Drug-induced thrombocytopenia. Clin Haematol 1980; 9: 505–19. 3 Moss RA. Drug-induced immune thrombocytopenia. Am J Hematol 1980; 9: 439–46. 4 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 5 Hilgard P, Hossfeld DK. Transient bleomycin-induced thrombocytopenia. A clinical study. Eur J Cancer 1978; 14: 1261–4. 6 Babcock RB, Dumper CW, Scharfman WB. Heparin-induced thrombocytopenia. N Engl J Med 1976; 295: 237–41. 7 Christie DJ, Weber RW, Mullen PC et al. Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets. J Lab Clin Med 1984; 104: 730–40. 8 Gary M, Ilfeld D, Kelton JG. Correlation of a quinidine-induced platelet-specific antibody with development of thrombocytopenia. Am J Med 1985; 79: 253–5. 9 Detrana C, Hurwitz RM. Painful purpura: an adverse effect to a thrombolysin. Arch Dermatol 1990; 126: 690–1. 10 Bruynzeel DP, van den Hoogenband HM, Koedijk F. Purpuric vasculitis-like eruption in a patient sensitive to balsam of Peru. Contact Dermatitis 1984; 11: 207–9. 11 Peterson WC, Manick KP. Purpuric eruptions associated with use of carbromal and meprobamate. Arch Dermatol 1967; 95: 40–2. 12 Carmel WJ, Dannenberg T. Nonthrombocytopenic purpura due to Miltown (2methyl-2-n-propyl-1,3-propanediol dicarbamate). N Engl J Med 1956; 255: 7701. 13 Nishioka K, Katayama I, Masuzawa M et al. Drug-induced chronic pigmented purpura. J Dermatol 1989; 16: 220–2. 14 Abeck D, Gross GE, Kuwert C et al. Acetaminophen-induced progressive pigmentary purpura (Schamberg’s disease). J Am Acad Dermatol 1992; 27: 123–4. 15 Tsao H, Lerner LH. Pigmented purpuric eruption associated with injection medroxyprogesterone acetate. J Am Acad Dermatol 2000; 43: 308–10. 16 Adams BB, Gadenne AS. Glipizide-induced pigmented purpuric dermatosis. J Am Acad Dermatol 1999; 41: 827–9. 17 Stratakis CA, Chrousos GP. Capillaritis (purpura simplex) associated with use of aminoglutethimide in Cushing’s syndrome. Am J Hosp Pharm 1994; 51: 2589–91. 18 Pang BK, Su D, Ratnam KV. Drug-induced purpura simplex: clinical and histological characteristics. Ann Acad Med Singapore 1993; 22: 870–2.

Annular erythema Erythema annulare centrifugum has been reported in association with chloroquine and hydroxychloroquine [1], oestrogens, cimetidine [2], penicillin, salicylates and piroxicam, as well as with hydrochlorothiazide [3], spironolactone [4], thioacetazone [5], the phenothiazine levomepromazine [6], etizolam [7] and finasteride [8]. Annular erythema has occurred with vitamin K [9].

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Chapter 75: Drug Reactions

Table 75.3 Drugs causing pityriasis rosea-like reactions. Acetylsalicylic acid Allopurinol Arsenicals Bismuth Barbiturates β-Blockers Clonidine Captopril Gold

Griseofulvin Hydrochlorothiazide Isotretinoin Methoxypromazine Metronidazole Nimesulide Omeprazole Pyribenzamine

References 1 Ashurst PJ. Erythema annulare centrifugum due to hydroxychloroquine sulfate and chloroquine sulfate. Arch Dermatol 1967; 95: 37–9. 2 Merrett AC, Marks R, Dudley FJ. Cimetidine-induced erythema annulare centrifugum: no cross-sensitivity with ranitidine. BMJ 1981; 283: 698. 3 Goette DK, Beatrice E. Erythema annulare centrifugum caused by hydrochlorothiazide-induced interstitial nephritis. Int J Dermatol 1988; 27: 129–30. 4 Carsuzaa F, Pierre C, Dubegny M. Érytheme annulaire centrifuge a l’aldactone. Ann Dermatol Vénéréol 1987; 114: 375–6. 5 Ramesh V. Eruption resembling erythema annulare centrifugum. Australas J Dermatol 1987; 28: 44. 6 Blazejak T, Hölzle E. Phenothiazin-induziertes Pseudolymphom. Hautarzt 1990; 41: 161–3. 7 Kuroda K, Yabunami H, Hisanaga Y. Etizolam-induced superficial erythema annulare centrifugum. Clin Exp Dermatol 2002; 27: 34–6. 8 Al Hammadi A, Asai Y, Patt ML, Sasseville D. Erythema annulare centrifugum secondary to treatment with finasteride. J Drugs Dermatol 2007; 6: 460–3. 9 Kay MH, Duvic M. Reactive annular erythema after intramuscular vitamin K. Cutis 1986; 37: 445–8.

Pityriasis rosea-like reactions The best-known drug cause of a pityriasiform rash is gold therapy [1], but several other drugs have been implicated, including metronidazole [2], captopril [3], isotretinoin [4] and omeprazole [5] (Table 75.3). An Italian series reported cases linked to: angiotensinconverting enzyme inhibitors, alone or in combination with hydrochlorothiazide, followed by one case each for hydrochlorothiazide plus sartan, allopurinol, nimesulide, and acetylsalicylic acid [6]. References 1 Wile UJ, Courville CJ. Pityriasis rosea-like dermatitis following gold therapy: report of two cases. Arch Dermatol 1940; 42: 1105–12. 2 Maize JC, Tomecki J. Pityriasis rosea-like drug eruption secondary to metronidazole. Arch Dermatol 1977; 113: 1457–8. 3 Wilkin JK, Kirkendall WM. Pityriasis rosea-like rash from captopril. Arch Dermatol 1982; 118: 186–7. 4 Helfman RJ, Brickman M, Fahey J. Isotretinoin dermatitis simulating acute pityriasis rosea. Cutis 1984; 33: 297–300. 5 Buckley C. Pityriasis rosea-like eruption in a patient receiving omeprazole. Br J Dermatol 1996; 135: 660–1. 6 Atzori L, Pinna AL, Ferreli C, Aste N. Pityriasis rosea-like adverse reaction: review of the literature and experience of an Italian drug-surveillance center. Dermatol Online J 2006; 12: 1.

Psoriasiform eruptions See Chapter 20 and Table 75.4.

Table 75.4 Drugs reported to exacerbate psoriasis. Antimalarials β-Blockers Lithium salts Non-steroidal anti-inflammatory drugs Ibuprofen Indometacin (indomethacin) (disputed) Meclofenamate sodium Pyrazolone derivatives (phenylbutazone, oxyphenbutazone) Miscellaneous Captopril Chlortalidone (chlorthalidone) Cimetidine Clonidine Gemfibrozil Interferon Methlydopa Penicillamine Penicillin Terfenadine Trazodone

Table 75.5 Drugs causing erythroderma and exfoliative dermatitis. Allopurinol p-Aminosalicylic acid Ampicillin Barbiturates Captopril Carbamazepine Cefoxitin Chloroquine Chlorpromazine Cimetidine Diltiazem Gold Griseofulvin

Hydantoins Isoniazid Lithium Nitrofurantoin Penicillamine Penicillin Phenylbutazone Quinidine Streptomycin Sulphonamides Sulphonylureas Thioacetazone (thiacetazone)

Exfoliative dermatitis Exfoliative dermatitis is one of the most dangerous patterns of cutaneous reaction to drugs [1–5]. It may follow exanthematic eruptions or may develop, as in some reactions to arsenicals and the heavy metals, as erythema and exudation in the flexures, rapidly generalizing. The eruption may start several weeks after initiation of the therapy. A dermatitis in patients previously sensitized by contact may also become universal. The main drugs implicated are listed in Table 75.5. In one large series, sulphonamides, antimalarials and penicillin were most frequently implicated [1]. In another series from India [3], the commonest associated drugs were isoniazid (20%), thioacetazone (15%), topical tar (15%) and a variety of homeopathic medicines (20%), with phenylbutazone, streptomycin and sulfadiazine (sulphadiazine) each accounting for 5% of cases. Phenytoin is a well-recognized cause [6]. Recently incriminated drugs have included captopril, cefoxitin, cimetidine and ampicillin.

Types of clinical reaction References 1 Nicolis GD, Helwig EB. Exfoliative dermatitis. A clinicopathologic study of 135 cases. Arch Dermatol 1973; 108: 788–97. 2 Hasan T, Jansén DT. Erythroderma: a follow-up of fifty cases. J Am Acad Dermatol 1983; 8: 836–40. 3 Sehgal VN, Srivastava G. Exfoliative dermatitis. A prospective study of 80 patients. Dermatologica 1986; 173: 278–84. 4 Sage T, Faure M. Conduite à tenir devant les érythrodermies de l’adulte. Ann Dermatol Vénéréol 1989; 116: 747–52. 5 Irvine C. ‘Skin failure’—a real entity: discussion paper. J R Soc Med 1991; 84: 412–3. 6 Danno K, Kume M, Ohta M et al. Erythroderma with generalized lymphadenopathy induced by phenytoin. J Dermatol 1989; 16: 392–6.

Anaphylaxis and anaphylactoid reactions This systemic reaction, which usually develops within minutes to hours (the vast majority within the first hour), is often severe and may be fatal [1–3]. Fatal drug-induced anaphylactic shock was estimated at 0.3 cases per million inhabitants per year, based on notifications to the Danish Committee on Adverse Drug Reactions and to the Central Death Register during the period 1968–90 [3]. The most frequent causes were contrast media for X-ray examinations, antibiotics and extracts of allergens. In less severe cases, there may be premonitory dizziness or faintness, skin tingling and reddening of the bulbar conjunctiva, followed by urticaria, angio-oedema, bronchospasm, abdominal pain and vasomotor collapse. It usually develops on second exposure to a drug, but may develop during the first treatment if this lasts sufficiently long for sensitization to occur. Anaphylaxis is unlikely to occur with a drug taken continuously for several months; in contrast, intermittent administration may predispose to anaphylaxis [1]. It is commoner after parenteral than oral drug administration. The β-blockers enhance anaphylactic reactions caused by other allergens, and may make resuscitation more difficult [4]. The principal drug causes are shown in Table 75.6. Antibiotics (especially penicillin) and radiocontrast media are the most common known causes of anaphylactic events [2]; the incidence of such reactions for each is about 1 in 5000 exposures [5,6], of which less than 10% are fatal [2]. The risk for recurrent anaphylactic reactions is 10–20% for penicillins [5] and 20–40% for radiocontrast media [7]. Anaphylaxis to paracetamol-containing tablets has occurred, although it was the additive polyvinyl pyrrolidone that was responsible [8]. Anaphylaxis does occur after non-mucosal topical drug administration, especially to skin wounds or to skin with impaired barrier function, but TEN or SJS following nonmucosal topical drug application seems to be extremely rare [9]. Anaphylactoid reactions are those that clinically resemble an immediate immune response but in which the mechanism is undetermined. Some drugs and agents, such as mannitol and radiographic contrast media, can stimulate mediator release by an as yet unknown direct mechanism independent of IgE or complement. Anaphylactoid reactions may be produced by non-steroidal analgesics and anti-inflammatory agents (NSAIDs) [10,11], including aspirin and other salicylates, indometacin (indomethacin), phenylbutazone, propyphenazone, metamizole and tolmetin [12], as well as by radiographic contrast media, d-tubocurarine, benzoic acid preservatives [13], tartrazine dyes, sulphite preservatives [14] and ciprofloxacin [15]. The HLA-DRB1*11 allele showed a positive

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Table 75.6 Drugs causing urticaria or anaphylaxis. Animal sera Vaccines containing egg protein Desensitizing agents including pollen vaccines Antibiotics Penicillins Cephalosporins Aminoglycosides Tetracyclines Sulphonamides Antifungal agents Fluconazole Ketoconazole Blood products Angiotensin-converting enzyme inhibitors Radiographic contrast media Non-steroidal anti-inflammatory drugs (NSAIDs) Salicylates Other NSAIDs (e.g. phenylbutazone, aminopyrine, propyphenazone, metamizole, tolmetin) Narcotic analgesics Anaesthetic agents: local and general Muscle relaxants Suxamethonium Curare

Dextrans Mannitol Sorbitol complexes Enzymes Trypsin Streptokinase Chymopapain Steroids Progesterone Hydrocortisone Polypeptide hormones Insulin Corticotrophin Vasopressin Food and drug additives Benzoates Sulphites Tartrazine dyes Hydantoins Hydralazine Quinidine Anticancer drugs Vitamins Protamine

association with NSAID-induced anaphylactoid systemic reactions but not with purely cutaneous reactions [16]. References 1 Sussman GL, Dolovich J. Prevention of anaphylaxis. Semin Dermatol 1989; 8: 158–65. 2 Bochner BS, Lichtenstein LM. Anaphylaxis. N Engl J Med 1991; 324: 1785–90. 3 Lenler-Petersen P, Hansen D, Andersen M et al. Drug-related fatal anaphylactic shock in Denmark 1968–1990. A study based on notifications to the Committee on Adverse Drug Reactions. J Clin Epidemiol 1995; 48: 1185–8. 4 Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988; 81: 1–5. 5 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 6 Ansell G, Tweedie MCK, West DR et al. The current status of reactions to intravenous contrast media. Invest Radiol 1980; 15 (Suppl. 6): S32–S39. 7 Greenberger P, Patterson R, Kelly J et al. Administration of radiographic contrast media in high-risk patients. Invest Radiol 1980; 15 (Suppl. 6): S40–S43. 8 Rönnau AC, Wulferink M, Gleichmann E et al. Anaphylaxis to polyvinylpyrrolidone in an analgesic preparation. Br J Dermatol 2000; 143: 1055–8. 9 Sachs B, Fischer-Barth W, Erdmann S et al. Anaphylaxis and toxic epidermal necrolysis or Stevens–Johnson syndrome after nonmucosal topical drug application: fact or fiction? Allergy 2007; 62: 877–83. 10 Antépara I, Martín-Gil D, Dominguez MA, Oehling A. Adverse drug reactions produced by analgesic drugs. Allergol Immunopathol 1981; 9: 545–54. 11 Stevenson DD. Diagnosis, prevention and treatment of adverse reactions to aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAID). J Allergy Clin Immunol 1984; 74: 617–22. 12 Rossi AC, Knapp DE. Tolmetin-induced anaphylactoid reactions. N Engl J Med 1982; 307: 499–500. 13 Michils A, Vandermoten G, Duchateau J, Yernault J-C. Anaphylaxis with sodium benzoate. Lancet 1991; 337: 1424–5. 14 Twarog FJ, Leung DYM. Anaphylaxis to a component of isoetharine (sodium bisulfite). JAMA 1982; 248: 2030–1. 15 Davis H, McGoodwin E, Reed TG. Anaphylactoid reactions reported after treatment with ciprofloxin. Ann Intern Med 1989; 111: 1041–3.

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Chapter 75: Drug Reactions

and radiocontrast media, may release mast cell mediators directly. Cyclo-oxygenase inhibitors, such as aspirin and indometacin, and ACE inhibitors, such as captopril and enalapril, may cause urticaria or angio-oedema by pharmacological mechanisms. ACE inhibitors may cause increased frequency, intensity and duration of bouts of idiopathic angio-oedema during long-term use [21,22].

Fig. 75.2 Urticaria induced by acetylsalicylic acid. (Courtesy of St John’s Institute of Dermatology, King’s College London, UK.)

16 Quiralte J, Sanchez-Garcia F, Torres MJ et al. Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1999; 103: 685–9.

Urticaria Urticaria (see Chapter 22) is, after an exanthematous eruption, the second most common type of ACDR [1,2] (Fig. 75.2). Drug-induced urticaria is seen in 0.16% of medical in-patients and accounts for 9% of chronic urticaria or angio-oedema seen in dermatology outpatient departments [1]. Occurring within 24–36 h of drug ingestion, it is most commonly caused by penicillins, sulphonamides and NSAIDs. Drug-induced urticaria is seen in association with anaphylaxis, angio-oedema and serum sickness. On rechallenge, lesions may develop within minutes. Angio-oedema, involving oedema of the deep dermis or subcutaneous and submucosal areas, is more rarely seen than urticaria as an ACDR, and occurs in less than 1% of patients receiving the particular drug. The commoner drug causes of urticaria/angio-oedema are listed in Table 75.6. The frequency of urticaria/angio-oedema or anaphylactic responses to aspirin and other NSAIDs is about 1% in an outpatient population and is familial [3]. Aspirin (salicylates) may also aggravate chronic urticaria [4,5]. In addition, an unsuspected agent, for example the yellow dye tartrazine, may really be responsible for an urticaria attributed to aspirin or another drug. The analgesic codeine is also a cause of urticaria [6]. Penicillin is a very well-documented cause of acute urticaria, but the role of this drug in chronic urticaria is controversial [7]. Urticaria develops in about 1% of patients receiving blood transfusions [8]. There have been numerous papers on the potential role of food and drug additives [9–17], including preservatives such as benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, sulphites and rarely aspartame, as well as tartrazine dyes, in the development of chronic urticaria. However, one study suggested that common food additives are seldom, if ever, of significance in urticaria [10]. Urticaria may follow alcohol consumption [18], intraarticular methylprednisolone [19] and even cetirizine [20]. Certain drugs, such as opiates, codeine, amfetamine, polymyxin B, d-tubocurarine, atropine, hydralazine, pentamidine, quinine

References 1 Shipley D, Ormerod AD. Drug-induced urticaria. Recognition and treatment. Am J Clin Dermatol 2001; 2: 151–8. 2 Mathelier-Fusade P. Drug-induced urticarias. Clin Rev Allergy Immunol 2006; 30: 19–23. 3 Settipane GA, Pudupakkam RK. Aspirin intolerance. III. Subtypes, familial occurrence and cross reactivity with tartrazine. J Allergy Clin Immunol 1975; 56: 215–21. 4 Settipane RA, Constantine HP, Settipane GA. Aspirin intolerance and recurrent urticaria in normal adults and children. Epidemiology and review. Allergy 1980; 35: 149–54. 5 Grattan CEH. Aspirin sensitivity and urticaria. Clin Exp Dermatol 2003; 28: 123–7. 6 De Groot AC, Conemans J. Allergic urticarial rash from oral codeine. Contact Dermatitis 1986; 14: 209–14. 7 Boonk WJ, Van Ketel WG. The role of penicillin in the pathogenesis of chronic urticaria. Br J Dermatol 1982; 106: 183–90. 8 Shulman IA. Adverse reactions to blood transfusion. Texas Med 1990; 85: 35– 42. 9 Simon RA. Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623–30. 10 Hannuksela M, Lahti A. Peroral challenge tests with food additives in urticaria and atopic dermatitis. Int J Dermatol 1986; 25: 178–80. 11 Supramaniam G, Warner JO. Artificial food additives intolerance in patients with angioedema and urticaria. Lancet 1986; ii: 907–9. 12 Juhlin L. Additives and chronic urticaria. Ann Allergy 1987; 59: 119–23. 13 Goodman DL, McDonnell JT, Nelson HS et al. Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). J Allergy Clin Immunol 1990; 86: 570–5. 14 Settipane GA. Adverse reactions to sulfites in drugs and foods. J Am Acad Dermatol 1984; 10: 1077–80. 15 Kulczycki A Jr. Aspartame-induced urticaria. Ann Intern Med 1986; 104: 207–8. 16 Neuman I, Elian R, Nahum H et al. The danger of ‘yellow dyes’ (tartrazine) to allergic subjects. J Allergy 1972; 50: 92–8. 17 Miller K. Sensitivity to tartrazine. BMJ 1982; 285: 1597–8. 18 Ormerod AD, Holt PJA. Acute urticaria due to alcohol. Br J Dermatol 1983; 108: 723–4. 19 Pollock B, Wilkinson SM, MacDonald Hull SP. Chronic urticaria associated with intra-articular methylprednisolone. Br J Dermatol 2001; 144: 1228–30. 20 Calista D, Schianchi S, Morri M. Urticaria induced by cetirizine. Br J Dermatol 2001; 144: 196. 21 Chin HL. Severe angioedema after long-term use of an angiotensin converting enzyme inhibitor. Ann Intern Med 1990; 112: 312. 22 Kozel MMA, Mekkes JR, Bos JD. Increased frequency and severity of angiooedema related to long-term therapy with angiotensin-converting enzyme inhibitor in two patients. Clin Exp Dermatol 1995; 20: 60–1.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome Synonyms • Drug hypersensitivity syndrome • Anticonvulsant hypersensitivity syndrome

The drug hypersensitivity syndrome [1–3], also known as drug rash with eosinophilia and systemic symptoms (dress) syndrome

Types of clinical reaction

[2] or as drug-induced delayed multiorgan hypersensitivity syndrome (didmohs) [4], has been reported with the anticonvulsants phenytoin, carbamazepine, phenobarbital and lamotrigine (anticonvulsant hypersensitivity syndrome; see also section on anticonvulsants, pp. 75.83–86), and with trimethoprim– sulfamethoxazole, minocycline, procarbazine, allopurinol, terbinafine, dapsone, abacavir and nevirapine. This syndrome should be distinguished from drug-induced pseudolymphoma syndrome, also caused especially by anticonvulsants, which has a more insidious beginning with nodules and infiltrated plaques appearing several weeks after starting the drug, without constitutional symptoms (see p. 75.44). Cross-reactivity occurs between different anticonvulsants [5–7]; even valproate has been incriminated [7]. Superimposed, or reactivation of, viral infection may have a role in the aetiology [8] (see also Classification and mechanisms of drug reactions, Cell-mediated (type IV) reactions, pp. 75.17–19). The syndrome comprises fever, facial oedema with infiltrated papules, generalized papulopustular or exanthematous rash which may extend to exfoliative dermatitis, lymphadenopathy, haematological abnormalities (hypereosinophilia in 90% of cases, atypical lymphocytes/mononucleosis in 40% of cases), and organ involvement such as hepatitis, possible nephritis, pneumonitis, myocarditis and hypothyroidism, and encephalitis, occurring after 3–6 weeks of drug therapy. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma. The mortality is of the order of 10%; the syndrome may proceed to Stevens–Johnson syndrome or TEN [9] (see Chapter 76). There has been some controversy as to whether the constellation of various symptoms and signs occurring in multiorgan drug-induced reactions should be classified as a single, clearly defined, unified entity [10,11], but the concept of dress is generally accepted [12]. Management is usually with systemic corticosteroids. A combination of systemic steroids and intravenous immunoglobulin was successful in four patients with anticonvulsant hypersensitivity [13].

References 1 Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol 2001; 137: 357–64. 2 Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 1996; 15: 250–7. 3 Carroll MC, Yueng-Yue KA, Esterly NB, Drolet BA. Drug-induced hypersensitivity syndrome in pediatric patients. Pediatrics 2001; 108: 485–92. 4 Sontheimer RD, Houpt KR. DIDMOHS: a proposed consensus nomenclature for the drug-induced delayed multiorgan hypersensitivity syndrome. Arch Dermatol 1998; 134: 874–5. 5 Allam JP, Paus T, Reichel C et al. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol 2004; 14: 339–42. 6 Mendiratta V, Bhushan P. Phenytoin-induced DRESS with cross-reactivity to carbamazepine in a 10-year-old Indian child. Clin Exp Dermatol 2006; 31: 720–1. 7 Yun SJ, Lee JB, Kim EJ et al. Drug rash with eosinophilia and systemic symptoms induced by valproate and carbamazepine: formation of circulating auto-antibody against 190-kDa antigen. Acta Derm Venereol 2006; 86: 241–4. 8 Aihara Y, Ito S-I, Kobayashi Y et al. Carbamazepine-induced hypersensitivity syndrome associated with transient hypogammaglobulinaemia and reactivation of human herpesvirus 6 infection demonstrated by real-time quantitative polymerase chain reaction. Br J Dermatol 2003; 149: 165–9.

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9 Wolf R, Matz H, Marcos B, Orion E. Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: the dilemma of classification. Clin Dermatol 2005; 23: 311–4. 10 Peyrière H, Dereure O, Breton H et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2006; 155: 422–8. 11 Kardaun SH, Sidoroff A, Valeyrie-Allanore L et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007; 156: 609–11. 12 Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007; 156: 1083–4. 13 Prais D, Straussberg R, Amir J et al. Treatment of anticonvulsant hypersensitivity syndrome with intravenous immunoglobulins and corticosteroids. J Child Neurol 2006; 21: 380–4.

Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis See Chapter 76.

Serum sickness Serum sickness, a type III immune complex-mediated reaction, may occur between 5 days and 3 weeks after initial exposure [1–5], and in its complete form combines fever, urticaria, angio-oedema, joint pain and swelling, lymphadenopathy, and occasionally nephritis or endocarditis, with eosinophilia. In minor forms of serum sickness, fever, urticaria and transitory joint tenderness may be the only manifestations. Drugs implicated include heterologous serum [1,2], immune globulin (as treatment for Kawasaki disease) [6], aspirin, antibiotics [7,8] such as penicillin [3,7,9], amoxicillin [7], flucloxacillin [7], cefaclor [10–14], cefprozil [15], piperacillin [16], ciprofloxacin [17], cefatrizine [18], cotrimoxazole [7], troleandomycin (triacetyloleandomycin) [7], streptomycin, sulphonamides and sulfasalazine [19], thiouracils, intravenous streptokinase [20,21], Nacetylcysteine [22], staphylococcal protein A immunomodulation [23] and amfebutamone (bupropion) [24]. Of 32 women in an in vitro fertilization programme, 15% developed serum sickness 8–12 days after oocyte retrieval by echographic puncture, when a medium containing bovine serum was employed for rinsing follicles [25]. Patients had specific IgG antibodies against, and positive intradermal skin testing to, bovine serum albumin. A characteristic serpiginous, erythematous and purpuric eruption developed on the hands and feet at the borders of palmar and plantar skin in a series of patients treated with intravenous infusions of horse antithymocyte globulin for bone marrow failure [1,2]. Circulating immune complexes, low serum C4 and C3 levels, and elevated plasma C3a anaphylatoxin levels were found. Direct immunofluorescence revealed the presence of immunoreactants including IgM, C3, IgE and IgA in the walls of dermal blood vessels. References 1 Lawley TJ, Bielory L, Gascon P et al. A prospective clinical and immunologic analysis of patients with serum sickness. N Engl J Med 1984; 311: 1407–13. 2 Bielory L, Yancey KB, Young NS et al. Cutaneous manifestations of serum sickness in patients receiving antithymocyte globulin. J Am Acad Dermatol 1985; 13: 411–7. 3 Erffmeyer JE. Serum sickness. Ann Allergy 1986; 56: 105–9. 4 Lin RY. Serum sickness syndrome. Am Fam Physician 1986; 33: 157–62. 5 Virella G. Hypersensitivity reactions. Immunol Ser 1993; 58: 329–41.

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6 Comenzo RL, Malachowski ME, Meissner HC et al. Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. J Pediatr 1992; 120: 926–8. 7 Martin J, Abbott G. Serum sickness-like illness and antimicrobials in children. NZ Med J 1995; 108: 123–4. 8 Smith JM. Serum sickness-like reactions with antibiotics. NZ Med J 1995; 108: 258. 9 Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral penicillin drugs: three case reports. Ann Allergy Asthma Immunol 2001; 86: 330–4. 10 Vial T, Pont J, Pham E et al. Cefaclor-associated serum sickness-like disease: eight cases and review of the literature. Ann Pharmacother 1992; 26: 910–4. 11 Parra FM, Igea JM, Martin JA et al. Serum sickness-like syndrome associated with cefaclor therapy. Allergy 1992; 47: 439–40. 12 Kearns GL, Wheeler JG, Childress SH, Letzig LG. Serum sickness-like reactions to cefaclor: role of hepatic metabolism and individual susceptibility. J Pediatr 1994; 125: 805–11. 13 Grammer LC. Cefaclor serum sickness. JAMA 1996; 275: 1152–3. 14 Isaacs D. Serum sickness-like reaction to cefaclor. J Paediatr Child Health 2001; 37: 298–9. 15 Lowery N, Kearns GL, Young RA, Wheeler JG. Serum sickness-like reactions associated with cefprozil therapy. J Pediatr 1994; 125: 325–8. 16 Rye PJ, Roberts G, Staugas RE, Martin AJ. Coagulopathy with piperacillin administration in cystic fibrosis: two case reports. J Paediatr Child Health 1994; 30: 278–9. 17 Guharoy SR. Serum sickness secondary to ciprofloxacin use. Vet Hum Toxicol 1994; 36: 540–1. 18 Plantin P, Milochau P, Dubois D. Maladie serique medicamenteuse apres prise de cefatrizine. Premier cas reporté. Presse Med 1992; 21: 1915. 19 Brooks H, Taylor HG, Nichol FE. The three week sulphasalazine syndrome. Clin Rheumatol 1992; 11: 566–8. 20 Patel A, Prussick R, Buchanan WW, Sauder DN. Serum sickness-like illness and leukocytoclastic vasculitis after intravenous streptokinase. J Am Acad Dermatol 1991; 24: 652–3. 21 Clesham GJ, Terry HJ, Jalihal S, Toghill PJ. Serum sickness and purpura following intravenous streptokinase. J R Soc Med 1992; 85: 638–9. 22 Mohammed S, Jamal AZ, Robison LR. Serum sickness-like illness associated with N-acetylcysteine therapy. Ann Pharmacother 1994; 28: 285. 23 Smith RE, Gottschall JL, Pisciotta AV. Life-threatening reaction to staphylococcal protein A immunomodulation. J Clin Apheresis 1992; 7: 4–5. 24 Davis JS, Boyle MJ, Hannaford R, Watson A. Bupropion and serum sickness-like reaction. Med J Aust 2001; 174: 479–80. 25 Morales C, Braso JV, Pellicer A et al. Serum sickness due to bovine serum albumin sensitization during in vitro fertilization. J Invest Allergol Clin Immunol 1994; 4: 246–9.

Fixed eruptions [1–9] A fixed drug eruption characteristically recurs in the same site or sites each time the drug is administered; with each exposure, however, the number of involved sites may increase. Usually, just one drug is involved, although independent lesions from more than one drug have been described [10]. Cross-sensitivity to related drugs may occur, such as between phenylbutazone and oxyphenbutazone, between tetracycline-type drugs, and between anticonvulsants [11]. There may be a refractory period after the occurrence of a fixed eruption. Acute lesions usually develop 30 min to 8 h after drug administration as sharply marginated, round or oval itchy plaques of erythema and oedema becoming dusky violaceous or brown, and sometimes vesicular or bullous (Fig. 75.3). The eruption may initially be morbilliform, scarlatiniform or erythema multiforme-like; urticarial, nodular or eczematous lesions are less common. Lesions are sometimes solitary at first, but with repeated attacks new

Fig. 75.3 Bullous fixed drug eruption with hyperpigmentation. (Courtesy of St John’s Institute of Dermatology, London, UK.)

lesions usually appear and existing lesions may increase in size. A multifocal bullous fixed drug eruption due to mefenamic acid resembled erythema multiforme [12]. Occasionally, involvement is so extensive as to mimic TEN [13,14]. Lesions are commoner on the limbs than on the trunk; the hands and feet, genitalia and perianal areas are favoured sites. Perioral and periorbital lesions may occur. Genital [15] and oral mucous membranes [16] may be involved in association with skin lesions, or alone. In the case of isolated male genital fixed drug eruption (often affecting only the glans penis), the drugs most commonly implicated in one series were co-trimoxazole (trimethoprim– sulfamethoxazole), tetracycline and ampicillin [15]. With oral fixed drug eruption, co-trimoxazole, oxyphenbutazone and tetracycline were the most common causative drugs [16]. Pigmentation of the tongue may occur as a form of fixed drug eruption in heroin addicts [17]. As healing occurs, crusting and scaling are followed by pigmentation, which may be very persistent and occasionally extensive, especially in pigmented individuals; pigmentation may be all that is visible between attacks. Non-pigmenting fixed reactions have been reported in association with the sympathomimetic agents pseudoephedrine [18,19] and tetryzoline (tetrahydrozoline) hydrochloride, diflunisal, thiopental (thiopentone), piroxicam, the radiopaque contrast medium iothalamate, arsphenamine [20], paracetamol [21], intra-articular triamcinolone acetonide [22] and eperisone hydrochloride [23]. The number of drugs capable of producing fixed drug eruption is very large. However, most fixed drug eruptions are due to one or other of the substances listed in Table 75.7. Earlier series incriminated particularly analgesics, sulphonamides and tetracyclines. In a report from Finland, phenazones caused most eruptions, with barbiturates, sulphonamides, tetracyclines and carbamazepine causing fewer reactions [24]. A series from India reported that

Types of clinical reaction Table 75.7 Drugs causing fixed eruptions. Antibacterial substances Sulphonamides (co-trimoxazole) Tetracyclines Penicillin Ampicillin Amoxicillin Erythromycin Trimethoprim Nystatin Griseofulvin Dapsone Arsenicals Mercury salts p-Aminosalicylic acid Thioacetazone (thiacetazone) Quinine Metronidazole Clioquinol

Barbiturates and other tranquillizers Barbiturate derivatives Opium alkaloids Chloral hydrate Benzodiazepines: chlordiazepoxide Anticonvulsants Dextromethorphan

Non-steroidal anti-inflammatory drugs Aspirin (acetylsalicylic acid) Oxyphenbutazone Phenazone (antipyrine) Metamizole Paracetamol (acetaminophen) Ibuprofen Various non-proprietary analgesic combinations Phenolphthalein and related compounds Miscellaneous Codeine Hydralazine Oleoresins Sympathomimetics Sympatholytics Parasympatholytics: hyoscine butylbromide Magnesium hydroxide Magnesium trisilicate Anthralin Chlorthiazone Chlorphenesin carbamate Food substitutes and flavours

acetylsalicylic acid was the drug most commonly implicated in children [25]; a more recent study found that co-trimoxazole was the usual culprit in children [26]. Co-trimoxazole has been implicated as the most frequent cause in many studies [6,8,27]. A fixed drug eruption apparently caused by co-trimoxazole was reported in a man following intercourse with his wife, who was taking the drug [28]. Trimethoprim has caused a linear fixed drug eruption [29]. A report in 1991 showed that co-trimoxazole caused the maximum incidence (36.3%), followed by tetracycline (15.9%), pyrazolones (14.2%), sulfadiazine (12.4%), dipyrine (9.3%), paracetamol (7.9%), aspirin (1.7%), thioacetazone (0.88%) and levamisole (0.88%) [27]. Co-trimoxazole was also the most common cause of fixed drug eruption (75%), followed by naproxen sodium (12.5%), dipyrone (9.5%), dimenhydrinate (1.5%) and paracetamol (1.5%) in a study in 2000 [8]. However, a survey of current causes of fixed drug eruption in the UK listed NSAIDs including aspirin, paracetamol, antibacterial agents, systemic antifungal agents, psychotropic drugs, proton pump inhibitors, calcium channel blockers, ACE inhibitors and hormonal preparations [9], reflecting the decreased use of co-trimoxazole. A drug-specific clinical pattern in fixed drug eruptions based on a study of 113 patients has been reported [8,27]. Sulphonamides, including co-trimoxazole, induced lesions on the lips, trunk and limbs, with only minimal involvement of mucosae. Naproxen predominantly affected the lips and face. Tetracycline and cotrimoxazole caused lesions mainly on the glans penis. Pyrazolones affected mainly the lips and mucosae, with a few lesions of the

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trunk and limbs. Dipyrine, aspirin and paracetamol caused lesions of the trunk and limbs, sparing the lips, genitalia and mucosae. Levamisole caused associated constitutional disturbances with extensive skin lesions, as did thioacetazone [27]. Paracetamol (acetaminophen) is a rare cause of fixed drug eruption [30–33]; other drugs implicated have included codeine [34], naproxen [35], rofecoxib [36], ciprofloxacin [37], clarithromycin [38], rifampicin [39], metronidazole [40], terbinafine [41], fluconazole [42], lamotrigine [43], dimenhydrinate [44], cetirizine [45], loratadine [46], ticlopidine [47], phenylpropanolamine hydrochloride [48], and lactulose in an injected botulinum toxin preparation [49]. Familial fixed drug eruption has occurred occasionally [50,51]. References 1 Korkij W, Soltani K. Fixed drug eruption. A brief review. Arch Dermatol 1984; 120: 520–4. 2 Kauppinen K, Stubb S. Fixed eruptions: causative drugs and challenge tests. Br J Dermatol 1985; 112: 575–8. 3 Sehgal VN, Gangwani OP. Fixed drug eruption. Current concepts. Int J Dermatol 1987; 26: 67–74. 4 Kanwar AJ, Bharija SC, Singh M, Belhaj MS. Ninety-eight fixed drug eruptions with provocation tests. Dermatologica 1988; 177: 274–9. 5 Sehgal VN, Gangwani OP. Fixed drug eruptions. A study of epidemiological, clinical and diagnostic aspects of 89 cases from India. J Dermatol 1988; 15: 50–4. 6 Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol 1998; 37: 833–8. 7 Lee A-Y. Topical provocation in 31 cases of fixed drug eruption: change of causative drugs in 10 years. Contact Dermatitis 1998; 38: 258–60. 8 Özkaya-Bayazit E, Bayazit H, Ozarmagan G. Drug related clinical pattern in fixed drug eruption. Eur J Dermatol 2000; 10: 288–91. 9 Savin JA. Current causes of fixed drug eruption in the UK. Br J Dermatol 2001; 145: 667–8. 10 Kivity S. Fixed drug eruption to multiple drugs: clinical and laboratory investigation. Int J Dermatol 1991; 30: 149–51. 11 Chan HL, Tan KC. Fixed drug eruption to three anticonvulsant drugs: an unusual case of polysensitivity. J Am Acad Dermatol 1997; 36: 259. 12 Sowden JM, Smith AG. Multifocal fixed drug eruption mimicking erythema multiforme. Clin Exp Dermatol 1990; 15: 387–8. 13 Saiag P, Cordoliani F, Roujeau JC et al. Érytheme pigmenté fixe bulleux disséminé simulant un syndrome de Lyell. Ann Dermatol Vénéréol 1987; 114: 1440–2. 14 Baird BJ, De Villez RL. Widespread bullous fixed drug eruption mimicking toxic epidermal necrolysis. Int J Dermatol 1988; 27: 170–4. 15 Gaffoor PMA, George WM. Fixed drug eruptions occurring on the male genitals. Cutis 1990; 45: 242–4. 16 Jain VK, Dixit VB, Archana. Fixed drug eruption of the oral mucous membrane. Ann Dent 1991; 50: 9–11. 17 Westerhof W, Wolters EC, Brookbakker JTW et al. Pigmented lesions of the tongue in heroin addicts: fixed drug eruption. Br J Dermatol 1983; 109: 605–10. 18 Vidal C, Prieto A, Perez-Carral C, Armisen M. Nonpigmenting fixed drug eruption due to pseudoephedrine. Ann Allergy Asthma Immunol 1998; 80: 309–10. 19 Hindioglu U, Sahin S. Nonpigmenting solitary fixed drug eruption caused by pseudoephedrine hydrochloride. J Am Acad Dermatol 1998; 38: 499–500. 20 Krivda SJ, Benson PM. Nonpigmenting fixed drug eruption. J Am Acad Dermatol 1994; 31: 291–2. 21 Galindo PA, Borja J, Feo F et al. Nonpigmented fixed drug eruption caused by paracetamol. J Invest Allergol Clin Immunol 1999; 9: 399–400. 22 Sener O, Caliskaner Z, Yazicioglu K et al. Nonpigmenting solitary fixed drug eruption after skin testing and intra-articular injection of triamcinolone acetonide. Ann Allergy Asthma Immunol 2001; 86: 335–6. 23 Choonhakarn C. Non-pigmenting fixed drug eruption: a new case due to eperisone hydrochloride. Br J Dermatol 2001; 144: 1288–9. 24 Stubb S, Alanko K, Reitamo S. Fixed drug eruptions: 77 cases from 1981 to 1985. Br J Dermatol 1989; 120: 583.

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25 Kanwar AJ, Bharija SC, Belhaj MS. Fixed drug eruptions in children: a series of 23 cases with provocative tests. Dermatologica 1986; 172: 315–8. 26 Morelli JG, Tay YK, Rogers M et al. Fixed drug eruptions in children. J Pediatr 1999; 134: 365–7. 27 Thankappan TP, Zachariah J. Drug-specific clinical pattern in fixed drug eruptions. Int J Dermatol 1991; 30: 867–70. 28 Gruber F, Stasic A, Lenkovic M, Brajac I. Postcoital fixed drug eruption in a man sensitive to trimethoprim–sulphamethoxazole. Clin Exp Dermatol 1997; 22: 144–5. 29 Özkaya-Bayazit E, Baykal C. Trimethoprim-induced linear fixed drug eruption. Br J Dermatol 1997; 137: 1028–9. 30 Zemtsov A, Yanase DJ, Boyd AS, Shehata B. Fixed drug eruption to Tylenol: report of two cases and review of the literature. Cutis 1992; 50: 281–2. 31 Hern S, Harman K, Clement M, Black MM. Bullous fixed drug eruption due to paracetamol with an unusual immunofluorescence pattern. Br J Dermatol 1998; 139: 1129–31. 32 Silva A, Proenca E, Carvalho C et al. Fixed drug eruption induced by paracetamol. Pediatr Dermatol 2001; 18: 163–4. 33 Hayashi H, Shimizu T, Shimizu H. Multiple fixed drug eruption caused by acetaminophen. Clin Exp Dermatol 2003; 28: 455–6. 34 Gonzalo-Garijo MA, Revenga-Arranz F. Fixed drug eruption due to codeine. Br J Dermatol 1996; 135: 498–9. 35 Gonzalo MA, Alvarado MI, Fernandez L et al. Fixed drug eruption due to naproxen: lack of cross-reactivity with other propionic acid derivatives. Br J Dermatol 2001; 144: 1291–2. 36 Kaur C, Sarkar R, Kanwar AJ. Fixed drug eruption to rofecoxib with crossreactivity to sulfonamides. Dermatology 2001; 203: 351. 37 Dhar S, Sharma VK. Fixed drug eruption due to ciprofloxacin. Br J Dermatol 1996; 134: 56–8. 38 Hamamoto Y, Ohmura A, Kinoshita E, Muto M. Fixed drug eruption due to clarithromycin. Clin Exp Dermatol 2001; 26: 48–9. 39 Goel A, Balachandran C. Bullous necrotizing fixed drug eruption with hepatitis due to rifampicin. Ind J Leprosy 2001; 73: 159–62. 40 Vila JB, Bernier MA, Gutierrez JV et al. Fixed drug eruption caused by metronidazole. Contact Dermatitis 2002; 46: 122. 41 Munn SE, Russell Jones R. Terbinafine and fixed drug eruption. Br J Dermatol 1995; 133: 815–6. 42 Ghislain PD, Ghislain E. Fixed drug eruption due to fluconazole: a third case. J Am Acad Dermatol 2002; 46: 467. 43 Hsiao CJ, Lee JY, Wong TW, Sheu HM. Extensive fixed drug eruption due to lamotrigine. Br J Dermatol 2001; 144: 1289–91. 44 Smola H, Kruppa A, Hunzelmann N et al. Identification of dimenhydrinate as the causative agent in fixed drug eruption using patch-testing in previously affected skin. Br J Dermatol 1998; 138: 920–1. 45 Kranke B, Kern T. Multilocalized fixed drug eruption to the antihistamine cetirizine. J Allergy Clin Immunol 2000; 106: 988. 46 Ruiz-Genao DP, Hernandez-Nunez A, Sanchez-Perez J, Garcia-Diez A. Fixed drug eruption due to loratadine. Br J Dermatol 2002; 146: 528–9. 47 Garcia CM, Carmena R, Garcia R et al. Fixed drug eruption from ticlopidine, with positive lesional patch test. Contact Dermatitis 2001; 44: 40–1. 48 Heikkilä H, Kariniemi A-L, Stubb S. Fixed drug eruption due to phenylpropanolamine hydrochloride. Br J Dermatol 2000; 142: 845–7. 49 Cox NH, Duffey P, Royle J. Fixed drug eruption caused by lactulose in an injected botulinum toxin preparation. J Am Acad Dermatol 1999; 40: 263–4. 50 Pellicano R, Silvestris A, Iannantuono M et al. Familial occurrence of fixed drug eruptions. Acta Derm Venereol (Stockh) 1992; 72: 292–3. 51 Hatzis J, Noutsis K, Hatzidakis E et al. Fixed drug eruption in a mother and her son. Cutis 1992; 50: 50–2.

Table 75.8 Drugs causing lichenoid eruptions. Gold salts Antimalarials Mepacrine (quinacrine, atabrine) Chloroquine Quinine Quinidine Pyrimethamine Penicillamine Diuretics Thiazides Furosemide (frusemide) Spironolactone Diazoxide Antihypertensive agents β-Blockers Angiotensin-converting enzyme inhibitors: captopril, enalapril Methyldopa Calcium channel blockers Nifedipine Phenothiazine derivatives Metopromazine Levomepromazine Chlorpromazine Sulphonylurea hypoglycaemic agents Chlorpropamide Tolazamide Non-steroidal anti-inflammatory drugs: phenylbutazone Sulfasalazine (sulphasalazine) and mesalazine

Antitubercular drugs Ethambutol Isoniazid p-Aminosalicylic acid Streptomycin Cycloserine Antifungal drugs: ketoconazole Chemotherapeutic agents Hydroxyurea 5-Fluorouracil Heavy metals Mercurials Arsenicals Bismuth Miscellaneous Tetracyclines Carbamazepine Phenytoin Procainamide Allopurinol Iodides and radiocontrast media Tiopronin Pyritinol Cyanamide Dapsone Amiphenazole Levamisole Nandrolone furylpropionate Cinnarizine Flunarizine

Fig. 75.4 Lichenoid photosensitivity eruption caused by thiazide diuretic. (Courtesy of Dr A. Ive, Durham, UK.)

Lichenoid eruptions Lichenoid drug eruptions and lichen planus are discussed in Chapter 41. Some of the drugs that induce this pattern of reaction are listed in Table 75.8. Photodistributed lichenoid lesions may occur with a number of drugs, including thiazide diuretics (Fig. 75.4).

Photosensitivity Drug–light reactions, which cause eruptions on exposed areas, with sparing of upper eyelids, submental and retroauricular areas, may be phototoxic or photoallergic; these cannot always be dis-

Types of clinical reaction Table 75.9 Drugs causing photosensitivity. Frequent Amiodarone Phenothiazines Chlorpromazine Promethazine Psoralens Sulphonamides: co-trimoxazole Tetracyclines: demeclocycline Thiazides Non-steroidal anti-inflammatory drugs Azapropazone Piroxicam Carprofen Tiaprofenic acid Benoxaprofen (withdrawn) Nalidixic acid Coal tar Less frequent: topical Antihistamines Local anaesthetics Benzydamine Hydrocortisone Sunscreens p-Aminobenzoic acid Benzophenone Halogenated salicylanilides

Less frequent: systemic Ampicillin Antidepressants (tricyclic) Imipramine Protriptyline Antidepressants (monoamine oxidase inhibitors): phenelzine Antifungal agents Griseofulvin Ketoconazole β-Blockers Carbamazepine Cimetidine Cytotoxic agents Dacarbazine Fluorouracil Mitomycin Vinblastine Diazepam Furosemide (frusemide) Methyldopa Oral contraceptives Quinine Quinidine Sulphonylureas Chlorpropamide Tolbutamide Retinoids Isotretinoin Etretinate Triamterene

tinguished clinically, and some drugs may produce cutaneous involvement by both mechanisms [1–6]. The main drugs implicated in photosensitivity reactions are listed in Table 75.9. References 1 Johnson BE, Ferguson J. Drug and chemical photosensitivity. Semin Dermatol 1990; 9: 39–46. 2 Elmets CA. Cutaneous phototoxicity. In: Lim HW, Soter NA, eds. Clinical Photomedicine. New York: Marcel Dekker, 1993: 207–26. 3 Deleo VA. Photoallergy. In: Lim HW, Soter NA, eds. Clinical Photomedicine. New York: Marcel Dekker, 1993: 227–39. 4 Gould JW, Mercurion MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995; 33: 551–73. 5 González E, González S. Drug photosensitivity, idiopathic photodermatoses, and sunscreens. J Am Acad Dermatol 1996; 35: 871–5. 6 Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf 2007; 6: 431–43.

Phototoxic reactions Phototoxic reactions are commoner than photoallergic reactions, and can be produced in almost all individuals given a high enough dose of drug and sufficient light irradiation. They occur within 5–20 h of the first exposure, and resemble exaggerated sunburn. Erythema, oedema, blistering, weeping, desquamation and resid-

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ual hyperpigmentation occur on exposed areas; there may be photo-onycholysis. The following are well-recognized causes of phototoxicity: • Tetracyclines [1–4], especially demeclocycline, less frequently doxycycline, oxytetracycline and tetracycline, and rarely minocycline and methacycline • Other antibacterials including sulphonamides and fluoroquinolones [4] • Phenothiazines, especially chlorpromazine, promethazine and, less commonly, thioridazine • Furosemide [5] and nalidixic acid [4,6], both of which produce a pseudoporphyria syndrome, with blistering of the exposed areas • NSAIDs, including ibuprofen [7], piroxicam [8–11], carprofen and tiaprofenic acid [12] • Psoralens • Amiodarone (which causes photosensitivity in over 50% of cases) [13] • Certain anticancer drugs [14], including dacarbazine [14,15], 5-fluorouracil, mitomycin and vinblastine • Coal tar and its derivatives • Fibric acid derivatives, including bezafibrate and fenofibrate [16,17] • The non-steroid antiandrogen flutamide given for prostatic carcinoma [18,19].

References 1 Cullen SI, Catalano PM, Helfmann RS. Tetracycline sun sensitivity. Arch Dermatol 1966; 93: 77. 2 Frost P, Weinstein GP, Gomez EC. Phototoxic potential of minocycline and doxycycline. Arch Dermatol 1972; 105: 681–3. 3 Layton AM, Cunliffe WJ. Phototoxic eruptions due to doxycycline: a dose-related phenomenon. Clin Exp Dermatol 1993; 18: 425–7. 4 Wainwright NJ, Collins P, Ferguson J. Photosensitivity associated with antibacterial agents. Drug Saf 1993; 9: 437–40. 5 Burry JN, Lawrence JR. Phototoxic blisters from high frusemide dosage. Br J Dermatol 1976; 94: 495–9. 6 Ramsay CA, Obreshkova E. Photosensitivity from nalidixic acid. Br J Dermatol 1974; 91: 523–8. 7 Bergner T, Przybilla B. Photosensitisation caused by ibuprofen. J Am Acad Dermatol 1992; 26: 114–6. 8 Stern RS. Phototoxic reactions to piroxicam and other nonsteroidal antiinflammatory agents. N Engl J Med 1983; 309: 186–7. 9 Serrano G, Bonillo J, Aliaga A et al. Piroxicam-induced photosensitivity. In vivo and in vitro studies of its photosensitizing potential. J Am Acad Dermatol 1984; 11: 113–20. 10 Figueiredo A, Fontes Ribeiro CA, Conçalo S et al. Piroxicam-induced photosensitivity. Contact Dermatitis 1987; 17: 73–9. 11 Serrano G, Fortea JM, Latasa JM. Oxicam-induced photosensitivity. Patch and photopatch testing studies with tenoxicam and piroxicam photoproducts in normal subjects and in piroxicam–droxicam photosensitive patients. J Am Acad Dermatol 1992; 26: 545–8. 12 Przybilla B, Ring J, Galosi A, Dorn M. Photopatch test reactions to tiaprofenic acid. Contact Dermatitis 1984; 1: 55–6. 13 Ferguson J, Addo HA, Jones S et al. A study of cutaneous photosensitivity induced by amiodarone. Br J Dermatol 1985; 113: 537–49. 14 Kerker BJ, Hood AF. Chemotherapy-induced cutaneous reactions. Semin Dermatol 1989; 8: 173–81. 15 Bonifazi E, Angelini G, Meneghini CL. Adverse photoreaction to dacarbazine (DITC). Contact Dermatitis 1981; 7: 161. 16 Leenutaphong V, Manuskiatti W. Fenofibrate-induced photosensitivity. J Am Acad Dermatol 1996; 35: 775–7.

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17 Serrano G, Fortea JM, Latasa JM et al. Photosensitivity induced by fibric acid derivatives and its relation to photocontact dermatitis to ketoprofen. J Am Acad Dermatol 1992; 27: 204–8. 18 Fujimoto M, Kikuchi K, Imakado S, Furue M. Photosensitive dermatitis induced by flutamide. Br J Dermatol 1996; 135: 496–7. 19 Kaur C, Thami GP. Flutamide-induced photosensitivity: is it a forme fruste of lupus? Br J Dermatol 2003; 148: 603–4.

Photoallergic reactions Photoallergic reactions require a latent period during which sensitization occurs, and usually appear within 24 h of re-exposure to drug and light in a sensitized individual; unlike phototoxic reactions, they may spread beyond irradiated areas. Most systemic drugs causing photoallergy also cause phototoxicity. There may be cross-reactivity with chemically related substances. Photoallergic reactions may occur as a result of local photocontact dermatitis to a topical photoallergen. Photocontact dermatitis is a relatively common cause of photosensitivity, accounting for 9% of cases in a multicentre study [1]. Topical photoallergens include antihistamines, chlorpromazine, local anaesthetics, benzydamine, hydrocortisone, desoximetasone (desoxymethasone) and sunscreens containing p-aminobenzoic acid (PABA) and its derivatives. Contact allergy and photoallergy to benzophenones in PABA-free sunscreens may be commoner than is realized [2]. Halogenated salicylanilides, previously used as a disinfectant in soaps, and related compounds also cause photocontact dermatitis. Photoallergic reactions may also occur as a result of systemically administered drugs [3], such as phenothiazines (chlorpromazine, promethazine), sulphonamides, aromatic sulphonamides such as thiazide diuretics [4,5] and oral hypoglycaemic agents (chlorpropamide and tolbutamide), griseofulvin [6] and quinidine [7,8]. Quinidine-induced photoeruptions may be either eczematous or lichenoid; a persistent livedo reticularis-like eruption may be seen in severe cases of quinidine photosensitivity. Enalapril has caused a photosensitive lichenoid eruption [9]. Tricyclic antidepressants may cause allergy as well as photosensitivity [10]. NSAIDs, disinfectants, sunscreens, phenothiazines and fragrances caused photoallergic reactions most often in a 5-year survey by the German, Austrian and Swiss photopatch test group [11]. References 1 Wennersten G, Thune P, Brodthagen H et al. The Scandinavian multicenter photopatch study. Preliminary results. Contact Dermatitis 1984; 10: 305–9. 2 Knobler E, Almeida L, Ruxkowski AM et al. Photoallergy to benzophenone. Arch Dermatol 1989; 125: 801–4. 3 Giudici PA, Maguire HC. Experimental photoallergy to systemic drugs. J Invest Dermatol 1985; 85: 207–11. 4 Robinson HN, Morison WL, Hood AF. Thiazide diuretic therapy and chronic photosensitivity. Arch Dermatol 1985; 121: 522–4. 5 Addo HA, Ferguson J, Frain-Bell W. Thiazide-induced photosensitivity: a study of 33 subjects. Br J Dermatol 1987; 116: 749–60. 6 Kojima T, Hasegawa T, Ishida H et al. Griseofulvin-induced photodermatitis. Report of six cases. J Dermatol 1988; 15: 76–82. 7 Bruce S, Wolf JE Jr. Quinidine-induced photosensitive livedo reticularis-like eruption. J Am Acad Dermatol 1985; 12: 332–6. 8 Schurer NY, Holzle E, Plewig G, Lehmann P. Photosensitivity induced by quinidine sulfate: experimental reproduction of skin lesions. Photodermatol Photoimmunol Photomed 1992; 9: 78–82. 9 Kanwar AJ, Dhar S, Ghosh S. Photosensitive lichenoid eruption due to enalapril. Dermatology 1993; 187: 80. 10 Ljunggren B, Bojs G. A case of photosensitivity and contact allergy to systemic tricyclic drugs, with unusual features. Contact Dermatitis 1991; 24: 259–65.

11 Hölzle E, Neumann N, Hausen B et al. Photopatch testing: the 5-year experience of the German, Austrian and Swiss photopatch test group. J Am Acad Dermatol 1991; 25: 59–68.

Porphyria and pseudoporphyria A number of drugs may precipitate porphyria cutanea tarda with resultant photosensitivity, or cause a pseudoporphyria syndrome with bulla formation. The reader is referred to Chapter 59.

Photorecall reactions A curious photorecall-like eruption, restricted to an area of sunburn sustained 1 month previously, occurred in a patient treated with cefazolin (cephazolin) and gentamicin [1]. An ultraviolet recalllike eruption has been reported with piperacillin, tobramycin and ciprofloxacin [2]. A recurrent cutaneous reaction localized to the site of pelvic radiotherapy for adenocarcinoma of the prostate followed sun exposure in one patient [3]. Methotrexate is associated with severe reactivation of sunburn [4,5]. References 1 Flax SH, Uhle P. Photo recall-like phenomenon following the use of cefazolin and gentamicin sulfate. Cutis 1990; 46: 59–61. 2 Krishnan RS, Lewis AT, Kass JS, Hsu S. Ultraviolet recall-like phenomenon occurring after piperacillin, tobramycin, and ciprofloxacin therapy. J Am Acad Dermatol 2001; 44: 1045–7. 3 Del Guidice SM, Gerstley JK. Sunlight-induced radiation recall. Int J Dermatol 1988; 27: 415–6. 4 Mallory SB, Berry DH. Severe reactivation of sunburn following methotrexate use. Pediatrics 1986; 78: 514–5. 5 Westwick TJ, Sherertz EF, McCarley D, Flowers FP. Delayed reactivation of sunburn by methotrexate: sparing of chronically sun-exposed skin. Cutis 1987; 39: 49–51.

Photo-onycholysis Photo-onycholysis may be caused by tetracycline, psoralens and UVA (PUVA) therapy, and the fluoroquinolone antibiotics pefloxacin and ofloxacin.

Pigmentation reactions Hyperpigmentation (Table 75.10) Drug-induced alteration in skin colour [1–3] may result from increased (or more rarely decreased) melanin synthesis, increased

Table 75.10 Drugs causing pigmentation. Oral contraceptives Minocycline Antimalarials Chloroquine Hydroxychloroquine Mepacrine Antidepressants Chlorpromazine Imipramine Heavy metals Gold Lead Silver

Chemotherapeutic agents Miscellaneous Amiodarone Carotene Clofazimine Pefloxacin Sulfasalazine (sulphasalazine)

Types of clinical reaction

lipofuscin synthesis, cutaneous deposition of drug-related material, or most commonly as a result of post-inflammatory hyperpigmentation (e.g. fixed drug eruption). Oral contraceptives may induce chloasma [4]. Other drugs implicated in cutaneous hyperpigmentation include minocycline [5,6], antimalarials [7,8], chlorpromazine [9,10], imipramine (photodistributed) [11–13] and desimipramine [14], amiodarone [15], carotene and heavy metals. Long-term (more than 4 months) antimalarial therapy may result in brownish or blue-black pigmentation, especially on the shin, face and hard palate or subungually. Yellowish discoloration may occur with mepacrine (quinacrine) or amodiaquine. Long-term, high-dose phenothiazine (especially chlorpromazine) therapy results in a blue-grey or brownish pigmentation of sun-exposed areas, the result of a phototoxic reaction, with pigment deposits in the lens and cornea [10]. The cancer chemotherapeutic agents may be associated with pigmentation as follows [16]: skin pigmentation may be caused by bleomycin, busulfan, topical carmustine, cyclophosphamide, daunorubicin, fluorouracil, hydroxyurea, topical mechlorethamine, methotrexate, mithramycin, mitomycin and thiotepa. Busulfan and doxorubicin cause mucous membrane pigmentation. Nail pigmentation may result from bleomycin, cyclophosphamide, daunorubicin, doxorubicin and fluorouracil. Methotrexate may induce pigmentation of the hair, and cyclophosphamide of teeth. Sulfasalazine has caused reversible hyperpigmentation [17], and pefloxacin blue-black pigmentation of the legs [18]. Gold may cause blue-grey pigmentation in light-exposed areas (chrysiasis) [19,20] and silver may cause a similar discoloration (argyria) [21]. Lead poisoning can cause a blue-black line at the gingival margin and grey discoloration of the skin. Clofazimine produces red-brown discoloration of exposed skin and the conjunctivae, together with red sweat, urine and faeces [22]. Slategrey to blue-black pigmentation may occur after long-term topical application of hydroquinone, causing ochronosis [23]. References 1 Levantine A, Almeyda J. Drug reactions: XXII. Drug induced changes in pigmentation. Br J Dermatol 1973; 89: 105–12. 2 Granstein RD, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol 1981; 5: 1–18. 3 Ferguson J, Frain-Bell W. Pigmentary disorders and systemic drug therapy. Clin Dermatol 1989; 7: 44–54. 4 Smith AG, Shuster S, Thody AJ et al. Chloasma, oral contraceptives, and plasma immunoreactive beta-melanocyte-stimulating hormone. J Invest Dermatol 1977; 68: 169–70. 5 Dwyer CM, Cuddihy AM, Kerr RE et al. Skin pigmentation due to minocycline treatment of facial dermatoses. Br J Dermatol 1993; 129: 158–62. 6 Pepine M, Flowers FP, Ramos-Caro FA. Extensive cutaneous hyperpigmentation caused by minocycline. J Am Acad Dermatol 1993; 28: 292–5. 7 Tuffanelli D, Abraham RK, Dubois EJ. Pigmentation from antimalarial therapy. Its possible relationship to the ocular lesions. Arch Dermatol 1963; 88: 419– 26. 8 Leigh IM, Kennedy CTC, Ramsey JD, Henderson WJ. Mepacrine pigmentation in systemic lupus erythematosus. New data from an ultrastructural, biochemical and analytical electron microscope investigation. Br J Dermatol 1979; 101: 147–53. 9 Benning TL, McCormack KM, Ingram P et al. Microprobe analysis of chlorpromazine pigmentation. Arch Dermatol 1988; 124: 1541–4. 10 Wolf ME, Richer S, Berk MA, Mosnaim AD. Cutaneous and ocular changes associated with the use of chlorpromazine. Int J Clin Pharmacol Ther Toxicol 1993; 31: 365–7.

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11 Hashimoto K, Joselow SA, Tye MJ. Imipramine hyperpigmentation: a slate-gray discoloration caused by long-term imipramine administration. J Am Acad Dermatol 1991; 25: 357–61. 12 Ming ME, Bhawan J, Stefanato CM et al. Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol 1999; 40: 159–66. 13 Sicari MC, Lebwohl M, Baral J et al. Photoinduced dermal pigmentation in patients taking tricyclic antidepressants: histology, electron microscopy, and energy dispersive spectroscopy. J Am Acad Dermatol 1999; 40: 290–3. 14 Steele TE, Ashby J. Desipramine-related slate-gray skin pigmentation. J Clin Psychopharmacol 1993; 13: 76–7. 15 Zachary CB, Slater DN, Holt DW et al. The pathogenesis of amiodarone-induced pigmentation and photosensitivity. Br J Dermatol 1984; 110: 451–6. 16 Kerber BJ, Hood AF. Chemotherapy-induced cutaneous reactions. Semin Dermatol 1989; 8: 173–81. 17 Gabazza EC, Taguchi O, Yamakami T et al. Pulmonary infiltrates and skin pigmentation associated with sulfasalazine. Am J Gastroenterol 1992; 87: 1654–7. 18 Le Cleach L, Chosidow O, Peytavin G et al. Blue-black pigmentation of the legs associated with pefloxacin therapy. Arch Dermatol 1995; 131: 856–7. 19 Leonard PA, Moatamed F, Ward JR et al. Chrysiasis: the role of sun exposure in dermal hyperpigmentation secondary to gold therapy. J Rheumatol 1986; 13: 58–64. 20 Smith RW, Leppard B, Barnett NL et al. Chrysiasis revisited: a clinical and pathological study. Br J Dermatol 1995; 133: 671–8. 21 Gherardi R, Brochard P, Chamak B et al. Human generalized argyria. Arch Pathol Lab Med 1984; 108: 181–2. 22 Thomsen K, Rothenborg HW. Clofazimine in the treatment of pyoderma gangrenosum. Arch Dermatol 1979; 115: 851–2. 23 Williams H. Skin lightening creams containing hydroquinone. The case for a temporary ban. BMJ 1992; 305: 903–4.

Hypopigmentation Topical thiotepa has produced periorbital leukoderma [1]. Hypopigmentation has occurred as a result of occupational exposure to monobenzyl ether of hydroquinone, p-tertiarybutylcatechol, p-tertiary-butylphenol, p-tertiary-amylphenol, monomethyl ether of hydroquinone and hydroquinone [2]. In addition, hypopigmentation may result from phenolic detergent germicides [3], and following use of diphencyprone for alopecia areata [4,5]. Depigmentation of the skin and hair occurred after a phenobarbital-induced eruption [6]. Photoleukomelanodermatitis occurred due to afloqualone for cervical spondylosis; photopatch and oral challenge tests were positive [7]. Generalized cutaneous depigmentation followed a sulphamide-induced ADR [8]. References 1 Harben DJ, Cooper PH, Rodman OG. Thiotepa-induced leukoderma. Arch Dermatol 1979; 115: 973–4. 2 Stevenson CJ. Occupational vitiligo: clinical and epidemiological aspects. Br J Dermatol 1981; 105 (Suppl. 21): 51–6. 3 Kahn G. Depigmentation caused by phenolic detergent germicides. Arch Dermatol 1970; 102: 177–87. 4 Hatzis J, Gourgiotou K, Tosca A et al. Vitiligo as a reaction to topical treatment with diphencyprone. Dermatologica 1988; 177: 146–8. 5 Henderson CA, Ilchyshyn A. Vitiligo complicating diphencyprone sensitization therapy for alopecia universalis. Br J Dermatol 1995; 133: 496–7. 6 Mion N, Fusade T, Mathelier-Fusade P et al. Depigmentation cutaneophanerienne consecutive à une toxidermie au phenobarbital. Ann Dermatol Vénéréol 1992; 119: 927–9. 7 Ishikawa T, Kamide R, Niimura M. Photoleukomelanodermatitis (Kobori) induced by afloqualone. J Dermatol 1994; 21: 430–3. 8 Martinez-Ruiz E, Ortega C, Calduch L et al. Generalized cutaneous depigmentation following sulfamide-induced drug eruption. Dermatology 2000; 201: 252–4.

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Chapter 75: Drug Reactions

Acneiform and pustular eruptions The term ‘acneiform’ is applied to eruptions that resemble acne vulgaris [1,2] (see Chapter 42). Lesions are papulopustular but comedones are usually absent. Adrenocorticotrophic hormone (ACTH), corticosteroids [3], dexamethasone in neurosurgical patients, anabolic steroids for body-building [4], androgens (in females), oral contraceptives, iodides and bromides may produce acneiform eruptions. Isoniazid may induce acne, especially in slow inactivators of the drug [5]. Other drugs implicated in the production of acneiform rashes include dantrolene [6], danazol [7], quinidine [8], lithium [9,10] and azathioprine [11]. Acne rosacea was temporally associated with daily high-dose vitamin B supplement therapy in one patient [12], and eosinophilic pustular folliculitis (Ofuji’s disease) developed in association with use of the cerebral activator indeloxazine hydrochloride [13]. References 1 Hitch JM. Acneform eruptions induced by drugs and chemicals. JAMA 1967; 200: 879–80. 2 Bedane C, Souyri N. Les acnés induites. Ann Dermatol Vénéréol 1990; 117: 53–8. 3 Hurwitz RM. Steroid acne. J Am Acad Dermatol 1989; 21: 1179–81. 4 Merkle T, Landthaler M, Braun-Falco O. Acne-conglobata-artige Exazerbation einer Acne vulgaris nach Einnahme von Anabolika und Vitamin-B-Komplexhaltigen Präparaten. Hautarzt 1990; 41: 280–2. 5 Cohen LK, George W, Smith R. Isoniazid-induced acne and pellagra. Occurrence in slow inactivators of isoniazid. Arch Dermatol 1974; 109: 377–81. 6 Pembroke AC, Saxena SR, Kataria M, Zilkha KD. Acne induced by dantrolene. Br J Dermatol 1981; 104: 465–8. 7 Greenberg RD. Acne vulgaris associated with antigonadotrophic (danazol) therapy. Cutis 1979; 24: 431–2. 8 Burkhart CG. Quinidine-induced acne. Arch Dermatol 1981; 117: 603–4. 9 Heng MCY. Cutaneous manifestations of lithium toxicity. Br J Dermatol 1982; 106: 107–9. 10 Kanzaki T. Acneiform eruption induced by lithium carbonate. J Dermatol 1991; 18: 481–3. 11 Schmoeckel C, von Liebe V. Akneiformes Exanthem durch Azathioprin. Hautarzt 1983; 34: 413–5. 12 Sherertz EF. Acneiform eruption due to ‘megadose’ vitamins B6 and B12. Cutis 1991; 48: 119–20. 13 Kimura K, Ezoe K, Yokozeki H et al. A case of eosinophilic pustular folliculitis (Ofuji’s disease) induced by patch and challenge tests with indeloxazine hydrochloride. J Dermatol 1996; 23: 479–83.

Acute generalized exanthematous pustulosis (toxic pustuloderma) Pustular reactions (toxic pustuloderma, acute generalized exanthematous pustulosis, AGEP) have been reported in association with a number of drugs [1]. The main differential diagnosis of a generalized pustular drug eruption is pustular psoriasis [2]. Two histological patterns may be seen: (i) a toxic pustuloderma with spongiform intraepidermal pustules, papillary oedema and a mixed upper dermal perivascular inflammatory infiltrate; or (ii) a leukocytoclastic vasculitis with neutrophil collections both below and within the epidermis, suggesting passive neutrophil elimination via the overlying epidermis [3,4]. The presence of eosinophils in the inflammatory infiltrate is a helpful pointer to a drug cause [2]. A responsible drug was found in 87% of a series of 63 patients with acute generalized exanthematous pustulosis; antibiotics were implicated as the causative agent in 80% of individuals [4]. The latter included particularly ampicillin, amoxicillin, spiramycin,

erythromycin and cyclins. Hypersensitivity to mercury was also recorded as a precipitating cause. Pustulosis developed within 24 h of drug administration. It often started on the face or in flexural areas, rapidly became disseminated, with fever, and settled spontaneously with desquamation. Facial oedema, purpura, vesicles, blisters and erythema multiforme-like lesions were also seen; transient renal failure was noted in 32% of cases. Occasionally, TEN may be mimicked [5]. Acute generalized exanthematic pustulosis is usually due to penicillins or macrolides, especially ampicillin/amoxicillin ± clavulanic acid, pristinamycin, quinolones, (hydroxy)chloroquine, anti-infective sulphonamides, terbinafine, diltiazem, carbamazepine and spiramycin ± metronidazole [6–10]. There may be positive patch test reactions to the suspected drug [9,11]. Fatalities are recorded [8]. There have been individual reports of pustular drug reactions with ampicillin (which may be localized [12]), amoxicillin (with or without clavulanic acid) [13], propicillin [14], imipenem [15], the cephalosporins cefalexin (cephalexin) and cefradine (cephradine) [16,17], co-trimoxazole [18], doxycycline [19], chloramphenicol [20], ciprofloxacin [21], norfloxacin [22], ofloxacin [23], teicoplanin [24], streptomycin [25], isoniazid, metronidazole [26], terbinafine [27–29], fluconazole [30], itraconazole [31], nystatin [32], salazosulfapyridine/salazopyrine [33], mesalazine [34], diltiazem [35], captopril [36] and enalapril [37], furosemide [38], hydrochlorothiazide [39], azathioprine [40], cytarabine [41], high-dose chemotherapy [42], sertraline [43], chlorpromazine [44], nitrazepam, morphine [45], acetylsalicylic acid [46], naproxen [47], allopurinol [48], hydroxychloroquine [49], pyrimethamine, piperazine ethionamate, the mucolytic agent eprazinone [50], pseudoephedrine [51], dextropropoxyphene [52], icodextrin [53], mexiletine [54], dalteparin [55] and intravenous non-ionic contrast media [56]. Cases of generalized pustulation in association with the anticonvulsant hypersensitivity syndrome caused by phenytoin [57] and carbamazepine [58] have been recorded. References 1 Webster GF. Pustular drug reactions. Clin Dermatol 1993; 11: 541–3. 2 Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol 1994; 130: 514–9. 3 Burrows NP, Russell Jones RR. Pustular drug eruptions: a histopathological spectrum. Histopathology 1993; 22: 569–73. 4 Roujeau J-C, Bioulac-Sage P, Bourseau C et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991; 127: 1333–8. 5 Cohen AD, Cagnano E, Halevy S. Acute generalized exanthematous pustulosis mimicking toxic epidermal necrolysis. Int J Dermatol 2001; 40: 458–61. 6 Manders SM, Heymann WR. Acute generalized exanthemic pustulosis. Cutis 1994; 54: 194–6. 7 Trevisi P, Patrizi A, Neri I, Farina P. Toxic pustuloderma associated with azithromycin. Clin Exp Dermatol 1994; 19: 280–1. 8 Saissi EH, Beau-Salinas F, Jonville-Béra AP et al. Drugs associated with acute generalized exanthematic pustulosis. Ann Dermatol Venereol 2003; 130: 612–8. 9 Gensch K, Hodzic-Avdagic N, Megahed M et al. Acute generalized exanthematous pustulosis with confirmed type IV allergy. Report of 3 cases. Hautarzt 2007; 58: 250–2, 254–5. 10 Sidoroff A, Dunant A, Viboud C et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007; 157: 989–96. 11 Moreau A, Dompmartin A, Castel B et al. Drug-induced acute generalized exanthematous pustulosis with positive patch tests. Int J Dermatol 1995; 34: 263–6.

Types of clinical reaction 12 Jay S, Kang J, Watcher MA et al. Localized pustular skin eruption. Localized pustular drug eruption secondary to ampicillin. Arch Dermatol 1994; 130: 787, 790. 13 Armster H, Schwarz T. Arzneimittelreaktion auf Amoxicillin unter dem Bild eines toxischen Pustuloderms. Hautarzt 1991; 42: 713–6. 14 Gebhardt M, Lustig A, Bocker T, Wollina U. Acute generalized exanthematous pustulosis (AGEP): manifestation of drug allergy to propicillin. Contact Dermatitis 1995; 33: 204–5. 15 Escallier F, Dalac S, Foucher JL et al. Pustulose exanthématique aiguë généralisée imputabilité a l’imipéneme (Tienam®). Ann Dermatol Vénéréol 1989; 116: 407–9. 16 Kalb RE, Grossman ME. Pustular eruption following administration of cephradine. Cutis 1986; 38: 58–60. 17 Jackson H, Vion B, Levy PM. Generalized eruptive pustular drug rash due to cephalexin. Dermatologica 1988; 177: 292–4. 18 MacDonald KJS, Green CM, Kenicer KJA. Pustular dermatosis induced by cotrimoxazole. BMJ 1986; 293: 1279–80. 19 Trueb RM, Burg G. Acute generalized exanthematous pustulosis due to doxycycline. Dermatology 1993; 186: 75–8. 20 Lee AY, Yoo SH. Chloramphenicol induced acute generalized exanthematous pustulosis proved by patch test and systemic provocation. Acta Derm Venereol (Stockh) 1999; 79: 412–3. 21 Hausermann P, Scherer K, Weber M, Bircher AJ. Ciprofloxacin-induced acute generalized exanthematous pustulosis mimicking bullous drug eruption confirmed by a positive patch test. Dermatology 2005; 211: 277–80. 22 Shelley ED, Shelley WB. The subcorneal pustular eruption: an example induced by norfloxacin. Cutis 1988; 42: 24–7. 23 Tsuda S, Kato K, Karashima T et al. Toxic pustuloderma induced by ofloxacin. Acta Derm Venereol (Stockh) 1993; 73: 382–4. 24 Chu CY, Wu J, Jean SS, Sun CC. Acute generalized exanthematous pustulosis due to teicoplanin. Dermatology 2001; 202: 141–2. 25 Kushimoto H, Aoki T. Toxic erythema with generalized follicular pustules caused by streptomycin. Arch Dermatol 1981; 117: 444–5. 26 Watsky KL. Acute generalised exanthematous pustulosis induced by metronidazole: the role of patch testing. Arch Dermatol 1999; 135: 93–4. 27 Kempinaire A, De Raeve L, Merckx M et al. Terbinafine-induced acute generalized exanthematous pustulosis confirmed by positive patch-test result. J Am Acad Dermatol 1997; 37: 653–5. 28 Condon CA, Downs AMR, Archer CB. Terbinafine-induced acute generalized exanthematous pustulosis. Br J Dermatol 1998; 138: 709–10. 29 Bennett ML, Jorizzo JL, White WL. Generalized pustular eruptions associated with oral terbinafine. Int J Dermatol 1999; 38: 596–600. 30 Alsadhan A, Taher M, Krol A. Acute generalized exanthematous pustulosis induced by oral fluconazole. J Cutan Med Surg 2002; 6: 122–4. 31 Heymann WR, Manders SM. Itraconazole-induced acute generalised exanthematic pustulosis. J Am Acad Dermatol 1996; 33: 130–1. 32 Kuchler A, Hamm H, Weidenthaler-Barth B et al. Acute generalized exanthematous pustulosis following oral nystatin therapy: a report of three cases. Br J Dermatol 1997; 137: 808–11. 33 Kawaguchi M, Mitsuhashi Y, Kondo S. Acute generalized exanthematous pustulosis induced by salazosulfapyridine in a patient with ulcerative colitis. J Dermatol 1999; 26: 359–62. 34 Gibbon KL, Bewley AP, Thomas K. Mesalazine-induced pustular drug eruption. J Am Acad Dermatol 2001; 45: S220–S221. 35 Vincente-Calleja JM, Aguirre A, Landa N et al. Acute generalized exanthematous pustulosis due to diltiazem: confirmation by patch testing. Br J Dermatol 1997; 137: 837–9. 36 Carroll J, Thaler M, Grossman E et al. Generalized pustular eruption associated with converting enzyme inhibitor therapy. Cutis 1995; 56: 276–8. 37 Ferguson JE, Chalmers RJ. Enalapril-induced toxic pustuloderma. Clin Exp Dermatol 1996; 21: 54–5. 38 Noce R, Paredes BE, Pichler WJ, Krahenbuhl S. Acute generalized exanthematic pustulosis (AGEP) in a patient treated with furosemide. Am J Med Sci 2000; 320: 331–3. 39 Petavy-Catala C, Martin L, Fontes V et al. Hydrochlorothiazide-induced acute generalized exanthematous pustulosis. Acta Derm Venereol (Stockh) 2001; 81: 209. 40 Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthematous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007; 32: 52–3.

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41 Chiu A, Kohler S, McGuire J, Kimball AB. Cytarabine-induced acute generalised exanthematous pustulosis. J Am Acad Dermatol 2002; 45: 633–5. 42 Valks R, Fraga J, Munoz E et al. Acute generalized exanthematous pustulosis in patients receiving high-dose chemotherapy. Arch Dermatol 1999; 135: 1418–20. 43 Thedenat B, Loche F, Albes B et al. Acute generalized exanthematous pustulosis with photodistribution pattern induced by sertraline. Dermatology 2001; 203: 87–8. 44 Burrows NP, Ratnavel RC, Norris PG. Pustular eruptions after chlorpromazine. BMJ 1994; 309: 97. 45 Kardaun SH, de Monchy JG. Acute generalized exanthematous pustulosis caused by morphine, confirmed by positive patch test and lymphocyte transformation test. J Am Acad Dermatol 2006; 55 (Suppl. 2): S21–3. 46 Ballmer-Weber BK, Widmer M, Burg G. Acetylsalicylsaure-induzierte generalisierte Pustulose. Schweiz Med Wochenschr 1993; 123: 542–6. 47 Grattan CEH. Generalized pustular drug rash due to naproxen. Dermatologica 1989; 179: 57–8. 48 Boffa MJ, Chalmers RJ. Allopurinol-induced toxic pustuloderma. Br J Dermatol 1994; 131: 447. 49 Paradisi A, Bugatti L, Sisto T et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: three cases and a review of the literature. Clin Ther 2008; 30: 930–40. 50 Faber M, Maucher OM, Stengel R, Goerttler E. Epraxinonenexanthem mit subkornealer Pustelbildung. Hautarzt 1984; 35: 200–3. 51 Padial MA, Alvarez-Ferreira J, Tapia B et al. Acute generalized exanthematous pustulosis associated with pseudoephedrine. Br J Dermatol 2004; 150: 139–42. 52 Machet L, Martin L, Machet MC et al. Acute generalized exanthematous pustulosis induced by dextropropoxyphene and confirmed by patch testing. Acta Derm Venereol (Stockh) 2000; 80: 224–5. 53 Al-Hoqail IA, Crawford RI. Acute generalized exanthematous pustulosis induced by icodextrin. Br J Dermatol 2001; 145: 1026–7. 54 Sasaki K, Yamamoto T, Kishi M et al. Acute exanthematous pustular drug eruption induced by mexiletine. Eur J Dermatol 2001; 11: 469–71. 55 Komericki P, Grims R, Kränke B, Aberer W. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol 2007; 57: 718–21. 56 Peterson A, Katzberg RW, Fung MA et al. Acute generalized exanthematous pustulosis as a delayed dermatotoxic reaction to IV-administered nonionic contrast media. AJR Am J Roentgenol 2006; 187: W198–201. 57 Kleier RS, Breneman DL, Boiko S. Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome. Arch Dermatol 1991; 127: 1361–4. 58 Commens CA, Fischer GO. Toxic pustuloderma following carbamazepine therapy. Arch Dermatol 1988; 124: 178–9.

Eczematous eruptions Allergic contact dermatitis is discussed in Chapter 26. This section concerns the entity termed ‘systemic contact-type dermatitis medicamentosa’ [1–5] (Table 75.11). A patient initially sensitized to a drug by way of allergic contact dermatitis may develop an eczematous reaction when the same, or a chemically related, substance is subsequently administered systemically. The eruption tends to be symmetrical, and may involve first, or most severely, the site(s) of the original dermatitis, before becoming generalized. Patients with a contact allergy to ethylenediamine may develop urticaria or systemic eczema following injection of aminophylline preparations containing ethylenediamine as a solubilizer for theophylline [6,7]. Patients with contact allergy to parabens may develop systemic eczema on medication with a drug containing parabens as a preservative [8]. Similarly, sensitized patients may develop eczema following oral ingestion of neomycin or hydroxyquinolines [9]. Diabetic patients sensitized by topical preparations containing p-amino compounds, such as p-phenylenediamine hair dyes, PABA sunscreens and certain local anaesthetic agents (e.g. benzocaine), may develop a systemic contact dermatitis

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Chapter 75: Drug Reactions

Table 75.11 Systemic drugs that can reactivate allergic contact eczema to chemically related topical medicaments. (From Fisher [1].) Systemic drug

Topical medicament

Ethylenediamine antihistamines

Aminophylline suppositories and ethylenediamine hydrochloride

Aminophylline Piperazine Organic and inorganic mercury compounds Tincture of benzoin inhalation Procaine Acetohexamide p-Aminosalicylic acid Azo dyes in foods and drugs Chlorothiazide Chlorpropamide Tolbutamide Chloral hydrate Iodochlorhydroxyquinoline Iodides, iodinated organic compounds, radiographic contrast media Streptomycin, kanamycin, paromycin, gentamicin Glyceryl trinitrate tablets Disulfiram (Antabuse)

Ammoniated mercury Balsam of Peru Benzocaine (p-amino compound) and glyceryl p-aminobenzoic acid sunscreens

Chlorobutanol Halogenated hydroxyquinoline creams (Vioform) Iodine

Neomycin sulphate Glyceryl trinitrate ointment Thiuram (rubber chemical)

with the hypoglycaemic agents tolbutamide or chlorpropamide. Sulphonylureas may also induce eczematous eruptions in sulphanilamide-sensitive patients as a result of cross reactivity. Phenothiazines can produce allergic contact dermatitis, photoallergic reactions and eczematous contact-type dermatitis, and may crossreact with certain antihistamines. Tetraethylthiuram disulphide (disulfiram, Antabuse) for the management of alcoholism can cause eczematous reactions in patients sensitized to thiurams via rubber gloves. ‘Systemic contact-type dermatitis’ reactions have also been described with [4] acetylsalicylic acid, codeine [10], phenobarbital, pseudoephedrine hydrochloride and norephedrine hydrochloride [11], ephedrine [12], erythromycin [13], isoniazid [14], dimethylsulfoxide, hydroxyquinone, nystatin, subcutaneous hydromorphone given for cancer pain [15], amlexanox [16], enoxolone [17], vitamin B1, vitamin C, parabens, butylated hydroxyanisole, hydroxytoluene and tea-tree oil [18]. Allergic eczematous reactions to endogenous or exogenous systemic corticosteroids, including hydrocortisone and methylprednisolone, have been documented in patients who are patch-test positive to topical corticosteroids [19,20]. The term ‘baboon syndrome’ denotes a characteristic pattern of systemic allergic contact dermatitis [21–23], in which there is diffuse erythema of the buttocks, upper inner thighs and axillae, provoked by penicillin [24], ampicillin, amoxicillin [25], nickel, heparin, mercury (including that found in a homeopathic medicine [26]), terbinafine [27] and hydroxyurea [28]. Patch tests are commonly positive and usually vesicular, although histology of the eruption itself may show leukocytoclastic vasculitis; oral

challenge with the suspected antigen may be required to substantiate the diagnosis. Disulfiram therapy of a nickel-sensitive alcoholic patient may induce this syndrome, as the drug leads to an initial acute increase in blood nickel concentration [21]. Cases have been described from Japan under the name ‘mercury exanthem’ following inhalation of mercury vapour from crushed thermometers in patients with a history of mercury allergy. The term ‘endogenic contact eczema’ [29] refers to the occurrence of an eczematous contact drug reaction following primary sensitization by oral therapy, as in the case of a patient with a drug-related exanthem who later develops localized dermatitis due to topical therapy. Thus, eczematous eruptions may develop following therapy with penicillin [30], methyldopa, allopurinol, indometacin, sulphonamides, gold, quinine, chloramphenicol, clonidine or bleomycin [31]. The alkylating agent mitomycin C administered intravesically for carcinoma of the bladder has been associated with an eczematous eruption, particularly on the face, palms and soles in some patients; these may have positive patch tests to the drug [32,33]. Some of the more important causes of eczematous drug reactions are listed in Table 75.11. Sensitivity to the suspected drug may be confirmed by subsequent patch testing, when the skin reaction has settled. References 1 Fisher AA. Contact Dermatitis. Philadelphia: Lea & Febiger, 1986. 2 Rycroft RJG, Menné T, Frosch PJ, Benezra CM, eds. Textbook of Contact Dermatitis. Berlin: Springer, 1992. 3 Cronin E. Contact dermatitis XVII. Reactions to contact allergens given orally or systemically. Br J Dermatol 1972; 86: 104–7. 4 Menné T, Veien NK, Maibach HI. Systemic contact-type dermatitis due to drugs. Semin Dermatol 1989; 8: 144–8. 5 Aquilina C, Sayag J. Eczéma par réactogenes internes. Ann Dermatol Vénéréol 1989; 116: 753–65. 6 Berman BA, Ross RN. Ethylenediamine: systemic eczematous contact-type dermatitis. Cutis 1983; 31: 594–8. 7 Hardy C, Schofield O, George CF. Allergy to aminophylline. BMJ 1983; 286: 2051–2. 8 Aeling JL, Nuss DD. Systemic eczematous ‘contact-type’ dermatitis medicamentosa caused by parabens. Arch Dermatol 1974; 110: 640. 9 Ekelund E-G, Möller H. Oral provocation in eczematous contact allergy to neomycin and hydroxy-quinolines. Acta Derm Venereol (Stockh) 1969; 49: 422–6. 10 Estrada JL, Puebla MJ, de Urbina JJ et al. Generalized eczema due to codeine. Contact Dermatitis 2001; 44: 185. 11 Tomb RR, Lepoittevin JP, Espinassouze F et al. Systemic contact dermatitis from pseudoephedrine. Contact Dermatitis 1991; 24: 86–8. 12 Villas Martinez F, Badas AJ, Garmendia Goitia JF, Aguirre I. Generalized dermatitis due to oral ephedrine. Contact Dermatitis 1993; 29: 215–6. 13 Fernandez Redondo V, Casas L, Taboada M, Toribio J. Systemic contact dermatitis from erythromycin. Contact Dermatitis 1994; 30: 311. 14 Meseguer J, Sastre A, Malek T, Salvador MD. Systemic contact dermatitis from isoniazid. Contact Dermatitis 1993; 28: 110–1. 15 de Cuyper C, Goeteyn M. Systemic contact dermatitis from subcutaneous hydromorphone. Contact Dermatitis 1992; 27: 220–3. 16 Hayakawa R, Ogino Y, Aris K, Matsunaga K. Systemic contact dermatitis due to amlexanox. Contact Dermatitis 1992; 27: 122–3. 17 Villas Martinez F, Joral Badas A, Garmendia Goitia JF, Aguirre I. Sensitization to oral enoxolone. Contact Dermatitis 1994; 30: 124. 18 de Groot AC, Weyland JW. Systemic contact dermatitis from tea tree oil. Contact Dermatitis 1992; 27: 279–80. 19 Lauerma AI, Reitamo S, Maibach HI. Systemic hydrocortisone/cortisol induces allergic skin reactions in presensitized subjects. J Am Acad Dermatol 1991; 24: 182–5.

Types of clinical reaction 20 Murata Y, Kumano K, Ueda T et al. Systemic contact dermatitis caused by systemic corticosteroid use. Arch Dermatol 1997; 133: 1053–4. 21 Andersen KE, Hjorth N, Menné T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis 1984; 10: 97–100. 22 Herfs H, Schirren CG, Przybilla B, Plewig G. Das ‘Baboon-Syndrom’. Eine besondere Manifestation einer hamatogenen Kontaktreaktion. Hautarzt 1993; 44: 466–9. 23 Duve S, Worret W, Hofmann H. The baboon syndrome: a manifestation of haematogenous contact-type dermatitis. Acta Derm Venereol (Stockh) 1994; 74: 480–1. 24 Panhans-Gross A, Gall H, Peter RU. Baboon syndrome after oral penicillin. Contact Dermatitis 1999; 41: 352–3. 25 Kick G, Przybilla B. Delayed prick test reaction identifies amoxicillin as elicitor of baboon syndrome. Contact Dermatitis 2000; 43: 366–7. 26 Audicana M, Bernedo N, Gonzalez I et al. An unusual case of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001; 45: 185. 27 Weiss JM, Mockenhaupt M, Schopf E, Simon JC. Reproducible drug exanthema to terbinafine with characteristic distribution of baboon syndrome. Hautarzt 2001; 52: 1104–6. 28 Chowdhury MM, Patel GK, Inaloz HS, Holt PJ. Hydroxyurea-induced skin disease mimicking the baboon syndrome. Clin Exp Dermatol 1999; 24: 336–7. 29 Pirilä V. Endogenic contact eczema. Allerg Asthma 1970; 16: 15–9. 30 Girard JP. Recurrent angioneurotic oedema and contact dermatitis due to penicillin. Contact Dermatitis 1978; 4: 309. 31 Lincke-Plewig H. Bleomycin-Exantheme. Hautarzt 1980; 31: 616–8. 32 Colver GB, Inglis JA, McVittie E et al. Dermatitis due to intravesical mitomycin C: a delayed-type hypersensitivity reaction? Br J Dermatol 1990; 122: 217–24. 33 De Groot AC, Conemans JMH. Systemic allergic contact dermatitis from intravesical instillation of the antitumor antibiotic mitomycin C. Contact Dermatitis 1991; 24: 201–9.

Bullous eruptions Bullous drug eruptions encompass many different clinical reactions and pathomechanisms [1,2]. Isolated blisters, often located preferentially on the extremities, may be caused by a wide variety of chemically distinct drugs. Fixed drug eruptions and druginduced vasculitis may have a bullous component; these are reviewed elsewhere in this chapter. Erythema multiforme, Stevens–Johnson syndrome and drug-induced TEN are discussed in Chapter 76. The specific drug-induced entities of porphyria and pseudoporphyria, bullous pemphigoid, pemphigus and linear IgA disease are discussed here.

Bullous eruption in drug overdosage Bullae, often at pressure areas, may be seen in patients comatose after overdosage with barbiturates (Fig. 75.5), methadone, meprobamate, imipramine, nitrazepam or glutethimide [1–5]. References 1 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 2 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 3 Brehmer-Andersson E, Pedersen NB. Sweat gland necrosis and bullous skin changes in acute drug intoxication. Acta Derm Venereol (Stockh) 1969; 49: 157–62. 4 Mandy S, Ackerman AB. Characteristic traumatic skin lesions in drug-induced coma. JAMA 1970; 213: 253–6. 5 Herschtal D, Robinson MJ. Blisters of the skin in coma induced by amitriptyline and chlorazepate dipotassium. Report of a case with underlying sweat gland necrosis. Arch Dermatol 1979; 115: 499.

Drug-induced porphyria Porphyria is discussed in Chapter 59. Drugs reported to exacerbate the acute hepatic porphyrias are listed in Table 75.12; these

75.37

Fig. 75.5 Bullous eruption in barbiturate overdose. (Courtesy of Charing Cross Hospital, London, UK.)

Table 75.12 Drugs that are unsafe to use in patients with acute intermittent porphyria, porphyria cutanea tarda or variegate porphyria. Aminoglutethimide Barbiturates Carbamazepine Carbromal Chlorpropamide Danazol Diclofenac Diphenylhydantoin (phenytoin) Ergot preparations Glutethimide Griseofulvin

Meprobamate Novobiocin Oestrogens Primidone Progestogens Pyrazolone derivatives Rifampicin Sulphonamides Tolbutamide Trimethadione Valproic acid

either cause excess destruction of haem or inhibit haem synthesis [1–3].

Pseudoporphyria Pseudoporphyria, in which porphyria-like blistering of exposed areas on the extremities occurs in the absence of abnormal porphyrin metabolism, may be caused by high-dose furosemide [4], naproxen [5,6] and other NSAIDs [7–9], combined carisoprodol and aspirin [10], nalidixic acid [11], tetracyclines [12] and sulphonylureas. Phototoxic mechanisms have been implicated in some cases. A similar syndrome has been reported in a patient taking very large doses of pyridoxine (vitamin B6) [13]. References 1 Targovnick SE, Targovnik JH. Cutaneous drug reactions in porphyrias. Clin Dermatol 1986; 4: 111–7. 2 Köstler E, Seebacher C, Riedel H, Kemmer C. Therapeutische und pathogenetische Aspekte der Porphyria cutanea tarda. Hautarzt 1986; 37: 210–6. 3 Ayala F, Santoianni P. Drug-induced cutaneous porphyria. Clin Dermatol 1993; 11: 535–9. 4 Burry JN, Lawrence JR. Phototoxic blisters from high frusemide dosage. Br J Dermatol 1976; 94: 495–9. 5 Judd LE, Henderson DW, Hill DC. Naproxen-induced pseudoporphyria: a clinical and ultrastructural study. Arch Dermatol 1986; 122: 451–4.

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6 Lang BA, Finlayson LA. Naproxen-induced pseudoporphyria in patients with juvenile rheumatoid arthritis. J Pediatr 1994; 124: 639–42. 7 Stern RS. Phototoxic reactions to piroxicam and other nonsteroidal anti-inflammatory agents. N Engl J Med 1983; 309: 186–7. 8 Taylor BJ, Duffill MB. Pseudoporphyria from nonsteroidal anti-inflammatory drugs. NZ Med J 1987; 100: 322–3. 9 Meggitt SJ, Farr PM. Pseudoporphyria and propionic acid non-steroidal antiinflammatory drugs. Br J Dermatol 1999; 141: 591–2. 10 Hazen PG. Pseudoporphyria in a patient receiving carisoprodol/aspirin therapy. J Am Acad Dermatol 1994; 31: 500. 11 Keane JT, Pearson RW, Malkinson FD. Nalidixic acid-induced photosensitivity in mice: a model for pseudoporphyria. J Invest Dermatol 1984; 82: 210–3. 12 Hawk JLM. Skin changes resembling hepatic cutaneous porphyria induced by oxytetracycline photosensitization. Clin Exp Dermatol 1980; 5: 321–5. 13 Baer R, Stilman RA. Cutaneous skin changes probably due to pyridoxine abuse. J Am Acad Dermatol 1984; 10: 527–8.

Drug-induced bullous pemphigoid Idiopathic bullous pemphigoid is discussed in Chapter 40. In drug-induced bullous pemphigoid, patients tend to be younger; tissue-bound and circulating anti-basement-membrane zone IgG antibodies may be absent, or additional antibodies such as intercellular or antiepidermal cytoplasmic antibodies may be detected. Some cases of drug-induced bullous pemphigoid are short-lived, whereas others become chronic. Drug-induced bullous or cicatricial pemphigoid have been reported with a number of medications [1–5], especially furosemide [6,7], but also bumetanide [8], spironolactone [9,10], penicillamine [11,12], the penicillamine analogue tiobutarit [13], penicillin [14] and its derivatives [15], ciprofloxacin [16], sulfasalazine, salicylazosulfapyridine, phenacetin [17], enalapril [18], fluoxetine [19], novoscabin, topical fluorouracil, and PUVA therapy [20]. In the case of enalapril-induced bullous pemphigoid, the IgG antibody was directed against the 230-kDa bullous pemphigoid antigen [18]. Cicatricial pemphigoid has been described in association with penicillamine [12] and clonidine [21]. An association with vaccination for influenza and with tetanus toxoid and induction of bullous pemphigoid has been noted rarely [22–25]. References 1 Ahmed AR, Newcomer VD. Drug-induced bullous pemphigoid. Clin Dermatol 1987; 5: 8–10. 2 Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol 1991; 30: 307–12. 3 Fellner MJ. Drug-induced bullous pemphigoid. Clin Dermatol 1993; 11: 515–20. 4 Van Joost T, Van’t Veen AJ. Drug-induced cicatricial pemphigoid and acquired epidermolysis bullosa. Clin Dermatol 1993; 11: 521–7. 5 Vassileva S. Drug-induced pemphigoid: bullous and cicatricial. Clin Dermatol 1998; 16: 379–87. 6 Fellner MJ, Katz JM. Occurrence of bullous pemphigoid after furosemide therapy. Arch Dermatol 1976; 112: 75–7. 7 Castel T, Gratacos R, Castro J et al. Bullous pemphigoid induced by furosemide. Clin Exp Dermatol 1981; 6: 635–8. 8 Boulinguez S, Bernard P, Bedane C et al. Bullous pemphigoid induced by bumetanide. Br J Dermatol 1998; 138: 548–9. 9 Bastuji-Garan S, Joly P, Picard-Dahan C et al. Drugs associated with bullous pemphigoid. Arch Dermatol 1996; 132: 272–6. 10 Grange F, Koessler A, Scrivener Y et al. Pemphigoide bulleuse induite par la spironolactone. Ann Dermatol Venereol 1996; 123: S110–S111. 11 Rasmussen HB, Jepsen LV, Brandrup F. Penicillamine-induced bullous pemphigoid with pemphigus-like antibodies. J Cutan Pathol 1989; 16: 154–7. 12 Bialy-Golan A, Brenner S. Penicillamine-induced bullous dermatoses. J Am Acad Dermatol 1996; 35: 732–42.

13 Yamaguchi R, Oryu F, Hidano A. A case of bullous pemphigoid induced by tiobutarit (d-penicillamine analogue). J Dermatol 1989; 16: 308–11. 14 Alcalay J, David M, Ingber A et al. Bullous pemphigoid mimicking bullous erythema multiforme: an untoward side effect of penicillins. J Am Acad Dermatol 1988; 18: 345–9. 15 Hodak E, Ben-Shetrit A, Ingber A, Sandbank M. Bullous pemphigoid: an adverse effect of ampicillin. Clin Exp Dermatol 1990; 15: 50–2. 16 Kimyai-Asadi A, Usman A, Nousari HC. Ciprofloxacin-induced bullous pemphigoid. J Am Acad Dermatol 2000; 42: 847. 17 Kashihara M, Danno K, Miyachi Y et al. Bullous pemphigoid-like lesions induced by phenacetin: report of a case and an immunopathologic study. Arch Dermatol 1984; 120: 1196–9. 18 Pazderka Smith E, Taylor TB, Meyer LJ, Zone JJ. Antigen identification in druginduced bullous pemphigoid. J Am Acad Dermatol 1993; 29: 879–82. 19 Rault S, Grosieux-Dauger C, Verraes S et al. Bullous pemphigoid induced by fluoxetine. Br J Dermatol 1998; 139: 1092–6. 20 Abel EA, Bennett A. Bullous pemphigoid. Occurrence in psoriasis treated with psoralens plus long-wave ultraviolet radiation. Arch Dermatol 1979; 115: 988–9. 21 Van Joost T, Faber WR, Manuel HR. Drug-induced anogenital cicatricial pemphigoid. Br J Dermatol 1980; 102: 715–8. 22 Bodokh I, Lacour JP, Bourdet JF et al. Réactivation de pemphigoïde bulleuse apres vaccination antigrippale. Thérapie 1994; 49: 154. 23 Venning VA, Wojnarowska F. Induced bullous pemphigoid. Br J Dermatol 1995; 132: 831–2. 24 Fournier B, Descamps V, Bouscarat F et al. Bullous pemphigoid induced by vaccination. Br J Dermatol 1996; 135: 153–4. 25 Downs AMR, Lear JT, Bower CPR, Kennedy CTC. Does influenza vaccination induce bullous pemphigoid? A report of four cases. Br J Dermatol 1998; 138: 363.

Drug-induced pemphigus The variants of idiopathic pemphigus are discussed in Chapter 40. A number of drugs have been implicated in drug-induced pemphigus (Table 75.13) [1,2], usually of foliaceus type, although the erythematosus, herpetiformis and urticaria-like forms also occur; drug-induced pemphigus vulgaris is rare. Most patients with drug-induced pemphigus have tissue-bound and/or low-titre circulating autoantibodies with the same antigenic specificity at a molecular level as autoantibodies from patients with the corresponding subtype of idiopathic pemphigus [3,4]; however, in the case of penicillamine-induced pemphigus, 10% do not have tissuebound, and more than 30% do not have circulating, autoantibodies. About 80% of cases are caused by drugs associated with a thiol group in the molecule, especially penicillamine [5–11], but also the structurally related ACE inhibitors captopril [3,12–14] and ramipril [15], gold sodium thiomalate, drugs with disulphide bonds such as pyritinol [16], S-thiopyridoxine, tiopronin (mercaptopropionylglycine, which is chemically related to penicillamine and used as an alternative therapy in penicillamine intolerance) [4,17,18], and bucillamine [19], as well as those with a sulphur-containing ring that may undergo metabolic change to the thiol form, such as piroxicam [20]. Penicillin [21–23], and its derivatives ampicillin [22], procaine penicillin and amoxicillin, may also cause pemphigus. Other drugs that cause pemphigus may contain an active amide group [24]. Rifampicin [25], cefalexin [26], cefadroxil, ceftazidime [27], pyrazolone derivatives [28] including dipyrone [29], propranolol, propranolol–meprobamate [30], optalidon, pentachlorophenol, phenobarbital [31], nifedipine [32], phosphamide, hydantoin, combinations of indometacin and aspirin [33], glibenclamide [34], as well as heroin [35], have all been established as rare causes of

Types of clinical reaction Table 75.13 Drugs implicated in the development of pemphigus. Thiol drugs Penicillamine Captopril, ramipril Gold sodium thiomalate Pyritinol Thiamazole (methimazole) Tiopronin (mercaptopropionylglycine) Non-thiol drugs Antibiotics Penicillin and derivatives Rifampicin Cefalexin (cephalexin) Cefadroxil Ceftazidine Pyrazolone derivatives Aminophenazone Aminopyrine Azapropazone Oxyphenbutazone Phenylbutazone Miscellaneous Glibenclamide Hydantoin Levodopa Lysine acetylsalicylate Nifedipine Phenobarbital (phenobarbitone) Piroxicam Progesterone Propranolol Interferon-β and interleukin-2 Heroin

a pemphigus-like reaction. Fatal pemphigus vulgaris has been recorded after IFN-β and IL-2 therapy for lymphoma [36]. Fludarabine has been implicated in the development of paraneoplastic pemphigus [37,38]. References 1 Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. I. A survey. Clin Dermatol 1993; 11: 501–5. 2 Ruocco V, De Angelis E, Lombardi ML. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 1993; 11: 507–13. 3 Korman NJ, Eyre RW, Stanley JR. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol 1991; 96: 273–6. 4 Verdier-Sevrain S, Joly P, Thomine E et al. Thiopronine-induced herpetiform pemphigus: report of a case studied by immunoelectron microscopy and immunoblot analysis. Br J Dermatol 1994; 130: 238–40. 5 Goldberg I, Kashman Y, Brenner S. The induction of pemphigus by phenol drugs. Int J Dermatol 1999; 38: 888–92. 6 Kishimoto K, Iwatsuki K, Akiba H et al. Subcorneal pustular dermatosis-type IgA pemphigus induced by thiol drugs. Eur J Dermatol 2001; 11: 41–4. 7 Zillikens D, Zentner A, Burger M et al. Pemphigus foliaceus durch Penicillamin. Hautarzt 1993; 44: 167–71. 8 Jones E, Sobkowski WW, Murray SJ, Walsh NMG. Concurrent pemphigus and myasthenia gravis as manifestations of penicillamine toxicity. J Am Acad Dermatol 1993; 28: 655–6.

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9 Bialy-Golan A, Brenner S. Penicillamine-induced bullous dermatoses. J Am Acad Dermatol 1996; 35: 732–42. 10 Peñas PF, Buezo GF, Carvajal I et al. d-Penicillamine-induced pemphigus foliaceus with autoantibodies to desmoglein-1 in a patient with mixed connective tissue disease. J Am Acad Dermatol 1997; 37: 121–3. 11 Toth GG, Jonkman MF. Successful treatment of recalcitrant penicillamineinduced pemphigus foliaceus by low-dose intravenous immunoglobulins. Br J Dermatol 1999; 141: 583–5. 12 Clement M. Captopril-induced eruptions. Arch Dermatol 1981; 117: 525–6. 13 Katz RA, Hood AF, Anhalt GJ. Pemphigus-like eruption from captopril. Arch Dermatol 1987; 123: 20–1. 14 Kaplan RP, Potter TS, Fox JN. Drug-induced pemphigus related to angiotensinconverting enzyme inhibitors. J Am Acad Dermatol 1992; 26: 364–6. 15 Vignes S, Paul C, Flageul B, Dubertret L. Ramipril-induced superficial pemphigus. Br J Dermatol 1996; 135: 657–8. 16 Civatte J, Duterque M, Blanchet P et al. Deux cas de pemphigus superficiel induit par le pyritinol. Ann Dermatol Vénéréol 1978; 105: 573–7. 17 Alinovi A, Benoldi D, Manganelli P. Pemphigus erythematosus induced by thiopronin. Acta Derm Venereol (Stockh) 1982; 62: 452–4. 18 Lucky PA, Skovby F, Thier SO. Pemphigus foliacaeus and proteinuria induced by α-mercaptopropionylglycine. J Am Acad Dermatol 1983; 8: 667–72. 19 Ogata K, Nakajima H, Ikeda M et al. Drug-induced pemphigus foliaceus with features of pemphigus vulgaris. Br J Dermatol 2001; 144: 421–2. 20 Martin RL, McSweeny GW, Schneider J. Fatal pemphigus vulgaris in a patient taking piroxicam. N Engl J Med 1983; 309: 795–6. 21 Duhra PL, Foulds IS. Penicillin-induced pemphigus vulgaris. Br J Dermatol 1988; 118: 307. 22 Fellner MJ, Mark AS. Penicillin- and ampicillin-induced pemphigus vulgaris. Int J Dermatol 1980; 19: 392–3. 23 Heymann AD, Chodick G, Kramer E et al. Pemphigus variant associated with penicillin use. Arch Dermatol 2007; 143: 704–7. 24 Wolf R, Brenner S. An active amide group in the molecule of drugs that induce pemphigus: a casual or causal relationship? Dermatology 1994; 189: 1–4. 25 Lee CW, Lim JH, Kang HJ. Pemphigus foliaceus induced by rifampicin. Br J Dermatol 1984; 111: 619–22. 26 Wolf R, Dechner E, Ophir J, Brenner S. Cephalexin. A nonthiol drug that may induce pemphigus vulgaris. Int J Dermatol 1991; 30: 213–5. 27 Pellicano R, Iannantuono M, Lomuto M. Pemphigus erythematosus induced by ceftazidime. Int J Dermatol 1993; 32: 675–6. 28 Chorzelski TP, Jablonska S, Blaszczyk M. Autoantibodies in pemphigus. Acta Derm Venereol (Stockh) 1966; 46: 26. 29 Brenner S, Bialy-Golan A, Crost N. Dipyrone in the induction of pemphigus. J Am Acad Dermatol 1997; 36: 488–90. 30 Goddard W, Lambert D, Gavanou J, Chapius JL. Pemphigus acquit après traitement par l’association propranolol–meprobamate. Ann Dermatol Vénéréol 1980; 107: 1213–6. 31 Dourmishev AL, Rahman MA. Phenobarbital-induced pemphigus vulgaris. Dermatologica 1986; 173: 256–8. 32 Kim SC, Won JH, Ahn SK. Pemphigus foliaceus induced by nifedipine. Acta Derm Venereol (Stockh) 1993; 73: 210–1. 33 Demento FJ, Grover RW. Acantholytic herpetiform dermatitis. Arch Dermatol 1973; 107: 883–7. 34 Paterson AJ, Lamey PJ, Lewis MA et al. Pemphigus vulgaris precipitated by glibenclamide therapy. J Oral Pathol Med 1993; 22: 92–5. 35 Fellner MJ, Winiger J. Pemphigus erythematosus and heroin addiction. Int J Dermatol 1978; 17: 308–11. 36 Ramseur WL, Richards F, Duggan DB. A case of fatal pemphigus vulgaris in association with beta interferon and interleukin-2 therapy. Cancer 1989; 63: 2005–7. 37 Anhalt GJ. Paraneoplastic pemphigus: the role of tumours and drugs. Br J Dermatol 2001; 144: 1102–4. 38 Gooptu C, Littlewood TJ, Frith P et al. Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 2001; 144: 1255–61.

Linear IgA disease Idiopathic linear IgA disease is discussed in Chapter 40. The drugs implicated as a cause of this condition have been reviewed [1–3],

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Chapter 75: Drug Reactions

and include vancomycin especially [1–9], but also amiodarone, ampicillin, atorvastatin [10], captopril [11], carbamazepine [12], cefamandole (cephamandole), diclofenac, furosemide [13], glibenclamide, IFN-γ, iodine, lithium, penicillin [14,15], phenytoin [16] and somatostatin, as well as tea-tree oil [17]. Most patients lack circulating antibodies to the basement membrane; resolution of the rash follows discontinuation of medication. References 1 Collier PM, Wojnarowska F. Drug-induced linear immunoglobulin A disease. Clin Dermatol 1993; 11: 529–33. 2 Kuechle ML, Stegemeir E, Maynard B et al. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol 1994; 30: 187–92. 3 Geissmann C, Beylot-Barry M, Doutre MS, Beylot C. Drug-induced linear IgA bullous dermatosis. J Am Acad Dermatol 1995; 32: 296. 4 Carpenter S, Berg D, Sidhu-Malik N et al. Vancomycin-associated linear IgA dermatosis. A report of three cases. J Am Acad Dermatol 1992; 26: 45–8. 5 Piketty C, Meeus F, Nochy D et al. Linear IgA dermatosis related to vancomycin. Br J Dermatol 1994; 130: 130–1. 6 Whitworth JM, Thomas I, Peltz S et al. Vancomycin-induced linear IgA bullous dermatosis (LABD). J Am Acad Dermatol 1996; 34: 890–1. 7 Palmer RA, Ogg G, Allen J et al. Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285. Br J Dermatol 2001; 145: 816–20. 8 Ahkami R, Thomas I. Linear IgA bullous dermatosis associated with vancomycin and disseminated varicella-zoster infection. Cutis 2001; 67: 423–6. 9 Dellavalle RP, Burch HM, Tyal S et al. Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. J Am Acad Dermatol 2003; 48: S56–S57. 10 Konig C, Eickert A, Scharfetter-Kochanek K et al. Linear IgA bullous dermatosis induced by atorvastatin. J Am Acad Dermatol 2001; 44: 689–92. 11 Friedman IS, Rudikoff D, Phelps RG, Sapadin AN. Captopril-triggered linear IgA bullous dermatosis. Int J Dermatol 1998; 37: 608–12. 12 Cohen LM, Ugent RB. Linear IgA bullous dermatosis occurring after carbamazepine. J Am Acad Dermatol 2002; 46: S32–S33. 13 Cerottini J-P, Ricci C, Guggisberg D, Panizzon RG. Drug-induced linear IgA bullous dermatosis probably induced by furosemide. J Am Acad Dermatol 1999; 41: 103–5. 14 Combemale P, Gavaud C, Cozzani E et al. Dermatose a IgA lineaire (DIAL) induite par penicilline G. Ann Dermatol Vénéréol 1993; 120: 847–8. 15 Wakelin S, Allen J, Zhou S, Wojnorowska F. Drug-induced linear IgA disease with antibodies to collagen VII. Br J Dermatol 1998; 138: 310–4. 16 Acostamadiedo JM, Perniciaro C, Rogers RS III. Phenytoin-induced linear IgA bullous disease. J Am Acad Dermatol 1998; 38: 352–6. 17 Perett CM, Evans AV, Russell-Jones R. Tea tree oil dermatitis associated with linear IgA disease. Clin Exp Dermatol 2003; 28: 167–70.

Table 75.14 Drugs recorded as inducing vasculitis. Additives Allopurinol Aminosalicylic acid Amfetamine (amphetamine) Amiodarone Ampicillin Arsenic Aspirin Captopril Carbamazepine Cimetidine Coumadin Didanosine Enalapril Erythromycin Etacrynic acid (ethacrynic acid) Fluoroquinolone antibiotics Fluoxetine Furosemide (frusemide) Griseofulvin Guanethidine Hydralazine Iodides

Levamisole Maprotiline Mefloquine Methotrexate Penicillin Phenacetin Phenothiazines Phenylbutazone Phenytoin Piperazine Procainamide Propylthiouracil Quinidine Radiocontrast media Streptomycin Sulphonamides Tetracycline Thiazides Trazodone Trimethadione Vaccines Zidovudine

furosemide [4], thiazide diuretics, phenylbutazone and other NSAIDs, quinidine, amiodarone [5], hydralazine [6], enalapril [7], propylthiouracil [8,9], mefloquine [10], cimetidine [11], coumadin [12,13], anticonvulsants including phenytoin and in isolated cases carbamazepine and trimethadione [14,15], zidovudine (azidothymidine) [16], indinavir [17], fluoxetine [18], didanosine [19], piperazine [20], centrally acting appetite suppressants [21], hyposensitization therapy [22,23], bacille Calmette–Guérin (BCG) vaccination (which may cause a papulonecrotic type of vasculitis) [24], radiographic contrast media [25], food and drug additives including dye excipients such as tartrazine (FD&C yellow no. 5), ponceau, sodium benzoate, 4-hydroxybenzoic acid [26,27], vitamin B6 [28] and the use of a nicotine patch [29]. Leukocytoclastic vasculitis and necrotizing angiitis have also been documented in drug abusers [30–32].

Drug-induced epidermolysis bullosa acquisita This entity has been linked to antibiotics, including vancomycin [1]. Reference 1 Delbaldo C, Chen M, Friedli A et al. Drug-induced epidermolysis bullosa acquisita with antibodies to type VII collagen. J Am Acad Dermatol 2002; 46: S161–S164.

Vasculitis Drug-induced cutaneous necrotizing vasculitis [1–3] may also involve internal organs, including the heart, liver and kidneys, with fatal results. The patterns of polyarteritis nodosa, Henoch– Schönlein vasculitis and hypocomplementaemic vasculitis are not seen commonly with drugs. Drugs that have been implicated are listed in Table 75.14. These include ampicillin, sulphonamides,

References 1 Mullick FG, McAllister HA Jr, Wagner BM, Fenoglio JJ Jr. Drug-related vasculitis. Clinicopathologic correlations in 30 patients. Hum Pathol 1979; 10: 313–25. 2 Mackel SE, Jordon RE. Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease. Arch Dermatol 1983; 118: 296–301. 3 Sanchez NP, Van Hale HM, Su WPD. Clinical and histopathologic spectrum of necrotizing vasculitis. Report of findings in 101 cases. Arch Dermatol 1985; 121: 220–4. 4 Hendricks WM, Ader RS. Furosemide-induced cutaneous necrotizing vasculitis. Arch Dermatol 1977; 113: 375–6. 5 Staubli M, Zimmerman A, Bircher J. Amiodarone-induced vasculitis and polyserositis. Postgrad Med J 1985; 61: 245–7. 6 Peacock A, Weatherall D. Hydralazine-induced necrotizing vasculitis. BMJ 1981; 282: 1121–2. 7 Carrington PR, Sanusi ID, Zahradka S, Winder PR. Enalapril-associated erythema and vasculitis. Cutis 1993; 51: 121–3. 8 Vasily DB, Tyler WB. Propylthiouracil-induced cutaneous vasculitis. Case presentation and review of literature. JAMA 1980; 243: 458–61.

Types of clinical reaction 9 Gammeltoft M, Kristensen JK. Propylthio-uracil-induced cutaneous vasculitis. Acta Derm Venereol (Stockh) 1982; 62: 171–3. 10 Scerri L, Pace JL. Mefloquine-associated cutaneous vasculitis. Int J Dermatol 1993; 32: 517–8. 11 Mitchell GG, Magnusson AR, Weiler JM. Cimetidine-induced cutaneous vasculitis. Am J Med 1983; 75: 875–6. 12 Tanay A, Yust I, Brenner S et al. Dermal vasculitis due to coumadin hypersensitivity. Dermatologica 1982; 165: 178–85. 13 Tamir A, Wolf R, Brenner S. Leukocytoclastic vasculitis: another coumarininduced hemorrhagic reaction. Acta Derm Venereol (Stockh) 1994; 74: 138–9. 14 Drory VE, Korczyn AD. Hypersensitivity vasculitis and systemic lupus erythematosus induced by anticonvulsants. Clin Neuropharmacol 1993; 16: 19–29. 15 Kaneko K, Igarashi J, Suzuki Y et al. Carbamazepine-induced thrombocytopenia and leucopenia complicated by Henoch–Schonlein purpura symptoms. Eur J Pediatr 1993; 152: 769–70. 16 Torres RA, Lin RY, Lee M, Barr MR. Zidovudine-induced leukocytoclastic vasculitis. Arch Intern Med 1992; 152: 850–1. 17 Rachline A, Lariven S, Descamps V et al. Leucocytoclastic vasculitis and indinavir. Br J Dermatol 2000; 143: 1112–3. 18 Roger D, Rolle F, Mausset J et al. Urticarial vasculitis induced by fluoxetine. Dermatology 1995; 191: 164. 19 Herranz P, Fernandez-Diaz ML, de Lucas R et al. Cutaneous vasculitis associated with didanosine. Lancet 1994; 344: 680. 20 Balzan M, Cacciottolo JM. Hypersensitivity vasculitis associated with piperazine therapy. Br J Dermatol 1994; 131: 133–4. 21 Papadavid E, Yu RC, Tay A, Chu AC. Urticarial vasculitis induced by centrally acting appetite suppressants. Br J Dermatol 1996; 134: 990–1. 22 Phanuphak P, Kohler PF. Onset of polyarteritis nodosa during allergic hyposensitisation treatment. Am J Med 1980; 68: 479–85. 23 Merk H, Kober ML. Vasculitis nach spezifischer Hyposensibilisierung. Z Hautkr 1982; 57: 1682–5. 24 Lübbe D. Vasculitis allergica vom papulonekrotischen Typ nach BCG-Impfung. Dermatol Monatsschr 1982; 168: 186–92. 25 Kerdel FA, Fraker DL, Haynes HA. Necrotizing vasculitis from radiographic contrast media. J Am Acad Dermatol 1984; 10: 25–9. 26 Michäelsson G, Petterson L, Juhlin L. Purpura caused by food and drug additives. Arch Dermatol 1974; 109: 49–52. 27 Lowry MD, Hudson CF, Callen FP. Leukocytoclastic vasculitis caused by drug additives. J Am Acad Dermatol 1994; 30: 854–5. 28 Ruzicka T, Ring J, Braun-Falco O. Vasculitis allergica durch vitamin B6. Hautarzt 1984; 35: 197–9. 29 Van der Klauw MM, Van Hillo B, Van den Berg WH et al. Vasculitis attributed to the nicotine patch (Nicotinell). Br J Dermatol 1996; 34: 361–4. 30 Citron BP, Halpen M, McCarron M et al. Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283: 1003–11. 31 Lignelli GJ, Bucheit WA. Angiitis in drug abusers. N Engl J Med 1971; 284: 112–3. 32 Gendelman H, Linzer M, Barland P et al. Leukocytoclastic vasculitis in an intravenous heroin abuser. NY State J Med 1983; 83: 984–6.

Lupus erythematosus-like syndrome A reaction resembling idiopathic LE has been reported in association with a large variety of drugs [1–46], although only about 5% of cases of SLE are drug induced. Cutaneous manifestations are in general rare: 18% and 26%, respectively, of patients with procainamide- and hydralazine-induced LE had skin changes in one series [6]. Photosensitivity may be prominent; some patients develop discoid LE lesions; urticarial or erythema multiforme-like lesions may also be seen. Constitutional symptoms may be present, and there may be evidence of Raynaud’s disease, arthritis or polyserositis. Renal involvement is rare, as is central nervous system involvement. The condition usually, but not always, resolves after discontinuation of the drug. Abnormal laboratory findings include the presence of LE cells, and of antinuclear antibodies directed against ribonucleoprotein, single-stranded DNA and especially

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Table 75.15 Drugs inducing lupus erythematosus-like syndromes. Allopurinol Aminoglutethimide p-Aminosalicylic acid Angiotensin-converting enzyme inhibitors (captopril) Anticonvulsants Carbamazepine Hydantoins Primidone Trimethadione Valproate β-Blockers Calcium channel blockers Clonidine Ethosuximide Gold salts Griseofulvin Hydralazine Ibuprofen Isoniazid

Lithium Methyldopa Methysergide Nitrofurantoin Oral contraceptives Penicillamine Penicillin Phenothiazines (chlorpromazine) Phenylbutazone Procainamide Quinidine Streptomycin Sulfasalazine co-trimoxazole (sulphasalazine) Sulphonamides Terbinafine Tetracycline Thiazide diuretics Thionamide Thiouracils

histones [11,12]. Antibodies against native double-stranded DNA are rarely found in drug-induced LE, and complement levels are normal; deposition of immunoreactants in uninvolved skin is rare. Patients with drug-induced LE may have the lupus anticoagulant [13,14]. A partial list of drugs reported to induce an SLE-like syndrome or exacerbate idiopathic LE is given in Table 75.15. Drugs most commonly implicated in inducing LE include especially hydralazine [15,16] and procainamide [17,18], and less commonly βblockers, methyldopa [19,20], isoniazid, most anticonvulsants in clinical use including phenytoin, carbamazepine, ethosuximide, trimethadione, primidone and valproate (but not phenobarbital or benzodiazepines) [21], and quinidine [22,23]. LE following penicillamine therapy [24,25], 2-mercaptopropionylglycine [26], rifampicin [27], etanercept [28] and the tetracycline derivative COL-3 used in antiangiogenesis [29] has also been documented. Minocycline may induce an autoimmune syndrome of which LE may form part [30–32]. Subacute LE with positive Ro/SSA antibodies has been reported in association with a number of drugs [9], including phenytoin [33], thiazide diuretics such as hydrochlorothiazide [34–37], ACE inhibitors [38,39], calcium channel blockers [40], terbinafine [41–43], griseofulvin [44], piroxicam, oxprenolol, interferons and statins. The oral contraceptive induced LE lesions on the palms and feet of a patient [45]. In addition, a number of drugs may exacerbate pre-existing SLE, such as griseofulvin, β-blockers, sulphonamides [46], testosterone and oestrogens. References 1 Reidenberg MM. The chemical induction of systemic lupus erythematosus and lupus-like illnesses. Arthritis Rheum 1981; 24: 1004–9. 2 Harmon CE, Portnova JP. Drug-induced lupus: clinical and serological studies. Clin Rheum Dis 1982; 8: 121–35. 3 Stratton MA. Drug-induced systemic lupus erythematosus. Clin Pharm 1985; 4: 657–63.

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4 Totoritis MC, Rubin RL. Drug-induced lupus. Genetic, clinical, and laboratory features. Postgrad Med 1985; 78: 149–52. 5 Moureaux P. Les formes cutanées du lupus. Allerg Immunol 1995; 27: 196–9. 6 Dubois EL. Serologic abnormalities in spontaneous and drug-induced systemic lupus erythematosus. J Rheumatol 1975; 2: 204–14. 7 Callen JP. Drug-induced cutaneous lupus erythematosus, a distinct syndrome that is frequently unrecognised. J Am Acad Dermatol 2001; 45: 315–6. 8 Callen JP. How frequently are drugs associated with the development or exacerbation of subacute cutaneous lupus? Arch Dermatol 2003; 139: 89–90. 9 Srivastava M, Rencic A, Diglio G et al. Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus. Arch Dermatol 2003; 139: 45–9. 10 Rubin RL. Drug-induced lupus. Toxicology 2005; 209: 135–47. 11 Hobbs RN, Clayton AL, Bernstein RM. Antibodies to the five histones and poly(adenosine diphosphateribose) in drug-induced lupus: implications for pathogenesis. Ann Rheum Dis 1987; 46: 408–16. 12 Totoritis MC, Tan EM, McNally EM et al. Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. N Engl J Med 1988; 318: 1431–6. 13 Bell WR, Boss GR, Wolfson JS. Circulating anticoagulant in the procainamideinduced lupus syndrome. Arch Intern Med 1977; 137: 1471–3. 14 Canoso RT, Sise HS. Chlorpromazine-induced lupus anticoagulant and associated immunologic abnormalities. Am J Hematol 1982; 13: 121–9. 15 Mansilla Tinoco R, Harland SJ, Ryan PJ et al. Hydralazine, antinuclear antibodies, and the lupus syndrome. BMJ 1982; 284: 936–9. 16 Russell GI, Bing RF, Jones JA et al. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. QJM 1987; 65: 845–52. 17 Dubois EL. Procainamide induction of a systemic lupus erythematosus-like syndrome. Presentation of six cases, review of the literature, and analysis and follow up of reported cases. Medicine (Baltimore) 1969; 48: 217–28. 18 Blomgren SE, Condemi JJ, Vaughan JH. Procainamide-induced lupus erythematosus. Clinical and laboratory observations. Am J Med 1972; 52: 338–48. 19 Harrington TM, Davis DE. Systemic lupus-like syndrome induced by methyldopa therapy. Chest 1981; 79: 696–7. 20 Dupont A, Six R. Lupus-like syndrome induced by methyldopa. BMJ 1982; 285: 693–4. 21 Drory VE, Korczyn AD. Hypersensitivity vasculitis and systemic lupus erythematosus induced by anticonvulsants. Clin Neuropharmacol 1993; 16: 19–29. 22 McCormack GD, Barth WF. Quinidine induced lupus syndrome. Semin Arthritis Rheum 1985; 15: 73–9. 23 Cohen MG, Kevat S, Prowse MV et al. Two distinct quinidine-induced rheumatic syndromes. Ann Intern Med 1988; 108: 369–71. 24 Chalmers A, Thompson D, Stein HE et al. Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis. Ann Intern Med 1982; 97: 659–63. 25 Condon C, Phelan M, Lyons JF. Penicillamine-induced type II bullous systemic lupus erythematosus. Br J Dermatol 1997; 136: 474–5. 26 Katayama I, Nishioka K. Lupus like syndrome induced by 2mercaptopropionylglycine. J Dermatol 1986; 13: 151–3. 27 Patel GK, Anstey AV. Rifampicin-induced lupus erythematosus. Clin Exp Dermatol 2001; 26: 260–2. 28 Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002; 359: 45–9. 29 Ghate JV, Turner ML, Rudek MA et al. Drug-induced lupus associated with COL-3. Report of 3 cases. Arch Dermatol 2001; 137: 471–4. 30 Crosson J, Stillman MT. Minocycline-related lupus erythematosus with associated liver disease. J Am Acad Dermatol 1997; 36: 867–8. 31 Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum 1999; 28: 392–7. 32 Dunphy J, Oliver M, Rands AL et al. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000; 142: 461–7. 33 Ross S, Dywer C, Ormerod AD et al. Subacute cutaneous lupus erythematosus associated with phenytoin. Clin Exp Dermatol 2002; 27: 474–6. 34 Darken M, McBurney EI. Subacute cutaneous lupus erythematosus-like drug eruption due to combination diuretic hydrochlorothiazide and triamterene. J Am Acad Dermatol 1988; 18: 38–42. 35 Wollenberg A, Meurer M. Thiazid-Diuretika-induzierter subakut-kutaner Lupus erythematodes. Hautarzt 1991; 42: 709–12.

36 Goodrich AL, Kohn SR. Hydrochlorothiazide-induced lupus erythematosus: a new variant? J Am Acad Dermatol 1993; 28: 1001–2. 37 Brown CW Jr, Deng JS. Thiazide diuretics induce cutaneous lupus-like adverse reaction. J Toxicol Clin Toxicol 1995; 33: 729–33. 38 Callen JP, Fernandez-Diaz MC, Herranz P et al. Subacute cutaneous lupus erythematosus associated with cilazapril. J Am Acad Dermatol 1997; 37: 781. 39 Patri P, Nigro A, Rebora A. Lupus erythematosus-like eruption from captopril. Acta Derm Venereol (Stockh) 1985; 65: 447–8. 40 Crowson AN, Magro CM. Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Hum Pathol 1997; 28: 67–73. 41 Brooke R, Coulson IH, Al-Dawoud A. Terbinafine-induced subacute cutaneous lupus erythematosus. Br J Dermatol 1998; 139: 1132–3. 42 Bonsmann G, Schiller M, Luger TA. Terbinafine-induced subacute cutaneous lupus erythematosus. J Am Acad Dermatol 2001; 44: 925–31. 43 Callen JP, Hughes AP, Kulp-Shorten CL. Terbinafine-exacerbated/induced subacute cutaneous lupus erythematosus: a report of 5 patients. Arch Dermatol 2001; 137: 1196–8. 44 Miyagawa S, Okuchi T, Shiomo Y et al. Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J Am Acad Dermatol 1989; 21: 343–6. 45 Furukawa F, Tachibana T, Imamura S, Tamura T. Oral contraceptive-induced lupus erythematosus in a Japanese woman. J Dermatol 1991; 18: 56–8. 46 Petri M, Allbritton J. Antibiotic allergy in systemic lupus erythematosus: a case– control study. J Rheumatol 1992; 19: 265–9.

Dermatomyositis reactions Dermatomyositis has been reported to be precipitated by a variety of drugs, including penicillamine [1–3], NSAIDs (niflumic acid and diclofenac) [4], carbamazepine [5] and vaccination, as with BCG [6]. Acral skin lesions simulating chronic dermatomyositis have been reported during long-term hydroxyurea therapy [7]. Allergy to benzalkonium chloride has caused a dermatomyositislike reaction [8]. References 1 Simpson NB, Golding JR. Dermatomyositis induced by penicillamine. Acta Derm Venereol (Stockh) 1979; 59: 543–4. 2 Wojnorowska F. Dermatomyositis induced by penicillamine. J R Soc Med 1980; 73: 884–6. 3 Carroll GC, Will RK, Peter JB et al. Penicillamine induced polymyositis and dermatomyositis. J Rheumatol 1987; 14: 995–1001. 4 Grob JJ, Collet AM, Bonerandi JJ. Dermatomyositis-like syndrome induced by nonsteroidal anti-inflammatory agents. Dermatologica 1989; 178: 58–9. 5 Simpson JR. ‘Collagen disease’ due to carbamazepine (Tegretol). BMJ 1966; ii: 1434. 6 Kass E, Staume S, Mellbye OJ et al. Dermatomyositis associated with BCG vaccination. Scand J Rheumatol 1979; 8: 187–91. 7 Richard M, Truchetet F, Friedel J et al. Skin lesions simulating chronic dermatomyositis during long-term hydroxyurea therapy. J Am Acad Dermatol 1989; 21: 797–9. 8 Cox NH. Allergy to benzalkonium chloride simulating dermatomyositis. Contact Dermatitis 1994; 31: 50.

Scleroderma-like reactions Penicillamine [1,2], bleomycin [3,4], bromocriptine [5], vitamin K (phytomenadione) [6,7], sodium valproate [8] and 5hydroxytryptophan combined with carbidopa [9,10] (see also the eosinophilia–myalgia syndrome below) have all been implicated in either localized or generalized morphoea-like, or systemic sclerosislike, reactions. Eosinophilic fasciitis has been associated with tryptophan ingestion in some cases [11], as well as with phenytoin [12]. References 1 Bernstein RM, Hall MA, Gostelow BE. Morphea-like reaction to d-penicillamine therapy. Ann Rheum Dis 1981; 40: 42–4.

Types of clinical reaction 2 Miyagawa S, Yoshioka A, Hatoko M et al. Systemic sclerosis-like lesions during long-term penicillamine therapy for Wilson’s disease. Br J Dermatol 1987; 116: 95–100. 3 Finch WR, Rodnan GP, Buckingham RB et al. Bleomycin-induced scleroderma. J Rheumatol 1980; 7: 651–9. 4 Snauwaert J, Degreef H. Bleomycin-induced Raynaud’s phenomenon and acral sclerosis. Dermatologica 1984; 169: 172–4. 5 Leshin B, Piette WW, Caplin RM. Morphea after bromocriptine therapy. Int J Dermatol 1989; 28: 177–9. 6 Brunskill NJ, Berth-Jones J, Graham-Brown RAC. Pseudosclerodermatous reaction to phytomenadione injection (Texier’s syndrome). Clin Exp Dermatol 1988; 13: 276–8. 7 Pujol RM, Puig L, Moreno A et al. Pseudoscleroderma secondary to phytonadione (vitamin K1) injections. Cutis 1989; 43: 365–8. 8 Goihman-Yahr M, Leal G, Essenfeld-Yahr E. Generalized morphea: a side effect of valproate sodium? Arch Dermatol 1980; 116: 621. 9 Chamson A, Périer C, Frey J. Syndrome sclérodermiforme et poïkilodermique observé au cours d’un traitement par carbidopa et 5-hydroxytryptophanne. Culture de fibroblastes avec analyse biochimique du métabolisme du collagene. Ann Dermatol Vénéréol 1986; 113: 71. 10 Joly P, Lampert A, Thomine E, Lauret P. Development of pseudo-bullous morphea and scleroderma-like illness during therapy with l-5hydroxytryptophan and carbidopa. J Am Acad Dermatol 1991; 25: 332–3. 11 Gordon ML, Lebwohl MG, Phelps RG et al. Eosinophilic fasciitis associated with tryptophan ingestion. A manifestation of eosinophilia–myalgia syndrome. Arch Dermatol 1991; 127: 217–20. 12 Buchanan RR, Gordon DA, Muckle TJ et al. The eosinophilic fasciitis syndrome after phenytoin (Dilantin) therapy. J Rheumatol 1980; 7: 733–6.

Chemical and industrial causes of scleroderma-like reactions [1] Scleroderma-like changes formed part of the clinical spectrum of the Spanish toxic oil syndrome, which resulted from contamination of rapeseed cooking oil with acetanilide [2]. Scleroderma-like changes have been induced by industrial exposure to vinyl chloride [3], epoxy resins [1,4], organic solvents [5] including perchlorethylene [6], trichlorethylene and trichlorethane [7], and in coalminers due to silica exposure [8,9]. References 1 Ishikawa O, Warita S, Tamura A, Miyachi Y. Occupational scleroderma. A 17-year follow-up study. Br J Dermatol 1995; 133: 786–9. 2 Rush PJ, Bell MJ, Fam AG. Toxic oil syndrome (Spanish oil disease) and chemically induced scleroderma-like conditions. J Rheumatol 1984; 11: 262–4. 3 Harris DK, Adams WGF. Acroosteolysis occurring in men engaged in the polymerisation of vinyl chloride. BMJ 1967; 3: 712–24. 4 Yamakage A, Ishikawa H, Saito Y, Hattori A. Occupational scleroderma-like disorders occurring in men engaged in the polymerization of epoxy resins. Dermatologica 1980; 161: 33–44. 5 Yamakage A, Ishikawa H. Generalized morphea-like scleroderma occurring in people exposed to organic solvents. Dermatologica 1982; 165: 186–93. 6 Sparrow GP. A connective tissue disease similar to vinyl chloride disease in a patient exposed to perchlorethylene. Clin Exp Dermatol 1977; 2: 17–22. 7 Flindt-Hansen H, Isager H. Scleroderma after occupational exposure to trichlorethylene and trichlorethane. Acta Derm Venereol (Stockh) 1987; 67: 263–4. 8 Rodnan GP, Benedek TG, Medsger TA Jr, Cammarata RJ. The association of progressive systemic sclerosis (scleroderma) with coalminers’ pneumoconiosis and other forms of silicosis. Ann Intern Med 1967; 66: 323–4. 9 Rustin MHA, Bull HA, Ziegler V et al. Silica-associated systemic sclerosis is clinically, serologically and immunologically indistinguishable from idiopathic systemic sclerosis. Br J Dermatol 1990; 123: 725–34.

Eosinophilia–myalgia syndrome Ingestion of tryptophan, taken as a mild antidepressant, a ‘natural hypnotic’, or by athletes to increase pain tolerance, was associated

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with eosinophilia–myalgia syndrome [1–4], characterized by eosinophilia, myalgia, arthralgia, limb swelling, fever, weakness and fatigue, respiratory complaints, pulmonary hypertension, arrhythmias, ascending polyneuropathy and a variety of cutaneous manifestations. The latter included diffuse morbilliform erythema, urticaria, angio-oedema, dermatographism, livedo reticularis, alopecia and papular mucinosis. Some patients developed chronic muscle weakness, with diffuse scleroderma-like or fasciitis-like skin changes. The eosinophilia–myalgia syndrome is now thought to have been caused by a contaminant of ltryptophan following a change in the manufacturing process between October 1988 and June 1989 [5,6]. References 1 Kaufman LD, Seidman RJ, Phillips ME, Gruber BL. Cutaneous manifestations of the l-tryptophan-associated eosinophilia–myalgia syndrome: a spectrum of sclerodermatous skin disease. J Am Acad Dermatol 1990; 23: 1063–9. 2 Reinauer S, Plewig G. Das Eosinophilie-Myalgie Syndrom. Hautarzt 1991; 42: 137–9. 3 Gordon ML, Lebwohl MG, Phelps RG et al. Eosinophilic fasciitis associated with tryptophan ingestion. A manifestation of eosinophilia–myalgia syndrome. Arch Dermatol 1991; 127: 217–20. 4 Connolly SM, Quimby SR, Griffing WL, Winkelmann RK. Scleroderma and l-tryptophan: a possible explanation of the eosinophilia–myalgia syndrome. J Am Acad Dermatol 1991; 23: 451–7. 5 Slutsker L, Hoesly FC, Miller LM et al. Eosinophilia–myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213–7. 6 Mayeno AN, Lin F, Foote CS et al. Characterization of ‘peak E’, a novel amino acid associated with eosinophilia–myalgia syndrome. Science 1990; 250: 1707–8.

Erythema nodosum [1] Sulphonamides, other antibiotics [2], a variety of analgesics, antipyretics and anti-infectious agents, as well as the contraceptive pill [2–5], oestrogen replacement therapy [6], treatment of haematological disorders with granulocyte colony-stimulating factor [7], all-trans-retinoic acid [8] and Echinacea herbal therapy [9] have all been implicated in the aetiology of erythema nodosum. Erythema nodosum leprosum was induced by prolonged treatment with recombinant IFN-γ (in 60% of patients within 7 months) [10] and by co-trimoxazole [11]. References 1 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 2 Puavilai S, Sakuntabhai A, Sriprachaya-Anunt S et al. Etiology of erythema nodosum. J Med Assoc Thailand 1995; 78: 72–5. 3 Posternal F, Orusco MMM, Laugier P. Eythème noueux et contraceptifs oraux. Bull Dermatol 1974; 81: 642–5. 4 Bombardieri S, Di Munno O, Di Punzio C, Pasero G. Erythema nodosum associated with pregnancy and oral contraceptives. BMJ 1977; i: 1509–10. 5 Muller-Ladner U, Kaufmann R, Adler G, Scherbaum WA. Rezidivierendes Erythema nodosum nach Einnahme eines niedrig dosierten oralen Antikonzeptivums. Med Klin 1994; 89: 100–2. 6 Yang SG, Han KH, Cho KH, Lee AY. Development of erythema nodosum in the course of oestrogen replacement therapy. Br J Dermatol 1997; 137: 319–20. 7 Nomiyama J, Shinohara K, Inoue H. Erythema nodosum caused by the administration of granulocyte colony-stimulating factor in a patient with refractory anemia. Am J Hematol 1994; 47: 333. 8 Hakimian D, Tallman MS, Zugerman C, Caro WA. Erythema nodosum associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Leukemia 1993; 7: 758–9. 9 Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001; 44: 298–9.

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Chapter 75: Drug Reactions

10 Sampaio EP, Moreira AL, Sarno EN et al. Prolonged treatment with recombinant interferon-gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med 1992; 175: 1729–37. 11 Nishioka SA, Goulart IM, Burgarelli MK et al. Necrotizing erythema nodosum leprosum triggered by cotrimoxazole? Int J Lepr Other Mycobact Dis 1994; 62: 296–7.

Pseudolymphomatous drug hypersensitivity syndrome This syndrome should be differentiated from dress (the drug hypersensitivity syndrome, anticonvulsant hypersensitivity syndrome), which has a more acute onset (see pp. 75.26–27). Skin involvement may consist of erythematous plaques, multiple infiltrative papules or solitary nodules; there may be facial oedema. Pseudolymphomatous syndrome develops between 2 weeks and 5 years after starting drug therapy, but usually within 7 weeks. Histopathologically, there is epidermotropism of atypical lymphocytes, often with Pautrier’s microabscess-like structures; pseudolymphomatous syndrome differs from mycosis fungoides in that there may be moderate to marked spongiosis, necrotic keratinocytes, epidermal eosinophils, papillary dermal oedema and extravasated erythrocytes, and a mixed dermal inflammatory infiltrate including neutrophils. Misdiagnosis of pseudolymphomatous syndrome as malignant lymphoma may lead to patients being treated unnecessarily with chemotherapy. A number of drugs may produce a reaction pattern that simulates a lymphoma [1–6]. Phenytoin especially, but also phenobarbital and carbamazepine, mephenytoin, trimethadione and sodium valproate have been implicated [7–12]. Cutaneous lesions in patients with reactions to phenytoin or carbamazepine may show histological features of mycosis fungoides; cutaneous lesions resembling those of mycosis fungoides in the absence of fever have been reported with phenytoin and carbamazepine. Phenobarbital has produced a hypersensitivity syndrome resembling Langerhans’ cell histiocytosis [13]. Other drugs have been associated with mycosis fungoides-like drug eruptions, including allopurinol, antidepressants (e.g. fluoxetine [14,15] and amitriptyline [15]), phenothiazines [16], thioridazine, benzodiazepines, methylphenidate hydrochloride [17], antihistamines [4], β-blockers (e.g. atenolol [18]), ACE inhibitors [19], calcium channel blockers, salazosulfapyridine [20], lipidlowering agents, mexiletine, ciclosporin [21], penicillamine, amiloride hydrochloride with hydrochlorothiazide, bromocriptine [22] and gemcitabine [23]. A generalized cutaneous B-cell pseudolymphoma was induced by neuroleptics [24]. Cutaneous T-cell lymphoma and Sézary syndrome have been reported in association with silicone breast implants [25,26]. Pseudolymphomatous syndrome usually responds to drug withdrawal, although not for many months in some cases [5]. Occasionally, a true lymphoma may develop. References 1 Kardaun SH, Scheffer E, Vermeer BJ. Drug-induced pseudolymphomatous skin reactions. Br J Dermatol 1988; 118: 545–52. 2 Sigal M, Pulik M. Pseudolymphomes medicamenteux a expression cutanée predominante. Ann Dermatol Vénéréol 1993; 120: 175–80. 3 Handfield-Jones SE, Jenkins RE, Whittaker SJ et al. The anticonvulsant hypersensitivity syndrome. Br J Dermatol 1993; 129: 175–7.

4 Magro CM, Crowson AN. Drugs with antihistaminic properties as a cause of atypical cutaneous lymphoid hyperplasia. J Am Acad Dermatol 1995; 32: 419–28. 5 Magro CM, Crowson AN. Drug-induced immune dysregulation as a cause of atypical cutaneous lymphoid infiltrates: a hypothesis. Hum Pathol 1996; 27: 125–32. 6 Choi TS, Doh KS, Kim SH et al. Clinicopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Br J Dermatol 2003; 148: 730–6. 7 Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol 1985; 121: 1181–2. 8 Rijlaarsdam U, Scheffer E, Meijer CJLM et al. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermatol 1991; 24: 216–20. 9 Shuttleworth D, Graham-Brown RAC, Williams AJ et al. Pseudo-lymphoma associated with carbamazepine. Clin Exp Dermatol 1984; 9: 421–3. 10 Welykyj S, Gradini R, Nakao J, Massa M. Carbamazepine-induced eruption histologically mimicking mycosis fungoides. J Cutan Pathol 1990; 17: 111–6. 11 Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol 1998; 38: 806–9. 12 Cogrel O, Beylot-Barry M, Vergier B et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol 2001; 144: 1235–8. 13 Nagata T, Kawamura N, Motoyama T et al. A case of hypersensitivity syndrome resembling Langerhans cell histiocytosis during phenobarbital prophylaxis for convulsion. Jpn J Clin Oncol 1992; 22: 421–7. 14 Gordon KB, Guitart J, Kuzel T et al. Pseudomycosis fungoides in a patient taking clonazepam and fluoxetine. J Am Acad Dermatol 1996; 34: 304–6. 15 Crowson AN, Magro CM. Antidepressant therapy. A possible cause of atypical cutaneous lymphoid hyperplasia. Arch Dermatol 1995; 131: 925–9. 16 Blazejak T, Hölzle E. Phenothiazin-induziertes Pseudolymphom. Hautarzt 1990; 41: 161–3. 17 Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis 2008; 81: 61–4. 18 Henderson CA, Shamy HK. Atenolol-induced pseudolymphoma. Clin Exp Dermatol 1990; 15: 119–20. 19 Furness PN, Goodfield MJ, MacLennan KA et al. Severe cutaneous reactions to captopril and enalapril: histological study and comparison with early mycosis fungoides. J Clin Pathol 1986; 39: 902–7. 20 Gallais V, Grange F, De Bandt M et al. Toxidermie a la salazosulfapyridine. Erythrodermie pustuleuse et syndrome pseudolymphomateux: 2 observations. Ann Dermatol Vénéréol 1994; 121: 11–4. 21 Harman KE, Morris SD, Higgins EM. Persistent anticonvulsant hypersensitivity syndrome responding to ciclosporin. Clin Exp Dermatol 2003; 28: 364–5. 22 Wiesli P, Joos L, Galeazzi RL, Dummer R. Cutaneous pseudolymphoma associated with bromocriptine therapy. Clin Endocrinol 2000; 53: 656–7. 23 Marucci G, Sgarbanti E, Maestri A et al. Gemcitabine-associated CD8+ CD30+ pseudolymphoma. Br J Dermatol 2001; 145: 650–2. 24 Luelmo Aguilar J, Mieras Barcelo C, Martin-Urda MT et al. Generalized cutaneous B-cell pseudolymphoma induced by neuroleptics. Arch Dermatol 1992; 128: 121–3. 25 Duvic M, Moore D, Menter A, Vonderheid EC. Cutaneous T-cell lymphoma in association with silicone breast implants. J Am Acad Dermatol 1995; 32: 939–42. 26 Sena E, Ledo A. Sézary syndrome in association with silicone breast implant. J Am Acad Dermatol 1995; 33: 1060–1.

Acanthosis nigricans-like and ichthyosiform eruptions See Chapter 19.

Erythromelalgia [1] Drugs implicated include iodide contrast media, vaccines (influenza and hepatitis), nifedipine, felodipine, nicardipine, bromocriptine, norephedrine, pergolide and ticlopidine.

Types of clinical reaction Table 75.17 Drugs causing hypertrichosis.

Table 75.16 Drugs causing alopecia. Anticoagulants Coumarins Dextran Heparin Heparinoids Anticonvulsants Carbamazepine Valproic acid Cytotoxic agents Drugs acting on the central nervous system Amitriptyline Doxepin Haloperidol Lithium Hypocholesterolaemic agents Clofibrate Nicotinic acid Triparanol Antithyroid drugs Carbimazole Thiouracils

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Retinoids Acitretin Etretinate Isotretinoin Miscellaneous Albendazole Allopurinol Amfetamine (amphetamine) Antithyroid drugs Bromocriptine Captopril Cholestyramine Cimetidine Dixyrazine Gentamicin Gold Ibuprofen Levodopa Metoprolol Oral contraceptives Propranolol Trimethadione

Reference 1 Cohen JS. Erythromelalgia: new theories and new therapies. J Am Acad Dermatol 2000; 43: 841–7.

Hair changes (see also Chapter 66) Drug-induced alopecia A considerable number of drugs have been reported to cause hair loss [1–5]; the most important causes are listed in Table 75.16. Cytotoxic drugs may cause alopecia by either anagen or telogen effluvium. Chemotherapeutic agents implicated in the production of alopecia include amsacrine, bleomycin, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, doxorubicin, etoposide, fluorouracil, methotrexate and the nitrosoureas [2]. Telogen alopecia has been caused by anticoagulants (heparins and coumarins), antithyroid drugs (carbimazole and thiouracils), levodopa, propranolol, albendazole and oral contraceptives. Retinoids cause alopecia by disrupting keratinization. Hydantoins may cause scalp alopecia and hypertrichosis elsewhere, and clofibrate may cause alopecia by interfering with keratinization. Temporary hair loss has been described after 5-aminosalicylic acid enemas [6] and bromocriptine [7], and danazol has induced generalized alopecia [8]. Certain β-blockers have caused increased hair loss [9–11], as have dixyrazine [12] and ibuprofen [13].

Drug-induced hirsutism and hypertrichosis The hirsutism induced in women by corticosteroids, androgens and certain progestogens is well recognized. Other drugs that may cause hypertrichosis are listed in Table 75.17 [3,4]. Up to 50% of children treated with diazoxide, and up to 40% of patients on ciclosporin, develop hypertrichosis. Zidovudine has caused excessive growth of eyelashes [14].

Androgens Corticosteroids Ciclosporin Diazoxide Minoxidil

Penicillamine Phenytoin Psoralens Streptomycin

References 1 Brodin MB. Drug-related alopecia. Dermatol Clin 1987; 5: 571–9. 2 Kerber BJ, Hood AF. Chemotherapy-induced cutaneous reactions. Semin Dermatol 1989; 8: 173–81. 3 Rook A, Dawber R. Diseases of the Hair and Scalp, 2nd edn. Oxford: Blackwell Scientific Publications, 1990. 4 Merk HF. Drugs affecting hair growth. In: Orfanos CE, Happle R, eds. Hair and Hair Diseases. Berlin: Springer, 1990: 601–9. 5 Pillans PI, Woods DJ. Drug-associated alopecia. Int J Dermatol 1995; 34: 149– 58. 6 Kutty PK, Raman KRK, Hawken K, Barrowman JA. Hair loss and 5-aminosalicylic acid enemas. Ann Intern Med 1982; 97: 785–6. 7 Blum I, Leiba S. Increased hair loss as a side effect of bromocriptine treatment. N Engl J Med 1980; 303: 1418. 8 Duff P, Mayer AR. Generalized alopecia: an unusual complication of danazol therapy. Am J Obstet Gynecol 1981; 141: 349–50. 9 England JR, England JD. Alopecia and propranolol therapy. Aust Fam Physician 1982; 11: 225–6. 10 Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis 1981; 28: 633–4. 11 Fraunfelder FT, Meyer SM, Menacker SJ. Alopecia possibly secondary to topical ophthalmic β-blockers. JAMA 1990; 263: 1493–4. 12 Poulsen J. Hair loss, depigmentation of hair, ichthyosis, and blepharoconjunctivitis produced by dixyrazine. Acta Derm Venereol (Stockh) 1981; 61: 85–8. 13 Meyer HC. Alopecia associated with ibuprofen. JAMA 1979; 242: 142. 14 Klutman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with AIDS being treated with zidovudine. N Engl J Med 1991; 324: 1896.

Drug-induced hair discoloration (see Chapter 66) Drug-induced change in hair colour, usually occurring 3–12 months after the onset of treatment, is a rare but well-recognized phenomenon [1,2]. Darkening of hair has occurred during treatment with verapamil [3], tamoxifen [4], carbidopa [5] and PABA. Etretinate has caused darkening as well as lightening, curling and kinking of hair [6]. Greying of hair has been reported with chloroquine and mephenesin [7]. Chloroquine depigmentation is reversible and occurs only in red- or blonde-haired individuals; both IFN-α [8] and chloroquine are capable of arresting phaeomelanin synthesis. References 1 Rook A. Some chemical influences on hair growth and pigmentation. Br J Dermatol 1965; 77: 115–29. 2 Bublin JG, Thompson DF. Drug-induced hair colour changes. Clin Pharmacol Ther 1992; 17: 297–302. 3 Read GM. Verapamil and hair colour change. Lancet 1991; 338: 1520. 4 Hampson JP, Donnelly A, Lewisones MS, Pye JK. Tamoxifen induced hair colour change. Br J Dermatol 1995; 132: 483–4. 5 Reynolds NJ, Crossley J, Ferguson I, Peachey RDG. Darkening of white hair in Parkinson’s disease. Clin Exp Dermatol 1989; 14: 317–8. 6 Vesper JL, Fenske A. Hair darkening and new growth associated with etretinate therapy. J Am Acad Dermatol 1996; 34: 860. 7 Spillane JD. Brunette to blonde. Depigmentation of hair during treatment with oral mephenesin. BMJ 1963; i: 997–8. 8 Fleming CJ, MacKie RM. Alpha interferon-induced hair discolouration. Br J Dermatol 1996; 135: 337–8.

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Chapter 75: Drug Reactions

Table 75.18 Drugs causing onycholysis. Antibiotics Cefaloridine (cephaloridine) Chloramphenicol Chlortetracycline Cloxacillin Demethylchlortetracycline Doxycycline Fluoroquinolones Minocycline Tetracycline hydrochloride Chemotherapeutic agents Adriamycin Bleomycin 5-Fluorouracil Mitoxantrone

Table 75.19 Drugs associated with xerostomia. Miscellaneous Acridine Captopril Norethindrone and mestranol Phenothiazines Practolol (discontinued) Psoralens Retinoids Sulpha-related drugs Thiazides Photo-onycholysis Fluoroquinolones Oral contraceptives Psoralens Tetracyclines

Nail changes Drug-induced nail abnormalities have been the subject of several reviews [1–7] (see Chapter 65). Heavy metals may induce the following changes: arsenic causes transverse, broad, white lines (Mee’s lines); silver causes blue discoloration of the lunulae; gold results in thin and brittle nails with longitudinal streaking, yellowbrown discoloration and onycholysis; and lead produces partial leukonychia. Penicillamine therapy is associated with the yellow nail syndrome and nail dystrophy. Cytotoxic agents may produce transverse or longitudinal pigmentation, splinter haemorrhages, Beau’s lines, leukonychia, Mee’s lines, onycholysis, shortening of lunulae, pallor, atrophy, nail shedding and slow growth; acute paronychia has occurred with methotrexate. The β-blockers may induce a psoriasiform nail dystrophy, with onycholysis and subungual hyperkeratosis. Thiazide diuretics may result in onycholysis. Discoloration or pigmentation occurs with antimalarials (blue-brown discoloration), lithium (golden discoloration), phenolphthalein (dark-blue discoloration), phenothiazines (blue-black or purple pigmentation), phenytoin (pigmentation), psoralens and tetracyclines (yellow pigmentation). Oral contraceptives may induce photo-onycholysis and onycholysis, and are associated with an increased growth rate and reduced splitting and fragility. In contrast, heparin reduces nail growth and causes transverse banding and subungual haematomas. Retinoids cause thinning and increased fragility, onychoschizia, onycholysis, temporary nail shedding, onychomadesis, ingrowing nails, periungual granulation tissue and paronychia.

Onycholysis Drugs causing onycholysis [6,7] and photo-onycholysis are listed in Table 75.18. References 1 Daniel CR III, Scher RK. Nail changes secondary to systemic drugs or ingestants. J Am Acad Dermatol 1984; 10: 250–8. 2 Fenton DA. Nail changes due to drugs. In: Samman PD, Fenton DA, eds. The Nails in Disease, 4th edn. London: Heinemann, 1986: 121–5. 3 Fenton DA, Wilkinson JD. The nail in systemic diseases and drug-induced changes. In: Baran R, Dawber RPR, eds. Diseases of the Nails and Their Management. Oxford: Blackwell Scientific Publications, 1984: 205–65.

Antidepressants (tricyclic) Amitriptyline Doxepin Imipramine Antidepressants (monoamine oxidase inhibitors) Isocarboxazid Phenelzine Psychotropic agents Chlorpromazine Haloperidol Prochlorperazine Thioridazine

Minor tranquillizers Chlordiazepoxide Diazepam Hydroxyzine Antiparkinsonian drugs Antihypertensives (ganglion blockers) Gastrointestinal antispasmodics Atropine Phenobarbital (phenobarbitone) Propantheline bromide

4 Daniel CR III, Scher RK. Nail changes secondary to systemic drugs or ingestants. In: Scher RK, Daniel CR III, eds. Nails: Therapy, Diagnosis, Surgery. Philadelphia: Saunders, 1990: 192–201. 5 Zaias N. The Nail in Health and Disease, 2nd edn. East Norwalk, CT: Appleton Lange, 1990. 6 Baran R, Juhlin L. Drug-induced photo-onycholysis. Three subtypes identified in a study of 15 cases. J Am Acad Dermatol 1987; 17: 1012–6. 7 Daniel CR. Onycholysis: an overview. Semin Dermatol 1991; 10: 34–40.

Oral conditions (see also Chapter 69) ADRs affecting the mouth have been extensively reviewed [1–6]. Disturbance of taste has been reported with a wide variety of drugs [3,4], including captopril, griseofulvin, metronidazole and protease inhibitor antiretrovirals. Orofacial effects of antiretroviral therapies have been reviewed [4]. These include mouth ulcers due to bone marrow suppression, erythema multiforme (e.g. with didanosine), lichenoid reactions with zidovudine, xerostomia (seen in up to one-third of patients taking didanosine), oral and perioral paraesthesiae (especially with ritonavir), and cheilitis with indinavir.

Xerostomia Dryness of the mouth (xerostomia) may result from anticholinergic side effects of drugs. Xerostomia has been recorded in association with antidepressants, tranquillizers, antiparkinsonian drugs, antihypertensives and gastrointestinal antispasmodics (Table 75.19). Parotitis with salivary sialadenitis has been reported in up to 15% of patients taking phenylbutazone, and may be associated with fever and a rash [7]. A similar syndrome may occur with repeated administration of iodinated contrast media [8] and with nitrofurantoin [9]. References 1 Porter SR, Scully C. Adverse drug reactions in the mouth. Clin Dermatol 2000; 18: 525–32. 2 Torpet LA, Kragelund C, Reibel J, Nauntofte B. Oral adverse drug reactions to cardiovascular drugs. Crit Rev Oral Biol Med 2004; 15: 28–46. 3 Griffin JP. Drug-induced disorders of taste. Adverse Drug React Toxicol Rev 1992; 11: 229–39. 4 Scully C, Diz Dios P. Orofacial effects of antiretroviral therapies. Oral Dis 2001; 7: 205–10. 5 Abdollahi M, Rahimi R, Radfar M. Current opinion on drug-induced oral reactions: a comprehensive review. J Contemp Dent Pract 2008; 9: 1–15. 6 Femiano F, Lanza A, Buonaiuto C et al. Oral manifestations of adverse drug reactions: guidelines. J Eur Acad Dermatol Venereol 2008; 22: 681–91.

Important or widely prescribed drugs Table 75.20 Drugs causing stomatitis or buccal ulceration. Chemotherapeutic agents Antirheumatic drugs Gold Indometacin (indomethacin) Naproxen Penicillamine Zomepirac Antidepressants Amitriptyline Doxepin Imipramine

Antihypertensive agents Captopril Hydralazine Methyldopa (rare) Miscellaneous Chlorpromazine Valproic acid

7 Speed BR, Spelman DW. Sialadenitis and systemic reactions associated with phenylbutazone. Aust NZ J Med 1982; 12: 261–4. 8 Chohen JC, Roxe DM, Said R et al. Iodide mumps after repeated exposure to iodinated contrast media. Lancet 1980; i: 762–3. 9 Meyboom RH, van Gent A, Zinkstok DJ. Nitrofurantoin-induced parotitis. BMJ 1982; 285: 1049.

Stomatitis Type I immediate hypersensitivity and type IV delayed hypersensitivity reactions may be involved in allergic stomatitis [1]. The allergic stomatitides may present with clinical appearances that mimic classic oral vesiculobullous and ulcerative lesions. Stomatitis may form a part of drug-induced lichenoid reactions, fixed drug reactions or erythema multiforme, but may also arise separately from these conditions as a side effect of a number of drugs (Table 75.20). Chemotherapeutic agents causing stomatitis or buccal ulceration include [2] actinomycin D, adriamycin, amsacrine, bleomycin, busulfan, chlorambucil, cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, fluorouracil, IL-2, mercaptopurine, methotrexate, mithramycin, mitomycin, nitrosoureas, procarbazine and vincristine. Penicillamine may induce stomatitis or ulceration as part of drug-induced pemphigus [3] or a lichenoid drug eruption. Gold therapy is another well-recognized cause of stomatitis [4–6]. Allergic reactions to dental materials and therapy may cause stomatitis. Positive patch tests to mercuric chloride were seen in 42%, and to copper sulphate in 16%, of patients with oral mucosal lesions associated with amalgam restorations, compared with 9% of controls, in one series [7]. It has been postulated that mercury released from dental amalgams can cause hypersensitivity/ toxic reactions resulting in lichen planus lesions, and may play a major role in the pathogenesis of gingivitis, periodontitis and periodontal disease [8]. Mercuric chloride caused statistically significant increased IFN-γ release, but not proliferation, in lymphocyte cultures from patients with hypersensitivity to amalgam restorations [9]. β-Blockers have been implicated in aphthous ulcers [10]. References 1 Jainkittivong A, Langlais RP. Allergic stomatitis. Semin Dermatol 1994; 13: 91–101. 2 Kerker BJ, Hood AF. Chemotherapy-induced cutaneous reactions. Semin Dermatol 1989; 8: 173–81. 3 Hay KD, Muller HK, Rade PC. d-Penicillamine-induced mucocutaneous lesions with features of pemphigus. Oral Surg 1978; 45: 385–95.

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4 Glenert U. Drug stomatitis due to gold therapy. Oral Surg 1984; 58: 52–6. 5 Gall H. Allergien auf zahnärztliche Werkstoffe und Dentalpharmaka. Hautarzt 1983; 34: 326–31. 6 Wiesenfeld D, Ferguson MM, Forsyth A et al. Allergy to dental gold. Oral Surg 1984; 57: 158–60. 7 Nordlind K, Liden S. Patch test reactions to metal salts in patients with oral mucosal lesions associated with amalgam restorations. Contact Dermatitis 1992; 27: 157–60. 8 Swartzendruber DE. The possible relationship between mercury from dental amalgam and diseases. I. Effects within the oral cavity. Med Hypotheses 1993; 41: 31–4. 9 Nordlind K, Liden S. In vitro lymphocyte reactivity to heavy metal salts in the diagnosis of oral mucosal hypersensitivity to amalgam restorations. Br J Dermatol 1993; 128: 38–41. 10 Boulinguez S, Reix S, Bedane C et al. Role of drug exposure in aphthous ulcers: a case–control study. Br J Dermatol 2000; 143: 1261–5.

Hyperpigmentation Hyperpigmentation of the buccal mucosa may occur with chemotherapeutic agents [1]. Oestrogen is associated with gingival hypermelanosis [2]. Amalgam tattoos with localized hyperpigmentation of the buccal mucosa result from implantation of amalgam in soft tissues, especially of the gingival or alveolar mucosa [3].

Reactions caused by antibacterial, antifungal and immunosuppressive therapy Systemic antibiotics or immunosuppressive medication [4], and corticosteroids administered by aerosol [5], may lead to the development of candidiasis of the buccal mucosa. Black hairy tongue may be associated with broad-spectrum antibiotic therapy and with griseofulvin treatment.

Gingival hyperplasia Gingival hyperplasia may be caused by phenytoin [6], nifedipine [7], diltiazem [8], felodipine, verapamil and ciclosporin [9]. References 1 Krutchik AN, Buzdar AU. Pigmentation of the tongue and mucous membranes associated with cancer chemotherapy. South Med J 1979; 72: 1615–6. 2 Hertz RS, Beckstead PC, Brown WJ. Epithelial melanosis of the gingiva possibly resulting from the use of oral contraceptives. J Am Dent Assoc 1980; 100: 713–4. 3 Buchner A, Hansen LS. Amalgam pigmentation (amalgam tattoo) of the oral mucosa: a clinicopathologic study of 268 cases. Oral Surg 1980; 49: 139–47. 4 Torack RM. Fungus infections associated with antibiotic and steroid therapy. Am J Med 1957; 22: 872–82. 5 Chervinsky P, Petraco AJ. Incidence of oral candidiasis during therapy with triamcinolone acetonide aerosol. Ann Allergy 1979; 43: 80–3. 6 Hassell TM, Page RC, Narayanan AS, Cooper CG. Diphenylhydantoin (Dilantin) gingival hyperplasia: drug induced abnormality of connective tissue. Proc Natl Acad Sci USA 1976; 73: 2909–12. 7 Benini PL, Crosti C, Sala F et al. Gingival hyperplasia by nifedipine. Report of a case. Acta Derm Venereol (Stockh) 1985; 65: 362–5. 8 Giustiniani S, Robustelli della Cuna F, Marieni M. Hyperplastic gingivitis during diltiazem therapy. Int J Cardiol 1987; 15: 247–9. 9 Frosch PJ, Ruder H, Stiefel A et al. Gingivahyperplasie und Seropapeln unter Cyclosporinbehandlung. Hautarzt 1988; 39: 611–6.

Important or widely prescribed drugs Antibacterial agents Antibiotic-induced drug reactions have been reviewed [1–4].

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References 1 Eschenauer GA, Regal RE, DePestel DD. Antibiotic allergy. N Engl J Med 2006; 354: 2293–4. 2 Iannini P, Mandell L, Felmingham J et al. Adverse cutaneous reactions and drugs: a focus on antimicrobials. J Chemother 2006; 18: 127–39. 3 Miller DD, Warshaw EM. Adverse cutaneous reactions to antimicrobials in patients with human immunodeficiency virus infection. Dermatitis 2007; 18: 8–25. 4 Baldo BA, Zhao Z, Pham NH. Antibiotic allergy: immunochemical and clinical considerations. Curr Allergy Asthma Rep 2008; 8: 49–55.

Beta-lactam antibiotics Inaccurate histories of allergy to antibiotics are frequently documented in medical records by hospital doctors [1]. Reactions to beta-lactam antibiotics may be immediate, accelerated or delayed [2–7]. Of 210 patients with a proven hypersensitivity reaction, 36.7% had urticaria occurring at any time as a single symptom; anaphylaxis without or with shock occurred in 19.1% and 17.6% respectively within 1 h after drug administration, and 19.1% had a maculopapular exanthem occurring after 24 h [6]. Nonimmediate reactions to beta-lactams include several clinical entities, from maculopapular rash to severe reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis [7]. Non-immediate reactions to penicillins are a reproducible phenomenon, suggesting that a specific mechanism is responsible [8]. In one study, 39% of 74 subjects with a cutaneous reaction to a penicillin derivative had a non-immediate reaction, in 93% to an aminopenicillin (10.3% ampicillin, 82.7% amoxicillin). There was a positive delayed direct challenge and a delayed skin-test response in 65% of cases, and a lymphomonocytic infiltrate on skin biopsy [8]. Cross-reactivity exists between several members of this group of antibiotics, but restricted sensitivity to a single penicillin derivative also occurs [9]. As a group, penicillins had a higher frequency of allergic reactions than cephalosporins in a study of patients with cystic fibrosis treated with parenteral beta-lactam antibiotics [10]. Serum sickness reactions occur [11]. (See also acute generalized exanthematous pustulosis (AGEP), p. 75.34.) References 1 Absy M, Glatt AE. Antibiotic allergy: inaccurate history taking in a teaching hospital. South Med J 1994; 87: 805–7. 2 Vega JM, Blanca M, Garcia JJ et al. Immediate allergic reactions to amoxicillin. Allergy 1994; 49: 317–22. 3 Warrington RJ, Silviu-Dan F, Magro C. Accelerated cell-mediated immune reactions in penicillin allergy. J Allergy Clin Immunol 1993; 92: 626–8. 4 Ortiz-Frutos FJ, Quintana I, Soto T et al. Delayed hypersensitivity to penicillin. Allergy 1996; 51: 134–5. 5 Lopez Serrano C, Villas F, Cabanas R, Contreras J. Delayed hypersensitivity to beta-lactams. J Invest Allergol Clin Immunol 1994; 4: 315–9. 6 Bousquet PJ, Kvedariene V, Co-Minh HB et al. Clinical presentation and time course in hypersensitivity reactions to beta-lactams. Allergy 2007; 62: 872–6. 7 Lopez S, Blanca-Lopez N, Cornejo-Garcia JA et al. Nonimmediate reactions to betalactams. Curr Opin Allergy Clin Immunol 2007; 7: 310–6. 8 Terrados S, Blanca M, Garcia J et al. Nonimmediate reactions to betalactams: prevalence and role of the different penicillins. Allergy 1995; 50: 563–7. 9 Blanca M, Vega JM, Garcia J et al. New aspects of allergic reactions to betalactams: crossreactions and unique specificities. Clin Exp Allergy 1994; 24: 407–15. 10 Pleasants RA, Walker TR, Samuelson WM. Allergic reactions to parenteral betalactam antibiotics in patients with cystic fibrosis. Chest 1994; 106: 1124–8. 11 Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral penicillin drugs: three case reports. Ann Allergy Asthma Immunol 2001; 86: 330–4.

Penicillin Toxic reactions to penicillin are extremely rare and usually only follow massive doses, but can occur with normal doses in patients with renal impairment; encephalopathy with epilepsy may result from binding of the beta-lactam ring to γ-aminobutyric acid receptors [1]. In contrast, immunological reactions are common [2–4]; allergy to penicillin has been reported in up to 10% of patients treated [5]. All forms of penicillin, including the semi-synthetic penicillins, are potentially cross-allergenic; in general, allergic reactions to semi-synthetic compounds are commoner than to natural penicillins. All four types of immunological reaction may occur: urticaria and anaphylactic shock (type I), haemolytic anaemia or agranulocytosis (type II), allergic vasculitis or serum sickness-like reaction (type III) and allergic contact dermatitis [6] (type IV). Immediate reactions occur within 1 h, and take the form of urticaria, laryngeal oedema, bronchospasm and/or anaphylactic shock. So-called accelerated reactions with the same clinical features develop 1–72 h later. Reactions occurring more than 72 h after exposure are termed late reactions; these include maculopapular rashes with scarlatiniform and morbilliform exanthems, urticaria, serum sickness, erythema multiforme, haemolytic anaemia, thrombocytopenia and neutropenia. Fever is the commonest reaction. The antigenic structures responsible for penicillin allergy include a ‘major determinant’, the penicilloyl group formed by spontaneous hydrolysis of penicillin (penicilloyl polylysine is used for skin testing), and additional antigenic compounds to which benzylpenicillin is metabolized, termed ‘minor determinants’ [3]. Most immediate-type anaphylactic hypersensitivity reactions are mediated by IgE antibodies to minor antigenic determinants, whereas accelerated reactions are usually the result of IgE antibodies directed against the major antigenic determinant [3,7]. For information on skin testing for penicillin, see the diagnosis section at the end of the chapter (p. 75.170). Anaphylactic reactions to penicillin reportedly occur in about 0.015% of treatment courses; fatal reactions occur in 0.0015–0.002% (i.e. 1 in 50 000 to 1 in 100 000) of treatment courses [8]. Young and middle-aged adults aged 20–49 years are at most risk [9]. Atopy does not augment the risk of a reaction to beta-lactam antibiotics, but may increase the risk of any reaction being severe [3]. Anaphylaxis is commoner after parenteral administration, and is very rare, but has been recorded, after oral ingestion [9]. Maculopapular reactions occur in about 2% of treatment courses [3]; where there is a history of a prior penicillin reaction, the risk of a subsequent reaction increases to about 10% [10]. A fair proportion (33% in one study) of children may lose their skin-test reactivity within a year [11]. In practice, when penicillin is given to children said to be allergic to penicillin, very few experience an adverse reaction [7]. In adults, the rate of disappearance of penicillinspecific IgE is highly variable, from 10 days to indefinite persistence [3]. For a group of penicillin-allergic patients, the time lapsed since a previous reaction is inversely related to the risk of a further IgE-mediated reaction [10]. In one study, 80–90% of patients were skin-test positive 2 months after an acute allergic reaction, but less than 20% were skin-test positive 10 years later [12]. Nevertheless, patients with a prior history of an IgE-dependent reaction remain at risk of recurrence, even though IgE antibodies

Important or widely prescribed drugs

become undetectable by skin testing [13]. Most serious and fatal allergic reactions to beta-lactam antibiotics occur in individuals who have never had a prior allergic reaction; a negative history should therefore not induce a false sense of security [3]. Continuous prophylactic treatment is associated with a very low incidence of reactions [14]. Activation of allergy in a sensitized individual may require only minute amounts of the drug, as from contaminated syringes, dental root-canal fillings, viral vaccines, contaminated milk or meat products, and contamination of transfused blood [15]. Urticaria and wheezing occurred in the penicillin-sensitive spouse of a man receiving parenteral mezlocillin, and was postulated to have arisen as a result of seminal fluid transmission of penicillin [16]. Hypersensitivity reactions have occurred after intrauterine placement, in penicillin-sensitive patients, of spermatozoa or embryos exposed to penicillin in vitro [17]. Penicillin has been reported to cause erythema multiforme [18], vesicular and bullous eruptions, exfoliative dermatitis [19], vascular purpura or fixed eruptions, serum sickness [20], post-inflammatory elastolysis (cutis laxa), which was generalized and eventually fatal in one case [21], and a very few cases of pemphigus vulgaris [22,23], pemphigoid [24] and pustular psoriasis [25]. It has been proposed that penicillin may have a role in chronic ‘idiopathic’ urticaria [26].

Cloxacillin and flucloxacillin Cloxacillins cross-react with penicillins, but unlike ampicillin do not produce distinctive eruptions. Flucloxacillin rarely elicits primary penicillin hypersensitivity. In one case report, parenteral cloxacillin was tolerated but oral administration caused progressive generalized erythema with pruritus, facial angio-oedema and tachycardia [27]. Flucloxacillin has been implicated as a cause of cholestatic jaundice; this complication is rare, and the risk is greater in elderly patients and those receiving therapy for more than 2 weeks [28]. References 1 Barrons RW, Murray KM, Richey RM. Populations at risk for penicillin-induced seizures. Ann Pharmacother 1992; 26: 26–9. 2 Erffmeyer JE. Penicillin allergy. Clin Rev Allergy 1986; 4: 171–88. 3 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 4 Weber EA, Knight A. Testing for allergy to antibiotics. Semin Dermatol 1989; 8: 204–12. 5 Van Arsdael PP. The risk of penicillin reactions. Ann Intern Med 1968; 69: 1071. 6 Stejskal VDM, Forsbeck M, Olin R. Side chain-specific lymphocyte responses in workers with occupational allergy induced by penicillins. Int Arch Allergy Appl Immunol 1987; 82: 461–4. 7 Anonymous. Penicillin allergy in childhood. Lancet 1989; i: 420. 8 Idsøe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin side reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968; 38: 159–88. 9 Simmonds J, Hodges S, Nicol F, Barnett D. Anaphylaxis after oral penicillin. BMJ 1978; ii: 1404. 10 Sogn DD. Penicillin allergy. J Allergy Clin Immunol 1984; 74: 589–93. 11 Chandra RK, Joglekar SA, Tomas E. Penicillin allergy: anti-penicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin. Arch Dis Child 1980; 55: 857–60. 12 Sullivan TJ, Wedner JH, Shatz GS et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol 1981; 68: 171–80.

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13 Adkinson NF Jr. Risk factors for drug allergy. J Allergy Clin Immunol 1984; 74: 567–72. 14 Wood HF, Simpson R, Feinstein AR et al. Rheumatic fever in children and adolescents. A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. I. Description of the investigative techniques and the population studied. Ann Intern Med 1964; 60 (Suppl. 5): 6–17. 15 Michel J, Sharon R. Non-haemolytic adverse reaction after transfusion of a blood unit containing penicillin. BMJ 1980; i: 152–3. 16 Burks JH, Fliegalman R, Sokalski SJ. An unforeseen complication of home parenteral antibiotic therapy. Arch Intern Med 1989; 149: 1603–4. 17 Smith YR, Hurd WW, Menge AC et al. Allergic reactions to penicillin during in vitro fertilization and intrauterine insemination. Fertil Steril 1992; 58: 847–9. 18 Staretz LR, Deboom GW. Multiple oral and skin lesions occurring after treatment with penicillin. J Am Dent Assoc 1990; 121: 436–7. 19 Levine BB. Skin rashes with penicillin therapy: current management. N Engl J Med 1972; 286: 42–3. 20 Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy 2006; 26: 705–8. 21 Kerl H, Burg G, Hashimoto K. Fatal, penicillin-induced, generalized, postinflammatory elastolysis (cutis laxa). Am J Dermatopathol 1983; 5: 267–76. 22 Duhra PL, Foulds IS. Penicillin-induced pemphigus vulgaris. Br J Dermatol 1988; 118: 307. 23 Fellner MJ, Mark AS. Penicillin- and ampicillin-induced pemphigus vulgaris. Int J Dermatol 1980; 19: 392–3. 24 Alcalay J, David M, Ingber A et al. Bullous pemphigoid mimicking bullous erythema multiforme: an untoward side effect of penicillins. J Am Acad Dermatol 1988; 18: 345–9. 25 Katz M, Seidenbaum M, Weinrauch L. Penicillin-induced generalized pustular psoriasis. J Am Acad Dermatol 1988; 17: 918–20. 26 Boonk WJ, Van Ketel WG. The role of penicillin in the pathogenesis of chronic urticaria. Br J Dermatol 1982; 106: 183–90. 27 Torres MJ, Blanca M, Fernandez J et al. Selective allergic reaction to oral cloxacillin. Clin Exp Allergy 1996; 26: 108–11. 28 Fairley CK, McNeil JJ, Desmond P et al. Risk factors for development of flucloxacillin-associated jaundice. BMJ 1993; 306: 233–5.

Ampicillin A morbilliform rash, with onset on the extremities and becoming generalized, occurs in 5–10% of patients treated with ampicillin, and usually develops 7–12 days after onset of therapy. This time interval suggests an allergic mechanism, although the rash disappears spontaneously even if ampicillin is continued, and may not develop on re-exposure [1]. Skin tests are generally negative. An urticarial reaction, present in about 1.5% of patients, indicates the presence of type I IgE-mediated general penicillin allergy [2,3]. Administration of ampicillin when a patient has infectious mononucleosis leads to florid morbilliform and sometimes purpuric eruptions in up to 100% of patients [4–6]. Cutaneous reactions to ampicillin are increased in cytomegalovirus infection [7], chronic lymphatic leukaemia [8], renal insufficiency or when allopurinol is administered concomitantly [9]. Ampicillin has been reported to cause a fixed drug eruption [10], erythema multiforme and Stevens–Johnson syndrome [11,12], TEN [13], Henoch–Schönlein purpura [14], serum sickness [15] and pemphigus vulgaris [16] in individual cases. Administration of ampicillin to a patient with a history of psoriasis resulted in erythroderma on two separate occasions [17]. A recurrent, localized, pustular skin eruption developed on the cheeks with ampicillin in one case [18]. Delayed intradermal skin tests and patch tests, indicating delayed hypersensitivity, were positive in about half of 60 subjects with maculopapular reactions to the aminopenicillins ampicillin and amoxicillin [19]; in another study, hypersensitivity to an

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Chapter 75: Drug Reactions

antigenic determinant in the side-chain structure was suggested, as intradermal and patch tests were positive to ampicillin but there was good tolerance to benzylpenicillin [20]. Re-exposure of patients to ampicillins and other penicillins is contraindicated after urticarial reactions; anaphylactic reactions to ampicillin have been recorded. The risk is far less after morbilliform rashes but is not negligible. References 1 Adcock BB, Rodman DP. Ampicillin-specific rashes. Arch Fam Med 1996; 5: 301–4. 2 Bass JW, Crowley DM, Steele RW et al. Adverse effects of orally administered ampicillin. J Pediatr 1973; 83: 106–8. 3 Anonymous. Ampicillin rashes. BMJ 1975; ii: 708–9. 4 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 5 Pullen H, Wright N, Murdoch JMcC. Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis. Lancet 1967; ii: 1176–8. 6 Renn CN, Straff W, Dorfmüller A et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol 2003; 147: 1166–7. 7 Klemola E. Hypersensitivity reactions to ampicillin in cytomegalovirus mononucleosis. Scand J Infect Dis 1970; 2: 29. 8 Cameron SJ, Richmond J. Ampicillin hypersensitivity in lymphatic leukaemia. Scott Med J 1972; 16: 425–7. 9 Jick H, Slone D, Shapiro S et al. Excess of ampicillin rashes associated with allopurinol or hyperuricemia. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N Engl J Med 1972; 286: 505–7. 10 Arndt KA, Parrish J. Ampicillin rashes. Arch Dermatol 1973; 107: 74. 11 Gupta HL, Dheman R. Ampicillin-induced Stevens–Johnson syndrome. J Indian Med Assoc 1979; 72: 188–9. 12 Garty BZ, Offer I, Livni E, Danon YL. Erythema multiforme and hypersensitivity myocarditis caused by ampicillin. Ann Pharmacother 1994; 28: 730–1. 13 Tagami H, Tatsuta K, Iwatski K, Yamada M. Delayed hypersensitivity in ampicillin-induced toxic epidermal necrolysis. Arch Dermatol 1983; 119: 910–3. 14 Beeching NJ, Gruer LD, Findlay CD, Geddes AM. A case of Henoch–Schönlein purpura syndrome following oral ampicillin. J Antimicrob Chemother 1982; 10: 479–82. 15 Caldwell JR, Cliff LE. Adverse reactions to antimicrobial agents. JAMA 1974; 230: 77–80. 16 Fellner MJ, Mark AS. Penicillin- and ampicillin-induced pemphigus vulgaris. Int J Dermatol 1980; 19: 392–3. 17 Saito S, Ikezawa Z. Psoriasiform intradermal test reaction to ABPC in a patient with psoriasis and ABPC allergy. J Dermatol 1990; 17: 677–83. 18 Lim JT, Ng SK. An unusual drug eruption to ampicillin. Cutis 1995; 56: 163–4. 19 Romano A, Di Fonso M, Papa G et al. Evaluation of adverse cutaneous reactions to aminopenicillins with emphasis on those manifested by maculopapular rashes. Allergy 1995; 50: 113–8. 20 Lopez Serrano C, Villas F, Cabanas R, Contreras J. Delayed hypersensitivity to beta-lactams. J Invest Allergol Clin Immunol 1994; 4: 315–9.

Amoxicillin Cutaneous eruptions including urticaria, morbilliform or maculopapular rashes occur in 1–2% of treatment courses with amoxicillin [1–3]. Immediate allergy (anaphylaxis or urticaria/ angio-oedema) to amoxicillin has occurred in patients with good tolerance of benzylpenicillin, aztreonam and ceftazidime [4,5]. However, amoxicillin has been reported to cross-react with penicillin on first exposure [6]. Amoxicillin caused an unusual intertriginous eruption in two patients [7]. Serum sickness has been reported with amoxicillin in children [8]. Amoxicillin has caused a fixed eruption [9], and a curious, recurrent, localized, pustular eruption [10]. This drug has also been implicated in the develop-

ment of an acute generalized exanthematous pustulosis [11]. There may be an increased frequency of rash with amoxicillin and clavulanate therapy in HIV-positive patients [12]. Amoxicillin, like clavulanic acid and flucloxacillin, may cause a cholestatic hepatitis [13]. This occurs at a frequency of 1 in 6000 adults when the drug is combined with clavulanic acid (co-amoxiclav) [14]. Amoxicillin has also been implicated in the baboon syndrome [15], palmar exfoliative exanthem [16] and localized peri-buccal pustulosis [17].

Methicillin Methicillin caused reappearance of a recently faded ampicillin rash in a patient with glandular fever [18]. References 1 Wise PJ, Neu HC. Experience with amoxicillin: an overall summary of clinical trials in the United States. J Infect Dis 1974; 129 (Suppl.): S266–S267. 2 Levine LR. Quantitative comparison of adverse reactions to cefaclor versus amoxicillin in a surveillance study. Pediatr Infect Dis 1985; 4: 358–61. 3 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63. 4 Vega JM, Blanca M, Garcia JJ et al. Immediate allergic reactions to amoxicillin. Allergy 1994; 49: 317–22. 5 Martin JA, Igea JM, Fraj J et al. Allergy to amoxicillin in patients who tolerated benzylpenicillin, aztreonam, and ceftazidime. Clin Infect Dis 1992; 14: 592–3. 6 Fellner MJ. Amoxicillin cross reacts with penicillin on first exposure. Int J Dermatol 1993; 32: 308–9. 7 Wolf R, Brenner S, Krakowski A. Intertriginous drug eruption. Acta Derm Venereol (Stockh) 1992; 72: 441–2. 8 Chopra R, Roberts J, Warrington RJ. Severe delayed-onset hypersensitivity reactions to amoxicillin in children. Can Med Assoc J 1989; 140: 921–3. 9 Chowdhury FH. Fixed genital drug eruption. Pract Med 1982; 226: 1450. 10 Shuttleworth D. A localized, recurrent pustular eruption following amoxycillin administration. Clin Exp Dermatol 1989; 14: 367–8. 11 Roujeau J-C, Bioulac-Sage P, Bourseau C et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991; 127: 1333–8. 12 Battegay M, Opravil M, Wütrich B, Lüthy R. Rash with amoxycillin–clavulanate therapy in HIV-infected patients. Lancet 1989; ii: 1100. 13 Anonymous. Drug-induced cholestatic hepatitis from common antibiotics. Med J Aust 1992; 157: 531. 14 Anonymous. Revised indications for co-amoxiclav (Augmentin). Curr Prob Pharmacovig 1997; 23: 8. 15 Kick G, Przybilla B. Delayed prick test reaction identifies amoxicillin as elicitor of baboon syndrome. Contact Dermatitis 2000; 43: 366–7. 16 Gastaminza G, Audicana MT, Fernandez E et al. Palmar exfoliative exanthema to amoxicillin. Allergy 2000; 55: 510–1. 17 Novalbos A, Bombin C, Figueredo E et al. Localized pustulosis induced by betalactams. J Invest Allergol Clin Immunol 2000; 10: 178–9. 18 Fields DA. Methicillin rash in infectious mononucleosis. West J Med 1981; 133: 521.

Cephalosporins [1] In general, cephalosporins are fairly well tolerated [1–3], adverse reactions ranging from 1 to 10% [1]; parenteral administration may cause minor adverse reactions, including thrombophlebitis and pain. The most common adverse effects are allergic reactions, occurring in 1–3% of patients [2]; haematological toxicity occurs in less than 1% of patients. Anaphylaxis is rare (less than 0.02%) [1]. Other reactions include localized gastrointestinal disturbances, hepatotoxicity, nephrotoxicity and mild central nervous system effects. The incidence of cephalosporin reactions in patients with histories of penicillin allergy has been reported as minimally, if at

Important or widely prescribed drugs

all, increased [1]. Post-marketing studies of second- and thirdgeneration cephalosporins showed no increase in allergic reactions in patients with a history of penicillin allergy. Cephalosporin antibiotics have been judged safe in penicillin-allergic patients and penicillin skin tests do not identify potential reactors [1]. In contrast with this, a more recent study reported a markedly increased risk of events after subsequent cephalosporins [4]. However, the risk of anaphylaxis was very low [4]. The R1 side chain, rather than the beta-lactam structure shared by penicillins and cephalosporins, seems to play a dominant role in determining the specificity of immunological reactions to cephalosporins [5]. Thus, penicillin can be administered safely to patients allergic to cephalosporins, with a negative skin test to penicillin determinants. Conversely, a negative result in skin testing to penicillin and cephalosporins with different side chains seems to be a good predictor of tolerance to a cephalosporin [6]. Isolated independent hypersensitivity to individual cephalosporins, such as cefazolin [7,8], cefonicid [9] and cefuroxime [10], with good tolerance to other beta-lactam antibiotics, has been described. Hypersensitivity reactions include various exanthems and contact urticaria [11]; cases of anaphylaxis to cefaclor [12] and of fatal anaphylactic shock related to cefalotin (cephalothin) [13] have been reported. Vulvovaginitis and pruritus ani are not uncommon. Delayed reactions have been reported with cefonicid [9] and cefuroxime [14]. Serum sickness reactions occur [15–18], especially with cefaclor; the last-mentioned drug may also cause urticaria and erythema multiforme [18]. Exfoliative dermatitis has been attributed to cefoxitin [19]. Disulfiram-like reactions to alcohol have been described with newer members of this group. Pustular reactions have been documented with cefradine, cefalexin and cefazolin [20–22]. Ceftazidime has been implicated in the development of erythema multiforme [23]. Cephalosporins [24], including cefalexin [25], have been reported to cause TEN, and cefalexin has precipitated pemphigus vulgaris [26]. Cefazolin has caused an unusual fixed drug eruption [27]. A curious photorecalllike phenomenon followed the use of cefazolin and gentamicin sulphate, in that the eruption was restricted to an area of sunburn sustained 1 month previously [28]. Cefotaxime has caused a photodistributed phototoxic telangiectasia [29]. References 1 Anne S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol 1995; 74: 167–70. 2 Thompson JW, Jacobs RF. Adverse effects of newer cephalosporins. An update. Drug Saf 1993; 9: 132–42. 3 Matsuno K, Kunihiro E, Yamatoya O et al. Surveillance of adverse reactions due to ciprofloxacin in Japan. Drugs 1995; 49 (Suppl. 2): 495–6. 4 Apter AJ, Kinman JL, Bilker WB et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med 2006; 119: 354.e11–9. 5 Antunez C, Blanca-Lopez N, Torres MJ et al. Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol 2006; 117: 404–10. 6 Moreno E, Macías E, Dávila I et al. Hypersensitivity reactions to cephalosporins. Expert Opin Drug Saf 2008; 7: 295–304. 7 Igea JM, Fraj J, Davila I et al. Allergy to cefazolin: study of in vivo cross reactivity with other betalactams. Ann Allergy 1992; 68: 515–9. 8 Warrington RJ, McPhillips S. Independent anaphylaxis to cefazolin without allergy to other beta-lactam antibiotics. J Allergy Clin Immunol 1996; 98: 460–2.

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9 Martin JA, Alonso MD, Lazaro M et al. Delayed allergic reaction to cefonicid. Ann Allergy 1994; 72: 341–2. 10 Marcos Bravo C, Luna Ortiz I, Gonzalez Vazquez R. Hypersensitivity to cefuroxime with good tolerance to other betalactams. Allergy 1995; 50: 359–61. 11 Tuft L. Contact urticaria from cephalosporins. Arch Dermatol 1975; 111: 1609. 12 Nishioka K, Katayama I, Kobayashi Y, Takijiri C. Anaphylaxis due to cefaclor hypersensitivity. J Dermatol 1986; 13: 226–7. 13 Spruell FG, Minette LJ, Sturner WQ. Two surgical deaths associated with cephalothin. JAMA 1974; 229: 440–1. 14 Romano A, Pietrantonio F, Di Fonso M, Venuti A. Delayed hypersensitivity to cefuroxime. Contact Dermatitis 1992; 27: 270–1. 15 Kearns GL, Wheeler JG, Childress SH, Letzig LG. Serum sickness-like reactions to cefaclor: role of hepatic metabolism and individual susceptibility. J Pediatr 1994; 125: 805–11. 16 Grammer LC. Cefaclor serum sickness. JAMA 1996; 275: 1152–3. 17 Isaacs D. Serum sickness-like reaction to cefaclor. J Paediatr Child Health 2001; 37: 298–9. 18 Joubert GI, Hadad K, Matsui D et al. Selection of treatment of cefaclor-associated urticarial, serum sickness-like reactions and erythema multiforme by emergency pediatricians: lack of a uniform standard of care. Can J Clin Pharmacol 1999; 6: 197–201. 19 Kannangara DW, Smith B, Cohen K. Exfoliative dermatitis during cefoxitin therapy. Arch Intern Med 1982; 142: 1031–2. 20 Kalb R, Grossman ME. Pustular eruption following administration of cephradine. Cutis 1986; 38: 58–60. 21 Jackson H, Vion B, Levy PM. Generalized eruptive pustular drug rash due to cephalexin. Dermatologica 1988; 177: 292–4. 22 Fayol J, Bernard P, Bonnetblanc JM. Pustular eruption following the administration of cefazolin: a second case report. J Am Acad Dermatol 1988; 19: 571. 23 Pierce TH, Vig SJ, Ingram PM. Ceftazidime in the treatment of lower respiratory tract infection. J Antimicrob Chemother 1983; 12 (Suppl. A): 21–5. 24 Nichter LS, Harman DM, Bryant CA et al. Cephalosporin-induced toxic epidermal necrolysis. J Burn Care Rehabil 1983; 4: 358–60. 25 Hogan DJ, Rooney ME. Toxic epidermal necrolysis due to cephalexin. J Am Acad Dermatol 1987; 17: 852. 26 Wolf R, Dechner E, Ophir J, Brenner S. Cephalexin. A non-thiol drug that may induce pemphigus vulgaris. Int J Dermatol 1991; 30: 213–5. 27 Sigal-Nahum M, Konqui A, Gauliet A, Sigal S. Linear fixed drug eruption. Br J Dermatol 1988; 118: 849–51. 28 Flax SH, Uhle P. Photo recall-like phenomenon following the use of cefazolin and gentamicin sulfate. Cutis 1990; 46: 59–61. 29 Borgia F, Vaccaro M, Guarneri F, Cannavo SP. Photodistributed telangiectasia following use of cefotaxime. Br J Dermatol 2000; 143: 674–8.

Monobactams Monobactams (e.g. aztreonam) show weak and rare cross-reactivity with IgE antibodies to penicillin [1–3], although immediate hypersensitivity on first exposure to aztreonam in penicillin-allergic patients has been recorded [4,5]. In general, aztreonam is well tolerated in high-risk patients allergic to other beta-lactam antibiotics, but there is a 20% sensitization rate following exposure [6]. However, aztreonam and the monobactams can be safely given to penicillin-allergic patients [7]. Generalized urticaria to aztreonam but good tolerance of the other beta-lactams has been recorded [8]. Carbapenems Cross-reactivity and allergic reactions to imipenem occur in patients known to be allergic to penicillin [9]. Carbapenems should be avoided in patients with penicillin allergy [7]. Imipenem combined with cilastatin, a non-antibiotic enzyme inhibitor that prevents breakdown of imipenem to nephrotoxic metabolites, may cause phlebitis or pain at the site of infusion [10]. Imipenem has been associated with a pustular eruption [11], and imipenem–

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cilastatin with palmoplantar pruritus during infusion in a child with AIDS [12]. References 1 Adkinson NF, Saxon A, Spence MR, Swabb EA. Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985; 7 (Suppl. 4): S613–S621. 2 Saxon A, Hassner A, Swabb EA et al. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin-allergic subjects. J Infect Dis 1984; 149: 16. 3 Adkinson NF Jr. Beta-lactam crossreactivity. Clin Exp Allergy 1998; 28 (Suppl. 4): 37–40. 4 Hantson P, de Coninck B, Horn JL, Mahieu P. Immediate hypersensitivity to aztreonam and imipenem. BMJ 1991; 302: 294–5. 5 Alvarez JS, Del Castillo JAS, Garcia IS, Ortiz MJA. Immediate hypersensitivity to aztreonam. Lancet 1990; 335: 1094. 6 Moss RB. Sensitization to aztreonam and cross-reactivity with other beta-lactam antibiotics in high-risk patients with cystic fibrosis. J Allergy Clin Immunol 1991; 87: 78–88. 7 Kishiyama JL, Adelman DC. The cross-reactivity and immunology of betalactam antibiotics. Drug Saf 1994; 10: 318–27. 8 de la Fuente Prieto R, Armentia Medina A, Sanchez Palla P et al. Urticaria caused by sensitization to aztreonam. Allergy 1993; 48: 634–6. 9 Saxon A, Adelman DC, Patel A et al. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol 1988; 82: 213–7. 10 Anonymous. Imipenem. cilastatin: a new type of antibiotic. Drug Ther Bull 1991; 29: 43–4. 11 Escallier F, Dalac S, Foucher JL et al. Pustulose exanthématique aiguë généralisée: imputabilité a l’imipéneme (Tienam®). Ann Dermatol Vénéréol 1989; 116: 407–9. 12 Machado ARL, Silva CLO, Galvão NAM. Unusual reaction to imipenem– cilastatin in a child with the acquired immunodeficiency syndrome. J Allergy Clin Immunol 1991; 87: 754.

Tetracyclines Many of the side effects are common to all drugs within the group, and cross-sensitivity occurs [1]. Nausea, vomiting and diarrhoea are well-recognized dose-related effects. Oral or vaginal candidiasis may occur as a result of overgrowth of commensals. Resumption of therapy does not necessarily lead to recurrence of the vaginitis [2].

Photosensitivity All tetracyclines, but especially demethylchlortetracycline, may cause phototosensitive eruptions [1,3–6], which clinically resemble exaggerated sunburn, sometimes with blistering. Phototoxicity is thought to be involved, in that high serum levels predispose to its occurrence. Reactions to both UVA and UVB have been reported. High concentrations of tetracycline are found in sun-damaged skin [3]. Symptoms may persist for months [1]. Photo-onycholysis may develop in fingernails and (if exposed) toenails; the thumb (normally less exposed) may be spared [7,8]. Tetracycline therapy is best avoided if there is a prospect of considerable sun exposure. Porphyria cutanea tarda-like changes may develop after chronic sun exposure [6,9]. A photosensitive lichenoid rash has been attributed to demethylchlortetracycline [10]. References 1 Wright AL, Colver GB. Tetracyclines: how safe are they? Clin Exp Dermatol 1988; 13: 57–61. 2 Hall JH, Lupton ES. Tetracycline therapy for acne: incidence of vaginitis. Cutis 1977; 20: 97–8. 3 Blank H, Cullen SI, Catalano PM. Photosensitivity studies with demethylchlortetracycline and doxycycline. Arch Dermatol 1968; 97: 1–2.

4 Frost P, Weinstein GP, Gomez EC. Phototoxic potential of minocycline and doxycycline. Arch Dermatol 1972; 105: 681–3. 5 Kaidbey KH, Kligman AM. Identification of systemic phototoxic drugs by human intradermal assay. J Invest Dermatol 1978; 70: 272–4. 6 Hawk JLM. Skin changes resembling hepatic cutaneous porphyria induced by oxytetracycline photosensitization. Clin Exp Dermatol 1980; 5: 321–5. 7 Baker H. Photo-onycholysis caused by tetracyclines. BMJ 1977; ii: 519–20. 8 Kestel JL Jr. Photo-onycholysis from minocycline. Side effects of minocycline therapy. Cutis 1981; 28: 53–4. 9 Epstein JH, Tuffanelli DL, Seibert JS, Epstein WL. Porphyria-like cutaneous changes induced by tetracycline hydrochloride photosensitization. Arch Dermatol 1976; 112: 661–6. 10 Jones HE, Lewis CW, Reisner JE. Photosensitive lichenoid eruption associated with demeclocycline. Arch Dermatol 1972; 106: 58–63.

Pigmentation Methacycline is a rare cause [1]. Long-term minocycline therapy for acne may result in pigmentation. Although this is generally held to be a rare event, it may occur in about 1.4% of patients [2–5]. The average time for the development of pigmentary changes was 5 months, and onset of this complication did not seem to be related to cumulative dosage of the drug [3]. Facial hyperpigmentation was reported in two sisters on longterm minocycline therapy, who were also being treated with Dianette (cyproterone acetate and ethinylestradiol); it was suggested that pigmentation occurred either as a result of a genetic alteration in the metabolic handling of the drug or because of accentuation by the concomitant therapy [6]. Other drugs, including amitriptyline [2], phenothiazines and 13-cis-retinoic acid, have been implicated in the accentuation of minocycline-related hyperpigmentation. Three types of pigmentation are described with minocycline and may occur in combination or isolation [3]. A focal type with well-demarcated blue-black macules is seen in areas of previous inflammation or scarring, especially in relation to acne scars. Minocycline has been associated with post-inflammatory hyperpigmentation in women who have undergone sclerotherapy [7]. Macular or more diffuse hyperpigmentation may appear distant from acne sites, especially on the extensor surface of the lower legs and forearms and on sun-exposed areas. These two types resolve on cessation of therapy, with a mean time to resolution of 12 months [3]. A more persistent diffuse brown-grey change may develop, especially in sun-exposed areas [5]. Minocycline pigmentation may respond well to laser therapy [8–11]. The oral cavity and lips may be involved [12,13]. Conjunctival pigmentation may occur with tetracyclines [14,15] and scleral pigmentation with minocycline [16,17]. Minocycline can cause nail pigmentation and longitudinal melanonychia [5,18,19], and tetracycline may produce yellow discoloration of the nail [20]. Cutaneous osteomas presenting as blue skin nodules that fluoresce yellow under UV light may rarely develop in patients being treated with tetracycline [21] or minocycline [22] for acne. Black galactorrhoea occurred in a patient taking both minocycline and phenothiazines [23]. Pigmentation may also involve bones, teeth, thyroid, aorta and endocardium [19,24]. Histological and electron microscopic studies have demonstrated increased melanin, haemosiderin and either minocycline or a metabolite in the skin [25–27]; pigment may be seen in dermal histiocytes and eccrine myoepithelial cells [26].

Important or widely prescribed drugs

Minocycline is metabolized to form a brown-black degradation product [28]. References 1 Möller H, Rausing A. Methacycline pigmentation: a five-year follow-up. Acta Derm Venereol (Stockh) 1980; 60: 495–501. 2 Basler RSW, Goetz CS. Synergism of minocycline and amitriptyline in cutaneous hyperpigmentation. J Am Acad Dermatol 1985; 12: 577. 3 Layton AM, Cunliffe WJ. Minocycline induced pigmentation in the treatment of acne: a review and personal observations. J Dermatol Treat 1989; 1: 9– 12. 4 Dwyer CM, Cuddihy AM, Kerr RE et al. Skin pigmentation due to minocycline treatment of facial dermatoses. Br J Dermatol 1993; 129: 158–62. 5 Pepine M, Flower FP, Ramos-Caro FA. Extensive cutaneous hyperpigmentation caused by minocycline. J Am Acad Dermatol 1993; 28: 292–5. 6 Eedy DJ, Burrows D. Minocycline-induced pigmentation occurring in two sisters. Clin Exp Dermatol 1991; 16: 55–7. 7 Leffell DJ. Minocycline hydrochloride hyperpigmentation complicating treatment of venous ectasia of the extremities. J Am Acad Dermatol 1991; 24: 501–2. 8 Collins P, Cotterill JA. Minocycline-induced pigmentation resolves after treatment with the Q-switched ruby laser. Br J Dermatol 1996; 135: 317–9. 9 Wilde JL, English JC III, Finley EM. Minocycline-induced hyperpigmentation. Treatment with the neodymium:Yag laser. Arch Dermatol 1997; 133: 1344–6. 10 Wood B, Munro CS, Bilsland D. Treatment of minocycline-induced pigmentation with the neodymium-Yag laser. Br J Dermatol 1998; 139: 562. 11 Green D, Friedman KJ. Treatment of minocycline-induced cutaneous pigmentation with the Q-switched Alexandrite laser and a review of the literature. J Am Acad Dermatol 2001; 44: 342–7. 12 Siller GM, Tod MA, Savage NW. Minocycline-induced oral pigmentation. J Am Acad Dermatol 1994; 30: 350–4. 13 Chu PSL, Yen TS, Berger TG. Minocycline hyperpigmentation localized to the lips: an unusual fixed drug reaction? J Am Acad Dermatol 1994; 30: 802–3. 14 Brothers DM, Hidayat AA. Conjunctival pigmentation associated with tetracycline medication. Ophthalmology 1981; 88: 1212–5. 15 Messmer E, Font RL, Sheldon G, Murphy D. Pigmented conjunctival cysts following tetracycline/minocycline therapy. Histochemical and electron microscopic observations. Ophthalmology 1983; 90: 1462–8. 16 Angeloni VL, Salasche SJ, Ortiz R. Nail, skin, and scleral pigmentation induced by minocycline. Cutis 1988; 42: 229–33. 17 Sabroe RA, Archer CB, Harlow D et al. Minocycline-induced discolouration of the sclerae. Br J Dermatol 1996; 135: 314–6. 18 Mallon E, Dawber RPR. Longitudinal melanonychia induced by minocycline. Br J Dermatol 1995; 130: 794–5. 19 Wolfe ID, Reichmister J. Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement. Cutis 1984; 33: 475–8. 20 Hendricks AA. Yellow lunulae with fluorescence after tetracycline therapy. Arch Dermatol 1980; 116: 438–40. 21 Walter JF, Macknet KD. Pigmentation of osteoma cutis caused by tetracycline. Arch Dermatol 1979; 115: 1087–8. 22 Moritz DL, Elewski B. Pigmented postacne osteoma cutis in a patient treated with minocycline: report and review of the literature. J Am Acad Dermatol 1991; 24: 851–3. 23 Basler RSW, Lynch PJ. Black galactorrhea as a complication of minocycline and phenothiazine therapy. Arch Dermatol 1985; 121: 417–8. 24 Butler JM, Marks R, Sutherland R. Cutaneous and cardiac valvular pigmentation with minocycline. Clin Exp Dermatol 1985; 10: 432–7. 25 Sato S, Murphy GF, Bernard JD et al. Ultrastructural and x-ray microanalytical observations on minocycline-related hyperpigmentation of the skin. J Invest Dermatol 1981; 77: 264–71. 26 Argenyi ZB, Finelli L, Bergfeld WF et al. Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy, electron microscopy and x-ray energy spectroscopy. J Cutan Pathol 1987; 14: 176–80. 27 Okada N, Moriya K, Nishida K et al. Skin pigmentation associated with minocycline therapy. Br J Dermatol 1989; 121: 247–54. 28 Nelis HJCF, DeLeenheer AP. Metabolism of minocycline in humans. Drug Metab Dispos 1982; 10: 142–6.

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Other cutaneous side effects Allergic reactions are far less common than with penicillin. Morbilliform, urticarial, erythema multiforme-like and bullous eruptions [1,2], exfoliative dermatitis and erythema nodosum [3] have been reported, as well as a recurrent follicular acneiform eruption in one patient [4]. Minocycline has caused eosinophilic cellulitis and pustular folliculitis with eosinophilia [5]. Gram-negative folliculitis of the face is uncommon but well recognized; Proteus may be responsible, and the condition responds to ampicillin [6]. Tetracyclines are a well-known cause of fixed drug eruptions [7–9], and minocycline [10] and doxycycline [11] have caused Stevens– Johnson syndrome. TEN has been recorded [12]. Doxycycline caused a severe drug hypersensitivity reaction [13]. It has been suggested that tetracyclines may exacerbate psoriasis [14,15]. An eruption resembling Sweet’s syndrome has occurred with minocycline, tetracycline and doxycycline [16–18]. Pruritus at the site of active acne has been recorded within 2–6 weeks of starting oral tetracyclines (oxytetracycline, doxycycline or minocycline) [19]. References 1 Shelley WB, Heaton CL. Minocycline sensitivity. JAMA 1973; 224: 125–6. 2 Fawcett IW, Pepys J. Allergy to a tetracycline preparation: a case report. Clin Allergy 1976; 6: 301–4. 3 Bridges AJ, Graziano FM, Calhoun W, Reizner GT. Hyperpigmentation, neutrophilic alveolitis, and erythema nodosum resulting from minocycline. J Am Acad Dermatol 1990; 22: 959–62. 4 Bean SF. Acneiform eruption from tetracycline. Br J Dermatol 1971; 85: 585–6. 5 Kaufmann D, Pichler W, Beer JH. Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne. Arch Intern Med 1994; 154: 1983–4. 6 Leyden JJ, Marples RR, Mills OH Jr, Kligman AM. Gram-negative folliculitis: a complication of antibiotic therapy in acne vulgaris. Br J Dermatol 1973; 88: 533–8. 7 Jolly HW, Sherman IJ Jr, Carpenter CL et al. Fixed drug eruptions to tetracyclines. Arch Dermatol 1978; 114: 1484–5. 8 Fiumara NJ, Yaqub M. Pigmented penile lesions (fixed drug eruptions) associated with tetracycline therapy for sexually transmitted diseases. Sex Transm Dis 1980; 8: 23–5. 9 Chan HL, Wong SN, Lo FL. Tetracycline-induced fixed drug eruptions: influence of dose and structure of tetracyclines. J Am Acad Dermatol 1985; 13: 302–3. 10 Shoji A, Someda Y, Hamada T. Stevens–Johnson syndrome due to minocycline therapy. Arch Dermatol 1987; 123: 18–20. 11 Curley RK, Verbov JL. Stevens–Johnson syndrome due to tetracyclines: a case report (doxycycline) and review of the literature. Clin Exp Dermatol 1987; 12: 124–5. 12 Tatnall FM, Dodd HJ, Sarkany I. Elevated serum amylase in a case of toxic epidermal necrolysis. Br J Dermatol 1985; 113: 629–30. 13 Robles DT, Leonard JL, Compton N et al. Severe drug hypersensitivity reaction in a young woman treated with doxycycline. Dermatology 2008; 217: 23–6. 14 Tsankov M, Botev-Zlatkov M, Lazarova AZ et al. Psoriasis and drugs: influence of tetracyclines on the course of psoriasis. J Am Acad Dermatol 1988; 19: 629– 32. 15 Bergner T, Przybilla B. Psoriasis and tetracyclines. J Am Acad Dermatol 1990; 23: 770. 16 Mensing H, Kowalzick L. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) caused by minocycline. Dermatologica 1991; 182: 43–6. 17 Thibault MJ, Billick RC, Srolovitz H. Minocycline-induced Sweet’s syndrome. J Am Acad Dermatol 1992; 27: 801–4. 18 Khan Durani B, Jappe U. Drug-induced Sweet’s syndrome in acne caused by different tetracyclines: case report and review of the literature. Br J Dermatol 2002; 147: 558–62. 19 Yee KC, Cunliffe WJ. Itching in acne: an unusual complication of therapy. Dermatology 1994; 189: 117–9.

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Gastrointestinal absorption and drug interactions Absorption of tetracyclines is reduced when taken with meals, especially those containing calcium or iron such as milk, or with drugs such as iron or antacids [1]. The decrease in serum levels following a test meal has been reported as follows: oxytetracycline 50% [1], minocycline 13% [1] and doxycycline 20% [2]. Oxytetracycline may have a hypoglycaemic effect in insulin-dependent diabetics [3]. Tetracyclines can potentiate the action of warfarin by depressing prothrombin activity, and elevate serum levels of lithium given simultaneously [4]. References 1 Leyden JJ. Absorption of minocycline HCl and tetracycline hydrochloride. Effect of food, milk and iron. J Am Acad Dermatol 1985; 12: 308–12. 2 Welling PG, Koch PA, Lau CC, Craig WA. Bioavailability of tetracycline and doxycycline in fasted and nonfasted subjects. Antimicrob Agents Chemother 1977; 11: 462–9. 3 Miller JB. Hypoglycaemic effect of oxytetracycline. BMJ 1966; 2: 1007. 4 McGennis AJ. Lithium carbonate and tetracycline interaction. BMJ 1978; i: 1183.

Systemic side effects of tetracyclines Long-term use of tetracycline for acne may rarely result in benign intracranial hypertension [1,2]. As retinoids may potentiate this effect, it is safest not to use them in combination with tetracycline therapy for acne. Oesophageal ulceration has been described in a number of patients [3]. With the exception of doxycycline and minocycline, tetracyclines may exacerbate renal failure. Combination therapy with tetracyclines and nephrotoxic drugs such as gentamicin or diuretics should be avoided [4]. Deteriorated tetracyclines have caused nephropathy accompanied by an exanthematic eruption. Patients should be warned not to use outdated or poorly stored tetracycline, because degraded tetracycline can cause a Fanconi-type syndrome comprising renal tubular acidosis and proteinuria [5,6] and lactic acidosis [7]. Dose-related vestibular disturbance has been reported with minocycline [8]. Reversible pulmonary infiltration with eosinophilic or neutrophilic alveolitis has been rarely described in association with tetracycline [9] and especially minocycline [10–12] therapy. There have been isolated case reports linking tetracycline with SLE [13]. Minocycline has been reported to cause other serious, albeit rare, adverse events. Serum sickness-like reactions occur at about 15 days [14,15]. A hypersensitivity syndrome may develop at about 23–35 days, with a severe self-limiting eruption, sometimes exfoliative dermatitis, associated with eosinophilia and acute hepatic failure, occasionally fatal [16–20]. A drug-induced autoimmune syndrome with hepatitis or vasculitis and some features of SLE occurs rarely with minocycline, on average 1–2 years after the start of therapy, and is commoner in women [20–25]. Hepatitis, sometimes with the histological features of chronic active hepatitis, may be associated with polyarthralgia and positive antinuclear antibodies but negative or only weakly positive anti-DNA antibodies, and is only rarely fatal; patients usually recover within 3 months of drug cessation. Perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) may be a marker for development of minocycline-induced autoimmunity [26–28]; in one study, all such patients were p-ANCA positive and had the haplotype HLA-DR4 or HLA-DR2, and all had the HLA-DQB1 allele, suggesting genetic susceptibility [28]. Systemic reactions to minocycline are certainly

more frequent than those to oxytetracycline or doxycycline [29], and it has therefore been suggested that the use of minocycline in acne should be restricted to patients unresponsive to other tetracyclines [30]. References 1 Walters BNJ, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. BMJ 1979; 282: 19–20. 2 Pearson MG, Littlewood SM, Bowden AN. Tetracycline and benign intracranial hypertension. BMJ 1981; 282: 568–9. 3 Channer KS, Hollanders D. Tetracycline-induced oesophageal ulceration. BMJ 1981; 282: 1359–60. 4 Wright AL, Colver GB. Tetracyclines: how safe are they? Clin Exp Dermatol 1988; 13: 57–61. 5 Moser RH. Bibliographies on diseases: medical progress. Reactions to tetracyclines. Clin Pharmacol Ther 1966; 7: 117–31. 6 Frimpter GW, Timpanelli AE, Eisenmenger WJ et al. Reversible ‘Fanconi syndrome’ caused by degraded tetracycline. JAMA 1963; 184: 111–3. 7 Montoliu J, Carrera M, Darnell A et al. Lactic acidosis and Fanconi’s syndrome due to degraded tetracycline. BMJ 1981; 281: 1576–7. 8 Allen JC. Minocycline. Ann Intern Med 1976; 85: 482–7. 9 Ho D, Tashkin DP, Bein ME, Sharma O. Pulmonary infiltrates with eosinophilia associated with tetracycline. Chest 1979; 76: 33–5. 10 Bando T, Fujimura M, Noda Y et al. Minocycline-induced pneumonitis with bilateral hilar lymphadenopathy and pleural effusion. J Intern Med 1994; 33: 177–9. 11 Sitbon O, Bidel N, Dussopt C et al. Minocycline and pulmonary eosinophilia. A report on eight patients. Arch Intern Med 1994; 154: 1633–40. 12 Dykhuizen RS, Zaidi AM, Godden DJ et al. Minocycline and pulmonary eosinophilia. BMJ 1995; 310: 1520–1. 13 Domz CA, Minamara DH, Hozapfel HF. Tetracycline provocation in lupus erythematosus. Ann Intern Med 1959; 50: 1217. 14 Landau M, Shachar E, Brenner S. Minocycline-induced serum sickness-like reaction. J Eur Acad Dermatol Venereol 2000; 14: 67–8. 15 Malakar S, Dhar S, Shah Malakar R. Is serum sickness an uncommon adverse effect of minocycline treatment? Arch Dermatol 2001; 137: 100–1. 16 Davies MG, Kersey PJW. Acute hepatitis and exfoliative dermatitis associated with minocycline. BMJ 1989; 298: 1523–4. 17 Kaufmann D, Pichler W, Beer JH. Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne. Arch Intern Med 1994; 154: 1983–4. 18 Knowles SR, Shapiro L, Shear NH. Serious adverse reactions induced by minocycline. Report of 13 patients and review of the literature. Arch Dermatol 1996; 132: 934–9. 19 MacNeil M, Haase DA, Tremaine R, Marrie TJ. Fever, lymphadenopathy, eosinophilia, lymphocytosis, hepatitis, and dermatitis: a severe adverse reaction to minocycline. J Am Acad Dermatol 1997; 36: 347–50. 20 Lawrenson RA, Seaman HE, Sundstrom A et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf 2000; 23: 333–49. 21 Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum 1999; 28: 392–7. 22 Byrne PAC, Williams BD, Pritchard MH. Minocycline-related lupus. Br J Rheumatol 1994; 33: 674–6. 23 Gordon PM, White MI, Herriot R et al. Minocyline-associated lupus erythematosus. Br J Dermatol 1995; 132: 120–1. 24 Gough A, Chapman S, Wagstaff K et al. Minocycline-induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169–72. 25 Crosson J, Stillman MT. Minocycline-related lupus erythematosus with associated liver disease. J Am Acad Dermatol 1997; 36: 867–8. 26 Shapiro LE, Uetrecht J, Shear NH. Minocycline, perinuclear antineutrophilic cytoplasmic antibody, and pigment: the biochemical basis. J Am Acad Dermatol 2001; 45: 787–9. 27 Schaffer JV, Davidson DM, McNiff JM, Bolognia JL. Perinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol 2001; 44: 198–206.

Important or widely prescribed drugs 28 Dunphy J, Oliver M, Rands AL et al. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000; 142: 461–7. 29 Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol 1997; 133: 1224–30. 30 Ferner RE, Moss C. Minocycline for acne. First line antibacterial treatment of acne should be with tetracycline or oxytetracycline. BMJ 1996; 312: 138.

Effects on the fetus and on teeth There is little evidence that tetracycline is teratogenic [1]. There is an isolated case report of congenital abnormalities in a child whose mother took clomocycline for acne [2]. Yellow discoloration of the teeth due to tetracycline exposure during mineralization of the deciduous or permanent teeth is well known [3–5]. A yellowbrown fluorescent discoloration is formed as a result of a complex with calcium orthophosphate. Tetracyclines should not be given to pregnant women or children under the age of 12 years. Tetracyclines are excreted in breast milk, but chelation with calcium decreases their absorption so that tooth discoloration is probably prevented [1]. Tetracycline may be deposited up to late adolescence in calcifying teeth such as the molars, but as these are not normally visible this is not a problem [5]. Minocycline may rarely stain the teeth of adults [6–8]. References 1 Wright AL, Colver GB. Tetracyclines: how safe are they? Clin Exp Dermatol 1988; 13: 57–61. 2 Corcoran R, Castles JM. Tetracycline for acne vulgaris and possible teratogenesis. BMJ 1977; ii: 807–8. 3 Conchie JM, Munroe JD, Anderson DO. The incidence of staining of permanent teeth by the tetracyclines. Can Med Assoc J 1970; 103: 351–6. 4 Moffitt JM, Cooley RO, Olsen NH, Hefferren JJ. Prediction of tetracycline-induced tooth discolouration. J Am Dent Assoc 1974; 88: 547–52. 5 Grossman ER. Tetracycline and staining of the teeth. JAMA 1986; 225: 2442. 6 Poliak SC, DiGiovanna JJ, Gross EG et al. Minocycline-associated tooth discoloration in young adults. JAMA 1985; 254: 2930–2. 7 Rosen T, Hoffmann TJ. Minocycline-induced discoloration of the permanent teeth. J Am Acad Dermatol 1989; 21: 569. 8 Berger RS, Mandel EN, Hayes TJ, Grimwood RR. Minocycline staining of the oral cavity. J Am Acad Dermatol 1989; 21: 1300–1.

Tetracyclines and the contraceptive pill Tetracyclines have been reported to interfere with the action of the contraceptive pill [1,2], and it is standard practice to inform female patients of this and to suggest use of an additional or alternative method of contraception while on medication. However, there is controversy as to whether there is really a significant risk of interaction [3–6]. It has been argued that there is a baseline pill failure rate of at least 1% per year, and that antibiotics commonly used in dermatology do not increase the risk of pregnancy [6]. References 1 Bacon JF, Shenfield GM. Pregnancy attributable to interaction between tetracycline and oral contraceptives. BMJ 1980; 280: 293. 2 Hughes BR, Cunliffe WJ. Interactions between the oral contraceptive pill and antibiotics. Br J Dermatol 1990; 122: 717–8. 3 Fleischer AB Jr, Resnick SD. The effect of antibiotics on the efficacy of oral contraceptives. Arch Dermatol 1989; 125: 1562–4. 4 Orme ML’E, Back DJ. Interactions between oral contraceptive steroids and broadspectrum antibiotics. Clin Exp Dermatol 1986; 11: 327–31.

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5 De Groot AC, Eshuis H, Stricker BHC. Oral contraceptives and antibiotics in acne. Br J Dermatol 1991; 124: 212. 6 Helms SE, Bredle DL, Zajic J et al. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol 1997; 36: 705–10.

Sulphonamides and trimethoprim Reactions occur in 1–5% of those exposed [1–6]. They are commoner in patients with AIDS [7–9], and slow acetylators are at greater risk [10]. Type I reactions (urticaria and anaphylaxis) are rare but recorded. Phototoxic and photoallergic eruptions occur [11,12]. Morbilliform and rubelliform rashes are seen, and erythema multiforme, Stevens–Johnson syndrome and TEN [13–18], erythema nodosum [1], generalized exfoliative dermatitis [1,19,20] and fixed eruptions [21] are all well known. In addition, an LE-like syndrome and allergic vasculitis [22] are documented. Agranulocytosis or haemolytic anaemia is occasionally precipitated. References 1 Koch-Weser J, Sidel VW, Dexter M et al. Adverse reactions to sulfisoxazole, sulfamethoxazole, and nitrofurantoin. Manifestations and specific reaction rates during 2,118 courses of therapy. Arch Intern Med 1971; 128: 399–404. 2 Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. A series of inpatients during a 10-year period. Acta Derm Venereol (Stockh) 1984; 64: 320–4. 3 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63. 4 Anonymous. Hypersensitivity to sulphonamides: a clue? Lancet 1986; ii: 958–9. 5 Rieder MJ, Uetrecht J, Shear NH et al. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9. 6 Dibbern DA Jr, Montanaro A. Allergies to sulfonamide antibiotics and sulfurcontaining drugs. Ann Allergy Asthma Immunol 2008; 100: 91–100. 7 De Raeve L, Song M, Van Maldergem L. Adverse cutaneous drug reactions in AIDS. Br J Dermatol 1988; 119: 521–3. 8 van der Ven AJAM, Koopmans PP, Vree TB, van der Meer JWM. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; 338: 431–3. 9 Roudier C, Caumes E, Rogeaux O et al. Adverse cutaneous reactions to trimethoprim–sulfamethoxazole in patients with the acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Arch Dermatol 1994; 130: 1383–6. 10 Carr A, Gross AS, Hoskins JM et al. Acetylation phenotype and cutaneous hypersensitivity to trimethoprim–sulphamethoxazole in HIV-infected patients. AIDS 1994; 8: 333–7. 11 Epstein JH. Photoallergy. A review. Arch Dermatol 1972; 106: 741–8. 12 Hawk JLM. Photosensitizing agents used in the United Kingdom. Clin Exp Dermatol 1984; 9: 300–2. 13 Kauppinen K. Cutaneous reactions to drugs. With special reference to severe mucocutaneous bullous eruptions and sulphonamides. Acta Derm Venereol Suppl (Stockh) 1972; 68: 1–89. 14 Jick H, Derby LE. A large population-based follow-up study of trimethoprim– sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity. Pharmacotherapeutica 1995; 15: 428–32. 15 Carrol OM, Bryan PA, Robinson RJ. Stevens–Johnson syndrome associated with long-acting sulfonamides. JAMA 1966; 195: 691–3. 16 Aberer W, Stingl G, Wolff K. Stevens–Johnson-Syndrom und toxische epidermale Nekrolyse nach Sulfonamideinahme. Hautarzt 1982; 33: 484–90. 17 Chan H-L, Stern RS, Arndt KA et al. The incidence of erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990; 126: 43–7. 18 Schöpf E, Stühmer A, Rzany B et al. Toxic epidermal necrolysis and Stevens– Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 1991; 127: 839–42.

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19 Nicolis GD, Helwig EB. Exfoliative dermatitis. A clinicopathologic study of 135 cases. Arch Dermatol 1973; 108: 788–97. 20 Sehgal VN, Srivastava G. Exfoliative dermatitis. A prospective study of 80 patients. Dermatologica 1986; 173: 278–84. 21 Sehgal VN, Gangwani OP. Fixed drug eruption. Current concepts. Int J Dermatol 1987; 26: 67–74. 22 Lehr D. Sulfonamide vasculitis. J Clin Pharmacol 1972; 2: 181–9.

Sulfasalazine Rashes occur in 1–5% of patients, and may be widespread as part of a hypersensitivity syndrome with hepatitis and encephalopathy [1–5], but desensitization is possible [6]. Blood disorders attributable to sulfasalazine occur at a rate of 3 per 1000 users [7]. An autoimmune syndrome has been described [8]. Photosensitivity [9] and a fixed eruption [10] have been documented. TEN, erythroid hypoplasia and agranulocytosis have been reported [11]. Bronchiolitis obliterans and alveolitis are well-recognized complications, and acute hypersensitivity pneumonia is recorded. LE, including cerebral LE, may be induced [12]. Reversible oligospermia may occur [13], and reversible hair loss has been attributed to use of this drug in enemas [14]. Many of the above adverse effects are attributable to the carrier molecule, sulfapyridine, which delivers 5-aminosalicylic acid, the component of sulfasalazine active in ulcerative colitis, to its site of action in the colon; patients who are slow acetylators may be especially prone to side effects [15]. Urticaria, and possibly the renal toxicity, are due to the 5-aminosalicylic acid component [16]. Mesalazine (5-aminosalicylic acid) Fever, erythematous skin eruption and lung involvement [17], and fever, diarrhoea, exfoliative dermatitis, marked atypical lymphocytosis and severe hepatotoxicity [18] have been described in patients with a previous history of sulfasalazine hypersensitivity. Additional cutaneous hypersensitivity reactions including vasculitis [19], a Kawasaki-like syndrome [20] and an LE-like syndrome [21] have been documented. This drug may cause renal damage, and is associated with blood dyscrasia [22], including fatal bone marrow suppression and thrombocytopenia [23]. A pustular reaction is recorded [24]. Olsalazine This drug, which consists of a dimer of two molecules of 5-aminosalicylic acid linked by an azo bond, dispenses with the unwanted effects of sulfapyridine. Nonetheless, up to one in five patients experience diarrhoea, rash, nausea and abdominal pain severe enough to stop treatment with the drug [16]. Sulfamethoxypyridazine Obliterative bronchiolitis and alveolitis have been documented in a patient with linear IgA disease of adults [25]. References 1 Leroux JL, Ghezail M, Chertok P, Blotman F. Hypersensitivity reaction to sulfasalazine: skin rash, fever, hepatitis and activated lymphocytes. Clin Exp Rheumatol 1992; 10: 427. 2 Gran JT, Myklebust G. Toxicity of sulphasalazine in rheumatoid arthritis. Possible protective effect of rheumatoid factors and corticosteroids. Scand J Rheumatol 1993; 22: 229–32.

3 Gabay C, De Bandt M, Palazzo E. Sulphasalazine-related life-threatening side effects: is N-acetylcysteine of therapeutic value? Clin Exp Rheumatol 1993; 11: 417–20. 4 Schoonjans R, Mast A, Van Den Abeele G et al. Sulfasalazine-associated encephalopathy in a patient with Crohn’s disease. Am J Gastroenterol 1993; 88: 1416–20. 5 Rubin R. Sulfasalazine-induced fulminant hepatic failure and necrotizing pancreatitis. Am J Gastroenterol 1994; 89: 789–91. 6 Koski JM. Desensitization to sulphasalazine in patients with arthritis. Clin Exp Rheumatol 1993; 11: 169–70. 7 Jick H, Myers MW, Dean AD. The risk of sulfasalazine- and mesalazine-associated blood disorders. Pharmacotherapeutica 1995; 15: 176–81. 8 Vyse T, So AK. Sulphasalazine-induced autoimmune syndrome. Br J Rheumatol 1992; 31: 115–6. 9 Watkinson G. Sulfasalazine: a review of 40 years’ experience. Drugs 1986; 32: 1–11. 10 Kanwar AJ, Singh M, Yunus M, Belhaj MS. Fixed eruption to sulphasalazine. Dermatologica 1987; 174: 104. 11 Maddocks JL, Slater DN. Toxic epidermal necrolysis, agranulocytosis and erythroid hypoplasia associated with sulphasalazine. J R Soc Med 1980; 73: 587–8. 12 Rafferty P, Young AC, Haeny MR. Sulphasalazine-induced cerebral lupus erythematosus. Postgrad Med J 1982; 58: 98–9. 13 Drife JO. Drugs and sperm. BMJ 1982; 284: 844–5. 14 Kutty PK, Raman KRK, Hawken K, Barrowman JA. Hair loss and 5-aminosalicylic acid enemas. Ann Intern Med 1982; 97: 785–6. 15 Das KM, Eastwood MA, McManus JPA, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 1973; 289: 491–5. 16 Anonymous. Olsalazine: a further choice in ulcerative colitis. Drug Ther Bull 1990; 28: 57–8. 17 Hautekeete ML, Bourgeois N, Potvin P et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992; 103: 1925–7. 18 Aparicio J, Carnicer F, Girona E, Gomez A. Cutaneous hypersensitivity reaction to mesalazine. Am J Gastroenterol 1996; 91: 620–1. 19 Lim AG, Hine KR. Fever, vasculitic rash, arthritis, pericarditis, and pericardial effusion after mesalazine. BMJ 1994; 308: 113. 20 Waanders H, Thompson J. Kawasaki-like syndrome after treatment with mesalazine. Am J Gastroenterol 1991; 86: 219–21. 21 Dent MT, Ganatpathy S, Holdworth CD, Channer KC. Mesalazine-induced lupus-like syndrome. BMJ 1992; 305: 159. 22 Anonymous. Blood dyscrasias and mesalazine. Curr Prob Pharmacovig 1995; 21: 5. 23 Daneshmend TK. Mesalazine-associated thrombocytopenia. Lancet 1991; 337: 1297–8. 24 Gibbon KL, Bewley AP, Thomas K. Mesalazine-induced pustular drug eruption. J Am Acad Dermatol 2002; 46: S220–S221. 25 Godfrey KM, Wojnarowska F, Friedland JS. Obliterative bronchiolitis and alveolitis associated with sulphamethoxypyridazine (Lederkyn) therapy for linear IgA disease of adults. Br J Dermatol 1990; 123: 125–31.

Sulfadoxine This sulphonamide is used in malaria prophylaxis in combination with pyrimethamine. The risk of reactions seems to be very low, but drug fever, TEN and photodermatitis have been recorded [1]. Stevens–Johnson syndrome may occur with Fansidar (pyrimethamine and sulfadoxine) for malaria prophylaxis [1–4] or with sulfadoxine alone [5]. TEN has occurred with Fansidar in an AIDS patient [6]. References 1 Koch-Weser J, Hodel C, Leimer R, Styk S. Adverse reactions to pyrimethamine/ sulfadoxine. Lancet 1982; ii: 1459. 2 Hornstein OP, Ruprecht KW. Fansidar-induced Stevens–Johnson syndrome. N Engl J Med 1982; 307: 1529–30. 3 Miller KD, Lobel HO, Satriale RF et al. Severe cutaneous reactions among

Important or widely prescribed drugs American travelers using pyrimethamine–sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986; 35: 451–8. 4 Ortel B, Sivayathorn A, Hönigsmann H. An unusual combination of phototoxicity and Stevens–Johnson syndrome due to antimalarial therapy. Dermatologica 1989; 178: 39–42. 5 Hernborg A. Stevens–Johnson syndrome after mass prophylaxis with sulfadoxine for cholera in Mozambique. Lancet 1985; i: 1072–3. 6 Raviglione MC, Dinan WA, Pablos-Mendez A et al. Fatal toxic epidermal necrolysis during prophylaxis with pyrimethamine and sulfadoxine in a human immunodeficiency virus-infected person. Arch Intern Med 1988; 148: 2863–5.

Trimethoprim–sulfamethoxazole (co-trimoxazole) The general incidence and patterns of reactions to this mixture of sulfamethoxazole and trimethoprim are about the same as for sulphonamides in general; cutaneous reactions are seen in 3.3% of patients [1–3]. Severe cutaneous reactions of all types occur in about 1 per 100 000 users of the drug [2,3]. In view of these severe reactions, the drug is now indicated primarily for Pneumocystis carinii pneumonia, and for acute exacerbations of chronic bronchitis and urinary tract infections, and otitis media in children, only where there is good reason to prefer this combination [4]. There is a greatly increased incidence of reactions in patients with AIDS [5–13]. In one study, 18 of 38 patients with AIDS and P. carinii pneumonia treated with trimethoprim–sulfamethoxazole developed cutaneous reactions within a median of 11 days. It is sometimes possible to continue treatment through a hypersensitivity reaction, as reported for 67% of cases in the above study [14]. Adjuvant corticosteroids reduce the incidence of adverse cutaneous reactions to co-trimoxazole in patients with AIDS who are treated for hypoxaemic P. carinii pneumonia, but the incidence of mucocutaneous herpes simplex virus infection is higher [15]. If it is deemed essential to continue the drug, desensitization can be attempted [16,17]. Fixed eruptions occur [18–22], and may be due to the sulphonamide or trimethoprim components; a widespread fixed eruption mimicking TEN has been documented in one case [23]. Pustular reactions [24] and Sweet’s syndrome [25] have been documented. Severe reactions have included erythema multiforme or Stevens– Johnson syndrome [26,27] that has been fatal [27], TEN in AIDS patients [5,11,12], cutaneous vasculitis [28] and fatal agranulocytosis [29]. One patient developed a rapidly progressive, subepidermal bullous eruption within hours of intravenous trimethoprim–sulfamethoxazole [30]. References 1 Jick J. Adverse reactions to trimethoprim–sulphamethoxazole in hospitalized patients. Rev Infect Dis 1982; 4: 426–8. 2 Lawson DH, Paice BJ. Adverse reactions to trimethoprim–sulfamethoxasole. Rev Infect Dis 1982; 4: 429–33. 3 Huisman MV, Buller HR, TenCate JW. Co-trimoxasole toxicity. Lancet 1984; ii: 1152. 4 Anonymous. Revised indications for co-trimoxazole (Septrin, Bactrim, various generic preparations). Curr Probl Pharmacovig 1995; 21: 5. 5 Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993; 328: 1670–4. 6 Mitsuyasu R, Groopman J, Volberding P. Cutaneous reaction to trimethoprim– sulfamethoxazole in patients with AIDS and Kaposi’s sarcoma. N Engl J Med 1983; 308: 1535–6. 7 Gordin FM, Simon GL, Wofsy CB et al. Adverse reactions to trimethoprim sulfamethoxazole in patients with the acquired immune deficiency syndrome. Ann Intern Med 1984; 100: 495–9.

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8 Cohn DL, Penley KA, Judson FN et al. The acquired immunodeficiency syndrome and a trimethoprim–sulfamethoxazole-adverse reaction. Ann Intern Med 1984; 100: 311. 9 Kovacs JA, Hiemenz JW, Macher AM et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984; 100: 663– 71. 10 De Raeve L, Song M, Van Maldergem L. Adverse cutaneous drug reactions in AIDS. Br J Dermatol 1988; 119: 521–3. 11 Arnold P, Guglielmo J, Hollander H. Severe hypersensitivity reaction upon rechallenge with trimethoprim–sulfamethoxazole in a patient with AIDS. Drug Intel Clin Phar 1988; 22: 43–4. 12 Coopman SA, Stern RS. Cutaneous drug reactions in human immunodeficiency virus infection. Arch Dermatol 1991; 127: 714–7. 13 Chanock SJ, Luginbuhl LM, McIntosh K, Lipshultz SE. Life-threatening reaction to trimethoprim/sulfamethoxazole in pediatric human immuno-deficiency virus infection. Pediatrics 1994; 93: 519–21. 14 Roudier C, Caumes E, Rogeaux O et al. Adverse cutaneous reactions to trimethoprim–sulfamethoxazole in patients with the acquired immuno-deficiency syndrome and Pneumocystis carinii pneumonia. Arch Dermatol 1994; 130: 1383–6. 15 Caumes E, Roudier C, Rogeaux O et al. Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim–sulfamethoxazole during treatment of AIDS-associated Pneumocystis carinii pneumonia. Clin Infect Dis 1994; 18: 319–23. 16 Kletzel M, Beck S, Elser J et al. Trimethoprim–sulfamethoxazole oral desensitization in hemophiliacs infected with human immunodeficiency virus with a history of hypersensitivity reactions. Am J Dis Child 1991; 145: 1428–9. 17 Carr A, Penny R, Cooper DA. Efficacy and safety of rechallenge with low-dose trimethoprim–sulphamethoxazole in previously hypersensitive HIV-infected patients. AIDS 1993; 7: 65–71. 18 Talbot MD. Fixed genital drug reaction. Practitioner 1980; 224: 823–4. 19 Varsano I, Amir Y. Fixed drug eruption due to co-trimoxazole. Dermatologica 1989; 178: 232. 20 Van Voorhees A, Stenn KS. Histological phases of Bactrim-induced fixed drug eruption. The report of one case. Am J Dermatopathol 1987; 9: 528–32. 21 Bharija SC, Belhaj MS. Fixed drug eruption due to cotrimoxazole. Australas J Dermatol 1989; 30: 43–4. 22 Lim JT, Chan HL. Fixed drug eruptions due to co-trimoxazole. Ann Acad Med Singapore 1992; 21: 408–10. 23 Baird BJ, De Villez RL. Widespread bullous fixed drug eruption mimicking toxic epidermal necrolysis. Int J Dermatol 1988; 27: 170–4. 24 MacDonald KJS, Green CM, Kenicer KJA. Pustular dermatosis induced by cotrimoxazole. BMJ 1986; 293: 1279–80. 25 Walker DC, Cohen PR. Trimethoprim–sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. J Am Acad Dermatol 1996; 34: 918–23. 26 Azinge NO, Garrick GA. Stevens–Johnson syndrome (erythema multiforme) following ingestion of trimethoprim–sulfamethoxazole on two separate occasions in the same person. A case report. J Allergy Clin Immunol 1978; 62: 125–6. 27 Beck MH, Portnoy B. Severe erythema multiforme complicated by fatal gastrointestinal involvement following co-trimoxasole therapy. Clin Exp Dermatol 1979; 4: 201–4. 28 Wåhlin A, Rosman N. Skin manifestations with vasculitis due to cotrimoxazole. Lancet 1976; ii: 1415. 29 Lawson DH, Henry DA, Jick H. Fatal agranulocytosis attributed to cotrimoxazole therapy. BMJ 1976; ii: 316. 30 Roholt NS, Lapiere JC, Traczyk T et al. A nonscarring sublamina densa bullous drug eruption. J Am Acad Dermatol 1995; 32: 367–71.

Trimethoprim Used alone, this substance causes fewer reactions than sulphonamides; fixed eruption has been proven [1–3] and was linear in one case [4]. Two patients experienced life-threatening immediate reactions and one patient developed generalized urticaria following oral trimethoprim–sulfamethoxazole; prick tests and

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oral challenge tests were positive with trimethoprim but not sulfamethoxazole [5]. References 1 Kanwar AJ, Bharija SC, Singh M, Belhaj MS. Fixed drug eruption to trimethoprim. Dermatologica 1986; 172: 230–1. 2 Hughes BR, Holt PJA, Marks R. Trimethoprim associated fixed drug eruption. Br J Dermatol 1987; 116: 241–2. 3 Lim JT, Chan HL. Fixed drug eruptions due to co-trimoxazole. Ann Acad Med Singapore 1992; 21: 408–10. 4 Özkaya-Bayazit E, Baykal C. Trimethoprim-induced linear fixed drug eruption. Br J Dermatol 1997; 137: 1028–9. 5 Alonso MD, Marcos C, Davila I et al. Hypersensitivity to trimethoprim. Allergy 1992; 47: 340–2.

Aminoglycosides Gentamicin, tobramycin, streptomycin and kanamycin cross-react and are all potentially ototoxic and nephrotoxic. Exanthematic eruptions are common with streptomycin, developing in 5% or more of patients. Continued treatment may lead to generalized exfoliative dermatitis in a minority [1], but in a proportion of patients the rash subsides and treatment can be continued. Fever and eosinophilia may be associated with the reactions. Urticaria [2], maculopapular rashes, fever and eosinophilia are well recognized with this group of drugs. Skin necrosis following subcutaneous injection of aminoglycoside antibiotics (gentamicin, sisomicin and netilmicin) has been reported in elderly females with a history of thrombosis being treated with heparin anticoagulant therapy [3–5]. The reaction has also occurred following intramuscular sisomicin in a patient with defective fibrinolysis and abnormal neutrophil function [6]. A toxic erythema with generalized follicular pustulosis has been documented with streptomycin [7]. Deafness has rarely followed topical therapy with neomycin, including administration of aerosol preparations in the treatment of extensive burns. An anaphylactic reaction due to streptomycin occurred during in vitro fertilization immediately after embryo transfer [8]. References 1 Karp S, Bakris G, Cooney A et al. Exfoliative dermatitis secondary to tobramycin sulfate. Cutis 1991; 47: 331–2. 2 Schretlen-Doherty JS, Troutman WG. Tobramycin-induced hypersensitivity reaction. Ann Pharmacother 1995; 29: 704–6. 3 Taillandier J, Manigaud G, Fixy P, Dumont D. Nécroses cutanées induites par la gentamicine sous-cutanée. Presse Med 1984; 13: 1574–5. 4 Duterque M, Hubert Asso AM, Corrard A. Lésions nécrotiques par injections sous cutanées de gentamicine et de sisomicine. Ann Dermatol Vénéréol 1985; 112: 707–8. 5 Bernard P, Paris M, Cantanzano G, Bonnetblanc JM. Vascularite cutanée localisée induite par la Nétilmicine. Presse Med 1987; 16: 915–6. 6 Grob JJ, Mege JL, Follano J et al. Skin necrosis after injection of aminoglycosides. Arthus reaction, local toxicity, thrombotic process or pathergy? Dermatologica 1990; 181: 258–62. 7 Kushimoto H, Aoki T. Toxic erythema with generalized follicular pustules caused by streptomycin. Arch Dermatol 1981; 117: 444–5. 8 Abeck D, Kuwert C, Segnini-Torres M et al. Streptomycin-induced anaphylactic reaction during in vitro fertilization (IVF). Allergy 1994; 49: 388–9.

Macrolide antibiotics Macrolides account for 10–15% of the worldwide oral antibiotic market, with severe adverse reactions being rare [1]. Gastrointes-

tinal reactions occur in 15–20% of patients on erythromycins and in 5% or fewer patients treated with some recently developed macrolide derivatives that seldom or never induce endogenous release of motilin, such as roxithromycin, clarithromycin, dirithromycin, azithromycin and rikamycin. Except for troleandomycin and some erythromycins administered at high dose and for long periods of time, the hepatotoxic potential of macrolides is low. Transient deafness and allergic reactions to macrolide antibacterials are highly unusual and are more common with the erythromycins than with the recently developed 14-, 15- and 16-membered macrolides.

Azithromycin This drug has caused toxic pustuloderma [2]. Clarithromycin Fixed drug eruption is recorded [3]. Erythromycin This is one of the most innocuous antibiotics in current use. Cholestasis caused by the estolate ester is the only potentially serious side effect. Hypersensitivity skin reactions are rare but when they occur skin tests may be positive [4,5]. Erythema multiforme, Stevens–Johnson syndrome, toxic pustuloderma [6], systemic contact dermatitis [7] and vasculitis have all been recorded. Spiramycin Rashes, usually transient erythema, may occur in up to 1% of cases. Spiramycin, given for toxoplasmosis in pregnancy, was associated in one case with an erythematous maculopapular pruritic eruption with eosinophilia and raised γ-glutamyl transpeptidase [8]. The drug has caused an allergic vasculitis [9]. References 1 Periti P, Mazzei T, Mini E, Novelli A. Adverse effects of macrolide antibacterials. Drug Saf 1993; 9: 346–64. 2 Trevisi P, Patrizi A, Neri I, Farina P. Toxic pustuloderma associated with azithromycin. Clin Exp Dermatol 1994; 19: 280–1. 3 Rosina P, Chieregato C, Schena D. Fixed drug eruption from clarithromycin. Contact Dermatitis 1998; 38: 105. 4 Van Ketel WG. Immediate and delayed-type allergy to erythromycin. Contact Dermatitis 1976; 2: 363–4. 5 Shirin H, Schapiro JM, Arber N et al. Erythromycin base-induced rash and liver function disturbances. Ann Pharmacother 1992; 26: 1522–3. 6 Roujeau J-C, Bioulac-Sage P, Bourseau C et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991; 127: 1333–8. 7 Fernandez Redondo V, Casas L, Taboada M, Toribio J. Systemic contact dermatitis from erythromycin. Contact Dermatitis 1994; 30: 311. 8 Ostlere LS, Langtry JAA, Staughton RCD. Allergy to spiramycin during prophlyactic treatment of fetal toxoplasmosis. BMJ 1991; 302: 970. 9 Galland MC, Rodor F, Jouglard J. Spiramycin allergic vasculitis: first report. Therapie 1987; 42: 227–9.

Clindamycin and lincomycin These antibiotics have become particularly associated with a potentially lethal pseudomembranous colitis due to superinfection with Clostridium difficile [1–3]. Vancomycin or metronidazole is the treatment of choice for this complication. Hypersensitivity skin reactions are rare with lincomycin but common with clinda-

Important or widely prescribed drugs

mycin, occurring in up to 10% of patients [4]. Erythema multiforme and anaphylaxis are very rare [5]. References 1 Dantzig PI. The safety of long-term clindamycin therapy for acne. Arch Dermatol 1976; 112: 53–4. 2 Tan SG, Cunliffe WJ. The unwanted effects of clindamycin in acne. Br J Dermatol 1976; 94: 313–5. 3 Anonymous. Antibiotic-associated colitis: a progress report. BMJ 1978; i: 669–71. 4 Lammintausta K, Tokola R, Kalimo K. Cutaneous adverse reactions to clindamycin: results of skin tests and oral exposure. Br J Dermatol 2002; 146: 643–8. 5 Lochmann O, Kohout P, Vymola F. Anaphylactic shock following the administration of clindamycin. J Hyg Epid Microb Immunol 1977; 21: 441–7.

Miscellaneous antibiotics Chloramphenicol Although contact dermatitis from topical application is common, hypersensitivity skin reactions to oral therapy are rare. Macular, papular and urticarial eruptions are reported [1], as is acute generalized exanthematous pustulosis [2]. Pruritus may be prominent. Erythema multiforme and TEN [3] occur rarely. There is a risk of aplastic anaemia [4] and death has exceptionally followed the use of eye drops [5]. References 1 Unsdek HE, Curtiss WP, Neill EJ. Skin eruption due to chloramphenicol (Chloromycetin®). Arch Dermatol Syphilol 1951; 64: 217. 2 Lee AY, Yoo SH. Chloramphenicol induced acute generalized exanthematous pustulosis proved by patch test and systemic provocation. Acta Derm Venereol (Stockh) 1999; 79: 412–3. 3 Mathe P, Aubert L, Labouche F et al. Syndrome de Lyell. Etiologie médicamenteuse: rôle probable de chloramphénicol. J Méd Bordeaux 1965; 42: 1367–76. 4 Hargraves MM, Mills SD, Heck FJ. Aplastic anemia associated with the administration of chloramphenicol. JAMA 1952; 149: 1293–300. 5 Fraunfelder FT, Bagby GC. Ocular chloramphenicol and aplastic anemia. N Engl J Med 1983; 308: 1536.

Fusidic acid Topical use can lead to contact dermatitis but hypersensitivity reactions to oral or parenteral use are very rare; jaundice has accompanied intravenous use. Acanthosis nigricans-like lesions have been reported after local application [1]. Reference 1 Teknetzis A, Lefaki I, Joannides D, Minas A. Acanthosis nigricans-like lesions after local application of fusidic acid. J Am Acad Dermatol 1993; 28: 501–2.

Metronidazole and tinidazole Metronidazole. Pruritus, fixed eruptions and generalized erythema [1–4] are rare. A pityriasis rosea-like eruption has been described [5]. A reversible peripheral neuropathy may complicate prolonged therapy. Tinidazole. A fixed eruption with cross-reactivity with metronidazole has been reported [6,7]. References 1 Naik RPC, Singh G. Fixed drug eruption due to metronidazole. Dermatologica 1977; 155: 59–60.

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2 Shelley WB, Shelley ED. Fixed drug eruption due to metronidazole. Cutis 1987; 39: 393–4. 3 Gastaminza G, Anda M, Audicana MT et al. Fixed-drug eruption due to metronidazole with positive topical provocation. Contact Dermatitis 2001; 44: 36. 4 Knowles S, Choudhury T, Shear NH. Metronidazole hypersensitivity. Ann Pharmacother 1994; 28: 325–6. 5 Maize JC, Tomecki KJ. Pityriasis rosea-like drug eruption secondary to metronidazole. Arch Dermatol 1977; 113: 1457–8. 6 Kanwar AJ, Sharma R, Rajagopalan M, Kaur S. Fixed drug eruption due to tinidazole with cross-reactivity with metronidazole. Dermatologica 1990; 181: 277. 7 Mishra D, Mobashir M, Zaheer MS. Fixed drug eruption and cross-reactivity between tinidazole and metronidazole. Int J Dermatol 1990; 29: 740.

Nitrofurantoin Pruritus, morbilliform rashes and urticaria may be seen occasionally. Erythema multiforme, erythema nodosum [1], exfoliative dermatitis and an LE-like syndrome [2] are documented. Acute or chronic pulmonary reactions may accompany these skin manifestations, and may lead to pulmonary fibrosis [3]. Polyneuritis is a dose-dependent toxic reaction. Hepatitis, cholestatic jaundice and marrow suppression may occur rarely. Abnormal immunoelectrophoretic patterns may be induced [4]. References 1 Chisholm JC, Hepner M. Nitrofurantoin induced erythema nodosum. J Natl Med Assoc 1981; 73: 59–61. 2 Selross O, Edgren J. Lupus-like syndrome associated with pulmonary reaction to nitrofurantoin. Acta Med Scand 1975; 197: 125–9. 3 Rantala H, Kirvelä O, Anttolainen I. Nitrofurantoin lung in a child. Lancet 1979; ii: 799–80. 4 Teppo AM, Haltia K, Wager O. Immunoelectrophoretic ‘tailing’ of albumin line due to albumin–IgG antibody complexes: a side effect of nitrofurantoin treatment? Scand J Immunol 1976; 5: 249–61.

Quinolones These compounds are related to nalidixic acid; central nervous system toxicity, upper gastrointestinal tract reactions and phototoxicity have been recorded [1–7]. Cross-reactivity occurs [8]. Gastrointestinal side effects occur in up to 6% of patients. Hypersensitivity reactions involving the skin have been reported in 0.5– 2% of patients, and in up to 2.4% of patients receiving cinoxacin; they most frequently manifest themselves as rash or pruritus. Delayed hypersensitivity reactions are recorded with ciprofloxacin, norfloxacin and moxifloxacin [9]. Fever, urticaria, angiooedema and anaphylactoid reactions are rare. Anaphylactic or anaphylactoid reactions have been documented with cinoxacin [10], ciprofloxacin (1.2 per 100 000 prescriptions) [11,12] and pipemidic acid [13]. Fixed drug eruption due to pipemidic acid is recorded [14]. Norfloxacin [15] and ofloxacin [16] have caused a pustular eruption, and ciprofloxacin acute generalized exanthematous pustulosis [17]. Ciprofloxacin [18–20], pefloxacin, fleroxacin [21] and enoxacin [22] have been associated with photosensitivity. Photolocalized purpura has occurred with ciprofloxacin [20]. Pefloxacin and ofloxacin have caused photo-onycholysis [23], and sparfloxacin has been implicated in photosensitivity and a lichenoid tissue reaction [24]. Levofloxacin has caused a radiation recall reaction [25]. Hypersensitivity leukocytoclastic vasculitis has been reported with both ofloxacin and ciprofloxacin [26,27], and serum sickness with ciprofloxacin [28]. Intravenous administration of ciprofloxacin through small veins on the dorsa of the hands may

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be associated with local reactions at the site of infusion [29]. Stevens–Johnson syndrome or TEN has been described with quinolones [30], including ciprofloxacin [31]. Ciprofloxacin has caused bullous pemphigoid [32]. Nalidixic acid. Cutaneous reactions are common, occurring in up to 5% of patients; various hypersensitivity reactions are seen, including exfoliative dermatitis. Phototoxicity is now well recognized [33–37]. A bullous photodermatitis may occur, usually on the hands or feet; chronic scarring and increased skin fragility may mimic porphyria cutanea tarda. Long-wave UV light is responsible [37]. An LE-like syndrome has been reported [38], as well as transient alopecia. References 1 Christ W, Lehnert T, Ulbrich B. Specific toxicologic aspects of the quinolones. Rev Infect Dis 1988; 10 (Suppl. 1): S141–S146. 2 Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989; 2: 378–424. 3 Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med 1991; 324: 384–94. 4 Sisca TS, Heel RC, Romankiewicz JA. Cinoxacin: a review of its pharmacological properties and therapeutic efficacy in the treatment of urinary tract infections. Drugs 1983; 25: 544–69. 5 Campoli-Richards DM, Monck JP, Price A et al. Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1988; 35: 373–447. 6 Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993; 45 (Suppl. 3): 59–64. 7 Matsuno K, Kunihiro E, Yamatoya O et al. Surveillance of adverse reactions due to ciprofloxacin in Japan. Drugs 1995; 49 (Suppl. 2): 495–6. 8 Davila I, Diez ML, Quirce S et al. Cross-reactivity between quinolones. Report of three cases. Allergy 1993; 48: 388–90. 9 Schmid DA, Depta JP, Pichler WJ. T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity. Clin Exp Allergy 2006; 36: 59–69. 10 Stricker BHC, Slagboom G, Demaeseneer R et al. Anaphylactic reactions to cinoxacin. BMJ 1988; 297: 1434–5. 11 Davis H, McGoodwin E, Reed TG. Anaphylactoid reactions reported after treatment with ciprofloxacin. Ann Intern Med 1989; 111: 1041–3. 12 Deamer RL, Prichard JG, Loman GJ. Hypersensitivity and anaphylactoid reactions to ciprofloxacin. Ann Pharmacother 1992; 26: 1081–4. 13 Gerber D. Anaphylaxis caused by pipemidic acid. S Afr Med J 1985; 67: 999. 14 Miyagawa S, Yamashina Y, Hirota S, Shirai T. Fixed drug eruption due to pipemidic acid. J Dermatol 1991; 18: 59–60. 15 Shelley ED, Shelley WB. The subcorneal pustular drug eruption: an example induced by norfloxacin. Cutis 1988; 42: 24–7. 16 Tsuda S, Kato K, Karashima T et al. Toxic pustuloderma induced by ofloxacin. Ann Dermatol Vénéréol 1993; 73: 382–4. 17 Hausermann P, Scherer K, Weber M, Bircher AJ. Ciprofloxacin-induced acute generalized exanthematous pustulosis mimicking bullous drug eruption confirmed by a positive patch test. Dermatology 2005; 211: 277–80. 18 Nederost ST, Dijkstra JWE, Handel DW. Drug-induced photosensitivity reaction. Arch Dermatol 1989; 125: 433–4. 19 Ferguson J, Johnson BE. Ciprofloxacin-induced photosensitivity: in vitro and in vivo studies. Br J Dermatol 1990; 123: 9–20. 20 Urbina F, Barrios M, Sudy E. Photolocalized purpura during ciprofloxacin therapy. Photodermatol Photo 2006; 22: 111–2. 21 Bowie WR, Willetts V, Jewesson PJ. Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin. Antimicrob Agents Chemother 1989; 33: 1778–82. 22 Izu R, Gardeazabal J, Gonzalez M et al. Enoxacin-induced photosensitivity: study of two cases. Photodermatol Photoimmunol Photomed 1992; 9: 86–8. 23 Baran R, Brun P. Photo-onycholysis induced by the fluoroquinolones pefloxacine and ofloxacine. Report on 2 cases. Dermatologica 1986; 173: 185–8.

24 Hamanaka H, Mizutani H, Shimizu M. Sparfloxacin-induced photosensitivity and the occurrence of a lichenoid tissue reaction after prolonged exposure. J Am Acad Dermatol 1998; 38: 945–9. 25 Cho S, Breedlove JJ, Gunning ST. Radiation recall reaction induced by levofloxacin. J Drugs Dermatol 2008; 7: 64–7. 26 Huminer C, Cohen JD, Majafla R, Dux S. Hypersensitivity vasculitis due to ofloxacin. BMJ 1989; 299: 303. 27 Choc U, Rothschield BM, Laitman L. Ciprofloxacin-induced vasculitis. N Engl J Med 1989; 320: 257–8. 28 Guharoy SR. Serum sickness secondary to ciprofloxacin use. Vet Hum Toxicol 1994; 36: 540–1. 29 Thorsteinsson SB, Bergan T, Johannesson G et al. Tolerance of ciprofloxacin at injection site, systemic safety and effect on electroencephalogram. Chemotherapy 1987; 33: 448–51. 30 Roujeau JC, Kelly JP, Naldi L et al. Medication use and the risk of Stevens– Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333: 1600–7. 31 Tham TCK, Allen G, Hayes D et al. Possible association between toxic epidermal necrolysis and ciprofloxacin. Lancet 1991; 338: 522. 32 Kimyai-Asadi A, Usman A, Nousari HC. Ciprofloxacin-induced bullous pemphigoid. J Am Acad Dermatol 2000; 42: 847. 33 Baes H. Photosensitivity caused by nalidixic acid. Dermatologica 1968; 136: 61–4. 34 Birkett DA, Garretts M, Stevenson CJ. Phototoxic bullous eruptions due to nalidixic acid. Br J Dermatol 1969; 81: 342–4. 35 Ramsay CA, Obreshkova E. Photosensitivity from nalidixic acid. Br J Dermatol 1974; 91: 523–8. 36 Rosén K, Swanbeck G. Phototoxic reactions from some common drugs provoked by a high-intensity UVA lamp. Acta Derm Venereol (Stockh) 1982; 62: 246–8. 37 Nederost ST, Dijkstra JWE, Handel DW. Drug-induced photosensitivity reaction. Arch Dermatol 1989; 125: 433–4. 38 Rubinstein A. LE-like disease caused by nalidixic acid. N Engl J Med 1979; 301: 1288.

Synergistins An eczema-like drug eruption is recorded after oral antibiotic synergistins, pristinamycin and virginiamycin, following contact sensitization with topical virginiamycin [1]. Pristinamycin is associated with acute generalized exanthematous pustulosis (AGEP) [2,3]. References 1 Michel M, Dompmartin A, Szczurko C et al. Eczematous-like drug eruption induced by synergistins. Contact Dermatitis 1996; 34: 86–7. 2 Saissi EH, Beau-Salinas F, Jonville-Béra AP et al. Drugs associated with acute generalized exanthematic pustulosis. Ann Dermatol Venereol 2003; 130: 612–8. 3 Sidoroff A, Dunant A, Viboud C et al. Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007; 157: 989–96.

Vancomycin Allergic skin reactions are not uncommon, occurring in up to 5% of patients. Rapid intravenous infusion of vancomycin can cause a histamine-induced anaphylactoid reaction characterized by flushing, a maculopapular eruption of the neck, face, trunk and extremities (so-called ‘red man syndrome’), prolonged hypotension and, in rare cases, cardiac arrest [1–3]. Desensitization has been successfully achieved in patients with vancomycin hypersensitivity [4–6]. TEN has occurred [7]. Vancomycin has been reported to have induced linear IgA bullous dermatosis [8–12], which may mimic TEN [13].

Important or widely prescribed drugs References 1 Pau AK, Khakoo R. Red-neck syndrome with slow infusion of vancomycin. N Engl J Med 1985; 313: 756–7. 2 Valero R, Gomar C, Fita G et al. Adverse reactions to vancomycin prophylaxis in cardiac surgery. J Cardiothor Vasc Anesth 1991; 5: 574–6. 3 Killian AD, Sahai JV, Memish ZA. Red man syndrome after oral vancomycin. Ann Intern Med 1991; 115: 410–31. 4 Lin RY. Desensitization in the management of vancomycin hypersensitivity. Arch Intern Med 1990; 150: 2197–8. 5 Anne S, Middleton E Jr, Reisman RE. Vancomycin anaphylaxis and successful desensitization. Ann Allergy 1994; 73: 402–4. 6 Wong JT, Ripple RE, MacLean JA et al. Vancomycin hypersensitivity: synergism with narcotics and ‘desensitization’ by a rapid continuous intravenous protocol. J Allergy Clin Immunol 1994; 94: 189–94. 7 Vidal C, Gonzalez Quintela A, Fuente R. Toxic epidermal necrolysis due to vancomycin. Ann Allergy 1992; 68: 345–7. 8 Baden LA, Apovian C, Imber MJ, Dover JS. Vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol 1988; 124: 1186–8. 9 Carpenter S, Berg D, Sidhu-Malik N et al. Vancomycin-associated linear IgA dermatosis. A report of three cases. J Am Acad Dermatol 1992; 26: 45–8. 10 Piketty C, Meeus F, Nochy D et al. Linear IgA dermatosis related to vancomycin. Br J Dermatol 1994; 130: 130–1. 11 Whitworth JM, Thomas I, Peltz S et al. Vancomycin-induced linear IgA bullous dermatosis (LABD). J Am Acad Dermatol 1996; 34: 890–1. 12 Palmer RA, Ogg G, Allen J et al. Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285. Br J Dermatol 2001; 145: 816–20. 13 Dellavalle RP, Burch HM, Tyal S et al. Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. J Am Acad Dermatol 2003; 48: S56–S57.

Topical antibiotics The side effects of topical antibiotics have been reviewed [1]. Allergic contact dermatitis is rare with topical clindamycin, erythromycin and tetracycline, polymyxin B, gentamicin and mupirocin, but is more frequent with neomycin.

Bacitracin Anaphylaxis due to bacitracin allergy has followed topical application of this antibiotic [2–5]. The patients had had multiple prior exposures and previous local reactions of pruritus, urticaria or possible allergic contact dermatitis. Two patients with anaphylactic reactions to Polyfax ointment, containing polymyxin B and bacitracin, have been reported; one had previously documented positive patch tests to Polyfax, and the other had clinical intolerance to the preparation [5]. Another patient developed anaphylaxis to a similar proprietary mixture (Polysporin) [6]. Intracutaneous injection of bacitracin in sensitive individuals induces histamine release with large weal-and-flare reactions [7]. Chloramphenicol Urticaria and angio-oedema have been described with topical use [8]. Fatal aplastic anaemia has followed the use of eye drops containing this antibiotic [9]. Sulphonamides Erythema multiforme and Stevens–Johnson syndrome have been reported from topical preparations [10,11]. References 1 Hirschmann JV. Topical antibiotics in dermatology. Arch Dermatol 1988; 124: 1691–700.

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2 Roupe G, Strannegård Ö. Anaphylactic shock elicited by topical administration of bacitracin. Arch Dermatol 1969; 100: 450–2. 3 Shechter JF, Wilkinson RD, Del Carpio J. Anaphylaxis following the use of bacitracin ointment: report of a case and review of the literature. Arch Dermatol 1984; 120: 909–11. 4 Katz BE, Fisher AA. Bacitracin: a unique topical antibiotic sensitiser. J Am Acad Dermatol 1987; 17: 1016–24. 5 Eedy DJ, McMillan JC, Bingham EA. Anaphylactic reactions to topical antibiotic combinations. Postgrad Med J 1990; 66: 858–9. 6 Knowles SR, Shear NH. Anaphylaxis from bacitracin and polymyxin B (Polysporin) ointment. Int J Dermatol 1995; 34: 572–3. 7 Bjorkner B, Moller H. Bacitracin: a cutaneous allergen and histamine releaser. Acta Derm Venereol (Stockh) 1973; 53: 487–91. 8 Schewach-Millet M, Shapiro D. Urticaria and angioedema due to topically applied chloramphenicol ointment. Arch Dermatol 1985; 121: 587. 9 Fraunfelder FT, Bagby GC. Ocular chloramphenicol and aplastic anemia. N Engl J Med 1983; 308: 1536. 10 Genvert GI, Cohen EJ, Donnenfeld ED, Blecher MH. Erythema multiforme after use of topical sulfacetamide. Am J Ophthalmol 1985; 99: 465–8. 11 Gottschalk HR, Stone OJ. Stevens–Johnson syndrome from ophthalmic sulphonamide. Arch Dermatol 1976; 112: 513–4.

Antituberculous drugs Side effects from first-line antituberculous medications (isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin) are common, and include hepatitis, cutaneous reactions, gastrointestinal intolerance, haematological reactions and renal failure [1]. Severe cutaneous reactions (such as Stevens–Johnson syndrome and TEN) and multiple drug reactions to antituberculous drugs (including thioacetazone, streptomycin and isoniazid) occur more often in HIV-positive patients [2–6]. The World Health Organization has advised against the use of thioacetazone in tuberculosis patients with known, or suspected, HIV infection in view of the severe cutaneous hypersensitivity [4–6]. The following drugs are reported to cause contact dermatitis: isoniazid, rifampicin, ethambutol, p-aminosalicylic acid, streptomycin and kanamycin [7]. The incidence of other reactions to individual drugs is difficult to assess because several drugs are usually used in combination.

Cycloserine A lichenoid drug eruption with positive patch tests and resolution 4 months after withdrawal has been reported [8]. Ethambutol Hypersensitivity reactions are very rare. Side effects are largely confined to visual disturbances, with loss of acuity, colour blindness and restricted visual fields; these are usually reversible if the drug is stopped promptly. Patients should have ophthalmic assessments prior to and during therapy. Lichenoid reactions occur and may be restricted to light-exposed sites [9,10]. Ethionamide Eczema chiefly affecting the forehead, acneiform eruptions, butterfly eruptions on the face, stomatitis, alopecia and purpura have been reported. Isoniazid Allergic skin reactions occur in fewer than 1% of patients. An acneiform eruption, usually occurring in slow inactivators of the drug, is well recognized [11,12]. Urticaria, purpura and an LE-like

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syndrome [13,14] have been reported, as have photosensitive lichenoid eruptions [15]. Rarely, a pellagra-like syndrome has been induced in malnourished patients, due to metabolic antagonism of nicotinic acid with resultant pyridoxine deficiency [11,16]. Exfoliative dermatitis [17] and Stevens–Johnson syndrome [3] have been reported.

Pyrazinamide Hepatitis, arthralgia, flushing, photosensitivity, lichenoid photodermatitis, maculopapular rashes, urticaria and pellagra are recorded [18]. Rifampicin Cutaneous hypersensitivity reactions are very uncommon but are recorded [19]. There have been isolated reports of LE [20], erythema nodosum leprosum-like eruption in borderline lepromatous leprosy [21], exacerbation of bullous erythema multiforme, TEN [22] and pemphigus [23,24]; existing pemphigus may also be exacerbated [25]. Altered liver function, usually transient, and thrombocytopenic purpura may occur. Rifampicin has precipitated porphyria cutanea tarda [26]. It induces liver enzymes and may thus reduce the effectiveness of a number of drugs, including oral contraceptives. Streptomycin See Aminoglycosides section on p. 75.58. Thioacetazone Severe cutaneous hypersensitivity reactions have been reported, including maculopapular rashes (which progress to mucosal involvement with constitutional symptoms), Stevens–Johnson syndrome and TEN, especially in HIV-seropositive patients [3,4,6,27,28]. Cutaneous hypersensitivity reactions have been reported in 20% of HIV-seropositive patients compared with 1% of HIV-seronegative patients who receive the drug as part of treatment for tuberculosis [26]. Figurate erythematous eruptions resembling erythema annulare centrifugum may occur [29]. References 1 Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 2006; 5: 231–49. 2 Pozniak AL, MacLeod GA, Mahari M et al. The influence of HIV status on single and multiple drug reactions to antituberculous therapy in Africa. AIDS 1992; 6: 809–14. 3 Dukes CS, Sugarman J, Cegielski JP et al. Severe cutaneous hypersensitivity reactions during treatment of tuberculosis in patients with HIV infection in Tanzania. Trop Geogr Med 1992; 44: 308–11. 4 Chintu C, Luo C, Bhat G et al. Cutaneous hypersensitivity reactions due to thiacetazone in the treatment of tuberculosis in Zambian children infected with HIV-I. Arch Dis Child 1993; 68: 665–8. 5 Nunn P, Porter J, Winstanley P. Thiacetazone: avoid like poison or use with care? Trans R Soc Trop Med Hyg 1993; 87: 578–82. 6 Kelly P, Buve A, Foster SD et al. Cutaneous reactions to thiacetazone in Zambia: implications for tuberculosis treatment strategies. Trans R Soc Trop Med Hyg 1994; 88: 113–5. 7 Holdiness MR. Contact dermatitis to antituberculous drugs. Contact Dermatitis 1986; 15: 282–8. 8 Shim JH, Kim TY, Kim HO, Kim CW. Cycloserine-induced lichenoid drug eruption. Dermatology 1995; 191: 142–4. 9 Frentz G, Wadskov S, Kssis V. Ethambutol-induced lichenoid eruption. Acta Derm Venereol (Stockh) 1981; 61: 89–91.

10 Grossman ME, Warren K, Mady A, Satra KH. Lichenoid eruption associated with ethambutol. J Am Acad Dermatol 1995; 33: 675–6. 11 Cohen LK, George W, Smith R. Isoniazid-induced acne and pellagra. Occurrence in slow acetylators of isoniazid. Arch Dermatol 1974; 109: 377–81. 12 Oliwiecki S, Burton JL. Severe acne due to isoniazid. Clin Exp Dermatol 1988; 13: 283–4. 13 Grunwald M, David M, Feuerman EJ. Appearance of lupus erythematosus in a patient with lichen planus treated by isoniazid. Dermatologica 1982; 165: 172–7. 14 Sim E, Gill EW, Sim RB. Drugs that induce systemic lupus erythematosus inhibit complement C4. Lancet 1984; ii: 422–4. 15 Lee AY, Jung SY. Two patients with isoniazid-induced photosensitive lichenoid eruptions confirmed by photopatch test. Photodermatol Photoimmunol Photomed 1998; 14: 77–8. 16 Schmutz JL, Cuny JF, Trechot P et al. Les érythemes pellagroïdes médicamenteux. Une observation d’érytheme pellagroïde secondaire a l’isoniazide. Ann Dermatol Vénéréol 1987; 114: 569–76. 17 Rosin MA, King LE Jr. Isoniazid-induced exfoliative dermatitis. South Med J 1982; 75: 81. 18 Choonhakarn C, Janma J. Pyrazinamide-induced lichenoid photodermatitis. J Am Acad Dermatol 1999; 40: 645–6. 19 Buergin S, Scherer K, Häusermann P, Bircher AJ. Immediate hypersensitivity to rifampicin in 3 patients: diagnostic procedures and induction of clinical tolerance. Int Arch Allergy Immunol 2006; 140: 20–6. 20 Patel GK, Anstey AV. Rifampicin-induced lupus erythematosus. Clin Exp Dermatol 2001; 26: 260–2. 21 Karthikeyan K, Thappa DM, Kadhiravan T. Rifampicin-induced erythema nodosum leprosum-like eruption in borderline lepromatous leprosy. Ind J Leprosy 2001; 73: 167–9. 22 Okano M, Kitano Y, Igarashi T. Toxic epidermal necrolysis due to rifampicin. J Am Acad Dermatol 1987; 17: 303–4. 23 Gange RW, Rhodes EL, Edwards CO, Powell MEA. Pemphigus induced by rifampicin. Br J Dermatol 1976; 95: 445–8. 24 Lee CW, Lim JH, Kang HJ. Pemphigus foliaceus induced by rifampicin. Br J Dermatol 1984; 111: 619–22. 25 Miyagawa S, Yamanashi Y, Okuchi T et al. Exacerbation of pemphigus by rifampicin. Br J Dermatol 1986; 114: 729–32. 26 Millar JW. Rifampicin-induced porphyria cutanea tarda. Br J Dis Chest 1980; 74: 405–8. 27 Fegan D, Glennon J. Cutaneous sensitivity to thiacetazone. Lancet 1991; 337: 1036. 28 Nunn P, Kibuga D, Gathua S et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991; 337: 627–30. 29 Ramesh V. Eruption resembling erythema annulare centrifugum. Australas J Dermatol 1987; 28: 44.

Antileprotic drugs Clofazimine This drug regularly causes a reversible, dose-dependent, brownorange pigmentation of the skin [1–3]. Biopsy specimens from two lepromatous leprosy patients on long-term clofazimine therapy revealed ceroid-lipofuscin pigment as well as clofazimine inside macrophage phagolysosomes [3]. Reddish-blue pigmentation occurred in scarred areas of LE in one patient [4]. Xeroderma, pruritus, phototoxicity, acne and non-specific rashes are described [2]. Gastrointestinal symptoms may occur early due to direct irritation of the gut and are quickly reversible; ulcerative enteritis may occur after 9–14 months of treatment. After prolonged highdose therapy, persistent diarrhoea, abdominal pain and weight loss, associated with deposition of crystalline clofazimine in the small intestinal submucosa and mesenteric lymph nodes, may occur [5,6]. Splenic infarction has been associated with this syndrome [7,8].

Important or widely prescribed drugs References 1 Thomsen K, Rothenborg HW. Clofazimine in the treatment of pyoderma gangrenosum. Arch Dermatol 1979; 115: 851–2. 2 Yawalker SJ, Vischer W. Lamprene (clofazimine) in leprosy. Basic information. Lepr Rev 1979; 50: 135–44. 3 Job CK, Yoder L, Jacobson RR, Hastings RC. Skin pigmentation from clofazimine therapy in leprosy patients: a reappraisal. J Am Acad Dermatol 1990; 23: 236–41. 4 Kossard S, Doherty E, McColl I, Ryman W. Autofluorescence of clofazimine in discoid lupus erythematosus. J Am Acad Dermatol 1987; 17: 867–71. 5 Harvey RF, Harman RRM, Black C et al. Abdominal pain and malabsorption due to tissue deposition of clofazimine (Lamprene) crystals. Br J Dermatol 1977; 97 (Suppl. 15): 19. 6 Venencie PY, Cortez A, Orieux G et al. Clofazimine enteropathy. J Am Acad Dermatol 1986; 15: 290–1. 7 Jopling WAH. Complications of treatment with clofazimine (Lamprene: B.663). Lepr Rev 1976; 47: 1–3. 8 McDougal AC, Horsfall WR, Hede JE, Chaplin AJ. Splenic infarction and tissue accumulation of crystals associated with the use of clofazimine (Lamprene: B.663) in the treatment of pyoderma gangrenosum. Br J Dermatol 1980; 102: 227–30.

Dapsone Reactions have been reviewed [1]. Fixed eruptions occur in 3% of West Africans being treated for leprosy. Erythema multiforme [2] and exfoliative dermatitis [3] have been described during leprosy treatment. Another uncommon side effect is a hypersensitivity reaction (dapsone or sulphone syndrome) within 2 to 7 weeks (mean 29 days), with fever, a widespread erythematous eruption studded with pustules, exfoliative dermatitis, hepatitis, lymphadenopathy and anaemia; it may progress to Stevens– Johnson syndrome [4–11]. In Vanuatu, 24% of 37 patients treated over 4 years with daily dapsone 100 mg, clofazimine, and monthly rifampicin and clofazimine for leprosy developed the dapsone syndrome, with a fatality rate of 11% [12]. The increase in reactions may have related to a high starting dose of dapsone, possibly enhanced by the combination with clofazimine and rifampicin and by a genetic susceptibility of the Melanesian population. Red cell life is always shortened, but clinical haemolytic anaemia is uncommon; patients with low red cell glucose-6-phosphate dehydrogenase levels [13] and those who are slow acetylators [14] are at a special risk of developing this complication. Methaemoglobinaemia and Heinz body formation are seen [15]. Agranulocytosis is rare but well recognized and may occur in the first weeks of therapy [16–19]. For patients receiving the drug for dermatitis herpetiformis, this side effect occurred at a median dosage of 100 mg/day and a median duration of therapy of 7 weeks [17]. The total risk was one case per 3000 patient-years of exposure to the drug; however, agranulocytosis was estimated to occur in 1 in 240 to 1 in 425 new patients receiving dapsone for dermatitis herpetiformis [17]. Agranulocytosis occurred in approximately 1 in 10 000 to 1 in 20 000 US soldiers receiving dapsone for malarial prophylaxis [19]. Elderly patients do not tolerate dapsone well, and sulfapyridine or sulfamethoxypyridazine (the latter obtainable on a named-patient basis from Lederle Laboratories) is to be preferred for IgA-related diseases. A fatal haematological reaction developed in a Burmese boy during induction of treatment for lepromatous leprosy [20]. Severe but usually reversible hypoalbuminaemia due to failure of albumin production [21,22] or an atypical nephrotic syndrome may occur. Rarely, dapsone causes a peripheral neuropathy,

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usually purely motor or mixed sensorimotor and usually recovering within a year [23–26], and optic atrophy [26]. Permanent retinal damage has followed overdosage [27]. Headaches [28], and occasionally a psychosis [29], may be precipitated. References 1 Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology. Overview and update. J Am Acad Dermatol 2001; 45: 420–34. 2 Dutta RK. Erythema multiforme bullosum due to dapsone. Lepr India 1980; 52: 306–9. 3 Browne SG. Antileprosy drugs. BMJ 1971; iv: 558–9. 4 Tomecki KJ, Catalano CJ. Dapsone hypersensitivity: the sulfone syndrome revisited. Arch Dermatol 1981; 117: 38–9. 5 Mohle-Boetani J, Akula SK, Holodniy M et al. The sulfone syndrome in a patient receiving dapsone prophylaxis for Pneumocystis carinii pneumonia. West J Med 1992; 156: 303–6. 6 Barnard GF, Scharf MJ, Dagher RK. Sulfone syndrome in a patient receiving steroids for pemphigus. Am J Gastroenterol 1994; 89: 2057–9. 7 Saito S, Ikezawa Z, Miyamoto H, Kim S. A case of the ‘dapsone syndrome’. Clin Exp Dermatol 1994; 19: 152–6. 8 Chalasani P, Baffoe-Bonnie H, Jurado RL. Dapsone therapy causing sulfone syndrome and lethal hepatic failure in an HIV-infected patient. South Med J 1994; 87: 145–6. 9 Bocquet H, Bourgault-Villada I, Delfau-Larue MH et al. Syndrome d’hypersensibilité à la dapsone. Clone T circulant transitoire. Ann Dermatol Vénéréol 1995; 122: 514–6. 10 Prussick R, Shear NH. Dapsone hypersensitivity syndrome. J Am Acad Dermatol 1996; 35: 346–9. 11 Agrawal S, Agarwalla A. Dapsone hypersensitivity syndrome: a clinico-epidemiological review. J Dermatol 2005; 32: 883–9. 12 Reeve PA, Ala J, Hall JJ. Dapsone syndrome in Vanuatu: a high incidence during multidrug treatment (MDT) of leprosy. J Trop Med Hyg 1992; 95: 266–70. 13 Beutler E. Glucose-6-phosphate dehydrogenase deficiency. Lancet 1991; 324: 169–74. 14 Ellard GA, Gammon PT, Savin LA, Tan RSH. Dapsone acetylation in dermatitis herpetiformis. Br J Dermatol 1974; 90: 441–4. 15 Wagner A, Marosi C, Binder M et al. Fatal poisoning due to dapsone in a patient with grossly elevated methaemoglobin levels. Br J Dermatol 1995; 133: 816–7. 16 Potter MN, Yates P, Slade R, Kennedy CTC. Agranulocytosis caused by dapsone therapy for granuloma annulare. J Am Acad Dermatol 1989; 20: 87–8. 17 Hörnstein P, Keisu M, Wiholm B-E. The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Arch Dermatol 1990; 126: 919–22. 18 Cockburn EM, Wood SM, Waller PC, Bleehen SS. Dapsone-induced agranulocytosis: spontaneous reporting data. Br J Dermatol 1993; 128: 702–3. 19 Ognibene AJ. Agranulocytosis due to dapsone. Ann Intern Med 1970; 75: 521–4. 20 Frey HM, Gershon AA, Borkowsky W, Bullock WE. Fatal reaction to dapsone during treatment of leprosy. Ann Intern Med 1981; 94: 777–9. 21 Kingham JG, Swain P, Swarbrick ET et al. Dapsone and severe hypoalbuminaemia: a report of two cases. Lancet 1979; ii: 662–4. 22 Cowan RE, Wright JT. Dapsone and severe hypoalbuminaemia in dermatitis herpetiformis. Br J Dermatol 1981; 104: 201–4. 23 Waldinger TP, Siegle RJ, Weber W et al. Dapsone-induced peripheral neuropathy. Case report and review. Arch Dermatol 1984; 120: 356–9. 24 Ahrens EM, Meckler RJ, Callen JP. Dapsone-induced peripheral neuropathy. Int J Dermatol 1986; 25: 314–6. 25 Rhodes LE, Coleman MD, Lewis-Jones MS. Dapsone-induced motor peripheral neuropathy in pemphigus foliaceus. Clin Exp Dermatol 1995; 20: 155–6. 26 Homeida M, Babikr A, Daneshmend TK. Dapsone-induced optic atrophy and motor neuropathy. BMJ 1980; 281: 1180. 27 Kenner DJ, Holt K, Agnello R, Chester GH. Permanent retinal damage following massive dapsone overdose. Br J Ophthalmol 1980; 64: 741–4. 28 Guillet G, Krausz I, Guillet MH, Carlhant D. Survenue de cephalées en cours de traitement par dapsone. Ann Dermatol Vénéréol 1992; 119: 46. 29 Fine J-D, Katz SI, Donahue MJ, Hendricks AA. Psychiatric reaction to dapsone and sulfapyridine. J Am Acad Dermatol 1983; 9: 274–5.

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Chapter 75: Drug Reactions

Thalidomide

Amphotericin

Teratogenicity (phocomelia), gastric intolerance, drowsiness, neuropsychiatric upset and a sensory peripheral neuropathy developing after several months have been reported [1]. Minor to moderate skin eruptions occur in up to 46% of patients taking thalidomide, including morbilliform, seborrhoeic, maculopapular and non-specific rashes; severe skin reactions such as exfoliative erythroderma, erythema multiforme and TEN are rare [2]. A dermatitis associated with eosinophilia develops in a few cases of erythema nodosum leprosum treated with thalidomide over several years [3]. Hypersensitivity reactions characterized by fever, tachycardia and an extensive erythematous macular eruption developed on rechallenge in a number of patients with HIV infection treated with thalidomide for severe aphthous oropharyngeal ulceration [4]. In addition, brittle fingernails, exfoliative erythroderma [5], toxic pustuloderma [6], face or limb oedema, pruritus, red palms and xerostomia have been described [7]. Deep vein thrombosis is documented [8].

Skin reactions are rare. The ‘grey syndrome’, characterized by ashen colour, acral cyanosis and prostration, may occur as an immediate reaction to infusion. Allergic reactions occur to liposomal amphotericin [1,2].

Fluconazole Angio-oedema has occurred [3], as has fixed drug eruption [4]. An anaphylactic reaction developed in a patient who had previously received ketoconazole and metronidazole, suggesting cross-sensitization [5], and Stevens–Johnson syndrome has been reported in a patient with AIDS [6]. Thrombocytopenia is described [7].

Flucytosine Transitory macular and urticarial rashes have been seen. A toxic erythema occurred in a patient [8]. Anaphylaxis has been reported in a patient with AIDS [9]. Bone marrow depression can occur.

Itraconazole References 1 Revuz J. Actualité du thalidomide. Ann Dermatol Vénéréol 1990; 117: 313–21. 2 Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV. Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 2003; 48: 548–52. 3 Waters MFR. An internally controlled double blind trial of thalidomide in severe erythema nodosum leprosum. Lepr Rev 1971; 42: 26–42. 4 Williams I, Weller IVD, Malin A et al. Thalidomide hypersensitivity in AIDS. Lancet 1991; 337: 436–7. 5 Bielsa I, Teixido J, Ribera M, Ferrandiz C. Erythroderma due to thalidomide: report of two cases. Dermatology 1994; 189: 179–81. 6 Darvay A, Basarab T, Russell-Jones R. Thalidomide-induced toxic pustuloderma. Clin Exp Dermatol 1997; 22: 297–9. 7 Tseng S, Pak G, Washenik K et al. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996; 35: 969–79. 8 Sharma NL, Sharma VC, Mahajan VK et al. Thalidomide: an experience in therapeutic outcome and adverse reactions. J Dermatolog Treat 2007; 18: 335–40.

Antifungal drugs Dermatological aspects of antifungal drugs have been reviewed [1–3]. Rashes occur as follows. • Itraconazole: in 1.1% of cases, with pruritus in 0.7%; the drug is teratogenic. • Fluconazole: in 1.8% of cases; exfoliative dermatitis is recorded. • Terbinafine: in 2.7% of cases, including erythema, urticaria, eczema, pruritus, and isolated Stevens–Johnson syndrome and TEN [3]. Relevant interactions between itraconazole, fluconazole and terbinafine have been discussed [4]. References 1 Lesher JL, Smith JG Jr. Antifungal agents in dermatology. J Am Acad Dermatol 1987; 17: 383–94. 2 Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part I. J Am Acad Dermatol 1994; 30: 677–98. 3 Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994; 30: 911–33. 4 Gupta AK, Katz HI, Shear NH. Drug interactions with itraconazole, fluconazole, and terbinafine and their management. J Am Acad Dermatol 1999; 41: 237–49.

Fixed drug eruption [10], serum sickness [11], and acute generalized exanthematous pustulosis [12] are recorded. References 1 Tollemar J, Ringden O, Andersson S et al. Randomized double-blind study of liposomal amphotericin B (AmBisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1993; 12: 577– 82. 2 Ringden O, Andstrom E, Remberger M et al. Allergic reactions and other rare side-effects of liposomal amphotericin. Lancet 1994; 344: 1156–7. 3 Abbott M, Hughes DL, Patel R, Kinghorn GR. Angio-oedema after fluconazole. Lancet 1991; 338: 633. 4 Heikkila H, Timonen K, Stubb S. Fixed drug eruption due to fluconazole. J Am Acad Dermatol 2000; 42: 883–4. 5 Neuhaus G, Pavic N, Pletscher M. Anaphylactic reaction after oral fluconazole. BMJ 1991; 302: 1341. 6 Gussenhoven MJE, Haak A, Peereboom-Wynia JDR, van’t Wout JW. Stevens– Johnson syndrome after fluconazole. Lancet 1991; 338: 120. 7 Mercurio MG, Elewski BE. Thrombocytopenia caused by fluconazole therapy. J Am Acad Dermatol 1996; 32: 525–6. 8 Thyss A, Viens P, Ticchioni M et al. Toxicodermie au cours d’un traitement par 5 fluorocytosine. Ann Dermatol Vénéréol 1987; 114: 1131–2. 9 Kotani S, Hirose S, Niiya K et al. Anaphylaxis to flucytosine in a patient with AIDS. JAMA 1988; 260: 3275–6. 10 Gupta R, Thami GP. Fixed drug eruption caused by itraconazole: reactivity and cross reactivity. J Am Acad Dermatol 2008; 58: 521–2. 11 Park H, Knowles S, Shear NH. Serum sickness-like reaction to itraconazole. Ann Pharmacother 1998; 32: 1249. 12 Park YM, Kim JW, Kim CW. Acute generalised exanthematous pustulosis induced by itraconazole. J Am Acad Dermatol 1997; 36: 794–7.

Griseofulvin Reactions to griseofulvin are uncommon and usually mild; headaches and gastrointestinal disturbances are the most frequent. Morbilliform, erythematous or, rarely, haemorrhagic eruptions are occasionally seen [1,2]. Photodermatitis [3,4] with sensitivity to wavelengths above 320 nm is by no means rare; clinically, the features are mainly eczematous, although pellagra-like changes may be seen [4]. The reaction is thought to be photoallergic and photopatch tests are positive in some cases; there may be photo cross-reactivity with penicillin [4]. Histology may be nonspecific; direct immunofluorescence showed immunoglobulin and

Important or widely prescribed drugs

complement at the dermal–epidermal junction and around papillary blood vessels in one series [4]. Urticaria and a fixed drug eruption [5,6], cold urticaria [7], severe angio-oedema [8], erythema multiforme [9,10], serum sickness [11], exfoliative dermatitis [12] and TEN [13,14] are recorded. Exacerbation of LE has been reported [15–19], with fatality in one case [18]. Patients with antiSSA/Ro and SSB/La antibodies may be at increased risk of developing a drug eruption [19,20]. Temporary granulocytopenia has been reported, and proteinuria may occur. Hepatitis and a morbilliform eruption are recorded [21]. Griseofulvin may interfere with the action of anticoagulants and the contraceptive pill [22], and should be avoided in pregnancy as potentially teratogenic; men should avoid conception for 6 months after taking the drug. References 1 Faergemann J, Maibach H. Griseofulvin and ketoconazole in dermatology. Semin Dermatol 1983; 2: 262–9. 2 Von Pöhler H, Michalski H. Allergisches Exanthem nach Griseofulvin. Dermatol Monatsschr 1972; 58: 383–90. 3 Jarratt M. Drug photosensitization. Int J Dermatol 1976; 15: 317–23. 4 Kojima T, Hasegawa T, Ishida H et al. Griseofulvin-induced photodermatitis. Report of six cases. J Dermatol 1988; 15: 76–82. 5 Feinstein A, Sofer E, Trau H, Schewach-Millet M. Urticaria and fixed drug eruption in a patient treated with griseofulvin. J Am Acad Dermatol 1984; 10: 915–7. 6 Savage J. Fixed drug eruption to griseofulvin. Br J Dermatol 1977; 97: 107–8. 7 Chang T. Cold urticaria and photosensitivity due to griseofulvin. JAMA 1965; 193: 848–50. 8 Goldblatt S. Severe reaction to griseofulvin: sensitivity investigation. Arch Dermatol 1961; 83: 936–7. 9 Rustin NHA, Bunker CB, Dowd P, Robinson TWE. Erythema multiforme due to griseofulvin. Br J Dermatol 1989; 120: 455–8. 10 Thami GP, Kaur S, Kanwar AJ. Erythema multiforme due to griseofulvin with positive re-exposure test. Dermatology 2001; 203: 84–5. 11 Colton RL, Amir J, Mimouni M, Zeharia A. Serum sickness-like reaction associated with griseofulvin. Ann Pharmacother 2004; 38: 609–11. 12 Reaves LE III. Exfoliative dermatitis occurring in a patient treated with griseofulvin. J Am Geriatr Soc 1964; 12: 889–92. 13 Taylor B, Duffill M. Toxic epidermal necrolysis from griseofulvin. J Am Acad Dermatol 1988; 19: 565–7. 14 Mion G, Verdon G, Le Gulluche Y et al. Fatal toxic epidermal necrolysis after griseofulvin. Lancet 1989; ii: 1331. 15 Alexander S. Lupus erythematosus in two patients after griseofulvin treatment of Trichophyton rubrum infection. Br J Dermatol 1962; 74: 72–4. 16 Anderson WA, Torre D. Griseofulvin and lupus erythematosus. J Med Soc NJ 1966; 63: 161–2. 17 Watsky MS, Linfield YL. Lupus erythematosus exacerbated by griseofulvin. Cutis 1976; 17: 361–3. 18 Madhok R, Zoma A, Capell H. Fatal exacerbation of systemic lupus erythematosus after treatment with griseofulvin. BMJ 1985; 291: 249–50. 19 Miyagawa S, Okuchi T, Shiomi Y, Sakamoto K. Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J Am Acad Dermatol 1989; 21: 343–6. 20 Miyagawa S, Sakamoto K. Adverse reactions to griseofulvin in patients with circulating anti-SSA/Ro and SSB/La autoantibodies. Am J Med 1989; 87: 100–2. 21 Gaudin JL, Bancel B, Vial T, Bel A. Hepatite aigue cytolytique et eruption morbiliforme imputables à la prise de griseofulvin. Gastroenterol Clin Biol 1993; 17: 145–6. 22 Coté J. Interaction of griseofulvin and oral contraceptives. J Am Acad Dermatol 1990; 22: 124–5.

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anaphylaxis has been observed in two patients, one of whom had previously reacted to topical miconazole [3]. Other adverse reactions include exfoliative erythroderma [4]. The drug may block testosterone synthesis, causing dose-dependent lowering of serum testosterone and resultant oligospermia, impotence, decreased libido and gynaecomastia in some men [5–7]. It also blocks the cortisol response to ACTH, and may lead to adrenal insufficiency [7–9]. Hypothyroidism has been documented [10]. The most serious side effect is idiosyncratic hepatitis, which occurs in about 1 in 10 000 patients, and which may lead to fulminant and potentially fatal hepatic necrosis [11–17]. Trichoptilosis has resulted from misuse of ketoconazole 2% shampoo [18]. References 1 Faergemann J, Maibach H. Griseofulvin and ketoconazole in dermatology. Semin Dermatol 1983; 2: 262–9. 2 Gonzalez-Delgado P, Florido-Lopez F, Saenz de San Pedro B et al. Hypersensitivity to ketoconazole. Ann Allergy 1994; 73: 326–8. 3 Van Dijke CPH, Veerman FR, Haverkamp HC. Anaphylactic reactions to ketoconazole. BMJ 1983; 287: 1673. 4 Rand R, Sober AJ, Olmstead PM. Ketoconazole therapy and exfoliative erythroderma. Arch Dermatol 1983; 119: 97–8. 5 Graybill JR, Drutz DJ. Ketoconazole: a major innovation for treatment of fungal disease. Ann Intern Med 1980; 93: 921–3. 6 Moncada B, Baranda L. Ketoconazole and gynecomastia. J Am Acad Dermatol 1982; 7: 557–8. 7 Pont A, Graybill JR, Craven PC et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 1984; 144: 2150–3. 8 Pont A, Williams P, Loose D et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982; 97: 370–2. 9 Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317: 812–8. 10 Kitching NH. Hypothyroidism after treatment with ketoconazole. BMJ 1986; 293: 993–4. 11 Horsburgh CR Jr, Kirkpatrick CJ, Teutsch CB. Ketoconazole and the liver. Lancet 1982; i: 860. 12 Stern RS. Ketoconazole: assessing its risks. J Am Acad Dermatol 1982; 6: 544. 13 Rollman O, Lööf L. Hepatic toxicity of ketoconazole. Br J Dermatol 1983; 108: 376–8. 14 Duarte PA, Chow CC, Simmons F, Ruskin J. Fatal hepatitis associated with ketoconazole therapy. Arch Intern Med 1984; 144: 1069–70. 15 Lewis J, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy: analysis of 33 cases. Gastroenterology 1984; 86: 503–13. 16 Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole in the United Kingdom. BMJ 1987; 294: 419–22. 17 Knight TE, Shikuma CY, Knight J. Ketoconazole-induced fulminant hepatitis necessitating liver transplantation. J Am Acad Dermatol 1991; 25: 398–400. 18 Aljabre SH. Trichoptilosis caused by misuse of ketoconazole 2% shampoo. Int J Dermatol 1993; 32: 150–1.

Nystatin A fixed drug eruption has been reported [1], as has Stevens– Johnson syndrome in an isolated case [2]. References 1 Pareek SS. Nystatin-induced fixed eruption. Br J Dermatol 1980; 103: 679–80. 2 Garty B-Z. Stevens–Johnson syndrome associated with nystatin treatment. Arch Dermatol 1991; 127: 741–2.

Terbinafine Ketoconazole Pruritus and gastrointestinal upset are the most frequent side effects [1]. Urticaria and angio-oedema are recorded [2]. Severe

This drug is well tolerated with relatively few side effects [1]. Idiosyncratic hepatitis has been reported [2], with serious hepatobiliary dysfunction occurring in 1 in 54 000 [3]. Neutropenia,

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pancytopenia and thrombocytopenia are recorded [4–8]. Cutaneous adverse effects occur in 3% of patients [3,9]; these include severe urticaria, pityriasiform rashes, erythroderma, erythema multiforme [10,11] and TEN [12], serum sickness-like reactions, acute generalized exanthematous pustulosis [13–17], LE-like rashes [18–20], induction or exacerbation of psoriasis which may be pustular [21–24], baboon syndrome [25], fixed drug eruption [26] and alopecia [27], and bullous pemphigoid [28].

Voriconazole This novel, second-generation triazole for treatment of severe fungal infections has been recorded as producing mucocutaneous retinoid-effects and facial erythema [29], pseudoporphyria [30], cheilitis, erythema, discoid lupus erythematosus, Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and photosensitivity reactions [31]. References 1 Villars V, Jones TC. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in the treatment of dermatomycoses of skin and nails. J Dermatol Treat 1990; 1 (Suppl. 2): 33–8. 2 Lowe G, Green C, Jennings P. Hepatitis associated with terbinafine treatment. BMJ 1993; 306: 248. 3 Gupta AK, Kopstein JB, Shear NH. Hypersensitivity reaction to terbinafine. J Am Acad Dermatol 1997; 36: 1018–9. 4 Kovacs MJ, Alshammari S, Guenther L, Bourcier M. Neutropenia and pancytopenia associated with oral terbinafine. J Am Acad Dermatol 1994; 31: 806. 5 Gupta AK, Soori G, Del Rosso JQ et al. Severe neutropenia associated with oral terbinafine therapy. J Am Acad Dermatol 1998; 38: 765–7. 6 Ornstein DL, Ely P. Reversible agranulocytosis associated with oral terbinafine for onychomycosis. J Am Acad Dermatol 1998; 39: 1023–4. 7 Shapiro M, Li L-J, Miller J. Terbinafine-induced neutropenia. Br J Dermatol 1999; 140: 1196–7. 8 Tsai H-H, Lee W-R, Hu C-H. Isolated thrombocytopenia associated with oral terbinafine. Br J Dermatol 2002; 147: 627–8. 9 Gupta AK, Lynde CW, Lauzon GJ et al. Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol 1998; 138: 529–32. 10 McGregor JM, Rustin MHA. Terbinafine and erythema multiforme. Br J Dermatol 1994; 131: 587–8. 11 Todd P, Halpern S, Munro DD. Oral terbinafine and erythema multiforme. Clin Exp Dermatol 1995; 20: 247–8. 12 White SI, Bowen-Jones D. Toxic epidermal necrolysis induced by terbinafine in a patient on long-term anti-epileptics. Br J Dermatol 1996; 134: 188–9. 13 Kempinaire A, De Raeve L, Merckx M et al. Terbinafine-induced acute generalized exanthematous pustulosis confirmed by positive patch-test result. J Am Acad Dermatol 1997; 37: 653–5. 14 Bennett ML, Jorizzo JL, White WL. Generalized pustular eruptions associated with oral terbinafine. Int J Dermatol 1999; 38: 596–600. 15 Hall AP, Tate B. Acute generalized exanthematous pustulosis associated with oral terbinafine. Australas J Dermatol 2000; 41: 42–5. 16 Lombardo M, Cerati M, Pazzaglia A. Acute generalized exanthematous pustulosis induced by terbinafine. J Am Acad Dermatol 2003; 49: 158–9. 17 Beltraminelli HS, Lerch M, Arnold A et al. Acute generalized exanthematous pustulosis induced by the antifungal terbinafine: case report and review of the literature. Br J Dermatol 2005; 152: 780–3. 18 Brooke R, Coulson IH, Al-Dawoud A. Terbinafine-induced subacute cutaneous lupus erythematosus. Br J Dermatol 1998; 139: 1132–3. 19 Holmes S, Kemmett D. Exacerbation of systemic lupus erythematosus induced by terbinafine. Br J Dermatol 1998; 139: 1133. 20 Murphy M, Barnes L. Terbinafine-induced lupus erythematosus. Br J Dermatol 1998; 138: 708–9. 21 Wach F, Stolz W, Hein R, Landthaler M. Severe erythema anulare centrifugumlike psoriatic drug eruption induced by terbinafine. Arch Dermatol 1995; 131: 960–1.

22 Gupta AK, Sibbald RG, Knowles SR et al. Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: four case reports and a review of drug-induced psoriasis. J Am Acad Dermatol 1997; 36: 858–62. 23 Papa CA, Miller OF. Pustular psoriasiform eruption with leukocytosis associated with terbinafine. J Am Acad Dermatol 1998; 39: 115–7. 24 Wilson NJE, Evans S. Severe pustular psoriasis provoked by oral terbinafine. Br J Dermatol 1998; 139: 168. 25 Weiss JM, Mockenhaupt M, Schopf E, Simon JC. Reproducible drug exanthema to terbinafine with characteristic distribution of baboon syndrome. Hautarzt 2001; 52: 1104–6. 26 Munn SE, Russell Jones R. Terbinafine and fixed drug eruption. Br J Dermatol 1995; 133: 815–6. 27 Richert B, Uhoda I, de la Brassinne M. Hair loss after terbinafine treatment. Br J Dermatol 2001; 145: 842. 28 Aksakal BA, Ozsoy E, Arnavut O, Ali Gürer M. Oral terbinafine-induced bullous pemphigoid. Ann Pharmacother 2003; 37: 1625–7. 29 Denning DW, Griffiths CE. Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole. Clin Exp Dermatol 2001; 26: 648–53. 30 Dolan CK, Hall MA, Blazes DL, Norwood CW. Pseudoporphyria as a result of voriconazole use: a case report. Int J Dermatol 2004; 43: 768–71. 31 Racette AJ, Roenigk HH Jr, Hansen R et al. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol 2005; 52 (5 Suppl. 1): S81–5.

Antiviral agents Aciclovir (acyclovir) In general, there are very few side effects [1]. Vesicular reactions, palm and sole dermatitis, peripheral oedema, erythema nodosum, exanthems, hyperhidrosis, acne, lichenoid eruption, pruritus, urticaria, vasculitis, alopecia and fixed drug eruption are recorded [2–4]. Intravenous use may cause inflammation and phlebitis. A nephropathy may develop with intravenous use, especially in patients with renal failure, due to renal precipitation of the drug; the dose should be reduced in patients with impaired renal function. An encephalopathy may occur. Peripheral oedema has been reported very rarely [5,6]. References 1 Arndt KA. Adverse reactions to acyclovir: topical, oral, and intravenous. J Am Acad Dermatol 1988; 18: 188–90. 2 Buck ML, Vittone SB, Zaglul HF. Vesicular eruptions following acyclovir administration. Ann Pharmacother 1993; 27: 1458–9. 3 Carrasco L, Pastor MA, Izquierdo MJ et al. Drug eruption secondary to aciclovir with recall phenomenon in a dermatome previously affected by herpes zoster. Clin Exp Dermatol 2002; 27: 132–4. 4 Montoro J, Basomba A. Fixed drug eruption due to acyclovir. Contact Dermatitis 1997; 36: 225. 5 Hisler BM, Daneshvar SA, Aronson PJ, Hashimoto K. Peripheral edema and oral acyclovir. J Am Acad Dermatol 1988; 18: 1142–3. 6 Medina S, Torrelo A, España A, Ledo A. Edema and oral acyclovir. Int J Dermatol 1991; 30: 305–6.

Idoxuridine This drug is used only topically for herpes simplex and herpes zoster, in view of its toxicity on systemic administration. Severe alopecia and loss of nails followed parenteral use [1]. Reference 1 Nolan DC, Carruthers MM, Lerner AM. Herpesvirus hominis encephalitis in Michigan: report of thirteen cases, including six treated with idoxuridine. N Engl J Med 1970; 282: 10–3.

Important or widely prescribed drugs

Foscarnet This drug is used for cytomegalovirus retinitis in AIDS, and for mucocutaneous herpes simplex virus unresponsive to aciclovir in immunocompromised patients. A generalized cutaneous rash has been reported with use of this drug in AIDS [1]. Genital ulceration, both of the penis [2,3] and vulva [4], is documented. In one study [2], 15% of 60 patients treated with intravenous foscarnet developed penile ulceration [2]. Eosinophilic folliculitis has been reported [5]. References 1 Green ST, Nathwani D, Goldberg DJ et al. Generalised cutaneous rash associated with foscarnet usage in AIDS. J Infect 1990; 21: 227–8. 2 Katlama C, Dohin E, Caumes E et al. Foscarnet induction therapy for cytomegalovirus retinitis in AIDS: comparison of twice-daily and three-times-daily regimens. J Acquir Immune Defic Syndr 1992; 5 (Suppl. 1): S18–S24. 3 Evans LM, Grossman ME. Foscarnet-induced penile ulcer. J Am Acad Dermatol 1992; 27: 124–6. 4 Caumes E, Gatineau M, Bricaire F et al. Foscarnet-induced vulvar erosion. J Am Acad Dermatol 1993; 28: 799. 5 Roos TC, Albrecht H. Foscarnet-associated eosinophilic folliculitis in a patient with AIDS. J Am Acad Dermatol 2001; 44: 546–7.

Ribavirin (tribavirin) This synthetic guanosine analogue used in the treatment of relapsing chronic hepatitis C infection has been implicated in the development of Grover’s disease [1]. Reference 1 Antunes I, Azevedo F, Mesquita-Guimaraes J et al. Grover’s disease secondary to ribavirin. Br J Dermatol 2000; 142: 1257–8.

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Highly active antiretroviral treatment (HAART) may elicit skin manifestations of the immune reconstitution inflammatory syndrome, including herpes zoster and warts. Long-term side effects, apart from the lipodystrophy syndrome, include dyslipidaemia, cardiovascular disease and diabetes. HLA-B*5701 has been linked with abacavir hypersensitivity, and HLA-DRB1*0101 in Caucasian Australians, and HLA-Cw8 in Sardinians and Japanese, with nevirapine hypersensitivity (see section Pharmacogenetic mechanisms and genetic influences, p. 75.12). References 1 Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356: 1423–30. 2 Ward HA, Russo GG, Shrum J. Cutaneous manifestations of antiretroviral therapy. J Am Acad Dermatol 2002; 46: 284–93. 3 Rotunda A, Hirsch RJ, Scheinfeld N, Weinberg JM. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol (Stockh) 2003; 83: 1–9. 4 Phillips EJ, Knowles SR, Shear N. Cutaneous manifestations of antiviral therapy. J Am Acad Dermatol 2003; 48: 985–6. 5 Kong HH, Myers SA. Cutaneous effects of highly active antiretroviral therapy in HIV-infected patients. Dermatol Ther 2005; 18: 58–66. 6 Martins CR. Cutaneous drug reactions associated with newer antiretroviral agents. J Drugs Dermatol 2006; 5: 976–82. 7 Luther J, Glesby MJ. Dermatologic adverse effects of antiretroviral therapy: recognition and management. Am J Clin Dermatol 2007; 8: 221–33. 8 Tymchuk CN, Currier JS. The safety of antiretroviral drugs. Expert Opin Drug Saf 2008; 7: 1–4. 9 Stankov MV, Behrens GM. HIV-therapy associated lipodystrophy: experimental and clinical evidence for the pathogenesis and treatment. Endocr Metab Immune Disord Drug Targets 2007; 7: 237–49. 10 Mehta U, Maartens G. Is it safe to switch between efavirenz and nevirapine in the event of toxicity? Lancet Infect Dis 2007; 7: 733–8.

Antiretroviral drugs Cutaneous side effects of antiretroviral agents have been reviewed [1–9]. There are three categories of agent: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Nucleoside reverse transcriptase inhibitors have resulted in alterations of the nails, nail and mucocutaneous pigmentation, hair changes, vasculitis and morbilliform eruptions. Drug hypersensitivity varying from a mild morbilliform rash to Stevens–Johnson syndrome, with drug-induced hepatitis, anaemia and lactic acidosis, is associated with the non-nucleoside reverse transcriptase inhibitors nevirapine, delavirdine and efavirenz, as well as the nucleoside reverse transcriptase inhibitor abacavir and the protease inhibitor amprenavir [2,7]. Recurrent reactions occurred in 12.6% of 239 reported patients with rash switched from nevirapine to efavirenz, compared with 50% of 16 patients switched from efavirenz to nevirapine. Thus, substituting efavirenz for nevirapine following hepatotoxicity or cutaneous hypersensitivity appears to be reasonable, providing that the adverse reaction to nevirapine was not life-threatening [10]. Protease inhibitors have been associated with lipodystrophy syndrome (lipoatrophy with or without lipohypertrophy), hypersensitivity reactions, urticaria, morbilliform eruptions and a large number of drug interactions. Potential management of lipoatrophy includes switching antiretrovirals and surgical treatment with facial fillers. The fusion inhibitor enfuvirtide causes injection-site reactions in the overwhelming majority of patients, although a new method of delivery has decreased their rate and severity [7].

Nucleoside reverse transcriptase inhibitors Abacavir. This drug is associated with a hypersensitivity syndrome in 4% of cases [1]. Stevens–Johnson syndrome is recorded [2]. Dideoxycytidine. A maculopapular reaction with oral ulceration developed in 70% of patients treated with this anti-AIDS agent, but resolved spontaneously in those who continued on therapy [3]. Lamivudine. Paronychia is recorded [4]. Tenofovir (disoproxil fumarate). Hypersensitivity consisting mainly of a maculopapular rash on the face, extremities and trunk is recorded [5]. Zidovudine. This drug may cause gastrointestinal upset and marrow suppression (with serious anaemia in 32% and leukopenia in 37%), myalgia, headache and insomnia [6–9]. Such side effects have been reported in healthcare workers treated with zidovudine for attempted prophylaxis of HIV infection following accidental needlestick injury [10,11]. Zidovudine-related thrombocytopenia resulted in ecchymoses around Kaposi’s sarcoma lesions in a patient with AIDS, simulating rapid intracutaneous spread of neoplasm [12]. Vaginal tumours have been documented in rodents. Diffuse pigmentation, as well as isolated hyperpigmented spots

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on the palms, soles and fingers, and pigmentation of the fingernails and toenails (usually starting at 4–8 weeks into therapy, but up to 1 year), and buccal mucosa, have been described [13–18]. Postural hypotension has been recorded [19]. Hypertrichosis of the eyelids has occurred [20]. A possible link with neutrophilic eccrine hidradenitis has been postulated in HIV-infected patients [21]. Hypersensitivity reactions, from rash to anaphylaxis, have been documented [22,23]. Other reported cutaneous reactions include acne, pruritus, urticaria and leukocytoclastic vasculitis [24]. References 1 Phillips EJ, Knowles SR, Shear N. Cutaneous manifestations of antiviral therapy. J Am Acad Dermatol 2003; 48: 985–6. 2 Bossi P, Roujeau JC, Bricaire F, Caumes E. Stevens–Johnson syndrome associated with abacavir therapy. Clin Infect Dis 2002; 35: 902. 3 McNeely MC, Yarchoan R, Broder S, Lawley TJ. Dermatologic complications associated with administration of 2′,3′-dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989; 21: 1213–7. 4 Tosti A, Piraccini BM, D’Antuono A et al. Paronychia associated with antiretroviral therapy. Br J Dermatol 1999; 140: 1165–8. 5 Lockhart SM, Rathbun RC, Stephens JR et al. Cutaneous reactions with tenofovir disoproxil fumarate: a report of nine cases. AIDS 2007; 21: 1370–3. 6 Gill PS, Rarick M, Brynes RK et al. Azidothymidine associated with bone marrow failure in AIDS. Ann Intern Med 1987; 107: 502–5. 7 Richman DD, Fiscal MA, Grieco MH et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS or AIDS-related complex: a double blind, placebo-controlled trial. N Engl J Med 1987; 317: 192–7. 8 Gelmon K, Montaner JS, Fanning M et al. Nature, time course and dose dependence of zidovudine-related side-effects: results from the Multicenter Canadian Azidothymidine Trial. AIDS 1989; 3: 555–61. 9 Moore RD, Creagh-Kirk T, Keruly J et al. Long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus infection. Arch Intern Med 1991; 151: 981–6. 10 Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine post-exposure use. MMWR 1990; 39: 1–14. 11 Jeffries DJ. Zidovudine after occupational exposure to HIV. Hospitals should be able to give it within an hour. BMJ 1991; 302: 1349–51. 12 Barnett JH, Gilson E. Zidovudine-related thrombocytopenia simulating rapid growth of Kaposi’s sarcoma. Arch Dermatol 1991; 127: 1068–9. 13 Azon-Masoliver A, Mallolas J, Gatell J, Castel T. Zidovudine-induced nail pigmentation. Arch Dermatol 1988; 124: 1570–1. 14 Fisher CA, McPoland PR. Azidothymidine-induced nail pigmentation. Cutis 1989; 43: 552–4. 15 Bendick C, Rasokat H, Steigleder GK. Azidothymidine-induced hyperpigmentation of skin and nails. Arch Dermatol 1989; 125: 1285–6. 16 Greenberg RG, Berger TG. Nail and mucocutaneous hyperpigmentation with azidothymidine therapy. J Am Acad Dermatol 1990; 22: 327–30. 17 Grau-Massanes M, Millan F, Febrer MI et al. Pigmented nail bands and mucocutaneous pigmentation in HIV-positive patients treated with zidovudine. J Am Acad Dermatol 1990; 22: 687–8. 18 Tadini G, D’Orso M, Cusini M et al. Oral mucosa pigmentation: a new side effect of azidothymidine therapy in patients with acquired immunodeficiency syndrome. Arch Dermatol 1991; 127: 267–8. 19 Loke RHT, Murray-Lyon IM, Carter GD. Postural hypotension related to zidovudine in a patient infected with HIV. BMJ 1990; 300: 163–4. 20 Klutman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with AIDS being treated with zidovudine. N Engl J Med 1991; 324: 1896. 21 Smith KJ, Skelton HG III, James WD et al. Neutrophilic eccrine hidradenitis in HIV-infected patients. J Am Acad Dermatol 1990; 23: 945–7. 22 Carr A, Penny R, Cooper DA. Allergy and desensitization to zidovudine in patients with acquired immunodeficiency syndrome (AIDS). J Allergy Clin Immunol 1993; 91: 683–5. 23 Wassef M, Keiser P. Hypersensitivity of zidovudine: report of a case of anaphylaxis and review of the literature. Clin Infect Dis 1995; 20: 1387–9.

24 Torres RA, Lin RY, Lee M, Barr MR. Zidovudine-induced leukocytoclastic vasculitis. Arch Intern Med 1992; 152: 850–1.

Non-nucleoside reverse transcriptase inhibitors Delavirdine. Various rashes occur in 18–50% of cases. Efavirenz. Mild rashes are recorded within the first 2 weeks of therapy [1]. A hypersensitivity reaction manifesting in a rash and hepatitis has been documented [2]. Nevirapine. Severe rashes have been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men [3,4]. A hypersensitivity syndrome is well recorded [5–7]. The drug is the leading cause of Stevens–Johnson syndrome and TEN related to AIDS in Europe [8–12]. References 1 Phillips EJ, Knowles SR, Shear N. Cutaneous manifestations of antiviral therapy. J Am Acad Dermatol 2003; 48: 985–6. 2 Leung JM, O’Brien JG, Wong HK, Winslow DL. Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis in a Latino male. Ann Pharmacother 2008; 42: 425–9. 3 Bersoff-Matcha SJ, Miller WC, Aberg JA et al. Sex differences in nevirapine rash. Clin Infect Dis 2001; 32: 124–9. 4 Anonymous. From the Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures: worldwide, 1997–2000. JAMA 2001; 285: 402–3. 5 Claudio GA, Martin AF, de Dios Perrino S, Velasco AA. DRESS syndrome associated with nevirapine therapy. Arch Intern Med 2001; 161: 2501–2. 6 Lanzafame M, Rovere P, De Checchi G et al. Hypersensitivity syndrome (DRESS) and meningoencephalitis associated with nevirapine therapy. Scand J Infect Dis 2001; 33: 475–6. 7 Wit FW, Kesselring AM, Gras L et al. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study. Clin Infect Dis 2008; 46: 933–40. 8 Wetterwald E, Le Cleach L, Michel C et al. Nevirapine-induced overlap Stevens– Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 1999; 140: 980–2. 9 Metry DW, Lahart CJ, Farmer KL, Hebert AA. Stevens–Johnson syndrome caused by the antiretroviral drug nevirapine. J Am Acad Dermatol 2001; 44 (Suppl. 2): 354–7. 10 Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN et al. Nevirapine and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. AIDS 2001; 15: 1843–8. 11 Dodi F, Alessandrini A, Camera M et al. Stevens–Johnson syndrome in HIV patients treated with nevirapine: two case reports. AIDS 2002; 16: 1197–8. 12 Mason AR, Cortes GY, Pollack RB. Nevirapine-induced Stevens–Johnson syndrome in a pediatric patient. Pediatr Dermatol 2008; 25: 128–9.

Protease inhibitors Saquinivir causes rashes, and indinavir causes taste disturbance and dry skin [1]. Indinavir has been associated with retinoid-like manifestations such as the development of cheilitis in 40% of cases, paronychia, scalp hair loss in 12%, ingrown toe-nails, curling of straight hair, diffuse cutaneous dryness and pruritus in 12%, and asteatotic dermatitis on the trunk, arms and thighs [2,3]. Multiple pyogenic granulomas were observed in the toenails in 6% and softening of the nail plate in 5% of subjects. Multiple subcutaneous lipomas are associated with protease inhibitors [4]. Paronychia is a recognized complication [5,6]. Angiolipomas shortly after initiation of therapy [7] and leukocytoclastic vasculitis [8] have been documented with indinavir. A peripheral lipodystro-

Important or widely prescribed drugs

phy syndrome has been linked to therapy with protease inhibitors [9–13] and was noted in 14% of patients on indinavir [2]. It comprises peripheral lipoatrophy, relative central adiposity, sometimes with a ‘buffalo hump’, insulin resistance and serum lipid abnormalities. The mix of features is variable in individual patients. References 1 Anonymous. Safety issues with anti-HIV drugs. Curr Prob Pharmacovig 1997; 23: 5. 2 Calista D, Boschini A. Cutaneous side effects induced by indinavir. Eur J Dermatol 2000; 10: 292–6. 3 Luther J, Glesby MJ. Dermatologic adverse effects of antiretroviral therapy: recognition and management. Am J Clin Dermatol 2007; 8: 221–33. 4 Bornhovd E, Sakrauski AK, Bruhl H et al. Multiple circumscribed subcutaneous lipomas associated with use of human immunodeficiency virus protease inhibitors? Br J Dermatol 2000; 143: 1113–4. 5 Tosti A, Piraccini BM, D’Antuono A et al. Paronychia associated with antiretroviral therapy. Br J Dermatol 1999; 140: 1165–8. 6 Daudén E, Pascual-López M, Martínez-Garcia C, García-Díez A. Paronychia and excess granulation tissue of the toes and finger in a patient treated with indinavir. Br J Dermatol 2000; 142: 1063–4. 7 Dank JP, Colven R. Protease inhibitor-associated angiolipomatosis. J Am Acad Dermatol 2000; 42: 129–31. 8 Rachline A, Lariven S, Descamps V et al. Leucocytoclastic vasculitis and indinavir. Br J Dermatol 2000; 143: 1112–3. 9 Ward HA, Russo GG, Shrum J. Cutaneous manifestations of antiretroviral therapy. J Am Acad Dermatol 2002; 46: 284–93. 10 Williamson K, Reboli AC, Manders SM. Protease-inhibitor-induced lipodystrophy. J Am Acad Dermatol 1999; 40: 635–6. 11 Panse I, Vasseur E, Raffin-Sanson ML et al. Lipodystrophy associated with protease inhibitors. Br J Dermatol 2000; 142: 496–500. 12 Pujol RM, Domingo P, Guiu X-M et al. HIV-1 protease inhibitor-associated partial lipodystrophy: clinicopathologic review of 14 cases. J Am Acad Dermatol 2000; 42: 193–8. 13 Mallon PW, Cooper DA, Carr A. HIV-associated lipodystrophy. HIV Med 2001; 2: 166–73.

Antimalarials [1–4] Pruritus, lichenoid eruptions [5], exfoliative dermatitis, pigment changes, bleaching of hair, alopecia, photosensitivity with exacerbation of psoriasis and porphyria cutanea tarda, retinopathy and corneal opacities have all been reported. References 1 Ribrioux A. Antipaludéens de synthese et peau. Ann Dermatol Vénéréol 1990; 117: 975–90. 2 Ochsendorf FR, Runne U. Chloroquin und Hydroxychloroquin: Nebenwirkungsprofil wichtiger Therapeutika. Hautarzt 1991; 42: 140–6. 3 Ziering CL, Rabinowitz LG, Esterly NB. Antimalarials for children. Indications, toxicities, and guidelines. J Am Acad Dermatol 1993; 28: 764–70. 4 Sowunmi A, Falade AG, Adedeji AA, Falade CO. Comparative clinical characteristics and responses to oral 4-aminoquinoline therapy of malarious children who did and did not develop 4-aminoquinoline-induced pruritus. Ann Trop Med Parasitol 2001; 95: 645–53. 5 Geraminejad P, Stone MS, Sontheimer RD. Antimalarial lichenoid tissue reactions in patients with pre-existing lupus erythematosus. Lupus 2004; 13: 473–7.

Chloroquine and hydroxychloroquine Adverse cutaneous reactions to hydroxychloroquine are commoner in patients with dermatomyositis than in those with cutaneous LE [1]. Pruritus is common in Africans on acute or prolonged treatment, but rare in Europeans [2–5]. Pigmentary changes develop in about 25% of patients receiving any of the antimalarials

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for more than 4 months [6–9]; chloroquine binds to melanin [9]. Blackish-purple patches on the shins are often seen, and browngrey pigmentation may appear in light-exposed skin [8]. The nail beds may be pigmented diffusely or in transverse bands, and the hard palate is diffusely pigmented. In contrast, red-blonde (but not dark) hair may be bleached [10]. Chloroquine has been associated with vitiligo-like depigmentation [11]. Photosensitivity may be seen [12]; in addition, certain types of porphyria may be provoked [13]. Effects on psoriasis are unpredictable, but precipitation of severe psoriasis has long been recognized [14–19], including erythroderma [19]. However, 88% of a series of 50 psoriatics who were treated with standard doses of chloroquine noted no change in their psoriasis [20]. Lichenoid eruptions are uncommon, and erythema annulare centrifugum is rare [21]. A pustular eruption with hydroxychloroquine has been reported [22]. Acute generalized exanthematous pustulosis is recorded [23]. TEN with oral involvement has been documented. Toxic psychosis has been described with hydroxychloroquine [24]. All antimalarials are potentially teratogenic. Chloroquine and hydroxychloroquine may cause serious ophthalmic side effects [25,26]. Corneal deposits occur in 95% of patients on long-term therapy, but of these 95% are asymptomatic [27]. A potentially irreversible retinopathy leading to blindness may develop in 0.5–2% of cases [28,29]. The retinal changes may progress after the drug is stopped. Use of less than 250 mg (or 4 mg/kg) daily of chloroquine, with pretreatment and 6-monthly ophthalmological assessment using an Amsler grid, is recommended. Malaria prophylaxis with two tablets weekly is said not to carry an appreciable risk. Ocular toxicity with hydroxychloroquine is rare below 6.5 mg/kg; guidelines for screening include baseline renal and liver function tests, assessment of near visual acuity and yearly visual acuity [30]. References 1 Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol 2002; 138: 1231–3. 2 Spencer HC, Poulter NR, Lury JD, Poulter CJ. Chloroquine-associated pruritus in a European. BMJ 1982; 285: 1703–4. 3 Salako LA. Toxicity and side-effects of antimalarials in Africa: a critical review. Bull WHO 1984; 62 (Suppl.): 63–8. 4 Mnyika KS, Kihamia CM. Chloroquine-induced pruritus: its impact on chloroquine utilization in malaria control in Dar es Salaam. J Trop Med Hyg 1991; 94: 27–31. 5 Ezeamuzie IC, Igbigbi PS, Ambakederemo AW et al. Halofantrine-induced pruritus amongst subjects who itch to chloroquine. J Trop Med Hyg 1991; 94: 184–8. 6 Dall JLC, Keane JA. Disturbances of pigmentation with chloroquine. BMJ 1959; i: 1387–9. 7 Tuffanelli D, Abraham RK, Dubois EJ. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Dermatol 1963; 88: 419–26. 8 Levy H. Chloroquine-induced pigmentation. Case reports. S Afr Med J 1982; 2: 735–7. 9 Sams WM, Epstein JH. The affinity of melanin for chloroquine. J Invest Dermatol 1965; 45: 482–8. 10 Dupré A, Ortonne J-P, Viraben R, Arfeux F. Chloroquine-induced hypopigmentation of hair and freckles. Association with congenital renal failure. Arch Dermatol 1985; 121: 1164–6. 11 Martín-García RF, Camacho N del R, Sánchez JL. Chloroquine-induced, vitiligolike depigmentation. J Am Acad Dermatol 2003; 48: 981–3.

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12 Van Weelden H, Boling HH, Baart de la Faille H, Van Der Leun JC. Photosensitivity caused by chloroquine. Arch Dermatol 1982; 118: 290. 13 Davis MJ, Vander Ploeg DE. Acute porphyria and coproporphyrinuria following chloroquine therapy: a report of two cases. Arch Dermatol 1957; 75: 796–800. 14 O’Quinn SE, Kennedy CB, Naylor LZ. Psoriasis, ultraviolet light and chloroquine. Arch Dermatol 1964; 90: 211–6. 15 Baker H. The influence of chloroquine and related drugs on psoriasis and keratoderma blenorrhagicum. Br J Dermatol 1966; 78: 161–6. 16 Abel EA, Dicicco LM, Orenberg EK et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007–22. 17 Nicolas J-F, Mauduit G, Haond J et al. Psoriasis grave induit par la chloroquine (nivaquine). Ann Dermatol Vénéréol 1988; 115: 289–93. 18 Luzar MJ. Hydroxychloroquine in psoriatic arthropathy: exacerbation of psoriatic skin lesions. J Rheumatol 1982; 9: 462–4. 19 Slagel GA, James WD. Plaquenil-induced erythroderma. J Am Acad Dermatol 1985; 12: 857–62. 20 Katugampola G, Katugampola S. Chloroquine and psoriasis. Int J Dermatol 1990; 29: 153–4. 21 Ashurst PJ. Erythema annulare centrifugum. Due to hydroxychloroquine sulfate and chloroquine sulfate. Arch Dermatol 1967; 95: 37–9. 22 Lotem M, Ingber A, Segal R, Sandbank M. Generalized pustular drug rash induced by hydroxychloroquine. Acta Derm Venereol (Stockh) 1990; 70: 250–1. 23 Paradisi A, Bugatti L, Sisto T et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: three cases and a review of the literature. Clin Ther 2008; 30: 930–40. 24 Ward WQ, Walter-Ryan WG, Shehi GM. Toxic psychosis: a complication of antimalarial therapy. J Am Acad Dermatol 1985; 12: 863–5. 25 Olansky AJ. Antimalarials and ophthalmologic safety. J Am Acad Dermatol 1982; 6: 19–23. 26 Portnoy JZ, Callen JP. Ophthalmologic aspects of chloroquine and hydroxychloroquine safety. Int J Dermatol 1983; 22: 273–8. 27 Easterbrook M. Ocular side effects and safety of antimalarial agents. Am J Med 1988; 85: 23–9. 28 Marks JS. Chloroquine retinopathy: is there a safe daily dose? Ann Rheum Dis 1982; 41: 52–8. 29 Easterbrook M. Dose relationships in patients with early chloroquine retinopathy. J Rheumatol 1987; 14: 472–5. 30 Jones SK. Ocular toxicity and hydroxychloroquine: guidelines for screening. Br J Dermatol 1999; 140: 3–7.

Mefloquine Dizziness, nausea, erythema and neurological disturbance are documented. Pruritus occurs in 4–10% and maculopapular rash in up to 30% of cases; urticaria, facial lesions, cutaneous vasculitis, Stevens–Johnson syndrome and TEN [1,2], and exfoliative dermatitis [3] have been recorded. References 1 Van Den Enden E, Van Gompel A, Colebunders R, Van Den Ende J. Mefloquineinduced Stevens–Johnson syndrome. Lancet 1991; 337: 683. 2 Smith HR, Croft AM, Black MM. Dermatological adverse effects with the antimalarial drug mefloquine: a review of 74 published case reports. Clin Exp Dermatol 1999; 24: 249–54. 3 Martin GJ, Malone JL, Ross EV. Exfoliative dermatitis during malarial prophylaxis with mefloquine. Clin Infect Dis 1993; 16: 341–2.

Mepacrine (atabrine, quinacrine) This drug constantly causes yellow staining of the skin, which may involve the conjunctiva and may mimic jaundice [1]. Lichenoid eruptions are well known. Large numbers of military personnel given mepacrine for malaria prophylaxis in the Second World War developed a tropical lichenoid dermatitis, which was quickly followed by anhidrosis, cutaneous atrophy, alopecia, nail changes,

altered pigmentation and keratoderma [2,3]. A few patients developed localized, bluish-black hyperpigmentation confined to the palate, face, pretibial area and nail beds after prolonged administration of more than a year. Years later, lichenoid nodules, scaly red plaques, atrophic lesions on the soles, erosions and leukoplakia of the tongue, and fungating warty growths appeared [3,4]. Progression to squamous cell carcinoma, especially on the palm, has occurred. Ocular toxicity is much less than with chloroquine. References 1 Leigh JM, Kennedy CTC, Ramsey JD, Henderson WJ. Mepacrine pigmentation in systemic lupus erythematosus. Br J Dermatol 1979; 101: 147–53. 2 Bauer F. Late sequelae of atabrine dermatitis: a new premalignant entity. Aust J Dermatol 1978; 19: 9–12. 3 Bauer F. Quinacrine hydrochloride drug eruption (tropical lichenoid dermatitis). Its early and late sequelae and its malignant potential. A review. J Am Acad Dermatol 1981; 4: 239–48. 4 Callaway JL. Late sequelae of quinacrine dermatitis, a new premalignant entity. J Am Acad Dermatol 1979; 1: 456.

Pyrimethamine This folate antagonist can cause agranulocytosis even in very low dosage, especially when combined with dapsone [1]. A lichenoid eruption has been reported [2], as has photosensitivity. The reported rate for all serious reactions to pyrimethamine–sulfadoxine (Fansidar) in one study was 1 in 2100 prescriptions and for cutaneous reactions including Stevens–Johnson syndrome 1 in 4900, with a fatality rate of 1 in 11 100 [3]. In another study [4], severe cutaneous adverse reactions to Fansidar, including erythema multiforme, Stevens–Johnson syndrome and TEN, were estimated at 1.1 (0.9–1.3) per million. Similar rates for severe reactions to pyrimethamine–dapsone (Maloprim) were 1 in 9100 prescriptions and for blood dyscrasias 1 in 20 000, with a fatality rate of 1 in 75 000. For developing countries with mainly single-dose use, the risk was estimated at 0.1 per million, compared with mainly prophylactic use in Europe and North America at a risk of 10 and 36 per million, respectively. Prophylactic use thus had a 40 times higher risk than single-dose therapeutic use [4]. Reactions to pyrimethamine are more common in patients with HIV infection [5]. Epidermal necrolysis, angio-oedema, bullous disorders and serious hepatic disorders also occurred. Because few serious reactions have been recorded with chloroquine and proguanil, it has been recommended that use of compound antimalarials should be restricted [3]. References 1 Friman G, Nyström-Rosander C, Jonsell G et al. Agranulocytosis associated with malaria prophylaxis with Maloprim. BMJ 1983; 286: 1244–5. 2 Cutler TP. Lichen planus caused by pyrimethamine. Clin Exp Dermatol 1980; 5: 253–6. 3 Phillips-Howard PA, West LJ. Serious adverse drug reactions to pyrimethamine– sulphadoxine, pyrimethamine–dapsone and to amodiaquine in Britain. J R Soc Med 1990; 83: 82–5. 4 Sturchler D, Mittelholzer ML, Kerr L. How frequent are notified severe cutaneous adverse reactions to Fansidar? Drug Saf 1993; 8: 160–8. 5 Piketty C, Weiss L, Picard-Dahan C et al. Toxidermies a la pyrimethamine chez les patients infectés par le virus de l’immunodeficience acquise. Presse Med 1995; 24: 1710.

Important or widely prescribed drugs

Quinine Purpura due to quinine may or may not be thrombocytopenic [1,2]. Erythematous, urticarial, photoallergic [3–5], bullous and fixed eruptions are recorded. Lichenoid eruptions are rare. If contact allergic sensitivity is already present, eczematous reactions may occur, as in ‘systemic contact-type eczema’ [6]. Splinter haemorrhages, and a maculopapular and a photosensitive papulonecrotic eruption, due to a lymphocytic vasculitis, have been recorded in one case [7].

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litis with a reticular livedo pattern due to circulating immune complexes [11], and cutaneous necrotizing vasculitis [12], have been reported. A distinctive purpuric eruption of the ears is recorded [13].

Niridazole Urticaria and a pellagra-like dermatitis have been described.

Piperazine References 1 Belkin GA. Cocktail purpura. An unusual case of quinine sensitivity. Ann Intern Med 1967; 66: 583–6. 2 Helmly RB, Bergin JJ, Shulman NR. Quinine-induced purpura: observation on antibody titers. Arch Intern Med 1967; 20: 59–62. 3 Ljunggren B, Sjövall P. Systemic quinine photosensitivity. Arch Dermatol 1986; 122: 909–11. 4 Ferguson J, Addo HA, Johnson BE et al. Quinine induced photosensitivity: clinical and experimental studies. Br J Dermatol 1987; 117: 631–40. 5 Diffey BL, Farr PM, Adams SJ. The action spectrum in quinine photosensitivity. Br J Dermatol 1988; 118: 679–85. 6 Calnan CD, Caron GA. Quinine sensitivity. BMJ 1961; ii: 1750–2. 7 Harland CC, Millard LG. Another quirk of quinine. BMJ 1991; 302: 295.

Anthelmintics

Occupational dermatitis has been caused [14]. Previous contact sensitization induced by ethylenediamine has led to severe crossreactions on subsequent oral administration of piperazine, including generalized exfoliative dermatitis [15].

Tetrachlorethylene This drug has caused TEN.

Tiabendazole An unusual body odour is well known after the administration of this drug. Skin reactions, consisting of urticaria or maculopapular rashes, are infrequent and usually mild and transient. Erythema multiforme [16] and TEN [17] have been reported.

Amocarzine (CGP 6140) This macrofilaricidal and microfilaricidal drug used for the therapy of onchocerciasis may be associated with dizziness and pruritus with or without a rash [1].

Benzimidazole compounds These are used for the therapy of both intestinal helminthiasis and hydatid disease; fever, gastrointestinal upset, reversible neutropenia and transient abnormalities in liver function are reported. Telogen effluvium has been documented with both albendazole [2,3] and mebendazole.

Ivermectin Fever, rash, pruritus, local swelling and tender regional lymphadenopathy are documented [4]. The incidence of moderate adverse reactions, including pruritus, localized rash and fever, was 4% in a study of patients with onchocerciasis from Ecuador [5], and increased itching and/or rash occurred in 8% of cases in another study [6]. Patients with reactive onchodermatitis (sowda) may have severe pruritus and limb swelling with ivermectin [7]. A 3-year, placebo-controlled, double-blind trial involving 7148 patients given ivermectin annually for onchocerciasis by mass distribution identified musculosketetal pains, oedema of the face or extremities, itching and papular rash as adverse reactions; bullous skin lesions that did not recur developed in five persons [8].

Levamisole Prolonged use at high dosage as an immunostimulant is associated with type I reactions, with itching, pruritus and urticaria. Lichenoid [9] and non-specific [10] rashes, leukocytoclastic vascu-

References 1 Poltera AA, Zea-Flores G, Guderian R et al. Onchocercacidal effects of amocarzine (CGP 6140) in Latin America. Lancet 1991; 337: 583–4. 2 Karawifa MA, Yasawi MI, Mohamed AE. Hair loss as a complication of albendazole therapy. Saudi Med J 1988; 9: 530. 3 Garcia-Muret MP, Sitjas D, Tuneu L, de Moragas JM. Telogen effluvium associated with albendazole therapy. Int J Dermatol 1990; 29: 669–70. 4 Bryan RT, Stokes SL, Spencer HC. Expatriates treated with ivermectin. Lancet 1991; 337: 304. 5 Guderian RH, Beck BJ, Proano S Jr, Mackenzie CD. Onchocerciasis in Ecuador, 1980–86: epidemiological evaluation of the disease in the Esmerldas province. Eur J Epidemiol 1989; 5: 294–302. 6 Whitworth JAG, Maude GH, Luty AJF. Expatriates treated with ivermectin. Lancet 1991; 337: 625–6. 7 Guderian RH, Anselmi M, Sempertegui R, Cooper PJ. Adverse reactions to ivermectin in reactive onchodermatitis. Lancet 1991; 337: 188. 8 Burnham GM. Adverse reactions to ivermectin treatment for onchocerciasis. Results of a placebo-controlled, double-blind trial in Malawi. Trans R Soc Trop Med Hyg 1993; 87: 313–7. 9 Kirby JD, Black MM, McGibbon D. Levamisole-induced lichenoid eruptions. J R Soc Med 1980; 73: 208–11. 10 Parkinson DR, Cano PO, Jerry LM et al. Complications of cancer immunotherapy with levamisole. Lancet 1977; ii: 1129–32. 11 Macfarlane DG, Bacon PA. Levamisole-induced vasculitis due to circulating immune complexes. BMJ 1978; i: 407–8. 12 Scheinberg MA, Bezera JBG, Almeida LA, Silveira LA. Cutaneous necrotising vasculitis induced by levamisole. BMJ 1978; i: 408. 13 Rongioletti F, Ghio L, Ginevri F et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999; 140: 948–51. 14 Calnan CD. Occupational piperazine dermatitis. Contact Dermatitis 1975; 1: 126. 15 Burry JN. Ethylenediamine sensitivity with a systemic reaction to piperazine treatment. Contact Dermatitis 1978; 4: 380. 16 Humphreys F, Cox NH. Thiabendazole-induced erythema multiforme with lesions around melanocytic naevi. Br J Dermatol 1988; 118: 855–6. 17 Robinson HM, Samorodin CS. Thiabendazole-induced toxic epidermal necrolysis. Arch Dermatol 1976; 112: 1757–60.

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Drugs for Pneumocystis Pentamidine This drug is increasingly being used in the treatment and prophylaxis of Pneumocystis carinii pneumonia in patients with AIDS. Urticaria, including contact urticaria [1], or maculopapular eruption proceeding to erythroderma have been reported with nebulized therapy [2,3]. TEN may occur with systemic therapy [4,5]. References 1 Belsito DV. Contact urticaria from pentamidine isethionate. Contact Dermatitis 1993; 29: 158–9. 2 Leen CLS, Mandal BK. Rash due to nebulised pentamidine. Lancet 1988; ii: 1250–1. 3 Berger TG, Tappero JW, Leoung GS, Jacobson MA. Aerosolized pentamidine and cutaneous eruptions. Ann Intern Med 1989; 110: 1035–6. 4 Wang JJ, Freeman AI, Gaeta JF, Sinks LF. Unusual complications of pentamidine in the treatment of Pneumocystis carinii pneumonia. J Pediatr 1970; 77: 311–4. 5 Walzer PD, Perl DP, Krogstadt DJ et al. Pneumocystis carinii pneumonia in the United States: epidemiologic, diagnostic and clinical features. Ann Intern Med 1974; 80: 83–93.

Non-steroidal anti-inflammatory drugs Acetylsalicylic acid and related compounds Aspirin Reactions to aspirin [1–4] occur in 0.3% of normal subjects [2,4]. These are usually sporadic, but occasionally more than one family member may be affected, and an HLA linkage has been reported [5]. Urticaria or angio-oedema is the commonest reaction [1]. Two types of specific IgE antibody were found in sera from aspirinsensitive patients with salicyloyl and O-methylsalicyloyl discs using radioallergosorbent tests, favouring an IgE-dependent mechanism [6]. Chronic idiopathic urticaria is often aggravated by aspirin [7,8]; this exacerbation probably has a non-allergic basis. It has been estimated that patients with chronic urticaria or angiooedema have a risk of up to 30% of developing a flare in the condition following administration of aspirin or an NSAID [3]. The reaction is dose dependent and is greater when the urticaria is in an active phase. Aspirin may render the skin of such patients more reactive to histamine [5]. The syndrome of nasal polyposis, bronchial asthma and aspirin intolerance is well known [4,9]; up to 40% of patients with nasal polyps, and 4% of patients with asthma, may develop bronchoconstriction on exposure to aspirin, but only 2% develop urticaria [4]. Anaphylactoid responses may occur [3]; these may involve abnormalities of platelet function [10]. Crosssensitivity between aspirin and tartrazine is now thought to be rare [3]. Oral desensitization is feasible if essential, and may be maintained by daily aspirin intake [3]. Other reported reactions include purpura, scarlatiniform erythema, erythema multiforme, fixed eruption and a lichenoid eruption (which recurred on challenge) [11], but all are rare [1]. Neonatal petechiae may result from aspirin therapy of the mother [12]. Aspirin has been reported to provoke generalized pustular psoriasis [13]. Oral ulceration may follow prolonged chewing of aspirin [14], and at the site of an insoluble aspirin tablet placed at the side of an aching tooth. Nephropathy, marrow depression and gastric haemorrhage are well-recognized hazards. The elderly are at increased risk of

developing such complications [15]. The drug may interfere with renal clearance, for example of methotrexate. Aspirin is safe to administer to patients with glucose-6-phosphate dehydrogenase deficiency [16]. References 1 Baker H, Moore-Robinson M. Drug reactions. IX. Cutaneous responses to aspirin and its derivatives. Br J Dermatol 1970; 82: 319–21. 2 Settipane RA, Constantine HP, Settipane GA. Aspirin intolerance and recurrent urticaria in normal adults and children. Epidemiol Rev Allergy 1980; 35: 149– 54. 3 Stevenson DD. Diagnosis, prevention and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1984; 74: 617–22. 4 Morassut P, Yang W, Karsh J. Aspirin intolerance. Semin Arthritis Rheum 1989; 19: 22–30. 5 Mullarkey MF, Thomas PS, Hansen JA et al. Association of aspirin-sensitive asthma with HLA-DQw2. Am Rev Respir Dis 1986; 133: 261–3. 6 Daxun Z, Becker WM, Schulz KH, Schlaak M. Sensitivity to aspirin: a new serological diagnostic method. J Invest Allergol Clin Immunol 1993; 3: 72–8. 7 Champion RH, Roberts SOB, Carpenter RG, Roger JH. Urticaria and angiooedema. A review of 554 patients. Br J Dermatol 1969; 81: 588–97. 8 Doeglas HMG. Reactions to aspirin and food additives in patients with chronic urticaria, including the physical urticarias. Br J Dermatol 1975; 93: 135–44. 9 Samter M, Beers RF. Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med 1968; 68: 975–83. 10 Wüthrich B. Azetylsalizylsäure-Pseudoallergie. Eine Anomalie der Thrombozyten-Funktion? Hautarzt 1988; 39: 631–4. 11 Bharija SC, Belhaj MS. Acetylsalicylic acid may induce a lichenoid eruption. Dermatologica 1988; 177: 19. 12 Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med 1982; 307: 909–12. 13 Shelley WB. Birch pollen and aspirin psoriasis. JAMA 1964; 189: 985–8. 14 Claman HN. Mouth ulcers associated with prolonged chewing of gum containing aspirin. JAMA 1967; 202: 651–2. 15 Karsh J. Adverse reactions and interactions with aspirin. Considerations in the treatment of the elderly patient. Drug Saf 1990; 5: 317–27. 16 Beutler E. Glucose-6-phosphate dehydrogenase deficiency. Lancet 1991; 324: 169–74.

Diflunisal Various cutaneous reactions have been reported in up to 5% of patients, including pruritus, urticaria, exanthems, Stevens– Johnson syndrome, erythroderma [1] and a lichenoid photoreactive rash [2]. A non-pigmenting fixed drug eruption has been documented [3]. References 1 Chan L, Winearls C, Oliver D et al. Acute interstitial nephritis and erythroderma associated with diflunisal. BMJ 1980; 280: 84–5. 2 Street ML, Winkelmann RK. Lichenoid photoreactive epidermal necrosis with diflunisal. J Am Acad Dermatol 1989; 20: 850–1. 3 Roetzheim RG, Herold AH, Van Durme DJ. Nonpigmenting fixed drug eruption caused by diflunisal. J Am Acad Dermatol 1991; 24: 1021–2.

Paracetamol (acetaminophen) This drug is a major metabolite of phenacetin, and has largely replaced it. Allergic reactions are very rare, considering that it has been estimated that more than 1.4 billion tablets are sold per annum in the UK [1,2]. Urticaria [3], anaphylaxis, a widespread maculopapular eruption, a fixed eruption [2,4–8] that may be nonpigmenting [8], exfoliative dermatitis [9], delayed hypersensitivity reactions [10], linear IgA bullous dermatosis [11] and figurate purpura [12] have been seen.

Important or widely prescribed drugs References 1 Stricker BHC, Meyboom RHB, Lindquist M. Acute hypersensitivity reactions to paracetamol. BMJ 1985; 291: 938–9. 2 Thomas RH, Munro DD. Fixed drug eruption due to paracetamol. Br J Dermatol 1986; 115: 357–9. 3 Cole FOA. Urticaria from paracetamol. Clin Exp Dermatol 1985; 10: 404. 4 Guin JD, Haynie LS, Jackson D, Baker GF. Wandering fixed drug eruption: a mucocutaneous reaction to acetaminophen. J Am Acad Dermatol 1987; 3: 399–402. 5 Guin JD, Baker GF. Chronic fixed drug eruption caused by acetaminophen. Cutis 1988; 41: 106–8. 6 Valsecchi R. Fixed drug eruption to paracetamol. Dermatologica 1989; 179: 51–8. 7 Duhra P, Porter DI. Paracetamol-induced fixed drug eruption with positive immunofluorescence findings. Clin Exp Dermatol 1990; 15: 293–5. 8 Galindo PA, Borja J, Feo F et al. Nonpigmented fixed drug eruption caused by paracetamol. J Invest Allergol Clin Immunol 1999; 9: 399–400. 9 Girdhar A, Bagga AK, Girdhar BF. Exfoliative dermatitis due to paracetamol. Indian J Dermatol Venereol Lepr 1984; 50: 162–3. 10 Ibanez MD, Alonso E, Munoz MC et al. Delayed hypersensitivity reaction to paracetamol (acetaminophen). Allergy 1996; 51: 121–3. 11 Avci O, Õkmen M, Cetiner S. Acetaminophen-induced linear IgA bullous dermatosis. J Am Acad Dermatol 2003; 48: 299–301. 12 Kwon SJ, Lee CW. Figurate purpuric eruptions on the trunk: acetaminopheninduced rashes. J Dermatol 1998; 25: 756–8.

Phenacetin Capillaritis, vasculitis and a bullous pemphigoid-like eruption [1] have been documented. Salicylamide Use of teething jellies containing this substance has resulted in severe urticaria in infants [2]. References 1 Kashihara M, Danno K, Miyachi Y et al. Bullous pemphigoid-like lesions induced by phenacetin. Report of a case and an immunopathologic study. Arch Dermatol 1984; 120: 1196–9. 2 Bentley-Phillips B. Infantile urticaria caused by salicylamide teething powder. Br J Dermatol 1968; 80: 341.

Other NSAIDs Dermatological aspects of the NSAIDs have been extensively reviewed [1–13]. All these drugs inhibit the enzyme cyclooxygenase, and decrease the production of prostaglandins and thromboxanes [6]. NSAIDs represent about 5% of all prescriptions in the UK [5] and USA [2]; nearly one in seven Americans were treated with an NSAID in 1984, and in 1986 100 million prescriptions for these drugs were written in the USA [14]. NSAIDs accounted for 25% of all suspected ADRs reported to the UK Committee on Safety of Medicines in 1986 [5,15]. Reactions to NSAIDs occur in about 1 in 50 000 administrations; NSAIDs should be avoided in patients known to be intolerant of aspirin [6]. In a large series, allergic or pseudoallergic reactions were observed in 0.2% of patients exposed to minor analgesics (including aspirin and pyrazolones, mainly metamizole, propyphenazone) and in 0.8% of patients exposed to NSAIDs (including the pyrazolone oxyphenbutazone); most reactions were cutaneous, mainly maculopapular exanthems, urticaria and angio-oedema [10]. Piroxicam, meclofenamate sodium, sulindac and zomepirac sodium had the highest reaction rates relative to the number of new prescriptions in the USA [1,2]. In contrast, naproxen, fenoprofen, ibuprofen and indo-

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metacin all had low rates of reaction; ibuprofen is available as a non-prescription drug in the USA and the UK. In another study of 2747 patients with rheumatoid arthritis, toxicity index scores computed from symptoms, laboratory abnormalities and hospitalizations attributed to NSAID therapy indicated that indometacin, tolmetin sodium and meclofenamate sodium were the most toxic, and buffered aspirin, salsalate and ibuprofen the least toxic [16]. Cutaneous adverse reactions to NSAIDs were, in order of frequency in one study [11], urticaria/angio-oedema, fixed eruptions, exanthems, erythema multiforme and Stevens–Johnson syndrome. Drug exanthems and urticaria occur in 0.2–9% of patients treated with NSAIDs [2,6]. Drug exanthems develop in 1% of patients on phenylbutazone and 0.3% of patients on indometacin [6]; they are most frequently associated with diflunisal, sulindac, meclofenamate sodium, piroxicam and phenylbutazone. All the NSAIDs, but particularly aspirin and tolmetin, may cause urticaria and anaphylactoid reactions, especially in a patient with a history of aspirin-induced urticaria. Pyrazolone NSAIDs, feprazone, nimesulide, piroxicam and flurbiprofen cause fixed drug eruptions. Although all NSAIDs may precipitate exfoliative erythroderma, this is commonest with phenylbutazone [6]. All the NSAIDs, but particularly phenylbutazone, piroxicam, fenbufen and sulindac, may cause Stevens–Johnson syndrome or TEN [6]. Oral lichenoid lesions have also been recorded with NSAIDs [17]. Psoriasis has been reported anecdotally to be exacerbated by indometacin and meclofenamate sodium, but there is no definitive evidence that NSAIDs consistently exacerbate psoriasis [5]. Contact dermatitis induced by topical NSAIDs is rare but increasing; ketoprofen and bufexamac are major contact allergens [13]. Children on NSAIDs were 2.4 times as likely to have shallow facial scars, as described in drug-induced pseudoporphyria, in one study; this relative risk was increased to 6 with naproxen [18]. Most of the NSAIDs causing photosensitivity are phenylpropionic acid derivatives: carprofen, ketoprofen, tiaprofenic acid, naproxen and nabumetone [19–24]. NSAIDs that cause photosensitivity absorb UV radiation at wavelengths longer than 310 nm, resulting in the generation of singlet oxygen molecules, which damage cell membranes [12]. The cutaneous photosensitivity appears to be elicited by a phototoxic mechanism [19–21,24]. The phototoxic reactions with NSAIDs are immediate, consisting of itching, burning, erythema and at higher fluences wealing; this contrasts with the delayed reactions associated with psoralens and tetracyclines, which produce abnormal delayed erythema or exaggerated sunburn. Propionic acid derivatives may also precipitate photourticaria by mast cell degranulation [23]. Piroxicam, an enolic acid derivative structurally unrelated to phenylpropionic acid, is the most frequently cited non-phenylpropionic acid NSAID to cause photosensitivity [20,21,25]; phototoxicity to the parent drug has not been elicited in volunteers or experimental animals, although a phototoxic metabolite has been identified in vitro. Indometacin, sulindac [26], meclofenamate sodium and phenylbutazone have all been associated with photosensitivity [2]. NSAIDs may cause pseudoporphyria changes [27]. Apart from the cutaneous complications, NSAIDs may cause a variety of adverse effects [14,28–30], including gastrointestinal bleeding, intestinal perforations and acute deterioration in renal function with interstitial nephritis [28]; the elderly and patients

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with impaired renal function or receiving concomitant diuretic therapy are most at risk. NSAIDs may inhibit platelet aggregation and increase bleeding times [29]. Aplastic anaemia is a recognized complication, and has occurred in the same individual with two different NSAIDs (sulindac and fenbufen) [31]. Hepatic syndromes [30], pneumonitis (naproxen, ibuprofen, fenoprofen and sulindac can elicit pulmonary infiltrates with eosinophilia [32]), and neurological problems, such as headache, aseptic meningitis and dizziness, are recorded [14]. Niflumic acid and diclofenac both precipitated a dermatomyositis-like syndrome in a patient [33]. The potential for adverse interactions between NSAIDs and other drugs is considerable [14]. References 1 Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroid anti-inflammatory drugs. Reports to a specialty-based system for spontaneous reporting of adverse reactions to drugs. JAMA 1984; 252: 1433–7. 2 Bigby M, Stern R. Cutaneous reactions to non-steroidal anti-inflammatory drugs. A review. J Am Acad Dermatol 1985; 12: 866–76. 3 O’Brien WM, Bagby GF. Rare reactions to nonsteroidal anti-inflammatory drugs. J Rheumatol 1985; 12: 13–20. 4 Roujeau JC. Clinical aspects of skin reactions to NSAIDs. Scand J Rheumatol 1987; 65 (Suppl.): 131–4. 5 Greaves MW. Pharmacology and significance of nonsteroidal antiinflammatory drugs in the treatment of skin diseases. J Am Acad Dermatol 1987; 16: 751–64. 6 Bigby M. Nonsteroidal anti-inflammatory drug reactions. Semin Dermatol 1989; 8: 182–6. 7 Arnaud A. Allergy and intolerance to nonsteroidal anti-inflammatory agents. Clin Rev Allergy Immunol 1995; 13: 245–51. 8 Van Arsdel PP Jr. Pseudoallergic reactions to nonsteroidal anti-inflammatory drugs. JAMA 1991; 266: 3343–4. 9 Bottoni A, Criscuolo D. Cutaneous adverse reactions following the administration of nonsteroidal antiinflammatory drugs and antibiotics: an Italian survey. Int J Clin Pharmacol Ther Toxicol 1992; 30: 257–9. 10 Oberholzer B, Hoigne R, Hartmann K et al. Die Haufigkeit von unerwunschten Arzneimittelwirkungen nach Symptomen und Syndrome. Aus den Erfahrungen des CHDM und der SANZ. Als Beispiel: die allergischen und pseudoallergischen Reaktionen unter leichten Analgetika und NSAIDs. Ther Umsch 1993; 50: 13–9. 11 Anonymous. Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. Analysis of reports to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia. Dermatology 1993; 186: 164–9. 12 Figueras A, Capella D, Castel JM, Laorte JR. Spontaneous reporting of adverse drug reactions to non-steroidal anti-inflammatory drugs. A report from the Spanish System of Pharmacovigilance, including an early analysis of topical and enteric-coated formulations. Eur J Clin Pharmacol 1994; 47: 297–303. 13 Gebhardt M, Wollina U. Kutane Nebenwirkungen nichtsteroidaler Antiphlogistika (NSAID). Z Rheumatol 1995; 54: 405–12. 14 Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs: differences and similarities. N Engl J Med 1991; 324: 1716–25. 15 Committee on Safety of Medicines. Nonsteroidal anti-inflammatory drugs and serious gastrointestinal adverse reaction: 1. BMJ 1986; 292: 614. 16 Fries JF, Williams CA, Bloch DA. The relative toxicity of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1991; 34: 1353–60. 17 Hamburger J, Potts AJC. Non-steroidal anti-inflammatory drugs and oral lichenoid reactions. BMJ 1983; 287: 1258. 18 Wallace CA, Farrow D, Sherry DD. Increased risk of facial scars in children taking nonsteroidal antiinflammatory drugs. J Pediatr 1994; 125: 819–22. 19 Ljunggren B. Propionic acid-derived nonsteroidal anti-inflammatory drugs are phototoxic in vitro. Photodermatology 1985; 2: 3–9. 20 Stern RS. Phototoxic reactions to piroxicam and other nonsteroidal antiinflammatory agents. N Engl J Med 1983; 309: 186–7. 21 Diffey BL, Daymond TJ, Fairgreaves H. Phototoxic reactions to piroxicam, naproxen and tiaprofenic acid. Br J Rheumatol 1983; 22: 239–42.

22 Przybilla B, Ring J, Schwab U et al. Photosensibilisierende Eigenschaften nichtsteroidaler Antirheumatika im Photopatch-Test. Hautarzt 1987; 38: 18–25. 23 Kaidbey KH, Mitchell FN. Photosensitizing potential of certain nonsteroidal anti-inflammatory agents. Arch Dermatol 1989; 125: 783–6. 24 Kochevar IE. Phototoxicity of nonsteroidal inflammatory drugs. Coincidence or specific mechanism? Arch Dermatol 1989; 125: 824–6. 25 Serrano G, Bonillo J, Aliaga A et al. Piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. J Am Acad Dermatol 1990; 23: 479–83. 26 Jeanmougin M, Manciet J-R, Duterque M et al. Photosensibilisation au sulindac. Ann Dermatol Vénéréol 1987; 114: 1400–1. 27 Taylor BJ, Duffill MB. Pseudoporphyria from nonsteroidal anti-inflammatory drugs. NZ Med J 1987; 100: 322–3. 28 Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984; 310: 563–72. 29 Ekenny GN. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992; 44 (Suppl. 5): 31–7. 30 Carson JL, Willett LR. Toxicity of nonsteroidal anti-inflammatory drugs. An overview of the epidemiological evidence. Drugs 1993; 46 (Suppl. 1): 243–8. 31 Andrews R, Russell N. Aplastic anaemia associated with a non-steroidal anti-inflammatory drug: relapse after exposure to another such drug. BMJ 1990; 301: 38. 32 Goodwin SD, Glenny RW. Nonsteroidal anti-inflammatory drug-associated pulmonary infiltrates with eosinophilia. Review of the literature and Food and Drug Administration Adverse Drug Reaction reports. Arch Intern Med 1992; 152: 1521–4. 33 Grob JJ, Collet AM, Bonerandi JJ. Dermatomyositis-like syndrome induced by nonsteroidal anti-inflammatory agents. Dermatologica 1989; 178: 58–9.

Propionic acid derivatives Carprofen. This drug causes photosensitivity [1]. Fenbufen. Morbilliform and erythematous rashes, erythema multiforme [2], Stevens–Johnson syndrome and allergic vasculitis have been recorded rarely. Fenbufen has caused exfoliative dermatitis, haemolytic anaemia and hepatitis [3], and was the drug implicated most commonly in adverse reactions reported to the UK Committee on Safety of Medicines in 1986 and 1987. A florid erythematous rash with pulmonary eosinophilia has been described in four cases [4]. Fenoprofen. This drug has caused pruritus, urticaria, vesicobullous eruption, thrombocytopenic purpura and TEN [5]. Ibuprofen. Pruritus is the only common cutaneous reaction. When used in rheumatoid arthritis, rashes are rare, although patients with SLE are liable to develop a generalized rash with fever and abdominal symptoms [6]. Angio-oedema/urticaria [7,8], anaphylaxis [9,10], fixed eruptions [8], a linear eruption [11], vesicobullous rashes, erythema multiforme, vasculitis [12] and alopecia [13] occur. Psoriasis has been reported to be exacerbated [14]. This drug is available over the counter in the UK. Ketoprofen. Topical application has caused photoallergic contact dermatitis [15] and systemic ketoprofen has caused pseudoporphyria. Naproxen. The incidence of side effects is low given the widespread and long-term use of naproxen. Rashes occur in about 5% of patients; pruritus is the commonest symptom. Naproxen is associated with a photosensitivity dermatitis [16] and pseudopor-

Important or widely prescribed drugs

phyria [17–21]; most photourticarial reactions are evoked by the UVA band. Urticaria/angio-oedema, anaphylaxis [22], purpura and thrombocytopenia [23], hyperhidrosis, acneiform problems in women [24], vasculitis [25,26], vesicobullous and fixed drug eruptions [27], erythema multiforme, a pustular reaction [28] and lichen planus-like reaction [29] have all been reported, as has recurrent allergic sialadenitis [30]. Tiaprofenic acid. This drug may cause photosensitivity [31]. References 1 Merot Y, Harms M, Saurat JH. Photosensibilisation au carprofén (imadyl), un nouvel anti-inflammatoire non stéroidien. Dermatologica 1983; 166: 301–7. 2 Peacock A, Ledingham J. Fenbufen-induced erythema multiforme. BMJ 1981; 283: 582. 3 Muthiah MM. Severe hypersensitivity reaction to fenbufen. BMJ 1988; 297: 1614. 4 Burton GH. Rash and pulmonary eosinophilia associated with fenbufen. BMJ 1990; 300: 82–3. 5 Stotts JS, Fang ML, Dannaker CJ, Steinman HK. Fenoprofen-induced toxic epidermal necrolysis. J Am Acad Dermatol 1988; 18: 755–7. 6 Shoenfeld Y, Livni E, Shaklai M, Pinkhas J. Sensitization to ibuprofen in SLE. JAMA 1980; 244: 547–8. 7 Shelley ED, Shelley WB. Ibuprofen urticaria. J Am Acad Dermatol 1987; 17: 1057–8. 8 Diaz Jara M, Perez Montero A, Gracia Bara MT et al. Allergic reactions due to ibuprofen in children. Pediatr Dermatol 2001; 18: 66–7. 9 Takahama H, Kubota Y, Mizoguchi M. A case of anaphylaxis due to ibuprofen. J Dermatol 2000; 27: 337–40. 10 Kang LW, Kidon MI, Chin CW et al. Severe anaphylactic reaction to ibuprofen in a child with recurrent urticaria. Pediatrics 2007; 120: e742–4. 11 Alfonso R, Belinchon I. Linear drug eruption. Eur J Dermatol 2001; 11: 122–3. 12 Davidson KA, Ringpfeil F, Lee JB. Ibuprofen-induced bullous leukocytoclastic vasculitis. Cutis 2001; 67: 303–7. 13 Meyer HC. Alopecia associated with ibuprofen. JAMA 1979; 242: 142. 14 Ben-Chetrit E, Rubinow A. Exacerbation of psoriasis by ibuprofen. Cutis 1986; 38: 45. 15 Alomar A. Ketoprofen photodermatitis. Contact Dermatitis 1985; 12: 112–3. 16 Shelley WB, Elpern DJ, Shelley ED. Naproxen photosensitization demonstrated by challenge. Cutis 1986; 38: 169–70. 17 Farr PM, Diffey BL. Pseudoporphyria due to naproxen. Lancet 1985; i: 1166–7. 18 Judd LE, Henderson DW, Hill DC. Naproxen-induced pseudoporphyria: a clinical and ultrastructural study. Arch Dermatol 1986; 122: 451–4. 19 Mayou S, Black MM. Pseudoporphyria due to naproxen. Br J Dermatol 1986; 114: 519–20. 20 Burns DA. Naproxen pseudoporphyria in a patient with vitiligo. Clin Exp Dermatol 1987; 12: 296–7. 21 Levy ML, Barron KS, Eichenfield A, Honig PJ. Naproxen-induced pseudoporphyria: a distinctive photodermatitis. J Pediatr 1990; 117: 660–4. 22 Cistero A, Urias S, Guindo J et al. Coronary artery spasm and acute myocardial infarction in naproxen-associated anaphylactic reaction. Allergy 1992; 47: 576–8. 23 Hunt PJ, Gibbons SS. Naproxen induced thrombocytopenia: a case report. NZ Med J 1995; 108: 483–4. 24 Hamman CO. Severe primary dysmenorrhea treated with naproxen. A prospective, double-blind crossover investigation. Prostaglandins 1980; 19: 651–7. 25 Grennan DM, Jolly J, Holloway LJ, Palmer DG. Vasculitis in a patient receiving naproxen. NZ Med J 1979; 89: 48–9. 26 Singhal PC, Faulkner M, Venkatesham J, Molho L. Hypersensitivity angiitis associated with naproxen. Ann Allergy 1989; 63: 107–9. 27 Habbema L, Bruynzeel DP. Fixed drug eruption due to naproxen. Dermatologica 1987; 174: 184–5. 28 Grattan CEH. Generalized pustular drug rash due to naproxen. Dermatologica 1989; 179: 57–8. 29 Heymann WR, Lerman JS, Luftschein S. Naproxen-induced lichen planus. J Am Acad Dermatol 1984; 10: 299–301.

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30 Knulst AC, Stengs CJ, Baart de la Faille H et al. Salivary gland swelling following naproxen therapy. Br J Dermatol 1995; 133: 647–9. 31 Neumann RA, Knobler RM, Lindemayr H. Tiaprofenic acid-induced photosensitivity. Contact Dermatitis 1989; 20: 270–3.

Phenylacetic acids Diclofenac. A variety of cutaneous adverse effects [1,2], including pruritus, urticaria, various exanthems, papulovesicular eruptions [3], delayed allergy [4], vasculitis [5], a bullous eruption associated with linear basement membrane deposition of IgA [6] and fatal erythema multiforme [1] have been recorded. References 1 Ciucci AG. A review of spontaneously reported adverse drug reactions with diclofenac sodium (Voltarol). Rheum Rehabil 1979; Suppl. 2: 116–21. 2 O’Brien WM. Adverse reactions to nonsteroidal antiinflammatory drugs. Diclofenac compared with other nonsteroidal antiinflammatory drugs. Am J Med 1986; 80: 70–80. 3 Seigneuric C, Nougué J, Plantavid M. Érythème polymorphe avec atteinte muqueuse: responsabilité du diclofénac? Ann Dermatol Vénéréol 1982; 109: 287. 4 Schiavino D, Papa G, Nucera E et al. Delayed allergy to diclofenac. Contact Dermatitis 1992; 26: 357–8. 5 Bonafé J-L, Mazières B, Bouteiller G. Trisymptôme de Gougerot induit par les anti-inflammatoires. Rôle du diclofénac? Ann Dermatol Vénéréol 1982; 109: 283–4. 6 Gabrielson TØ, Staerfelt F, Thune PO. Drug induced bullous dermatosis with linear IgA deposits along the basement membrane. Acta Derm Venereol (Stockh) 1981; 61: 439–41.

Oxicams Piroxicam. This drug may cause adverse cutaneous reactions in 2–3% of patients [1,2]. More than two-thirds of affected patients have photosensitivity; lesions may be vesicobullous or eczematous, and occur within 3 days of starting therapy in 50% of cases [3–10]. Photosensitivity may result from phototoxic metabolites [7]. Photocontact dermatitis developed in three patients after the application of a gel containing 0.5% piroxicam. Patch tests were positive to thiomersal and thiosalicylic acid, and photopatch tests with piroxicam were positive. Patch tests in patients with systemic photosensitivity to piroxicam were also positive for thiomersal and thiosalicylic acid. Contact allergic sensitivity to the latter is a marker for patients with a high risk of developing photosensitivity reactions to piroxicam [10,11]. Other eruptions include urticaria, maculopapular [12] or lichenoid rashes, alopecia, erythema multiforme [13] and vasculitis [14]. Piroxicam was well tolerated in patients with an urticarial reaction to a single NSAID, but provoked urticaria in 27% of patients with allergy to at least two different NSAIDs, indicating that mechanisms other than interference with prostaglandin synthesis and release of inflammatory mediators participate in allergic reactions to NSAIDs [15]. Classical fixed drug eruption [16,17] and a nonpigmenting fixed drug reaction [18], with cross-sensitivity among piroxicam, tenoxicam and droxicam in one case [19], have also been reported. Contact sensitivity to piroxicam is recorded [20]. Piroxicam was thought to have triggered subacute LE in a patient with Sjögren’s syndrome and seronegative arthritis [21]. Isolated case reports of linear IgA bullous dermatosis [22], fatal pemphigus vulgaris [23] and fatal TEN [24] have appeared. The drug has caused peripheral neuropathy and erythroderma [25]. Blood dyscrasias have been reported.

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References 1 Pitts N. Efficacy and safety of piroxicam. Am J Med 1982; 72 (Suppl. 2A): 77–87. 2 Gerber D. Adverse reactions of piroxicam. Drug Intel Clin Phar 1987; 21: 707–10. 3 Stern RS. Phototoxic reactions to piroxicam and other nonsteroidal antiinflammatory agents. N Engl J Med 1983; 309: 186–7. 4 Diffey BL, Daymond TJ, Fairgreaves H. Phototoxic reactions to piroxicam, naproxen and tiaprofenic acid. Br J Rheumatol 1983; 22: 239–42. 5 Serrano G, Bonillo J, Aliaga A et al. Piroxicam-induced photosensitivity. J Am Acad Dermatol 1984; 11: 113–20. 6 McKerrow KJ, Greig DE. Piroxicam-induced photosensitive dermatitis. J Am Acad Dermatol 1986; 15: 1237–41. 7 Kocheva IE, Morison WL, Lamm JL et al. Possible mechanism of piroxicaminduced photosensitivity. Arch Dermatol 1986; 122: 1283–7. 8 Kaidbey KH, Mitchell FN. Photosensitizing potential of certain nonsteroidal anti-inflammatory agents. Arch Dermatol 1989; 125: 783–6. 9 Kocheva IE. Phototoxicity of nonsteroidal inflammatory drugs. Coincidence or specific mechanism? Arch Dermatol 1989; 125: 824–6. 10 Serrano G, Bonillo J, Aliaga AET et al. Piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. J Am Acad Dermatol 1990; 23: 479–83. 11 Trujillo MJ, de Barrio M, Rodriguez A et al. Piroxicam-induced photodermatitis. Cross-reactivity among oxicams. A case report. Allergol Immunopathol 2001; 29: 133–6. 12 Faure M, Goujon C, Perrot H et al. Accidents cutanés provoqués par le piroxicam. A propos de trois observations. Ann Dermatol Vénéréol 1982; 109: 255–8. 13 Bertail M-A, Cavelier B, Civatte J. Réaction au piroxicam (Feldène®). A type d’ectoderme érosive pluri-orificielle. Ann Dermatol Vénéréol 1982; 109: 261–2. 14 Goebel KN, Mueller-Brodman W. Reversible overt nephropathy with Henoch– Schönlein purpura due to piroxicam. BMJ 1982; 284: 311–2. 15 Carmona MJ, Blanca M, Garcia A et al. Intolerance to piroxicam in patients with adverse reactions to nonsteroidal antiinflammatory drugs. J Allergy Clin Immunol 1992; 90: 873–9. 16 Stubb S, Reitamo S. Fixed drug eruption caused by piroxicam. J Am Acad Dermatol 1990; 22: 1111–2. 17 de la Hoz B, Soria C, Fraj J et al. Fixed drug eruption due to piroxicam. Int J Dermatol 1990; 29: 672–3. 18 Valsecchi R, Cainelli T. Nonpigmenting fixed drug reaction to piroxicam. J Am Acad Dermatol 1989; 21: 1300. 19 Ordoqui E, De Barrio M, Rodriguez VM et al. Cross-sensitivity among oxicams in piroxicam-caused fixed drug eruption: two case reports. Allergy 1995; 50: 741–4. 20 Valsecchi R, Pansera B, di Landro A, Cainelli T. Contact sensitivity to piroxicam. Contact Dermatitis 1993; 29: 167. 21 Roura M, Lopez-Gil F, Umbert P. Systemic lupus erythematosus exacerbated by piroxicam. Dermatologica 1991; 182: 56–8. 22 Camilleri M, Pace JL. Linear IgA bullous dermatosis induced by piroxicam. J Eur Acad Dermatol Venereol 1998; 10: 70–2. 23 Martin RL, McSweeny GW, Schneider J. Fatal pemphigus vulgaris in a patient taking piroxicam. N Engl J Med 1983; 309: 795–6. 24 Roujeau JC, Revuz I, Touraine R et al. Syndrome de Lyell au cours d’un traitement par un nouvel antiinflammatoire. Nouv Presse Med 1981; 10: 3407–8. 25 Sangla I, Blin O, Jouglard J et al. Neuropathic axonale et toxidermie iatrogene par le piroxicam. Manifestations d’hypersensibilite? Rev Neurol 1993; 149: 217–8.

Anthranilic acids Meclofenamate sodium. Rashes occur in up to 9% of patients. More than two-thirds of reactions have been exanthematous, with prominent pruritus; vasculitic, purpuric or petechial reactions are also noted, as well as occasional urticaria, fixed drug eruption, erythema multiforme [1], exfoliative erythroderma and a vesicobullous reaction. It has been reported to exacerbate psoriasis [2]. Selective adverse reactions to glafenine and meclofenamate occurred in a patient tolerating aspirin and other cyclo-oxygenase inhibitors [3].

Mefenamic acid. Urticaria, a morbilliform eruption, fixed drug eruption [4,5], pseudoporphyria [6] and generalized exfoliative dermatitis are documented. Acute renal failure, severe thrombocytopenia and jaundice developed after a small dose of mefenamic acid in one patient with drug-dependent antibodies reacting against platelets [7]. References 1 Harrington T, Davis D. Erythema multiforme induced by meclofenamate sodium. J Rheumatol 1983; 10: 169–70. 2 Meyerhoff JO. Exacerbation of psoriasis with meclofenamate. N Engl J Med 1983; 309: 496. 3 Fernandez-Rivas M, de la Hoz B, Cuevas M et al. Hypersensitivity reactions to anthranilic acid derivatives. Ann Allergy 1993; 71: 515–8. 4 Wilson DL, Otter A. Fixed drug eruption associated with mefenamic acid. BMJ 1986; 293: 1243. 5 Watson A, Watt G. Fixed drug eruption to mefenamic acid. Australas J Dermatol 1986; 27: 6–7. 6 O’Hagan AH, Irvine AD, Allen GE, Walsh M. Pseudoporphyria induced by mefenamic acid. Br J Dermatol 1998; 139: 1131–2. 7 Schwartz D, Gremmel F, Kurz R et al. Case report: acute renal failure, thrombocytopenia and nonhemolytic icterus probably caused by mefenamic acid (Parkemed)-dependent antibodies. Beitr Infusionsther 1992; 30: 413–5.

Heterocyclic acetic acids Indometacin (indomethacin). Allergic reactions are very uncommon, but pruritus, urticaria, purpura and morbilliform eruptions are documented. Stomatitis [1] and thrombocytopenia occur rarely, as well as a generalized exfoliative dermatitis and TEN [2]. Vasculitis has been documented [3]. There have been rare reports of exacerbation of psoriasis [4,5]; however, indometacin in a standard dose of 75 mg/day had no significant harmful effect on psoriasis in a series of patients treated with the Ingram regimen of coal-tar bath, suberythemal UVB phototherapy and dithranol in Lassar’s paste [6]. Exacerbation of dermatitis herpetiformis has been recorded [7]. References 1 Guggenheimer J, Ismail YH. Oral ulcerations associated with indomethacin therapy: report of three cases. J Am Dent Assoc 1975; 90: 632–4. 2 O’Sullivan M, Hanly JG, Molloy M. A case of toxic epidermal necrolysis secondary to indomethacin. Br J Rheumatol 1983; 22: 47–9. 3 Marsh FP, Almeyda JR, Levy IS. Non-thrombocytopenic purpura and acute glomerulonephritis after indomethacin therapy. Ann Rheum Dis 1971; 30: 501–5. 4 Katayama H, Kawada A. Exacerbation of psoriasis induced by indomethacin. J Dermatol 1981; 8: 323–7. 5 Powles AV, Griffiths CEM, Seifert MH, Fry L. Exacerbation of psoriasis by indomethacin. Br J Dermatol 1987; 117: 799–800. 6 Sheehan-Dare RA, Goodfield MJD, Rowell NR. The effect of oral indomethacin on psoriasis treated with the Ingram regime. Br J Dermatol 1991; 125: 253–5. 7 Griffiths CEM, Leonard JN, Fry L. Dermatitis herpetiformis exacerbated by indomethacin. Br J Dermatol 1985; 112: 443–5.

Sulindac. Rashes occur in up to 9% of patients. The drug has caused anaphylaxis [1] and anaphylactoid reactions [2], photosensitivity [3], facial and oral erythema, a pernio-like reaction [4] and fixed drug eruption [5]. Stevens–Johnson syndrome [6–8], TEN [6,9], serum sickness and exfoliative erythroderma are documented. Blood dyscrasias, toxic hepatitis, pancreatitis and aseptic meningitis in patients with SLE are recorded.

Important or widely prescribed drugs

Tolmetin. Anaphylactoid reactions are well recognized [10]. TEN has been recorded. References 1 Smith F, Lindberg P. Life-threatening hypersensitivity to sulindac. JAMA 1980; 244: 269–70. 2 Hyson CP, Kazakoff MA. A severe multisystem reaction to sulindac. Arch Intern Med 1991; 151: 387–8. 3 Jeanmougin M, Manciet J-R, Duterque M et al. Photosensibilisation au sulindac. Ann Dermatol Vénéréol 1987; 114: 1400–1. 4 Reinertsen J. Unusual pernio-like reaction to sulindac. Arthritis Rheum 1981; 24: 1215. 5 Aram HA. Fixed drug eruption due to sulindac. Int J Dermatol 1984; 23: 421. 6 Levitt L, Pearson RW. Sulindac-induced Stevens–Johnson toxic epidermal necrolysis syndrome. JAMA 1980; 243: 1262–3. 7 Husain Z, Runge LA, Jabbs JM, Hyla JA. Sulindac-induced Stevens–Johnson syndrome: report of 3 cases. J Rheumatol 1981; 8: 176–9. 8 Maguire FW. Stevens–Johnson syndrome due to sulindac: a case report and review of the literature. Del Med J 1981; 53: 193–7. 9 Chevrant Breton J, Pibouin M, Allain H et al. Toxic epidermal necrolysis induced by sulindac. Thérapie 1985; 40: 67–9. 10 Rossi A, Knapp D. Tolmetin-induced anaphylactoid reactions. N Engl J Med 1982; 307: 499–500.

Pyrazolones Amidopyrine (aminophenazone). This is the most dangerous of all analgesics and has caused hundreds of deaths due to blood dyscrasias. It has been withdrawn from western Europe and North America but is still available in certain parts of the world. TEN, exfoliative dermatitis and erythema multiforme are all well known. Azapropazone. Photosensitivity is recognized [1]. A multifocal, bullous fixed drug eruption resembling erythema multiforme has been reported [2]. A bullous eruption on the face and extremities, with histological features suggestive of pemphigoid but negative immunofluorescence, has been reported [3]. The drug is contraindicated in patients receiving warfarin, as the latter medication is potentiated [4]. References 1 Olsson S, Biriell C, Boman G. Photosensitivity during treatment with azapropazone. BMJ 1985; 291: 939. 2 Sowden JM, Smith AG. Multifocal fixed drug eruption mimicking erythema multiforme. Clin Exp Dermatol 1990; 15: 387–8. 3 Barker DJ, Cotterill JA. Skin eruptions due to azapropazone. Lancet 1977; i: 90. 4 Win N, Mitchell DC. Azapropazone and warfarin. BMJ 1991; 302: 969–70.

Phenylbutazone and oxyphenbutazone. Reactions have been frequent and often fatal [1,2]. Therefore, in the UK oxyphenbutazone has been withdrawn and phenylbutazone is restricted to hospital use for ankylosing spondylitis. Pruritus, morbilliform eruptions, urticaria and buccal ulceration are most common; erythema multiforme, fixed eruptions (especially with oxyphenbutazone), generalized exfoliative dermatitis and TEN [3] are all well-documented hazards. Drug exanthems or erythroderma may occur in up to 4% of patients treated with phenylbutazone. Occasional reports of exacerbation of psoriasis have occurred [4]. Rarer reactions have included generalized lymphadenopathy, a Sjögren-like syndrome, non-thrombocytopenic purpura, allergic vasculitis [5] and polyarteritis nodosa. Provocation of temporal

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arteritis has been reported. A haemorrhagic bullous eruption of the hands was observed in three patients [6]. Cutaneous necrosis has been seen after intramuscular injection. Phenylbutazone causes fluid retention, gastrointestinal bleeding and bone marrow depression [2]; the hazards of the latter are greatly increased if the dose exceeds 200 mg/day. References 1 Van Joost T, Asghar SS, Cormane RH. Skin reactions caused by phenylbutazone. Immunologic studies. Arch Dermatol 1974; 110: 929–33. 2 Inman WHW. Study of fatal bone marrow depression with special reference to phenylbutazone and oxyphenbutazone. BMJ 1977; i: 1500–5. 3 Montgomery PR. Toxic epidermal necrolysis due to phenylbutazone. Br J Dermatol 1970; 83: 220. 4 Reshad H, Hargreaves GK, Vickers CFH. Generalized pustular psoriasis precipitated by phenylbutazone and oxyphenbutazone. Br J Dermatol 1983; 109: 111–3. 5 Von Paschoud J-M. Vasculitis allergica cutis durch phenylbutazon. Dermatologica 1966; 133: 76–86. 6 Millard LG. A haemorrhagic bullous eruption of the hands caused by phenylbutazone: a report of 3 cases. Acta Derm Venereol (Stockh) 1977; 57: 83–6.

Cyclo-oxygenase-2 inhibitors Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN) have rarely been reported with the cyclo-oxygenase (COX)-2 selective inhibitors celecoxib, rofecoxib, etoricoxib and valdecoxib [1,2]. Celecoxib. Angio-oedema [3], fixed drug eruption [4] and Sweet’s syndrome [5] are documented. Nabumetone. A severe, immediate reaction with pruritus, erythema, palm erythema, a morbilliform eruption and a sensation of a swollen tongue has been documented [6]. Nimesulide. A fixed eruption is recorded [7]. Valdecoxib. Erythematous, target-like skin eruptions with facial oedema and dyspnoea occur [8]. References 1 Layton D, Marshall V, Boshier A et al. Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England. Drug Saf 2006; 29: 687–96. 2 La Grenade L, Lee L, Weaver J et al. Comparison of reporting of Stevens–Johnson syndrome and toxic epidermal necrolysis in association with selective COX-2 inhibitors. Drug Saf 2005; 28: 917–24. 3 Liccardi G, Cazzola M, De Giglio C et al. Safety of celecoxib in patients with adverse skin reactions to acetaminophen (paracetamol) and other non-steroidal anti-inflammatory drugs. J Investig Allergol Clin Immunol 2005; 15: 249–53. 4 Bandyopadhyay D. Celecoxib-induced fixed drug eruption. Clin Exp Dermatol 2003; 28: 452. 5 Fye KH, Crowley E, Berger TG et al. Celecoxib-induced Sweet’s syndrome. J Am Acad Dermatol 2001; 45: 300–2. 6 Gonzalo-Garijo MA, Cordobés-Duran C, Lamilla-Yerga AM, Moreno-Gastón I. Severe immediate reaction to nabumetone. J Investig Allergol Clin Immunol 2007; 17: 274–6. 7 Malheiro D, Cadinha S, Rodrigues J et al. Nimesulide-induced fixed drug eruption. Allergol Immunopathol (Madr) 2005; 33: 285–7. 8 Ziemer M, Wiesend CL, Vetter R et al. Cutaneous adverse reactions to valdecoxib distinct from Stevens–Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2007; 143: 711–6.

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Miscellaneous anti-inflammatory agents Benzydamine Photoallergy has been described to both topical and systemic administration of this drug [1]. Reference 1 Frosch PJ, Weickel R. Photokontakallergie durch Benzydamin (Tantum). Hautarzt 1989; 40: 771–3.

Allopurinol Dermatological complications occur in up to 10% of cases [1–7]. Acute sensitivity reactions are well known, including scarlatiniform erythema, morbilliform rashes, urticaria or generalized exfoliative dermatitis, which may be associated with fever, eosinophilia, hepatic abnormalities and a nephropathy. Vasculitis (perhaps triggered by oxypurinol, the principal metabolite of allopurinol, which has a long half-life and accumulates in renal failure [5]), erythema multiforme [7], Stevens–Johnson syndrome and TEN [5,8,9] have been reported. Cell-mediated immunity directed towards allopurinol, and more importantly to its oxypurinol metabolite, is thought to be involved in the pathogenesis of allopurinol-induced hypersensitivity [10]. Hypersensitivity reactions occur on average within 2–6 weeks of starting the drug, although the interval may be much longer. Eruptions are commoner in the setting of impaired renal function [11] and with concomitant thiazide therapy [12], and may first appear up to 3 weeks after the drug has been discontinued [13]. The mortality is about 20% [5]. Other allopurinol-induced cutaneous changes include alopecia and ichthyosis [14]. Allopurinol potentiates the risk of a reaction to ampicillin [15] and increases blood ciclosporin levels [16]. Desensitization may be successful in cases with minor rashes induced by allopurinol [17–19]. References 1 Lupton GP. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol 1979; 1: 365–74. 2 McInnes GT, Lawson DH, Jick H. Acute adverse reactions attributed to allopurinol in hospitalised patients. Ann Rheum Dis 1981; 40: 245–9. 3 Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum 1986; 29: 82–7. 4 Foucault V, Pibouin M, Lehry D et al. Accidents médicamenteux sévères et allopurinol. Ann Dermatol Vénéréol 1988; 115: 1169–72. 5 Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993; 27: 337–43. 6 Elasy T, Kaminsky D, Tracy M, Mehler PS. Allopurinol hypersensitivity syndrome revisited. West J Med 1995; 162: 360–1. 7 Kumar A, Edward N, White MI et al. Allopurinol, erythema multiforme, and renal insufficiency. BMJ 1996; 312: 173–4. 8 Bennett TO, Sugar J, Sahgal S. Ocular manifestations of toxic epidermal necrolysis associated with allopurinol use. Arch Ophthalmol 1977; 95: 1362–4. 9 Dan M, Jedwab M, Peled M et al. Allopurinol-induced toxic epidermal necrolysis. Int J Dermatol 1984; 23: 142–4. 10 Braden GL, Warzynski MJ, Golightly M, Ballow M. Cell-mediated immunity in allopurinol-induced hypersensitivity. Clin Immunol Immunopathol 1994; 70: 145–51. 11 Handke KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984; 76: 47–56. 12 Handke KR. Evaluation of a thiazide allopurinol drug interaction. Am J Med Sci 1986; 292: 213–6. 13 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63.

14 Auerbach R, Orentreich N. Alopecia and ichthyosis secondary to allopurinol. Arch Dermatol 1968; 98: 104. 15 Jick H, Slone D, Shapiro S et al. Excess of ampicillin rashes associated with allopurinol or hyperuricemia. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N Engl J Med 1972; 286: 505–7. 16 Gorrie M, Beaman M, Nicholls A, Backwell A. Allopurinol interaction with cyclosporin. BMJ 1994; 308: 113. 17 Fam AG, Lewtas J, Stein J, Paton TW. Desensitization to allopurinol in patients with gout and cutaneous reactions. Am J Med 1992; 93: 299–302. 18 Kelso JM, Keating RM. Successful desensitization for treatment of a fixed drug eruption to allopurinol. J Allergy Clin Immunol 1996; 97: 1171–2. 19 Walz-LeBlanc BA, Reynolds WJ, MacFadden DK. Allopurinol sensitivity in a patient with chronic tophaceous gout: success of intravenous desensitization after failure of oral desensitization. Arthritis Rheum 1991; 34: 1329–31.

Drugs acting on the central nervous system Psychotropic medication The adverse effects of psychotropic medication have been reviewed [1–4]; the prevalence of skin reactions to psychotropic medications is about 5% [2]. References 1 Gupta MA, Gupta AK, Haberman HF. Psychotropic drugs in dermatology. A review and guidelines for use. J Am Acad Dermatol 1986; 14: 633–45. 2 Srebrnik A, Hes JP, Brenner S. Adverse cutaneous reactions to psychotropic drugs. Acta Derm Venereol Suppl (Stockh) 1991; 158: 1–12. 3 Kimyai-Asadi A, Harris JC, Nousari HC. Critical overview: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry 1999; 60: 714–25. 4 Warnock JK, Morris DW. Adverse cutaneous reactions to mood stabilizers. Am J Clin Dermatol 2003; 4: 21–30.

Antidepressants Tricyclics and related compounds Antidepressants are associated with a range of idiosyncratic reactions affecting the liver, skin, haematological and central nervous systems; reactions are mediated by chemically reactive metabolites formed by the cytochrome P-450 enzyme system either directly or indirectly via an immune mechanism. Individual susceptibility is determined by genetic and environmental factors, which result in inadequate detoxification of the chemically reactive metabolite [1]. Sedative, cardiovascular, anticholinergic and gastrointestinal side effects are well known [2,3]. Agranulocytosis may occur occasionally. Cutaneous reactions are rare [2] but include maculopapular rashes, photosensitivity (protriptyline and imipramine), urticaria, pruritus, hyperhidrosis, vasculitis or acne (maprotiline), and TEN (amoxapine). Amineptine. Severe acne [4,5] and rosacea [6] have been reported. Amitriptyline. A bullous reaction in a patient with overdosage of amitriptyline and clorazepate dipotassium has been reported [7]. Alopecia is documented. Clomipramine. A photoallergic eruption [8] and a hypersensitivity reaction associated with human herpesvirus-6 reactivation [9] have been documented.

Important or widely prescribed drugs

Imipramine. This drug has caused urticarial or exanthematic eruptions occasionally [10] and agranulocytosis has occurred. Oedema of the feet is seen in older people. Glossitis and stomatitis are rare, as are transient erythema of the face, photosensitivity and exfoliative dermatitis. Slate-grey pigmentation of exposed skin may develop; golden-yellow granules, which ultrastructurally are electron-dense inclusion bodies in phagocytes, fibroblasts and dendrocytes, are seen in the papillary dermis [11–13]. Q-switched alexandrite and ruby lasers may be helpful in treating the pigmentation [14]. Cutaneous vasculitis is well documented. Atypical cutaneous lymphoid hyperplasia has been documented [15]. Maprotiline. Acne [16] and vasculitis [17] are recorded. Mianserin. Erythema multiforme has recently been reported [18], as has a severe allergic reaction [19]. Trazodone. This drug has caused leukonychia [20], erythema multiforme [21] and vasculitis [22], and has been implicated in causing a psoriasiform eruption. Skin swelling is recorded [23]. References 1 Pirmohamed M, Kitteringham NR, Park BK. Idiosyncratic reactions to antidepressants: a review of the possible mechanisms and predisposing factors. Pharmacol Ther 1992; 53: 105–25. 2 Gupta MA, Gupta AK, Haberman HF. Psychotropic drugs in dermatology. A review and guidelines for use. J Am Acad Dermatol 1986; 14: 633–45. 3 Gupta MA, Gupta AK, Ellis CN. Antidepressant drugs in dermatology. An update. Arch Dermatol 1987; 123: 647–52. 4 Thioly-Bensoussan D, Edelson Y, Cardinne A, Grupper C. Acné monstrueuse iatrogène provoquée par le Survector®: première observation mondiale à propos de deux cas. Nouv Dermatol 1987; 6: 535–7. 5 De Galvez Aranda MV, Sanchez PS, Alonso Corral MJ et al. Acneiform eruption caused by amineptine. A case report and review of the literature. J Eur Acad Dermatol Venereol 2001; 15: 337–9. 6 Jeanmougin M, Civatte J, Cavelier-Balloy B. Toxiderme rosaceiforme a l’amineptine (Survector). Ann Dermatol Vénéréol 1988; 115: 1185–6. 7 Herschtal D, Robinson MJ. Blisters of the skin in coma induced by amitriptyline and clorazepate dipotassium. Report of a case with underlying sweat gland necrosis. Arch Dermatol 1979; 115: 499. 8 Ljunggren B, Bojs G. A case of photosensitivity and contact allergy to systemic tricyclic drugs, with unusual features. Contact Dermatitis 1991; 24: 259–65. 9 Nishimura Y, Kitoh A, Yoshida Y, Tanaka T. Clomipramine-induced hypersensitivity syndrome with unusual clinical features. J Am Acad Dermatol 2005; 53 (5 Suppl. 1): S231–3. 10 Almeyda J. Drug reactions XIII. Cutaneous reactions to imipramine and chlordiazepoxide. Br J Dermatol 1971; 84: 298–9. 11 Hashimoto K, Joselow SA, Tye MJ. Imipramine hyperpigmentation: a slate-gray discoloration caused by long-term imipramine administration. J Am Acad Dermatol 1991; 25: 357–61. 12 Ming ME, Bhawan J, Stefanato CM et al. Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol 1999; 40: 159–66. 13 Sicari MC, Lebwohl M, Baral J et al. Photoinduced dermal pigmentation in patients taking tricyclic antidepressants: histology, electron microscopy, and energy dispersive spectroscopy. J Am Acad Dermatol 1999; 40: 290–3. 14 Atkin DH, Fitzpatrick RE. Laser treatment of imipramin-induced hyperpigmentation. J Am Acad Dermatol 2000; 43: 77–80. 15 Crowson AN, Magro CM. Antidepressant therapy. A possible cause of atypical cutaneous lymphoid hyperplasia. Arch Dermatol 1995; 131: 925–9. 16 Ponte CD. Maprotiline-induced acne. Am J Psychiatry 1982; 139: 141. 17 Oakley AM, Hodge L. Cutaneous vasculitis from maprotiline. Aust NZ J Med 1985; 15: 256–7.

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18 Quraishy E. Erythema multiforme during treatment with mianserin. Br J Dermatol 1981; 104: 481. 19 Bazin N, Beaufils B, Feline A. A severe allergic reaction to mianserin. Am J Psychiatry 1991; 148: 1088–9. 20 Longstreth GF, Hershman J. Trazodone-induced hepatotoxicity and leukonychia. J Am Acad Dermatol 1985; 13: 149–50. 21 Ford HE, Jenike MA. Erythema multiforme associated with trazodone therapy. J Clin Psychiatry 1985; 46: 294–5. 22 Mann SC, Walker MM, Messenger GG et al. Leukocytoclastic vasculitis secondary to trazodone treatment. J Am Acad Dermatol 1984; 10: 669–70. 23 Fisher S, Bryant SG, Kent TA. Postmarketing surveillance by patient selfmonitoring: trazodone versus fluoxetine. J Clin Psychopharmacol 1993; 13: 235–42.

Monoamine oxidase inhibitors Iproniazid. Vasculitis and peripheral neuritis are documented. Phenelzine. Hypersensitivity skin reactions are rare.

Selective serotonin reuptake inhibitors Fluoxetine. This drug has caused urticaria [1], urticarial vasculitis [2], hypersensitivity [3], and serum sickness [4]; familial cases are documented [5]. Atypical cutaneous lymphoid hyperplasia [6], including pseudomycosis fungoides [6–8], is recorded. Paroxetine. Exanthematous hypersensitivity [9] and vasculitis [10,11] have been reported.

Miscellaneous selective serotonin reuptake inhibitors The 5-HT3 receptor antagonists granisetron, ondansetron and tropisetron are antiemetic medications used during chemotherapy. Effects include headache and gastrointestinal symptoms, and rarely hypersensitivity reactions [12]. There were no cross-over reactions to citalopram or paroxetine among patients hypersensitive to zimeldine [13]. Alopecia has been caused rarely with sertraline and citalopram [14]. Mirtazapine This presynaptic alpha2 adrenoreceptor antagonist has caused increased liver enzymes, cutaneous oedema and collapse [15]. References 1 Leznoff A, Binkley KE, Joffee RT et al. Adverse cutaneous reactions associated with fluoxetine strategy for reintroduction of this drug in selected patients. J Clin Psychopharmacol 1992; 12: 355–7. 2 Roger D, Rolle F, Mausset J et al. Urticarial vasculitis induced by fluoxetine. Dermatology 1995; 191: 164. 3 Beer K, Albertini J, Medenica M, Busbey S. Fluoxetine-induced hypersensitivity. Arch Dermatol 1994; 130: 803–4. 4 Shapiro LE, Knowles SR, Shear NH. Fluoxetine-induced serum sickness-like reaction. Ann Pharmacother 1997; 31: 927. 5 Olfson M, Wilner MT. A family case history of fluoxetine-induced skin reactions. J Nerv Ment Dis 1991; 179: 504–5. 6 Crowson AN, Magro CM. Antidepressant therapy. A possible cause of atypical cutaneous lymphoid hyperplasia. Arch Dermatol 1995; 131: 925–9. 7 Gordon KB, Guitart J, Kuzel T et al. Pseudomycosis fungoides in a patient taking clonazepam and fluoxetine. J Am Acad Dermatol 1996; 34: 304–6. 8 Vermeer MH, Willemze R. Is mycosis fungoides exacerbated by fluoxetine? J Am Acad Dermatol 1996; 35: 635–6. 9 Mera MT, Pérez BV, Fernández RO, Iglesias JF. Hypersensitivity to paroxetine. Allergol Immunopathol (Madr) 2006; 34: 125–6. 10 Margolese HC, Chouinard G, Beauclair L, Rubino M. Cutaneous vasculitis induced by paroxetine. Am J Psychiatry 2001; 158: 497.

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11 Welsh JP, Cusack CA, Ko C. Urticarial vasculitis secondary to paroxetine. J Drugs Dermatol 2006; 5: 1012–4. 12 Kataja V, de Bruijn KM. Hypersensitivity reactions associated with 5hydroxytryptamine(3)-receptor antagonists: a class effect? Lancet 1996; 347: 584–5. 13 Bengtsson BO, Lundmark J, Walinder J. No crossover reactions to citalopram or paroxetine among patients hypersensitive to zimeldine. Br J Psychiatry 1991; 158: 853–5. 14 Hedenmalm K, Sundström A, Spigset O. Alopecia associated with treatment with selective serotonin reuptake inhibitors (SSRIs). Pharmacoepidemiol Drug Saf 2006; 15: 719–25. 15 Degner D, Grohmann R, Kropp S. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004; 37 (Suppl. 1): S39–45.

Lithium Skin reactions [1–5] are relatively uncommon. Pustular and psoriasiform lesions induced by this drug have received particular attention [6]. The pustular propensities of lithium have been attributed to lysosomal enzyme release and increased neutrophil chemotaxis [2]. Tetracycline should be avoided in treating these pustular eruptions as it may precipitate serious lithium toxicity. The acneiform ‘erysipelas’ eruption consists of monomorphic pustules on an erythematous base, tends to affect mainly the arms and legs, is not associated with comedones or cystic lesions, and may be very persistent. Various patterns of folliculitis may occur. Lithium can aggravate pre-existing psoriasis, making it more difficult to control [6–10], and may precipitate a palmoplantar pustular reaction [11] or even generalized pustular psoriasis [12]. Psychiatrists should avoid the use of lithium in psoriatics if possible. Darier’s disease may also be exacerbated or initiated [13,14]. Additional reactions described include morbilliform rashes, erythema multiforme [15], a dermatitis herpetiformis-like rash [16], linear IgA bullous dermatosis [17] and a generalized exfoliative eruption [18]. An LE-like syndrome [19] with increased prevalence of antinuclear antibodies [20], toenail dystrophy [21] and hair loss [22,23] have been reported. Keratoderma has been documented [24], as has hidradenitis suppurativa [25]. None of these effects is related to excessive blood levels of lithium or other evidence of toxicity. References 1 Callaway CL, Hendrie HC, Luby ED. Cutaneous conditions observed in patients during treatment with lithium. Am J Psychiatry 1968; 124: 1124–5. 2 Heng MCY. Cutaneous manifestations of lithium toxicity. Br J Dermatol 1982; 106: 107–9. 3 Deandrea D, Walker N, Mehlmauer M, White K. Dermatological reactions to lithium: a review. J Clin Psychopharmacol 1982; 2: 199–204. 4 Sarantidis D, Waters B. A review and controlled study of cutaneous conditions associated with lithium carbonate. Br J Psychiatry 1983; 143: 42–50. 5 Albrecht G. Unerwünschte Wirkungen von Lithium an der Haut. Hautarzt 1985; 36: 77–82. 6 Chan HH, Wing Y, Su R et al. A control study of the cutaneous side effects of chronic lithium therapy. J Affective Disord 2000; 57: 107–13. 7 Lazarus GS, Gilgor RS. Psoriasis, polymorphonuclear leukocytes, and lithium carbonate. An important clue. Arch Dermatol 1979; 115: 1183–4. 8 Skoven I, Thormann J. Lithium compound treatment and psoriasis. Arch Dermatol 1979; 115: 1185–7. 9 Abel EA, Dicicco LM, Orenberg EK et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007–22. 10 Sasaki T, Saito S, Aihara M et al. Exacerbation of psoriasis during lithium treatment. J Dermatol 1989; 16: 59–63.

11 White SW. Palmoplantar pustular psoriasis provoked by lithium therapy. J Am Acad Dermatol 1982; 7: 660–2. 12 Lowe NJ, Ridgway HB. Generalized pustular psoriasis precipitated by lithium. Arch Dermatol 1978; 114: 1788–9. 13 Milton GP, Peck GL, Fu J-J et al. Exacerbation of Darier’s disease by lithium carbonate. J Am Acad Dermatol 1990; 23: 926–8. 14 Rubin MB. Lithium-induced Darier’s disease. J Am Acad Dermatol 1996; 32: 674–5. 15 Balldin J, Berggren U, Heijer A, Mobacken H. Erythema multiforme caused by lithium. J Am Acad Dermatol 1991; 24: 1015–6. 16 Meinhold JM, West DP, Gurwich E et al. Cutaneous reaction to lithium carbonate: a case report. J Clin Psychiatry 1980; 41: 395–6. 17 McWhirter JD, Hashimoto K, Fayne S et al. Linear IgA bullous dermatosis related to lithium carbonate. Arch Dermatol 1987; 123: 1120–2. 18 Kuhnley EJ, Granoff AL. Exfoliative dermatitis during lithium treatment. Am J Psychiatry 1979; 136: 1340–1. 19 Shukla VR, Borison RL. Lithium and lupus-like syndrome. JAMA 1982; 248: 921–2. 20 Presley AP, Kahn A, Williamson N. Antinuclear antibodies in patients on lithium carbonate. BMJ 1976; ii: 280–1. 21 Hooper JF. Lithium carbonate and toenails. Am J Psychiatry 1981; 138: 1519. 22 Dawber R, Mortimer P. Hair loss during lithium treatment. Br J Dermatol 1982; 107: 124–5. 23 Orwin A. Hair loss following lithium therapy. Br J Dermatol 1983; 108: 503–4. 24 Labelle A, Lapierre YD. Keratodermia: side effects of lithium. J Clin Psychopharmacol 1991; 11: 149–50. 25 Gupta AK, Knowles SR, Gupta MA et al. Lithium therapy associated with hidradenitis suppurativa: case report and a review of the dermatologic side effects of lithium. J Am Acad Dermatol 1995; 32: 382–6.

Hypnotics, sedatives and anxiolytics Barbiturates A toxic bullous eruption may appear at pressure points in comatose patients after overdosage [1–4]. In one series, 8% of patients admitted with drug-induced coma had such bullae [3] (see Fig. 75.5). The bullae are few, large and may lead to ulceration [2]. Necrotic lesions are seen in 4% of patients recovering from, and in 40% of fatalities related to, barbiturate-induced coma [4]. Allergic reactions are very uncommon and may be scarlatiniform or morbilliform. Exfoliative dermatitis has proved fatal [5], as has erythema multiforme. Urticaria and serum sickness are very rare, as is purpuric capillaritis. Fixed eruptions are well known [6] and particularly occur on the glans penis. TEN, LE-like syndrome, purpura and photosensitivity are recorded [7]. Phenobarbital is one cause of the anticonvulsant hypersensitivity syndrome (see p. 75.44) [8,9]. In one case, a syndrome resembling Langerhans’ cell histiocytosis was produced [10]. Hypopigmentation may follow a severe reaction [11]. Exfoliative dermatitis is recorded [12]. References 1 Beveridge GW, Lawson AAH. Occurrence of bullous lesions in acute barbiturate intoxication. BMJ 1965; i: 835–7. 2 Gröschel D, Gerstein AR, Rosenbaum JM. Skin lesions as a diagnostic aid in barbiturate poisoning. N Engl J Med 1970; 283: 409–10. 3 Pinkus NB. Skin eruptions in drug-induced coma. Med J Aust 1971; 2: 886–8. 4 Almeyda J, Levantine A. Drug reactions XVII. Cutaneous reactions to barbiturates, chloralhydrate and its derivatives. Br J Dermatol 1972; 86: 313–6. 5 Sneddon IB, Leishman AWD. Severe and fatal phenobarbitone eruptions. BMJ 1952; i: 1276–8. 6 Korkij W, Soltani K. Fixed drug eruption. A brief review. Arch Dermatol 1984; 120: 520–4. 7 Gupta MA, Gupta AK, Haberman HF. Psychotropic drugs in dermatology. A review and guidelines for use. J Am Acad Dermatol 1986; 14: 633–45.

Important or widely prescribed drugs 8 Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995; 155: 2285–90. 9 De Vriese AS, Philippe J, Van Renterghem DM et al. Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature. Medicine (Baltimore) 1995; 74: 144–51. 10 Nagata T, Kawamura N, Motoyama T et al. A case of hypersensitivity syndrome resembling Langerhans cell histiocytosis during phenobarbital prophylaxis for convulsion. Jpn J Clin Oncol 1992; 22: 421–7. 11 Mion N, Fusade T, Mathelier-Fusade P et al. Depigmentation cutaneo-phanerienne consecutive a une toxidermie au phenobarbital. Ann Dermatol Vénéréol 1992; 119: 927–9. 12 Sawaishi Y, Komatsu K, Takeda O et al. A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity. Eur J Pediatr 1992; 151: 69–72.

Benzodiazepines Allergic reactions are very rare [1]. Alprazolam. Photosensitivity has been recorded with this newer benzodiazepine [2]. Chlordiazepoxide. Morbilliform erythema, urticaria [3], fixed eruption [4], photoallergic eczema [5] and exacerbation of porphyria have been recorded. Erythema multiforme and chronic pigmented purpuric eruption occur rarely [6]. Clobazam. A generalized erythematous pruritic eruption [7] and TEN confined to light-exposed areas [8] have been reported. There has been a report of coma-induced bullae and sweat gland necrosis associated with the drug [9]. Diazepam and nitrazepam. Bullae similar to those seen after barbiturates may occur in comatose patients after overdosage [10,11]. Thrombophlebitis may follow intravenous injection of diazepam [12]. Hyperpigmentation in previously dermabraded scars has been attributed to diazepam [13]. Vasculitis is documented [14]. An eruption comprising oedema, moon face and generalized erythema, with erosions of cheeks, axillae and the genitocrural area was attributed to nitrazepam; a provocation test was positive [15]. Lormetazepam. A fixed drug eruption has been reported [16]. Temazepam. An extensive fixed drug eruption has been reported [17]. Extravasation following attempted femoral vein injection of a suspension of the contents of capsules in tap water, by an addict, resulted in extensive necrosis of genital and pubic skin [18]. References 1 Edwards JG. Adverse effects of antianxiety drugs. Drugs 1981; 22: 495–514. 2 Kanwar AJ, Gupta R, Das Mehta S, Kaur S. Photosensitivity to alprazolam. Dermatologica 1990; 181: 75. 3 Almeyda J. Drug reactions XIII. Cutaneous reactions to imipramine and chlordiazepoxide. Br J Dermatol 1971; 84: 298–9. 4 Blair HM III. Fixed drug eruption from chlordiazepoxide: report of a case. Arch Dermatol 1974; 109: 914. 5 Luton EF, Finchum RN. Photosensitivity reaction to chlordiazepoxide. Arch Dermatol 1965; 91: 362–3. 6 Nishioka K, Katayama I, Masuzawa M et al. Drug-induced chronic pigmented purpura. J Dermatol 1989; 16: 220–2.

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7 Machet L, Vaillant L, Dardaine V, Lorette G. Patch testing with clobazam: relapse of generalised drug eruption. Contact Dermatitis 1992; 26: 347–8. 8 Redondo P, Vicente J, España A et al. Photo-induced toxic epidermal necrolysis caused by clobazam. Br J Dermatol 1996; 135: 999–1002. 9 Setterfield JF, Robinson R, MacDonald D, Calonje E. Coma-induced bullae and sweat gland necrosis following clobazam. Clin Exp Dermatol 2000; 25: 215–8. 10 Ridley CM. Bullous lesions in nitrazepam-overdosage. BMJ 1971; iii: 28. 11 Varma AJ, Fisher BK, Sarin MK. Diazepam-induced coma with bullae and eccrine sweat gland necrosis. Arch Intern Med 1977; 137: 1207–10. 12 Langdon DE, Harlan JR, Bailey RL. Thrombophlebitis with diazepam used intravenously. JAMA 1973; 223: 184–5. 13 Fereira JA. The role of diazepam in skin hyperpigmentation. Aesthetic Plast Surg 1980; 4: 343–8. 14 Olcina GM, Simonart T. Severe vasculitis after therapy with diazepam. Am J Psychiatry 1999; 156: 972–3. 15 Shoji A, Kitajima J, Hamada T. Drug eruption caused by nitrazepam in a patient with severe pustular psoriasis successfully treated with methotrexate and etretinate. J Dermatol 1987; 14: 274–8. 16 Jafferany M, Haroon TS. Fixed drug eruption with lormetazepam (Noctamid). Dermatologica 1988; 177: 386. 17 Archer CB, English JSC. Extensive fixed drug eruption induced by temazepam. Clin Exp Dermatol 1988; 13: 336–8. 18 Meshikhes AN, Duthie JS. Untitled report. BMJ 1991; 303: 478.

Miscellaneous hypnotics, sedatives and anxiolytics Carbromal This drug, now rarely used, commonly produced a characteristic capillaritis with punctate purpura and haemosiderin giving a golden-brown discoloration of the skin, especially on the legs [1].

Chloral hydrate Hypersensitivity reactions are very rare. Chloral is now virtually only given in tablet form as dichloralphenazone, in which the phenazone may cause a fixed eruption [2]. Ethchlorvynol Overdose has caused bullous lesions [3]. Glutethimide Dermographism with subsequent erythema, and vesicles that lasted several days, were reported in one comatose patient [4] and bullae in another patient [5] following overdosage. Fixed eruptions are recorded [6]. Meprobamate Anorexia, drowsiness, dizziness, flushing and gastrointestinal symptoms may occur, especially with high doses. Fixed eruptions may occur [7]. The most characteristic cutaneous reaction, preceded by itching, malaise and fever, is an erythema starting in the limb flexures that rapidly gives way to a fierce non-thrombocytopenic purpura [8]. A widespread toxic erythema was associated with an anaphylactoid reaction in a patient in whom patch testing proved useful in diagnosis [9]. References 1 Peterson WC Jr, Manick KP. Purpuric eruptions associated with use of carbromal and meprobamate. Arch Dermatol 1967; 95: 40–2. 2 McCulloch H, Zeligman I. Fixed drug eruption and epididymitis due to antipyrine. Arch Dermatol Syphilol 1951; 64: 198–9.

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3 Brodin MD, Redmon WJ. Bullous eruptions due to ethchlorvynol. J Cutan Pathol 1980; 7: 326–9. 4 Leavell UW Jr, Coyer JR, Taylor RJ. Dermographism and erythematous lines in glutethimide overdose. Arch Dermatol 1972; 106: 724–5. 5 Burdon JGW, Cade JF. ‘Barbiturate burns’ caused by glutethimide. Med J Aust 1979; 1: 101–2. 6 Fisher M, Lerman JS. Fixed eruption due to glutethimide. Arch Dermatol 1971; 104: 87–9. 7 Gore HC Jr. Fixed drug eruption cross reaction of meprobamate and carisoprodol. Arch Dermatol 1965; 91: 627. 8 Levan NE. Meprobamate reaction. Arch Dermatol 1957; 75: 437–8. 9 Felix RH, Comaish JS. The value of patch and other skin tests in drug eruptions. Lancet 1974; i: 1017–9.

Antipsychotics The most important clinical side effects include those on the central nervous and cardiovascular systems and the ocular effects [1,2]. Drugs with high potency, such as haloperidol and pimozide, tend to have fewer cardiovascular and anticholinergic effects and are less sedating, but have more neurological effects. Long-term use of antipsychotic agents results in tardive dyskinesia.

Phenothiazines The side effects of this group of drugs have been reviewed [1–4]. Chlorpromazine. This drug is still widely used, although many related compounds are now available. Pigmentation of the skin in light-exposed areas after chronic use may be a problem, especially in women and black people [5–11]. Rarely, a purplish or slate-grey pigmentation develops [6]. There may be brown discoloration of cornea and lens [5], and bulbar conjunctiva [7]. Chlorpromazine has an affinity for melanin in vitro [8]. Electron microscopy shows many melanosome complexes within lysosomes of dermal macrophages, and electron-dense ‘chlorpromazine bodies’ in macrophages, endothelial cells and Schwann cells [9,10]; energy-dispersive X-ray microanalysis has revealed the abundant presence of sulphur in these granules, which is a constituent of the chlorpromazine molecule [10]. Similar pigmentary deposits are found in internal organs [11] and in blood neutrophils and monocytes. Chlorpromazine has caused lichenoid eruptions [12], exfoliative dermatitis, erythema multiforme, an LE-like illness [13] with positive antinuclear factor [14] and the lupus anticoagulant [15], and Henoch–Schönlein vasculitis [16]. Phototoxicity is well known [17–19] and phenothiazine-derived antihistamines may cause photosensitivity in atopics and subsequent development of actinic reticuloid [19]. Photocontact urticaria has been documented [20]. A pustular reaction is recorded [21]. Cholestatic jaundice is an important hazard. Fluspirilene. Subcutaneous nodules may develop at injection sites after long-term high doses of this depot preparation [22]. Thioridazine. Vasculitis is documented [23]. Thiothixene. A sensitivity reaction has been recorded [24]. Trifluoperazine. A fixed eruption has been recorded [25].

Loxapine. Dermatitis, pruritus and seborrhoea have been recorded, and photosensitivity eruptions may occur occasionally [26]. Levomepromazin. An erythema annulare centrifugum-like pseudolymphomatous eruption has been reported [27]. References 1 Simpson GM, Pi EH, Sramek JJ Jr. Adverse effects of antipsychotic agents. Drugs 1981; 21: 138–51. 2 Gupta MA, Gupta AK, Haberman HF. Psychotropic drugs in dermatology. A review and guidelines for use. J Am Acad Dermatol 1986; 14: 633–45. 3 Hägermark Ö, Wennersten G, Almeyda J. Drug reactions XIV. Cutaneous side effects of phenothiazines. Br J Dermatol 1971; 84: 605–7. 4 Bond WS, Yee GC. Ocular and cutaneous effects of chronic phenothiazine therapy. Am J Hosp Pharm 1980; 37: 74–8. 5 Greiner AC, Berry K. Skin pigmentation and corneal and lens opacities with prolonged chlorpromazine therapy. Can Med Assoc J 1964; 90: 663–5. 6 Hays GB, Lyle CB Jr, Wheeler CE Jr. Slate-grey color in patients receiving chlorpromazine. Arch Dermatol 1964; 90: 471–6. 7 Satanove A. Pigmentation due to phenothiazines in high and prolonged dosage. JAMA 1965; 191: 263–8. 8 Blois MS Jr. On chlorpromazine binding in vivo. J Invest Dermatol 1965; 45: 475–81. 9 Hashimoto K, Wiener W, Albert J, Nelson RG. An electron microscopic study of chlorpromazine pigmentation. J Invest Dermatol 1966; 47: 296–306. 10 Benning TL, McCormack KM, Ingram P et al. Microprobe analysis of chlorpromazine pigmentation. Arch Dermatol 1988; 124: 1541–4. 11 Greiner AC, Nicolson GA. Pigment deposition in viscera associated with prolonged chlorpromazine therapy. Can Med Assoc J 1964; 90: 627–35. 12 Matsuo I, Ozawa A, Niizuma K, Ohkido M. Lichenoid dermatitis due to chlorpromazine phototoxicity. Dermatologica 1979; 159: 46–9. 13 Pavlidakey GP, Hashimoto K, Heller GL, Daneshvar S. Chlorpromazine-induced lupuslike disease: case report and review of the literature. J Am Acad Dermatol 1985; 13: 109–15. 14 Zarrabi MH, Zucker S, Miller F et al. Immunologic and coagulation disorders in chlorpromazine-treated patients. Ann Intern Med 1979; 91: 194–9. 15 Canoso RT, Sise HS. Chlorpromazine-induced lupus anticoagulant and associated immunologic abnormalities. Am J Hematol 1982; 13: 121–9. 16 Aram H. Henoch–Schönlein purpura induced by chlorpromazine. J Am Acad Dermatol 1987; 17: 139–40. 17 Johnson BE. Cellular mechanisms of chlorpromazine photosensitivity. Proc R Soc Med 1974; 67: 871–3. 18 Ljunggren B. Phenothiazine phototoxicity: toxic chlorpromazine photoproducts. J Invest Dermatol 1977; 69: 383–6. 19 Amblard P, Beani J-C, Reymond J-L. Photo-allergie rémanente aux phénothiazines chez l’atopique. Ann Dermatol Vénéréol 1982; 109: 225–8. 20 Lovell CR, Cronin E, Rhodes EL. Photocontact urticaria from chlorpromazine. Contact Dermatitis 1986; 14: 290–1. 21 Burrows NP, Ratnavel RC, Norris PG. Pustular eruptions after chlorpromazine. BMJ 1994; 309: 97. 22 UK Committee on Safety of Medicines. Current Problems 1981; 7. 23 Greenfield JR, McGrath M, Kossard S et al. ANCA-positive vasculitis induced by thioridazine: confirmed by rechallenge. Br J Dermatol 2003; 147: 1265–7. 24 Matsuoka LY. Thiothixene drug sensitivity. J Am Acad Dermatol 1982; 7: 405–6. 25 Kanwar AJ, Singh M, El-Sheriff AK, Belhaj MS. Fixed eruption due to trifluoperazine hydrochloride. Br J Dermatol 1987; 117: 798–9. 26 Anonymous. Cloxapine and loxapine for schizophrenia. Drug Ther Bull 1991; 29: 41–2. 27 Blazejak T, Hölzle E. Phenothiazin-induziertes Pseudolymphom. Hautarzt 1990; 41: 161–3.

Miscellaneous antipsychotic agents Clozapine. An acute severe adverse reaction resembling SLE is recorded [1].

Important or widely prescribed drugs

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Anticonvulsants

develop into TEN. These drugs are oxidized by the cytochrome P-450 enzyme system into potentially reactive toxic arene oxide intermediates; the anticonvulsant hypersensitivity syndrome is associated with an inherited deficiency of liver microsomal epoxide hydrolase, which converts such reactive intermediates to nontoxic dihydrodiols (see section on Pharmacogenetic mechanisms, pp. 75.12–13). There may be associated reactivation of herpes-type viruses [14], and/or ethnic predisposition with certain HLA subtypes [5]. The occurrence of a severe reaction indicates that the drug should be ceased, and this can be done abruptly with minimal risk of status epilepticus [15,16]. Patients with a history of antiepileptic drug hypersensitivity should avoid further use of any aromatic anticonvulsant drug. In addition, family members should be instructed that they may be at increased risk for developing severe reactions to aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe in these circumstances are valproic acid, benzodiazepines, and other non-aromatic anticonvulsant drugs. Generalized pustulation may be a manifestation of anticonvulsant hypersensitivity [17]. A severe form of hypersensitivity vasculitis, with extensive visceral involvement and poor prognosis, is seen very rarely with phenytoin and in isolated cases with carbamazepine and trimethadione [18]. Drug-induced SLE is much more frequent, and has been described with most anticonvulsants in clinical use (phenytoin, carbamazepine, ethosuximide, trimethadione, primidone and valproate) [18]. Of the newer anticonvulsant drugs, vigabatrin is usually well tolerated, but lamotrigine is associated with rashes [19,20]. Anticonvulsants may be associated with pseudolymphoma syndrome (see p. 75.44).

In a recent study of 1890 outpatients, the average rate of antiepileptic drug-related rashes was 2.8% [1]. Rash rates were highest with phenytoin (5%), lamotrigine (4.8%), and carbamazepine (3.7%), and lowest (<1%) with clobazam, felbamate, gabapentin, levetiracetam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, vigabatrin, valproate and zonisamide. In another study of 663 patients with 2567 exposures to 15 different antiepileptic drugs [2], reactions were found in 14% of patients and in 5% of exposures; 97% of reactions were to either carbamazepine (11%), phenytoin (8%), lamotrigine (8%), oxcarbazepine (8%) or phenobarbital (2%), and reactions were commoner in females. Reaction rates are approximately five times greater in patients with a history of a reaction to another antiepileptic drug [1]. Carbamazepine and oxcarbazepine caused rashes in the range of 27– 35%, and lamotrigine in 17%, of patients with a history of another antiepileptic drug-related rash [3]. There may be 40–80% crossreactivity in terms of clinical reactions to the aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine, primidone and clonazepam), as well as to tricyclic antidepressant agents [4,5]. Allergic rashes to antiepileptic drugs are usually mild, taking the form of urticarial or morbilliform eruptions. However, all of the aromatic anticonvulsants may cause dress (drug hypersensitivity syndrome, anticonvulsant hypersensitivity syndrome) (see pp. 75.26–27), which reportedly occurs at a rate of 1 in 1000 to 1 in 10 000 exposures [4,5]. Clinical features of the syndrome include fever, mucocutaneous eruptions, lymphadenopathy and hepatitis, 1 week to 3 months into therapy; there may be multiorgan involvement with renal and pulmonary lesions [6–14]. The reaction may

References 1 Arif H, Buchsbaum R, Weintraub D et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology 2007; 68: 1701–9. 2 Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia 2007; 48: 1360–5. 3 Alvestad S, Lydersen S, Brodtkorb E. Cross-reactivity pattern of rash from current aromatic antiepileptic drugs. Epilepsy Res 2008; 80: 194–200. 4 Seitz CS, Pfeuffer P, Raith P et al. Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents. Ann Allergy Asthma Immunol 2006; 97: 698–702. 5 Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care. Pharmacotherapy 2007; 27: 1425–39. 6 Chang DK, Shear NH. Cutaneous reactions to anticonvulsants. Semin Neurol 1992; 12: 329–37. 7 Handfield-Jones SE, Jenkins RE, Whittaker SJ et al. The anticonvulsant hypersensitivity syndrome. Br J Dermatol 1993; 129: 175–7. 8 Richens A, Davidson DL, Cartlidge NE, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group. J Neurol Neurosurg Psychiatry 1994; 57: 682–7. 9 Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995; 155: 2285–90. 10 Licata AL, Louis ED. Anticonvulsant hypersensitivity syndrome. Compr Ther 1996; 22: 152–5. 11 Allam JP, Paus T, Reichel C et al. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol 2004; 14: 339–42. 12 Mendiratta V, Bhushan P. Phenytoin-induced DRESS with cross-reactivity to carbamazepine in a 10-year-old Indian child. Clin Exp Dermatol 2006; 31: 720–1. 13 Yun SJ, Lee JB, Kim EJ et al. Drug rash with eosinophilia and systemic symptoms induced by valproate and carbamazepine: formation of circulating autoantibody against 190-kDa antigen. Acta Derm Venereol 2006; 86: 241–4.

Haloperidol. This drug causes reactions at injection sites [2,3]. Olanzapine. A pustular reaction [4] and vasculitis [5] are documented. Quetiapine. Erythema multiforme minor has been reported [6]. Methylphenidate hydrochloride (Risperidone). This ubiquitously prescribed medication for attention deficit hyperactivity disorder has produced erythema multiforme minor [7] and pseudolymphoma [8]. References 1 Reinke M, Wiesert KN. High incidence of haloperidol decanoate injection site reactions (letter). J Clin Psychiatry 1992; 53: 415–6. 2 Maharaj K, Guttmacher LB, Moeller R. Haloperidol decanoate: injection site reactions. J Clin Psychiatry 1995; 56: 172–3. 3 Wickert WA, Campbell NR, Martin L. Acute severe adverse clozapine reaction resembling systemic lupus erythematosus. Postgrad Med J 1994; 70: 940–1. 4 Adams BB, Mutasim DF. Pustular eruption induced by olanzapine, a novel antipsychotic agent. J Am Acad Dermatol 1999; 41: 851–3. 5 Duggal MK, Singh A, Arunabh et al. Olanzapine-induced vasculitis. Am J Geriatr Pharmacother 2005; 3: 21–4. 6 Lin GL, Chiu CH, Lin SK. Quetiapine-induced erythema multiforme minor: a case report. J Clin Psychopharmacol 2006; 26: 668–9. 7 Desarkar P, Nizamie SH. Risperidone-induced erythema multiforme minor. Br J Clin Pharmacol 2006; 62: 504–5. 8 Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis 2008; 81: 61–4.

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14 Aihara Y, Ito S-I, Kobayashi Y et al. Carbamazepine-induced hypersensitivity syndrome associated with transient hypogammaglobulinaemia and reactivation of human herpesvirus 6 infection demonstrated by real-time quantitative polymerase chain reaction. Br J Dermatol 2003; 149: 165–9. 15 Hebert AA, Ralston JP. Cutaneous reactions to anticonvulsant medications. J Clin Psychiatry 2001; 62 (Suppl. 14): 22–6. 16 Pelekanos J, Camfield P, Camfield C, Gordon K. Allergic rash due to antiepileptic drugs: clinical features and management. Epilepsia 1991; 32: 554–9. 17 Kleier RS, Breneman DL, Boiko S. Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome. Arch Dermatol 1991; 127: 1361–4. 18 Drory VE, Korczyn AD. Hypersensitivity vasculitis and systemic lupus erythematosus induced by anticonvulsants. Clin Neuropharmacol 1993; 16: 19–29. 19 Schmidt D, Kramer G. The new anticonvulsant drugs. Implications for avoidance of adverse effects. Drug Saf 1994; 11: 422–31. 20 Brodie MJ. Lamotrigine versus other antiepileptic drugs: a star rating system is born. Epilepsia 1994; 35 (Suppl. 5): S41–S46.

Carbamazepine [1] Eruptions occur in 3% [2–5] to 12% [6–8] of patients and include diffuse erythema, miliary exanthem, maculopapular or speckled morbilliform reddish rash, urticaria, purpuric petechiae or a mucocutaneous syndrome, any of which may occur from day 8 to 60. The drug hypersensitivity syndrome [9–11], erythroderma and exfoliative dermatitis, erythema multiforme and TEN [3,4,12] are well recognized. Eczema and photosensitivity [13], an LE-like syndrome and dermatomyositis [14], as well as a pustular [15–17] and a lichenoid [3,18] reaction, are very rare. Lesions with clinical and histological features suggestive of mycosis fungoides (pseudolymphoma) have been reported [18–21]. Patch testing has been advocated for the diagnosis of carbamazepine eruptions [9,10,22,23], but has resulted in reinduction of exfoliative dermatitis [24]. A psoriasiform eruption has been reported [25], as has thrombocytopenia and leukopenia complicated by Henoch–Schönlein purpura [26]. Cross-reactivity may occur with oxcarbazepine [27,28]. Other adverse effects include nausea, vomiting, ataxia, vertigo and drowsiness. Abnormal liver function [29] and bone marrow suppression with occasional deaths due to aplastic anaemia have been recorded [3]. Development of a rash may act as an early warning of marrow toxicity. Carbamazepine therapy during pregnancy carries a 1% risk of development of spina bifida in the offspring [30]. Oral steroid therapy enabled 16 of 20 patients successfully to continue on carbamazepine after development of a rash shortly after introduction of the drug [31]. Desensitization has been achieved by induction of tolerance in patients in whom there was no suitable alternative therapy [32,33]. References 1 Pasmans SG, Bruijnzeel-Koomen CA, van Reijsen FC. Skin reactions to carbamazepine. Allergy 1999; 54: 649–50. 2 Harman PRM. Carbamazepine (Tegretol) drug eruptions. Br J Dermatol 1967; 79: 500–1. 3 Roberts DL, Marks R. Skin reactions to carbamazepine. Arch Dermatol 1981; 117: 273–5. 4 Breathnach SM, McGibbon DH, Ive FA et al. Carbamazepine (‘Tegretol’) and toxic epidermal necrolysis: report of three cases with histopathological observations. Clin Exp Dermatol 1982; 7: 585–91. 5 Chadwick D, Shan M, Foy P et al. Serum anticonvulsant concentrations and the risk of drug-induced skin eruptions. J Neurol Neurosurg Psychiatry 1984; 47: 642–4.

6 Richens A, Davidson DL, Cartlidge NE, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group. J Neurol Neurosurg Psychiatry 1994; 57: 682–7. 7 Kramlinger KG, Phillips KA, Post RM. Rash complicating carbamazepine treatment. J Clin Psychopharmacol 1994; 14: 408–13. 8 Konishi T, Naganuma Y, Hongo K et al. Carbamazepine-induced skin rash in children with epilepsy. Eur J Pediatr 1993; 152: 605–8. 9 Scerri L, Shall L, Zaki I. Carbamazepine-induced anticonvulsant hypersensitivity syndrome: pathogenic and diagnostic considerations. Clin Exp Dermatol 1993; 18: 540–2. 10 De Vriese AS, Philippe J, Van Renterghem DM et al. Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature. Medicine (Baltimore) 1995; 74: 144–51. 11 Okuyama R, Ichinohasama R, Tagami H. Carbamazepine induced erythroderma with systemic lymphadenopathy. J Dermatol 1996; 23: 489–94. 12 Reed MD, Bertino JA, Blumer JL. Carbamazepine-associated exfoliative dermatitis. Clin Pharmacol 1982; 1: 78–9. 13 Terui T, Tagami H. Eczematous drug eruption from carbamazepine: coexistence of contact and photocontact sensitivity. Contact Dermatitis 1989; 20: 260–4. 14 Simpson JR. ‘Collagen disease’ due to carbamazepine (Tegretol). BMJ 1966; ii: 1434. 15 Staughton RCD, Harper JI, Rowland Payne CME et al. Toxic pustuloderma: a new entity? J R Soc Med 1984; 77: 6–8. 16 Commens CA, Fischer GO. Toxic pustuloderma following carbamazepine therapy. Arch Dermatol 1988; 124: 178–9. 17 Mizoguchi S, Setoyama M, Higashi Y et al. Eosinophilic pustular folliculitis induced by carbamazepine. J Am Acad Dermatol 1998; 38: 641–3. 18 Atkin SL, McKenzie TMM, Stevenson CJ. Carbamazepine-induced lichenoid eruption. Clin Exp Dermatol 1990; 15: 382–3. 19 Welykyj S, Gradini R, Nakao J, Massa M. Carbamazepine-induced eruption histologically mimicking mycosis fungoides. J Cutan Pathol 1990; 17: 111–6. 20 Rijlaarsdam U, Scheffer E, Meijer CJLM et al. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermatol 1991; 24: 216–20. 21 Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol 1998; 38: 806–9. 22 Houwerzijl J, De Gast GC, Nater JP et al. Lymphocyte-stimulation tests and patch tests in carbamazepine hypersensitivity. Clin Exp Immunol 1977; 29: 272–7. 23 Silva R, Machado A, Brandao M, Gonçalo S. Patch test diagnosis in carbamazepine erythroderma. Contact Dermatitis 1986; 15: 254–5. 24 Vaillant L, Camenen I, Lorette G. Patch testing with carbamazepine: reinduction of an exfoliative dermatitis. Arch Dermatol 1989; 125: 299. 25 Brenner S, Wolf R, Landau M, Politi Y. Psoriasiform eruption induced by anticonvulsants. Isr J Med Sci 1994; 30: 283–6. 26 Kaneko K, Igarashi J, Suzuki Y et al. Carbamazepine-induced thrombocytopenia and leucopenia complicated by Henoch–Schönlein purpura symptoms. Eur J Pediatr 1993; 152: 769–70. 27 Beran RG. Cross-reactive skin eruption with both carbamazepine and oxcarbazepine. Epilepsia 1993; 34: 163–5. 28 Dam M. Practical aspects of oxcarbazepine treatment. Epilepsia 1994; 35 (Suppl. 3): S23–S25. 29 Ramsey ID. Carbamazepine-induced jaundice. BMJ 1967; 4: 155. 30 Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324: 674–7. 31 Murphy JM, Mashman J, Miller JD, Bell JB. Suppression of carbamazepineinduced rash with prednisone. Neurology 1991; 41: 144–5. 32 Eames P. Adverse reaction to carbamazepine managed by desensitization. Lancet 1989; i: 509–10. 33 Boyle N, Lawlor BA. Desensitization to carbamazepine-induced skin rash. Am J Psychiatry 1996; 153: 1234.

Diphenylhydantoin (phenytoin, Dilantin) Cutaneous manifestations related to phenytoin have been reviewed [1–7]. The various diverse presentations share certain histopathological findings: adhesion of the infiltrated cells to the basal layer of the epidermis, cell infiltration into the epidermis, vacuolation of the basal cells, and dyskeratotic cells in the epidermis and

Important or widely prescribed drugs

epidermal necrosis, with CD8+ T cells predominant in the epidermis [5]. About 5% of children develop a mild, transient maculopapular rash within 3 weeks of starting treatment. This is more likely to occur if high loading doses are given initially [3,4]. In other series, between 8.5% [8] and 19% [9] of patients receiving phenytoin developed exanthematic rashes [10]. A phenytoin-induced hypersensitivity state, with generalized lymphadenopathy, hepatosplenomegaly, fever, arthralgia and eosinophilia, occurs in about 1% of patients, and may be accompanied by hepatitis, nephritis and haematological abnormalities [7,11–13]. Skin involvement may lead to a suspicion of lymphoma, the phenytoin-induced pseudolymphoma syndrome [14–19]. Cutaneous lesions may be restricted to a few erythematous plaques [18], or cutaneous nodules [15], or consist of a generalized erythematous maculopapular rash [14], generalized exfoliative dermatitis [16,20] or TEN [21,22]. Generalized pustulation has been recorded as a manifestation of the anticonvulsant drug hypersensitivity syndrome [23]. Universal depigmentation has resulted from TEN [24]. Cutaneous histopathology in the pseudolymphoma syndrome is often indistinguishable from that of mycosis fungoides, with infiltrating cells having cerebriform nuclei and forming Pautrier microabscesses [17,19]. The rash resolves after cessation of the drug; systemic corticosteroids may aid resolution [25]. However, there is a threefold risk of true lymphoma on long-term therapy [26–28], and Tcell lymphoma has been reported in an adult [29]. Long-term treatment causes fibroblast proliferation, and may result in dose-dependent gingival hyperplasia [30,31] or coarsening of the features [32]; hypertrophic retroauricular folds were reported in an isolated case [33]. Hypertrichosis may be seen. Other reactions have included fixed eruptions [34], including a widespread fixed drug eruption mimicking TEN [35], erythema multiforme [1,3], TEN with cholestasis [36], cutaneous vasculitis [37], an LE-like syndrome [38,39] and eosinophilic fasciitis [40]. Linear IgA bullous dermatosis has been provoked [41]. Localized reactions to intravenous phenytoin have included delayed bluish discoloration, erythema and oedema, sometimes with bullae, distal to the site of injection; immediate burning pain and swelling, and a delayed erythematous eruption with superficial sloughing, partial epidermal necrosis and frequent multinucleate keratinocytes on histology have also been reported [42,43]. Treatment during pregnancy may lead to a characteristic ‘fetal hydantoin syndrome’, with general underdevelopment and hypoplasia of phalanges and nails [44]; neonatal acne may be associated [45]. However, recent controlled observations suggest that acne is neither caused nor worsened by hydantoins [46], despite reports to the contrary [47]. References 1 Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol 1988; 18: 721–41. 2 Levantine A, Almeyda J. Drug reactions XX. Cutaneous reactions to anticonvulsants. Br J Dermatol 1972; 87: 646–9. 3 Pollack MA, Burk PG, Nathanson G. Mucocutaneous eruptions due to antiepileptic drug therapy in children. Ann Neurol 1979; 5: 262–7. 4 Wilson JT, Höjer B, Tomson G et al. High incidence of a concentration-dependent skin reaction in children treated with phenytoin. BMJ 1978; i: 1583–6.

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5 Tone T, Nishioka K, Kameyama K et al. Common histopathological processes of phenytoin drug eruption. J Dermatol 1992; 19: 27–34. 6 Potter T, DiGregorio F, Stiff M, Hashimoto K. Dilantin hypersensitivity syndrome imitating staphylococcal toxic shock. Arch Dermatol 1994; 130: 856–8. 7 Conger LA Jr, Grabski WJ. Dilantin hypersensitivity reaction. Cutis 1996; 57: 223–6. 8 Leppik IE, Lapora A, Loewenson R. Seasonal incidence of phenytoin allergy unrelated to plasma levels. Arch Neurol 1985; 42: 120–2. 9 Rapp RP, Norton JA, Young B, Tibbs PA. Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis. Neurosurgery 1983; 13: 272–5. 10 Robinson HM, Stone JH. Exanthem due to diphenylhydantoin therapy. Arch Dermatol 1970; 101: 462–5. 11 Stanley J, Fallon-Pellici V. Phenytoin hypersensitivity reaction. Arch Dermatol 1978; 114: 1350–3. 12 Brown M, Schubert T. Phenytoin hypersensitivity hepatitis and mononucleosis syndrome. J Clin Gastroenterol 1986; 8: 469–77. 13 Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1989; 82: 1826–32. 14 Charlesworth EN. Phenytoin-induced pseudolymphoma syndrome. An immunologic study. Arch Dermatol 1977; 113: 477–80. 15 Adams JD. Localized cutaneous pseudolymphoma associated with phenytoin therapy: a case report. Australas J Dermatol 1981; 22: 28–9. 16 Rosenthal CJ, Noguera CA, Coppola A, Kapelner SN. Pseudolymphoma with mycosis fungoides manifestations, hyperresponsiveness to diphenyl-hydantoin, and lymphocyte disregulation. Cancer 1982; 49: 2305–14. 17 Kardaun SH, Scheffer E, Vermeer BJ. Drug-induced pseudolymphomatous skin reactions. Br J Dermatol 1988; 118: 545–52. 18 Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol 1985; 121: 1181–2. 19 Rijlaarsdam U, Scheffer E, Meijer CJLM et al. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermatol 1991; 24: 216–20. 20 Danno K, Kume M, Ohta M et al. Erythroderma with generalized lymphadenopathy induced by phenytoin. J Dermatol 1989; 16: 392–6. 21 Sherertz EF, Jegasothy BV, Lazarus GS. Phenytoin hypersensitivity reaction presenting with toxic epidermal necrolysis and severe hepatitis: report of a patient treated with corticosteroid ‘pulse therapy’. J Am Acad Dermatol 1985; 12: 178–81. 22 Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following reexposure to phenytoin. A case report. Epilepsia 1983; 24: 440–3. 23 Kleier RS, Breneman DL, Boiko S. Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome. Arch Dermatol 1991; 127: 1361–4. 24 Smith DA, Burgdorf WHC. Universal cutaneous depigmentation following phenytoin-induced toxic epidermal necrolysis. J Am Acad Dermatol 1984; 10: 106–9. 25 Chopra S, Levell NJ, Cowley G, Gilkes JJ. Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol 1996; 134: 1109–12. 26 Tashima CK, De Los Santos R. Lymphoma and anticonvulsant therapy. JAMA 1974; 228: 287–8. 27 Bichel J. Hydantoin derivatives and malignancies of the haemopoietic system. Acta Med Scand 1975; 198: 327–8. 28 Li FP, Willard DR, Goodman R et al. Malignant lymphoma after diphenylhydantoin (Dilantin) therapy. Cancer 1975; 36: 1359–62. 29 Isobe T, Horimatsu T, Fujita T et al. Adult T cell lymphoma following diphenylhydantoin therapy. Acta Haematol Jpn 1980; 43: 711–4. 30 Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surg 1972; 34: 898–906. 31 Hassell TM, Page RC, Narayanan AS, Cooper CG. Diphenylhydantoin (Dilantin) gingival hyperplasia: drug induced abnormality of connective tissue. Proc Natl Acad Sci USA 1976; 73: 2909–12. 32 Lefebvre EB, Haining RG, Labbé RF. Coarse facies, calvarial thickening and hyperphosphatasia associated with long-term anticonvulsant therapy. N Engl J Med 1972; 286: 1301–2. 33 Trunnell TN, Waisman M. Hypertrophic retroauricular folds attributable to diphenylhydantoin. Cutis 1982; 30: 207–9. 34 Sweet RD. Fixed skin eruption due to phenytoin sodium. Lancet 1950; i: 68.

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35 Baird BJ, De Villez RL. Widespread bullous fixed drug eruption mimicking toxic epidermal necrolysis. Int J Dermatol 1988; 27: 170–4. 36 Spechler SJ, Sperber H, Doos WG, Koff RS. Cholestasis and toxic epidermal necrolysis associated with phenytoin sodium ingestion: the role of bile duct injury. Ann Intern Med 1981; 95: 455–6. 37 Yermakov VM, Hitti IF, Sutton AL. Necrotizing vasculitis associated with diphenylhydantoin: two fatal cases. Hum Pathol 1983; 14: 182–4. 38 Gleichman H. Systemic lupus erythematosus triggered by diphenylhydantoin. Arthritis Rheum 1982; 25: 1387–8. 39 Ross S, Dywer C, Ormerod AD et al. Subacute cutaneous lupus erythematosus associated with phenytoin. Clin Exp Dermatol 2002; 27: 474–6. 40 Buchanan RR, Gordon DA, Muckle TJ et al. The eosinophilic fasciitis syndrome after phenytoin (Dilantin) therapy. J Rheumatol 1980; 7: 733–6. 41 Acostamadiedo JM, Perniciaro C, Rogers RS III. Phenytoin-induced linear IgA bullous disease. J Am Acad Dermatol 1998; 38: 352–6. 42 Hunt SJ. Cutaneous necrosis and multinucleate epidermal cells associated with intravenous phenytoin. Am J Dermatopathol 1995; 17: 399–402. 43 Kilarski DJ, Buchanan C, Von Behren L. Soft tissue damage associated with intravenous phenytoin. N Engl J Med 1984; 311: 1186–7. 44 Nagy R. Fetal hydantoin syndrome. Arch Dermatol 1981; 117: 593–5. 45 Stankler L, Campbell AGM. Neonatal acne vulgaris: a possible feature of the fetal hydantoin syndrome. Br J Dermatol 1980; 103: 453–5. 46 Greenwood R, Fenwick PBC, Cunliffe WJ. Acne and anticonvulsants. BMJ 1983; 287: 1669–70. 47 Jenkins RB, Ratner AC. Diphenylhydantoin and acne. N Engl J Med 1972; 287: 148.

Gabapentin This drug given for postherpetic neuralgia has caused leukocytoclastic vasculitis [1]. Reference 1 Sahin S, Comert A, Akin O et al. Cutaneous drug eruptions by current antiepileptics: case reports and alternative treatment options. Clin Neuropharmacol 2008; 31: 93–6.

Lamotrigine Dosage-related allergic rashes occur in about 5–10% of patients, usually in the first 8 weeks, leading to a withdrawal rate of 2% of patient exposures [1–4]. In one study, six of eight patients with a prior lamotrigine-related rash had no recurrence on rechallenge, and two other patients had only mild rashes [5]. Rashes leading to hospitalization, including hypersensitivity syndrome [6], Stevens–Johnson syndrome and TEN [7,8], occurred in 1 in 100 to 1 in 300 individuals in clinical trials, and appeared to be increased with over-rapid titration when starting therapy and with concurrent valproate medication [3,9].

9 Anonymous. Lamotrigine (Lamictal): increased risk of serious skin reactions in children. Curr Probl Pharmacovig 1997; 23: 8.

Sodium valproate Occasional transient rashes and stomatitis are documented. Temporary hair loss may be followed by increasing curliness of the regrowing hair [1]. Alteration in hair colour has been noted [2]. One case of generalized morphoea [3] and two cases of cutaneous leukocytoclastic vasculitis recurring on challenge [4] have been reported. An extrapyramidal syndrome may be induced [5], and the drug may be teratogenic [6]. Yellow nail pigmentation is recorded [7]. References 1 Jeavons PM, Clark JE, Harding GFA. Valproate and curly hair. Lancet 1977; i: 359. 2 Herranz JL, Arteaga R, Armijo JA. Change in hair colour induced by valproic acid. Dev Med Child Neurol 1981; 23: 386–7. 3 Goihman-Yahr M, Leal H, Essenfeld-Yahr E. Generalized morphea: a side effect of valproate sodium? Arch Dermatol 1980; 116: 621. 4 Kamper AM, Valentijn RM, Stricker BHC, Purcell PM. Cutaneous vasculitis induced by sodium valproate. Lancet 1991; 337: 497–8. 5 Lautin A, Stanley M, Angrist B, Gershon S. Extrapyramidal syndrome with sodium valproate. BMJ 1979; ii: 1035–6. 6 Gomez MR. Possible teratogenicity of valproic acid. J Pediatr 1981; 98: 508–9. 7 Buka R, Hille R, McCormack P. Yellow nail pigmentation following Depakote therapy. J Drugs Dermatol 2003; 2: 545–7.

Trimethadione Serious hypersensitivity reactions may occur, including erythema multiforme, urticaria and generalized exfoliative dermatitis. Vigabatrin An allergic vasculitis developed in one patient 6 months after commencement of this drug [1]. Zonisamide Toxic epidermal necrolysis associated with reactivation of human herpesvirus 6 is recorded [2]. References 1 Dieterle L, Becker EW, Berg PA et al. Allergische Vaskulitis durch Vigabatrin. Nervenarzt 1994; 65: 122–4. 2 Teraki Y, Murota H, Izaki S. Toxic epidermal necrolysis due to zonisamide associated with reactivation of human herpesvirus 6. Arch Dermatol 2008; 144: 232–5.

Opioid analgesics and amfetamine (amphetamine) References 1 Richens A. Safety of lamotrigine. Epilepsia 1994; 35 (Suppl. 5): S37–S40. 2 Calabrese JR, Sullivan JR, Bowden CL et al. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry 2002; 63: 1012–9. 3 Guberman AH, Besag FM, Brodie MJ et al. Lamotrigine-associated rash: risk/ benefit considerations in adults and children. Epilepsia 1999; 40: 985–91. 4 Messenheimer JA. Lamotrigine. Epilepsia 1995; 36 (Suppl. 2): S87–S94. 5 Tavernor SJ, Wong IC, Newton R, Brown SW. Rechallenge with lamotrigine after initial rash. Seizure 1995; 4: 67–71. 6 Jones D, Chhiap V, Resor S et al. Phenytoin-like hypersensitivity associated with lamotrigine. J Am Acad Dermatol 1997; 36: 1016–8. 7 Sterker M, Berrouschot J, Schneider D. Fatal course of toxic epidermal necrolysis under treatment with lamotrigine. Int J Clin Pharmacol Ther 1995; 33: 595–7. 8 Sahin S, Comert A, Akin O et al. Cutaneous drug eruptions by current antiepileptics: case reports and alternative treatment options. Clin Neuropharmacol 2008; 31: 93–6.

Cutaneous side effects common to drug abuse, most frequently cocaine, heroin and pentazocine, following parenteral injection include [1,2] infections, abscesses, septic phlebitis, subcutaneous and deep dermal cellulitis, necrosis, tetanus, widespread urticaria, cutaneous manifestations of primary and secondary syphilis; HIV infection and endocarditis occur. Starch and talc granulomas, lymphangitis and lymphadenitis in draining lymph nodes, pigmentary abnormalities including hyperpigmentation over the injected veins, accidental ‘soot’ tattoos (caused by needles sterilized over an open flame), scarring, ulceration, necrotizing angiitis and leukocytoclastic vasculitis may supervene. Skin popping refers to injection of drugs beneath the skin without concern for vascular access; this may result in delayed development of ulcers [3]. Injection drug use may lead to venous disease [4].

Important or widely prescribed drugs References 1 Rosen VJ. Cutaneous manifestations of drug abuse by parenteral injections. Am J Dermatopathol 1985; 7: 79–83. 2 Smith DJ, Busito MJ, Velanovich V et al. Drug injection injuries of the upper extremity. Ann Plastic Surg 1989; 22: 19–24. 3 Pardes JB, Falanga V, Kerdel FA. Delayed cutaneous ulcerations arising at sites of prior parenteral drug abuse. J Am Acad Dermatol 1993; 29: 1052–4. 4 Pieper B, Kirsner RS, Templin TN, Birk TJ. Injection drug use. An understudied cause of venous disease. Arch Dermatol 2007; 143: 1305–9.

Methylamfetamine A link with necrotizing angiitis has been recorded when this drug is used alone or with heroin or d-lysergic acid diethylamide [1]. Reference 1 Citron BP, Halpern M, McCarron M et al. Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283: 1003–11.

Buprenorphine An addict accidentally injected a suspension of crushed tablets into the superficial pudendal artery instead of the femoral vein, and developed pain, oedema and mottling of the penis [1]. Hypersensitivity reactions, and local or systemic infection have been reported [2]. References 1 Naylor AR, Gordon M, Jenkins AMcL. Untitled report. BMJ 1991; 303: 478. 2 Del Giudice P. Cutaneous complications of intravenous drug abuse. Br J Dermatol 2004; 150: 1–10.

Codeine This drug has been associated with pruritus, urticaria (usually due to non-immunological release of histamine) [1,2], angio-oedema, macular and maculopapular eruptions, scarlatiniform rashes [1,3,4], fixed eruption, bullous eruption, generalized eczema [5], erythema multiforme and erythema nodosum, and a hypersensitivity reaction [6]. References 1 Hunskaar S, Dragsund S. Scarlatiniform rash and urticaria due to codeine. Ann Allergy 1985; 54: 240–1. 2 De Groot AC, Conemans J. Allergic urticarial rash from oral codeine. Contact Dermatitis 1986; 14: 209–14. 3 Voohost R, Sparreboom S. Four cases of recurrent pseudo-scarlet fever caused by phenanthrene alkaloids with a 6-hydroxy group (codeine and morphine). Ann Allergy 1980; 44: 116–20. 4 Mohrenschlager M, Glockner A, Jessberger B et al. Codeine caused pruritic scarlatiniform exanthemata: patch test negative but positive to oral provocation test. Br J Dermatol 2000; 143: 663–4. 5 Estrada JL, Puebla MJ, de Urbina JJ et al. Generalized eczema due to codeine. Contact Dermatitis 2001; 44: 185. 6 Enomoto M, Ochi M, Teramae K et al. Codeine phosphate-induced hypersensitivity syndrome. Ann Pharmacother 2004; 38: 799–802.

Heroin Use of the dorsal vein of the penis for administration of the drug has produced ulceration [1]. Systemic infections, such as candidiasis, may supervene [2]. Leukocytoclastic vasculitis and necrotizing angiitis have been reported in drug abusers [3–5]. Pigmentation of the tongue may occur as a form of fixed drug eruption in heroin addicts [6]. A possible association with development of pemphigus erythematosus has been suggested [7].

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References 1 White WB, Barrett S. Penile ulcer in heroin abuse: a case report. Cutis 1982; 29: 62–3. 2 Bielsa I, Miro JM, Herrero C et al. Systemic candidiasis in heroin abusers. Int J Dermatol 1987; 26: 314–9. 3 Citron BP, Halpern M, McCarron M et al. Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283: 1003–11. 4 Lignelli GJ, Bucheit WA. Angiitis in drug abusers. N Engl J Med 1971; 284: 112–3. 5 Gendelman H, Linzer M, Barland P et al. Leukocytoclastic vasculitis in an intravenous heroin abuser. NY State J Med 1983; 83: 984–6. 6 Westerhof W, Wolters EC, Brookbakker JTW et al. Pigmented lesions of the tongue in heroin addicts: fixed drug eruption. Br J Dermatol 1983; 109: 605–10. 7 Fellner MJ, Winiger J. Pemphigus erythematosus and heroin addiction. Int J Dermatol 1978; 17: 308–11.

Morphine Morphine is a potent histamine releaser and may cause pruritus and urticaria [1]. Profuse sweating is a common effect. Morphine provokes facial flushing blocked by naloxone [2]. Local skin irritation during subcutaneous morphine infusion is recorded [3]. Acute generalized exanthematous pustulosis, pseudoallergic anaphylactoid reactions and blisters are reported [4]. Nefopam Reactions to this analgesic include pruritus, erythema, urticaria, angio-oedema and anaphylactic shock [5]. References 1 McLelland J. The mechanism of morphine-induced urticaria. Arch Dermatol 1986; 122: 138–9. 2 Cohen RA, Coffman JD. Naloxone reversal of morphine-induced peripheral vasodilatation. Clin Pharmacol Ther 1980; 28: 541–4. 3 Shvartzman P, Bonneh D. Local skin irritation in the course of subcutaneous morphine infusion: a challenge. J Palliat Care 1994; 10: 44–5. 4 Kardaun SH, de Monchy JG. Acute generalized exanthematous pustulosis caused by morphine, confirmed by positive patch test and lymphocyte transformation test. J Am Acad Dermatol 2006; 55 (Suppl. 2): S21–3. 5 Durrieu G, Olivier P, Bagheri H et al. Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance database. Fundam Clin Pharmacol 2007; 21: 555–8.

Pentazocine Woody induration of the skin and subcutaneous tissues at injection sites, perhaps with central ulceration and peripheral pigmentation, and a granulomatous histology, is well recognized [1–8]. Pigmentation, ulceration and a chronic panniculitis have supervened after many years of use. Phlebitis, cellulitis, fibrous myopathy [9] and limb contractures can complicate these changes. Generalized eruptions are rare [10]. There is an isolated report of TEN [11]. References 1 Parks DL, Perry HO, Muller SA. Cutaneous complications of pentazocine injections. Arch Dermatol 1971; 104: 231–5. 2 Schlicher JE, Zuehlke RL, Lynch PJ. Local changes at the site of pentazocine injection. Arch Dermatol 1971; 104: 90–1. 3 Swanson DW, Weddige RL, Morse RM. Hospitalised pentazocine abusers. Mayo Clin Proc 1973; 48: 85–93. 4 Schiff BL, Kern AB. Unusual cutaneous manifestations of pentazocine addiction. JAMA 1977; 238: 1542–3. 5 Padilla RS, Becker LE, Hoffman H, Long G. Cutaneous and venous complications of pentazocine abuse. Arch Dermatol 1979; 115: 975–7.

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6 Palestine RF, Millns JL, Spigel GT et al. Skin manifestations of pentazocine abuse. J Am Acad Dermatol 1980; 2: 47–55. 7 Mann RJ, Gostelow BE, Meacock DJ, Kennedy CTC. Pentazocine ulcers. J R Soc Med 1982; 75: 903–5. 8 Jain A, Bhattacharya SN, Singal A et al. Pentazocine induced widespread cutaneous and myo-fibrosis. J Dermatol 1999; 26: 368–70. 9 Johnson KR, Hsueh WA, Glusman SM, Arnett FC. Fibrous myopathy: a rheumatic complication of drug abuse. Arthritis Rheum 1976; 19: 923–6. 10 Pedragosa R, Vidal J, Fuentes R, Huguet P. Tricotropism by pentazocine. Arch Dermatol 1987; 123: 297–8. 11 Hunter JAA, Davison AM. Toxic epidermal necrolysis associated with pentazocine therapy and severe reversible renal failure. Br J Dermatol 1973; 88: 287–90.

Antiparkinsonian drugs Amantadine Reversible livedo reticularis has occurred in a high percentage of patients receiving amantadine, a tricyclic amine used in the treatment of Parkinson’s disease [1,2].

Apomorphine Panniculitis, ranging from mild pruritic erythema to painful nodules, has been observed [3]. Bromocriptine Transient livedo reticularis [4], erythromelalgia [5], acrocyanosis with Raynaud’s phenomenon [6,7], morphoea [8] and swelling of the legs with a sclerodermatous histology [9] have been reported rarely, as have alopecia [10], pseudolymphoma [11] and psychosis. Carbidopa Scleroderma-like reactions have occurred when this drug has been given in conjunction with tryptophan [12,13]. Levodopa There have been several isolated reports of the occurrence of malignant melanoma [14–16], in certain instances involving multiple primaries, but the association may be by chance alone. References 1 Shealy CN, Weeth JB, Mercier D. Livedo reticularis in patients with parkinsonism receiving amantadine. JAMA 1970; 212: 1522–3. 2 Hayes BB, Cook-Norris RH, Miller JL et al. Amantadine-induced livedo reticularis: a report of two cases. J Drugs Dermatol 2006; 5: 288–9. 3 Acland KM, Churchyard A, Fletcher CL et al. Panniculitis in association with apomorphine infusion. Br J Dermatol 1998; 138: 480–2. 4 Calne DB, Plotkin C, Neophytides A et al. Long-term treatment of Parkinsonism with bromocriptine. Lancet 1978; i: 735–7. 5 Eisler T, Hall RP, Kalavar KAR, Calne DB. Erythromelalgia-like eruption in parkinsonian patients treated with bromocriptine. Neurology 1981; 37: 1368–70. 6 Duvoisin RC. Digital vasospasm with bromocriptine. Lancet 1976; ii: 204. 7 Pearce I, Pearce JMS. Bromocriptine in Parkinsonism. BMJ 1978; i: 1402–4. 8 Leshin B, Piette WW, Caplin RM. Morphea after bromocriptine therapy. Int J Dermatol 1989; 28: 177–9. 9 Dupont E, Olivarius B, Strong MJ. Bromocriptine-induced collagenosis-like symptomatology in Parkinson’s disease. Lancet 1982; i: 850–1. 10 Blum I, Leiba S. Increased hair loss as a side effect of bromocriptine treatment. N Engl J Med 1980; 303: 1418. 11 Wiesli P, Joos L, Galeazzi RL, Dummer R. Cutaneous pseudolymphoma associated with bromocriptine therapy. Clin Endocrinol 2000; 53: 656–7. 12 Sternberg EM, Van Woert MH, Young SN et al. Development of a sclerodermalike illness during therapy with l-5-hydroxytryptophan and carbidopa. N Engl J Med 1980; 303: 782–7.

13 Chamson A, Périer C, Frey J. Syndrome sclérodermiforme et poïkilodermique observé au cours d’un traitement par carbidopa et 5-hydroxytryptophane. Culture de fibroblastes avec analyse biochimique du métabolisme du collagene. Ann Dermatol Vénéréol 1986; 113: 71. 14 Sober AJ, Wick MM. Levodopa therapy and malignant melanoma. JAMA 1978; 240: 554–5. 15 Bernstein JE, Medenica M, Soltani K et al. Levodopa administration and multiple primary cutaneous melanomas. Arch Dermatol 1980; 116: 1041–4. 16 Rosin MA, Braun M III. Malignant melanoma and levodopa. Cutis 1984; 33: 572–4.

Antivertigo drugs and cerebrovascular dilators Cinnarizine This drug [1], and its derivative flunarizine [2], have been implicated in the precipitation of lichenoid eruptions. In the case of cinnarizine, clinical and immunofluorescence features of lichen planus were combined with the presence of a circulating antibasement-membrane zone IgG antibody [2]. Other side effects include drowsiness, depression and parkinsonism. References 1 Miyagawa W, Ohi H, Muramatsu T et al. Lichen planus pemphigoides-like lesions induced by cinnarizine. Br J Dermatol 1985; 112: 607–13. 2 Suys E, De Coninck A, De Pauw I, Roseeuw D. Lichen planus induced by flunarizine. Dermatologica 1990; 181: 71–2.

Miscellaneous nervous system drugs Drugs for alcoholism Cyanamide. This inhibitor of alcohol dehydrogenase, used in the treatment of alcoholism in some countries, has been implicated in the development of a lichen planus-like eruption with oesophageal involvement [1,2], as well as exfoliative dermatitis [2]. Disulfiram. This drug causes vasomotor flushing, morbilliform rash and urticaria, as well as eczema in patients sensitized to rubber; it cross-reacts with rubber [3–5]. A toxic pustular eruption is recorded [6]. References 1 Torrelo A, Soria C, Rocamora A et al. Lichen planus-like eruption with esophageal involvement as a result of cyanamide. J Am Acad Dermatol 1990; 23: 1168–9. 2 Kawana S. Drug eruption induced by cyanamide (carbimide): a clinical and histopathologic study of 7 patients. Dermatology 1997; 195: 30–4. 3 Webb PK, Gibbs SC, Mathias CT et al. Disulfiram hypersensitivity and rubber contact dermatitis. JAMA 1979; 241: 2061. 4 Fischer AA. Dermatologic aspects of disulfiram use. Cutis 1982; 30: 461–524. 5 Minet A, Frankart M, Eggers S et al. Réactions allergiques aux implants de disulfirame. Ann Dermatol Vénéréol 1989; 116: 543–5. 6 Larbre B, Larbre JP, Nicolas JF et al. Toxicodermie pustuleuse aus disulfirame. A propos d’un cas. Ann Dermatol Vénéréol 1990; 117: 721–2.

Drugs to aid smoking cessation Amfebutamone. This antidepressant drug, structurally related to the phenylethylamines (amfetamines) and used in aiding smoking cessation, has been implicated in causing liver dysfunction, pruritus and urticaria [1], serum sickness [2,3], and generalized pustular and erythrodermic psoriasis [4]. References 1 Fays S, Tréchot P, Schmutz JL et al. Bupropion and generalised acute urticaria: eight cases. Br J Dermatol 2003; 148: 177–8.

Important or widely prescribed drugs 2 McCollom RA, Elbe DH, Ritchie AH. Bupropion-induced serum sickness-like reaction. Ann Pharmacother 2000; 34: 471–3. 3 Davis JS, Boyle MJ, Hannaford R, Watson A. Bupropion and serum sickness-like reaction. Med J Aust 2001; 174: 479–80. 4 Cox NH, Gordon PM, Dodd H. Generalized pustular and erythrodermic psoriasis associated with bupropion treatment. Br J Dermatol 2002; 146: 1061–3.

Appetite suppressants and stimulants Centrally acting appetite suppressants may induce urticarial vasculitis [1]. Megestrol, a synthetic orally active progesterone derivative used to stimulate appetite and weight gain in cachectic patients, caused a generalized morbilliform rash in a man; skin testing with progesterone acetate was positive [2]. Sibutramine, a centrally acting drug used in weight management, caused an erythema multiforme-like reaction [3]. Pyritinol This drug, given for cerebral concussion, caused an unusual erythema multiforme-like eruption and severe headache after 10 days’ treatment [4]. References 1 Papadavid E, Yu RC, Tay A, Chu AC. Urticarial vasculitis induced by centrally acting appetite suppressants. Br J Dermatol 1996; 134: 990–1. 2 Fisher DA. Drug-induced progesterone dermatitis. J Am Acad Dermatol 1996; 34: 863–4. 3 Goh BK, Ng PPL, Giam YC. Severe bullous drug eruption due to sibutramine (Reductil©). Br J Dermatol 2003; 149: 215–6. 4 Nachbar F, Korting HC, Vogl T. Erythema multiforme-like eruption in association with severe headache following pyritinol. Dermatology 1993; 187: 42–6.

Drugs acting on the cardiovascular system Adverse cutaneous reactions due to cardiovascular and antiarrhythmic drug therapy have been reviewed [1–3]. References 1 Reiner DM, Frishman WH, Luftschein S, Grossman M. Adverse cutaneous reactions from cardiovascular drug therapy. NY State J Med 1992; 92: 137–47. 2 Sun DK, Reiner D, Frishman W et al. Adverse dermatologic reactions from antiarrhythmic drug therapy. J Clin Pharmacol 1994; 34: 953–66. 3 Torpet LA, Kragelund C, Reibel J, Nauntofte B. Oral adverse drug reactions to cardiovascular drugs. Crit Rev Oral Biol Med 2004; 15: 28–46.

Cardiac antiarrhythmic drugs Amiodarone This iodinated antiarrhythmic drug causes photosensitivity in around 40% of patients [1–13]. Symptoms develop within 2 h of sun exposure as a burning sensation followed by erythema; the action spectrum is UVA, extending to a degree into visible light wavebands above 400 nm [4]. Light sensitivity may persist for up to 4 months after the drug is stopped [1,2]. Blue or grey pigmentation of the face and other sun-exposed areas, resembling that in argyria, is a much less common late effect, occurring in 2–5% of cases; areas not exposed to the sun may also be involved [3,6–12]. It is induced by a phototoxic reaction involving both UVB and UVA [3,6], and is related to both duration and dosage of the drug [11]. However, although cutaneous side effects are more likely with increasing duration of treatment and cumulative dosage, neither the serum amiodarone level nor the serum metabolite level

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have any predictive power [13]. Amiodarone-pigmented skin contains the drug and its metabolities in higher concentrations than non-pigmented skin [3]. Iodine-rich amiodarone and its metabolites have been detected bound to lipofuscin within secondary lysosomes in perivascular dermal macrophages [7–10]. Electrondense granules and myelin-like bodies are also found in peripheral blood leukocytes [12]. The cutaneous pigmentation slowly fades after discontinuation of therapy, but may persist for months to years [8]. Iododerma has occurred with long-term therapy. Vasculitis [14] and linear IgA disease [15] have been recorded. A fatal case of TEN has been reported [16]. The most severe adverse effect seen with amiodarone is pulmonary fibrosis, which occurs in 5–10% of exposed patients and which has a 10% mortality rate. Other problems have been cardiac dysrhythmias, thyroid dysfunction, peripheral neuropathy and reversible corneal deposits [17]. References 1 Marcus FI, Fontaine GH, Frank R, Grosgogeat Y. Clinical pharmacology and therapeutic applications of the antiarrhythmic agent amiodarone. Am Heart J 1981; 101: 480–93. 2 Chalmers RJ, Muston HL, Srinivas V, Bennett DH. High incidence of amiodarone-induced photosensitivity in North-west England. BMJ 1982; 285: 341. 3 Zachary CB, Slater DN, Holt DW et al. The pathogenesis of amiodarone-induced pigmentation and photosensitivity. Br J Dermatol 1984; 110: 451–6. 4 Ferguson J, Addo HA, Jones S et al. A study of cutaneous photosensitivity induced by amiodarone. Br J Dermatol 1985; 113: 537–49. 5 Roupe G, Larkö O, Olsson SB et al. Amiodarone photoreactions. Acta Derm Venereol (Stockh) 1987; 67: 76–9. 6 Waitzer S, Butany J, From L et al. Cutaneous ultrastructural changes and photosensitivity associated with amiodarone therapy. J Am Acad Dermatol 1987; 16: 779–87. 7 McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. BMJ 1983; 287: 175–9. 8 Miller RAW, McDonald ATJ. Dermal lipofuscinosis associated with amiodarone therapy. Report of a case. Arch Dermatol 1984; 120: 646–9. 9 Holt DW, Adams PC, Campbell RWF et al. Amiodarone and its desethyl-metabolite: tissue distribution and ultrastructural changes in amiodarone treated patients. Br J Clin Pharmacol 1984; 17: 195–6. 10 Török L, Szekeres L, Lakatos A, Szücs M. Amiodaronebedingte Hyperpigmentierung. Hautarzt 1986; 37: 507–10. 11 Heger JJ, Prystowsky EN, Zipes DP. Relationships between amiodarone dosage, drug concentrations, and adverse side effects. Am Heart J 1983; 106: 931–5. 12 Rappersberger K, Konrad K, Wieser E et al. Morphological changes in peripheral blood cells and skin in amiodarone-treated patients. Br J Dermatol 1986; 114: 189–96. 13 Shukla R, Jowett NI, Thompson DR, Pohl JE. Side effects with amiodarone therapy. Postgrad Med J 1994; 70: 492–8. 14 Staubli M, Zimmerman A, Bircher J. Amiodarone-induced vasculitis and polyserositis. Postgrad Med J 1985; 61: 245–7. 15 Primka EJ III, Liranzo MO, Bergfeld W et al. Amiodarone-induced linear IgA disease. J Am Acad Dermatol 1996; 31: 809–11. 16 Bencini PL, Crosti C, Sala F et al. Toxic epidermal necrolysis and amiodarone. Arch Dermatol 1985; 121: 838. 17 Morgan DJR. Adverse reactions profile: 3. Amiodarone. Drug Ther Bull 1991; 31: 104–11.

Digoxin Allergic reactions are very rare [1], but exanthematic erythema, urticaria, bullous eruptions and thrombocytopenic purpura are documented. In one patient, a psoriasiform rash occurred, confirmed by later re-exposure [2].

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References 1 Martin SJ, Shah D. Cutaneous hypersensitivity reaction to digoxin. JAMA 1994; 271: 1905. 2 David M, Livni E, Stern E et al. Psoriasiform eruption induced by digoxin: confirmed by reexposure. J Am Acad Dermatol 1981; 5: 702–3.

Procainamide This drug is well known for precipitating an LE-like syndrome [1–6], perhaps partly as a result of binding of the hydroxylamine metabolite of procainamide to complement component C4, with resultant impaired complement-mediated clearance of immune complexes [5,6]. A lichenoid eruption followed the occurrence of drug-induced LE in one case [7]. Urticarial vasculitis has been reported [8]. References 1 Dubois EL. Procainamide induction of a systemic lupus erythematosus-like syndrome. Presentation of six cases, review of the literature, and analysis and followup of reported cases. Medicine (Baltimore) 1969; 48: 217–8. 2 Blomgren SE, Condemi JJ, Vaughan JH. Procainamide-induced lupus erythematosus. Clinical and laboratory observations. Am J Med 1972; 52: 338–48. 3 Whittle TS Jr, Ainsworth SK. Procainamide-induced systemic lupus erythematosus. Renal involvement with deposition of immune complexes. Arch Pathol Lab Med 1976; 100: 469–74. 4 Tan EM, Rubin RL. Autoallergic reactions induced by procainamide. J Allergy Clin Immunol 1984; 74: 631–4. 5 Sim E, Stanley L, Gill EW, Jones A. Metabolites of procainamide and practolol inhibit complement components C3 and C4. Biochem J 1988; 251: 323–6. 6 Sim E. Drug-induced immune complex disease. Complement Inflamm 1989; 6: 119–26. 7 Sherertz EF. Lichen planus following procainamide-induced lupus erythematosus. Cutis 1988; 42: 51–3. 8 Knox JP, Welykyj SE, Gradini R, Massa MC. Procainamide-induced urticarial vasculitis. Cutis 1988; 42: 469–72.

Quinidine An eczematous photosensitivity is well described [1–5]; fever is common. Thrombocytopenic purpura may be induced, resulting from antibodies to drug–platelet conjugates [6,7]. Urticarial, scarlatiniform and morbilliform eruptions occur; the latter may proceed to generalized exfoliative dermatitis if the drug is continued. Fixed and lichenoid eruptions [8–14], often induced by light, are recorded, as well as an acneiform rash [15]. Livedo reticularis has been documented; the mechanism is unknown, although recent exposure to sunlight was a feature common to all cases [16–18]. Drug-induced LE [19–21] and Henoch–Schönlein vasculitis [22,23] have been seen. Psoriasis may be exacerbated [24,25]. Localized blue-grey pigmentation of the shins, hard palate, nails, nose, ears and forearms has been recorded [26]. References 1 Berger TG, Sesody SJ. Quinidine-induced lichenoid photodermatitis. Cutis 1982; 29: 595–8. 2 Marx JL, Eisenstat BA, Gladstein AH. Quinidine photosensitivity. Arch Dermatol 1983; 119: 39–43. 3 Armstrong RB, Leach EE, Whitman G et al. Quinidine photosensitivity. Arch Dermatol 1985; 121: 525–8. 4 Jeanmougin M, Sigal M, Djian B et al. Photo-allergie à la quinidine. Ann Dermatol Vénéréol 1986; 113: 985–7. 5 Schürer NY, Lehmann P, Plewig G. Chinidininduzierte Photoallergie. Eine klinische und experimentelle Studie. Hautarzt 1991; 42: 158–61.

6 Christie DJ, Weber RW, Mullen PC et al. Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets. J Lab Clin Med 1984; 104: 730–40. 7 Gary M, Ilfeld D, Kelton JG. Correlation of a quinidine-induced plateletspecific antibody with development of thrombocytopenia. Am J Med 1985; 79: 253–5. 8 Anderson TE. Lichen planus following quinidine therapy. Br J Dermatol 1967; 79: 500. 9 Pegum JS. Lichenoid quinidine eruption. Br J Dermatol 1968; 80: 343. 10 Maltz BL, Becker LE. Quinidine-induced lichen planus. Int J Dermatol 1980; 19: 96–7. 11 Bonnetblanc J-M, Bernard P, Catanzano G, Souyri N. Eruptions lichénoides photinduites aux quinidiniques. Ann Dermatol Vénéréol 1987; 114: 957–61. 12 Wolf R, Dorfman B, Krakowski A. Quinidine induced lichenoid and eczematous photodermatitis. Dermatologica 1987; 174: 285–9. 13 De Larrard G, Jeanmougin M, Moulonguet I et al. Toxidermie lichénoïde alopéciante à la quinidine. Ann Dermatol Vénéréol 1988; 115: 1172–4. 14 Jeanmougin M, Elkara-Marrak H, Pons A et al. Éruption lichénoïde photo-induite a l’hydroxyquinidine. Ann Dermatol Vénéréol 1987; 114: 1397–9. 15 Burckhart CG. Quinidine-induced acne. Arch Dermatol 1987; 117: 603–4. 16 Marion DF, Terrien CM. Photosensitive livedo reticularis. Arch Dermatol 1973; 108: 100–1. 17 De Groot WP, Wuite J. Livedo racemosa-like photosensitivity reaction during quinidine durettes medication. Dermatologica 1974; 148: 371–6. 18 Bruce S, Wolf JE Jr. Quinidine-induced photosensitive livedo reticularis-like eruption. J Am Acad Dermatol 1985; 12: 332–6. 19 Lavie CJ, Biundo J, Quinet RJ, Waxman J. Systemic lupus erythematosus (SLE) induced by quinidine. Arch Intern Med 1985; 145: 446–8. 20 McCormack GD, Barth WF. Quinidine induced lupus syndrome. Semin Arthritis Rheum 1985; 15: 73–9. 21 Cohen MG, Kevat S, Prowse MV et al. Two distinct quinidine-induced rheumatic syndromes. Ann Intern Med 1988; 108: 369–71. 22 Aviram A. Henoch–Schönlein syndrome associated with quinidine. JAMA 1980; 243: 432–4. 23 Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis. Serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol 1990; 126: 69–72. 24 Baker H. The influence of chloroquine and related drugs on psoriasis and keratoderma blenorrhagicum. Br J Dermatol 1966; 78: 161–6. 25 Brenner S, Cabili S, Wolf R. Widespread erythematous scaly plaques in an adult. Psoriasiform eruption induced by quinidine. Arch Dermatol 1993; 129: 1331–2, 1334–5. 26 Mahler R, Sissons W, Watters K. Pigmentation induced by quinidine therapy. Arch Dermatol 1986; 122: 1062–4.

b-Adrenoceptor-blocking agents This group of drugs shares certain potential side effects in common [1,2]. Peripheral ischaemia may be aggravated, and cold extremities and Raynaud’s phenomenon [3] may present as new symptoms. Peripheral gangrene and peripheral skin necrosis have been reported [4,5]. An LE-like syndrome [6,7], and eczematous or lichenoid eruptions [1,2] may be induced rarely. Psoriasis vulgaris is occasionally aggravated or precipitated by a number of βblockers including atenolol, oxprenolol and propranolol [8–14]. Cross-sensitivity is not usual [15], but cross-reactivity between atenolol, oxprenolol and propranolol has been reported [16]. Peyronie’s disease (induratio penis plastica) has been attributed to labetalol, metoprolol and propranolol [17,18]. Aphthous ulcers have been linked to β-blockers [19], and vasculitis occurred with sotalol [20]. β-Blockers may enhance anaphylactic reactions caused by other allergens, and may make resuscitation more difficult [21–23]. Vitiligo may be exacerbated [24]. Topical ophthalmic βblockers, especially timolol, have been implicated in pruritus [25], alopecia [26], chronic erythroderma [27] and LE [28].

Important or widely prescribed drugs References 1 Felix RH, Ive FA, Dahl MGC. Skin reactions to beta-blockers. BMJ 1975; i: 626. 2 Hödl S. Nebenwirkungen der Betarezeptorenblocker an der Haut. Übersicht und eigene Beobachtungen. Hautarzt 1985; 36: 549–57. 3 Marshall AJ, Roberts CJC, Barritt DW. Raynaud’s phenomenon as a side effect of beta-blockers in hypertension. BMJ 1976; i: 1498–9. 4 Gokal R, Dornan TL, Ledingham JGG. Peripheral skin necrosis complicating beta-blockade. BMJ 1979; i: 721–2. 5 Hoffbrand BI. Peripheral skin necrosis complicating beta-blockade. BMJ 1979; i: 1082. 6 Hughes GRV. Hypotensive agents, beta-blockers, and drug-induced lupus. BMJ 1982; 284: 1358–9. 7 McGuinness M, Frye RA, Deng J-S. Atenolol-induced lupus erythematosus. J Am Acad Dermatol 1997; 37: 298–9. 8 Arntzen N, Kavli G, Volden G. Psoriasis provoked by β-blocking agents. Acta Derm Venereol (Stockh) 1984; 64: 346–8. 9 Abel EA, Dicicco LM, Orenberg EK et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007–22. 10 Heng MCY, Heng MK. Beta-adrenoceptor antagonist-induced psoriasiform eruption. Clinical and pathogenetic aspects. Int J Dermatol 1988; 27: 619–27. 11 Gold MH, Holy AK, Roenigk HH Jr. Beta-blocking drugs and psoriasis. A review of cutaneous side effects and retrospective analysis of their effects on psoriasis. J Am Acad Dermatol 1988; 19: 837–41. 12 Halevy S, Livni E. Psoriasis and psoriasiform eruptions associated with propranolol: the role of an immunologic mechanism. Arch Dermatol Res 1990; 283: 472–3. 13 Steinkraus V, Steinfath M, Mensing H. Beta-adrenergic blocking drugs and psoriasis. J Am Acad Dermatol 1992; 27: 266–7. 14 Halevy S, Livni E. Beta-adrenergic blocking drugs and psoriasis: the role of an immunologic mechanism. J Am Acad Dermatol 1993; 29: 504–5. 15 Furhoff A-K, Norlander M, Peterson C. Cross-sensitivity between practolol and other beta-blockers? BMJ 1976; i: 831. 16 Van Joost T, Smitt JHS. Skin reactions to propranolol and cross sensitivity to β-adrenoreceptor blocking agents. Arch Dermatol 1981; 117: 600–1. 17 Yudkin JS. Peyronie’s disease in association with metoprolol. Lancet 1977; ii: 1355. 18 Jones HA, Castleden WM. Peyronie’s disease. Med J Aust 1981; ii: 514–5. 19 Boulinguez S, Reix S, Bedane C et al. Role of drug exposure in aphthous ulcers: a case–control study. Br J Dermatol 2000; 143: 1261–5. 20 Rustmann WC, Carpenter MT, Harmon C, Botti CF. Leukocytoclastic vasculitis associated with sotalol therapy. J Am Acad Dermatol 1998; 38: 111–2. 21 Hannaway PJ, Hopper GDK. Severe anaphylaxis and drug-induced betablockade. N Engl J Med 1983; 308: 1536. 22 Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988; 81: 1–5. 23 Hepner MJ, Ownby DR, Anderson JA et al. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 1990; 86: 407–11. 24 Schallreuter KU. Beta-adrenergic blocking drugs may exacerbate vitiligo. Br J Dermatol 1995; 132: 168–9. 25 Lazarov A, Amicha B. Skin reactions due to eye drops: report of two cases. Cutis 1996; 58: 363–4. 26 Fraunfelder FT, Meyer SM, Menacker SJ. Alopecia possibly secondary to topical ophthalmic β-blockers. JAMA 1990; 263: 1493–4. 27 Shelley WB, Shelley ED. Chronic erythroderma induced by β-blocker (timolol maleate). J Am Acad Dermatol 1997; 37: 799–800. 28 Zamber RW, Starkebaum G, Rubin RL et al. Drug induced systemic lupus erythematosus due to ophthalmic timolol. J Rheumatol 1992; 19: 977–9.

Acebutolol Rashes with mixed lichenoid and LE-like features have been reported [1]. The LE syndrome may have pleuropulmonary features [2]. Atenolol Conjunctivitis and a periocular dermatitis [3], as well as a psoriasiform rash [4], pseudolymphomatous reaction [5] and vasculitis [6], are recorded.

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Cetamolol A psoriasiform eruption has been documented [7]. Labetalol Mixed eruptions with psoriasiform and pityriasis rubra pilarislike changes [8], a bullous lichenoid eruption [9] and an SLE-like syndrome [10] are documented. Metoprolol Various psoriasiform or eczematous rashes may follow long-term therapy [11,12]. Conjunctivitis and periocular dermatitis have occurred [3]. Peyronie’s disease appears to be a rare but confirmed side effect and may be reversible. Telogen effluvium has been noted [13]. Oxprenolol This drug, like practolol, has caused an oculocutaneous syndrome [14]. An eruption combining well-defined, eroded or scaly red rings with a lichenoid histology [15,16] is recognized. Acute psoriasis with arthropathy has been described [17]. Peripheral skin necrosis associated with Raynaud’s phenomenon, an LE syndrome, various patterns of dermatitis [3] and generalized pigmentation [18] are all documented. Practolol This drug has been withdrawn, but is discussed in view of its important side-effect profile. It caused an oculocutaneous syndrome comprising dry eyes and scarring, fibrosis and metaplasia of the conjunctiva; a psoriasiform, lichenoid or mixed eruption with a characteristic histology; pleural and pericardial reactions; fibrinous peritonitis; and serous otitis media [19,20]. Subsequent treatment with another β-blocker did not elicit cross-sensitivity reactivation of the syndrome [21]. Ocular cicatricial pemphigoid was seen [22], and exacerbation of psoriasis was recorded [23]. Pindolol Psoriasiform [24] and lichenoid rashes with pemphigus-like antibodies demonstrated by immunofluorescence have been seen, as well as an SLE syndrome [25]. Propranolol This is probably the most widely used β-blocker, and many adverse cutaneous reactions have been reported [26–29]. Rashes may be lichenoid [30], psoriasiform [29] or generalized and exfoliative. Other miscellaneous reported reactions include alopecia [31], erythema multiforme [32] and a cheilostomatitis with ulceration of the lips. Peyronie’s disease has developed. Generalized pustular psoriasis [33] and pemphigus [34] have occurred. References 1 Taylor AEM, Hindson C, Wacks H. A drug eruption due to acebutolol with combined lichenoid and lupus erythematosus features. Clin Exp Dermatol 1982; 7: 219–21. 2 Record NB. Acebutolol-induced pleuropulmonary lupus syndrome. Ann Intern Med 1981; 95: 326–7. 3 Van Joost T, Middelkamp Hup H, Ros FE. Dermatitis as a side-effect of long-term topical treatment with certain beta-blocking agents. Br J Dermatol 1979; 101: 171–6.

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Chapter 75: Drug Reactions

4 Gawkrodger DJ, Beveridge GW. Psoriasiform reaction to atenolol. Clin Exp Dermatol 1984; 9: 92–4. 5 Henderson CA, Shamy HK. Atenolol-induced pseudolymphoma. Clin Exp Dermatol 1990; 15: 119–20. 6 Wolf R, Ophir J, Elman M, Krakowski A. Atenolol-induced cutaneous vasculitis. Cutis 1989; 43: 231–3. 7 White WB, Schulman P, McCabe EJ. Psoriasiform cutaneous eruptions induced by cetamolol hydrochloride. Arch Dermatol 1986; 122: 857–8. 8 Finlay AY, Waddington E, Savage RL et al. Cutaneous reactions to labetalol. BMJ 1978; i: 987. 9 Gange RW, Wilson Jones E. Bullous lichen planus caused by labetalol. BMJ 1978; i: 816–7. 10 Brown RC, Cooke M, Losowsky MS. SLE syndrome, probably induced by labetalol. Postgrad Med J 1981; 57: 189–90. 11 Neumann HAM, van Joost T, Westerhof W. Dermatitis as a side-effect of longterm metoprolol. Lancet 1979; ii: 745. 12 Neumann HAM, van Joost T. Adverse reactions of the skin to metoprolol and other beta-adrenergic-blocking agents. Dermatologica 1981; 162: 330–5. 13 Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis 1981; 28: 633–4. 14 Holt PJA, Waddington E. Oculocutaneous reaction to oxprenolol. BMJ 1975; ii: 539–40. 15 Levene GM, Gange RW. Eruption during treatment with oxprenolol. BMJ 1978; i: 784. 16 Gange RW, Levene GM. A distinctive eruption in patients receiving oxprenolol. Clin Exp Dermatol 1979; 4: 87–97. 17 MacFarlane DG, Settas L. Acute psoriatic arthropathy precipitated by oxprenolol. Ann Rheum Dis 1984; 43: 102–4. 18 Harrower ADB, Strong JA. Hyperpigmentation associated with oxprenolol administration. BMJ 1977; ii: 296. 19 Felix RH, Ive FA, Dahl MGC. Cutaneous and ocular reactions to practolol. BMJ 1974; iv: 321–4. 20 Wright P. Untoward effects associated with practolol administration: oculomucocutaneous syndrome. BMJ 1975; i: 595–8. 21 Furhoff A-K, Norlander M, Peterson C. Cross-sensitivity between practolol and other beta-blockers? BMJ 1976; i: 831. 22 Van Joost T, Crone RA, Overdijk AD. Ocular cicatricial pemphigoid associated with practolol therapy. Br J Dermatol 1976; 94: 447–50. 23 Søndergaard J, Wadskov S, Ærenlund-Jensen H, Mikkelsen HI. Aggravation of psoriasis and occurrence of psoriasiform cutaneous eruptions induced by practolol (Eraldin®). Acta Derm Venereol (Stockh) 1976; 56: 239–43. 24 Bonerandi J-J, Follana J, Privat Y. Apparition d’un psoriasis au cours d’un traitement par bêta-bloquants (Pindolol). Ann Dermatol Syphiligr 1976; 103: 604–6. 25 Bensaid J, Aldigier J-C, Gualde N. Systemic lupus erythematosus syndrome induced by pindolol. BMJ 1979; i: 1603–4. 26 Ærenlund-Jensen H, Mikkelsen HI, Wadskov S, Søndergaard J. Cutaneous reactions to propranolol (Inderal®). Acta Med Scand 1976; 199: 363–7. 27 Cochran REI, Thomson J, McQueen A, Beevers DG. Skin reactions associated with propranolol. Arch Dermatol 1976; 112: 1173–4. 28 Scribner MD. Propranolol therapy. Arch Dermatol 1977; 113: 1303. 29 Faure M, Hermier C, Perrot H. Accidents cutanés provoqués par le propranolol. Ann Dermatol Vénéréol 1979; 106: 161–5. 30 Hawk JLM. Lichenoid drug eruption induced by propranolol. Clin Exp Dermatol 1980; 5: 93–6. 31 Hilder RJ. Propranolol and alopecia. Cutis 1979; 24: 63–4. 32 Pimstone B, Joffe B, Pimstone N et al. Clinical response to long-term propranolol therapy in hyperthyroidism. S Afr Med J 1969; 43: 1203–5. 33 Hu C-H, Miller AC, Peppercorn R, Farber EM. Generalized pustular psoriasis provoked by propranolol. Arch Dermatol 1985; 121: 1326–7. 34 Godard W, Lambert D, Gavanou J, Chapuis J-L. Pemphigus induit après traitement par l’association propranolol–méprobamate. Ann Dermatol Vénéréol 1980; 107: 1213–6.

Antihypertensive drugs and vasodilators The dermatological side effects of antihypertensive agents have been reviewed [1].

Reference 1 Thestrup-Pedersen K. Adverse reactions in the skin from antihypertensive drugs. Dan Med Bull 1987; 34: 3–5.

ACE inhibitors In addition to dermatological problems, these drugs may be nephrotoxic, cause cough and electrolyte disturbances, and are teratogenic [1,2]. The overall incidence of adverse effects from ACE inhibitors is estimated at 28%, of which about 50% occur in the skin. Cutaneous reactions comprise life-threatening angio-oedema, pruritus, bullous eruptions, urticaria, other generalized rashes, photosensitivity and hair loss [3]. Angio-oedema has been reported with captopril, enalapril maleate and lisinopril [4–11]. The cumulative incidence of angio-oedema, almost always on the head and neck, has been estimated at 0.1–0.7% of cases treated; it usually occurs in the first week of treatment [5,9], although onset more than 6 weeks after starting treatment occurs in 20% of patients [6]. In addition, increased frequency, intensity and duration of bouts of angio-oedema have been recorded during long-term use of ACE inhibitors [7–9]. There may be cross-reactivity between drugs; angio-oedema has developed after substituting lisinopril for captopril [10]. Fatal angio-oedema occurred in a patient on captopril for 2 years [11]. Anaphylactoid reactions have been reported during haemodialysis with AN69 membranes in patients receiving ACE inhibitors; the role of bacterial contamination of dialysate is controversial [12–14]. Anaphylactoid reactions have also occurred with LDL apheresis with dextran sulphate [15]. ACE inhibitors have been implicated in both the exacerbation and induction of psoriasis [16–19]. ACE inhibitors most commonly produce a dose-related pruritic maculopapular eruption on the upper trunk and arms, especially with captopril (2.4–7%) and less with enalapril (1.5%), which is often transitory and rarely requires discontinuation of the drug. Urticaria, a pemphigoid-like reaction, a pityriasis rosea-like reaction, a lichenoid eruption, erythroderma, alopecia and Stevens–Johnson syndrome have been reported [20]. Captopril and enalapril may produce eruptions with histological similarities to mycosis fungoides [21]. An interstitial granulomatous drug reaction characterized by violaceous plaques with a predilection for skinfold areas and by histology resembling the diffuse interstitial phase of granuloma annulare without complete collagen necrobiosis has been documented with ACE inhibitors [22]. References 1 Ferner RE. Adverse effects of angiotensin-converting-enzyme inhibitors. Adverse Drug React Bull 1990; 141: 528–31. 2 Parish RC, Miller LJ. Adverse effects of angiotensin converting enzyme inhibitors: an update. Drug Saf 1992; 7: 14–31. 3 Steckelings UM, Artuc M, Wollschlager T et al. Angiotensin-converting enzyme inhibitors as inducers of adverse cutaneous reactions. Acta Derm Venereol (Stockh) 2001; 81: 321–5. 4 Orfan N, Patterson R, Dykewicz MS. Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA 1990; 264: 1287–9. 5 Slater EE, Merill DD, Guess HA et al. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 1988; 260: 967– 70. 6 Hedner T, Samuelsson O, Lindholm L et al. Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1992; 304: 941–6.

Important or widely prescribed drugs 7 Chin HL. Severe angioedema after long-term use of an angiotensin converting enzyme inhibitor. Ann Intern Med 1990; 112: 312. 8 Kozel MMA, Mekkes JR, Bos JD. Increased frequency and severity of angiooedema related to long-term therapy with angiotensin-converting enzyme inhibitor in two patients. Clin Exp Dermatol 1995; 20: 60–1. 9 Sabroe RA, Kobza Black A. Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema. Br J Dermatol 1997; 136: 153–8. 10 McElligott S, Perlroth M, Raish L. Angioedema after substituting lisinopril for captopril. Ann Intern Med 1992; 116: 426–7. 11 Jason DR. Fatal angioedema associated with captopril. J Forensic Sci 1992; 37: 1418–21. 12 Verresen L, Waer M, Vanrenterghem Y, Michielsen P. Angiotensin-convertingenzyme inhibitors and anaphylactoid reactions to high-flux membrane dialysis. Lancet 1990; 336: 1360–2. 13 Tielemans C, Madhoun P, Lenears M et al. Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int 1990; 38: 982–4. 14 Verresen L, Waer M, Vanrenterghem Y, Michielsen P. Anaphylactoid reactions, haemodialysis, and ACE inhibitors. Lancet 1991; 337: 1294. 15 Keller C, Grutzmacher P, Bahr F et al. LDL-apheresis with dextran sulphate and anaphylactoid reactions to ACE inhibitors. Lancet 1993; 341: 60–1. 16 Wolf R, Tamir A, Brenner S. Psoriasis related to angiotensin-converting enzyme inhibitors. Dermatologica 1990; 181: 51–3. 17 Coulter DM, Pillans PI. Angiotensin-converting enzyme inhibitors and psoriasis. NZ Med J 1993; 106: 392–3. 18 Tamir A, Wolf R, Brenner S. Exacerbation and induction of psoriasis by angiotensin-converting enzyme inhibitors. J Am Acad Dermatol 1994; 30: 1045. 19 Ikai K. Exacerbation and induction of psoriasis by angiotensin-converting enzyme inhibitors. J Am Acad Dermatol 1996; 32: 819. 20 Vollenweider Roten S, Mainetti C, Donath R, Saurat J-H. Enalapril-induced lichen planus-like eruption. J Am Acad Dermatol 1995; 32: 293–5. 21 Furness PN, Goodfield MJ, MacLennan KA et al. Severe cutaneous reactions to captopril and enalapril: histological study and comparison with early mycosis fungoides. J Clin Pathol 1986; 39: 902–7. 22 Perrin C, Lacour JP, Castanet J, Michiels JF. Interstitial granulomatous drug reaction with a histological pattern of interstitial granulomatous dermatitis. Am J Dermatopathol 2001; 23: 295–8.

Captopril. Dermatological complications occur in 4% [1] to 12% [2] of patients treated with captopril, and less commonly with other ACE inhibitors; side effects are more likely with renal impairment. Loss of sense of taste (ageusia), or a metallic taste, ulceration of the tongue and aphthous stomatitis [3] are reported. Early changes within the first months [4–6] include pruritus, urticaria [7] and angio-oedema, which occurs in about 1 in 1000 patients and may occasionally be fatal [8], and pityriasis rosea-like [9] and morbilliform rashes. These are dose dependent and have a good prognosis. Late changes [4–6] consist of pemphigus-like [10–12] and lichenoid [13–17] eruptions. SLE-like eruptions have been recorded [18,19]. Antinuclear antibodies may develop [20,21]. Oral changes may be due to a leukocytoclastic vasculitis [22], and a serum sickness-like syndrome has been induced [23]. Psoriasis has been reported to be exacerbated or triggered [24,25]. Severe reactions [26,27] have included exfoliative dermatitis [28–30], and marrow depression with neutropenia or agranulocytosis [31]. Lymphadenopathy may be induced [32]. Alopecia [33] and an acquired IgA deficiency [34] have been reported. The merits of skin testing in the prediction of captopril reactions have been discussed [35]. It has been postulated that some toxic effects are related to the presence of a sulphydryl group, as enalapril (another ACE inhibitor lacking this group) has been safely substituted in certain cases of captopril hypersensitivity [36].

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Cilazapril. Cilazapril had more neurological (mainly headache) but fewer skin reactions than the other ACE inhibitors, lisinopril, enalapril and captopril [37]. Enalapril. Enalapril produces rashes in approximately 1.4% of patients, requiring discontinuation in about 0.4% [38]. Toxic pustuloderma is recorded [38]. A single report of pemphigus foliaceus has appeared; part of the structure of this drug is identical to that of captopril, although it does not contain a sulphydryl group [39]. Bullous eruptions [40] and lichenoid eruptions [41] occur. Lisinopril [42]. Vasculitis has been recorded [43], as has pallor, flushing and oedema [44]. Ramipril. Superficial pemphigus [45] and Stevens–Johnson syndrome [46] are recorded. References 1 Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med 1988; 319: 1517–25. 2 Wilkin JK, Hammond JJ, Kirkendall WM. The captopril-induced eruption. A possible mechanism: cutaneous kinin potentiation. Arch Dermatol 1980; 116: 902–5. 3 Seedat YK. Aphthous ulcers of mouth from captopril. Lancet 1979; ii: 1297–8. 4 Clement M. Captopril-induced eruptions. Arch Dermatol 1981; 117: 525–6. 5 Luderer JR, Lookingbill DP, Schneck DW et al. Captopril-induced skin eruptions. J Clin Pharmacol 1982; 22: 151–9. 6 Daniel F, Foix C, Barbet M et al. Captopril-induced eruptions: occurrence over a three-year period. Ann Dermatol Vénéréol 1983; 110: 441–6. 7 Wood SM, Mann RD, Rawlins MD. Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. BMJ 1987; 294: 91–2. 8 Slater EE, Merrill DD, Guess HA et al. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 1988; 260: 967–70. 9 Wilkin JK, Kirkendall WM. Pityriasis rosea-like rash from captopril. Arch Dermatol 1982; 118: 186–7. 10 Parfrey PS, Clement M, Vandenburg MJ, Wright P. Captopril-induced pemphigus. BMJ 1980; 281: 194. 11 Katz RA, Hood AF, Anhalt GJ. Pemphigus-like eruption from captopril. Arch Dermatol 1987; 123: 20–1. 12 Korman NJ, Eyre RW, Stanley JR. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol 1991; 96: 273–6. 13 Reinhardt LA, Wilkin JK, Kirkendall WM. Lichenoid eruption produced by captopril. Cutis 1983; 31: 98–9. 14 Bravard P, Barbet M, Eich D et al. Éruption lichénoïde au captopril. Ann Dermatol Vénéréol 1983; 110: 433–8. 15 Flageul B, Foldes C, Wallach D et al. Captopril-induced lichen planus pemphigoides with pemphigus-like features. A case report. Dermatologica 1986; 173: 248–55. 16 Bretin N, Dreno B, Bureau B, Litoux P. Immunohistological study of captoprilinduced late cutaneous reactions. Dermatologica 1988; 177: 11–5. 17 Rotstein E, Rotstein H. Drug eruptions with lichenoid histology produced by captopril. Australas J Dermatol 1989; 30: 9–14. 18 Patri P, Nigro A, Rebora A. Lupus erythematosus-like eruption from captopril. Acta Derm Venereol (Stockh) 1985; 65: 447–8. 19 Sieber C, Grimm E, Follath F. Captopril and systemic lupus erythematosus syndrome. BMJ 1990; 301: 669. 20 Reidenberg MM, Case DB, Drayer DE et al. Development of antinuclear antibodies in patients treated with high doses of captopril. Arthritis Rheum 1984; 27: 579–81. 21 Kallenberg CGM. Autoantibodies during captopril treatment. Arthritis Rheum 1985; 28: 597–8. 22 Viraben R, Adoue D, Dupre A, Touron P. Erosions and ulcers of the mouth. Arch Dermatol 1982; 118: 959.

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23 Hoorntje SJ, Weening JJ, Kallenberg GGM et al. Serum-sickness-like syndrome with membranous glomerulopathy in a patient on captopril. Lancet 1979; ii: 1297. 24 Hauschild TT, Bauer R, Kreysel HW. Erstmanifestation einer eruptivexanthematischen Psoriasis vulgaris unter Captoprilmedikation. Hautarzt 1986; 37: 274–7. 25 Wolf R, Dorfman B, Krakowski A. Psoriasiform eruption induced by captopril and chlorthalidone. Cutis 1987; 40: 162–4. 26 Goodfield MJ, Millard LG. Severe cutaneous reactions to captopril. BMJ 1985; 290: 1111. 27 Furness PN, Goodfield MJ, MacLennan KA et al. Severe cutaneous reactions to captopril and enalapril: histological study and comparison with early mycosis fungoides. J Clin Pathol 1986; 39: 902–7. 28 Solinger AM. Exfoliative dermatitis from captopril. Cutis 1982; 29: 473–4. 29 O’Neill PG, Rajan N, Charlat ML, Bolli R. Captopril-related exfoliative dermatitis. Texas Med 1989; 85: 40–1. 30 Daniel F, Foix C, Barbet M et al. Toxidermies au captopril: incidences au cours d’un traitement de 1321 mois/patients. Ann Dermatol Vénéréol 1983; 110: 441–6. 31 Edwards CRW, Drury P, Penketh A, Damluji SA. Successful reintroduction of captopril following neutropenia. Lancet 1981; i: 723. 32 Åberg H, Mörlin C, Frithz G. Captopril-associated lymphadenopathy. BMJ 1981; 283: 1297–8. 33 Motel PJ. Captopril and alopecia: a case report and review of known cutaneous reactions in captopril use. J Am Acad Dermatol 1990; 23: 124–5. 34 Hammarström L, Smith CIE, Berg U. Captopril-induced IgA deficiency. Lancet 1991; 337: 436. 35 Smit AJ, van der Laan S, De Monchy J et al. Cutaneous reactions to captopril. Predictive values of skin tests. Clin Allergy 1984; 14: 413–9. 36 Gavras I, Gavras H. Captopril and enalapril. Ann Intern Med 1983; 98: 556–7. 37 Coulter DM. Short term safety assessment of cilazapril. NZ Med J 1993; 106: 497–9. 38 Ferguson JE, Chalmers RJ. Enalapril-induced toxic pustuloderma. Clin Exp Dermatol 1996; 21: 54–5. 39 Shelto RM. Pemphigus foliaceus associated with enalapril. J Am Acad Dermatol 1991; 24: 503–4. 40 Mullins PD, Choudhury SL. Enalapril and bullous eruptions. BMJ 1994; 309: 1411. 41 Vollenweider Roten S, Mainetti C, Donath R, Saurat J-H. Enalapril-induced lichen planus-like eruption. J Am Acad Dermatol 1995; 32: 293–5. 42 Horiuchi Y, Matsuda M. Eruptions induced by the ACE inhibitor, lisinopril. J Dermatol 1999; 26: 128–30. 43 Barlow RJ, Schulz EJ. Lisinopril-induced vasculitis. Clin Exp Dermatol 1988; 13: 117–20. 44 Fallowfield JM, Blenkinsopp J, Raza A et al. Post-marketing surveillance of lisinopril in general practice in the UK. Br J Clin Pract 1993; 47: 296–304. 45 Vignes S, Paul C, Flageul B, Dubertret L. Ramipril-induced superficial pemphigus. Br J Dermatol 1996; 135: 657–8. 46 Oskay T, Ozçelik T, Kutluay L. Stevens–Johnson syndrome associated with ramipril. Int J Dermatol 2003; 42: 580–1.

Angiotensin II receptor antagonists Sartans, angiotensin II receptor antagonists, have been implicated in the induction of psoriasis [1] and of Henoch–Schönlein purpura [2]. Candersartan has been implicated in erythema multiforme [3]. References 1 Marquart-Elbaz C, Grosshans E, Alt M, Lipsker D. Sartans, angiotensin II receptor antagonists, can induce psoriasis. Br J Dermatol 2002; 147: 617–8. 2 Brouard M, Piguet V, Chavaz P, Borradori L. Schönlein–Henoch purpura associated with losartan treatment and presence of antineutrophil cytoplasmic antibodies of x specificity. Br J Dermatol 2001; 145: 362–3. 3 Ejaz AA, Walsh JS, Wasiluk A. Erythema multiforme associated with candesartan cilexetil. South Med J 2004; 97: 614–5.

Calcium-channel blockers Calcium-channel blockers are commonly used as antihypertensive medications. Cutaneous reactions are comparatively rare and

have been reported in six per million prescriptions of nifedipine, 17 per million prescriptions of verapamil, and six per million prescriptions of diltiazem [1,2]. In one study, reactions to the dihydropyridine drugs (including nicardipine, nifedipine and nisoldipine), verapamil and diltiazem occurred after an average of 95 days (range 7 days to 10 years) [3]. These drugs have been associated with cutaneous reactions ranging from exanthems to severe adverse events [4]. The most common are ankle or pedal oedema (up to 30%), gingival hyperplasia (up to 21%) and flushing (up to 10%). Less common are facial or truncal telangiectasia, photosensitivity reactions, new-onset psoriasis (as well as exacerbation of it) [3], purpuric exanthems, pemphigoid manifestations, subacute cutaneous lupus erythematosus, gynaecomastia, erythromelalgia and oral ulcers [4]. Pruritus, maculopapular rashes, and urticaria/angio-oedema, alopecia and a hypersensitivity syndrome have been described with all these drugs, as have Stevens–Johnson syndrome and erythema multiforme; TEN has occurred with diltiazem. There is a suggestion that the more severe reactions are commoner with diltiazem. Peripheral oedema as a side effect is common with the dihydropyridine calcium antagonists, including nifedipine, nicardipine, isradipine and amlodipine; it is usually mild [5]. Amlodipine has caused pruritus [6], a lichenoid eruption [7] and photosensitivity presenting as telangiectasia [8]. Felodipine has also been associated with photodistributed telangiectasia [9]. References 1 Stern R, Khalsa JH. Cutaneous adverse reactions associated with calcium channel blockers. Arch Intern Med 1989; 149: 829–32. 2 Sadick NS, Katz AS, Schreiber TL. Angioedema from calcium channel blockers. J Am Acad Dermatol 1989; 21: 132–3. 3 Kitamura K, Kanasashi M, Suga C et al. Cutaneous reactions induced by calcium channel blockers: high frequency of psoriasiform eruptions. J Dermatol 1993; 20: 279–86. 4 Ioulios P, Charalampos M, Efrossini T. The spectrum of cutaneous reactions associated with calcium antagonists: a review of the literature and the possible etiopathogenic mechanisms. Dermatol Online J 2003; 9: 6. 5 Maclean D, MacConnachie AM. Selected side-effects: 1. Peripheral oedema with dihydropyridine calcium antagonists. Prescribers J 1991; 31: 4–6. 6 Orme S, da Costa D. Generalised pruritus associated with amlodipine. BMJ 1997; 315: 463. 7 Swale VJ, McGregor JM. Amlodipine-associated lichen planus. Br J Dermatol 2001; 144: 920–1. 8 Grabczynska SA, Cowley N. Amlodipine-induced photosensitivity presenting as telangiectasia. Br J Dermatol 2000; 142: 1255–6. 9 Silvestre JF, Albares P, Carnero L, Botella R. Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45: 323–4.

Diltiazem. Cutaneous reactions to diltiazem have been reviewed [1–3]. They include pruritic macular exanthem, toxic erythema with fever and occasionally facial angio-oedema [4–6], generalized cutaneous reactions [7], erythema multiforme [8], subcorneal pustular dermatosis, a generalized pustular dermatitis [9,10], a lichenoid photodistributed eruption with pigmentary incontinence [11], photodistributed hyperpigmentation [12,13], a photosensitive erythroderma [14], psoriasiform eruptions [2], exfoliative dermatitis in a patient with psoriasis [15], a subacute cutaneous LE-like syndrome [16], vasculitis [17] and vasculitic leg ulcers [18], recurrent nail dystrophy, hyperplastic gingivitis [19], and proptosis and periorbital oedema [20]. Generalized lymphadenopathy has

Important or widely prescribed drugs

occurred [21]. Patch tests may be positive in diltiazem reactions [5,6,10]. Dermatological cross-sensitivity between diltiazem and amlodipine is reported [22]. References 1 Kitamura K, Kanasashi M, Suga C et al. Cutaneous reactions induced by calcium channel blocker: high frequency of psoriasiform eruptions. J Dermatol 1993; 20: 279–86. 2 Knowles S, Gupta AK, Shear NH. The spectrum of cutaneous reactions associated with diltiazem: three cases and a review of the literature. J Am Acad Dermatol 1998; 38: 201–6. 3 Gonzalo Garijo MA, Pérez Calderón R, de Argila Fernández-Durán D, Rangel Mayoral JF. Cutaneous reactions due to diltiazem and cross reactivity with other calcium channel blockers. Allergol Immunopathol (Madr) 2005; 33: 238–40. 4 Wakeel RA, Gavin MP, Keefe M. Severe toxic erythema caused by diltiazem. BMJ 1988; 296: 1071. 5 Hammentgen R, Lutz G, Köhler U, Nitsch J. Makulopapulöses Exanthem bei Diltiazem-Therapie. Dtsch Med Wochenschr 1988; 113: 1283–5. 6 Romano A, Pietrantonio F, Garcovich A et al. Delayed hypersensitivity to diltiazem in two patients. Ann Allergy 1992; 69: 31–2. 7 Sousa-Basto A, Azenha A, Duarte ML, Pardal-Oliveira F. Generalized cutaneous reaction to diltiazem. Contact Dermatitis 1993; 29: 44–5. 8 Berbis P, Alfonso MJ, Levy JL, Privat Y. Diltiazem associated erythema multiforme. Dermatologica 1990; 179: 90. 9 Lambert DG, Dalac S, Beer F et al. Acute generalized exanthematous pustular dermatitis induced by diltiazem. Br J Dermatol 1988; 118: 308–9. 10 January V, Machet L, Gironet N et al. Acute generalized exanthematous pustulosis induced by diltiazem: value of patch testing. Dermatology 1998; 197: 274–5. 11 Scherschun L, Lee MW, Lim HW. Diltiazem-associated photodistributed hyperpigmentation: a review of 4 cases. Arch Dermatol 2001; 137: 179–82. 12 Boyer M, Katta R, Markus R. Diltiazem-induced photodistributed hyperpigmentation. Dermatol Online J 2003; 9: 10. 13 Kuykendall-Ivy T, Collier SL, Johnson SM. Diltiazem-induced hyperpigmentation. Cutis 2004; 73: 239–40. 14 Hashimoto M, Tanaka S, Horio T. Photosensibility due to diltiazem hydrochloride. Acta Dermatol 1979; 74: 181–4. 15 Larvijsen APM, Van Dijke C, Vermeer B-J. Diltiazem-associated exfoliative dermatitis in a patient with psoriasis. Acta Derm Venereol (Stockh) 1986; 66: 536–8. 16 Crowson AN, Magro CM. Diltiazem and subacute cutaneous lupus erythematosus-like lesions. N Engl J Med 1995; 333: 1429. 17 Sheehan-Dare RA, Goodfield MJ. Severe cutaneous vasculitis induced by diltiazem. Br J Dermatol 1988; 119: 134. 18 Carmichael AJ, Paul CJ. Vasculitic leg ulcers associated with diltiazem. BMJ 1988; 297: 562. 19 Giustiniani S, Robustelli della Cuna F, Marieni M. Hyperplastic gingivitis during diltiazem therapy. Int J Cardiol 1987; 15: 247–9. 20 Friedland S, Kaplan S, Lahav M, Shapiro A. Proptosis and periorbital edema due to diltiazem treatment. Arch Ophthalmol 1993; 111: 1027–8. 21 Scolnick B, Brinberg D. Diltiazem and generalized lymphadenopathy. Ann Intern Med 1985; 102: 558. 22 Baker BA, Cacchione JG. Dermatologic cross-sensitivity between diltiazem and amlodipine. Ann Pharmacother 1994; 28: 118–9.

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in one case confirmed by rechallenge [17], gynaecomastia [18], erysipelas-like lesions on the shins with erythematous plaques on the trunk [19], exfoliative dermatitis [20,21] and pemphigoid nodularis [22]. Verapamil. Erythema multiforme has been reported [23], as have gingival hyperplasia, gynaecomastia [24], alopecia, maculopapular eruptions, ecchymosis, vasculitis, urticaria and hyperkeratosis.

Nicorandil. Oral, anal and parastomal ulceration are documented [2–7].

References 1 Levesque H, Moore N, Wolfe LM, Courtoid H. Erythromelalgia induced by nicardipine (inverse Raynaud’s phenomenon?). BMJ 1989; 298: 1252–3. 2 Cribier B, Marquart-Elbaz C, Lipsker D et al. Chronic buccal ulceration induced by nicorandil. Br J Dermatol 1998; 138: 372–3. 3 Desruelles R, Bahadoran P, Lacour J-P et al. Giant oral aphthous ulcers induced by nicorandil. Br J Dermatol 1998; 138: 712–3. 4 Baker RP, Al-Kubati W, Atuf M et al. Nicorandil-induced severe perianal ulceration. Tech Coloproctol 2007; 11: 343–5. 5 Akbar F, Maw A, Bhowmick A. Anal ulceration induced by nicorandil. BMJ 2007; 335: 936–7. 6 Williams C, Tamuno P, Smith AJ et al. Perianal ulcerations and other cutaneous ulcerations complicating nicorandil therapy. J Am Acad Dermatol 2007; 56 (Suppl. 5): S116–7. 7 Egred M. Nicorandil-associated ulcerations. Eur J Gastroenterol Hepatol 2007; 19: 395–8. 8 Benini PL, Crosti C, Sala F et al. Gingival hyperplasia by nifedipine. Report of a case. Acta Derm Venereol (Stockh) 1985; 65: 362–5. 9 Bridgman JF. Erythematous edema of the legs due to nifedipine. BMJ 1978; i: 578. 10 Fisher JR, Padnick MB, Olstein S. Nifedipine and erythromelalgia. Ann Intern Med 1983; 98: 671–2. 11 Brodmerkel GJ Jr. Nifedipine and erythromelalgia. Ann Intern Med 1983; 99: 415. 12 Alcalay J, David M, Sandbank M. Cutaneous reactions to nifedipine. Dermatologica 1987; 175: 191–3. 13 Parish LC, Witkowski JA. Truncal morbilliform eruption due to nifedipine. Cutis 1992; 49: 113–4. 14 Alcalay J, David M. Generalized fixed drug eruptions associated with nifedipine. BMJ 1986; 292: 450. 15 Brenner S, Brau S. Vasculitis following nifedipine. Harefuah 1985; 108: 139–40. 16 Thomas SE, Wood ML. Photosensitivity reactions associated with nifedipine. BMJ 1986; 292: 992. 17 Zenarola P, Gatti S, Lomuto M. Photodermatitis due to nifedipine: report of 2 cases. Dermatologica 1991; 182: 196–8. 18 Clyne CAC. Unilateral gynaecomastia and nifedipine. BMJ 1986; 292: 380. 19 Leibovici V, Zlotogorski A, Heyman A et al. Polymorphous drug eruption due to nifedipine. Cutis 1988; 41: 367. 20 Reynolds NJ, Jones SK, Crossley J, Harman RRM. Exfoliative dermatitis due to nifedipine. Br J Dermatol 1989; 121: 401–4. 21 Mohammed KN. Nifedipine-induced exfoliative dermatitis and pedal edema. Ann Pharmacother 1994; 28: 967. 22 Ameen M, Harman KE, Black MM. Pemphigoid nodularis associated with nifedipine. Br J Dermatol 2000; 142: 575–7. 23 Kürkçüoglu N, Alaybeyi F. Erythema multiforme after verapamil treatment. J Am Acad Dermatol 1991; 24: 511–2. 24 Rodriguez LaG, Jick H. Risk of gynaecomastia associated with cimetidine, omeprazole, and other antiulcer drugs. BMJ 1994; 308: 503–6.

Nifedipine. Headache, tachycardia and flushing are common side effects. Gingival hyperplasia is well recognized [8]. Burning sensations, erythema, painful oedema and erythromelalgia have been described [9–12]. There have been isolated reports of a truncal morbilliform rash [13], fixed drug eruption [14], a generalized bullous eruption, vasculitis [15], purpura, photosensitivity [16]

Centrally acting antihypertensive drugs Clonidine. Hypersensitivity rashes occur in up to 5% of patients. A pityriasis rosea-like and LE-like syndrome, exacerbation of psoriasis [1] and an isolated instance of anogenital cicatricial pemphigoid [2] have been documented. Transdermally administered clonidine has caused allergic contact dermatitis, but also erythema,

Nicardipine. Erythromelalgia is recorded [1].

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scaling, vesiculation, excoriation, induration and dyspigmentation [3]. References 1 Wilkin JK. Exacerbation of psoriasis during clonidine therapy. Arch Dermatol 1981; 117: 4. 2 Van Joost T, Faber WR, Manuel HR. Drug-induced anogenital cicatricial pemphigoid. Br J Dermatol 1980; 102: 715–8. 3 Prisant LM. Transdermal clonidine skin reactions. J Clin Hypertens 2002; 4: 136–8.

Methyldopa. An eczematous eruption of discoid or seborrhoeic pattern is characteristic, is more likely to occur in previously eczematous subjects and persists until the drug is stopped [1]. Eczema of the palms and soles has also been described and may become widespread. The reaction is probably allergic as it may be dose related. Purpuric, erythematous and lichenoid rashes occur, sometimes in association with fever and other allergic symptoms [2,3]. Lichenoid eruptions may be ulcerated [4,5] and persistent ulceration of the tongue has been described. Fixed eruptions are very rare. An LE-like syndrome is documented [6,7] and an autoimmune haemolytic anaemia is well known [5]. Psoriasis may be precipitated. An extensive erythematous skin eruption, fever, lymphadenopathy and eosinophilia due to methyldopa, recurrent on re-exposure, has been recorded [8].

2 Koblenzer PJ, Baker J. Hypertrichosis lanuginosa associated with diazoxide therapy in prepubertal children: a clinicopathologic study. Ann NY Acad Sci 1968; 150: 373–82. 3 Menter MA. Hypertrichosis lanuginosa and a lichenoid eruption due to diazoxide therapy. Proc R Soc Med 1973; 66: 326–7. 4 Okun R, Russell RP, Wilson WR. Use of diazoxide with trichlormethiazide for hypertension. Arch Intern Med 1963; 112: 882–6.

Hydralazine. The LE-like syndrome due to this drug is well known [1–7]. Hydralazine binds to complement component C4 and inhibits its function; this may impair clearance of immune complexes, and predispose to development of an LE syndrome [6,7]. Orogenital ulceration may be part of the picture [8], and the syndrome has presented as a leg ulcer [9]. Cutaneous vasculitis may be severe and necrotizing [10,11]. An association between hydralazine-induced LE syndrome and the development of Sweet’s syndrome has been noted rarely [12]. Fixed drug eruption has been reported [13]. Characteristic lung changes are attributed to the drug [14].

Reference 1 Dewar HA, Peaston MJT. Three cases resembling polyarteritis nodosa arising during treatment with guanethidine. BMJ 1964; ii: 609–11.

References 1 Alarcon-Segovia D, Wakin KG, Worthington JW et al. Clinical and experimental studies on the hydralazine syndrome and its relationship to systemic lupus erythematosus. Medicine (Baltimore) 1967; 46: 1–33. 2 Batchelor JR, Welsh KI, Mansilla Tinoco R et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex upon susceptibility. Lancet 1980; i: 1107–9. 3 Dubroff LM, Reid R Jr, Papalian M. Molecular models for hydralazine-related systemic lupus erythematosus. Arthritis Rheum 1981; 24: 1082–5. 4 Perry HM Jr. Possible mechanisms of the hydralazine-related lupus-like syndrome. Arthritis Rheum 1981; 24: 1093–105. 5 Mansilla Tinoco R, Harland SJ, Ryan P et al. Hydralazine, antinuclear antibodies, and the lupus syndrome. BMJ 1982; 284: 936–9. 6 Sim E, Law S-KA. Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products. FEBS Lett 1985; 184: 323–7. 7 Sim E. Drug-induced immune complex disease. Complement Inflamm 1989; 6: 119–26. 8 Neville E, Graham PY, Brewis RA. Orogenital ulcers, SLE and hydralazine. Postgrad Med J 1981; 57: 378–9. 9 Kissin MW, Williamson RCN. Hydrallazine-induced SLE-like syndrome presenting as a leg ulcer. BMJ 1979; ii: 1330. 10 Bernstein RM, Egerton-Vernon J, Webster J. Hydrallazine-induced cutaneous vasculitis. BMJ 1980; 280: 156–7. 11 Peacock A, Weatherall D. Hydralazine-induced necrotising vasculitis. BMJ 1981; 282: 1121–2. 12 Servitje O, Ribera M, Juanola X, Rodriguez-Moreno J. Acute neutrophilic dermatosis associated with hydralazine-induced lupus. Arch Dermatol 1988; 123: 1435–6. 13 Sehgal VN, Gangwani OP. Hydralazine-induced fixed drug eruption. Int J Dermatol 1986; 25: 394. 14 Bass BH. Hydralazine lung. Thorax 1981; 36: 695–6.

Vasodilator antihypertensive drugs Diazoxide. Transient flushing is common. During long-term treatment, up to half the patients develop hypertrichosis without other signs of virilization [1]. A clinical picture resembling hypertrichosis lanuginosa may develop [2,3]. Oedema occurs in at least 10% of patients; photosensitivity is very uncommon but well recognized. Lichenoid [3,4] and other rashes occur rarely.

Minoxidil. This arterial vasodilator causes hypertrichosis, especially of the arms and face, which may be unacceptable to women [1,2]; the hair disappears slowly after the drug is withdrawn. Fluid retention may require diuretic therapy to control it. Thrombocytopenia [3], bullous eruptions [4], erythema multiforme or Stevens–Johnson syndrome [5] and pseudoacromegaly [6] have been described.

References 1 Burton JL, Schutt WH, Caldwell JW. Hypertrichosis due to diazoxide. Br J Dermatol 1975; 93: 707–11.

References 1 Burton JL, Marshall A. Hypertrichosis due to minoxidil. Br J Dermatol 1979; 101: 593–5.

References 1 Church R. Eczema provoked by methyldopa. Br J Dermatol 1974; 91: 373–8. 2 Stevenson CJ. Lichenoid eruptions due to methyldopa. Br J Dermatol 1971; 85: 600. 3 Burry JN, Kirk J. Lichenoid drug reaction from methyldopa. Br J Dermatol 1974; 91: 475–6. 4 Burry JN. Ulcerative lichenoid eruption from methyldopa. Arch Dermatol 1976; 112: 880. 5 Furhoff A-K. Adverse reactions with methyldopa: a decade’s reports. Acta Med Scand 1978; 203: 425–8. 6 Harrington TM, Davis DE. Systemic lupus-like syndrome induced by methyldopa therapy. Chest 1981; 79: 696–7. 7 Dupont A, Six R. Lupus-like syndrome induced by methyldopa. BMJ 1982; 285: 693–4. 8 Wolf R, Tamir A, Werbin N, Brenner S. Methyldopa hypersensitivity syndrome. Ann Allergy 1993; 71: 166–8.

Adrenergic neurone-blocking agents Guanethidine. Hypersensitivity eruptions are very rare but polyarteritis nodosa has been attributed to this drug [1].

Important or widely prescribed drugs 2 Ryckmanns F. Hypertrichose durch Minoxidil. Hautarzt 1980; 31: 205–6. 3 Peitzmann SJ, Martin C. Thrombocytopenia and minoxidil. Ann Intern Med 1980; 92: 874. 4 Rosenthal T, Teicher A, Swartz J, Boichis H. Minoxidil-induced bullous eruption. Arch Intern Med 1978; 138: 1856–7. 5 DiSantis DJ, Flanagan J. Minoxidil-induced Stevens–Johnson syndrome. Arch Intern Med 1981; 141: 1515. 6 Nguyen KH, Marks JG Jr. Pseudoacromegaly induced by the long-term use of minoxidil. J Am Acad Dermatol 2003; 48: 962–5.

Nitrate vasodilators Glyceryl and pentaerythritol tetranitrate. Reactions to nitrate vasodilators are rare, but erythroderma with cross-reactivity to glyceryl trinitrate has been caused by this drug [1]. Reference 1 Ryan FP. Erythroderma due to peritrate and glyceryl trinitrate. Br J Dermatol 1972; 87: 498–500.

Diuretics Carbonic anhydrase inhibitor Acetazolamide. This drug has caused hirsutism in a child [1]. Hypersensitivity reactions are rare. Reference 1 Weiss IS. Hirsutism after chronic administration of acetazolamide. Am J Ophthalmol 1974; 78: 327–8.

Loop diuretics Bumetanide. Occasional hypersensitivity rashes occur. Pseudoporphyria has been reported with this sulphonamide-derived drug [1]. Etacrynic acid (ethacrynic acid). A Henoch–Schönlein type of vasculitis has been documented. Furosemide (frusemide). Reactions are rare: only two patients of 3830 receiving this medication in one study developed cutaneous complications [2]. Phototoxic blistering has followed very high dosage (2.0 g/day) in chronic renal failure [3] but erythema multiforme [4,5], bullous pemphigoid [6,7], other bullous haemorrhagic eruptions [8] and an acquired blistering disorder with skin fragility [9] have apparently been precipitated by conventional dosage. The skin changes may mimic those of porphyria. Several cases of generalized exfoliative dermatitis have been documented. Anaphylaxis [10], a necrotizing vasculitis [11] and an eruption resembling Sweet’s syndrome [12] have been reported. Crossreactivity between furosemide, hydrochlorothiazide and sulphonamides is recorded, but the use of one of these drugs in a patient known to have allergy to another involves only low risk [13]. References 1 Leitao EA, Person JR. Bumetanide-induced pseudoporphyria. J Am Acad Dermatol 1990; 23: 129–30. 2 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63. 3 Burry JN, Lawrence JR. Phototoxic blisters from high frusemide dosage. Br J Dermatol 1976; 94: 493–9.

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4 Gibson TP, Blue P. Erythema multiforme and furosemide therapy. JAMA 1970; 212: 1709. 5 Zugerman C, La Voo EJ. Erythema multiforme caused by oral furosemide. Arch Dermatol 1980; 116: 518–9. 6 Fellner MI, Katz JM. Occurrence of bullous pemphigoid after furosemide therapy. Arch Dermatol 1976; 112: 75–7. 7 Castel T, Gratacos R, Castro J et al. Bullous pemphigoid induced by frusemide. Clin Exp Dermatol 1981; 6: 635–8. 8 Ebringer A, Adam WR, Parkin JD. Bullous haemorrhagic eruption associated with frusemide. Med J Aust 1969; 1: 768–71. 9 Kennedy AC, Lyell A. Acquired epidermolysis bullosa due to high dose frusemide. BMJ 1976; i: 1509–10. 10 Hansbrough JR, Wedner HJ, Chaplin DD. Anaphylaxis to intravenous furosemide. J Allergy Clin Immunol 1987; 80: 538–41. 11 Hendricks WM, Ader RS. Furosemide-induced cutaneous necrotizing vasculitis. Arch Dermatol 1977; 113: 375. 12 Cobb MW. Furosemide-induced eruption simulating Sweet’s syndrome. J Am Acad Dermatol 1989; 21: 339–43. 13 Sullivan TJ. Cross-reactions among furosemide, hydrochlorothiazide, and sulfonamides. JAMA 1991; 265: 120–1.

Potassium-sparing diuretics Spironolactone. This drug, which is also used for the treatment of acne vulgaris and hirsutism [1], may cause gynaecomastia [2–4], gastrointestinal upset, hyperkalaemia and rarely agranulocytosis [1]. Spironolactone has an antiandrogenic effect [4] and may result in loss of libido and impotence or menstrual irregularities. A maculopapular eruption [5], LE-like syndrome [6], annular LE [7], erythema annulare centrifugum [8] and a lichenoid eruption [9] have been seen. References 1 Shaw JC. Spironolactone in dermatologic therapy. J Am Acad Dermatol 1991; 24: 236–43. 2 Clarke E. Spironolactone therapy and gynecomastia. JAMA 1965; 193: 157–8. 3 Loriaux DL, Meuard R, Taylor A et al. Spironolactone and endocrine dysfunction. Ann Intern Med 1976; 85: 630–6. 4 Rose LI, Underwood RH, Newmark SR et al. Pathophysiology of spironolactoneinduced gynecomastia. Ann Intern Med 1977; 87: 398–403. 5 Gupta AK, Knowles SR, Shear NH. Spironolactone-associated cutaneous effects: a case report and a review of the literature. Dermatology 1994; 189: 402–5. 6 Uddin MS, Lynfield YL, Grosberg SJ, Stiefler R. Cutaneous reaction to spironolactone resembling lupus erythematosus. Cutis 1979; 24: 198–200. 7 Leroy D, Dompmartin A, Le Jean S et al. Toxidermie a l’aldactone® à type d’érytheme annulaire centrifuge lupique. Ann Dermatol Vénéréol 1987; 114: 1237–40. 8 Carsuzaa F, Pierre C, Dubegny M. Erytheme annulaire centrifuge à l’aldactone. Ann Dermatol Vénéréol 1987; 114: 375–6. 9 Downham TF III. Spironolactone-induced lichen planus. JAMA 1978; 240: 1138.

Thiazides and related diuretics Photosensitivity is uncommon, occurring in 1 in 1000 to 1 in 100 000 prescriptions [1–7]. Hydrochlorothiazide causes considerably more reactions than bendroflumethiazide (bendrofluazide). The mechanism is unknown, and both phototoxic [1,4,7] and photoallergic [2,3] mechanisms have been proposed. The commonest reaction is lichenoid [8], but petechial and erythematous eruptions may occur in exposed skin. Xerostomia has been reported, as has a vasculitis [9]. An eruption resembling subacute cutaneous LE has been described in patients taking a combination of hydrochlorothiazide and triamterene [10,11] and with hydrochlorothiazide alone [12]. Other side effects include hypokalaemia, short-term

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elevation of LDL cholesterol, impotence, a diabetogenic effect and exacerbation of gout [13]. Chlortalidone (chlorthalidone). Pseudoporphyria has been documented with this thiazide-related diuretic [14]. Psoriasis has been triggered in a patient also receiving captopril [15]. References 1 Diffey BL, Langtry J. Phototoxic potential of thiazide diuretics in normal subjects. Arch Dermatol 1989; 125: 1355–8. 2 Harber LC, Lashinsky AM, Baer RL. Photosensitivity to chlorothiazide and hydrochlorothiazide. N Engl J Med 1959; 261: 1378–81. 3 Torinuki W. Photosensitivity due to hydrochlorothiazide. J Dermatol 1980; 7: 293–6. 4 Rosén K, Swanbeck G. Phototoxic reactions from some common drugs provoked by a high-intensity UVA lamp. Acta Derm Venereol (Stockh) 1982; 62: 246–8. 5 Hawk JLM. Photosensitizing agents used in the United Kingdom. Clin Exp Dermatol 1984; 9: 300–2. 6 Robinson HN, Morison WL, Hood AF. Thiazide diuretic therapy and chronic photosensitivity. Arch Dermatol 1985; 121: 522–4. 7 Addo HA, Ferguson J, Frain-Bell W. Thiazide-induced photosensitivity: a study of 33 subjects. Br J Dermatol 1987; 116: 749–60. 8 Johnston GA. Thiazide-induced lichenoid photosensitivity. Clin Exp Dermatol 2002; 27: 670–2. 9 Björnberg A, Gisslén H. Thiazides: a cause of necrotising vasculitis? Lancet 1965; ii: 982–3. 10 Berbis P, Vernay-Vaisse C, Privat Y. Lupus cutané subaigu observé au cours d’un traitement par diurétiques thiazidiques. Ann Dermatol Vénéréol 1986; 113: 1245–8. 11 Darken M, McBurney EI. Subacute cutaneous lupus erythematosus-like drug eruption due to combination diuretic hydrochlorothiazide and triamterene. J Am Acad Dermatol 1988; 18: 38–42. 12 Reed BR, Huff JC, Jones SK et al. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49–51. 13 Orme M. Thiazides in the 1990s. The risk : benefit ratio still favours the drug. BMJ 1990; 300: 1168–9. 14 Baker EJ, Reed KD, Dixon SL. Chlorthalidone-induced pseudoporphyria: clinical and microscopic findings of a case. J Am Acad Dermatol 1989; 21: 1026–9. 15 Wolf R, Dorfman B, Krakowski A. Psoriasiform eruption induced by captopril and chlorthalidone. Cutis 1987; 40: 162–4.

2 Cernek PK. Dermal cellulitis: a hypersensitivity reaction from dobutamine hydrochloride. Ann Pharmacother 1994; 28: 964. 3 Green SI, Smith JW. Dopamine gangrene. N Engl J Med 1976; 294: 114. 4 Boltax RS, Dineen JP, Scarpa FJ. Gangrene resulting from infiltrated dopamine solution. N Engl J Med 1977; 296: 823. 5 Park JY, Kanzler M, Swetter SM. Dopamine-associated symmetric peripheral gangrene. Arch Dermatol 1997; 133: 247–8. 6 Ross M. Dopamine-induced localized cutaneous vasoconstriction and piloerection. Arch Dermatol 1991; 127: 586–7. 7 Merola B, Sarnacchiaro F, Colao A et al. Allergy to ergot-derived dopamine agonists. Lancet 1992; 339: 620. 8 Kalajian AH, Turpen KB, Donovan KO et al. Phenylephrine-induced microvascular occlusion syndrome in a patient with a heterozygous factor V Leiden mutation. Arch Dermatol 2007; 143: 1314–7.

Vasopressin This drug, when used intravenously for control of bleeding oesophageal varices or as a local vasoconstrictor agent, has caused cutaneous necrosis at sites of extravasation, and occasionally at distant sites, a bullous eruption [1]. Mottling, cyanosis, ecchymoses, bullae, ulcers and gangrene are often preceded by coolness and paraesthesiae [2]. References 1 Korenberg RJ, Landau-Price D, Penneys NS. Vasopressin-induced bullous disease and cutaneous necrosis. J Am Acad Dermatol 1986; 15: 393–8. 2 Maceyko RF, Vidimos AT, Steck WD. Vasopressin-associated cutaneous infarcts, alopecia, and neuropathy. J Am Acad Dermatol 1994; 31: 111–3.

Rutosides (Paroven) This mixture of oxerutins, used for relief of symptoms of oedema related to chronic venous insufficiency and for reduction of lymphoedema, has been associated with transient urticaria [1]. Reference 1 Anonymous. Paroven: not much effect in trials. Drug Ther Bull 1992; 30: 7–8.

Drugs acting on the respiratory system Miscellaneous cardiovascular drugs Dobutamine Two patients with local dermal hypersensitivity at the site of dobutamine hydrochloride injection, consisting of erythema, pruritus and phlebitis with or without bullae, have been described [1]. Dermal cellulitis has also been reported [2].

Dopamine This positive inotropic agent has caused local skin necrosis, due to extravasation at the site of an intravenous cannula [3], and acral gangrene secondary to distal vasoconstriction [4,5]. Localized piloerection and vasoconstriction proximal to the site of infusion have been documented [6]. Allergic reactions may occur [7]. Phenylephrine A microvascular occlusion syndrome in a patient with a heterozygous factor V Leiden mutation has been recorded [8]. References 1 Wu CC, Chen WJ, Cheng J. Local dermal hypersensitivity from dobutamine hydrochloride (Dobutrex solution) injection. Chest 1991; 99: 1547–8.

b-Agonists Albuterol Patchy erythema of the hands developed in a pregnant patient following infusion [1].

Salbutamol LE-like acral erythema developed after infusion in three pregnant patients with premature labour [2]. Salmeterol An urticarial reaction that recurred on challenge was attributed to this drug administered from a metered dose inhaler [3]. References 1 Morin Leport LRM, Loisel JC, Feuilly C. Hand erythema due to infusion of sympathomimetics. Br J Dermatol 1990; 122: 116–7. 2 Reygagne P, Lacour JP, Ortonne J-P. Palmar and plantar erythema due to infusion of sympathomimetics in pregnant women. Br J Dermatol 1991; 124: 210. 3 Hatton MQF, Allen MB, Mellor EJ, Cooke NJ. Salmeterol rash. Lancet 1991; 337: 1169–70.

Important or widely prescribed drugs

Aminophylline This drug is a mixture of theophylline and ethylenediamine. Urticaria, generalized erythema and exfoliative dermatitis have followed systemic administration, probably as a result of reactions to the ethylenediamine component rather than to theophylline itself [1]. Cross-reactions may occur with ethylenediamine in antihistamines and topical preparations [1,2]. Patch tests may or may not be positive [3].

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2 Divino Fiho JC. Allergic reactions to icodextrin in patients with renal failure. Lancet 2000; 355: 1364–5. 3 Valance A, Lebrun-Vignes B, Descamps V. Icodextrin cutaneous hypersensitivity: report of 3 psoriasiform cases. Arch Dermatol 2001; 137: 309–10. 4 Al-Hoqail IA, Crawford RI. Acute generalized exanthematous pustulosis induced by icodextrin. Br J Dermatol 2001; 145: 1026–7.

Drugs acting on the skeletal system Alendronate

References 1 Gibb W, Thompson PJ. Allergy to aminophylline. BMJ 1983; 287: 501. 2 Elias JA, Levinson AI. Hypersensitivity reactions to ethylenediamine in aminophylline. Am Rev Respir Dis 1981; 123: 550–2. 3 Kradjan WA, Lakshminarayan S. Allergy to aminophylline: lack of predictability by skin testing. Am J Hosp Pharm 1981; 38: 1031–3.

Miscellaneous respiratory system drugs Sodium cromoglicate (sodium cromoglycate) Hypersensitivity reactions are rare, but urticaria, angio-oedema and anaphylactic shock are recorded [1]. Reference 1 Scheffer AL, Rocklin RE, Goetzl EJ. Immunologic components of hypersensitivity reactions to cromolyn sodium. N Engl J Med 1975; 293: 1220–4.

Pseudoephedrine This drug is present in nasal decongestants and has caused a fixed drug eruption [1–3], recurrent pseudoscarlatina [4,5], allergic reactions [6], systemic contact dermatitis [7] and a reaction simulating recurrent toxic shock syndrome [8]. References 1 Shelley WB, Shelley ED. Nonpigmenting fixed drug reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetra-hydrozoline. J Am Acad Dermatol 1987; 17: 403–7. 2 Hauken M. Fixed drug eruption and pseudoephedrine. Ann Intern Med 1994; 120: 442. 3 Quan MB, Chow WC. Nonpigmenting fixed drug eruption after pseudoephedrine. Int J Dermatol 1996; 35: 367–70. 4 Taylor BJ, Duffill MB. Recurrent pseudo-scarlatina and allergy to pseudoephedrine hydrochloride. Br J Dermatol 1988; 118: 827–9. 5 Rochina A, Burches E, Morales C et al. Adverse reaction to pseudoephedrine. J Invest Allergol Clin Immunol 1995; 5: 235–6. 6 Heydon J, Pillans P. Allergic reaction to pseudoephedrine. NZ Med J 1995; 108: 112–3. 7 Tomb RR, Lepoittevin JP, Espinassouze F et al. Systemic contact dermatitis from pseudoephedrine. Contact Dermatitis 1991; 24: 86–8. 8 Cavanah DK, Ballas ZK. Pseudoephedrine reaction presenting as recurrent toxic shock syndrome. Ann Intern Med 1993; 119: 302–3.

Drugs acting on the renal system Icodextrin This osmotic agent used in peritoneal dialysis has caused a variety of allergic reactions [1,2], a psoriasiform eruption limited to the palms and soles [3], and acute generalized exanthematous pustulosis [4]. References 1 Goldsmith D, Jayawardene S, Sabharawal N, Cooney K. Allergic reactions to the polymeric glucose-based peritoneal dialysis fluid icodextrin in patients with renal failure. Lancet 2000; 355: 897.

This drug for osteoporosis has caused urticaria [1] and a gyrate erythema [2].

Other bisphosphonates Symptoms of influenza-like illness have been associated with both oral and intravenous bisphosphonates. Osteonecrosis of the jaw has also been associated with intravenous bisphosphonate treatment, as for metastatic bone disease [3,4]. Earlier generation intravenous bisphosphonates (e.g. etidronate) were associated with acute renal failure, but late-generation intravenous bisphosphonates (i.e. ibandronate) have a better safety profile. References 1 Kontoleon P, Ilias I, Stavropoulos PG, Papapetrou PD. Urticaria after administration of alendronate. Acta Derm Venereol (Stockh) 2000; 80: 398. 2 High WA, Cohen JB, Wetherington W, Cockerell CJ. Superficial gyrate erythema as a cutaneous reaction to alendronate for osteoporosis. J Am Acad Dermatol 2003; 48: 945–6. 3 Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf 2007; 30: 755–63. 4 Diel IJ, Bergner R, Grötz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol 2007; 5: 475–82.

Drugs for erectile dysfunction Sildenafil (Viagra) A lichenoid reaction is reported [1]. Reference 1 Goldman BD. Lichenoid drug reaction due to sildenafil. Cutis 2000; 65: 282–3.

Metals and metal antagonists Metals Arsenic Features of acute [1] and chronic [2] arsenic poisoning have been reviewed. Bullous eruptions, photosensitivity, exfoliative dermatitis, erythroderma with pustulation, and alopecia may be acute manifestations of arsenic toxicity. Occupational exposure may occur, especially in agriculture. Inorganic arsenic is sometimes present in Chinese proprietary medicines [2]. Fowler’s solution (containing 1% potassium arsenite) and sodium arsenate were used in the past for psoriasis; as little as 0.19 g has been carcinogenic and the interval between exposure and tumour induction may be as long as 47 years [3]. Subjects with an abnormally high retention of ingested arsenic may be at particular risk [4]. The cutaneous manifestations of arsenic exposure, including macular pigmentation, palmoplantar punctate keratoses, basal cell and squamous cell carcinomas, are well known [2–11]. Keratoses and

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tumours may be present without pigmentation. In one series of patients, there was a dose-related development of palmar and plantar keratoses in 40%, and carcinomas of the skin in 8%, of patients who received arsenic in the form of Fowler’s solution for 6–26 years; the minimum latent period before development of keratoses was 2.5 years, and the average was 6 years [5]. In another series, Bowen’s disease occurred within 10 years and invasive carcinomas within 20 years [9]. The lag times for development of keratoses, Bowen’s disease and squamous cell cancer were, respectively, 28, 39 and 41 years in another series [2]. Arsenic contamination of well water in Taiwan resulted in numerous affected individuals with arsenical keratoses and cutaneous carcinomas [7]. Carcinomas may arise in the arsenical keratoses [7]. Groundwater contamination leads to an endemic problem [12,13]. Cutaneous electron microscopic changes are said to be characteristic [10]. The diagnostic significance of the skin arsenic content is disputed. A 42-year-old man who took arsenic for 35 years for psoriasis developed melanoderma, keratoses, muscular dystrophies, hyperlipidaemia, testicular atrophy, gynaecomastia, skin tumours and an obliterating angiitis of leg vessels, which led to amputation [6]. The role of arsenic in causing internal malignancy is the subject of controversy [9,14,15]. References 1 Bartolomé B, Córdoba S, Nieto S et al. Acute arsenic poisoning: clinical and histopathological features. Br J Dermatol 1999; 141: 1106–9. 2 Wong SS, Tan KC, Goh CL. Cutaneous manifestations of chronic arsenicism: review of seventeen cases. J Am Acad Dermatol 1998; 38: 179–85. 3 Evans S. Arsenic and cancer. Br J Dermatol 1977; 97 (Suppl. 15): 13–4. 4 Bettley FR, O’Shea JA. The absorption of arsenic and its relation to carcinoma. Br J Dermatol 1975; 92: 563–8. 5 Fierz U. Katamnestische Untersuchungen über die Nebenwirkungen der Therapie mit anorganischem Arsen bei Hautkrankheiten. Dermatologica 1965; 131: 41–58. 6 Meyhofer W, Knoth W. Über die Auswirkung einer langjährigen antipsoriatischen Arsentherapie auf mehrere Organe unter besonderer Berücksichtigung andrologischer Befunde. Hautarzt 1966; 117: 309–13. 7 Yeh S. Skin cancer in chronic arsenicism. Hum Pathol 1973; 4: 469–85. 8 Weiss J, Jänner M. Multiple Basaliome und Menigiom nach mehrjähriger Arsentherapie. Hautarzt 1980; 31: 654–6. 9 Miki Y, Kawatsu T, Matsuda K et al. Cutaneous and pulmonary cancers associated with Bowen’s disease. J Am Acad Dermatol 1982; 6: 26–31. 10 Ohyama K, Sonoda K, Kuwahara H. Electron microscopic observations of arsenical keratoses and Bowen’s disease associated with chronic arsenicism. Dermatologica 1982; 64: 161–6. 11 Ratnam KV, Espy MJ, Muller SA et al. Clinicopathologic study of arsenic-induced skin lesions: no definite association with human papillomavirus. J Am Acad Dermatol 1992; 27: 120–2. 12 Woollons A, Russell-Jones R. Chronic endemic hydroarsenicism. Br J Dermatol 1998; 139: 1092–6. 13 Kurokawa M, Ogata K, Idemori M et al. Investigation of skin manifestations of arsenicism due to intake of arsenic-contaminated groundwater in residents of Samta, Jessore, Bangladesh. Arch Dermatol 2001; 137: 102–3. 14 Reymann F, Møller R, Nielsen A. Relationship between arsenic intake and internal malignant neoplasms. Arch Dermatol 1978; 114: 378–81. 15 Callen JP, Headington J. Bowen’s and non-Bowen’s squamous intraepidermal neoplasia of the skin. Relationship to internal malignancy. Arch Dermatol 1980; 116: 422–6.

Gold The use of gold in rheumatoid arthritis is associated with a 23–30% incidence of reactions [1–3]; most of these are minor, but about

15% may be severe or even fatal [4]. Possession of the HLA-DR3 and HLA-B8 phenotypes reportedly predisposes to thrombocytopenia, leukopenia and nephrotoxicity, HLA-DR4 is linked to leukopenia, and HLA-B7 is associated with cutaneous adverse reactions [2]. In another study, HLA-DR5 was significantly associated with mucocutaneous lesions, whereas HLA-B8 and HLADR3 antigens were associated with proteinuria in rheumatoid arthritis patients after gold therapy; HLA-DR7 was negatively associated with reactions and may confer protection, and HLAB27 was associated with chrysiasis due to gold therapy [5]. A further study showed that gold dermatitis in patients with rheumatoid arthritis was associated with HLA-B35 and disease duration [6]. Antibodies to the Ro 52-kDa antigen are associated with skin eruptions in rheumatoid arthritis patients treated with gold [7]. Rashes and mouth ulcers are common [1,2,8–13], representing about 50% of all complications with parenteral gold and 35% of those with oral gold. Localized or generalized pruritus is an important warning sign of potential toxicity. Gold reactions may simulate exanthematic eruptions [14], erythema annulare centrifugum [15], seborrhoeic dermatitis or lichen planus [16,17]; a mixture of these patterns, sometimes with discoid eczematoid lesions, is characteristic. Lichen planus is often of the hypertrophic variety, especially on the scalp, and severe and irreversible alopecia may follow [18]. There may be striking and persistent postinflammatory hyperpigmentation. Permanent nail dystrophy has followed onycholysis [19]. Yellow nails have been described [20]. In one study, eczematous or lichenoid rashes persisted up to 11 months after cessation of therapy [21]. Histology was characterized by a sparse dermal perivascular infiltrate, predominantly of CD4+ HLA-DR-positive helper T lymphocytes, an increase in the number of dermal Langerhans’ cells and epidermal macrophagelike cells, and Langerhans’ cell apposition to mononuclear cells. A patient with a lichenoid and seborrhoeic dermatitis-like rash on gold sodium thiomalate therapy had a positive intradermal test to gold thiomalate; patch tests were positive to thiomalate (the thiol carrier of gold thiomalate) but negative to gold itself [22]. Interestingly, the same patient subsequently developed a seborrhoeic dermatitis-like eruption, but not a lichenoid eruption, while on auranofin; this time, patch tests were positive to both auranofin and gold. A previous contact dermatitis from gold jewellery may be reactivated [23]. Other reactions documented include erythema nodosum [24], severe hypersensitivity reactions [25], vasculitis [26], polyarteritis, an SLE-like syndrome, generalized exfoliative dermatitis and TEN. Psoriasis was reported to be exacerbated in a patient with arthritis treated with gold [27]. Prolonged administration of gold may cause a distinct grey, blue or purple pigmentation of exposed skin (chrysiasis), which is a dose-dependent reaction that occurs above a threshold of 20 mg/ kg; gold granules are seen within dermal endothelial cells and macrophages [28–32]. Even in the absence of pigmentation, gold can be detected histochemically in the skin up to 20 years after therapy. Localized argyria with chrysiasis has been caused by implanted acupuncture needles [33]. An unusual late cutaneous reaction involved the appearance of widespread keloid-like angiofibromatoid lesions [34].

Important or widely prescribed drugs

A benign vasodilatory ‘nitritoid’ reaction, consisting of flushing, light-headedness and transient hypotension, may occur immediately after the first injection of gold [2,35]. It occurs in roughly 5% of patients taking gold sodium thiomalate. Non-vasomotor effects, including arthralgia, myalgia and constitutional symptoms within the first 24 h, are recognized. Mucous membrane symptoms include loss of taste, metallic taste, stomatitis, glossitis and diarrhoea. Punctate stomatitis may occur with or without skin lesions. Gold is also deposited in the cornea and may cause a keratitis with ulceration. A polyneuropathy is recorded. In general, auranofin is less toxic than intramuscular gold [2]. Eosinophilia is common and may sometimes herald another complication; serum IgE may be raised [36]. Other immunological reactions are rare, although pulmonary fibrosis is recorded [37]. Blood dyscrasias, especially thrombocytopenic purpura, and occasionally fatal neutropenia or aplastic anaemia occur in a small proportion of cases and usually present within the first 6 months of therapy. Jaundice occurs in about 3% of cases, and may result from idiosyncratic intrahepatic cholestasis [38]. Proteinuria and renal damage are well known. References 1 Thomas I. Gold therapy and its indications in dermatology. A review. J Am Acad Dermatol 1987; 16: 845–54. 2 Pullar T. Adverse reactions profile: 1. Gold. Prescribers J 1991; 31: 22–6. 3 Lemmel EM. Comparison of pyritinol and auranofin in the treatment of rheumatoid arthritis. The European Multicentre Study Group. Br J Rheumatol 1993; 32: 375–82. 4 Girdwood RH. Death after taking medicaments. BMJ 1974; i: 501–4. 5 Rodriguez-Perez M, Gonzalez-Dominguez J, Mataran L et al. Association of HLA-DR5 with mucocutaneous lesions in patients with rheumatoid arthritis receiving gold sodium thiomalate. J Rheumatol 1994; 21: 41–3. 6 van Gestel A, Koopman R, Wijnands M et al. Mucocutaneous reactions to gold: a prospective study of 74 patients with rheumatoid arthritis. J Rheumatol 1994; 21: 1814–9. 7 Tishler M, Nyman J, Wahren M, Yaron M. Anti-Ro (SSA) antibodies in rheumatoid arthritis patients with gold-induced side effects. Rheumatol Int 1997; 17: 133–5. 8 Almeyda J, Baker H. Drug reactions XII. Cutaneous reactions to anti-rheumatic drugs. Br J Dermatol 1970; 83: 707–11. 9 Penneys NS, Ackerman AB, Gottlieb NL. Gold dermatitis: a clinical and histopathological study. Arch Dermatol 1974; 109: 372–6. 10 Penneys NS. Gold therapy: dermatologic uses and toxicities. J Am Acad Dermatol 1979; 1: 315–20. 11 Webster CG, Burnett JW. Gold dermatitis. Cutis 1994; 54: 25–8. 12 Lizeaux-Parmeix V, Bedane C, Lavignac C et al. Reactions cutanées aux sels d’or. Ann Dermatol Vénéréol 1994; 121: 793–7. 13 Laeijendecker R, van Joost T. Oral manifestations of gold allergy. J Am Acad Dermatol 1994; 30: 205–9. 14 Möller H, Björkner B, Bruze M. Clinical reactions to systemic provocation with gold sodium thiomalate in patients with contact allergy to gold. Br J Dermatol 1996; 135: 423–7. 15 Tsuji T, Nishimura M, Kimura S. Erythema annulare centrifugum associated with gold sodium thiomalate therapy. J Am Acad Dermatol 1992; 27: 284–7. 16 Lasarowa AZ, Tsankov NK, Stoimenov AP. Lichenoide Eruptionen nach Goldtherapie. Bericht uber zwei Falle. Hautarzt 1992; 43: 514–6. 17 Russell MA, King LE Jr, Boyd AS. Lichen planus after consumption of a goldcontaining liquor. N Engl J Med 1996; 334: 603. 18 Burrows NP, Grant JW, Crisp AJ, Roberts SO. Scarring alopecia following gold therapy. Acta Derm Venereol (Stockh) 1994; 74: 486. 19 Voigt K, Holzegel K. Bleibende nagelveränderungen nach Goldtherapie. Hautarzt 1977; 28: 421–3. 20 Roest MAB, Ratnavel R. Yellow nails associated with gold therapy for rheumatoid arthritis. Br J Dermatol 2001; 145: 855–6.

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21 Ranki A, Niemi K-M, Kanerva L. Clinical, immunohistochemical, and electronmicroscopic findings in gold dermatitis. Am J Dermatopathol 1989; 11: 22–8. 22 Ikezawa Z, Kitamura K, Nakajima H. Gold sodium thiomalate (GTM) induces hypersensitivity to thiomalate, the thiol carrier of GTM. J Dermatol 1990; 17: 550–4. 23 Rennie T. Local gold toxicity. BMJ 1976; ii: 1294. 24 Stone RL, Claflin A, Penneys NS. Erythema nodosum following gold sodium thiomalate therapy. Arch Dermatol 1973; 107: 603–4. 25 Walzer RA, Feinstein R, Shapiro L, Einbinder J. Severe hypersensitivity reaction to gold. Positive lymphocyte transformation test. Arch Dermatol 1972; 106: 231–4. 26 Roenigk HR, Handel D. Gold vasculitis. Arch Dermatol 1974; 109: 253–5. 27 Smith DL, Wernick R. Exacerbation of psoriasis by chrysotherapy. Arch Dermatol 1991; 127: 268–70. 28 Beckett VL, Doyle JA, Hadley GA et al. Chrysiasis resulting from gold therapy in rheumatoid arthritis: identification of gold by X-ray microanalysis. Mayo Clin Proc 1982; 57: 773–5. 29 Pelachyk IM, Bergfeld WF, McMahon JT. Chrysiasis following gold therapy for rheumatoid arthritis. J Cutan Pathol 1984; 11: 491–4. 30 Smith RW, Leppard B, Barnett NL et al. Chrysiasis revisited: a clinical and pathological study. Br J Dermatol 1995; 133: 671–8. 31 Fleming CJ, Salisbury ELC, Kirwan P et al. Chrysiasis after low-dose gold and UV light exposure. J Am Acad Dermatol 1996; 34: 349–51. 32 Keen CE, Brady K, Kirkham N, Levison DA. Gold in the dermis following chrysotherapy: histopathology and microanalysis. Histopathology 1993; 23: 355–60. 33 Suzuki H, Baba S, Uchigasaki S, Murase M. Localized argyria with chrysiasis caused by implanted acupuncture needles. Distribution and chemical forms of silver and gold in cutaneous tissue by electron microscopy and X-ray microanalysis. J Am Acad Dermatol 1993; 29: 833–7. 34 Herbst WM, Hornstein OP, Grießmeyer G. Ungewöhnliche kutane Angiofibromatose nach Goldtherapie einer primär chronischen Polyarthritis. Hautarzt 1989; 40: 568–72. 35 Arthur AB, Klinkhoff A, Teufel A. Nitritoid reactions: case reports, review, and recommendations for management. J Rheumatol 2001; 28: 2209–12. 36 Davis P, Ezeoke A, Munro J et al. Immunological studies on the mechanism of gold hypersensitivity reactions. BMJ 1973; iii: 676–8. 37 Morley TF, Komansky HJ, Adelizzi RA et al. Pulmonary gold toxicity. Eur J Respir Dis 1984; 65: 627–32. 38 Favreau M, Tannebaum H, Lough J. Hepatic toxicity associated with gold therapy. Ann Intern Med 1977; 87: 717–9.

Iron Iron-induced brownish discoloration has been noted at the site of local injection (local siderosis) [1]. Reference 1 Bork K. Lokalisierte kutane Siderose nach intramuskulären Eiseninjekition. Hautarzt 1984; 35: 598–9.

Mercury Skin manifestations of mercury exposure have been reviewed [1,2]. Mercury-containing teething powders have long been banned, but occasional occupational or environmental exposure can occur. Mercury amalgam in dental fillings has caused buccal pigmentation. Stomatitis may occur as a toxic reaction. Allergic reactions may be scarlatiniform or morbilliform, and can progress to generalized exfoliative dermatitis. Eczema is recorded [3]. Pink disease or acrodynia, a distinctive pattern of reaction to chronic exposure to mercury in young infants and children, is now very rare [4]. Painful extremities, pinkish acral discoloration, peeling of the palms and soles, gingivitis and various systemic complications may occur. Acrodynia developed in a child following inhalation of mercury-containing vapours from phenyl-mercuric acetate

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contained in latex paint [5]. A mercury-containing drug given for 3 weeks to a patient with long-standing pustular psoriasis of the palms was associated with development of generalized pustular psoriasis [6]. (See also exogenous ochronosis from topical mercurycontaining preparations, p. 75.165.) Cutaneous granulomas are recorded [1], and a nodular reaction occurred after intake of a duck soup that contained metallic mercury for a neck abscess 18 years previously [7]. References 1 Boyd AS, Seger D, Vannucci S et al. Mercury exposure and cutaneous disease. J Am Acad Dermatol 2000; 43: 81–90. 2 Chan MHM, Cheung RCK, Chan IHS, Lam CWK. An unusual case of mercury intoxication. Br J Dermatol 2001; 144: 192–4. 3 Adachi A, Horikawa T, Takashima T, Ichihashi M. Mercury-induced nummular eczema. J Am Acad Dermatol 2000; 43: 383–5. 4 Dinehart SM, Dillard R, Raimer SS et al. Cutaneous manifestations of acrodynia (pink disease). Arch Dermatol 1988; 124: 107–9. 5 Anonymous. From the MMWR. Mercury exposure from interior latex paint: Michigan. Arch Dermatol 1990; 126: 577. 6 Wehner-Caroli J, Scherwitz C, Schweinsberg F, Fierlbeck G. Exazerbation einer Psoriasis pustulosa bei Quecksilber-Intoxikation. Hautarzt 1994; 45: 708–10. 7 June JB, Min PK, Kim DW et al. Cutaneous nodular reaction to oral mercury. J Am Acad Dermatol 1997; 37: 131–3.

Silver Ingestion of silver or topical application of silver preparations to the oral mucosa or upper respiratory tract can produce slate-blue discoloration, especially of exposed skin, including oral and conjunctival mucosae [1–8]. Argyria localized to the left hand occurred in an antique restorer due to polishing silver [9]. Scar-localized argyria is recorded following application of topical silver sulfadiazine cream [10]. Topical application may also cause systemic argyria, in which visceral organs are also discoloured [11]. Localized argyria can result when the backs of earrings become embedded [12]. In some patients, the nail beds of the fingers but not the toes may show bluish discoloration [13]. Silver granules are found free within the dermis; melanin may be increased in the epidermis or within melanophages [14–16]. References 1 Pariser RJ. Generalized argyria. Clinicopathologic features and histochemical studies. Arch Dermatol 1978; 114: 373–7. 2 Reynold J-L, Stoebner P, Amblard P. Argyrie cutanée. Étude en microscopie electronique et en microanalyse X de 4 cas. Ann Dermatol Vénéréol 1980; 107: 251–5. 3 Johansson EA, Kanerva L, Niemi K-M et al. Generalized argyria with low ceruloplasmin and copper levels in the serum. A case report with clinical and microscopical findings and a trial of penicillamine treatment. Clin Exp Dermatol 1982; 7: 169–76. 4 Pezzarossa E, Alinovi A, Ferrari C. Generalized argyria. J Cutan Pathol 1983; 10: 361–3. 5 Gherardi R, Brochard P, Chamak B et al. Human generalized argyria. Arch Pathol Lab Med 1984; 108: 181–2. 6 Jurecka W. Generalisierte Argyrose. Hautarzt 1986; 37: 628–31. 7 Mittag H, Knecht J, Arnold R et al. Zur Frage der Argyrie. Ein klinische, analytisch-chemische und mikromorphologische Untersuchung. Hautarzt 1987; 38: 670–7. 8 Tanner LS, Gross DJ. Generalized argyria. Cutis 1990; 45: 237–9. 9 Kapur N, Landon G, Yu RC. Localized argyria in an antique restorer. Br J Dermatol 2001; 144: 191–2. 10 Fisher NM, Marsh E, Lazova R. Scar-localized argyria secondary to silver sulfadiazine cream. J Am Acad Dermatol 2003; 49: 730–2.

11 Marshall IP, Schneider RP. Systemic argyria secondary to topical silver nitrate. Arch Dermatol 1977; 113: 1077–9. 12 van den Nieuwenhijsen IJ, Calame JJ, Bruynzeel DP. Localized argyria caused by silver earrings. Dermatologica 1988; 177: 189–91. 13 Plewig G, Lincke H, Wolff HH. Silver-blue nails. Acta Derm Venereol (Stockh) 1977; 57: 413–9. 14 Hönigsmann H, Konrad K, Wolff K. Argyrose (Histologie und Ultrastruktur). Hautarzt 1973; 24: 24–30. 15 Shelley WB, Shelley ED, Burmeister V. Argyria: the intradermal ‘photograph’, a manifestation of passive photosensitivity. J Am Acad Dermatol 1987; 16: 211–7. 16 Sato S, Sueki H, Nishijima A. Two unusual cases of argyria: the application of an improved tissue processing method for X-ray microanalysis of selenium and sulphur in silver-laden granules. Br J Dermatol 1999; 140: 158–63.

Metal antagonists Deferoxamine (desferrioxamine) Itching, erythema and urticaria are occasionally seen [1]. An indurated erythema with oedema lasting 2 weeks has been reported following infusion of this drug [2]. References 1 Bousquet J, Navarra M, Robert G et al. Rapid desensitisation for desferrioxamine anaphylactoid reactions. Lancet 1983; ii: 859–60. 2 Venencie P-Y, Rain B, Blanc A, Tertian G. Toxidermie a la déféroxamine (Desféral). Ann Derm Vénéréol 1988; 115: 1174.

Penicillamine There is a fourfold increase in toxicity with this drug in patients with rheumatoid arthritis who have a genetically determined poor capacity to sulphoxidate the structurally related mucolytic agent carbocysteine [1,2]. In addition, penicillamine toxicity is independently associated with HLA phenotype [1–3]. HLA-DR3 and HLA-B8 are associated with renal toxicity, HLA-DR3, HLA-B7 and HLA-DR2 with haematological toxicity, and HLA-A1 and HLADR4 with thrombocytopenia. Cutaneous adverse reactions are linked to HLA-DRw6. Anti-Ro(SSA)-positive patients with rheumatoid arthritis more often developed rashes and acute febrile reactions [4]. The cutaneous side effects of this chelating agent comprise three distinct types: (i) acute hypersensitivity reactions occurring early during treatment; (ii) late reactions including disturbances of autoimmune mechanisms leading to pemphigus foliaceus or erythematosus and cicatricial pemphigoid; and (iii) lathyrogenic effects on connective tissue [2,5–9]. Hypersensitivity reactions are common and consist of urticarial or morbilliform rashes appearing within the first few weeks; the eruption clears on drug withdrawal and does not always recur on re-exposure. It is possible to desensitize patients to penicillamine [10]. Autoimmune syndromes caused by penicillamine are well documented. The development of pemphigus during the treatment of both Wilson’s disease and rheumatoid arthritis with penicillamine was first noted in the French literature [11,12]. Since then, there have been numerous case reports [13–25]; about 7% of patients receiving penicillamine for more than 6 months develop druginduced pemphigus [13]. The reader is referred to the section on drug-induced pemphigus (pp. 75.38–39). Findings with direct immunofluorescence mimic the idiopathic disorder, with epidermal intercellular deposition of immunoreactants [16]. Most patients develop pemphigus foliaceus, although there have been

Important or widely prescribed drugs

isolated reports of pemphigus vulgaris [14] and of pemphigus erythematosus with both epidermal intercellular and subepidermal deposition of IgG [15,17]. In some patients, clinical appearances may resemble dermatitis herpetiformis [21,22]. Oral lesions may be indistinguishable from those seen in idiopathic pemphigus, with cheilosis, glossitis and stomatitis [23]. Painful erosive vulvovaginitis may lead to scarring. Penicillamine-induced pemphigus usually subsides rapidly after cessation of the drug; occasionally it may be more persistent [13] and fatalities have occurred [24,25]. A curious bullous dermatosis without the features of pemphigus has been described recently [26]. Other autoimmune manifestations include a bullous pemphigoid-like reaction [27], cicatricial pemphigoid [28,29], both discoid and systemic LE [30– 33], dermatomyositis [34–37], and both morphoea and systemic sclerosis [38,39]. Pre-existing lichen planus [40] may be exacerbated, and lichenoid eruptions develop de novo [41,42]. Alopecia, facial dryness and scaling, nail changes and hypertrichosis are recorded. The yellow nail syndrome has been reported frequently in association with penicillamine [43]. Prolonged high-dose therapy for more than a year, as for Wilson’s disease, has effects on collagen and elastin [44,45], resulting from inhibition of the condensation of soluble tropocollagen to insoluble collagen. There is anisodiametricity of connective tissue fibres, resulting in the ‘lumpy-bumpy’ elastic fibre [46–48]. The skin becomes wrinkled and thin, aged looking and abnormally fragile; asymptomatic, violaceous, friable, haemorrhagic macules, papules and plaques develop on pressure sites, and minor trauma causes ecchymoses [49]. There may be light-blue anetoderma-like lesions [50], and small white papules at venepuncture sites. Lymphangiectasis may develop [49]. Blisters may occur, with a picture resembling epidermolysis bullosa with scarring and milia formation (Fig. 75.6) [51]. Cutis laxa and elastosis perforans serpiginosa [52–58], which may be verruciform [52,53], are described. Lesions resembling pseudoxanthoma elasticum have been documented rarely [59–62]. Penicillamine may induce impaired taste sensation in up to 25% of patients, but other gastrointestinal effects are usually minor. Important non-dermatological complications [2,8] include: marrow suppression; various renal problems, such as reversible proteinuria, in up to 30% of patients on therapy for more than 6 months; established nephrotic syndrome; and Goodpasture’s syndrome. Thrombocytopenia occurs in up to 3% of patients, and may be either of gradual or precipitous onset. Immunological abnormalities include acquired IgA deficiency [63] and development of myasthenia gravis [64]. The bones may be involved in the connective tissue disorder. A chronic bronchoalveolitis is recognized [65]. Breast enlargement and breast gigantism [66] are documented. References 1 Emery P, Panayi GS, Huston G et al. d-Penicillamine-induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3. J Rheumatol 1984; 11: 626–32. 2 Dasgupta B. Adverse reactions profile: 2. Penicillamine. Prescribers J 1991; 31: 72–7. 3 Wooley PH, Griffin J, Panayi GS et al. HLA-DR antigens and toxic reaction to sodium aurothiomalate and d-penicillamine in patients with rheumatoid arthritis. N Engl J Med 1980; 303: 300–2.

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Fig. 75.6 Penicillamine dermopathy with milia. (Courtesy of St John’s Institute of Dermatology, King’s College London, UK.)

4 Vlachoyiannopoulos PG, Zerva LV, Skopouli FN et al. d-Penicillamine toxicity in Greek patients with rheumatoid arthritis: anti-Ro(SSA) antibodies and cryoglobulinemia are predictive factors. J Rheumatol 1991; 18: 44–9. 5 Katz R. Penicillamine-induced skin lesions. Occurrence in a patient with hepatolenticular degeneration (Wilson’s disease). Arch Dermatol 1967; 95: 196–8. 6 Greer KE, Askew FC, Richardson DR. Skin lesions induced by penicillamine. Arch Dermatol 1976; 112: 1267–9. 7 Sternlieb I, Fisher M, Scheinberg IH. Penicillamine-induced skin lesions. J Rheumatol 1981; 8 (Suppl. 7): 149–54. 8 Levy RS, Fisher M, Alter JN. Penicillamine: review and cutaneous manifestations. J Am Acad Dermatol 1983; 8: 548–58. 9 Bialy-Golan A, Brenner S. Penicillamine-induced bullous dermatoses. J Am Acad Dermatol 1996; 35: 732–42. 10 Chan CY, Baker AL. Penicillamine hypersensitivity: successful desensitization of a patient with severe hepatic Wilson’s disease. Am J Gastroenterol 1994; 89: 442–3. 11 Degos R, Touraine R, Belaïch S et al. Pemphigus chez un malade traité par pénicillamine pour maladie de Wilson. Bull Soc Fr Dermatol Syphiligr 1969; 76: 751–3. 12 Benveniste M, Crouzet J, Homberg JC et al. Pemphigus induit par la dpénicillamine dans la polyarthrite rhumatoïde. Nouv Presse Med 1975; 4: 3125–8. 13 Marsden RA, Ryan TJ, Vanhegan RI et al. Pemphigus foliaceus induced by penicillamine. BMJ 1976; ii: 1423–4. 14 From E, Frederiksen P. Pemphigus vulgaris following d-penicillamine. Dermatologica 1976; 152: 358–62. 15 Thorvaldsen J. Two cases of penicillamine-induced pemphigus erythematosus. Dermatologica 1979; 159: 167–70. 16 Santa Cruz DJ, Prioleau PG, Marcus MD, Uitto J. Pemphigus-like lesions induced by d-penicillamine. Analysis of clinical, histopathological, and immunofluorescence features in 34 cases. Am J Dermatopathol 1981; 3: 85–92. 17 Yung CW, Hambrick GW Jr. d-Penicillamine-induced pemphigus syndrome. J Am Acad Dermatol 1982; 6: 317–24. 18 Bahmer FA, Bambauer R, Stenger D. Penicillamine-induced pemphigus foliaceus-like dermatosis. A case with unusual features, successfully treated by plasmapheresis. Arch Dermatol 1985; 121: 665–8. 19 Kind P, Goerz G, Gleichmann E, Plewig G. Penicillamininduzierter Pemphigus. Hautarzt 1987; 38: 548–52.

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20 Civatte J. Durch Medikamente induzierte Pemphigus-Erkrankungen. Dermatol Monatsschr 1989; 175: 1–7. 21 Marsden RA, Dawber RPR, Millard PR, Mowat AG. Herpetiform pemphigus induced by penicillamine. Br J Dermatol 1977; 97: 451–2. 22 Weltfriend S, Ingber A, David M, Sandbank M. Pemphigus herpetiformis nach d-Penicillamin bei einem Patienten mit HLA B8. Hautarzt 1988; 39: 587–8. 23 Eisenberg E, Ballow M, Wolfe SH et al. Pemphigus-like mucosal lesions: a side effect of penicillamine therapy. Oral Surg 1981; 51: 409–14. 24 Sparrow GP. Penicillamine pemphigus and the nephrotic syndrome occurring simultaneously. Br J Dermatol 1978; 98: 103–5. 25 Matkaluk RM, Bailin PL. Penicillamine-induced pemphigus foliaceus. A fatal outcome. Arch Dermatol 1981; 117: 156–7. 26 Fulton RA, Thomson J. Penicillamine-induced bullous dermatosis. Br J Dermatol 1982; 107 (Suppl. 22): 95–6. 27 Brown MD, Dubin HV. Penicillamine-induced bullous pemphigoid-like eruption. Arch Dermatol 1987; 123: 1119–20. 28 Pegum JS, Pembroke AC. Benign mucous membrane pemphigoid associated with penicillamine treatment. BMJ 1977; i: 1473. 29 Shuttleworth D, Graham-Brown RAC, Hutchinson PE, Jolliffe DS. Cicatricial pemphigoid in d-penicillamine treated patients with rheumatoid arthritis: a report of three cases. Clin Exp Dermatol 1985; 10: 392–7. 30 Burns DA, Sarkany I. Penicillamine induced discoid lupus erythematosus. Clin Exp Dermatol 1979; 4: 389–92. 31 Walshe JM. Penicillamine and the SLE syndrome. J Rheumatol 1981; 8 (Suppl. 7): 155–60. 32 Chalmers A, Thompson D, Stein HE et al. Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis. Ann Intern Med 1982; 97: 659–63. 33 Tsankov NK, Lazarov AZ, Vasileva S, Obreshkova EV. Lupus erythematosus-like eruption due to d-penicillamine in progressive systemic sclerosis. Int J Dermatol 1990; 29: 571–4. 34 Simpson NB, Golding JR. Dermatomyositis induced by penicillamine. Acta Derm Venereol (Stockh) 1979; 59: 543–4. 35 Wojnarowska F. Dermatomyositis induced by penicillamine. J R Soc Med 1980; 73: 884–6. 36 Carroll GC, Will RK, Peter JB et al. Penicillamine induced polymyositis and dermatomyositis. J Rheumatol 1987; 14: 995–1001. 37 Wilson CL, Bradlow A, Wojnarowska F. Cutaneous problems with drug therapy in rheumatoid arthritis. Int J Dermatol 1991; 30: 148–9. 38 Bernstein RM, Hall MA, Gostelow BE. Morphea-like reaction to d-penicillamine therapy. Ann Rheum Dis 1981; 40: 42–4. 39 Miyagawa S, Yoshioka A, Hatoko M et al. Systemic sclerosis-like lesions during long-term penicillamine therapy for Wilson’s disease. Br J Dermatol 1987; 116: 95–100. 40 Powell FC, Rogers RS III, Dickson ER. Lichen planus, primary biliary cirrhosis and penicillamine. Br J Dermatol 1982; 107: 616. 41 Seehafer JR, Rogers RS III, Fleming R, Dickson ER. Lichen planus-like lesions caused by penicillamine in primary biliary cirrhosis. Arch Dermatol 1981; 117: 140–2. 42 Van Hecke E, Kint A, Temmerman L. A lichenoid eruption induced by penicillamine. Arch Dermatol 1981; 117: 676–7. 43 Ilchyshyn A, Vickers CFH. Yellow nail syndrome associated with penicillamine therapy. Acta Derm Venereol (Stockh) 1983; 63: 554–5. 44 Poon E, Mason GH, Oh C. Clinical and histological spectrum of elastotic changes induced by penicillamine. Australas J Dermatol 2002; 43: 147–50. 45 Iozumi K, Nakagawa H, Tamaki K. Penicillamine-induced degenerative dermatoses: report of a case and brief review of such dermatoses. J Dermatol 1997; 24: 458–65. 46 Bardach H, Gebhart W, Niebauer G. ‘Lumpy-bumpy’ elastic fibers in the skin and lungs of a patient with a penicillamine-induced elastosis perforans serpiginosa. J Cutan Pathol 1979; 6: 243–52. 47 Gebhart W, Bardach H. The ‘lumpy-bumpy’ elastic fiber. A marker for long-term administration of penicillamine. Am J Dermatopathol 1981; 3: 33–9. 48 Hashimoto K, McEvoy B, Belcher R. Ultrastructure of penicillamine-induced skin lesions. J Am Acad Dermatol 1981; 4: 300–15. 49 Goldstein JB, McNutt S, Hambrick GW. Penicillamine dermatopathy with lymphangiectases. A clinical, immunohistologic, and ultrastructural study. Arch Dermatol 1989; 125: 92–7.

50 Davis W. Wilson’s disease and penicillamine-induced anetoderma. Arch Dermatol 1977; 113: 976. 51 Beer WE, Cooke KB. Epidermolysis bullosa induced by penicillamine. Br J Dermatol 1967; 79: 123–5. 52 Guilane J, Benhamou JP, Molas G. Élastome perforant verruciforme chez un malade traité par pénicillamine pour maladie de Wilson. Bull Soc Fr Derm Syph 1972; 79: 450–3. 53 Sfar Z, Lakhua M, Kamoun MR et al. Deux cas d’élastomes verruciforme après administration prolongée de d-pénicillamine. Ann Dermatol Vénéréol 1982; 109: 813–4. 54 Reymond JL, Stoebner P, Zambelli P et al. Penicillamine induced elastosis perforans serpiginosa: an ultrastructural study of two cases. J Cutan Pathol 1982; 9: 352–7. 55 Price RG, Prentice RSA. Penicillamine-induced elastosis perforans serpiginosa. Tip of the iceberg? Am J Dermatopathol 1986; 8: 314–20. 56 Sahn EE, Maize JC, Garen PD et al. d-Penicillamine-induced elastosis perforans serpiginosa in a child with juvenile rheumatoid arthritis. Report of a case and review of the literature. J Am Acad Dermatol 1989; 20: 979–88. 57 Wilhelm K, Wolff HH. Penicillamin-induzierte Elastosis perforans serpiginosa. Hautarzt 1994; 45: 45–7. 58 Hill VA, Seymour CA, Mortimer PS. Penicillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson’s disease. Br J Dermatol 2000; 142: 560–1. 59 Meyrick-Thomas RH, Light N, Stephens AD et al. Pseudoxanthoma elasticumlike skin changes induced by penicillamine. J R Soc Med 1984; 77: 794–8. 60 Meyrick-Thomas RH, Kirby JDT. Elastosis perforans serpiginosa and pseudoxanthoma elasticum-like skin change due to d-penicillamine. Clin Exp Dermatol 1985; 10: 386–91. 61 Light N, Meyrick Thomas RH, Stephens A et al. Collagen and elastin changes in d-penicillamine-induced pseudoxanthoma elasticum. Br J Dermatol 1986; 114: 381–8. 62 Burge S, Ryan T. Penicillamine-induced pseudo-pseudoxanthoma elasticum in a patient with rheumatoid arthritis. Clin Exp Dermatol 1988; 13: 255–8. 63 Hjalmarson O, Hanson L-Å. IgA deficiency during d-penicillamine treatment. BMJ 1977; i: 549. 64 Garlepp MJ, Dawkins RL, Christiansen FT. HLA antigens and acetylcholine receptor antibodies in penicillamine induced myasthenia gravis. BMJ 1983; 286: 338–40. 65 Murphy KC, Atkins CJ, Offer RC et al. Obliterative bronchiolitis in two rheumatoid arthritis patients treated with penicillamine. Arthritis Rheum 1981; 24: 557–60. 66 Passas C, Weinstein A. Breast gigantism with penicillamine therapy. Arthritis Rheum 1978; 21: 167–8.

Tiopronin (N-(2-mercaptopropionyl) glycine) This drug, used in Japan for the treatment of liver disease, mercury intoxication, cataracts and allergic dermatoses, dissociates disulphide bonds, like penicillamine. Morbilliform, urticarial and lichenoid eruptions, bullous in one case, have occurred [1]. Reference 1 Hsiao L, Yoshinaga A, Ono T. Drug-induced bullous lichen planus in a patient with diabetes mellitus and liver disease. J Am Acad Dermatol 1986; 15: 103–5.

Anticoagulants, fibrinolytic agents and antiplatelet drugs Oral anticoagulants Adverse reactions to oral anticoagulant drugs have been reviewed [1–3]. References 1 Baker H, Levene GM. Drug reactions V. Cutaneous reactions to anticoagulants. Br J Dermatol 1969; 81: 236–8. 2 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865–75.

Important or widely prescribed drugs 3 Gallerani M, Manfredini R, Moratelli S. Non-haemorrhagic adverse reactions of oral anticoagulant therapy. Int J Cardiol 1995; 49: 1–7.

Coumarins There may be cross-sensitivity across the group comprising acenocoumarol (nicoumalone), phenprocoumon and warfarin [1]. Phenprocoumon. A patient on long-term anticoagulation developed repeated episodes of skin and subcutaneous fat necrosis related to episodes of excessive anticoagulation with acquired functional deficiency of protein C, thought to be due to hepatic dysfunction resulting from congestive cardiac failure [2]. Warfarin. Haemorrhage is the commonest adverse reaction. Maculopapular rashes occur [1], and may be seen after a single dose of warfarin [3]. Rarely, an oral loading dose may lead to one or more areas of painful erythema and ecchymosis, which rapidly progress to central blistering and massive cutaneous and subcutaneous necrosis (Fig. 75.7) [4–12]; if extensive, the condition may be fatal [3]. The lesions usually start after 2–14 days of treatment (most often 3–5 days), tend to be symmetrical, and occur over fatty areas, for example the breasts, buttocks, thighs, calves and abdomen. Most patients have been women, but lesions of the penis may occur [6]. Warfarin necrosis has been associated with the heterozygous state for deficiency of protein C, a vitamin Kdependent serine protease [8–10]. Activated protein C is a potent anticoagulant that selectively inactivates co-factors Va and VIIIa, and inhibits platelet coagulant activity by inactivation of platelet factor Va. Continued coumarin therapy does not aggravate the condition, but resumption of therapy with loading doses may lead to new lesions [7]. The condition is preventable by vitamin K1 injections. Other side effects are rare, and include urticaria [13], dermatitis, gastrointestinal upset, purple erythema of the dependent parts (purple toe syndrome) [14–16], acral purpura [17] and alopecia [18]. Oral anticoagulants and quinidine act synergistically to depress vitamin K-sensitive hepatic clotting synthesis [19]. Their combined use can precipitate serious hypoprothrombinaemic haemorrhage. Azapropazone displaces warfarin from protein-binding sites and

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also alters renal clearance of R and S isomers of warfarin; this may lead to effective warfarin overdosage [20]. Itraconazole may potentiate the action of warfarin [21]. References 1 Kruis-de Vries MH, Stricker BHC, Coenraads PJ, Nater JP. Maculopapular rash due to coumarin derivatives. Dermatologica 1989; 178: 109–11. 2 Teepe RGC, Broekmans AW, Vermeer BJ et al. Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol 1986; 122: 1408–12. 3 Antony SJ, Krick SK, Mehta PM. Unusual cutaneous adverse reaction to warfarin therapy. South Med J 1993; 86: 1413–4. 4 Lacy JP, Goodin RR. Warfarin-induced necrosis of skin. Ann Intern Med 1975; 82: 381–2. 5 Schleicher SM, Fricker MP. Coumarin necrosis. Arch Dermatol 1980; 116: 444–5. 6 Weinberg AC, Lieskovsky G, McGehee WG, Skinner DG. Warfarin necrosis of the skin and subcutaneous tissue of the male external genitalia. J Urol 1983; 130: 352–4. 7 Slutzki S, Bogokowsky H, Gilboa Y, Halpern Z. Coumadin-induced skin necrosis. Int J Dermatol 1984; 23: 117–9. 8 Kazmier FJ. Thromboembolism, coumarin necrosis, and protein C. Mayo Clin Proc 1985; 60: 673–4. 9 Gladson CL, Groncy P, Griffin JH. Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. Arch Dermatol 1988; 123: 1701a–1706a. 10 Auletta MJ, Headington JT. Purpura fulminans. A cutaneous manifestation of severe protein C deficiency. Arch Dermatol 1988; 124: 1387–91. 11 Sharafuddin MJ, Sanaknaki BA, Kibbi AG. Erythematous, hemorrhagic, and necrotic plaques in an elderly man. Coumarin-induced skin necrosis. Arch Dermatol 1992; 128: 105, 108. 12 Comp PC. Coumarin-induced skin necrosis. Incidence, mechanisms, management and avoidance. Drug Saf 1993; 8: 128–35. 13 Sheps ES, Gifford RW. Urticaria after administration of warfarin sodium. Am J Cardiol 1959; 3: 118–20. 14 Feder W, Auerbach R. ‘Purple toes’: an uncommon sequela of oral coumarin drug therapy. Ann Intern Med 1961; 55: 911–7. 15 Akle CA, Joiner CL. Purple toe syndrome. J R Soc Med 1981; 74: 219. 16 Lebsack CS, Weibert RT. Purple toes syndrome. Postgrad Med 1982; 71: 81–4. 17 Stone MS, Rosen T. Acral purpura: an unusual sign of coumarin necrosis. J Am Acad Dermatol 1986; 14: 797–802. 18 Umlas J, Harken DE. Warfarin-induced alopecia. Cutis 1988; 42: 63–4. 19 Koch-Weser J. Quinidine-induced hypoprothrombinemic hemorrhage in patients on chronic warfarin therapy. Ann Intern Med 1968; 68: 511–7. 20 Win N, Mitchell DC. Azapropazone and warfarin. BMJ 1991; 302: 969–70. 21 Yeh J, Soo SC, Summerton C, Richardson C. Potentiation of action of warfarin by itraconazole. BMJ 1990; 301: 669.

Indandiones Hypersensitivity reactions occur in up to 0.3% of patients within 3 months of onset of treatment with phenindione. Scarlatiniform, eczematous, erythema multiforme-like or generalized exfoliative eruptions are seen [1,2]. Alopecia and stomatitis may accompany the rash. Brownish-yellow or orange discoloration of the palmar or finger skin on handling the tablets develops after contact with soap alkali [3]. Cutaneous necrosis occurs rarely. References 1 Hollman A, Wong HO. Phenindione sensitivity. BMJ 1964; ii: 730–2. 2 Copeman PWM. Phenindione toxicity. BMJ 1965; ii: 305. 3 Silverton NH. Skin pigmentation by phenindione. BMJ 1966; i: 675.

Fig. 75.7 Warfarin necrosis. (Courtesy of Dr A. Ive, Durham, UK.)

Heparin: parenteral anticoagulant The most frequent side effect is haemorrhage [1,2]. Other common side effects include osteoporosis and (temporary) telogen

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effluvium 6–16 weeks after administration. Hypoaldosteronism may occur. Hypersensitivity reactions including urticaria and anaphylactic shock are well documented but very uncommon [3]. Rapid desensitization was achieved in a patient with heparin urticarial hypersensitivity who required cardiac surgery [4]. Hypereosinophilia is recorded [5]. Vasospastic reactions, including pain, cyanosis and severe itching or burning plantar sensations, are described. Erythematous infiltrated plaques developing 3–21 days after commencement of heparin therapy [6–14] may closely mimic contact dermatitis both clinically and histologically, and patch tests may be positive [8,9]. Delayed-type hypersensitivity reactions in patients receiving heparin may occur with both unfractionated and low-molecular-weight heparins. Delayed-type hypersensitivity to heparins is characterized by considerable cross-reactivity between low-molecular-weight heparins, unfractionated heparins and danaparoid [13]. Unfractionated heparins may be tolerated even if low-molecular-weight heparins are not. Subcutaneous provocation testing with a panel of heparins, danaparoid and desirudin (hirudin) is recommended for determining acceptable treatment options for patients allergic to specific heparins. Low-molecular-weight heparin analogues may be satisfactorily substituted in some patients with this reaction [6,15], but are not always tolerated [7,16,17]; a panel of different low-molecularweight heparin preparations should be checked by subcutaneous provocation tests before reinstitution of heparin therapy. Chlorocresol may be responsible for some reactions attributed to heparin [7,18], including anaphylactoid reactions. Skin necrosis occurring 6–8 days after onset of subcutaneous heparin is rare, but may occur at injection sites and occasionally at distal sites elsewhere [19–27]. Diabetic women on high-dose antibiotics are predisposed to this complication. A sclerodermalike evolution has been recorded [22]. Clinically, the skin necrosis resembles that of coumarin necrosis [25]. It may occur with use of low-molecular-weight heparin [23,26]. Heparin may cause an allergic thrombocytopenia [28–35]. Thrombocytopenia is usually asymptomatic, but may be associated with arterial or venous thrombosis in about 0.4% of cases [29,33,34]; thromboembolism may occasionally be lethal [30]. Thrombocytopenia usually begins 3–15 days after initiation of therapy, but may occur within hours in previously exposed patients, and is thought to be caused by an IgG–heparin immune complex involving both the Fab and Fc portions of the IgG molecule [29]. Heparin-induced antiendothelial cell antibodies, which recognize heparin-like glycans on the cell surface of platelets and endothelial cells, may lead to platelet aggregation and endothelial cell expression of procoagulant tissue factor, with resultant thrombocytopenia and thrombosis [21]. Thrombocytopenia may occur with both unfractionated and low-molecular-weight heparins [20]. Clinical cross-reactivity between heparin and the polysulphated chondroitin-like substance Arteparon, used in the treatment of degenerative joint disease, has been described [32]. References 1 Tuneu A, Moreno A, de Moragas JM. Cutaneous reactions secondary to heparin injections. J Am Acad Dermatol 1985; 12: 1072–7. 2 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565–74.

3 Curry N, Bandana EJ, Pirofsky B. Heparin sensitivity: report of a case. Arch Intern Med 1973; 132: 744–5. 4 Patriarca G, Rossi M, Schiavino D et al. Rush desensitization in heparin hypersensitivity: a case report. Allergy 1994; 49: 292–4. 5 Bircher AJ, Itin PH, Buchner SA. Skin lesions, hypereosinophilia, and subcutaneous heparin. Lancet 1994; 343: 861. 6 Zimmermann R, Harenberg J, Weber E et al. Behandlung bei heparin-induzierter kutaner Reaktion mit einem niedermolekularen Heparin-Analog. Dtsch Med Wochenschr 1984; 109: 1326–8. 7 Klein GF, Kofler H, Wol H, Fritsch PO. Eczema-like, erythematous, infiltrated plaques: a common side-effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989; 21: 703–7. 8 Guillet G, Delaire P, Plantin P, Guillet MH. Eczema as a complication of heparin therapy. J Am Acad Dermatol 1989; 21: 1130. 9 Bircher AJ, Flückiger R, Buchner SA. Eczematous infiltrated plaques to subcutaneous heparin: a type IV allergic reaction. Br J Dermatol 1990; 123: 507–14. 10 Koch P, Hindi S, Landwehr D. Delayed allergic skin reactions due to subcutaneous heparin-calcium, enoxaparin-sodium, pentosan polysulfate and acute skin lesions from systemic sodium-heparin. Contact Dermatitis 1996; 34: 156–8. 11 Koch P, Münßinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612–9. 12 Szolar-Platzer C, Aberer W, Kranke B. Delayed-type skin reaction to the heparinalternative danaparoid. J Am Acad Dermatol 2000; 43: 920–2. 13 Grassegger A, Fritsch P, Reider N. Delayed-type hypersensitivity and crossreactivity to heparins and danaparoid: a prospective study. Dermatol Surg 2001; 27: 47–52. 14 Wutschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 1999; 20: 515–25. 15 Koch P, Bahmer FA, Schafer H. Tolerance of intravenous low-molecular-weight heparin after eczematous reaction to subcutaneous heparin. Contact Dermatitis 1991; 25: 205–6. 16 Bosch A, Las Heras G, Martin E, Oller G. Skin reaction with low molecular weight heparins. Br J Haematol 1993; 85: 637. 17 Phillips JK, Majumdar G, Hunt BJ, Savidge GF. Heparin-induced skin reaction due to two different preparations of low molecular weight heparin (LMWH). Br J Haematol 1993; 84: 349–50. 18 Ainley EJ, Mackie IG, MacArthur D. Adverse reaction to chlorocresol preserved heparin. Lancet 1977; i: 705. 19 Shelley WB, Säyen JJ. Heparin necrosis: an anticoagulant-induced cutaneous infarct. J Am Acad Dermatol 1982; 7: 674–7. 20 Levine LE, Bernstein JE, Soltani K et al. Heparin-induced skin necrosis unrelated to injection sites: a sign of potentially lethal complications. Arch Dermatol 1983; 119: 400–3. 21 Mathieu A, Avril MF, Schlumberger M et al. Un cas de nécrose cutanée induite par l’héparine. Ann Dermatol Vénéréol 1984; 111: 733–4. 22 Barthelemy H, Hermier C, Perrot H. Nécrose cutanée avec évolution scléridermiforme après l’injection souscutanée d’heparinate de calcium. Ann Dermatol Vénéréol 1985; 112: 245–7. 23 Cordoliani F, Saiag P, Guillaume J-C et al. Nécrose cutanés étendues induites par la fraxiparine. Ann Dermatol Vénéréol 1987; 114: 1366–8. 24 Rongioletti F, Pisani S, Ciaccio M, Rebora A. Skin necrosis due to intravenous heparin. Dermatologica 1989; 178: 47–50. 25 Gold JA, Watters AK, O’Brien E. Coumadin versus heparin necrosis. J Am Acad Dermatol 1987; 16: 148–50. 26 Ojeda E, Perez MC, Mataix R et al. Skin necrosis with a low molecular weight heparin. Br J Haematol 1992; 82: 620. 27 Yates P, Jones S. Heparin skin necrosis: an important indicator of potentially fatal heparin hypersensitivity. Clin Exp Dermatol 1993; 18: 138–41. 28 Cine DB, Tomaski A, Tannenbaum S. Immune endothelial cell injury in heparinassociated thrombocytopenia. N Engl J Med 1987; 316: 581–9. 29 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Annu Rev Med 1989; 40: 31–44. 30 Jaffray B, Welch GH, Cooke TG. Fatal venous thrombosis after heparin therapy. Lancet 1991; 337: 561.

Important or widely prescribed drugs 31 Eichinger S, Kyrle PA, Brenner B et al. Thrombocytopenia associated with lowmolecular-weight heparin. Lancet 1991; 337: 1425–6. 32 Greinacher A, Michels I, Schafer M et al. Heparin-associated thrombocytopenia in a patient treated with polysulphated chondroitin sulphate: evidence for immunological crossreactivity between heparin and polysulphated glycosaminoglycan. Br J Haematol 1992; 81: 252–4. 33 Gross AS, Thompson FL, Arzubiaga MC et al. Heparin-associated thrombocytopenia and thrombosis (HATT) presenting with livedo reticularis. Int J Dermatol 1993; 32: 276–9. 34 O’Bryan-Tear G. Heparin induced thrombosis. Datasheet warns of risk. BMJ 1993; 307: 561. 35 Ouellette D, Menkis AH. Heparin-induced thrombocytopenia. Ann Thorac Surg 1993; 55: 809.

Protamine: heparin antagonist This low-molecular-weight protein, derived from salmon sperm and/or testes, is used for neutralization of heparin anticoagulation after cardiac surgery. Adverse reactions have been reviewed [1]. Idiosyncratic responses or those related to complement generation of anaphylatoxins are recorded [2]. IgE-dependent anaphylaxis [3], as well as delayed reactions causing skin nodules [4–6], which may be granulomatous [6], may occur in diabetics treated with protamine-containing insulin. References 1 Cormack JG, Levy JH. Adverse reactions to protamine. Coron Artery Dis 1993; 4: 420–5. 2 Sussman GL, Dolovich J. Prevention of anaphylaxis. Semin Dermatol 1989; 8: 158–65. 3 Kim R. Anaphylaxis to protamine masquerading as an insulin allergy. Del Med J 1993; 65: 17–23. 4 Sarche MB, Paolillo M, Chacon RS et al. Protamine as a cause of generalized allergic reactions to NPH insulin. Lancet 1982; i: 1243. 5 Kollner A, Senff H, Engelmann L et al. Protaminallergie vom Spattyp und Insulinallergie vom Soforttyp. Dtsch Med Wochenschr 1991; 116: 1234–8. 6 Hulshof MM, Faber WR, Kniestedt WF et al. Granulomatous hypersensitivity to protamine as a complication of insulin therapy. Br J Dermatol 1992; 127: 286–8.

Fibrinolytic drugs Haemorrhage is the most common untoward effect from use of thrombolysins [1]. Allergic complications are rare, particularly with alteplase or urokinase. These agents should be used electively in all patients previously exposed to streptokinase or anistreplase [2].

Alteplase (tissue-type plasminogen activator) Painful purpura occurring within hours of administration has been recorded [3]. Aminocaproic acid A maculopapular eruption occurring 12–72 h after administration of ε-aminocaproic acid, with positive patch tests to the drug, has been described [4]. A transient, non-inflammatory, subepidermal, bullous eruption on the legs, with fibrin thrombi in papillary dermal vessels, has also been recorded [5]. Anistreplase (anisoylated plasminogen streptokinase activator complex) Anistreplase given for acute myocardial infarction was associated with leukocytoclastic vasculitis [6]. Maculopapular rashes and urticaria are described; patients with maculopapular rashes had

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significantly higher rises in serum IgM, IgG, IgA and IgE antistreptokinase level [7]. References 1 Chesebro JH, Knatterud G, Roberts R et al. Thrombolysis in myocardial infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 1987; 76: 142–54. 2 de Bono DP. Complications of thrombolysis and their clinical management. Z Kardiol 1993; 82 (Suppl. 2): 147–51. 3 DeTrana C, Hurwitz RM. Painful purpura: an adverse effect to a thrombolysin. Arch Dermatol 1990; 126: 690–1. 4 Gonzalez Gutierrez ML, Esteban Lopez MI, Ruiz Ruiz MD. Positivity of patch tests in cutaneous reaction to aminocaproic acid: two case reports. Allergy 1995; 50: 745–6. 5 Brooke CP, Spiers EM, Omura EF. Noninflammatory bullae associated with epsilon-aminocaproic acid infusion. J Am Acad Dermatol 1992; 27: 880–2. 6 Burrows N, Russell Jones R. Vasculitis occurring after intravenous anistreplase. J Am Acad Dermatol 1992; 26: 508. 7 Dykewicz MS, McMorrow NK, Davison R et al. Drug eruptions and isotypic antibody responses to streptokinase after infusions of anisoylated plasminogen– streptokinase complex (APSAC, anistreplase). J Allergy Clin Immunol 1995; 95: 1020–8.

Streptokinase Allergic reactions have been reported in up to 6% of patients [1–3], ranging from minor rashes to angio-oedema or anaphylaxis (which may be fatal [4–6]), bleeding, strokes and a syndrome resembling adult respiratory distress syndrome [3]. Patients who develop reactions to streptokinase cannot be predicted on the basis of antistreptokinase IgG antibody titres at presentation; minor reactions to streptokinase would not appear to be antibody mediated [7]. However, streptokinase-related thrombolytic agents should be avoided in reinfarction thrombolysis therapy in patients with raised antistreptokinase antibody titres, as hypersensitivity reactions including serum sickness may occur [8–10]. This drug has been reported in association with a hypersensitivity vasculitis [11,12], serum sickness with leukocytoclastic vasculitis [13,14] and a lymphocytic angiitis [15]. Skin necrosis is recorded [16]. Urokinase Haemorrhagic bullae occurred as a complication of urokinase therapy for haemodialysis catheter thrombosis [17]. References 1 Dykewicz MS, McGratt KG, Davison R et al. Identification of patients at risk for anaphylaxis due to streptokinase. Arch Intern Med 1986; 146: 305–7. 2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349–60. 3 Siebert WJ, Ayres RW, Bulling MT et al. Streptokinase morbidity: more common than previously recognised. Aust NZ J Med 1992; 22: 129–33. 4 Allpress SM, Cluroe AD, Vuletic JC, Kolemeyer TD. Death after streptokinase. NZ Med J 1993; 106: 295. 5 Hohage H, Schulte B, Pfeiff B, Pullmann H. Anaphylaktische Reaktion unter Streptokinase-Therapie. Wien Klin Wochenschr 1993; 105: 176–8. 6 Cooper JP, Quarry DP, Beale DJ, Chappell AG. Life-threatening, localized angiooedema associated with streptokinase. Postgrad Med J 1994; 70: 592–3. 7 Lynch M, Pentecost BL, Littler WA, Stockley RA. Why do patients develop reactions to streptokinase? Clin Exp Immunol 1993; 94: 279–85. 8 Lee HS, Yule S, McKenzie A et al. Hypersensitivity reactions to streptokinase in patients with high pretreatment antistreptokinase antibody and neutralisation titres. Eur Heart J 1993; 14: 1640–3.

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9 Cross DB. Should streptokinase be readministered? Insights from recent studies of antistreptokinase antibodies. Med J Aust 1994; 161: 100–1. 10 Jennings K. Antibodies to streptokinase. BMJ 1996; 312: 393–4. 11 Ong ACM, Handler CE, Walker JM. Hypersensitivity vasculitis complicating intravenous streptokinase therapy in acute myocardial infarction. Int J Cardiol 1988; 21: 71–3. 12 Thompson RF, Stratton MA, Heffron WA. Hypersensitivity vasculitis associated with streptokinase. Clin Pharmacol 1985; 4: 383–8. 13 Patel IA, Prussick R, Buchanan WW, Sauder DN. Serum sickness-like illness and leukocytoclastic vasculitis after intravenous streptokinase. J Am Acad Dermatol 1991; 24: 652–3. 14 Totto WG, Romano T, Benian GM et al. Serum sickness following streptokinase therapy. Am J Rheumatol 1982; 138: 143–4. 15 Sorber WA, Herbst V. Lymphocytic angiitis following streptokinase therapy. Cutis 1988; 42: 57–8. 16 Penswick J, Wright AL. Skin necrosis induced by streptokinase. BMJ 1994; 309: 378. 17 Ejaz AA, Aijaz M, Nawab ZM et al. Hemorrhagic bullae as a complication of urokinase therapy for hemodialysis catheter thrombosis. Am J Nephrol 1995; 15: 178–9.

Antiplatelet drugs Clopidogrel This drug, a novel thienopyridine derivative chemically related to ticlopidine and used in patients at risk of thromboembolic disorders, has caused a photosensitive lichenoid eruption [1] and a hypersensitivity disorder [2]. The USA Food and Drug Administration reported 50 hypersensitivity reactions after coronary stent placement but later concluded these were in fact due to concomitantly prescribed medications such as clopidogrel [3].

Ticlopidine This antiplatelet drug, indicated for coronary artery disease, cerebrovascular disease, peripheral vascular disease and diabetic retinopathy, is also a thienopyridine derivative [4,5]. Gastrointestinal symptoms, thrombocytopenia with minor bleeding including bruising, neutropenia, rashes in 10–15% of patients, and hepatic dysfunction in 4% of cases have been reported. Thrombotic thrombocytopenic purpura has also been documented [6]. Cutaneous reactions, including urticaria, pruritus, maculopapular and fixed drug eruptions, erythromelalgia and erythema multiforme, are recorded in up to 11.8% of patients [7]. Acute generalized exanthematous pustulosis has been documented [8]. References 1 Dogra S, Kanwar AJ. Clopidogrel bisulphate-induced photosensitive lichenoid eruption: first report. Br J Dermatol 2003; 148: 593–611. 2 Doogue MP, Begg EJ, Bridgman P. Clopidogrel hypersensitivity syndrome with rash, fever, and neutropenia. Mayo Clin Proc 2005; 80: 1368–70. 3 Nebeker JR, Virmani R, Bennett CL et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006; 47: 175–81. 4 McTavish D, Faulds D, Goa KL. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40: 238–59. 5 Anonymous. Ticlopidine. Lancet 1991; 337: 459–60. 6 Page Y, Tardy B, Zeni F et al. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet 1991; 337: 774–6. 7 Yosipovitch G, Rechavia E, Feinmesser M, David M. Adverse cutaneous reactions to ticlopidine in patients with coronary stents. J Am Acad Dermatol 1999; 41: 473–6. 8 Cannavò SP, Borgia F, Guarneri F, Vaccaro M. Acute generalized exanthematous pustulosis following use of ticlopidine. Br J Dermatol 2000; 142: 577–8.

Vitamins including retinoids Vitamin A Generalized peeling may be a delayed manifestation of acute intoxication [1]. Chronic intoxication produces the following epithelial problems: pruritus, erythema, hyperkeratosis, dryness of mouth, nose and eyes, epistaxis, fissuring, dryness and scaling of the lips, peeling of the palms and soles, and alopecia. A yelloworange skin discoloration, photosensitivity and nail changes have also been observed [2–5]. Headache, pseudotumour cerebri, anaemia, hepatomegaly and skeletal pain may be present. Cortical hyperostoses and periosteal reaction of tubular bone [6], and more rarely premature epiphyseal closure and change in the contour of long bones [7], are seen. References 1 Nater P, Doeglas HMG. Halibut liver poisoning in 11 fishermen. Acta Derm Venereol (Stockh) 1970; 50: 109–13. 2 Oliver TK. Chronic vitamin A intoxication. Report of a case in an older child and a review of the literature. Am J Dis Child 1959; 95: 57–67. 3 Muenter MD, Perry HO, Ludwig J. Chronic vitamin A intoxication in adults. Hepatic, neurologic and dermatologic complications. Am J Med 1971; 50: 129–36. 4 Teo ST, Newth J, Pascoe BJ. Chronic vitamin A intoxication. Med J Aust 1973; 2: 324–6. 5 Bobb R, Kieraldo JH. Cirrhosis due to hypervitaminosis A. West J Med 1978; 128: 244–6. 6 Frame B, Jackson CE, Reynolds WA, Umphrey JE. Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med 1974; 80: 44–8. 7 Ruby LK, Mital MA. Skeletal deformities following chronic hypervitaminosis A. J Bone Joint Surg 1974; 56: 1283–7.

Retinoids The cutaneous and systemic side effects of these synthetic vitamin A-related compounds resemble those of hypervitaminosis A, and have been extensively reviewed [1–12]. References 1 Orfanos CE, Braun-Falco O, Farber EM et al., eds. Retinoids. Advances in Basic Research and Therapy. Berlin: Springer, 1981. 2 Foged E, Jacobsen F. Side-effects due to Ro 10-3959 (Tigason). Dermatologica 1982; 164: 395–403. 3 Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. J Am Acad Dermatol 1982; 4: 675–82. 4 Cunliffe WJ, Miller AJ, eds. Retinoid Therapy. A Review of Clinical and Laboratory Research. Lancaster: MTP Press, 1984. 5 Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985. 6 Yob EH, Pochi PE. Side effects and long-term toxicity of synthetic retinoids. Arch Dermatol 1987; 123: 1375–8. 7 Bigby M, Stern RS. Adverse reactions to isotretinoin. A report from the Adverse Drug Reaction Reporting System. J Am Acad Dermatol 1988; 18: 543–52. 8 Saurat J-H. Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992; 27: S23–S28. 9 Vahlquist A. Long-term safety of retinoid therapy. J Am Acad Dermatol 1992; 27: S29–S33. 10 Gollnick HPM. Oral retinoids: efficacy and toxicity in psoriasis. Br J Dermatol 1996; 135 (Suppl. 49): 6–17. 11 Mørk N-J, Kolbenstvedt A, Austad J. Skeletal side-effects of 5 years’ acitretin treatment. Br J Dermatol 1996; 134: 1156–7. 12 Hermann G, Jungblut RM, Goerz G. Skeletal changes after long-term therapy with synthetic retinoids. Br J Dermatol 1997; 136: 469–70.

Important or widely prescribed drugs

Acitretin The side effects of this principal metabolite of etretinate, which it has replaced are similar to those of the parent compound [1–6], comprising cheilitis, alopecia, conjunctivitis, peeling of the palms and soles, xerosis, myalgia and pancreatitis; elevated levels of serum triglyceride, cholesterol and liver transaminase are seen. There has been no biopsy-proven hepatotoxicity [7]. Alopecia is particularly frequent [4], and scaling of the palms and soles appears more prominent than with etretinate [5]. There is a higher occurrence of vulvovaginal candidiasis during acitretin exposure [8]. Multiple milia have occurred [9]. Skeletal effects may be significant, but are not an absolute contraindication to therapy [10]. Acitretin does not seem to cause osteoporosis [11]. Persistent levels of etretinate have been detected in plasma following a change to acitretin therapy. Detectable plasma etretinate was present in 45% of current acitretin users and 18% of those who had stopped acitretin, whereas detectable subcutaneous tissue etretinate was present in 83% of current acitretin users and 86% of those who had discontinued the drug [12]. Inability to detect plasma etretinate is therefore a poor predictor of the absence of etretinate in fat. Acitretin and/or etretinate were detectable in fat, and in some cases plasma, from women who had ceased acitretin therapy for up to 29 months [12]. It has been proposed that subcutaneous tissue levels of acitretin and etretinate should be monitored when plasma measurements are negative, and that the recommended contraception period of 2 years after cessation of acitretin therapy should be reconsidered to avoid the risk of teratogenicity [13]. It has been suggested that acitretin is only converted to etretinate following alcohol intake [14]. References 1 Geiger J-M, Czarnetzki BM. Acitretin (Ro 10-1670, Etretin): overall evaluation of clinical studies. Dermatologica 1988; 176: 182–90. 2 Gupta AK, Goldfarb MT, Ellis CN, Voorhees JJ. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol 1989; 21: 1088–93. 3 Ruzicka T, Sommerburg C, Braun-Falco O et al. Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis. Arch Dermatol 1990; 126: 482–6. 4 Murray HE, Anhalt AW, Lessard R et al. A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter study. J Am Acad Dermatol 1991; 24: 598–602. 5 Blanchet-Bardon C, Nazzaro V, Rognin C et al. Acitretin in the treatment of severe disorders of keratinization. Results of an open study. J Am Acad Dermatol 1991; 24: 982–6. 6 Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol 1999; 41: S7–S12. 7 Roenigk HH Jr, Callen JP, Guzzo CA et al. Effects of acitretin on the liver. J Am Acad Dermatol 1999; 41: 584–8. 8 Sturkenboom MC, Middelbeek A, de Jong van den Berg LT et al. Vulvo-vaginal candidiasis associated with acitretin. J Clin Epidemiol 1995; 48: 991–7. 9 Chang A, Kuligowski ME, van de Kerkhof PC. Multiple milia during treatment with acitretin for mycosis fungoides. Acta Derm Venereol (Stockh) 1993; 73: 235. 10 Mørk N-J, Kolbenstvedt A, Austad J. Skeletal side-effects of 5 years’ acitretin treatment. Br J Dermatol 1996; 134: 1156–7. 11 McMullen EA, McCarron P, Irvine D et al. Association between long-term acitretin therapy and osteoporosis: no evidence of increased risk. Clin Exp Dermatol 2003; 28: 307–9. 12 Lambert WE, De Leenheer AP, De Bersaques JP, Kint A. Persistent etretinate levels in plasma after changing the therapy to acitretin. Arch Dermatol Res 1990; 282: 343–4. 13 Sturkenboom MC, de Jong van den Berg LT, van Voorst Vader PC et al. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of

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these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994; 38: 229–35. 14 Grønhøy Larsen F, Steinkjer B, Jakobsen P et al. Acitretin is converted to etretinate only during concomitant alcohol intake. Br J Dermatol 2000; 143: 1164–9.

Etretinate This drug is discussed because of its relationship to acitretin. The dermatological side effects are dose dependent, and resemble those associated with isotretinoin therapy [1–3]. With dosage over 0.5 mg/kg, cheilitis with dryness, scaling and fissuring of the lips is almost universal. There may be pruritus, a dry mouth, dry nose, epistaxis, meatitis, desquamation including the face, hands and feet, and reduced tolerance of sunlight [4] and therapeutic products such as tar or dithranol. Pseudoporphyria has been reported in a renal transplant recipient treated with etretinate to suppress cutaneous neoplasia [5]. A ‘retinoid dermatitis’ resembling asteatotic eczema may develop in up to 50% of patients [6]. Increased stickiness of the palms and soles, possibly due to increased quantities of carcinoembryonic antigen and other glycoproteins in eccrine sweat [7,8], has been reported. Mucosal erosions, conjunctivitis, paronychia, alopecia [9] and curling, kinking or darkening of hair [10] are all well documented. Intertriginous erosions have also been described [11]. Oedema [12], excess granulation tissue [13] and multiple pyogenic granulomas [14] develop rarely. Erythroderma has been reported [15]. Prolonged therapy may lead to skin fragility [16,17]; blistering, erosions and scarring have been reported in one patient [18]. Softening of the nails is seen [19], and chronic paronychia, onycholysis, onychomadesis, nail shedding, onychoschizia and fragility may occur [20,21]. Parakeratotic digitate keratoses appearing after treatment of disseminated superficial actinic porokeratosis may arise as a result of etretinate-resistant regions in the ring of the cornoid lamella [22]. There has been a single case of generalization of palmoplantar pustulosis following cessation of etretinate therapy [23]. Systemic side effects of etretinate include benign intracranial hypertension [24]. Minor disturbances in tests of liver function are not uncommon, and may not always be reversible; liver changes range from non-specific reactive hepatitis to acute hepatitis, chronic active hepatitis and severe fibrosis or cirrhosis [25–28]. Fatal liver necrosis occurred in a patient with ichthyosiform erythroderma [29], but other factors may have been relevant. However, several studies involving liver biopsies have indicated good tolerance of etretinate without significant hepatotoxic side effects [30– 32]; in one study, patients were followed for 3 years [32]. Etretinate, like isotretinoin, can cause increase in triglycerides and cholesterol [33–36] but to a lesser extent [36]. There have been isolated reports of possible etretinate-related thrombocytopenia [37]. Retinal toxicity has been postulated [38], although a recent report has not confirmed this [39]. Erectile dysfunction has been documented occasionally [40]. Skeletal abnormalities, such as periosteal thickening, vertebral hyperostosis, disc degeneration, osteoporosis and calcification of spinal ligaments, occur in a significant number of adults receiving long-term therapy for disorders of keratinization, but the severity of the changes is minor [41,42]. Radiological evidence of thinning of long bones may be seen in children [43], and premature epiphyseal closure has been recorded [44].

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Etretinate, like isotretinoin, is grossly teratogenic, and because of its deposition in body fat stores is excreted only very slowly, especially in the obese [45]. Detectable serum levels have been found in some patients more than 2 years after discontinuation of therapy. It is therefore recommended that female patients of childbearing years should be advised to prevent pregnancy not only during the course of treatment but also for at least 2 years after stopping therapy; if pregnancy is contemplated after this period of time, an estimation of circulating levels of retinoid metabolites should be obtained. References 1 Foged E, Jacobsen F. Side-effects due to Ro 10-3959 (Tigason). Dermatologica 1982; 164: 395–403. 2 Ellis CN, Voorhees JJ. Etretinate therapy. J Am Acad Dermatol 1987; 16: 267– 91. 3 Halioua B, Saurat J-H. Risk: benefit ratio in the treatment of psoriasis with systemic retinoids. Br J Dermatol 1990; 122 (Suppl. 36): 135–50. 4 Collins MRL, James WD, Rodman OG. Etretinate photosensitivity. J Am Acad Dermatol 1986; 14: 274. 5 McDonagh AJG, Harrington CI. Pseudoporphyria complicating etretinate therapy. Clin Exp Dermatol 1989; 14: 437–8. 6 Taieb A, Maleville J. Retinoid dermatitis mimicking ‘eczéma craquelé’. Acta Derm Venereol (Stockh) 1985; 65: 570. 7 Pennys NS, Hernandez D. A sticky problem with etretinate. N Engl J Med 1991; 325: 521. 8 Higgins EM, Pembroke AC. Sticky palms: an unusual side-effect of etretinate therapy. Clin Exp Dermatol 1993; 18: 389–90. 9 Berth-Jones J, Shuttleworth D, Hutchinson PE. A study of etretinate alopecia. Br J Dermatol 1990; 122: 751–5. 10 Vesper JL, Fenske A. Hair darkening and new growth associated with etretinate therapy. J Am Acad Dermatol 1996; 34: 860. 11 Shelley ED, Shelley WB. Inframammary, intertriginous, and decubital erosion due to etretinate. Cutis 1991; 47: 111–3. 12 Allan S, Christmas T. Severe edema associated with etretinate. J Am Acad Dermatol 1988; 19: 140. 13 Hodak E, David M, Feuerman EJ. Excess granulation tissue during etretinate therapy. J Am Acad Dermatol 1984; 11: 1166–7. 14 Williamson DM, Greenwood R. Multiple pyogenic granulomata occurring during etretinate therapy. Br J Dermatol 1983; 109: 615–7. 15 Levin J, Almeyda J. Erythroderma due to etretinate. Br J Dermatol 1985; 112: 373. 16 Williams ML, Elias PM. Nature of skin fragility in patients receiving retinoids for systemic effect. Arch Dermatol 1981; 117: 611–9. 17 Neild VS, Moss RF, Marsden RA et al. Retinoid-induced skin fragility in a patient with hepatic disease. Clin Exp Dermatol 1985; 10: 459–65. 18 Ramsay B, Bloxham C, Eldred A et al. Blistering, erosions and scarring in a patient on etretinate. Br J Dermatol 1989; 121: 397–400. 19 Lindskov R. Soft nails after treatment with aromatic retinoids. Arch Dermatol 1982; 118: 535–6. 20 Baran R. Action thérapeutique et complications du rétinoïde aromatique sur l’appareil unguéal. Ann Dermatol Vénéréol 1982; 109: 367–71. 21 Baran R. Etretinate and the nails (study of 130 cases): possible mechanisms of some side-effects. Clin Exp Dermatol 1986; 11: 148–52. 22 Carmichael AJ, Tan CY. Digitate keratoses: a complication of etretinate used in the treatment of disseminated superficial actinic porokeratosis. Clin Exp Dermatol 1990; 15: 370–1. 23 Miyagawa S, Muramatsu T, Shirai T. Generalization of palmoplantar pustulosis after withdrawal of etretinate. J Am Acad Dermatol 1991; 24: 305–6. 24 Viraben R, Mathieu C. Benign intracranial hypertension during etretinate therapy for mycosis fungoides. J Am Acad Dermatol 1985; 13: 515–7. 25 Schmidt H, Foged E. Some hepatotoxic side effects observed in patients treated with aromatic retinoid (Ro 10-9359). In: Orfanos CE, Braun-Falco O, Farber EM et al., eds. Retinoids. Advances in Basic Research and Therapy. Berlin: Springer, 1981: 359–62. 26 Van Voorst Vader P, Houthoff H, Eggink H, Gips C. Etretinate (Tigason) hepatitis in two patients. Dermatologica 1984; 168: 41–6.

27 Kano Y, Fukuda M, Shiohara T, Nagashima M. Cholestatic hepatitis occurring shortly after etretinate therapy. J Am Acad Dermatol 1994; 31: 133–4. 28 Sanchez MR, Ross B, Rotterdam H et al. Retinoid hepatitis. J Am Acad Dermatol 1993; 28: 853–8. 29 Thune P, Mørk NJ. A case of centrolobular necrosis of the liver due to aromatic retinoid: Tigason (Ro-10-9359). Dermatologica 1980; 160: 405–8. 30 Foged E, Bjerring P, Kragballe K et al. Histologic changes in the liver during etretinate treatment. J Am Acad Dermatol 1984; 11: 580–3. 31 Zachariae H, Foged E, Bjerring P et al. Liver biopsy during etretinate (Tigason®) treatment. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 494–7. 32 Roenigk HH Jr. Retinoids: effect on the liver. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 476–88. 33 Ellis CN, Swanson NA, Grekin RC et al. Etretinate therapy causes increases in lipid levels in patients with psoriasis. Arch Dermatol 1982; 118: 559–62. 34 Michaëlsson G, Bergquist A, Vahlquist A, Vessby B. The influence of ‘Tigason’ (R 10-9359) on the serum lipoproteins in man. Br J Dermatol 1981; 105: 201–5. 35 Vahlquist C, Michaëlsson G, Vahlquist A, Vessby B. A sequential comparison of etretinate (Tigason®) and isotretinoin (Roaccutane®) with special regard to their effects on serum lipoproteins. Br J Dermatol 1985; 112: 69–76. 36 Marsden J. Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences. Br J Dermatol 1986; 114: 401–7. 37 Naldi L, Rozzoni M, Finazzi G et al. Etretinate therapy and thrombocytopenia. Br J Dermatol 1991; 124: 395. 38 Weber U, Melink B, Goerz G, Michaelis L. Abnormal retinal function associated with long-term etretinate? Lancet 1988; i: 235–6. 39 Pitts JF, MacKie RM, Dutton GN et al. Etretinate and visual function: a 1-year follow-up study. Br J Dermatol 1991; 125: 53–5. 40 Reynolds OD. Erectile dysfunction in etretinate treatment. Arch Dermatol 1991; 127: 425–6. 41 DiGiovanna JJ, Gerber LH, Helfgott RK et al. Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. N Engl J Med 1986; 315: 1177–82. 42 Halkier-Sørensen L, Andresen J. A retrospective study of bone changes in adults treated with etretinate. J Am Acad Dermatol 1989; 20: 83–7. 43 Halkier-Sørensen L, Laurberg G, Andresen J. Bone changes in children on longterm treatment with etretinate. J Am Acad Dermatol 1987; 16: 999–1006. 44 Prendiville J, Bingham EA, Burrows D. Premature epiphyseal closure: a complication of etretinate therapy in children. J Am Acad Dermatol 1986; 15: 1259–62. 45 DiGiovanna JJ, Zech LA, Ruddel ME et al. Etretinate: persistent serum levels after long-term therapy. Arch Dermatol 1989; 125: 246–51.

Isotretinoin (13-cis-retinoic acid) Dermatological complications have been reviewed [1,2]; erythema and scaling of the face, generalized xerosis, skin fragility, pruritus, epistaxis, dry nose and dry mouth may be seen in up to 80% of cystic acne patients; hoarseness is documented. A dose-related cheilitis occurs in over 90% and conjunctivitis in about 40% of patients. Transient exacerbation of acne may occur, especially in the early stages of therapy. Exuberant granulation tissue, or pyogenic granulomas at the site of healing acne lesions, has been reported frequently [3–7]. Rashes, including erythema, and thinning of the hair (in rare cases persistent) occur in fewer than 10% of patients. Both isotretinoin and etretinate have caused curliness or kinking of hair [8]. Nasolabial follicular sebaceous casts have been reported [9]. The following have occurred in approximately 5% of cases: peeling of the palms and soles, skin infections and possible increased susceptibility to sunburn. Phototesting confirmed photosensitivity in some patients in one study [10] but not another [11]. A photoaggravated allergic reaction has been documented in which the patient had positive patch tests to isotretinoin [12]. Reversible melasma is recorded [13], as is facial cellulitis [14]. Angio-oedema and urticaria [15], facial oedema [16], and pyoderma gangrenosum

Important or widely prescribed drugs

[17] are recorded. Scarring, which may be keloidal, may occur after dermabrasion or laser therapy within a year of isotretinoin therapy; such procedures are best postponed during this period [18–20]. References 1 Yob EH, Pochi PE. Side effects and long-term toxicity of synthetic retinoids. Arch Dermatol 1987; 123: 1375–8. 2 Bigby M, Stern RS. Adverse reactions to isotretinoin. A report from the Adverse Drug Reaction Reporting System. J Am Acad Dermatol 1988; 18: 543–52. 3 Campbell JP, Grekin RC, Ellis CN et al. Retinoid therapy is associated with excess granulation tissue responses. J Am Acad Dermatol 1983; 9: 708–13. 4 Exner JH, Dahod S, Pochi PE. Pyogenic granuloma-like acne lesions during isotretinoin therapy. Arch Dermatol 1983; 119: 808–11. 5 Valentic JP, Barr RJ, Weinstein GD. Inflammatory neovascular nodules associated with oral isotretinoin treatment of severe acne. Arch Dermatol 1983; 119: 871–2. 6 Stary A. Acne conglobata: Ungewöhnlicher Verlauf unter 13-cis-Retinsäuretherapie. Hautarzt 1986; 37: 28–30. 7 Blanc D, Zultak M, Wendling P, Lonchampt F. Eruptive pyogenic granulomas and acne fulminans in two siblings treated with isotretinoin. A possible common pathogenesis. Dermatologica 1988; 177: 16–8. 8 Bunker CB, Maurice PDL, Dowd PM. Isotretinoin and curly hair. Clin Exp Dermatol 1990; 15: 143–5. 9 Plewig G. Nasolabial follicular sebaceous casts: a novel complication of isotretinoin therapy. Br J Dermatol 2001; 144: 919. 10 Ferguson J, Johnson BE. Photosensitivity due to retinoids: clinical and laboratory studies. Br J Dermatol 1986; 115: 275–83. 11 Wong RC, Gilber M, Woo TY et al. Photosensitivity and isotretinoin therapy. J Am Acad Dermatol 1986; 15: 1095–6. 12 Auffret N, Bruley C, Brunetiere RA et al. Photoaggravated allergic reaction to isotretinoin. J Am Acad Dermatol 1990; 23: 321–2. 13 Burke H, Carmichael AJ. Reversible melasma associated with isotretinoin. Br J Dermatol 1996; 135: 862. 14 Boffa MJ, Dave VK. Facial cellulitis during oral isotretinoin treatment for acne. J Am Acad Dermatol 1994; 31: 800–2. 15 Saray Y, Seçkin D. Angioedema and urticaria due to isotretinoin therapy. J Eur Acad Dermatol Venereol 2006; 20: 118–20. 16 Scheinfeld N, Bangalore S. Facial edema induced by isotretinoin use: a case and a review of the side effects of isotretinoin. J Drugs Dermatol 2006; 5: 467–8. 17 Freiman A, Brassard A. Pyoderma gangrenosum associated with isotretinoin therapy. J Am Acad Dermatol 2006; 55 (Suppl. 5): S107–8. 18 Rubenstein R, Roenigk HH Jr, Stegman SJ et al. Atypical keloids after dermabrasion of patients taking isotretinoin. J Am Acad Dermatol 1986; 15: 280–5. 19 Zachariae H. Delayed wound healing and keloid formation following argon laser treatment or dermabrasion during isotretinoin treatment. Br J Dermatol 1988; 118: 703–6. 20 Katz BE, MacFarlane DF. Atypical facial scarring after isotretinoin therapy in a patient with previous dermabrasion. J Am Acad Dermatol 1994; 30: 852–3.

Systemic side effects. These include headache, which is not uncommon; anorexia, nausea and vomiting are much more common than with etretinate, as are lethargy, irritability and fatigue [1]. Isotretinoin therapy has been associated with benign intracranial hypertension [2]; in some cases, there was concomitant use of tetracyclines, so this combination should be avoided. A variety of central nervous system reactions have been reported, but may bear no relationship to therapy. Patients treated for disorders of keratinization have developed corneal opacities, which improved when the drug was withdrawn [3]. Blepharoconjunctivitis, dry eyes with decreased tolerance of contact lenses and blurred vision due to myopia may occur [4]. Decreased night vision has been documented rarely, as have cataracts and other visual disturbances [5,6]; decreased night vision after isotretinoin therapy may be more permanent than generally

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suspected [7,8], and many asymptomatic patients have abnormal electroretinograms [6]. Loss of sense of taste is recorded [9]. Transient chest pain is uncommon. Non-specific urogenital findings and non-specific gastrointestinal symptoms have occurred in approximately 5% of cases. Isotretinoin therapy has been associated with onset of inflammatory bowel disease [10,11] and with impairment of pulmonary function in patients with systemic sclerosis [12,13]. Proteinuria is recorded. Approximately 16% of patients develop musculoskeletal symptoms, including arthralgia, of mild to moderate degree; cases of acute knee aseptic arthritis have been documented [14]. High-dose prolonged therapy in a child for epidermolytic hyperkeratosis was associated with premature closure of epiphyses [15]. A high prevalence of skeletal hyperostosis has been noted in patients on prolonged (1 year or more), relatively high-dose (2 mg/kg daily) isotretinoin therapy for disorders of keratinization [16–20]. The syndrome of diffuse idiopathic skeletal hyperostosis (dish) includes ossification of ligaments and accretion of bone onto vertebral bodies, especially of the cervical spine. Mild osteoporosis has also been seen. X-ray changes have been minimal in prospective studies of patients with cystic acne treated with a single course of isotretinoin at recommended doses [21–23]. Nasal bone osteophytosis has been described with short-term therapy for acne [24]. Mild to moderate elevation of liver enzymes occurs in about 15% of cases; in some patients these return to normal despite continued administration of the drug. A single case of fatty liver developing in a patient (with low to normal levels of α1-antitrypsin) on low-dose isotretinoin has been reported [25]. Elevated sedimentation rates occur in about 40% of patients. Between 10 and 20% of patients show decreased red blood cell parameters and white blood cell counts, elevated platelet counts and pyuria. Thrombocytopenia may occur [26]. Isotretinoin induces reversible changes in serum lipids in a significant number of treated subjects [27–32]. A dose-related increase in triglycerides occurs in about 25% of individuals according to the Roche data sheet; five of 135 cystic acne patients, and 32 of 298 patients treated for all diagnoses, showed triglyceride levels above 500 mg/dL. In another study, 17% of patients taking isotretinoin for 20 weeks exhibited hypertriglyceridaemia, but in 15% this was of only mild to moderate degree [30]. About 15% showed a mild to moderate decrease in serum high density lipoprotein levels, and 7% experienced minimal elevations of serum cholesterol during therapy; some patients had increases in LDL cholesterol [30]. Lipid abnormalities peaked within 4 weeks in men, but not until 12 weeks in women. If sustained over a long period, these alterations in lipoproteins might be risk factors for coronary artery disease. Patients with an increased tendency to develop hypertriglyceridaemia include those with diabetes mellitus, obesity, increased alcohol intake or a familial history. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing the drug. An obese male patient with Darier’s disease developed elevated triglycerides and subsequent eruptive xanthomas [33]. References 1 Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. J Am Acad Dermatol 1982; 4: 675–82.

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2 Anonymous. Adverse effects with isotretinoin. J Am Acad Dermatol 1984; 10: 519–20. 3 Cunningham WJ. Use of isotretinoin in the ichthyoses. In: Cunliffe WJ, Miller AJ, eds. Retinoid Therapy. A Review of Clinical and Laboratory Research. Lancaster: MTP Press, 1984: 321–5. 4 Fraunfelder FT, La Braico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol 1985; 100: 534–7. 5 Brown RD, Grattan CEH. Visual toxicity of synthetic retinoids. Br J Ophthalmol 1989; 73: 286–8. 6 Gold JA, Shupack JL, Nemec MA. Ocular side effects of the retinoids. Int J Dermatol 1989; 28: 218–25. 7 Denman ST, Welebar RG, Hanifin JM et al. Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne. J Am Acad Dermatol 1986; 14: 692–3. 8 Maclean H, Wright M, Choie D, Tidman MJ. Abnormal night vision with isotretinoin therapy for acne. Clin Exp Dermatol 1995; 20: 86. 9 Halpern SM, Todd PM, Kirby JD. Loss of taste associated with isotretinoin. Br J Dermatol 1996; 134: 378. 10 Gold MH, Roenigk HH. The retinoids and inflammatory bowel disease. Arch Dermatol 1988; 124: 325–6. 11 Passier JL, Srivastava N, van Puijenbroek EP. Isotretinoin-induced inflammatory bowel disease. Neth J Med 2006; 64: 52–4. 12 Bunker CB, Sheron N, Maurice PDL et al. Isotretinoin and eosinophilic pleural effusion. Lancet 1989; i: 435–6. 13 Bunker CB, Maurice PDL, Little S et al. Isotretinoin and lung function in systemic sclerosis. Clin Exp Dermatol 1991; 16: 11–3. 14 Matsuoka LY, Wortsman J, Pepper JJ. Acute arthritis during isotretinoin treatment for acne. Arch Intern Med 1984; 144: 1870–1. 15 Milstone LM, McGuire J, Ablow RC. Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. J Am Acad Dermatol 1982; 7: 663–6. 16 Pittsley R, Yoder K. Retinoid hyperostosis. Skeletal toxicity associated with longterm administration of 13 cis-retinoic acid for refractory ichthyosis. N Engl J Med 1983; 308: 1012–4. 17 Ellis CN, Madison KC, Pennes DR et al. Isotretinoin is associated with early skeletal radiographic changes. J Am Acad Dermatol 1984; 10: 1024–9. 18 Gerber L, Helfgott R, Gross E et al. Vertebral abnormalities associated with synthetic retinoid use. J Am Acad Dermatol 1984; 10: 817–23. 19 Pennes D, Ellis C, Madison K et al. Early skeletal hyperostosis secondary to 13cis-retinoic acid. Am J Roentgenol 1984; 142: 979–83. 20 McGuire J, Milstone L, Lawson J. Isotretinoin administration alters juvenile and adult bone. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 419–39. 21 Ellis CN, Pennes DR, Madison KC et al. Skeletal radiographic changes during retinoid therapy. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 440–4. 22 Kilcoyne RF, Cope R, Cunningham W et al. Minimal spinal hyperostosis with low-dose isotretinoin therapy. Invest Radiol 1986; 21: 41–4. 23 Carey BM, Parkin GJS, Cunliffe WJ, Pritlove J. Skeletal toxicity with isotretinoin therapy: a clinico-radiological evaluation. Br J Dermatol 1988; 119: 609–14. 24 Novick NL, Lawson W, Schwartz IS. Bilateral nasal bone osteophytosis associated with short-term oral isotretinoin therapy for cystic acne vulgaris. Am J Med 1984; 77: 736–9. 25 Taylor AEM, Mitchison H. Fatty liver following isotretinoin. Br J Dermatol 1991; 124: 505–6. 26 Johnson TM, Rainin R. Isotretinoin-induced thrombocytopenia. J Am Acad Dermatol 1987; 17: 838–9. 27 Nigra TP, Katz RA, Jorgensen H. Elevation of serum triglyceride levels from oral 13-cis-retinoic acid. In: Orfanos CE, Braun-Falco O, Farber EM et al., eds. Retinoids. Advances in Basic Research and Therapy. Berlin: Springer, 1981: 363–9. 28 Lyons F, Laker MF, Marsden JR et al. Effect of oral 13-cis-retinoic acid on serum lipids. Br J Dermatol 1982; 107: 591–5. 29 Zech LA, Gross EG, Peck GL, Brewer HB. Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study. Arch Dermatol 1983; 119: 987–93. 30 Bershad S, Rubinstein A, Paterniti JR Jr et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985; 313: 981–5.

31 Gollnick H, Schwartzkopff W, Pröschle W et al. Retinoids and blood lipids: an update and review. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 445–60. 32 Marsden J. Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences. Br J Dermatol 1986; 114: 401–7. 33 Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 1980; 16: 951–2.

Effects on mood. The issue of whether isotretinoin may be associated with initiation or exacerbation of depression is a particular matter of controversy [1,2]. Anecdotal reports suggested this possibility; resolution usually, but not always [3], occurs within a few weeks of cessation of therapy. Psychiatric symptoms occurred in seven of 700 patients in one study, with recurrence of depression following rechallenge in some cases [4]. Of 5 million individuals exposed to isotretinoin in the USA between 1982 and 2000, 37 patients committed suicide, 100 were hospitalized for treatment of depression and 284 were managed as out-patients [5]. This incidence of suicide is less than that predicted for a group of comparable age and sex distribution. A large study comparing 7195 patients treated with isotretinoin with 13 700 patients treated with antibiotics, drawn from Canadian and UK databases, concluded that there was no increase in depression or suicide in the isotretinoin-treated group [6]. However, the study has been criticized as flawed with regard to the UK data, because it was provided by general practitioners who were not responsible for prescribing the drug, and there may have been selection bias in the ascertainment of mental disorders. A study of 2821 patients found no evidence to support an association between use of isotretinoin and onset of depression [7]. The field is complicated by the fact that there may be a confounding effect of acne on the development of psychological or psychiatric effects [8,9]. In addition, there is an increased frequency of pretreatment anxiety in patients and their families [5]. Conversely, isotretinoin therapy may lead to an improvement in mental state in some patients [8–11]. The majority of recent surveys have failed to show any increase in depression in isotretinoin-treated patients [10–13]. However, a single report has documented a slight increase in the risk of depression [14]. References 1 Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol 2001; 45 (Suppl.): S150–S157. 2 O’Connell KA, Wilkin JK, Pitts M. Isotretinoin (Accutane) and serious psychiatric adverse events. J Am Acad Dermatol 2003; 48: 306–8. 3 Gatti S, Serri F. Acute depression from isotretinoin. J Am Acad Dermatol 1991; 25: 132. 4 Scheinman PL, Peck GL, Rubinow DR et al. Acute depression from isotretinoin. J Am Acad Dermatol 1990; 23: 1112–4. 5 Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45: 515–9. 6 Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide and attempted suicide. Arch Dermatol 2000; 136: 1231–6. 7 Hersom K, Neary MP, Levaux HP et al. Isotretinoin and antidepressant pharmacotherapy: a prescription sequence symmetry analysis. J Am Acad Dermatol 2003; 49: 424–32. 8 Rubinow DR, Peck GL, Sqillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987; 17: 25–32. 9 Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol 1999; 140: 273–82.

Important or widely prescribed drugs 10 Chia CY, Lane W, Chibnall J et al. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 2005; 141: 557–60. 11 Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2007; 26: 210–20. 12 Kaymak Y, Kalay M, Ilter N, Taner E. Incidence of depression related to isotretinoin treatment in 100 acne vulgaris patients. Psychol Rep 2006; 99: 897–906. 13 Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol 2007; 14: e227–33. 14 Azoulay L, Blais L, Koren G et al. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry 2008; 69: 526–32.

Effects on pregnancy. Major human fetal abnormalities related to isotretinoin therapy during pregnancy have been documented [1–4]. The most frequently reported abnormalities involve the central nervous system (microcephaly or hydrocephalus and cerebellar malformation) and cardiovascular system (anomalies of the great vessels). Microtia or absence of external ears, microphthalmia, facial dysmorphia and thymus gland abnormalities have also been reported. There is an increased risk of spontaneous abortion. Women of child-bearing potential should sign a consent form and be instructed that they should not be pregnant when isotretinoin therapy is started (preferably on the second or third day of the next normal menstrual period) and should use effective contraception (two methods, one of which should be a barrier method) during, and for 1 month after stopping, therapy. The guidelines state that women of child-bearing age should be monitored monthly with screening pregnancy tests whilst on treatment and a month after stopping the drug. Isotretinoin has a much shorter half-life than etretinate, so that pregnancy is permissible 1 month after stopping therapy. Unfortunately, despite the guidelines, women continue to become pregnant whilst on the drug [5,6]. In one recent series, of 53 pregnant women exposed to isotretinoin, only 41% reported using any birth control, and only one patient used two methods; 45% of exposed pregnancies were terminated before delivery, and 22% delivered a healthy child; two babies were born with malformations [6]. Analysis of data voluntarily reported to Hoffmann La Roche Inc. in the USA enabled prospective study of 88 patients who had completed or discontinued isotretinoin therapy prior to becoming pregnant; 90% of all pregnancies occurred within 2 months after cessation of therapy, and 64% within 1 month [7]. There were no significant increases in the rates of spontaneous abortion or of congenital malformations among the live births. There appears to be no adverse effect of isotretinoin on male reproductive function [8,9]. References 1 Ellis Hill RM. Isotretinoin teratogenicity. Lancet 1984; i: 1465. 2 Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol 1984; 10: 851–4. 3 Chen DT. Human pregnancy experience with the retinoids. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 398–406. 4 Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A cogeners, the outcome of pregnancies in patients who had taken isotretinoin. Teratology 1986; 33: 355–64. 5 Robertson J, Polifka JE, Avner M et al. A survey of pregnant women using isotretinoin. Birth Defects Res A Clin Mol Teratol 2005; 73: 881–7.

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6 Garcia-Bournissen F, Tsur L, Goldstein LH et al. Fetal exposure to isotretinoin— an international problem. Reprod Toxicol 2008; 25: 124–8. 7 Dai WS, Hsu M-A, Itri L. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 1989; 125: 362–5. 8 Schill W-B, Wagner A, Nikolowski J, Plewig G. Aromatic retinoid and 13-cisretinoic acid: spermatological investigations. In: Orfanos CE, Braun-Falco O, Farber EM et al., eds. Retinoids. Advances in Basic Research and Therapy. Berlin: Springer, 1981: 389–95. 9 Töröck L, Kása M. Spermatological and endocrinological examinations connected with isotretinoin treatment. In: Saurat JH, ed. Retinoids: New Trends in Research and Therapy. Basel: Karger, 1985: 407–10.

Tazarotene Pyogenic granuloma-like lesions have been associated with the use of this topical retinoid in the treatment of psoriasis [1,2]. Tretinoin Oral tretinoin administered as differentiation therapy of acute promyelocytic leukaemia was associated with mild rashes, the nature of which was unspecified [3]. An acute neutrophilic dermatosis with a myeloblastic infiltrate occurred in a leukaemic patient receiving all-trans-retinoic acid therapy [4]. References 1 Dawkins MA, Clark AR, Feldman SR. Pyogenic granuloma-like lesion associated with topical tazarotene therapy. J Am Acad Dermatol 2000; 43: 154–5. 2 Pierson JC, Owens NM. Pyogenic granuloma-like lesions associated with topical retinoid therapy. J Am Acad Dermatol 2001; 45: 967–8. 3 Warrell RP, Frankel SR, Miller WH et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991; 324: 1385–93. 4 Piette WW, Trapp JF, O’Donnell MJ et al. Acute neutrophilic dermatosis with myeloblastic infiltrate in a leukemia patient receiving all-trans-retinoic acid therapy. J Am Acad Dermatol 1994; 30: 293–7.

Vitamin B Vitamin B1 Anaphylaxis following intravenous administration has occurred [1].

Vitamin B6 (pyridoxine) Vasculitis is recorded [2], as is a pseudoporphyria syndrome with megadosage [3]. A photosensitive eruption [4] and rosacea fulminans (with concommitant vitamin B12 therapy) are documented [5]. Nicotinic acid Flushing is common; other transient rashes, urticaria, pruritus, scaling, hyperpigmentation and an acanthosis nigricans-like eruption [6,7] are all documented. Persistent rashes and hair loss have rarely occurred. References 1 Kolz R, Lonsdorf G, Burg G. Unverträgslichkeitsreaktionen nach parenteraler Gabe von Vitamin B1. Hautarzt 1980; 31: 657–9. 2 Ruzicka T, Ring J, Braun-Falco O. Vasculitis allergica durch Vitamin B6. Hautarzt 1984; 35: 197–9. 3 Baer R, Stilman MA. Cutaneous skin changes probably due to pyridoxine abuse. J Am Acad Dermatol 1984; 10: 527–8. 4 Murata Y, Kumano K, Ueda T et al. Photosensitive dermatitis caused by pyridoxine hydrochloride. J Am Acad Dermatol 1998; 39: 314–7. 5 Jansen T, Romiti R, Kreuter A, Altmeyer P. Rosacea fulminans triggered by highdose vitamins B6 and B12. J Eur Acad Dermatol Venereol 2001; 15: 484–5.

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6 Tromovitch TA, Jacobs PH, Kern S. Acanthosis nigricans-like lesions from nicotinic acid. Arch Dermatol 1964; 89: 222–3. 7 Elgart ML. Acanthosis nigricans and nicotinic acid. J Am Acad Dermatol 1981; 5: 709–10.

Vitamin C (ascorbic acid) Patients with cutaneous and respiratory allergy have been described.

Vitamin E (a-tocopherol) White hair developed at injection sites in infants given intramuscular vitamin E for epidermolysis bullosa, probably due to quinones formed during vitamin E degradation [1]. Reference 1 Sehgal VN. Vitamin E: a melanotoxic agent. A preliminary report. Dermatologica 1972; 145: 56–9.

Vitamin K Skin reactions with vitamin K have been reviewed [1–11]. Three distinct types of cutaneous reaction are seen: (i) localized eczematous at the injection site (onset 4–16 days, dose range 10–410 mg); (ii) localized morphoea-form (average onset 8.5 months, range 5 weeks to 1.5 years, dose range 30–2080 mg); and (iii) very rarely, a diffuse maculopapular eruption [10,11]. The pruritic, erythematous, macular lesions or plaques may last for up to 6 months, whereas the prognosis for resolution of the morphoea-form changes is very poor. Patch and intradermal skin tests may be positive, suggesting an immunological basis. Most, but not all [3,6,8], cases have occurred in patients with liver disease. In addition, a proportion of these reactions progress to produce scleroderma-like changes [9,12–16]. An annular erythema has been documented [17]. References 1 Barnes HM, Sarkany I. Adverse skin reactions from vitamin K1. Br J Dermatol 1976; 95: 653–6. 2 Bullen AW, Miller JP, Cunliffe WJ, Losowsky MS. Skin reactions caused by vitamin K in patients with liver disease. Br J Dermatol 1978; 98: 561–5. 3 Sanders MN, Winkelmann RK. Cutaneous reactions to vitamin K. J Am Acad Dermatol 1988; 19: 699–704. 4 Mosser C, Janin-Mercier A, Souteyrand P. Les réactions cutanées apres administration parentérale de vitamine K. Ann Dermatol Vénéréol 1987; 114: 243–51. 5 Finkelstein H, Champion MC, Adam JE. Cutaneous hypersensitivity to vitamin K1 injection. J Am Acad Dermatol 1987; 16: 540–5. 6 Joyce JP, Hood AF, Weiss MM. Persistent cutaneous reaction to intramuscular vitamin K injection. Arch Dermatol 1988; 124: 27–8. 7 Tuppal R, Tremaine R. Cutaneous eruption from vitamin K1 injection. J Am Acad Dermatol 1992; 27: 105–6. 8 Lee MM, Gellis S, Dover JS. Eczematous plaques in a patient with liver failure. Fat-soluble vitamin K hypersensitivity. Arch Dermatol 1992; 128: 257, 260. 9 Lemlich G, Green M, Phelps R et al. Cutaneous reactions to vitamin K1 injections. J Am Acad Dermatol 1993; 28: 345–7. 10 Wong DA, Freeman S. Cutaneous allergic reaction to intramuscular vitamin K1. Australas J Dermatol 1999; 40: 147–52. 11 Wilkins K, DeKoven J, Assaad D. Cutaneous reactions associated with vitamin K1. J Cutan Med Surg 2000; 4: 164–8. 12 Texier L, Gendre PH, Gauthier O et al. Hypodermites sclérodermiformes lombofessières induites par des injections médicamenteuses intramusculaires associées a la vitamine K1. Ann Dermatol Syphiligr 1972; 99: 363–71. 13 Janin-Mercier A, Mosser C, Souteyrand P, Bourges M. Subcutaneous sclerosis with fasciitis and eosinophilia after phytonadione injections. Arch Dermatol 1985; 121: 1421–3.

14 Brunskill NJ, Berth-Jones J, Graham-Brown RAC. Pseudosclerodermatous reaction to phytomenadione injection (Texier’s syndrome). Clin Exp Dermatol 1988; 13: 276–8. 15 Pujol RM, Puig L, Moreno A et al. Pseudoscleroderma secondary to phytonadione (vitamin K1) injections. Cutis 1989; 43: 365–8. 16 Guidetti MS, Vincenzi C, Papi M, Tosti A. Sclerodermatous skin reaction after vitamin K1 injections. Contact Dermatitis 1994; 31: 45–6. 17 Kay MH, Duvic M. Reactive annular erythema after intramuscular vitamin K. Cutis 1986; 37: 445–8.

Hormones and related compounds ACTH and systemic corticosteroids The side effects of these agents have been reviewed [1–13]. Wellknown side effects include acne, cutaneous thinning and atrophy, telangiectasia, striae distensae, purpura and ecchymoses, hypertrichosis, impaired wound healing, pigmentary changes, cushingoid (moon) facies, truncal adiposity [14] and buffalo hump of the upper back. Acne occurred in one of 51 patients treated with intravenous corticosteroids in one study [15]. Other systemic side effects include fluid and electrolyte abnormalities, weight gain, oedema, hypertension, cardiac failure, peptic ulcer disease, pancreatitis, diabetes, muscular weakness, myopathy, tendon rupture, glaucoma, posterior subcapsular cataracts, mental changes including psychosis, osteoporosis, vertebral collapse, necrosis of the femoral head, growth suppression in children, opportunistic infection, masking of infection or reactivation of a dormant infection (e.g. tuberculosis), polycythaemia and suppression of the hypothalamic–pituitary axis. Pulse steroid therapy with systemic methylprednisolone has resulted in sudden death due to anaphylaxis, arrhythmia or ischaemic heart disease, but not particularly in dermatological patients [16].

Adrenocorticotrophic hormone Allergic reactions to ACTH are recorded but are uncommon. Urticaria and dizziness, nausea and weakness are the most frequent, but severe anaphylactic shock has occurred. Synthetic ACTH is usually tolerated by patients sensitive to animal ACTH [17]. Depot preparations containing tetracosactide (tetracosactrin) adsorbed on a zinc phosphate complex have produced reactions [18] and may induce melanoderma [19]. References 1 Lucky AW. Principles of the use of glucocorticosteroids in the growing child. Pediatr Dermatol 1984; 1: 226–35. 2 Fritz KA, Weston WL. Systemic glucocorticosteroid therapy of skin disease in children. Pediatr Dermatol 1984; 1: 236–45. 3 Davis GF. Adverse effects of corticosteroids. II. Systemic. Clin Dermatol 1986; 4: 161–9. 4 Gallant C, Kenny P. Oral glucocorticoids and their complications. A review. J Am Acad Dermatol 1986; 14: 161–77. 5 Seale PS, Compton MR. Side-effects of corticosteroid agents. Med J Aust 1986; 144: 139–42. 6 Chosidow O, Étienne SD, Herson S, Puech AJ. Pharmacologie des corticoides. Notions classiques et nouvelles. Ann Dermatol Vénéréol 1989; 116: 147–66. 7 Fine R. Glucocorticoids (1989). Int J Dermatol 1990; 29: 377–9. 8 Kyle V, Hazleman BL. Treatment of polymyalgia rheumatica and giant cell arteritis. II. Relation between steroid dose and steroid associated side effects. Ann Rheum Dis 1989; 48: 662–6. 9 Truhan AP, Ahmed AR. Corticosteroids: a review with emphasis on complications of prolonged systemic therapy. Ann Allergy 1989; 62: 375–90.

Important or widely prescribed drugs 10 Weiss MM. Corticosteroids in rheumatoid arthritis. Semin Arthritis Rheum 1989; 19: 9–21. 11 Rasanen L, Hasan T. Allergy to systemic and intralesional corticosteroids. Br J Dermatol 1993; 128: 407–11. 12 Dooms-Goossens A. Sensitisation to corticosteroids. Consequences for antiinflammatory therapy. Drug Saf 1995; 13: 123–9. 13 Imam AP, Halpern GM. Uses, adverse effects of abuse of corticosteroids. Part II. Allergol Immunopathol 1995; 23: 2–15. 14 Horber HH, Xurcher RM, Herren H et al. Altered body fat distribution in patients with glucocorticoid treatment and in patients on long-term dialysis. Am J Clin Nutr 1986; 43: 758–69. 15 Fung MA, Berger TG. A prospective study of acute-onset steroid acne associated with administration of intravenous corticosteroids. Dermatology 2000; 200: 43–4. 16 White KP, Driscoll MS, Rothe MJ, Grant-Kels JM. Severe adverse cardiovascular effects of pulse steroid therapy: is continuous cardiac monitoring necessary? J Am Acad Dermatol 1994; 30: 768–73. 17 Patriarca G. Allergy to tetracosactrin-depot. Lancet 1971; i: 138. 18 Clee MD, Ferguson J, Browning MCK et al. Glucocorticoid hypersensitivity in an asthmatic patient: presentation and treatment. Thorax 1985; 40: 477–8. 19 Khan SA. Melanoderma caused by depot tetracosactrin. Trans St John’s Hosp Dermatol Soc 1970; 56: 168–71.

Systemic corticosteroids In addition to those listed above, the cutaneous side effects of systemic corticosteroids include allergic and immediate reactions [1,2]. In one study, seven of 25 patients with cutaneous delayed-type hypersensitivity to hydrocortisone had an immediate reaction following intradermal injection of hydrocortisone sodium succinate, and had significantly increased levels of IgG antibodies to hydrocortisone. These patients are at risk of developing type III and possibly type I reactions following systemic hydrocortisone [3]. Protein binding of hydrocortisone or a degradation product may be important in the development of corticosteroid allergy [4]. Urticarial reactions have followed the intra-arterial injection of prednisone, prednisolone, hydrocortisone [5] or methylprednisolone [6], but are rare. Anaphylaxis occurred after intradermal injection of triamcinolone for alopecia areata [7]. Anaphylactoid reactions have been reported to topical and parenteral hydrocortisone, but may represent pseudoallergic reactions rather than IgE-mediated immediate hypersensitivity [8,9]. Generalized skin reactions, including urticaria and maculopapular eruptions, developed in patients after therapy with oral triamcinolone acetonide [10], prednisone [11], or dexamethasone and betamethasone [12]; the patients were subsequently shown to be patch-test positive to these corticosteroids. In another study, five patients reacted with diffuse erythema principally on the trunk or on the face, appearing within a few hours to 24 h and fading in 1–3 days, on treatment with systemic or intralesional hydrocortisone, methylprednisolone, prednisolone or betamethasone [2]. On patch testing, one patient reacted to prednisolone and methylprednisolone and two patients were positive to pivalone. Patients sensitive to hydrocortisone or methylprednisolone reacted to these corticosteroids in intradermal tests. A combination of intradermal and patch tests is recommended when allergy to systemic or intralesional corticosteroids is suspected [2]. Other cases of generalized, delayed systemic corticosteroid reactions, including eczematous or exanthematous eruptions and erythroderma, with or without bullae or purpura, often with positive patch or intradermal testing, have been recorded [13–18].

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Systemic administration of hydrocortisone, and provocation of endogenous cortisol secretion by injection of the ACTH analogue tetracosactide, provoked dose-dependent allergic skin reactions at sites of previous allergic reactions to topical steroids in two patients with proven topical corticosteroid sensitivity (i.e. systemic allergic contact-type dermatitis); in one case, this was at a positive patchtest site to hydrocortisone 17-butyrate [19]. Thus, it has been postulated that high stress levels, which cause increased secretion of endogenous adrenocortical hormones, could be implicated in exacerbations of eczema in corticosteroid-sensitive patients, and a persistent autoimmune skin reaction to cortisol might occur following topical sensitization to topical hydrocortisone [19]. The fact that, in steroid-sensitive patients, systemic provocation testing with hydrocortisone results in a reaction confined to the skin may be partly explained by the observation in vitro that only enriched Langerhans’ cells, and not peripheral blood mononuclear antigenpresenting cells, are capable of presenting corticosteroid to T cells of corticosteroid-sensitive subjects [20]. Perioral dermatitis has been recorded in renal transplant recipients on corticosteroids and immunosuppressive therapy [21]. Panniculitis following short-term high-dose steroid therapy in children manifests as subcutaneous nodules on the cheeks, arms and trunk [22]. Reversible panniculitis occurred in a child treated with steroids for hepatic encephalopathy [23]. Juxta-articular adiposis dolorosa developed in a patient treated with high doses of prednisone for the l-tryptophan-induced eosinophilia myalgia syndrome [24]. Acanthosis nigricans may occur with corticosteroid therapy [25]. Immunosuppression with corticosteroids has been associated with the development of Kaposi’s sarcoma during the treatment of temporal arteritis [26]. Inhaled corticosteroids have been associated with purpura and dermal thinning [27] as well as acne [28,29], perioral dermatitis and tongue hypertrophy [30], allergic reactions [31], an eczematous dermatitis [32] and adrenal suppression [29]. Nasal corticosteroids may cause nasal congestion, pruritus, burning and perforation of the septum, urticaria and eczema of the face [33]. Intralesional corticosteroid injection may also lead to allergic reactions [34], including a disseminated morbilliform and persistent urticarial dermatitis following intra-articular triamcinolone acetonide [35], erythroderma following intradermal budesonide [36] and erythema multiforme after intradural injection of prednisolone acetate [37]. Facial flushing and/or generalized erythema has followed epidural steroid injection [38]. Anaphylactic shock has been recorded after intra-articular injections of corticosteroids containing carboxymethylcellulose, benzylic acid, polysorbate 80 and merthiolate; skin tests to carboxymethylcellulose were positive [39]. References 1 Preuss L. Allergic reactions to systemic glucocorticoids: a review. Ann Allergy 1985; 55: 772–5. 2 Rasanen L, Hasan T. Allergy to systemic and intralesional corticosteroids. Br J Dermatol 1993; 128: 407–11. 3 Wilkinson SM, Mattey DL, Beck MH. IgG antibodies and early intradermal reactions to hydrocortisone in patients with cutaneous delayed-type hypersensitivity to hydrocortisone. Br J Dermatol 1994; 131: 495–8. 4 Wilkinson SM, English JS, Mattey DL. In vitro evidence of delayed-type hypersensitivity to hydrocortisone. Contact Dermatitis 1993; 29: 241–5.

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5 Ashford RF, Bailey A. Angioneurotic oedema and urticaria following hydrocortisone: a further case. Postgrad Med J 1980; 56: 437. 6 Pollock B, Wilkinson SM, MacDonald Hull SP. Chronic urticaria associated with intra-articular methylprednisolone. Br J Dermatol 2001; 144: 1228–30. 7 Downs AMR, Lear JT, Kennedy CTC. Anaphylaxis to intradermal triamcinolone acetonide. Arch Dermatol 1998; 134: 1163–4. 8 King RA. A severe anaphylactoid reaction to hydrocortisone. Lancet 1960; ii: 1093–4. 9 Peller JS, Bardana EL Jr. Anaphylactoid reaction to corticosteroid: case report and review of the literature. Ann Allergy 1985; 54: 302–5. 10 Brambilla L, Boneschi V, Chiappino G et al. Allergic reactions to topical desoxymethasone and oral triamcinolone. Contact Dermatitis 1989; 21: 272–3. 11 De Corres LF, Bernaola G, Urrutia I et al. Allergic dermatitis from systemic treatment with corticosteroids. Contact Dermatitis 1990; 22: 104–5. 12 Maucher O, Faber M, Knipper H et al. Kortikoidallergie. Hautarzt 1987; 38: 577–82. 13 Whitmore SE. Delayed systemic allergic reactions to corticosteroids. Contact Dermatitis 1995; 32: 193–8. 14 Torres V, Tavares-Bello R, Melo H, Soares AP. Systemic contact dermatitis from hydrocortisone. Contact Dermatitis 1993; 29: 106. 15 Vidal C, Tome S, Fernandex-Redondo V, Tato F. Systemic allergic reaction to corticosteroids. Contact Dermatitis 1994; 31: 273–4. 16 Whitmore SE. Dexamethasone injection-induced generalised dermatitis. Br J Dermatol 1994; 131: 296–7. 17 Fernandez de Corres L, Urrutia I, Audicana M et al. Erythroderma after intravenous injection of methylprednisolone. Contact Dermatitis 1991; 25: 68–70. 18 Yawalkar N, Hari Y, Helbling A et al. Elevated serum levels of interleukins 5, 6, and 10 in a patient with drug-induced exanthem caused by systemic corticosteroids. J Am Acad Dermatol 1998; 39: 790–3. 19 Lauerma AI, Reitamo S, Maibach HI. Systemic hydrocortisone/cortisol induces allergic skin reactions in presensitized subjects. J Am Acad Dermatol 1991; 24: 182–5. 20 Lauerma AI, Räsänen L, Reunala T, Reitamo S. Langerhans cells but not monocytes are capable of antigen presentation in vitro in corticosteroid contact hypersensitivity. Br J Dermatol 1991; 123: 699–705. 21 Adams SJ, Davison AM, Cunliffe WJ, Giles GR. Perioral dermatitis in renal transplant recipients maintained on corticosteroids and immunosuppressive therapy. Br J Dermatol 1982; 106: 589–92. 22 Roenigk HH, Haserick JR, Arundell FD. Poststeroid panniculitis. Arch Dermatol 1964; 90: 387–91. 23 Saxena AK, Nigam PK. Panniculitis following steroid therapy. Cutis 1988; 42: 341–2. 24 Greenbaum SS, Varga J. Corticosteroid-induced juxta-articular adiposis dolorosa. Arch Dermatol 1991; 127: 231–3. 25 Brown J, Winkelmann RK. Acanthosis nigricans: a study of 90 cases. Medicine (Baltimore) 1968; 47: 33–51. 26 Leung F, Fam AG, Osoba D. Kaposi’s sarcoma complicating corticosteroid therapy for temporal arteritis. Am J Med 1981; 71: 320–2. 27 Capewell S, Reynolds S, Shuttleworth D et al. Purpura and dermal thinning associated with high-dose inhaled corticosteroids. BMJ 1990; 300: 1548–51. 28 Monk B, Cunliffe WJ, Layton AM, Rhodes DJ. Acne induced by inhaled corticosteroids. Clin Exp Dermatol 1993; 18: 148–50. 29 Bong JL, Connell JM, Lever R. Intranasal betamethasone induced acne and adrenal suppression. Br J Dermatol 2000; 142: 579–80. 30 Dubus JC, Marguet C, Deschildre A et al. Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device. Allergy 2001; 56: 944–8. 31 Lauerma AH, Kiistala R, Makinen-Kiljunen S et al. Allergic skin reaction after inhalation of budesonide. Clin Exp Allergy 1993; 23: 232–3. 32 Holmes P, Cowen P. Spongiotic (eczematous-type) dermatitis after inhaled budesonide. Aust NZ J Med 1992; 22: 511. 33 Isaksson M. Skin reactions to inhaled corticosteroids. Drug Saf 2001; 24: 369–73. 34 Saff DM, Taylor JS, Vidimos AT. Allergic reaction to intralesional triamcinolone acetonide: a case report. Arch Dermatol 1995; 131: 742–3. 35 Ijsselmuiden OE, Knegt-Junk KJ, van Wijk RG, van Joost T. Cutaneous adverse reactions after intra-articular injection of triamcinolone acetonide. Acta Derm Venereol (Stockh) 1995; 75: 57–8.

36 Wilkinson SM, Smith AG, English JS. Erythroderma following the intradermal injection of the corticosteroid budesonide. Contact Dermatitis 1992; 27: 121–2. 37 Lavabre C, Chevalier X, Larget-Piet B. Erythema multiforme after intradural injection of prednisolone acetate. Br J Rheumatol 1992; 31: 717–8. 38 DeSio JM, Kahn CH, Warfield CA. Facial flushing and/or generalized erythema after epidural steroid injection. Anesth Analg 1995; 80: 617–9. 39 Beaudouin E, Kanny G, Gueant JL, Moneret-Vautrin DA. Anaphylaxie à la carboxymethylcellulose: à propos de deux cas de chocs à des corticoides injectables. Allerg Immunol 1992; 24: 333–5.

Topical corticosteroids The dermatological complications of topical corticosteroids have been reviewed [1–5]. Concerns have been expressed about the illegal availability of potent topical steroids in the UK, and their consequent unregulated use [6]. Many of the adverse reactions are related to the potency of the preparation; thus, in general, fluorinated steroids are associated with more significant side effects. Topical steroids cause decreased epidermal kinetic activity [7], decreased synthesis of dermal collagen types I and III and ground substance, and thinning of the dermis and epidermis [8–12]. Initial vasoconstriction of the superficial small vessels is followed by rebound vasodilatation, which becomes permanent in later stages. There are resultant striae, easy bruising, purpura, hypertrichosis and telangiectasia; stellate pseudoscars or ulcerated areas may be seen. Reversible hypopigmentation may develop. Local injection of a potent steroid may result in atrophy with telangiectasia, and localized lipoatrophy may occur. Perilymphatic atrophy is recorded following intradermal steroid injection. Long-term daily use of a potent steroid, especially under plastic occlusion as for fingertip eczema, may result in acroatrophy of terminal phalanges of the fingers [13,14]. Topical steroids may exacerbate acne, or lead to acne rosacea, with papules, pustules and telangiectasia, or perioral dermatitis, characterized by erythema, papules and pustules in the perioral area [15–17]. They decrease the number and antigen-presenting capacity of epidermal Langerhans’ cells [18], and mask or potentiate skin infections, including fungal (tinea incognito) and bacterial infections and verruca vulgaris. They may delay wound healing. Their withdrawal may provoke conversion of plaque- to pustulartype psoriasis [19]. Topical steroid therapy around the eye has been associated with development of glaucoma. Topical corticosteroids may induce allergic contact dermatitis [20–25]. The prevalence of positive patch tests to corticosteroids in contact dermatitis clinics ranges from 2 to 5%. The allergen may be the steroid itself, or a preservative or stabilizer such as ethylenediamine. There may be cross-reactivity between different steroids [20–22]. Cross-reactivity is more likely between steroids with similar substitutions at C-6 and C-9 positions. Intradermal tests may be a more sensitive means of detecting corticosteroid hypersensitivity than patch testing [23]. Systemic side effects of topical corticosteroids occur particularly from the use of large amounts of high-potency topical corticosteroids, especially under plastic occlusion [26,27]. Oedema due to sodium retention occurs more frequently with halogenated corticosteroids [27]. Hypothalamic–pituitary axis suppression may occur [28,29]; a single application of 25 g of 0.05% clobetasol propionate ointment suppressed plasma cortisol for 96 h [30]. Cushing’s syndrome [31,32] may result, and growth retardation in

Important or widely prescribed drugs

children is a hazard [33]. Glycosuria and hyperglycaemia may rarely occur [34]. References 1 Miller JA, Munro DD. Topical corticosteroids: clinical pharmacology and therapeutic use. Drugs 1980; 19: 119–34. 2 Behrendt H, Korting HC. Klinische Prüfung von erwünschten und unerwünschten Wirkungen topisch applizierbarer Glukokortikosteroide am Menschen. Hautarzt 1990; 41: 2–8. 3 Coskey RJ. Adverse effects of corticosteroids. I. Topical and intralesional. Clin Dermatol 1986; 4: 155–60. 4 Kligman AM. Adverse effects of topical corticosteroids. In: Christophers E, Schöpf E, Kligman AM, Stoughton RB, eds. Topical Corticosteroid Therapy: a Novel Approach to Safer Drugs. New York: Raven Press, 1988: 181–7. 5 Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006; 54: 1–15. 6 Keane FM, Munn SE, Taylor NF, du Vivier AW. Unregulated use of clobetasol propionate. Br J Dermatol 2001; 144: 1095–6. 7 Marshall RC, Du Vivier RA. The effects on epidermal DNA synthesis of the butyrate esters of clobetasone and clobetasol, and the propionate ester of clobetasol. Br J Dermatol 1978; 98: 355–9. 8 Smith JG, Wehr RF, Chalker DK. Corticosteroid-induced cutaneous atrophy and telangiectasia. Arch Dermatol 1976; 112: 1115–7. 9 Winter GD, Burton JL. Experimentally induced steroid atrophy in the domestic pig and man. Br J Dermatol 1976; 94: 107–9. 10 Lehmann P, Zheng P, Lacker RM, Kligman AM. Corticosteroid atrophy in human skin: a study by light, scanning and transmission electron microscopy. J Invest Dermatol 1983; 81: 169–76. 11 Oikarinen A, Haapasaari KM, Sutinen M, Tasanen K. The molecular basis of glucocorticoid-induced skin atrophy: topical glucocorticoid apparently decreases both collagen synthesis and the corresponding collagen mRNA level in human skin in vivo. Br J Dermatol 1998; 139: 1106–10. 12 Oishi Y, Fu ZW, Ohnuki Y et al. Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: effects on the synthesis of collagen type I and III, collagenase, and tissue inhibitors of metalloproteinases. Br J Dermatol 2002; 147: 859–68. 13 Requena L, Zamora E, Martin L. Acroatrophy secondary to long-standing applications of topical steroids. Arch Dermatol 1990; 126: 1013–4. 14 Wolf R, Tur E, Brenner S. Corticosteroid-induced ‘disappearing digit’. J Am Acad Dermatol 1990; 23: 755–6. 15 Sneddon I. Perioral dermatitis. Br J Dermatol 1972; 87: 430–2. 16 Cotterill JA. Perioral dermatitis. Br J Dermatol 1979; 101: 259–62. 17 Edwards EK Jr, Edwards ED Sr. Perioral dermatitis secondary to the use of a corticosteroid ointment as moustache wax. Int J Dermatol 1987; 26: 649. 18 Ashworth J, Booker J, Breathnach SM. Effect of topical corticosteroid therapy on Langerhans cell function in human skin. Br J Dermatol 1988; 118: 457–69. 19 Boxley JD, Dawber RPR, Summerly R. Generalised pustular psoriasis on withdrawal of clobetasol propionate ointment. BMJ 1975; 2: 225–6. 20 Lepoittevin JP, Drieghe J, Dooms-Goossens A. Studies in patients with corticosteroid contact allergy. Understanding cross-reactivity among different steroids. Arch Dermatol 1995; 131: 31–7. 21 Wilkinson SM, Hollis S, Beck MH. Cross-reaction patterns in patients with allergic contact dermatitis from hydrocortisone. Br J Dermatol 1995; 132: 766–71. 22 Wilkinson M, Hollis S, Beck M. Reactions to other corticosteroids in patients with positive patch test reactions to budesonide. J Am Acad Dermatol 1995; 33: 963–8. 23 Wilkinson SM, Heagerty AHM, English JSC. A prospective study into the value of patch and intradermal tests in identifying topical corticosteroid allergy. Br J Dermatol 1992; 127: 22–5. 24 Sommer S, Wilkinson SM, English JSC et al. Type-IV hypersensitivity to betamethasone valerate and clobetasol propionate: results of a multicentre study. Br J Dermatol 2002; 147: 266–9. 25 Scheuer E, Warshaw E. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics, and structural cross-reactivity. Am J Contact Dermat 2003; 14: 179–87. 26 Vickers CFH, Fritsch WC. A hazard of plastic film therapy. Arch Dermatol 1963; 87: 633–5.

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27 Fitzpatrick TB, Griswold MC, Hicks JH. Sodium retention and edema from percutaneous absorption of fluorcortisone acetate. JAMA 1955; 158: 1149–52. 28 Carruthers JA, August PJ, Staughton RCD. Observations on the systemic effect of topical clobetasol propionate (Dermovate). BMJ 1975; 4: 203–4. 29 Weston WL, Fennessey PV, Morelli J et al. Comparison of hypothalamus–pituitary–adrenal axis suppression from superpotent topical steroids by standard endocrine function testing and gas chromatographic mass spectrometry. J Invest Dermatol 1988; 90: 532–5. 30 Hehir M, du Vivier A, Eilon L et al. Investigation of the pharmacokinetics of clobetasol propionate and clobetasone butyrate after a single application of ointment. Clin Exp Dermatol 1983; 8: 143–51. 31 May P, Stein ES, Ryler RJ et al. Cushing syndrome from percutaneous absorption of triamcinolone cream. Arch Intern Med 1976; 136: 612–3. 32 Himathongkam T, Dasanabhairochana P, Pitchayayothin N, Sriphrapradang A. Florid Cushing’s syndrome and hirsutism induced by desoximetasone. JAMA 1978; 239: 430–1. 33 Bode HH. Dwarfism following long-term topical corticosteroid therapy. JAMA 1980; 244: 813–4. 34 Gomez EC, Frost P. Induction of glycosuria and hyperglycemia by topical corticosteroid therapy. Arch Dermatol 1976; 112: 1559–62.

Sex hormones Gonadotrophins These drugs may cause allergic reactions [1]. Menotrophin (Pergonal) has been associated with localized keratosis follicularis (Darier’s disease) [2]. Intracutaneous administration of two human menopausal gonadotrophin preparations (Organon and Pergonal) caused local induration and erythema [3]. References 1 Dore PC, Rice C, Killick S. Human gonadotrophin preparations may cause allergic reaction. BMJ 1994; 308: 1509. 2 Telang GH, Atillasoy E, Stierstorfer M. Localized keratosis follicularis associated with menotropin treatment and pregnancy. J Am Acad Dermatol 1994; 30: 271–2. 3 Odink J, Zuiderwijk PB, Schoen ED, Gan RA. A prospective, double-blind, splitsubject study on local skin reactions after administration of human menopausal gonadotrophin preparations to healthy female volunteers. Hum Reprod 1995; 10: 1045–7.

Gonadorelin analogues Buserelin. A pigmented roseola-like eruption has been documented [1]. Leuprorelin. This drug, given for precocious puberty, has caused anaphylaxis [2], rashes [3] and local reactions [4]. References 1 Kono T, Ishii M, Taniguchi S. Intranasal buserelin acetate-induced pigmented roseola-like eruption. Br J Dermatol 2000; 143: 658–9. 2 Taylor JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Aust 1994; 161: 455. 3 Carel JC, Lahlou N, Guazzarotti L et al. Treatment of central precocious puberty with depot leuprorelin. French Leuprorelin Trial Group. Eur J Endocrinol 1995; 132: 699–704. 4 Manasco PK, Pescovitz OH, Blizzard RM. Local reactions to depot leuprolide therapy for central precocious puberty. J Pediatr 1993; 123: 334–5.

Oestrogens and related compounds Oestrogens. Spider naevi and melanocytic naevi may develop under oestrogen therapy, as may chloasma. Severe premenstrual exacerbation of papulovesicular eruptions, urticaria, eczema or generalized pruritus occurred in seven women; several had a positive delayed tuberculin-type skin test to oestrogen [1]. Patients

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with generalized chronic urticaria had an urticarial reaction to intradermal oestrogens. Elimination of oral oestrogen therapy or antioestrogen therapy with tamoxifen proved effective. In another patient, a premenstrual urticarial reaction was exacerbated by oestrogen; oophorectomy cured the eruption [2]. A bullous autoimmune oestrogen dermatitis has been delineated [3]. Diethylstilbestrol therapy of pregnant women has been associated with female and male genital tract abnormalities in the offspring. Diethylstilbestrol is a transplacental carcinogen and has caused adenocarcinoma of the vagina 20 years later in young women whose mothers took the drug in the first 18 weeks of pregnancy [4–6]. Acanthosis nigricans has resulted from use of diethylstilbestrol [7]. Hyperkeratosis of the nipples developed in a man treated for adenocarcinoma of the prostate with diethylstilbestrol [8]. Porphyria cutanea tarda may also be precipitated [9,10]. References 1 Shelley WB, Shelley ED, Talanin NY, Santoso-Pham J. Estrogen dermatitis. J Am Acad Dermatol 1995; 32: 25–31. 2 Mayou SC, Charles-Holmes R, Kenney A et al. A premenstrual urticarial eruption treated with bilateral oophorectomy and hysterectomy. Clin Exp Dermatol 1988; 13: 114–6. 3 Mutasim DF, Baumbach JL. Bullous autoimmune estrogen dermatitis. J Am Acad Dermatol 2003; 49: 130–1. 4 Monaghan JM, Sirisena LAW. Stilboestrol and vaginal clear-cell adenocarcinoma syndrome. BMJ 1978; i: 1588–90. 5 Wingfield M. The daughters of stilboestrol. Grown up now but still at risk. BMJ 1991; 302: 1414–5. 6 Anonymous. Diethylstilboestrol: effects of exposure in utero. Drug Ther Bull 1991; 29: 49–50. 7 Banuchi SR, Cohen L, Lorincz AL, Morgan J. Acanthosis nigricans following diethylstilbestrol therapy. Arch Dermatol 1974; 109: 544–6. 8 Mold DE, Jegasothy BV. Estrogen-induced hyperkeratosis of the nipple. Cutis 1980; 26: 95–6. 9 Becker FT. Porphyria cutanea tarda induced by estrogens. Arch Dermatol 1965; 92: 252–6. 10 Roenigk HH, Gottlob ME. Estrogen-induced porphyria cutanea tarda. Arch Dermatol 1970; 102: 260–6.

Oral contraceptives. Cutaneous complications of oral contraceptives have been reviewed [1–4]. These drugs combine an oestrogen with a progestogen. Candidiasis is common; the sexual partner may suffer penile irritation after coitus without physical signs of frank candidal balanoposthitis. Genital warts may increase. Facial hyperpigmentation (chloasma) is well recognized [5,6], as are hirsutism and acne. Gingival epithelial melanosis has been recorded [7]. Alopecia related to contraceptive therapy may be of either androgenic or postpartum telogen pattern following withdrawal of the drug. Erythema nodosum is a well-recognized but rare complication [8,9]. The relapse of herpes gestationis is well documented [10]. Rare lichenoid, eczematous and fixed eruptions have been described, as have a lymphocytic cutaneous vasculitis and an eruption resembling Sweet’s syndrome [11]. Oral contraceptives have been implicated in both the provocation [12] and induction of remission of pityriasis lichenoides. An SLE-like reaction has also been reported [13]. An oral contraceptive-induced LE-like eruption, with erythematous lesions on the palms and feet in association with a weakly positive antinuclear factor and C1q deposition at the

dermal–epidermal junction on direct immunofluorescence, developed in a patient. It resolved on cessation of medication [14]. The jaundice rarely induced by these drugs resembles cholestatic jaundice of pregnancy. The hepatotoxic effects may result in provocation of variegate porphyria, porphyria cutanea tarda [15,16] and hereditary coproporphyria [17]; onycholysis may occur [16]. Photosensitivity unrelated to porphyrin disturbances has also been reported [18,19]. Benign hepatomas may also be a hazard [20]. Other hormonal contraceptives. Keloid formation has followed levonorgestrel implantion [21]. Vaginal erythematous areas were associated with use of a levonorgestrel-releasing contraceptive ring in 48 of 139 subjects [22]. Rosacea has been associated with a progesterone-releasing intrauterine contraceptive device [23]. Hormone replacement therapy. Melasma of the arms is recorded [24–26]. References 1 Baker H. Drug reactions VIII. Adverse cutaneous reaction to oral contraceptives. Br J Dermatol 1969; 81: 946–9. 2 Jelinek JE. Cutaneous complications of oral contraceptives. Arch Dermatol 1970; 101: 181–6. 3 Coskey RJ. Eruptions due to oral contraceptives. Arch Dermatol 1977; 113: 333–4. 4 Girard M. Évaluation des risques cutanés de la pilule. Ann Dermatol Vénéréol 1990; 117: 436–40. 5 Resnik S. Melasma induced by oral contraceptive drugs. JAMA 1967; 199: 601. 6 Smith AG, Shuster S, Thody AJ et al. Chloasma, oral contraceptives, and plasma immunoreactive beta melanocyte-stimulating hormone. J Invest Dermatol 1977; 68: 169–70. 7 Hertz RS, Beckstead PC, Brown WJ. Epithelial melanosis of the gingiva possibly resulting from the use of oral contraceptives. J Am Dent Assoc 1980; 100: 713–4. 8 Posternal F, Orusco MMM, Laugier P. Eythème noueux et contraceptifs oraux. Bull Dermatol 1974; 81: 642–5. 9 Bombardieri S, Di Munno O, Di Punzio C, Pasero G. Erythema nodosum associated with pregnancy and oral contraceptives. BMJ 1977; i: 1509–10. 10 Morgan JK. Herpes gestationis influenced by an oral contraceptive. Br J Dermatol 1968; 80: 456–8. 11 Tefany FJ, Georgouras K. A neutrophilic reaction of Sweet’s syndrome type associated with the oral contraceptive. Australas J Dermatol 1991; 32: 55–9. 12 Hollander A, Grotts IA. Mucha–Habermann disease following estrogen– progesterone therapy. Arch Dermatol 1973; 107: 465. 13 Garrovich M, Agudelo C, Pisko E. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum 1980; 23: 1396–8. 14 Furukawa F, Tachibana T, Imamura S, Tamura T. Oral contraceptive-induced lupus erythematosus in a Japanese woman. J Dermatol 1991; 18: 56–8. 15 Degos R, Touraine R, Kalis B et al. Porphyrie cutanée tardive après prise prolongé de contraceptifs oraux. Ann Dermatol Syphiligr 1969; 96: 5–14. 16 Byrne JPH, Boss JM, Dawber RPR. Contraceptive pill-induced porphyria cutanea tarda presenting with onycholysis of the finger nails. Postgrad Med J 1976; 52: 535–8. 17 Roberts DT, Brodie MJ, Moore MR et al. Hereditary coproporphyria presenting with photosensitivity induced by the contraceptive pill. Br J Dermatol 1977; 96: 549–54. 18 Erickson LR, Peterka ES. Sunlight sensitivity from oral contraceptives. JAMA 1968; 203: 980–1. 19 Cooper SM, George S. Photosensitivity reaction associated with use of the combined oral contraceptive. Br J Dermatol 2001; 144: 641–2. 20 Baum JK, Holtz F, Bookstein JJ, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973; ii: 926–8.

Important or widely prescribed drugs 21 Nuovo J, Sweha A. Keloid formation from levonorgestrel implant (Norplant System) insertion. J Am Board Family Pract 1994; 7: 152–4. 22 Bounds W, Szarewski A, Lowe D, Guillebaud J. Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring. Eur J Obstet Gynecol Reprod Biol 1993; 48: 123–5. 23 Choudry K, Humphreys F, Menage J. Rosacea in association with the progesterone-releasing intrauterine contraceptive device. Clin Exp Dermatol 2001; 26: 102. 24 Johnston GA, Sviland L, McLelland J. Melasma of the arms associated with hormone replacement therapy. Br J Dermatol 1998; 139: 932. 25 Varma S, Roberts DL. Melasma of the arms associated with hormone replacement therapy. Br J Dermatol 1999; 141: 592. 26 O’Brien TJ, Dyall-Smith D, Hall AP. Melasma of the arms associated with hormone replacement therapy. Br J Dermatol 1999; 141: 592–3.

Antioestrogens Clomifene (clomiphene). Hot flushes [1] and recurrent petechiae and palpable purpura of the legs with neutrophilic infiltration in a woman treated for infertility with multiple courses of clomifene [2] have been reported. References 1 Derman SG, Adashi EY. Adverse effects of fertility drugs. Drug Saf 1994; 11: 408–21. 2 Coots NV, McCoy CE, Gehlbach DL, Becker LE. A neutrophilic drug reaction to Clomid. Cutis 1996; 57: 91–3.

Tamoxifen. This oestrogen receptor antagonist used in the therapy of breast cancer in women has caused hirsutism, hair loss, dry skin and a variety of rashes [1]. Reference 1 Descamps V, Bouscarat F, Boui M et al. Delayed appearance of maculopapular eruptions induced by tamoxifen. Ann Dermatol Vénéreol 1999; 126: 716–7.

Progesterone and progestogens Autoimmune progesterone dermatitis. A number of eruptions, including urticaria, eczema, pompholyx, erythema annulare centrifugum and erythema multiforme, have been reported to recur cyclically in the second (luteal) phase of the menstrual cycle, with a peak in severity immediately before menstruation [1–8]. Oral and perineal lesions may occur. It has been proposed that they result from sensitization to endogenous progesterone. There is frequently, but not always, a history of prior exposure to synthetic progesterones [1,3]. Confirmation is with a positive intradermal test with progesterone, preferably in an aqueous or aqueous alcohol solution, and/or existence of circulating antibody to progesterone, and by suppression of symptoms with agents that inhibit ovulation and result in decreased serum progesterone [7]. Two patients with recurrent premenstrual erythema multiforme and autoreactivity to 17α-hydroxyprogesterone have been described [5,6]; in one case, the eruption spread in pregnancy, cleared after abortion and was associated with a high-affinity binding factor to 17α-hydroxyprogesterone in the serum [6]. In another case with recurrent erythema multiforme, cured by oophorectomy, progesterone sensitivity was confirmed by challenge with medroxyprogesterone acetate [9]. Medroxyprogesterone acetate. A pigmented purpura [10] and skin necrosis following intramuscular Depo-Provera [11] are recorded.

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Megestrol. A generalized morbilliform rash developed in a cachectic man treated with this synthetic, orally active progesterone derivative to stimulate appetite and weight gain; skin testing with progesterone acetate was positive [12]. References 1 Hart R. Autoimmune progesterone dermatitis. Arch Dermatol 1977; 113: 426– 30. 2 Wojnarowska F, Greaves MW, Peachey RDG et al. Progesterone-induced erythema multiforme. J R Soc Med 1985; 78: 407–8. 3 Stephens CJM, Black MM. Perimenstrual eruptions: autoimmune progesterone dermatitis. Semin Dermatol 1989; 8: 26–9. 4 Yee KC, Cunliffe WJ. Progesterone-induced urticaria: response to buserelin. Br J Dermatol 1994; 130: 121–3. 5 Cheesman KL, Gaynor LV, Chatterton RT Jr et al. Identification of a 17αhydroxyprogesterone-binding immunoglobulin in the serum of a woman with periodic rashes. J Clin Endocrinol Metab 1982; 55: 597–9. 6 Pinta JS, Sobrinho L, da Silva MB et al. Erythema multiforme associated with autoreactivity to 17α-hydroxyprogesterone. Dermatologica 1990; 180: 146–50. 7 Herzberg AJ, Strohmeyer CR, Cirillo-Hyland VA. Autoimmune progesterone dermatitis. J Am Acad Dermatol 1995; 32: 333–8. 8 Halevy S, Cohen AD, Lunenfeld E, Grossman N. Autoimmune progesterone dermatitis manifested as erythema annulare centrifigum: confirmation of progesterone sensitivity by in vitro interferon-γ release. J Am Acad Dermatol 2002; 47: 311–3. 9 Ródenas JM, Herranz MT, Tercedor J. Autoimmune progesterone dermatitis: treatment with oophorectomy. Br J Dermatol 1998; 139: 508–11. 10 Tsao H, Lerner LH. Pigmented purpuric eruption associated with injection medroxyprogesterone acetate. J Am Acad Dermatol 2000; 43: 308–10. 11 Clark SM, Lanigan SW. Acute necrotic skin reaction to intramuscular DepoProvera®. Br J Dermatol 2000; 143: 1356–7. 12 Fisher DA. Drug-induced progesterone dermatitis. J Am Acad Dermatol 1996; 34: 863–4.

Androgens Anabolic steroids. Exacerbation of acne vulgaris with development of acne conglobata has been reported [1]. Both the size of sebaceous glands and the rate of sebum secretion are increased [2,3]. A lichenoid eruption was reported in a patient with aplastic anaemia treated with nandrolone furylpropionate (Cemelon) [4]. Danazol. This 17-ethinyltestosterone derivative, which is an inhibitor of pituitary gonadotrophin, is a very weak androgen. Of 530 recipients of danazol, 29% reported at least one adverse event within 45 days after receiving the drug, but there were no known long-term sequelae [5]. Acne, hirsutism, seborrhoea, rash and generalized alopecia are documented [6–8]. Exacerbation of LE-like eruptions has been reported in patients receiving this drug for non-C1-esterase inhibitor-dependent angio-oedema [9] or for hereditary angio-oedema [10]. Gestrinone. This derivative of 19-nortestosterone, like danazol, may cause weight gain, hirsutism, acne, voice change or irregular menstrual bleeding [11]. Testosterone. Severe acne or acne fulminans has followed therapy with testosterone, with [2,12] or without [13] anabolic steroids. Yohimbine. Yohimbine is an indole alkaloid obtained from the yohimbe tree in West Africa and is used in the treatment of male impotence. A case of generalized erythrodermic skin eruption, progressive renal failure and LE-like syndrome is recorded [14].

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References 1 Merkle T, Landthaler M, Braun-Falco O. Acne-conglobata-artige Exazerbation einer Acne vulgaris nach Einnahme von Anabolika und Vitamin-B-Komplexhaltigen Präparaten. Hautarzt 1990; 41: 280–2. 2 Király CL, Collan Y, Alén M. Effect of testosterone and anabolic steroids on the size of sebaceous glands in power athletes. Am J Dermatopathol 1987; 9: 515–9. 3 Király CL, Alén M, Rahkila P, Horsmanheimo M. Effect of androgenic and anabolic steroids on the sebaceous gland in power athletes. Acta Derm Venereol (Stockh) 1987; 67: 36–40. 4 Aihara M, Kitamura K, Ikezawa Z. Lichenoid drug eruption due to nandrolone furylpropionate (Cemelon). J Dermatol 1989; 16: 330–4. 5 Jick SS, Myers MW. A study of danazol’s safety. Pharmacotherapy 1995; 15: 40–1. 6 Spooner JB. Classification of side-effects to danazol therapy. J Int Med Res 1977; 5 (Suppl. 3): 15–7. 7 Greenberg RD. Acne vulgaris associated with antigonadotrophic (Danazol) therapy. Cutis 1979; 24: 431–2. 8 Duff P, Mayer AR. Generalized alopecia: an unusual complication of danazol therapy. Am J Obstet Gynecol 1981; 141: 349–50. 9 Fretwell MD, Altman LC. Exacerbation of a lupus-erythematosus-like syndrome during treatment of non-C1-esterase-inhibitor dependent angioedema with danazol. J Allergy Clin Immunol 1982; 69: 306–10. 10 Sassolas B, Guillet G. Lupus, hereditary angioneurotic oedema and the risks of danazol treatment. Br J Dermatol 1991; 125: 190–1. 11 Anonymous. Gestrinone (Dimetriose): another option in endometriosis. Drug Ther Bull 1991; 29: 45. 12 Heydenreich G. Testosterone and anabolic steroids and acne fulminans. Arch Dermatol 1989; 125: 571–2. 13 Traupe H, von Mühlendahl KE, Brämswig J, Happle R. Acne of the fulminans type following testosterone therapy in three excessively tall boys. Arch Dermatol 1988; 124: 414–7. 14 Sandler B, Aronson P. Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome. Urology 1993; 41: 343–5.

Antiandrogens Cyproterone acetate. Fixed drug eruption is recorded [1]. Finasteride. Erythema annulare centrifugum has been reported [2]. References 1 Galindo PA, Borja J, Feo F et al. Fixed drug eruption caused by cyproterone acetate. Allergy 1998; 53: 813. 2 Al Hammadi A, Asai Y, Patt ML, Sasseville D. Erythema annulare centrifugum secondary to treatment with finasteride. J Drugs Dermatol 2007; 6: 460–3.

Insulin Adverse reactions to insulin [1–5] used to be relatively common, with bovine insulin having the most potential for production of allergic reactions, followed by porcine and human insulin. Insulin allergy and other local cutaneous reactions are rarely seen with highly purified and biosynthetic preparations [2,3], although local symptoms still occur in approximately 5% of patients [2]. Lipoatrophy, which was reported in 10–55% of patients treated with non-purified bovine/porcine insulin preparations, has almost disappeared since the advent of exclusive human insulin treatment. Allergic symptoms to human insulin are found in less than 1% of de novo-treated patients, but still occur when human insulin is used in the insulin-allergic patient [3]. Anaphylaxis may occur with recombinant human insulin [6]. Local allergic reactions are often of immediate hypersensitivity type; they are more common in the first few months, and usually subside with continued

therapy. Generalized pruritus and urticaria occur rarely. Typically, more severe anaphylactoid reactions follow reintroduction of insulin in patients who have previously received long-term therapy. Delayed reactions may also occur, and take the form of pruritic erythema and induration, sometimes with papulation, within 24 h of injection [7]. Biphasic responses may be seen in the same individual, with initial immediate urticaria and a delayed reaction after 4–6 h. Allergy may develop to the insulin itself (i.e. bovine or porcine protein), to preservatives such as parabens and zinc [8,9], protamine (Surfen) present in depot preparations [10– 14], or to cresol [15,16]. Sterile furunculoid lesions at injection sites, which heal with scars and which have a granulomatous histology, may result. Lipoatrophy at injection sites, or more rarely distally, occurred especially with longer-acting preparations; affected patients had lesional immunoglobulin deposits and circulating anti-insulin antibodies [17]. Exceptionally, hypertrophic lipodystrophy [18], or hyperkeratotic verrucous plaques at the site of repeated injections [19], may develop. References 1 De Shazo RD, Mather P, Grant W et al. Evaluation of patients with local reactions to insulin with skin tests and in vitro techniques. Diabetes Care 1987; 10: 330–6. 2 Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993; 16 (Suppl. 3): 155–65. 3 Patrick AW, Williams G. Adverse effects of exogenous insulin. Clinical features, management and prevention. Drug Saf 1993; 8: 427–44. 4 Barbaud A, Got I, Trechot P et al. Allergies cutanées et insulinotherapie. Aspects recents, conduite a tenir. Ann Dermatol Vénéréol 1996; 123: 214–8. 5 Hoffman AG, Schram SE, Ercan-Fang NG, Warshaw EM. Type I allergy to insulin: case report and review of localized and systemic reactions to insulin. Dermatitis 2008; 19: 52–8. 6 Fineberg SE, Galloway JA, Fineberg NS et al. Immunogenicity of recombinant human insulin. Diabetologica 1983; 25: 465–9. 7 White WN, DeMartino SA, Yoshida T. Severe delayed inflammatory reactions from injected insulin. Am J Med 1983; 74: 909–13. 8 Feinglos MN, Jegasothy BV. ‘Insulin’ allergy due to zinc. Lancet 1979; i: 122–4. 9 Jordaan HF, Sandler M. Zinc-induced granuloma: a unique complication of insulin therapy. Clin Exp Dermatol 1989; 14: 227–9. 10 Kim R. Anaphylaxis to protamine masquerading as an insulin allergy. Del Med J 1993; 65: 17–23. 11 Kollner A, Senff H, Engelmann L et al. Protaminallergie vom Spattyp und Insulinallergie vom Soforttyp. Dtsch Med Wochenschr 1991; 116: 1234–8. 12 Hulshof MM, Faber WR, Kniestedt WF et al. Granulomatous hypersensitivity to protamine as a complication of insulin therapy. Br J Dermatol 1992; 127: 286–8. 13 Lee AY, Chey WY, Choi J, Jeon JS. Insulin-induced drug eruptions and reliability of skin tests. Acta Derm Venereol (Stockh) 2002; 82: 114–7. 14 Bodtger U, Wittrup M. A rational clinical approach to suspected insulin allergy: status after five years and 22 cases. Diabet Med 2005; 22: 102–6. 15 Rajpar SF, Foulds IS, Abdullah A, Maheshwari M. Severe adverse cutaneous reaction to insulin due to cresol sensitivity. Contact Dermatitis 2006; 55: 119–20. 16 Kim D, Baraniuk J. Delayed-type hypersensitivity reaction to the meta-cresol component of insulin. Ann Allergy Asthma Immunol 2007; 99: 194–5. 17 Reeves WG, Allen BR, Tattersal RB. Insulin-induced lipoatrophy: evidence for an immune pathogenesis. BMJ 1980; 280: 1500–3. 18 Johnson DA, Parlette HL. Insulin-induced hypertrophic lipodystrophy. Cutis 1983; 32: 273–4. 19 Fleming MG, Simon SI. Cutaneous insulin reaction resembling acanthosis nigricans. Arch Dermatol 1986; 122: 1054–6.

Thyroxine Chronic urticaria and angio-oedema was reported in a patient, associated with exogenous thyrotoxicosis, related to thyroid replacement therapy [1].

Important or widely prescribed drugs Reference 1 Pandya AG, Beaudoing DL. Chronic urticaria associated with exogenous thyroid use. Arch Dermatol 1990; 126: 1238–9.

Antithyroid drugs Thiouracils Hypersensitivity reactions include drug fever, pruritus, urticaria, angio-oedema, exanthems, acneiform rashes, depigmentation of hair and LE-like syndromes. Propylthiouracil has caused allergic vasculitis [1–3], and methylthiouracil has resulted in erythema multiforme. Thiouracils may cause excessive hair loss. These drugs may cause marrow failure [4]. References 1 Vasily DB, Tyler WB. Propylthiouracil-induced cutaneous vasculitis. JAMA 1980; 243: 458–60. 2 Gammeltoft M, Kristensen JK. Propylthiouracil-induced cutaneous vasculitis. Acta Derm Venereol (Stockh) 1982; 62: 171–3. 3 Otsuka S, Kinebuchi A, Tabata H et al. Myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis following propylthiouracil therapy. Br J Dermatol 2000; 142: 828–30. 4 International Agranulocytosis and Aplastic Anemia Study. Risk of agranulocytosis and aplastic anemia in relation to use of antithyroid drugs. BMJ 1988; 287: 262–5.

Chemotherapeutic (cytotoxic) agents General side effects There have been a number of excellent reviews of the dermatological complications of these compounds [1–13], including histopathological reactions [14,15]. Women experience greater toxicity from certain chemotherapeutic drugs than men [16]. In attributing a given reaction to a chemotherapeutic agent, one should always consider the possibility that a different drug might be the responsible agent [17]. Bone marrow depression, with aplastic anaemia, agranulocytosis or thrombocytopenia, and gastrointestinal intolerance may occur with any of these drugs. Mucocutaneous surfaces are especially vulnerable to the toxic effects of this group of drugs on rapidly dividing cells. Common side effects therefore include alopecia (see p. 75.45) and stomatitis [18]. Cytotoxic drugs may cause alopecia by either anagen or telogen effluvium. Severe alopecia of anagen type within 2 weeks of administration of the drug is frequently seen with cyclophosphamide, doxorubicin and the nitrosoureas; it is usually reversible with cessation of therapy. Other chemotherapeutic agents implicated in the production of alopecia include amsacrine, bleomycin, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, etoposide, fluorouracil and methotrexate. Stomatitis occurs most frequently with acridinyl anisidide, dactinomycin, daunorubicin, doxorubicin, fluorouracil and methotrexate; it may respond to reduced dosage. Similarly, a number of drugs may cause pigmentation of the buccal mucosa [19] or of the nails [20–22]. Onycholysis may be induced [23]. Hypersensitivity or allergic reactions such as urticaria and angio-oedema [24,25] occur with all cancer chemotherapeutic agents except altretamine, the nitrosoureas and dactinomycin. With l-asparaginase and mitomycin (administered intravesically) they occur in about 10% of patients, and are relatively frequent

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with cisplatin; they are very rare with methotrexate. Type I reactions are commonest, but all four types of reactions are represented. Many of these agents have distinctive cutaneous side effects, ranging from localized or diffuse hyperpigmentation to less usual ones, including radiation enhancement and recall phenomena, photosensitivity and hypersensitivity reactions, and phlebitis or chemical cellulitis. Confluent erythematous and hyperpigmented patches, with focal basal layer vacuolar degeneration, occurred within flexural areas during the first month after autologous peripheral stem cell transplantation [26]. Photosensitivity reactions occur with dacarbazine, fluorouracil, mitomycin and vinblastine. Radiation recall effects involve reactivation of an inflammatory response in areas irradiated months or years previously. Clinically, these range from erythema to vesiculation, with erosions and subsequent hyperpigmentation. They have most often been reported in association with dactinomycin and doxorubicin therapy [27], but also with edatrexate [28] and gemcitabine [29]; melphalan, etoposide, vinblastine, bleomycin, fluorouracil, hydroxyurea, methotrexate and gatifloxacin [30] may also cause radiation enhancement. An unusual radiation recall reaction in the form of lipodermatosclerosis of the buttocks occurred 3 months after irradiation for carcinoma of the anus, on subsequent chemotherapy with 5-fluorouracil and cisplatin [31]. UV recall is recorded with mitomycin and the combination of etoposide and cyclophosphamide [32]. Rare complications such as diffuse sclerosis of the hands and feet, Raynaud’s phenomenon [33], sterile folliculitis and flushing reactions may also occur. Multiple drug regimens may pose special problems in trying to elucidate the cause of a specific reaction, such as white-banded nails [34] or multiple Beau’s lines [35]. A pityriasis lichenoides-like eruption occurred during therapy for myelogenous leukaemia with vincristine and mercaptopurine, antibiotics and aciclovir [36]. Fingertip necrosis occurred during chemotherapy with bleomycin, vincristine and methotrexate for HIV-related Kaposi’s sarcoma [37]. Most cytotoxic drugs are teratogenic and are contraindicated during pregnancy, especially during the first trimester. Alkylating drugs usually cause sterility in males, and may shorten reproductive life in women. References 1 Weiss RB. Hypersensitivity reactions to cancer chemotherapy. Semin Oncol 1982; 9: 5–13. 2 Bronner AK, Hood AF. Cutaneous complications of chemotherapeutic agents. J Am Acad Dermatol 1983; 9: 645–63. 3 McDonald CJ. Cytotoxic agents for use in dermatology. I. J Am Acad Dermatol 1985; 12: 753–5. 4 McDonald CJ. Use of cytotoxic drugs in dermatologic diseases. II. J Am Acad Dermatol 1985; 12: 965–75. 5 Hood AF. Cutaneous side effects of cancer chemotherapy. Med Clin North Am 1986; 70: 187–209. 6 Delaunay M. Effets cutanés indésirables de la chimiothérapie antitumorale. Ann Dermatol Vénéréol 1989; 116: 347–61. 7 Kerker BJ, Hood AF. Chemotherapy-induced cutaneous reactions. Semin Dermatol 1989; 8: 173–81. 8 Rapini RP. Cytotoxic drugs in the treatment of skin disease. Int J Dermatol 1991; 30: 313–22. 9 Mansouri S, Dubertret L, Bastuji-Garin S et al. Role of drugs in cutaneous eruptions after chemotherapy for acute myelogenous leukemia. Arch Dermatol 1998; 134: 881–2.

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10 Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999; 40: 367–98. 11 Payne AS, James WD, Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol 2006; 33: 86–97. 12 Sanborn RE, Sauer DA. Cutaneous reactions to chemotherapy: commonly seen, less described, little understood. Dermatol Clin 2008; 26: 103–19, ix. 13 Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol 2008; 58: 545–70. 14 Fitzpatrick JE, Hood AF. Histopathologic reactions to chemotherapeutic agents. Adv Dermatol 1988; 3: 161–84. 15 Fitzpatrick JE. The cutaneous histopathology of chemotherapeutic reactions. J Cutan Pathol 1993; 20: 1–14. 16 Wang J, Huang Y. Pharmacogenomics of sex difference in chemotherapeutic toxicity. Curr Drug Discov Technol 2007; 4: 59–68. 17 Bursztejn AC, Tréchot P, Cuny JF et al. Cutaneous adverse drug reactions during chemotherapy: consider non-antineoplastic drugs. Contact Dermatitis 2008; 58: 365–8. 18 Bottomley WK, Perlin E, Ross GR. Antineoplastic agents and their oral manifestations. Oral Surg 1977; 44: 527–34. 19 Krutchik AN, Buzdar AU. Pigmentation of the tongue and mucous membranes associated with cancer chemotherapy. South Med J 1979; 72: 1615–6. 20 Sulis E, Floris C. Nail pigmentation following cancer chemotherapy: a new genetic entity? Eur J Cancer 1980; 16: 1517–9. 21 Daniel CR III, Scher RK. Nail changes secondary to systemic drugs or ingestants. J Am Acad Dermatol 1984; 10: 250–8. 22 Daniel CR III, Scher PK. Nail changes secondary to systemic drugs or ingestants. In: Scher RK, Daniel CR III, eds. Nails: Therapy, Diagnosis, Surgery. Philadelphia: Saunders, 1990: 192–201. 23 Makris A, Mortimer P, Powles TJ. Chemotherapy-induced onycholysis. Eur J Cancer 1996; 32A: 374–5. 24 Weiss RB. Hypersensitivity reactions. Semin Oncol 1992; 19: 458–77. 25 O’Brien ME, Souberbielle BE. Allergic reactions to cytotoxic drugs: an update. Ann Oncol 1992; 3: 605–10. 26 Brazzelli V, Ardigo M, Chiesa MG et al. Flexural erythematous eruption following autologous peripheral blood stem cell transplantation: a study of four cases. Br J Dermatol 2001; 145: 490–5. 27 Solberg LA Jr, Wick MR, Bruckman JE. Doxorubicin-enhanced skin reaction after whole-body electron beam irradiation for leukemia cutis. Mayo Clin Proc 1980; 55: 711–5. 28 Perez EA, Campbell DL, Ryu JK. Radiation recall dermatitis induced by edatrexate in a patient with breast cancer. Cancer Invest 1995; 13: 604–7. 29 Jeter MD, Janne PA, Brooks S et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys 2002; 53: 394–400. 30 Jain S, Agarwal J, Laskar S et al. Radiation recall dermatitis with gatifloxacin: a review of literature. J Med Imaging Radiat Oncol 2008; 52: 191–3. 31 Sroa N, Bartholomew DA, Magro CM. Lipodermatosclerosis as a form of vascular compromise-associated radiation recall dermatitis: case report and a review of literature. J Cutan Pathol 2006; 33 (Suppl. 2): 55–9. 32 Williams BJ, Roth DJ, Callen JP. Ultraviolet recall associated with etoposide and cyclophosphamide therapy. Clin Exp Dermatol 1993; 18: 452–3. 33 Vogelzang NJ, Bosl GJ, Johnson D et al. Raynaud’s phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 1981; 95: 288–92. 34 James WD, Odom RB. Chemotherapy-induced transverse white lines in the fingernails. Arch Dermatol 1983; 119: 334–5. 35 Singh M, Kaur S. Chemotherapy-induced multiple Beau’s lines. Int J Dermatol 1986; 25: 590–1. 36 Isoda M. Pityriasis lichenoides-like eruption occurring during therapy for myelogenous leukemia. J Dermatol 1989; 16: 73–5. 37 Pechère M, Zulian GB, Vogel J-J et al. Fingertip necrosis during chemotherapy with bleomycin, vincristine and methotrexate for HIV-related Kaposi’s sarcoma. Br J Dermatol 1996; 134: 378–9.

Extravasation Extravasation, leading to skin necrosis with ulceration, occurs with several agents [1–5]. Phlebitis and chemical cellulitis have been recorded with most antimitotic agents. Residual drug should

be aspirated and the limb elevated; plastic surgical advice should be sought as soon as possible. High dermal concentrations of doxorubicin have been documented as late as 28 days after accidental extravasation [6]. Histological examination of doxorubicin-related extravasation lesions demonstrated exaggerated interface-type dermatitis with thrombosis of venous tributaries [7]. References 1 Ignoffo RJ, Friedman MA. Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7: 17–27. 2 Harwood KV, Aisner J. Treatment of chemotherapy extravasation: current status. Cancer Treat Rep 1984; 68: 939–45. 3 Banerjee A, Brotherston TM, Lamberty BGH et al. Cancer chemotherapy agentinduced perivenous extravasation injury. J Postgrad Med 1987; 63: 5–9. 4 Rudolph R, Larson DL. Etiology and treatment of chemotherapeutic agent extravasation injuries: a review. J Clin Oncol 1987; 5: 1116–26. 5 Dufresne RG Jr. Skin necrosis from intravenously infused materials. Cutis 1989; 39: 197–8. 6 Sonneveld P, Wassenaar HA, Nooter K. Long persistence of doxorubicin in human skin after extravasation. Cancer Treat Rep 1984; 68: 895–6. 7 Bhawan J, Petry J, Rybak ME. Histologic changes induced in skin by extravasation of doxorubicin (adriamycin). J Cutan Pathol 1989; 16: 158–63.

Acral erythema Several cytotoxic drugs (especially cytosine arabinoside, fluorouracil, docetaxel and doxorubicin, and rarely cyclophosphamide, hydroxyurea, mercaptopurine, methotrexate and mitotane) can cause dose-dependent acral erythema, often preceded by paraesthesiae, either alone or in combination [1–17]. Bulla formation, desquamation and subsequent re-epithelialization may occur. Reactions may occur sooner (from 24 h to 3 weeks) and more severely with bolus or short-term chemotherapy than with lowdose continuous infusion, and are usually reproducible on challenge. Intravenous ciclosporin, given in bone marrow transplant patients, reportedly worsens the pain of acral erythema [12]. The condition should be distinguished from graft-versus-host disease in patients who receive chemotherapy followed by bone marrow transplantation, and from chemotherapy-induced Raynaud’s phenomenon. This may not be easy, as histological changes may suggest graft-versus-host disease [18]. References 1 Doyle LA, Berg C, Bottino G, Chabner E. Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983; 98: 611–2. 2 Feldman LD, Jaffer A. Fluorouracil-associated palmar-plantar erythro-dysesthesia syndrome. JAMA 1985; 254: 3479. 3 Crider MK, Jansen J, Norins AL, McHale MS. Chemotherapy-induced acral erythema in patients receiving bone marrow transplantation. Arch Dermatol 1986; 122: 1023–7. 4 Cox GJ, Robertson DB. Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. Arch Dermatol 1986; 122: 1413–4. 5 Guillaume J-C, Carp E, Rougier P et al. Effets secondaires cutanéo-muqueux des perfusions continues de 5-fluorouracile: 12 observations. Ann Dermatol Vénéréol 1988; 115: 1167–9. 6 Horwitz LJ, Dreizen S. Acral erythemas induced by chemotherapy and graftversus-host disease in adults with hematogenous malignancies. Cutis 1990; 46: 397–404. 7 Baack BR, Burgdorf WHC. Chemotherapy-induced acral erythema. J Am Acad Dermatol 1991; 24: 457–61. 8 Reynaert H, De Coninck A, Neven AM et al. Chemotherapy-induced acral erythema and acute graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 10: 185–7.

Important or widely prescribed drugs 9 Cohen PR. Acral erythema: a clinical review. Cutis 1993; 51: 175–9. 10 Pirisi M, Soardo G. Images in clinical medicine. Chemotherapy-induced acral erythema. N Engl J Med 1994; 330: 1279. 11 Komamura H, Higashiyama M, Hashimoto K et al. Three cases of chemotherapyinduced acral erythema. J Dermatol 1995; 22: 116–21. 12 Kampmann KK, Graves T, Rogers SD. Acral erythema secondary to high-dose cytosine arabinoside with pain worsened by cyclosporin infusions. Cancer 1989; 63: 2482–5. 13 Revenga Arranz F, Fernandez-Duran DA, Grande C et al. Acute and painful erythema of the hands and feet. Acral erythema induced by chemotherapy. Arch Dermatol 1997; 133: 499–500, 502–3. 14 Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (‘hand–foot’) syndrome. Incidence, recognition and management. Am J Clin Dermatol 2000; 1: 225–34. 15 Tsuruta D, Mochida K, Hamada T et al. Chemotherapy-induced acral erythema: report of a case and immunohistochemical findings. Clin Exp Dermatol 2000; 25: 386–8. 16 Soker M, Akdeniz S, Devecioglu C, Haspolat K. Chemotherapy-induced bullous acral erythema in a subject with B-cell lymphoma. J Eur Acad Dermatol Venereol 2001; 15: 490–1. 17 de Bono JS, Stephenson J Jr, Baker SD et al. Troxacitabine, an l-stereoisomeric nucleoside analog, on a five-times-daily schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 2002; 20: 96–109. 18 Beard JS, Smith KJ, Skelton HG. Combination chemotherapy with 5-fluorouracil, folinic acid, and α-interferon producing histologic features of graft-versus-host disease. J Am Acad Dermatol 1993; 29: 325–30.

Neutrophilic eccrine hidradenitis Neutrophilic eccrine hidradenitis may represent a reaction pattern to a variety of chemotherapeutic agents [1–8], but particularly cytarabine and bleomycin. It has been induced by granulocyte– macrophage colony stimulating factor [9]. Clinically, erythematous papules or plaques or nodules are most frequent, although hyperpigmented plaques, pustules, purpura and urticaria have been described. Lesions resolve spontaneously over several days. The histology is characterized by infiltration of eccrine coils with neutrophils and necrosis of the secretory epithelium. The condition has also been described in a patient receiving haemodialysis without chemotherapy [10] and in a patient without a malignancy who was taking paracetamol [11]. References 1 Fitzpatrick JE, Bennion SD, Reed OM et al. Neutrophilic eccrine hidradenitis associated with induction chemotherapy. J Cutan Pathol 1987; 14: 272–8. 2 Scallan PJ, Kettler AH, Levy ML et al. Neutrophilic eccrine hidradenitis. Cancer 1988; 62: 2532–6. 3 Fernández Cogolludo E, Ambrojo Antunez P, Aguilar Martínez A et al. Neutrophil eccrine hidradenitis: a report of two additional cases. Clin Exp Dermatol 1989; 14: 341–6. 4 Burg G, Bieber T, Langecker P. Lokalisierte neutrophile ekkrien Hidraden-itis unter Mitoxantron: eine typische Zytostatikanebenwirkung. Hautarzt 1988; 39: 233–6. 5 Allegue F, Soria C, Rocamora A et al. Neutrophilic eccrine hidradenitis in two neutropenic patients. J Am Acad Dermatol 1990; 23: 1110–3. 6 Margolis DJ, Gross PR. Neutrophilic eccrine hidradenitis: a case report and review of the literature. Cutis 1991; 48: 198–200. 7 Thorisdottir K, Tomecki KJ, Bergfeld WF et al. Neutrophilic eccrine hidradenitis. J Am Acad Dermatol 1993; 28: 775–7. 8 Kanzki H, Takashi O, Makino E et al. Neutrophilic eccrine hidradenitis: report of two cases. J Dermatol 1995; 22: 137–42. 9 Bachmeyer C, Chaibi P, Aractingi S. Neutrophilic eccrine hidradenitis induced by granulocyte-stimulating factor. Br J Dermatol 1998; 139: 354–5. 10 Moreno A, Barnadas MA, Ravella A, Moragas JM. Infectious eccrine hidradenitis in a patient undergoing hemodialysis. Arch Dermatol 1985; 121: 1106–7.

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11 Kuttner BJ, Kurban RS. Neutrophilic eccrine hidradenitis in the absence of an underlying malignancy. Cutis 1988; 41: 403–5.

Syringosquamous metaplasia A related but distinct entity termed ‘syringosquamous metaplasia’, which may be confused with well-differentiated squamous cell carcinoma histologically, has been described in patients receiving chemotherapy for leukaemia and other cancers [1–3]. Clinically, this may appear as an erythematous, blanching, papular crusted eruption, or as erythematous oedematous plaques or confluent erythematous macular areas, in the axillae or groins, with painful erythema and oedema on the palms and soles [4]. References 1 Bhawan J, Malhotra R. Syringosquamous metaplasia. A distinctive eruption in patients receiving chemotherapy. Am J Dermatopathol 1990; 12: 1–6. 2 Hurt MA, Halvorson RD, Petr FC Jr et al. Eccrine squamous syringometaplasia. A cutaneous sweat gland reaction in the histologic spectrum of ‘chemotherapyassociated eccrine hidradenitis’ and ‘neutrophilic eccrine hidradenitis’. Arch Dermatol 1990; 126: 73–7. 3 Valks R, Buezo GF, Dauden E et al. Eccrine squamous syringometaplasia in intertriginous areas. Br J Dermatol 1996; 134: 984–6. 4 Valks R, Fraga J, Porras-Luque J et al. Chemotherapy-induced eccrine squamous syringometaplasia. A distinctive eruption in patients receiving hematopoietic progenitor cells. Arch Dermatol 1997; 133: 873–8.

Side effects related to immunosuppression The cutaneous manifestations of immunosuppression have been reviewed [1–4]. Immunosuppressive therapy, such as azathioprine and prednisone for renal transplant patients, may encourage skin infections of various types, for example warts, herpes simplex and herpes zoster [5], pityriasis versicolor and fungal infections [6]. Development of disseminated superficial actinic porokeratosis [7–9], porokeratosis of Mibelli [10–13] and increased numbers of benign [14,15] or eruptive dysplastic [16] melanocytic naevi may be promoted. Eruptive keratoacanthomas occurred in a patient with SLE on prednisolone and cyclophosphamide [17]. References 1 Cohen EB, Komorowski RA, Clowry LJ. Cutaneous complications in renal transplant recipients. Am J Clin Pathol 1987; 88: 32–7. 2 Abel EA. Cutaneous manifestations of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989; 21: 167–79. 3 Boitard C, Nach J-F. Long-term complications of conventional immuno-suppressive treatment. Adv Nephrol 1989; 18: 335–54. 4 Paller AS, Mallory SB. Acquired forms of immunosuppression. J Am Acad Dermatol 1991; 24: 482–8. 5 Spencer ES, Anderson HK. Viral infections in renal allograft recipients treated with long-term immunosuppression. BMJ 1979; 2: 829–30. 6 Shelley WB. Induction of tinea cruris by topical nitrogen mustard and systemic chemotherapy. Acta Derm Venereol (Stockh) 1981; 61: 164–5. 7 Bencini PL, Crosti C, Sala F. Porokeratosis: immunosuppression and exposure to sunlight. Br J Dermatol 1987; 116: 113–6. 8 Neumann RA, Knobler RM, Metze D, Jurecka W. Disseminated superficial porokeratosis and immunosuppression. Br J Dermatol 1988; 119: 375–80. 9 Lederman JS, Sober AJ, Lederman GS. Immunosuppression: a cause of porokeratosis? J Am Acad Dermatol 1985; 13: 75–9. 10 Grattan CEH, Christopher AP. Porokeratosis and immunosuppression. J R Soc Med 1987; 80: 597–8. 11 Tatnall FM, Sarkany I. Porokeratosis of Mibelli in an immunosuppressed patient. J R Soc Med 1987; 80: 180–1. 12 Wilkinson SM, Cartwright PH, English JSC. Porokeratosis of Mibelli and immunosuppression. Clin Exp Dermatol 1991; 16: 61–2.

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13 Herranz P, Pizarro A, De Lucas R et al. High incidence of porokeratosis in renal transplant recipients. Br J Dermatol 1997; 136: 176–9. 14 McGregor JM, Barker JNWN, MacDonald DM. The development of excess numbers of melanocytic naevi in an immunosuppressed identical twin. Clin Exp Dermatol 1991; 16: 131–2. 15 Hughes BR, Cunliffe WJ, Bailey CC. Excess benign melanocytic naevi after chemotherapy for malignancy in childhood. BMJ 1989; 299: 88–91. 16 Barker JNWN, MacDonald DM. Eruptive dysplastic naevi following renal transplantation. Clin Exp Dermatol 1988; 13: 123–5. 17 Dessoukey MW, Omar MF, Abdel-Dayem H. Eruptive keratoacanthomas associated with immunosuppressive therapy in a patient with systemic lupus erythematosus. J Am Acad Dermatol 1997; 37: 478–80.

Internal malignancy The frequency of internal cancers common in the general population is not increased in transplant patients. However, that of a variety of otherwise uncommon malignancies is increased [1–3], including: non-Hodgkin’s lymphoma (mostly B-cell, with 14% of T-cell, and less than 1% of null-cell, origin), which accounts for 21% of cancers in transplant recipients; Kaposi’s sarcoma; other sarcomas; carcinoma of the vulva and perineum; carcinoma of the kidney; and hepatobiliary tumours. Non-Hodgkin’s lymphoma appears commoner and develops earlier where potent immunosuppressive agents such as ciclosporin and/or the monoclonal antibody OKT3 have been used; however, although cancer develops in 6% of all transplant recipients, only 1% of patients die from this complication [3]. Leukaemia may develop following chemotherapy [4], and bladder cancer has been associated with cyclophosphamide therapy [5].

Skin cancers Actinic keratoses, squamous cell and basal cell cancer of the lip and skin [6–12], and malignant melanoma [13] have been reported to be more common, especially in immunosuppressed renal transplant patients. The majority of these patients have received azathioprine and corticosteroids. Interestingly, the immunosuppressed renal transplant recipients have been reported to be at high risk for skin cancer unless they express the HLA class I allele A11 [14]. Furthermore, patients with long-standing renal grafts mismatched for HLA-B have a significantly higher incidence of squamous cell cancers than other mismatches, and patients who are homozygous for HLA-DR are at increased risk for actinic keratoses and skin cancer [15]. These findings imply that MHC gene products participate in the pathogenesis of skin cancer in immunosuppressed patients, probably via influences on T-cell recognition of neoantigens [16]. There was no difference from control levels in the number of CD1+ HLA-DR+ antigen-presenting Langerhans’ cells in the epidermis of immunosuppressed renal transplant recipients treated with either azathioprine/prednisone or ciclosporin/ prednisone [17]. References 1 Penn I. Depressed immunity and the development of cancer. Clin Exp Immunol 1981; 146: 459–74. 2 Penn I. Tumors of the immunocompromised patient. Annu Rev Med 1988; 39: 63–73. 3 Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323: 1767–9. 4 Williams CJ. Leukaemia and cancer chemotherapy. The risk is acceptably small but may be reducible further. BMJ 1990; 301: 73–4.

5 Elliot RW, Essenhigh DM, Morley AR. Cyclophosphamide treatment of systemic lupus erythematosus: risk of bladder cancer exceeds benefit. Blood 1970; 35: 543–8. 6 Walder BK, Robertson MR, Jeremy D. Skin cancer and immunosuppression. Lancet 1971; ii: 1282–3. 7 Lowney ED. Antimitotic drugs and aggressive squamous cell tumors. Arch Dermatol 1972; 105: 924. 8 Kinlen LJ, Sheil AGR, Peto J, Doll R. Collaborative United Kingdom– Australasian study of cancer in patients treated with immunosuppressive drugs. BMJ 1979; ii: 1461–6. 9 Boyle J, Briggs JD, MacKie RM et al. Cancer, warts and sunshine in renal transplant patients. Lancet 1984; i: 702–5. 10 McLelland J, Rees A, Williams G et al. The incidence of immunosuppressionrelated skin disease in long-term transplant patients. Transplantation 1988; 46: 871–4. 11 Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms in patients with renal transplants. Arch Dermatol 1986; 122: 1288–93. 12 Hintner H, Fritsch P. Skin neoplasia in the immunodeficient host. Curr Probl Dermatol 1989; 18: 210–7. 13 Greene MH, Young TI. Malignant melanoma in renal transplant recipients. Lancet 1981; i: 1196–9. 14 Bouwes Bavinck JN, Koottee AMM, van der Woude FJ et al. HLA-A11 associated resistance to skin cancer in renal-transplant recipients. N Engl J Med 1990; 323: 1350. 15 Bouwes Bavinck JM, Vermeer BJ, vans der Woude FJ et al. Relation between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med 1991; 325: 843–8. 16 Streilein JW. Immunogenetic factors in skin cancer. N Engl J Med 1991; 325: 884–7. 17 Scheibner KG, Murray A, Sheil R et al. T6 and HLA-DR cell numbers in epidermis of immunosuppressed renal transplant recipients. J Cutan Pathol 1987; 14: 202–6.

Alkylating agents These drugs interfere with cell replication by damaging DNA. Gametogenesis is often severely affected, and their use is associated with a marked increase in non-lymphocytic leukaemia, especially when used in conjunction with radiotherapy.

Alkyl sulphonates Busulfan. Reactions are rare, but have included urticaria, bullous erythema multiforme [1], Addisonian-like pigmentation [2,3] due to increased epidermal and dermal melanin, and drug-induced porphyria cutanea tarda [4]. Vasculitis has been reported. Keratinocyte nuclear abnormalities with abundant pale cytoplasm have been described [5]. Progressive pulmonary fibrosis may occur. References 1 Dosik H, Hurewitz DJ, Rosner F, Schwartz JM. Bullous eruptions and elevated leukocyte alkaline phosphatase in the course of busulphan-treated chronic granulocytic leukaemia. Blood 1970; 35: 543–8. 2 Harrold BP. Syndrome resembling Addison’s disease following prolonged treatment with busulphan. BMJ 1966; 1: 463–4. 3 Burns WA, McFarland W, Matthews MJ. Toxic manifestations of busulfan therapy. Med Ann DC 1971; 40: 567–9. 4 Kyle RA, Dameshek W. Porphyria cutanea tarda associated with chronic granulocytic leukemia treated with busulfan. Blood 1964; 23: 776–85. 5 Hymes SR, Simonton SC, Farmer ER et al. Cutaneous busulfan effect in patients receiving bone marrow transplanation. J Cutan Pathol 1985; 12: 125–9.

Nitrogen mustard derivatives Chlorambucil. Morbilliform rashes occur; urticarial plaques and periorbital oedema have been described rarely [1–4]. A delayed allergic reaction on the third cycle of chemotherapy, with general-

Important or widely prescribed drugs

ized erythroderma with exfoliation and oedema of the face and arms, as well as immune haemolytic anaemia and TEN, have been described [5]. Alopecia is uncommon. Sterility with azoospermia and amenorrhoea is documented. References 1 Knisely RE, Settipane GA, Albala MM. Unusual reaction to chlorambucil in a patient with chronic lymphocytic leukemia. Arch Dermatol 1971; 104: 77–9. 2 Millard LG, Rajah SM. Cutaneous reaction to chlorambucil. Arch Dermatol 1977; 113: 1298. 3 Peterman A, Braunstein B. Cutaneous reaction to chlorambucil therapy. Arch Dermatol 1986; 122: 1358–60. 4 Zervas J, Karkantaris C, Kapiri E et al. Allergic reaction to chlorambucil in chronic lymphocytic leukaemia: case report. Leuk Res 1992; 16: 329–30. 5 Torricelli R, Kurer SB, Kroner T, Wuthrich B. Allergie vom Spattyp auf Chlorambucil (Leukeran). Fallbeschreibung und Literaturubersicht. Schweiz Med Wochenschr 1995; 125: 1870–3.

Cyclophosphamide and mesna. Alopecia is common and occurs in 5–30% of cases [1]. Pigmentation, which may be widespread or localized to the palms, soles or nails, is well documented and usually reversible [2,3]. Nail dystrophy may be seen. Allergic exanthems are rare, but anaphylactic and urticarial reactions less so [4–7]. Type I hypersensitivity with a markedly delayed onset (from 8 to 16 h up to 10 days), associated with immediate skin-test results to cyclophosphamide metabolites but not the parent drug, has been documented [7]. There may be cross-sensitivity to other alkylating agents, especially mechlorethamine and chlorambucil [8]. Sterility may supervene. Haemorrhagic cystitis, the result of toxicity of the metabolite acrolein, is a complication in up to 40% of cases if cyclophosphamide is used alone. Introduction of the thiol compound mesna (2-mercaptoethane sulphonate) has virtually eliminated this complication. There have been recent reports of urticaria, angiooedema, allergic maculopapular pruritic rashes, generalized fixed drug eruption, and occasional more severe reactions with flushing, widespread erythema and ulceration or blistering of mucous membranes related to mesna; patch tests may be positive [9–13]. References 1 Ahmed AR, Hombal SM. Cyclophosphamide (Cytoxan). J Am Acad Dermatol 1984; 11: 1115–26. 2 Harrison BM, Wood CBS. Cyclophosphamide and pigmentation. BMJ 1972; 1: 352. 3 Shah PC, Rao KRP, Patel AR. Cyclophosphamide induced nail pigmentation. Br J Dermatol 1978; 98: 675–80. 4 Murti L, Horsman LR. Acute hypersensitivity reaction to cyclophosphamide. J Pediatr 1979; 94: 844–5. 5 Lakin JD, Cahill RA. Generalized urticaria to cyclophosphamide: type I hypersensitivity to an immunosuppressive agent. J Allergy Clin Immunol 1976; 58: 160–71. 6 Knysak DJ, McLean JA, Solomon WR et al. Immediate hypersensitivity reaction to cyclophosphamide. Arthritis Rheum 1994; 37: 1101–4. 7 Popescu NA, Sheehan MG, Kouides PA et al. Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients. J Allergy Clin Immunol 1996; 97: 26–33. 8 Kritharides L, Lawrie K, Varigos GA. Cyclophosphamide hypersensitivity and cross-reactivity with chlorambucil. Cancer Treat Rep 1987; 71: 1323–4. 9 Pratt CB, Sandlund JT, Meyer WH, Cain AM. Mesna-induced urticaria. Drug Intel Clin Phar 1988; 22: 914. 10 Seidel A, Andrassy K, Ritz E et al. Allergic reactions to mesna. Lancet 1991; 338: 381.

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11 Gross WL, Mohr J, Christophers E. Allergic reactions to mesna. Lancet 1991; 338: 381. 12 D’Cruz D, Haga H-J, Hughes GRV. Allergic reactions to mesna. Lancet 1991; 338: 705–6. 13 Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol 1992; 128: 80–2.

Lomustine. Flushing has been reported. Mechlorethamine. Angio-oedema and pruritus have been recorded [1]; however, in view of the large number of patients receiving this drug as part of the MOPP (mechlorethamine, Oncovin (vincristine), procarbazine, prednisone) regimen for lymphoma, these side effects must be exceedingly rare. Topical mechlorethamine [2] used to treat psoriasis or mycosis fungoides may cause hyperpigmentation of involved and uninvolved skin [3], contact sensitization [4,5] and rarely immediate-type hypersensitivity with urticaria or anaphylactoid reactions [6]. References 1 Wilson KS, Alexander S. Hypersensitivity to mechlorethamine. Ann Intern Med 1981; 94: 823. 2 Price NM, Deneau DG, Hoppe RT. The treatment of mycosis fungoides with ointment-based mechlorethamine. Arch Dermatol 1982; 118: 234–7. 3 Flaxman BA, Sosis AC, Van Scott EJ. Changes in melanosome distribution in Caucasoid skin following topical application of nitrogen mustard. J Invest Dermatol 1973; 60: 321–6. 4 Van Scott EJ, Winters PL. Responses of mycosis fungoides to intensive external treatment with nitrogen mustard. Arch Dermatol 1970; 102: 507–14. 5 Ramsay DL, Halperin PS, Zeleniuch-Jacquotte A. Topical mechlorethamine therapy for early stage mycosis fungoides. J Am Acad Dermatol 1988; 19: 684–91. 6 Daughters D, Zackheim H, Maibach H. Urticaria and anaphylactoid reactions after topical application of mechlorethamine. Arch Dermatol 1973; 107: 429–30.

Melphalan. Trivial morbilliform rashes are relatively common [1]. Severe anaphylactic reactions may occur after intravenous use, especially in patients with IgA κ myeloma [2]. Urticaria or angiooedema after oral use is very rare [3]. Vasculitis has been documented, and melanonychia striata has been recorded [4]. Scleroderma has supervened after isolated limb perfusion [5]. Radiation recall is uncommon [6]. Sterility with azoospermia and amenorrhoea are recorded. References 1 Costa GG, Engle RL Jr, Schilling A et al. Melphalan and prednisone: an effective combination for the treatment of multiple myeloma. Am J Med 1973; 54: 589–99. 2 Cornwell GG, Pajak TF, McIntyre OR. Hypersensitivity reactions to i.v. melphalan during the treatment of multiple myeloma: cancer and leukemia group B experience. Cancer Treat Rep 1979; 63: 399–403. 3 Lawrence BV, Harvey HA, Lipton A. Anaphylaxis due to oral melphalan. Cancer Treat Rep 1980; 64: 731–2. 4 Malacarne P, Zavagli G. Melphalan-induced melanonychia striata. Arch Dermatol Res 1977; 258: 81–3. 5 Landau M, Brenner S, Gat A et al. Reticulate scleroderma after isolated limb perfusion with melphalan. J Am Acad Dermatol 1998; 39: 1011–2. 6 Kellie SJ, Plowman PN, Malpas JS. Radiation recall and radio-sensitization with alkylating agents. Lancet 1987; i: 1149–50.

Ethylenemine derivatives Thiotepa (triethylenethiophosphoramide) Intravesical installation caused pruritus, urticaria or angio-oedema in five of 164 patients with bladder carcinoma [1]. Intravenous

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administration resulted in patterned hyperpigmentation confined to skin occluded by adhesive bandages or electrocardiograph pads, probably due to secretion of the drug in sweat [2]. Diffuse erythema with progression to desquamation and hyperpigmentation, originating in intertriginous and occluded areas, occurred in nearly 80% of paediatric patients receiving high-dose chemotherapy with autologous stem cell transplantation [3]. Topical thiotepa has produced periorbital leukoderma [4].

References 1 Glovsky MM, Braunwald J, Opelz G, Alenty A. Hypersensitivity to procarbazine associated with angio-edema, urticaria and low serum complement activity. J Allergy Clin Immunol 1976; 57: 134–40. 2 Andersen E, Videbaeck A. Procarbazine-induced skin reactions in Hodgkin’s disease and other malignant lymphomas. Scand J Haematol 1980; 24: 149–51. 3 Coyle T, Bushunow P, Winfield J et al. Hypersensitivity reactions to procarbazine with mechlorethamine, vincristine, and procarbazine chemotherapy in the treatment of glioma. Cancer 1992; 69: 2532–40.

References 1 Veenema RJ, Dean AL, Uson AC et al. Thiotepa bladder installations: therapy and prophylaxis for superficial bladder tumors. J Urol 1969; 101: 711–5. 2 Horn TD, Beveridge RA, Egorine MJ et al. Observations and proposed mechanism of N,N′,N′-triethylenethiophosphoramide (thiotepa)-induced hyperpigmentation. Arch Dermatol 1989; 125: 524–7. 3 Rosman IS, Lloyd BM, Hayashi RJ, Bayliss SJ. Cutaneous effects of thiotepa in pediatric patients receiving high-dose chemotherapy with autologous stem cell transplantation. J Am Acad Dermatol 2008; 58: 575–8. 4 Harben DJ, Cooper PH, Rodman OG. Thiotepa-induced leukoderma. Arch Dermatol 1979; 115: 973–4.

Cytotoxic antibiotics Bleomycin

Nitrosoureas Carmustine Topical carmustine (BCNU) used for the treatment of cutaneous T-cell lymphoma may result in erythema, skin tenderness and telangiectasia. Contact sensitization may develop [1]. Mild bone marrow suppression has been recorded. Reference 1 Zackheim HS, Epstein EH Jr, Crain WR. Topical carmustine (BCNU) for cutaneous T cell lymphoma: a 15-year experience in 143 patients. J Am Acad Dermatol 1990; 22: 802–10.

Dacarbazine (DTIC) Photosensitivity [1,2] and a fixed eruption-like rash [3] have been reported. A patient with malignant melanoma treated with DTIC developed sudden hepatic vein thrombosis (Budd–Chiari syndrome) following intravenous administration [4]. Increasing blood eosinophilia appears to be a sign of the imminent development of this complication. Chemical cellulitis occurs following extravasation. References 1 Bolling R, Meyer-Hamme S, Schauder S. Lichtsensibilisierung unter DTIC-Therapie beim metastasierenden malignen Melanom. Hautarzt 1980; 31: 602–5. 2 Yung CW, Winston EM, Lorincz AL. Dacarbazine-induced photosensitivity reaction. J Am Acad Dermatol 1981; 4: 451–3. 3 Koehn GG, Balizet LR. Unusual local cutaneous reaction to dacarbazine. Arch Dermatol 1982; 118: 1018–9. 4 Swensson-Beck H, Trettel WH. Budd–Chiari-Syndrom bei DTIC-Therapie. Hautarzt 1981; 33: 30–1.

Procarbazine Type I reactions are rare; recurrent angio-oedema, urticaria and arthralgia with decreased serum complement have been reported [1,2]. Hypersensitivity to procarbazine in patients treated with mechlorethamine, vincristine and procarbazine (MOP) for highgrade glioma manifested as a maculopapular rash, fever, reversible abnormal liver function and interstitial pneumonitis [3].

The principal problem of systemic therapy is progressive pulmonary fibrosis. Alopecia, glossitis and buccal ulceration occur, and drug fever is common, usually 1–4 h after injection. Distinctive, localized, erythematous, tender macules, nodules or infiltrated plaques on the hands, elbows, knees and buttocks have been documented [1–3]. Their causation is uncertain, and the rash may resolve despite continued therapy [4]. Raynaud’s phenomenon with or without ischaemic ulcerations, and systemic sclerosis-like changes in men, have been described [5–7]. Capillary microscopy has been advocated for the investigation of bleomycin acral vascular toxicity [8]. In normal human skin, intradermal bleomycin induced a localized time- and dose-dependent inflammatory reaction and persistent post-inflammatory hyperpigmentation; histology showed neutrophilic eccrine hidradenitis, with keratinocyte necrosis, HLA-DR and ICAM-1 expression, and endothelial cell ICAM-1 up-regulation and E-selectin induction [9]. Intralesional bleomycin therapy for warts induced keratinocyte apoptosis and complete epidermal necrosis with diffuse neutrophil accumulation and microabscess formation at the granular layer [10]. Clinically, intralesional therapy may cause persistent Raynaud’s phenomenon [11,12] and loss of nails [13]. Cutaneous erythema or hyperpigmentation, which may be diffuse [14], patchy or linear, and prominent over pressure areas, especially the elbows or in striae distensae [15], is seen in approximately 30% of patients [16]. ‘Flagellate’ streaked erythema or pigmentation [17–25] on the trunk and proximal extremities is common (Fig. 75.8); it recurs in previously involved sites, and develops in new sites, within 24 h of rechallenge [21]. It has been proposed that trauma from scratching induces localized vasodilatation, with increased concentration of cutaneous bleomycin; hyperpigmentation has been documented in a patient treated with bleomycin where a heating pad had been applied [26]. There may be darkening of the nail cuticle and palmar creases. References 1 Lincke-Plewig H. Bleomycin-Exanthem. Hautarzt 1980; 31: 616–8. 2 Cohen IS, Mosher MB, O’Keefe EJ. Cutaneous toxicity of bleomycin therapy. Arch Dermatol 1973; 107: 553–5. 3 Haerslev T, Avnstorp C, Joergensen M. Sudden onset of adverse effects due to low-dosage bleomycin indicates an idiosyncratic reaction. Cutis 1993; 52: 45–6. 4 Bennett JP, Burns CP. Absence of progression of recurrent bleomycin skin toxicity without postponement or attenuation of therapy. Am J Med 1988; 85: 585–6. 5 Finch WR, Rodnan GP, Buckingham RB et al. Bleomycin-induced scleroderma. J Rheumatol 1980; 7: 651–9. 6 Bork K, Korting GW. Symptomatische Sklerodermie durch Bleomyzin. Hautarzt 1983; 34: 10–2. 7 Snauwaert J, Degreef H. Bleomycin-induced Raynaud’s phenomenon and acral sclerosis. Dermatologica 1984; 169: 172–4.

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21 Mowad CM, Nguyen TV, Elenitsas R, Leyden JJ. Bleomycin-induced flagellate dermatitis: a clinical and histopathological review. Br J Dermatol 1994; 131: 700–2. 22 Nigro MG, Hsu S. Bleomycin-induced flagellate pigmentation. Cutis 2001; 68: 285–6. 23 von Hilsheimer GE, Norton SA. Delayed bleomycin-induced hyperpigmentation and pressure on the skin. J Am Acad Dermatol 2002; 46: 642–3. 24 Abess A, Keel DM, Graham BS. Flagellate hyperpigmentation following intralesional bleomycin treatment of verruca plantaris. Arch Dermatol 2003; 139: 337–9. 25 Arseculeratne G, Berroeta L, Meiklejohn D et al. Bleomycin-induced ‘flagellelate dermatitis’. Arch Dermatol 2007; 143: 1461–2. 26 Kukla LJ, McGuire WP. Heat-induced recall of bleomycin skin changes. Cancer 1982; 50: 2283–4.

Dactinomycin (actinomycin D) A papulopustular acneiform sterile folliculitis, spreading from the face to the trunk and buttocks, and which may mimic septic cutaneous emboli, is common [1]. Dactinomycin-related lesions with the histology of an interface dermatitis with syringometaplasia developed in the axillae, groins and central line exit site of two children [2]. Radiation recall occurs [3]. Persistent serpentine supravenous hyperpigmentation was recorded in combination dactinomycin and vincristine therapy [4].

Fig. 75.8 Flagellate pigmentation caused by bleomycin. (Courtesy of Dr A. Ilchyshyn, Coventry and Warwickshire Hospital, Coventry, UK.)

8 Bellmunt J, Navarro M, Morales S et al. Capillary microscopy is a potentially useful method for detecting bleomycin vascular toxicity. Cancer 1990; 65: 303–9. 9 Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study. Arch Dermatol 1994; 130: 577–83. 10 James MP, Collier PM, Aherne W et al. Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts. J Am Acad Dermatol 1993; 28: 933–7. 11 Epstein E, O’Keefe EJ, Hayes M, Bovenmyer DA. Persisting Raynaud’s phenomenon following intralesional bleomycin treatment of finger warts. J Am Acad Dermatol 1985; 13: 468–71. 12 Epstein E. Intralesional bleomycin and Raynaud’s phenomenon. J Am Acad Dermatol 1991; 24: 785–6. 13 Gonzalez FU, Gil MCC, Martinez AA et al. Cutaneous toxicity of intralesional bleomycin in the treatment of periungual warts. Arch Dermatol 1986; 122: 974–5. 14 Wright AL, Bleehen SS, Champion AE. Reticulate pigmentation due to bleomycin: light- and electron-microscopic studies. Dermatologica 1990; 181: 255–7. 15 Tsuji T, Sawabe M. Hyperpigmentation in striae distensae after bleomycin treatment. J Am Acad Dermatol 1993; 28: 503–5. 16 Ohnuma T, Selawry OS, Holland JF et al. Clinical study with bleomycin: tolerance to twice weekly dosage. Cancer 1972; 30: 914–22. 17 Cortina P, Garrido JA, Tomas JF et al. ‘Flagellate’ erythema from bleomycin, with histopathological findings suggestive of inflammatory oncotaxis. Dermatologica 1990; 180: 106–9. 18 Fernandez-Obregon AC, Hogan KP, Bibro MK. Flagellate pigmentation from intrapleural bleomycin. A light and electron microscopic study. J Am Acad Dermatol 1985; 13: 464–8. 19 Polla BS, Saurat JG, Merot Y, Slosman D. Flagellate pigmentation from bleomycin. J Am Acad Dermatol 1986; 14: 690. 20 Rademaker M, Meyrick Thomas RH, Lowe DG, Munro DD. Linear streaking due to bleomycin. Clin Exp Dermatol 1987; 12: 457–9.

References 1 Epstein EH, Lutzner MA. Folliculitis induced by actinomycin D. N Engl J Med 1969; 281: 1094–6. 2 Kanwar VS, Gajjar A, Ribeiro RC et al. Unusual cutaneous toxicity following treatment with dactinomycin: a report of two cases. Med Pediatr Oncol 1995; 24: 329–33. 3 Coppes MJ, Jorgenson K, Arlette JP. Cutaneous toxicity following the administration of dactinomycin. Med Pediatr Oncol 1997; 29: 226–7. 4 Marcoux D, Anex R, Russo P. Persistent serpentine supravenous hyperpigmented eruption as an adverse reaction to chemotherapy combining actinomycin and vincristine. J Am Acad Dermatol 2000; 43: 540–6.

Daunorubicin Angio-oedema with generalized urticaria [1], and hyperpigmentation of the oral mucosa, skin and nails [2–4] have been described. References 1 Freeman AI. Clinical note. Allergic reaction to daunomycin (NSC-82151). Cancer Chemother Rep 1970; 54: 475–6. 2 Kelly TM, Fishman LM, Lessner HE. Hyperpigmentation with daunorubicin therapy. Arch Dermatol 1984; 120: 262–3. 3 Anderson LL, Thomas ED, Berger TG et al. Cutaneous pigmentation after daunorubicin chemotherapy. J Am Acad Dermatol 1992; 26: 255–6. 4 Kroumpouzos G, Travers R, Allan A. Generalised hyperpigmentation with daunorubicin chemotherapy. J Am Acad Dermatol 2002; 46: S1–S3.

Doxorubicin (Adriamycin) Short-lived, localized erythema or urticaria with pruritus along the vein proximal to the injection site may occur in up to 3% of patients [1]. Angio-oedema, generalized urticaria with or without anaphylaxis and chronic urticaria have been reported rarely [2]. Cutaneous and nail pigmentation are well recognized [3,4]. Erythema and desquamation of palmar and plantar skin, with or without onycholysis, occurs frequently in patients receiving doxorubicin [5–7]. Liposomal doxorubicin is associated with a dose-limiting hand–foot syndrome with palmar–plantar erythro-

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dysesthesia, stomatitis [8,9], psoriasiform pustular reactions [10], diffuse follicular rash, intertrigo-like eruption, morbilliform eruptions, and new formation of melanotic macules [11–13]. Pyridoxine has been advocated as prophylactic therapy for the palmar–plantar erythrodysesthesia [14]. Allergic cross-reaction occurs with daunorubicin. Toxic epidermal injury after intra-arterial injection [15], phlebitis and chemical cellulitis with extensive tissue necrosis and ulceration following extravasation [16] are well documented. References 1 Vogelzang NJ. ‘Adriamycin flare’: a skin reaction resembling extravasation. Cancer Treat Rep 1979; 63: 2067–9. 2 Hatfield AK, Harder L, Abderhalden RT. Chronic urticarial reactions caused by doxorubicin-containing regimens. Cancer Chemother Rep 1981; 65: 353–4. 3 Giacobetti R, Esterly NB, Morgan ER. Nail hyperpigmentation secondary to therapy with doxorubicin. Am J Dis Child 1981; 135: 317–8. 4 Curran CF. Doxorubicin-associated hyperpigmentation. NZ Med J 1990; 103: 517. 5 Vogelzang NJ, Ratain MJ. Cancer chemotherapy and skin changes. Ann Intern Med 1985; 103: 303–4. 6 Jones AP, Crawford SM. Anthracycline-induced toxicity affecting palmar and plantar skin. Br J Cancer 1989; 59: 814. 7 Curran CF. Onycholysis in doxorubicin-treated patients. Arch Dermatol 1990; 126: 1244. 8 Uziely B, Jeffers S, Isacson R et al. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995; 13: 1777–85. 9 Gordon KB, Tajuddin A, Guitart J et al. Hand–foot syndrome associated with liposome-encapsulated doxorubicin therapy. Cancer 1995; 75: 2169–73. 10 Kreuter A, Gambichler T, Schlottmann R et al. Psoriasiform pustular eruptions from pegylated-liposomal doxorubicin in AIDS-related Kaposi’s sarcoma. Acta Derm Venereol (Stockh) 2001; 81: 224. 11 Lotem M, Hubert A, Lyass O et al. Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 2000; 136: 1475–80. 12 Campanelli A, Kerl K, Lübbe J. Severe palmoplantar erythrodysesthesia and intertrigolike eruption induced by polyethylene glycol-coated liposomal doxorubicin. J Eur Acad Dermatol Venereol 2006; 20: 1022–4. 13 Cady FM, Kneuper-Hall R, Metcalf JS. Histologic patterns of polyethylene glycol-liposomal doxorubicin-related cutaneous eruptions. Am J Dermatopathol 2006; 28: 168–72. 14 Rossi D, Catalano G. Pyridoxine as prophylactic therapy for palmar-plantar erythrodysesthesia associated with administration of pegylated liposomal doxorubicin (caelyx): a single-center experience. Oncology 2007; 73: 277–8. 15 Von Eyben FE, Bruze M, Eksborg S et al. Toxic epidermal injury following intraarterial adriamycin treatment. Cancer 1981; 48: 1535–8. 16 Reilly JJ, Neifeld JP, Rosenberg SA. Clinical course and management of accidental adriamycin extravasation. Cancer 1977; 40: 2053–6.

Mitomycin Urticaria and dermatitis [1–3], particularly on the face, palms and soles, or genitals and sometimes more generalized, have been reported after intravesical therapy. Sunlight-induced recall of ulceration following extravasation has been recorded [4]. References 1 Colver GB, Inglis JA, McVittie E et al. Dermatitis due to intravesical mitomycin C: a delayed-type hypersensitivity reaction? Br J Dermatol 1990; 122: 217–24. 2 De Groot AC, Conemans JMH. Systemic allergic contact dermatitis from intravesical instillation of the antitumor antibiotic mitomycin C. Contact Dermatitis 1991; 24: 201–9. 3 Arregui MA, Aguirre A, Gil N et al. Dermatitis due to mitomycin C bladder instillations: study of 2 cases. Contact Dermatitis 1991; 24: 368–70. 4 Fuller B, Lind M, Bonomi P. Mitomycin C extravasation exacerbated by sunlight. Ann Intern Med 1981; 94: 542.

Antimetabolites Aminoglutethimide This inhibitor of adrenal steroid synthesis has been reported to induce SLE [1]. Reference 1 McCraken M, Benson EA, Hickling P. Systemic lupus erythematosus induced by aminoglutethimide. BMJ 1980; 281: 1254.

Azathioprine The dermatological aspects of this derivative of the antimetabolite mercaptopurine have been reviewed [1–3]. Bone marrow suppression is the main problem; blood counts should be performed weekly for the first month, then monthly thereafter. Homozygotes for the low-activity allele for thiopurine methyltransferase are at risk of myelosuppression [4–7]. It is therefore recommended that thiopurine methyltransferase levels should be measured before commencing patients on azathioprine [6]. Gastrointestinal upset is common and may necessitate discontinuation of therapy. Hypersensitivity reactions [8–10], including fever [11], maculopapular rashes, urticaria, vasculitis, erythema multiforme or erythema nodosum [12], cholestatic jaundice, hepatitis, liver necrosis, interstitial pneumonitis, polyneuropathy, pancreatitis, shock [13] with hypotension, nephritis and oliguria are well recognized. An acneiform exanthem has been described, confirmed on challenge [14]. An eruption comprising tiny superficial blisters and peeling in the flexures is described [15]. Acute generalized exanthematous pustulosis is recorded [16]. Multiple large resistant warts are common on the hands of renal transplant recipients maintained on long-term azathioprine and prednisolone therapy; herpes simplex and herpes zoster infection may occur [17], and Norwegian scabies may be promoted [18]. Disseminated superficial actinic porokeratosis [19] and porokeratosis of Mibelli [20] have been documented. Keratoacanthomas and squamous cell carcinomas may develop [21]. Long-term therapy may predispose to the development of malignancy, especially non-Hodgkin’s lymphoma [22]. Azathioprine crosses the placenta, although there is little evidence that it is teratogenic in humans, and detailed analysis of successful pregnancies notified to the European Dialysis and Transplant Association did not suggest an excessive rate of congenital abnormality [23]. However, depressed fetal haemopoiesis and resultant neonatal thrombocytopenia and leukopenia have been documented [24]. Pregnancy may be best avoided in patients receiving this drug [25]. Allopurinol may potentiate the effect of azathioprine by inhibiting its metabolism; the dose of azathioprine should therefore be reduced to one-quarter of the regular dose. References 1 Speerstra F, Boerbooms AM, van de Putte LB et al. Side effects of azathioprine treatment in rheumatoid arthritis: analysis of ten years of experience. Ann Rheum Dis 1982; 41: 37–9. 2 Gendler E. Azathioprine for use in dermatology. J Dermatol Surg Oncol 1984; 10: 462–4. 3 Younger IR, Harris DWS, Colver GB. Azathioprine in dermatology. J Am Acad Dermatol 1991; 25: 281–6. 4 Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1995; 131: 193–7.

Important or widely prescribed drugs 5 Snow JL, Gibson LE. A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients. J Am Acad Dermatol 1995; 32: 114–6. 6 Jackson AP, Hall AG, McLelland J. Thiopurine methyltransferase levels should be measured before commencing patients on azathioprine. Br J Dermatol 1997; 136: 133–4. 7 Tavadia SMB, Mydlarski PR, Reis MD et al. Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol 2000; 42: 628–32. 8 Stetter M, Schmidl M, Krapf R. Azathioprine hypersensitivity mimicking Goodpasture’s syndrome. Am J Kidney Dis 1994; 23: 874–7. 9 Knowles SR, Gupta AK, Shear NH, Sauder D. Azathioprine hypersensitivity-like reactions: a case report and a review of the literature. Clin Exp Dermatol 1995; 20: 353–6. 10 Parnham AP, Dittmer I, Mathieson PW et al. Acute allergic reactions associated with azathioprine. Lancet 1996; 348: 542–3. 11 Smak Gregoor PJ, van Saase JL, Weimar W, Kramer P. Fever and rigors as sole symptoms of azathioprine hypersensitivity. Neth J Med 1995; 47: 288–90. 12 de Fonclare A-L, Khosrotehrani K, Aractingi S et al. Erythema nodosum-like eruption as a manifestation of azathioprine hypersensitivity in patients with inflammatory bowel disease. Arch Dermatol 2007; 143: 744–8. 13 Jones JJ, Ashworth J. Azathioprine-induced shock in dermatology patients. J Am Acad Dermatol 1993; 29: 795–6. 14 Schmoeckel C, von Liebe V. Akneiformes Exanthem durch Azathioprin. Hautarzt 1983; 34: 413–5. 15 Hermanns-Le T, Pierard GE. Azathioprine-induced skin peeling syndrome. Dermatology 1997; 194: 175–6. 16 Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthematous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007; 32: 52–3. 17 Spencer ES, Anderson HK. Viral infections in renal allograft recipients treated with long-term immunosuppression. BMJ 1979; 2: 829–30. 18 Paterson WD, Allen BR, Beveridge GW. Norwegian scabies during immunosuppressive therapy. BMJ 1983; 4: 211–2. 19 Neumann RA, Knobler RM, Metze D et al. Disseminated superficial porokeratosis and immunosuppression. Br J Dermatol 1988; 119: 375–80. 20 Tatnell FM, Sarkany I. Porokeratosis of Mibelli in an immunosuppressed patient. J R Soc Med 1987; 80: 180–1. 21 McLelland J, Rees A, Williams G et al. The incidence of immunosuppressionrelated skin disease in long-term transplant patients. Transplantation 1988; 46: 871–4. 22 Phillips LT, Salisbury J, Leigh I, Baker H. Non-Hodgkin’s lymphoma associated with long-term azathioprine therapy. Clin Exp Dermatol 1987; 12: 444–5. 23 Registration Committee of the European Dialysis and Transplant Association. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980; 87: 839–45. 24 Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 1985; 92: 233–9. 25 Gebhart DOE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol 1983; 61: 270.

Cytarabine (cytosine arabinoside) This drug interferes with pyrimidine synthesis. A self-limited palmoplantar erythema, occasionally with bullae, may occur [1–4]. Neutrophilic eccrine hidradenitis has been reported [5]. A syndrome with fever, malaise, arthralgia, conjunctivitis and diffuse erythematous maculopapular rash is documented [6]. The overall incidence of cutaneous reactions, including morbilliform eruptions, acral erythema, swelling and generalized urticaria, was almost 53% in one series [7]. References 1 Walker IR, Wilson WEB, Sauder DN et al. Cytarabine-induced palmar–plantar erythema. Arch Dermatol 1985; 121: 1240–1.

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2 Shall L, Lucas GS, Whittaker JA, Holt PJA. Painful red hands: a side-effect of leukaemia therapy. Br J Dermatol 1988; 119: 249–53. 3 Brown J, Burck K, Black D, Collins C. Treatment of cytarabine acral erythema with corticosteroids. J Am Acad Dermatol 1991; 24: 1023–5. 4 Richards C, Wujcik D. Cutaneous toxicity associated with high-dose cytosine arabinoside. Oncol Nurs Forum 1992; 19: 1191–5. 5 Flynn TC, Harrist TJ, Murphy GF et al. Neutrophilic eccrine hidradenitis: a distinctive type of neutrophilic dermatosis associated with cytarabine therapy and acute leukemia. J Am Acad Dermatol 1984; 11: 584–90. 6 Shah SS, Rybak ME, Griffin TW. The cytarabine syndrome in an adult. Cancer Treat Rep 1983; 67: 405–6. 7 Cetkovska P, Pizinger K, Cetkovsky P. High-dose cytosine arabinoside-induced cutaneous reactions. J Eur Acad Dermatol Venereol 2002; 16: 481–5.

Fluorouracil Anaphylaxis is rare; alopecia and recall phenomena [1] may be seen. Erythema followed by hyperpigmentation of sun-exposed areas occurs in up to 5% of patients [2]. Hyperpigmentation may be reticulate [3]. Photosensitivity is recorded; pellagra may be caused by direct inhibition of the transformation of tryptophan into nicotinamide. Rarely, hyperpigmented streaks (serpentine supravenous hyperpigmentation) develop over arm veins used for injection [2,4–6]. Continuous infusion may be followed by the development of erythema, oedema and desquamation of the hands [7–11]. Pyridoxine may decrease the intensity and pain of fluorouracil-induced acral erythema [9]. Oral administration resulted in painful erythema multiforme-like erosions and blisters on the soles and arms in one case [10]. Systemic fluorouracil may result in marked inflammation of metastatic skin lesions [12] and of solar keratoses [13]. Topical application may lead to hyperpigmentation with or without a preceding irritant or allergic contact dermatitis [14]. Capecitabine Capecitabine is a fluoropyrimidine carbamate that is metabolized to fluorouracil, and has been recorded as causing hand–foot syndrome in 50% of patients, and rarely leopard-like vitiligo, onycholysis and periungual pyogenic granulomas [15]. Gemcitabine This drug has caused radiation recall [16]. References 1 Prussick R, Thibault A, Turner ML. Recall of cutaneous toxicity from fluorouracil. Arch Dermatol 1993; 129: 644–5. 2 Hrushesky WJ. Unusual pigmentary changes associated with 5-fluorouracil therapy. Cutis 1980; 26: 181–2. 3 Jogi R, Garman M, Pielop J et al. Reticulate hyperpigmentation secondary to 5-fluorouracil and idarubicin. J Drugs Dermatol 2005; 4: 652–6. 4 Hrushesky WJ. Serpentine supravenous 5-fluorouracil (NSC-19893) hyperpigmentation. Cancer Treat Rep 1976; 60: 639. 5 Vukelja SJ, Bonner MW, McCollough M et al. Unusual serpentine hyperpigmentation associated with 5-fluorouracil. Case report and review of cutaneous manifestations associated with systemic 5-fluorouracil. J Am Acad Dermatol 1991; 25: 905–8. 6 Pujol RM, Rocamora V, Lopez-Pousa A et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol 1998; 39: 839–42. 7 Feldman LD, Jaffer A. Fluorouracil-associated palmar–plantar erythrodysesthesia syndrome. JAMA 1985; 254: 3479. 8 Guillaume J-C, Carp E, Rougier P et al. Effects secondaires cutanéo-muqueux des perfusions continues de 5-fluorouracile: 12 observations. Ann Dermatol Vénéréol 1988; 115: 1167–9.

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9 Vukelja SJ, Lombardo RA, James WD et al. Pyridoxine for the palmar–plantar erythrodysesthesia syndrome. Ann Intern Med 1989; 111: 688–9. 10 Ueki H, Namba M. Arzneimittelexanthem durch ein neues 5-Fluorourazilderivat. Hautarzt 1980; 31: 207–8. 11 Chiara S, Nobile MT, Barzacchi C et al. Hand–foot syndrome induced by highdose, short-term, continuous 5-fluorouracil infusion. Eur J Cancer 1997; 33: 967–9. 12 Schlang HA. Inflammation of malignant skin involvement with fluorouracil. JAMA 1977; 238: 1722. 13 Bataille V, Cunningham D, Mansi J, Mortimer P. Inflammation of solar keratoses following systemic 5-fluorouracil. Br J Dermatol 1996; 135: 478–80. 14 Goette DK, Odom RB. Allergic contact dermatitis to topical fluorouracil. Arch Dermatol 1977; 113: 1058–61. 15 Piguet V, Borradori L. Pyogenic granuloma-like lesions during capecitabine therapy. Br J Dermatol 2002; 147: 1270–2. 16 Jeter MD, Janne PA, Brooks S et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys 2002; 53: 394–400.

Methotrexate Dermatological aspects. These have been reviewed [1–3]. Methotrexate is a folic acid analogue and antagonist that inactivates dihydrofolate reductase. There is marked individual variation in absorption from the gastrointestinal tract, and hence in expression of toxic effects. Alopecia occurs in 6% of patients receiving lowdose therapy for psoriasis and in 8% of patients on high-dose regimens for malignancy, and is usually the result of telogen effluvium. Intermittent high dosage has resulted in horizontal pigmented banding of hair (the ‘flag sign’ of chemotherapy) [4]. Urticaria develops in about 4% of patients on low-dose oral or parenteral therapy for psoriasis [5]. Exacerbation of urticarial vasculitis has been documented [6]. Photosensitivity occurs in up to 5% of cases. Methotrexate use has been associated with severe reactivation of sunburn [7,8]; in one case, there was sparing of chronically sun-exposed skin [8]. Chronic viral wart and molluscum infections may result from immunosuppression. Cutaneous toxicity with local epidermal necrosis may occasionally occur [9,10]. A macular erythema occurring in 15% of patients, and biopsy-proven capillaritis, have been reported with high-dose therapy [3]. An eruption of erythematous indurated papules on the proximal parts of the limbs has been documented in patients with collagen vascular disease [11]. Anaphylactic reactions [12] and pain, burning, erythema and desquamation of the palms and soles [13–15] are seen with high-dose intravenous methotrexate, but are extremely rare. Vasculitis has been very rarely documented with both intermediate dosage therapy for leukaemia [16] and high-dose therapy [17]. TEN is recorded [18,19], and occurred after a single injection of 25 mg for pustular psoriasis [19]. References 1 Plantin P, Saraux A, Guillet G. Méthotrexate en dermatologie: aspects actuels. Ann Dermatol Vénéréol 1989; 116: 109–15. 2 Zachariae H. Methotrexate side-effects. Br J Dermatol 1990; 122 (Suppl. 36): 127–33. 3 Olsen EA. The pharmacology of methotrexate. J Am Acad Dermatol 1991; 25: 306–18. 4 Wheeland RG, Burgdorf WH, Humphrey GB. The flag sign of chemotherapy. Cancer 1983; 51: 1356–8. 5 Weinstein GD, Frost P. Methotrexate for psoriasis. A new therapeutic schedule. Arch Dermatol 1971; 103: 33–8. 6 Borcea A, Greaves MW. Methotrexate-induced exacerbation of urticarial vasculitis: an unusual adverse reaction. Br J Dermatol 2000; 143: 203–4.

7 Mallory SB, Berry DH. Severe reactivation of sunburn following methotrexate use. Pediatrics 1986; 78: 514–5. 8 Westwick TJ, Sherertz EF, McCarley D, Flowers FP. Delayed reactivation of sunburn by methotrexate: sparing of chronically sun-exposed skin. Cutis 1987; 39: 49–51. 9 Harrison PV. Methotrexate-induced epidermal necrosis. Br J Dermatol 1987; 116: 867–9. 10 Kaplan DL, Olsen EA. Erosion of psoriatic plaques after chronic methotrexate administration. Int J Dermatol 1988; 27: 59–62. 11 Goerttler E, Kutzner H, Peter HH, Requena L. Methotrexate-induced papular eruption in patients with rheumatic diseases: a distinctive adverse cutaneous reaction produced by methotrexate in patients with collagen vascular diseases. J Am Acad Dermatol 1999; 40: 702–7. 12 Klimo P, Ibrahim E. Anaphylactic reaction to methotrexate used in high doses as an adjuvant treatment of osteogenic sarcoma. Cancer Treat Rep 1981; 65: 725. 13 Doyle LA, Berg C, Bottino G et al. Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983; 98: 611–2. 14 Martins da Cunha AC, Rappersberger K, Gadner H. Toxic skin reaction restricted to palms and soles after high-dose methotrexate. Pediatr Hematol Oncol 1991; 8: 277–80. 15 Aractingi S, Briant E, Marolleau J et al. Décollements cutanés induits par le methotrexate. Presse Med 1992; 21: 1668–70. 16 Fondevila CG, Milone GA, Pavlovsky S. Cutaneous vasculitis after intermediate dose of methotrexate (IDMTX). Br J Haematol 1989; 72: 591–2. 17 Navarro M, Pedragosa R, Lafuerza A et al. Leukocytoclastic vasculitis after highdose methotrexate. Ann Intern Med 1986; 105: 471–2. 18 Collins P, Rogers S. The efficacy of methotrexate in psoriasis: a review of 40 cases. Clin Exp Dermatol 1992; 17: 257–60. 19 Primka EJ III, Camisa C. Methotrexate-induced toxic epidermal necrolysis in a patient with psoriasis. J Am Acad Dermatol 1997; 36: 815–8.

Systemic complications. Because folic acid is an essential cofactor for DNA synthesis and cell division, bone marrow suppression may occur even on low-dose therapy [1–4]. Thrombocytopenia may develop after a single test dose [5]. Severe bone marrow suppression [6] with the dosage used in the therapy of psoriasis is fortunately not common. Stomatitis may be a warning sign of overdosage. The risk of myelosuppression is much greater in the presence of renal impairment. Gastrointestinal upset is common. Abnormalities of taste sensation occur rarely [7]. The main hazard is hepatotoxicity with long-term use [8]. The risk of developing severe hepatotoxicity is related to the daily dose, the dose frequency and the cumulative dose [9]. Alcohol consumption, underlying liver disease and obesity, especially in the presence of diabetes, are aggravating factors. Previous monitoring recommendations included obtaining baseline haematological, renal and hepatic function tests and a liver biopsy before or within 4 months of starting therapy, and repeating after every 1.5 g [10]. Liver function tests may be unreliable indicators of fibrosis or cirrhosis. These guidelines appeared prudent but have never been rigorously tested, and are variously applied in clinical practice [10,11]. There seems to be a discrepancy between the degree of hepatotoxicity in rheumatoid arthritis and that in psoriasis, and many rheumatologists do not routinely carry out liver biopsy [11]. The requirement for liver biopsies in psoriasis patients on long-term, low-dose, once-weekly oral methotrexate has been questioned [12]. Radionuclide liver scans are thought to be of little value in the detection of methotrexate-induced liver disease, but liver ultrasound may be of some assistance [13]. Abnormal liver biopsy may improve after cessation of therapy [14]. Assay of serum levels of the aminopropeptide of type III procollagen is

Important or widely prescribed drugs

increasingly used to screen for patients in whom liver biopsy is really mandatory [15–17]. Acute renal failure may follow high-dose methotrexate therapy, although renal damage is rare in patients treated for psoriasis. Pulmonary complications, such as pneumonitis or fibrosis, are rare [18,19]. Hepatotoxicity with methotrexate is more common in psoriatic arthritis, and pulmonary toxicity in rheumatoid arthritis [20]. There do not appear to be adverse effects on humoral or cellular immunity from low weekly doses as given for rheumatoid arthritis or psoriasis [21]. A survey of systemic complications of methotrexate therapy in rheumatoid arthritis patients over the period between 1986 and 1999 found that 10.7% of all patients stopped because of inefficacy or patient choice, 5.5% stopped due to abnormal haematology (usually low neutrophils), and 5.5% stopped due to abnormalities in liver function tests. Life-threatening side-effects were identified in 1.8%, including cytopenias, pneumonitis and disseminated varicella zoster, and were fatal in 0.3% of cases [22]. Methotrexate is a known teratogen, and may cause oligospermia [23,24]. It is recommended that patients avoid pregnancy or impregnation during, and for at least 12 weeks after cessation of, methotrexate therapy [25]. Care must be taken with regard to potential drug interactions with methotrexate [26,27]. Drugs that also interfere with folate metabolism, such as trimethoprim–sulfamethoxazole [28–30], may cause pancytopenia; both trimethoprim and sulfamethoxazole bind to dihydrofolate reductase. Drugs that displace methotrexate from plasma protein-binding sites, such as salicylates, sulphonamides and diphenylhydantoin, as well as drugs that impair the renal clearance of methotrexate, such as NSAIDs and sulphonamides, may also cause pancytopenia. A toxic reaction occurred in a patient treated with penicillin and furosemide [31]. References 1 MacKinnon SK, Starkebaum G, Wilkens RF. Pancytopenia associated with low-dose pulse methotrexate in the treatment of rheumatoid arthritis. Semin Arthitis Rheum 1985; 15: 119–26. 2 Shupack JL, Webster GF. Pancytopenia following low-dose oral methotrexate therapy for psoriasis. JAMA 1988; 259: 3594–6. 3 Abel EA, Farber EM. Pancytopenia following low-dose methotrexate therapy. JAMA 1988; 259: 3612. 4 Copur S, Dahut W, Chu E, Allegra CJ. Bone marrow aplasia and severe skin rash after a single low dose of methotrexate. Anticancer Drugs 1995; 6: 154–7. 5 Jih DM, Werth VP. Thrombocytopenia after a single test dose of methotrexate. J Am Acad Dermatol 1998; 39: 349–51. 6 Takami M, Kuniyoshi Y, Oomukai T et al. Severe complications after high-dose methotrexate treatment. Acta Oncol 1995; 34: 611–2. 7 Duhra P, Foulds IS. Methotrexate-induced impairment of taste acuity. Clin Exp Dermatol 1988; 13: 126–7. 8 Zachariae H, Kragballe K, Søgaard H. Methotrexate induced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102: 407–12. 9 Lewis JH, Schiff E. ACG Committee on FDA-Related Matters. Methotrexateinduced chronic liver injury: guidelines for detection and prevention. Am J Gastroenterol 1988; 88: 1337–45. 10 Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19: 145–56. 11 Petrazzuoli M, Rothe MJ, Grin-Jorgensen C et al. Monitoring patients taking methotrexate for hepatotoxicity. Does the standard of care match published guidelines? J Am Acad Dermatol 1994; 31: 969–77.

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12 Boffa MJ, Chalmers RJG, Haboubi NY et al. Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal. Br J Dermatol 1995; 133: 774–8. 13 Coulson IH, McKenzie J, Neild VS et al. A comparison of liver ultrasound with liver biopsy histology in psoriatics receiving long-term methotrexate therapy. Br J Dermatol 1987; 116: 491–5. 14 Newman M, Auerbach R, Feiner H et al. The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment. Improvement in liver abnormalities after cessation of therapy. Arch Dermatol 1989; 125: 1218–24. 15 Zachariae H, Søgaard H, Heickendorff L. Serum aminoterminal propeptide of type III procollagen. Acta Derm Venereol (Stockh) 1989; 69: 241–4. 16 Boffa MJ, Smith A, Chalmer RJG et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol 1996; 135: 538–44. 17 Zachariae H, Heickendorff L, Søgaard H. The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10 year follow up. Br J Dermatol 2001; 144: 100–3. 18 Phillips TJ, Jones DH, Baker H. Pulmonary complications following methotrexate therapy. J Am Acad Dermatol 1987; 16: 373–5. 19 Carson CW, Cannon GW, Egger MJ et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16: 186–95. 20 Helliwell PS, Taylor WJ; CASPAR Study Group. Treatment of psoriatic arthritis and rheumatoid arthritis with disease modifying drugs—comparison of drugs and adverse reactions. J Rheumatol 2008; 35: 472–6. 21 Andersen PA, West SG, O’Dell JR et al. Weekly pulse methotrexate in rheumatoid arthritis: clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 1985; 103: 489–96. 22 Kinder AJ, Hassell AB, Brand J et al. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 2005; 44: 61–6. 23 Sussman A, Leonard JM. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980; 116: 215–7. 24 Shamberger RC, Rosenberg SA, Seipp CA et al. Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat Rep 1981; 65: 739–46. 25 Morris LF, Harrod MJ, Menter MA, Silverman AK. Methotrexate and reproduction in men: case report and recommendations. J Am Acad Dermatol 1993; 29: 913–6. 26 Evans WE, Christensen ML. Drug interactions with methotrexate. J Rheumatol 1985; 12 (Suppl. 12): 15–20. 27 Liddle BJ, Marsden JR. Drug interactions with methotrexate. Br J Dermatol 1989; 120: 582–3. 28 Thomas DR, Dover JS, Camp RDR. Pancytopenia induced by the interaction between methotrexate and trimethoprim–sulfamethoxazole. J Am Acad Dermatol 1987; 17: 1055–6. 29 Ferrazzini G, Klein J, Sulh H et al. Interaction between trimethoprim– sulfamethoxazole and methotrexate in children with leukemia. J Pediatr 1990; 117: 823–6. 30 Groenendal H, Rampen FHJ. Methotrexate and trimethoprim–sulphamethoxazole: a potentially hazardous combination. Clin Exp Dermatol 1990; 15: 358–60. 31 Nierenberg DW, Mamelok RD. Toxic reaction to methotrexate in a patient receiving penicillin and furosemide. Arch Dermatol 1983; 119: 449–50.

Vinca alkaloids and etoposide These drugs cause metaphase arrest by interfering with microtubule assembly.

Etoposide (VP-16) This semi-synthetic podophyllotoxin derivative causes bone marrow suppression, alopecia and gastrointestinal symptoms. It has caused Stevens–Johnson syndrome and radiation recall. Four cases of a diffuse, erythematous, maculopapular rash occurring 5–9 days after initiation of therapy, with spontaneous resolution within 3 weeks, have been reported [1]. On histology, scattered,

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markedly enlarged individual keratinocytes with a ‘starburst’ nuclear chromatin pattern were seen. Hypersensitivity reactions are generally held to be rare [2–4], but 51% of patients with newly diagnosed Hodgkin’s disease had one or more acute hypersensitivity reactions to etoposide administration, including flushing, respiratory problems, changes in blood pressure and abdominal pain [5].

Vincristine Peripheral neuropathy is well recognized with long-term therapy [6]. Vinblastine Photosensitivity is common [7]. Acute alopecia and radiation recall are documented. Erythema multiforme-like reactions are described following intravenous injection [8]. References 1 Yokel BK, Friedman KJ, Farmer ER, Hood AF. Cutaneous pathology following etoposide therapy. J Cutan Pathol 1987; 14: 326–30. 2 Kasperek C, Black CD. Two cases of suspected immunologic-based hypersensitivity reactions to etoposide therapy. Ann Pharmacother 1992; 26: 1227–30. 3 de Souza P, Friedlander M, Wilde C et al. Hypersensitivity reactions to etoposide. A report of three cases and review of the literature. Am J Clin Oncol 1994; 17: 387–9. 4 Hoetelmans RM, Schornagel JH, ten Bokkel Huinink WW, Beijnen JH. Hypersensitivity reactions to etoposide. Ann Pharmacother 1996; 30: 367–71. 5 Hudson MM, Weinstein HJ, Donaldson SS et al. Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin’s disease. J Clin Oncol 1993; 11: 1080–4. 6 Watkins SM, Griffin JP. High incidence of vincristine-induced neuropathy in lymphomas. BMJ 1978; i: 610–2. 7 Breza TS, Halprin KM, Taylor JR. Photosensitivity reaction to vinblastine. Arch Dermatol 1975; 111: 1168–70. 8 Arias D, Requena L, Hasson A et al. Localized epidermal necrolysis (erythema multiforme-like reactions) following intravenous injection of vinblastine. J Cutan Pathol 1991; 18: 344–6.

Enzymes L-Asparaginase (crisantaspase) Dose-dependent IgE-mediated hypersensitivity reactions, including urticaria and anaphylaxis, are frequent, especially when the drug is used alone [1]. Allergic reactions to intramuscular lasparaginase include local painful erythema, and urticaria or a general exanthem; continuous infusion is better tolerated [2]. References 1 Ertel IJ, Nesbit ME, Hammond D et al. Effective dose of l-asparaginase for induction of remission in previously treated children with acute lymphocytic leukemia: a report from Children’s Cancer Study Group. Cancer Res 1979; 39: 3893–6. 2 Rodriguez T, Baumgarten E, Fengler R et al. Langzeitinfusion von l-Asparaginase: eine Alternative zur intramuskularen Injektion? Klin Pediatr 1995; 207: 207–10.

Inhibitors of epidermal growth factor receptor (anti-EGFR therapy) Anti-EGFR (epidermal growth factor receptor) therapies are active against certain solid tumours, including colorectal, head and neck, pancreatic and lung cancers; they include tyrosine kinase inhibitors and monoclonal antibodies which act via different mechanisms. Monoclonal antibodies bind to the extracellular domain of EGFR, preventing ligand binding and interrupting the signalling

cascade, whereas tyrosine kinase inhibitors bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR ligand binding [1]. Adverse effects of these agents have been extensively reviewed [2–10]. Several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side effects [3,7]. Cutaneous adverse reactions to monoclonal antibodies may be limited to infusion reactions, local inflammation at injection sites and ill-defined transient eruptions; however, their use in gastrointestinal and head and neck cancer has been frequently associated with significant skin reactions [6]. Key cutaneous manifestations include papulopustular follicular acneiform eruptions, superinfection with Staphylococcus aureus, hair and nail disorders including paronychia, pruritus, hyperpigmentation, mucositis, xerosis, eczema and desquamation [2,4,5,8–10]. Cetuximab [8–16]. The most common toxicities are rash, diarrhoea, fever, headache, nausea, hypomagnesaemia and hypersensitivity reactions. Paronychia and aphthous ulcers, follicular papulopustules, and a facial acneiform follicular eruption are recorded with this chimeric antiepidermal growth factor receptor antibody. Adverse cutaneous reactions appear to be a marker for response. Erlotinib. Acneiform reactions occur [17]. Imatinib [18,19]. This protein tyrosine kinase inhibitor, used in the therapy of chronic myeloid leukaemia, commonly causes maculopapular exanthematous eruptions, oedema, and periorbital oedema; reactions are usually self-limited despite continuation of the drug. Rarer side effects include: hypopigmentation, lichenoid reactions [20,21], pityriasiform eruptions, pityriasis rosea, psoriasis, exfoliative dermatoses, acute generalized exanthematous pustulosis, purpuric vasculitis, erythema nodosum, reactivation or induction of porphyria cutanea tarda, neutrophilic eccrine hidradenitis, Sweet’s syndrome [22], EBV-positive cutaneous Bcell lymphoproliferative disease [23], follicular mucinosis, pseudolymphoma-type drug eruptions, lymphomatoid granulomatosis [24], eosinophilia, fasciitis, and a mycosis fungoides-like reaction with antinuclear autoantibodies [25], Stevens–Johnson syndrome [26], and toxic epidermal necrolysis. Sorafenib. A hand–foot skin reaction is a distinctive cutaneous side effect of this antineoplastic tyrosine kinase inhibitor for metastatic cancer. Well-demarcated, tender, erythematous papules and plaques with greyish blisters, or hyperkeratotic, callus-like formations on palmoplantar surfaces and distal phalanges occur. Other skin toxicities encompassed angular cheilitis, seborrhoeic dermatitis and perianal dermatitis. Histopathological findings include keratinocyte vacuolar degeneration, presence of intracytoplasmic eosinophilic bodies, and intraepidermal blisters [27]. References 1 Vokes EE, Chu E. Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. Oncology (Williston Park) 2006; 20 (5 Suppl. 2): 15–25. 2 Fox LP. Pathology and management of dermatologic toxicities associated with anti-EGFR therapy. Oncology (Williston Park) 2006; 20 (5 Suppl. 2): 26–34.

Important or widely prescribed drugs

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3 Robert C, Soria JC, Spatz A et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005; 6: 491–500. 4 Boone SL, Rademaker A, Liu D et al. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 2007; 72: 152–9. 5 Galimont-Collen AF, Vos LE, Lavrijsen AP et al. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer 2007; 43: 845–51. 6 Myskowski PL, Halpern AC. Cutaneous adverse reactions to therapeutic monoclonal antibodies for cancer. Curr Allergy Asthma Rep 2008; 8: 63–8. 7 Hammond-Thelin LA. Cutaneous reactions related to systemic immunomodulators and targeted therapeutics. Dermatol Clin 2008; 26: 121–59, ix. 8 Mitchell EP, Perez-Soler R, Van Cutsem E, Lacouture ME. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. Oncology (Williston Park) 2007; 21 (11 Suppl. 5): 4–9. 9 Yamazaki N, Muro K. Clinical management of EGFRI dermatologic toxicities: the Japanese perspective. Oncology (Williston Park) 2007; 21 (11 Suppl. 5): 27–8. 10 Segaert S, Van Cutsem E. Clinical management of EGFRI dermatologic toxicities: the European perspective. Oncology (Williston Park) 2007; 21 (11 Suppl. 5): 22–6. 11 Busam KJ, Capodieci P, Motzer R et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001; 144: 1169–76. 12 Boucher KW, Davidson K, Mirakhur B et al. Paronychia induced by cetuximab, an antiepidermal growth factor receptor antibody. J Am Acad Dermatol 2002; 45: 632–3. 13 Kimyai-Asadi A, Jih MH. Follicular toxic effects of chimeric anti-epidermal growth factor receptor antibody cetuximab used to treat human solid tumors. Arch Dermatol 2002; 138: 129–31. 14 Wong SF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 2005; 27: 684–94. 15 Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007; 67: 2585–607. 16 Saif MW, Kim R. Incidence and management of cutaneous toxicities associated with cetuximab. Expert Opin Drug Saf 2007; 6: 175–82. 17 Schalock PC, Zug KA. Acneiform reaction to erlotinib. Dermatitis 2007; 18: 230–1. 18 Valeyrie L, Bastuji-Garin S, Revuz J et al. Adverse cutaneous reactions to imatinib (ST1571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol 2003; 48: 201–6. 19 Scheinfeld N. Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate. J Drugs Dermatol 2006; 5: 228–31. 20 Ena P, Chiarolini F, Siddi GM, Cossu A. Oral lichenoid eruption secondary to imatinib (Glivec). J Dermatolog Treat 2004; 15: 253–5. 21 Pascual JC, Matarredona J, Miralles J et al. Oral and cutaneous lichenoid reaction secondary to imatinib: report of two cases. Int J Dermatol 2006; 45: 1471–3. 22 Ayirookuzhi SJ, Ma L, Ramshesh P, Mills G. Imatinib-induced Sweet syndrome in a patient with chronic myeloid leukemia. Arch Dermatol 2005; 141: 368–70. 23 Bekkenk MW, Vermeer MH, Meijer CJ et al. EBV-positive cutaneous B-cell lymphoproliferative disease after imatinib mesylate. Blood 2003: 102: 4243. 24 Yazdi AS, Metzler G, Weyrauch SI et al. Lymphomatoid granulomatosis induced by imatinib-treatment. Arch Dermatol 2007; 143: 1222–3. 25 Jardin F, Courville P, Lenain P et al. Concomitant eosinophilia, fasciitis, and mycosis fungoides-like reaction with antinuclear autoantibodies in chronic myeloid leukaemia: role of a T-cell clone induced by imatinib. Lancet Oncol 2005; 6: 728–9. 26 Mahapatra M, Mishra P, Kumar R. Imatinib-induced Stevens–Johnson syndrome: recurrence after re-challenge with a lower dose. Ann Hematol 2007; 86: 537–8. 27 Yang CH, Lin WC, Chuang CK et al. Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol 2008; 158: 592–6.

Reference 1 Rosenfelt FP, Rosenbloom BE, Weinstein IM. Allergic reaction following administration of AMSA. Cancer Treat Rep 1982; 66: 549–50.

Miscellaneous chemotherapeutic agents Acridinyl anisidide (AMSA)

References 1 Hendrick AM, Simmons D, Cantwell BM. Allergic reactions to carboplatin. Ann Oncol 1992; 3: 239–40. 2 Tonkin KS, Rubin P, Levin L. Carboplatin hypersensitivity: case reports and review of the literature. Eur J Cancer 1993; 29A: 1356–7.

Skin reactions are rare, but widespread erythema has been reported [1].

Bortezomib Skin reactions to this proteasome inhibitor used in the treatment of multiple myeloma have been reviewed [1–4]. These include sharply-demarcated erythematous plaques or nodules on the trunk, generalized morbilliform erythema with ulcerations and fever, and a neutrophilic dermatitis. The time between the first bortezomib dose and occurrence of the cutaneous eruptions was at least 30 days; eruptions usually resolved within a few days. Histological findings ranged from perivascular dermatitis to interstitial and interface dermatitis [2]. References 1 Agterof MJ, Biesma DH. Images in clinical medicine. Bortezomib-induced skin lesions. N Engl J Med 2005; 352: 2534. 2 Wu KL, Heule F, Lam K, Sonneveld P. Pleomorphic presentation of cutaneous lesions associated with the proteasome inhibitor bortezomib in patients with multiple myeloma. J Am Acad Dermatol 2006; 55: 897–900. 3 Paiva CM, Kurtis B, Mekki M et al. Neutrophilic dermatitis associated with bortezomib in a patient with multiple myeloma. Ann Oncol 2007; 18: 1744–5. 4 Sanchez-Politta S, Favet L, Kerl K et al. Bortezomib-induced skin eruption. Dermatology 2008; 216: 156–8.

Bromodeoxyuridine A distinctive eruption comprising linear supravenous papules and erythroderma has been described with bromodeoxyuridine given in combination with radiotherapy for central nervous system tumours [1]. Ipsilateral facial dermatitis with epilation of eyebrows and eyelashes, ocular irritation, bilateral nail dystrophy, oral ulceration, exanthem or erythema multiforme have also been described [2]. References 1 Fine J-D, Breathnach SM. Distinctive eruption characterized by linear supravenous papules and erythroderma following broxuridine (bromodeoxyuridine) therapy and radiotherapy. Arch Dermatol 1986; 122: 199–200. 2 McCuaig CM, Ellis CN, Greenberg HS et al. Mucocutaneous complications of intra-arterial 5-bromodeoxyuridine and radiation. J Am Acad Dermatol 1989; 21: 1235–40.

Carboplatin Hypersensitivity reactions occur in 1–30% of patients [1–6]; acute allergic reactions include urticaria, bronchospasm, hypotension, facial erythema and facial swelling. Desensitization can be successful [7]. A pruritic maculopapular rash occurred in 10 of 40 patients treated with carboplatin, etoposide and ifosfamide plus mesna followed by autologous stem cell reinfusion; the rash was distributed at the extremities or was confluent on the trunk and face, with facial oedema and painful swelling of hands and feet, and resolved spontaneously with hyperpigmentation in all patients [6].

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3 Weidmann B, Mulleneisen N, Bojko P, Niederle N. Hypersensitivity reactions to carboplatin. Report of two patients, review of the literature, and discussion of diagnostic procedures and management. Cancer 1994; 73: 2218–22. 4 Chang SM, Fryberger S, Crouse V et al. Carboplatin hypersensitivity in children. A report of five patients with brain tumors. Cancer 1995; 75: 1171–5. 5 Broome CB, Schiff RI, Friedman HS. Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions. Med Pediatr Oncol 1996; 26: 105–10. 6 Zorzou MP, Efstathiou E, Galani E et al. Carboplatin hypersensitivity reactions: a single institution experience. J Chemother 2005; 17: 104–10. 7 Beyer J, Grabbe J, Lenz K et al. Cutaneous toxicity of high-dose carboplatin, etoposide and ifosfamide followed by autologous stem cell reinfusion. Bone Marrow Transplant 1992; 10: 491–4.

Cisplatin Periungual hyperpigmentation [1] and acral erythema [2] or digital necrosis [3] have been documented. Severe hypersensitivity reactions, including flushing, erythema, maculopapular eruptions, urticaria and anaphylaxis, occur in about 5% of cases when this drug is used as a single agent, and in up to 20% when given with other chemotherapeutic agents [4,5]. Cross-reactivity with carboplatin may occur [5]. Atopic subjects are especially at risk. Local reactions follow extravasation [6]. Severe allergic exfoliative dermatitis with ischaemia and necrosis of the hands developed in a patient who had received multiple doses of cisplatin [7]. Oxaliplatin Hypersensitivity reactions are recorded [8]. References 1 Kim KJ, Chang SE, Choi JH et al. Periungal hyperpigmentation induced by cisplatin. Clin Exp Dermatol 2002; 27: 118–9. 2 Vakalis D, Ioannides D, Lazaridou E et al. Acral erythema induced by chemotherapy with cisplatin. Br J Dermatol 1998; 139: 750–1. 3 Marie I, Levesque H, Plissonier D et al. Digital necrosis related to cisplatin in systemic sclerosis. Br J Dermatol 2000; 142: 833–4. 4 Vogl SE, Zaravinos T, Kaplan BH. Toxicity of cis-diaminedichloro-platinum II given in a two-hour outpatient regimen of diuresis and hydration. Cancer 1980; 45: 11–5. 5 Shlebak AA, Clark PI, Green JA. Hypersensitivity and cross-reactivity to cisplatin and analogues. Cancer Chemother Pharmacol 1995; 35: 349–51. 6 Fields S, Koeller J, Topper RL et al. Local soft tissue toxicity following cisplatin extravasation. J Natl Cancer Inst 1990; 82: 1649–50. 7 Lee TC, Hook CC, Long HJ. Severe exfoliative dermatitis associated with hand ischemia during cisplatin therapy. Mayo Clin Proc 1994; 69: 80–2. 8 Siu SW, Chan RT, Au GK. Hypersensitivity reactions to oxaliplatin: experience in a single institute. Ann Oncol 2006; 17: 259–61.

Colchicine Alopecia is recorded [1]. Reference 1 Haarms M. Haarausfall und Haarveränderungen nach Kolchizintherapie. Hautarzt 1980; 31: 161–3.

Flutamide A photosensitive dermatitis [1,2] and pseudoporphyria [3] have been reported with this non-steroid antiandrogen used in the treatment of prostatic carcinoma. References 1 Fujimoto M, Kikuchi K, Imakado S, Furue M. Photosensitive dermatitis induced by flutamide. Br J Dermatol 1996; 135: 496–7.

2 Yokote R, Tokura Y, Igarashi N et al. Photosensitive drug eruption induced by flutamide. Eur J Dermatol 1998; 8: 427–9. 3 Borroni G, Brazzelli V, Baldini F et al. Flutamide-induced pseudoporphyria. Br J Dermatol 1998; 138: 711–2.

Hydroxycarbamide (hydroxyurea) Dermatological aspects of this drug have been reviewed [1–6]. Impaired renal function has been reported in some, but not all, studies [3]. A modest fall in haemoglobin and development of macrocytosis is almost constant. Stomatitis occurs especially with high-dose therapy and has been accompanied by soreness, violet erythema, and oedema of the palms and soles with subsequent intense universal hyperpigmentation [7], but alopecia is rare. Morbilliform erythema occurs, and hyperpigmentation, generalized or localized to pressure areas, was recorded in up to 5% of cases [2]. A more recent survey reported mucocutaneous adverse reactions after a mean duration of 6.4 weeks of treatment in up to 65% of patients, with pigmentation of nails, skin or mucosa seen in 58.6% [6]. Other less common findings were xerosis, diffuse alopecia, oedema of the legs, oral ulcers and actinic psoriasis; scleral pigmentation and acquired ichthyosis were also noted. Nail changes including pigmentation [8], multiple pigmented nail bands [9], nail ridging, partial leukonychia, and longitudinal melanonychia [10], or onycholysis with nail dystrophy, occur. Fixed drug eruption has been reported [3], as has baboon syndrome [11]. Dermatomyositis-like acral erythema, scaling, and atrophy especially on the dorsum of the hands, with lesser involvement of the feet [1,4,12–15], and palmar and plantar keratoderma have been rarely described with long-term therapy for chronic myeloid leukaemia. Photosensitivity is documented, and LE [16] and vasculitis have been reported. An ulcerative lichen planus-like dermatitis has been recorded [17]. Lichenoid eruptions similar to graft-versushost disease are documented [18,19]. Several reports have recorded an association with leg ulcers [13,14,20–24]. Treatment of these with a protease-modulating matrix has been described [25]. Accelerated development of skin malignancies occurs, and eruptive squamous and basal cell cancers on light-exposed areas may be seen [26]. Radiation recall occurs [27]. References 1 Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch Dermatol 1975; 111: 183–7. 2 Layton AM, Sheehan-Dare RA, Goodfield MJD, Cotterill JA. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol 1989; 121: 647– 53. 3 Boyd AS, Neldner KH. Hydroxyurea therapy. J Am Acad Dermatol 1991; 25: 518–24. 4 Kelly RI, Bull RH, Marsden A. Cutaneous manifestations of long-term hydroxyurea therapy. Australas J Dermatol 1994; 35: 61–4. 5 Chaine B, Neonato M-G, Girot R, Aractingi S. Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease. Arch Dermatol 2001; 137: 467–70. 6 Kumar B, Saraswat A, Kaur I. Mucocutaneous adverse effects of hydroxyurea: a prospective study of 30 psoriasis patients. Clin Exp Dermatol 2002; 27: 8–13. 7 Brincker H, Christensen BE. Acute mucocutaneous toxicity following high-dose hydroxyurea. Cancer Chemother Pharmacol 1993; 32: 496–7. 8 Aste N, Gumo G, Contu F et al. Nail pigmentation caused by hydroxyurea: report of 9 cases. J Am Acad Dermatol 2002; 47: 146–7. 9 Vomvouras S, Pakula AS, Shaw JM. Multiple pigmented nail bands during hydroxyurea therapy: an uncommon finding. J Am Acad Dermatol 1991; 24: 1016–7.

Important or widely prescribed drugs 10 Zargari O, Kimyai-Asadi A, Jafroodi M. Cutaneous adverse reactions to hydroxyurea in patients with intermediate thalassemia. Pediatr Dermatol 2004; 21: 633–5. 11 Chowdhury MM, Patel GK, Inaloz HS, Holt PJ. Hydroxyurea-induced skin disease mimicking the baboon syndrome. Clin Exp Dermatol 1999; 24: 336–7. 12 Richard M, Truchetet F, Friedel J et al. Skin lesions simulating chronic dermatomyositis during long-term hydroxyurea therapy. J Am Acad Dermatol 1989; 21: 797–9. 13 Suehiro M, Kishimoto S, Wakabayashi T et al. Hydroxyurea dermopathy with a dermatomyositis-like eruption and a large leg ulcer. Br J Dermatol 1998; 139: 748–9. 14 Varma S, Lanigan SW. Dermatomyositis-like eruption and leg ulceration caused by hydroxyurea in a patient with psoriasis. Clin Exp Dermatol 1999; 24: 164–6. 15 Dacey MJ, Callen JP. Hydroxyurea-induced dermatomyositis-like eruption. J Am Acad Dermatol 2003; 48: 439–41. 16 Layton AM, Cotterill JA, Tomlinson IW. Hydroxyurea-induced lupus erythematosus. Br J Dermatol 1994; 130: 687–8. 17 Renfro L, Kamino H, Raphael B et al. Ulcerative lichen planus-like dermatitis associated with hydroxyurea. J Am Acad Dermatol 1991; 24: 143–5. 18 Daoud MS, Gibson LE, Pittelkow MR. Hydroxyurea dermopathy: a unique lichenoid eruption complicating long-term therapy with hydroxyurea. J Am Acad Dermatol 1997; 36: 178–82. 19 Eming SA, Peters T, Hartmann K et al. Lichenoid chronic graft-versus-host disease-like acrodermatitis induced by hydroxyurea. J Am Acad Dermatol 2001; 45: 321–3. 20 Weinlich G, Schuler G, Greil R et al. Leg ulcers associated with long-term hydroxyurea therapy. J Am Acad Dermatol 1998; 39: 372–4. 21 Kido M, Tago O, Fujiwara H et al. Leg ulcer associated with hydroxyurea treatment in a patient with chronic myelogenous leukaemia: successful treatment with prostaglandin E1 and pentoxifylline. Br J Dermatol 1998; 139: 1124–6. 22 Sirieix ME, Debure C, Baudot N et al. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol 1999; 135: 818–20. 23 Weinlich G, Fritsch P. Leg ulcers in patients treated with hydroxyurea for myeloproliferative disorders: what is the trigger? Br J Dermatol 1999; 141: 171–2. 24 Aragane Y, Ikamoto T, Yajima A et al. Hydroxyurea-induced foot ulcer successfully treated with a topical basic fibroblast growth factor product. Br J Dermatol 2003; 148: 599–600. 25 Romanelli M, Dini V, Romanelli P. Hydroxyurea-induced leg ulcers treated with a protease-modulating matrix. Arch Dermatol 2007; 143: 1310–3. 26 Papi M, Didona B, DePita O et al. Multiple skin tumors on light-exposed areas during long-term treatment with hydroxyurea. J Am Acad Dermatol 1993; 28: 485–6. 27 Sears ME. Erythema in areas of previous irradiation in patients treated with hydroxyurea (NSC-32065). Cancer Chemother Rep 1964; 40: 31–2.

Suramin Suramin sodium, a polysulphonated naphthylurea used in the treatment of metastatic prostatic and other cancers, has caused generalized, erythematous, maculopapular eruptions within the first 24 h of therapy (which were self-limited despite continued drug infusion), keratoacanthoma and disseminated superficial actinic porokeratosis [1–3]. Distinctive findings include scaling erythematous papules (suramin keratoses) and a predilection for previously sun-exposed areas (UV recall). Severe cutaneous reactions occur in 10% of cases [3]. Histopathological findings have included hyperkeratosis, parakeratosis, spongiosis, acanthosis, exocytosis, apoptosis, a perivascular lymphohistiocytic infiltrate, upper dermal oedema and increased dermal mucin [3]. Erythema multiforme [4] and TEN [5,6] are recorded. References 1 O’Donnell BP, Dawson NA, Weiss RB et al. Suramin-induced skin reactions. Arch Dermatol 1992; 128: 75–9.

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2 Wichterich K, Tebbe B, Handke A et al. Kutane Arzneimittelreaktion durch Suramin bei 4 Patienten mit metastasierendem Prostata-Karzinom. Hautarzt 1994; 45: 84–7. 3 Lowitt MH, Eisenberger M, Sina B, Kao GF. Cutaneous eruptions from suramin. A clinical and histopathologic study of 60 patients. Arch Dermatol 1995; 131: 1147–53. 4 Katz SK, Medenica MM, Kobayashi K et al. Erythema multiforme induced by suramin. J Am Acad Dermatol 1995; 32: 292–3. 5 May E, Allolio B. Fatal toxic epidermal necrolysis during suramin therapy. Eur J Cancer 1991; 28A: 1294. 6 Falkson G, Rapoport BL. Lethal toxic epidermal necrolysis during suramin therapy. Eur J Cancer 1992; 27: 1338.

Taxanes Docetaxel. Docetaxel, a semi-synthetic analogue of paclitaxel from the needles of the European yew Taxus baccata, and used in the treatment of advanced and/or metastatic cancer, caused neutropenia, skin reactions (81%) and nail changes (41%), neurosensory toxicity (59%), fluid retention with oedema and hypersensitivity reactions (16–55%) [1–3]. The commonest skin reaction is characterized by discrete erythematous to violaceous patches or oedematous plaques similar to acral erythema [4]. Nail changes recorded [5,6] include horizontal banding [7], dyschromia [8] and subungual abscess [9]. Squamous syringometaplasia [10] and supravenous discoloration of the skin are documented [11]. References 1 ten Bokkel Huinink WW, Prove AM, Piccard M et al. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer. A study of the EORTC Early Clinical Trials Group. Ann Oncol 1994; 5: 527–32. 2 Pazdur R, Lassere Y, Soh LT et al. Phase II trial of docetaxel (Taxotere) in metastatic colorectal carcinoma. Ann Oncol 1994; 5: 468–70. 3 Mertens WC, Eisenhauer EA, Jolivet J et al. Docetaxel in advanced renal carcinoma. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 1994; 5: 185–7. 4 Zimmerman GC, Keeling JH, Burris HA et al. Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. Arch Dermatol 1995; 131: 202–6. 5 Valero V, Holmes FA, Walters RS et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracyclineresistant metastatic breast cancer. J Clin Oncol 1995; 13: 2886–94. 6 Pavithran K, Doval DC. Nail changes due to docetaxel. Br J Dermatol 2002; 146: 709–10. 7 Llombart-Cussac A, Pivot X. Docetaxel chemotherapy induces transverse superficial loss of the nail plate. Arch Dermatol 1997; 133: 1466–7. 8 Jacob CI, Frunza Patten S. Nail bed dyschromia secondary to docetaxel therapy. Arch Dermatol 1998; 134: 1167–8. 9 Vanhooteghem O, Richert B, Vindevoghel A et al. Subungual abscess: a new ungual side-effect related to docetaxel therapy. Br J Dermatol 2000; 143: 462–4. 10 Karam A, Metges JP, Labat JP et al. Squamous syringometaplasia associated with docetaxel. Br J Dermatol 2002; 146: 524–5. 11 Schrijvers D, van den Brande J, Vermorken JB. Supravenous discoloration of the skin due to docetaxel treatment. Br J Dermatol 2000; 142: 1069–70.

Paclitaxel. Paclitaxel, a diterpenoid taxane derivative found in the bark and needles of the western yew Taxus brevifolia, interrupts mitosis by promoting and stabilizing microtubule formation, and shows substantial activity against advanced refractory cancer. Neutropenia is the major dose-limiting toxic effect; other adverse effects include severe hypersensitivity reactions including anaphylaxis, cardiac toxicity, neurotoxicity, arthralgia or myalgia, mucositis, nausea and vomiting, and alopecia [1–6]. Local necrosis has followed accidental subcutaneous extravasation of paclitaxel

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[7], and administration via a central vein has produced a recall reaction at a site of prior extravasation [8]. Bullous fixed drug eruption is recorded [9], as is a scleroderma-like reaction [10,11]. Desensitization is possible [12]. References 1 Onetto N, Canetta R, Winograd B et al. Overview of Taxol safety. Monogr Natl Cancer Inst 1993; 15: 131–9. 2 Schiller JH, Storer B, Tutsch K et al. A phase I trial of 3-hour infusions of paclitaxel (Taxol) with or without granulocyte colony-stimulating factor. Semin Oncol 1994; 21 (Suppl. 8): 9–14. 3 Gelmon K. The taxoids: paclitaxel and docetaxel. Lancet 1994; 344: 1267–72. 4 van Herpen CM, van Hoesel QG, Punt CJ. Paclitaxel-induced severe hypersensitivity reaction occurring as a late toxicity. Ann Oncol 1995; 6: 852. 5 Berghmans T, Klastersky J. Paclitaxel-induced cutaneous toxicity. Support Care Cancer 1995; 3: 203–4. 6 Payne JY, Holmes F, Cohen P et al. Paclitaxel: severe mucocutaneous toxicity in a patient with hyperbilirubinemia. South Med J 1996; 89: 542–5. 7 Raymond E, Cartier S, Canuel C et al. Extravasation de paclitaxel (Taxol). Rev Med Int 1995; 16: 141–2. 8 Meehan JL, Sporn JR. Case report of Taxol administration via central vein producing a recall reaction at a site of prior Taxol extravasation. J Natl Cancer Inst 1994; 86: 1250–1. 9 Young PC, Montemarano AD, Lee N et al. Hypersensitivity to paclitaxel manifested as a bullous fixed drug eruption. J Am Acad Dermatol 1996; 34: 313–4. 10 Läuchli S, Trüeb RM, Fehr M, Hafner J. Scleroderma-like drug reaction to paclitaxel (Taxol®). Br J Dermatol 2002; 147: 619–21. 11 Kupfer I, Balguerie X, Courville P et al. Scleroderma-like cutaneous lesions induced by paclitaxel: a case study. J Am Acad Dermatol 2003; 48: 279–81. 12 Essayan DM, Kagey-Sobotka A, Colarusso PJ et al. Successful parenteral desensitization to paclitaxel. J Allergy Clin Immunol 1996; 97: 42–6.

Triazinate Acanthosis nigricans-like hyperpigmentation has been recorded [1]. Reference 1 Greenspan AH, Shupack JL, Foo S-H. Acanthosis nigricans-like hyperpigmentation secondary to triazinate therapy. Arch Dermatol 1985; 121: 232–5.

Topical nitrogen mustard Urticaria, anaphylactoid reactions and a local bullous reaction have been recorded [1,2]. Contact dermatitis is well recognized. References 1 Daughters D, Zackheim H, Maibach H. Urticaria and anaphylactoid reactions after topical application of mechlorethamine. Arch Dermatol 1973; 107: 429–30. 2 Goday JJ, Aguirre A, Raton JA et al. Local bullous reaction to topical mechlorethamine (mustine). Contact Dermatitis 1990; 22: 306–7.

Drugs affecting the immune response Ciclosporin Ciclosporin is a ligand for the immunophilin, cyclophilin A, and is thought to block early events in T-cell gene activation by interfering with the intracellular translocation of a substance known as nuclear factor of activated T cells [1,2]. It selectively inhibits antigen-induced activation of, and IL-2 production by, CD4+ helper T lymphocytes, thereby blocking T-cell proliferation [3,4]. It inhibits transcription of genes encoding for IL-2 and IFN-γ [5], and blocks expression of IL-2 receptors. Ciclosporin also inhibits Langerhans’ cell antigen-presenting function [6–8] and suppresses

ICAM-1 expression by papillary endothelium in inflamed skin, thus reducing T-cell recruitment [9]. Much of the information on side effects was derived from patients who underwent organ transplants, and in diseases such as rheumatoid arthritis [10]. The drug is now used by dermatologists [11–18], especially in the management of difficult psoriasis [13–16], refractory atopic eczema [17] and a number of other conditions [16]. Dermatological complications. Hypertrichosis develops in a high proportion of patients; it affects especially the face and eyebrows, the upper back along the spinal column and the lateral upper arms [18–23]. The hypertrichosis is reversible, and children and adolescents seem to be at greater risk of developing this complication [23]. Other cutaneous complications include gingival hyperplasia [21,24], angio-oedema [25] and hyperplastic pseudofolliculitis barbae [26]. Acne keloidalis is recorded [27]. Anaphylaxis may occur in response to intravenous ciclosporin [11], probably due to the solvent. A mild capillary leak syndrome has resulted in purpuric lesions in the flexures and at pressure points [28], and cutaneous vasculitis is recorded [29]. There have been isolated reports of the development of benign lymphocytic infiltrates in patients with psoriasis or alopecia areata [30,31], of pseudolymphoma after therapy of actinic reticuloid [32] and of an aggressive T-cell lymphoma after ciclosporin therapy for Sézary syndrome [33]. Squamous cell skin cancer may develop [34,35] and could potentially be predisposed to by previous PUVA [36]. A study showed no difference in the incidence of cutaneous malignancy in renal allograft recipients treated with either ciclosporin or azathioprine [34]. Kaposi’s sarcoma may occur; a renal transplant patient treated with ciclosporin and methylprednisolone developed a Kaposi’s sarcoma, which completely regressed on reducing the dosage of both drugs [37]. There have been isolated reports of development of malignant melanoma in ciclosporin-treated patients, but the incidence of this complication does not seem to be increased above the risk in the general population [38,39]. Systemic side effects. Headache and rarely seizures [40], gastrointestinal and musculoskeletal symptoms are well recognized. There is an increased risk of nephrotoxicity [41,42], which appears to be caused by arteriolar vasoconstriction due to local thromboxane A2 release [43], and consequent hypertension [44]. Impaired renal function may develop after short- as well as long-term treatment for psoriasis [45]. Both renal dysfunction and hypertension are reversible, and lymphoma development unlikely, in patients on short-term low-dose (less than 5 mg/kg) therapy. Adverse effects on renal function and systolic blood pressure appear greater in psoriasis patients receiving higher doses [15]. Some degree of renal impairment is inevitable with longer-term therapy [46]. Rarely, a serious capillary leak syndrome occurs, with marked fluid retention and periorbital oedema, and may be fatal; there may be associated gastrointestinal bleeding, pneumonitis, uraemia and urinary sodium loss followed by hypertension and convulsions [21]. Hepatotoxicity is a complication [47] and hypercholesterolaemia is recorded [48]. Ciclosporin may be associated with myopathy without rhabdomyolysis or with rhabdomyolysis; the latter

Important or widely prescribed drugs

occurs in the setting of concomitant lovastatin or colchicine therapy [49]. Lymphoma and other cancers have developed on high dosage, as used for organ grafting [19,50]. Transplant patients treated with ciclosporin have not been shown to have a higher incidence of neoplasms than those receiving other immunosuppressive agents. Successful pregnancies have occurred in patients receiving ciclosporin for psoriasis [51,52]. There is no evidence of a teratogenic effect in humans, based on the experience of 107 transplant recipients [53]. Interactions of ciclosporin and other drugs have been reviewed [54]. Ciclosporin blood levels may be increased by concomitant therapy with erythromycin or ketoconazole, as a result of inhibition of the hepatic microsomal cytochrome P-450 enzyme system [55], as well as with danazol, oral contraceptives and calcium channel antagonists. Decreased blood levels may be caused by drugs that induce hepatic enzymes, including phenytoin, phenobarbital and tuberculostatic therapy with rifampicin and isoniazid. Aminoglycoside antibiotics, melphalan, amphotericin and trimethoprim (alone or in combination with sulfamethoxazole) interact with ciclosporin by altering renal function. Patients should avoid grapefruit juice taken within 1 h of oral ciclosporin as it contains a psoralen that inhibits the CYP 3A subfamily of cytochrome P-450 and reduces metabolism of ciclosporin [56]. References 1 Gallagher RB, Cambier JC. Signal transmission pathways and lymphocyte function. Immunol Today 1990; 11: 187–9. 2 Anonymous. Unmasking immunosuppression. Lancet 1991; 338: 789. 3 Ryffel B. Pharmacology of cyclosporine. 6. Cellular activation: regulation of intracellular events by cyclosporine. Pharmacol Rev 1989; 41: 407–22. 4 Borel JF. Pharmacology of cyclosporin (Sandimmune). 4. Pharmacological properties in vivo. Pharmacol Rev 1989; 41: 259–371. 5 Granelli-Piperno A. Lymphokine gene expression in vivo is inhibited by cyclosporin A. J Exp Med 1990; 171: 533–44. 6 Furue M, Katz SI. The effects of cyclosporin on epidermal cells. I. Cyclosporin inhibits accessory cell functions of epidermal Langerhans cells in vitro. J Immunol 1988; 140: 4139–43. 7 Demidem A, Taylor JR, Grammer SF, Streilein JW. Comparison of effects of transforming growth factor-beta and cyclosporin A on antigen-presenting cells of blood and epidermis. J Invest Dermatol 1991; 96: 401–7. 8 Dupuy P, Bagot M, Michel L et al. Cyclosporin A inhibits the antigen-presenting functions of freshly isolated human Langerhans cells in vitro. J Invest Dermatol 1991; 96: 408–13. 9 Petzelbauer P, Stingl G, Wolff K, Volc-Platzer B. Cyclosporin A suppresses ICAM1 expression by papillary endothelium in healing psoriatic plaques. J Invest Dermatol 1991; 96: 362–9. 10 Dougados M, Awada H, Amor B. Cyclosporin in rheumatoid arthritis: a double blind placebo controlled study in 52 patients. Ann Rheum Dis 1988; 47: 127–33. 11 Gupta AK, Brown MD, Ellis CN et al. Cyclosporine in dermatology. J Am Acad Dermatol 1989; 21: 1245–56. 12 Fradin MS, Ellis CN, Voorhees JJ. Management of patients and side effects during cyclosporine therapy for cutaneous disorders. J Am Acad Dermatol 1990; 23: 1265–74. 13 De Rie MA, Meinardi MMHM, Bos JD. Analysis of side-effects of medium- and low-dose cyclosporin maintenance therapy in psoriasis. Br J Dermatol 1990; 123: 347–53. 14 Mihatsch MJ, Wolff K, eds. Risk/benefit ratio of cyclosporin A (Sandimmun®) in psoriasis. Br J Dermatol 1990; 122 (Suppl. 36): 1–115. 15 Ellis CN, Fradin MS, Messana JM et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med 1991; 324: 277–84. 16 Ellis CN, ed. Cyclosporine in dermatology. Proceedings of a symposium. J Am Acad Dermatol 1991; 23: 1231–4.

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17 Sowden JM, Berth-Jones J, Ross JS et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991; 338: 137–40. 18 Fradin MS, Ellis CN, Voorhees JJ. Management of patients and side effects during cyclosporine therapy for cutaneous disorders. J Am Acad Dermatol 1990; 23: 1265–75. 19 European Multicentre Trial. Cyclosporin A as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Preliminary results. Lancet 1982; ii: 57–60. 20 Mortimer PS, Thompson JF, Dawber RP et al. Hypertrichosis and multiple cutaneous squamous cell carcinomas in association with cyclosporin A therapy. J R Soc Med 1983; 76: 786–7. 21 Harper JI, Kendra JR, Desai S et al. Dermatological aspects of the use of cyclosporin A for prophylaxis of graft-versus-host disease. Br J Dermatol 1984; 110: 469–74. 22 Bencini PL, Montagnino G, Sala F et al. Cutaneous lesions in 67 cyclosporin-treated renal transplant recipients. Dermatologica 1986; 172: 24– 30. 23 Wysocki GP, Daley TD. Hypertrichosis in patients receiving cyclosporine therapy. Clin Exp Dermatol 1987; 12: 191–6. 24 Bennett JA, Christian JM. Cyclosporin-induced gingival hyperplasia: case report and literature review. J Am Dent Assoc 1985; 3: 272–3. 25 Isenberg DA, Snaith ML, Al-Khader AA et al. Cyclosporin relieves arthralgia, causes angioedema. N Engl J Med 1980; 303: 754. 26 Lear J, Bourke JF, Burns DA. Hyperplastic pseudofolliculitis barbae associated with cyclosporin. Br J Dermatol 1997; 136: 132–3. 27 Azurdia RM, Graham RM, Weismann K et al. Acne keloidalis in Caucasian patients on cyclosporin following organ transplantation. Br J Dermatol 2000; 143: 465–7. 28 Ramon D, Bettloch E, Jimenez A et al. Remission of Sézary’s syndrome with cyclosporin A. Mild capillary leak syndrome as an unusual side effect. Acta Derm Venereol (Stockh) 1986; 66: 80–2. 29 Gupta MN, Sturrock RD, Gupta G. Cutaneous leucocytoclastic vasculitis caused by cyclosporin A. Ann Rheum Dis 2000; 59: 319. 30 Brown MD, Ellis CN, Billings J et al. Rapid occurrence of nodular cutaneous T-lymphocyte infiltrates with cyclosporine therapy. Arch Dermatol 1988; 124: 1097–100. 31 Gupta AK, Cooper KD, Ellis CN et al. Lymphocytic infiltrates of the skin in association with cyclosporine therapy. J Am Acad Dermatol 1990; 23: 1137– 41. 32 Thestrup-Pedersen K, Zachariae C, Kaltoft K et al. Development of cutaneous pseudolymphoma following ciclosporin therapy of actinic reticuloid. Dermatologica 1988; 177: 376–81. 33 Catterall MD, Addis BJ, Smith JL, Coode PE. Sézary syndrome: transformation to a high grade T-cell lymphoma after treatment with cyclosporin A. Clin Exp Dermatol 1983; 8: 159–69. 34 Bunney MH, Benton EC, Barr BB et al. The prevalence of skin disorders in renal allograft recipients receiving cyclosporin A compared with those receiving azathioprine. Nephrol Dial Transplant 1990; 5: 379–82. 35 Paul C, Ho VC, McGeown C et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 year cohort study. J Invest Dermatol 2003; 120: 211–6. 36 Stern RS. Risk assessment of PUVA and cyclosporine. Lessons from the past: challenges for the future. Arch Dermatol 1989; 125: 545–7. 37 Pilgrim M. Spontane Manifestation und Regression eines Kaposi-Sarkoms unter Cyclosporin A. Hautarzt 1988; 39: 368–70. 38 Mérot Y, Miescher PA, Balsiger F et al. Cutaneous malignant melanomas occurring under cyclosporin A therapy: a report of two cases. Br J Dermatol 1990; 123: 237–9. 39 Arellano F, Krupp PF. Cutaneous malignant melanoma occurring after cyclosporin A therapy. Br J Dermatol 1991; 124: 611. 40 Humphreys TR, Leyden JJ. Acute reversible central nervous system toxicity associated with low-dose oral cyclosporin therapy. J Am Acad Dermatol 1993; 29: 490–2. 41 Myers BD, Ross J, Newton L et al. Cyclosporine-associated chronic nephropathy. N Engl J Med 1984; 311: 699–705. 42 Myers BD, Sibley R, Newton L et al. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int 1988; 33: 590–600.

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43 Coffman TM, Carr DR, Yarger WE, Klotman PE. Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity. Transplantation 1987; 43: 282–5. 44 Porter GAM, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. Arch Intern Med 1990; 150: 280–3. 45 Powles AV, Carmichael D, Julme B et al. Renal function after long-term low-dose cyclosporin for psoriasis. Br J Dermatol 1990; 122: 665–9. 46 Markham T, Watson A, Rogers S. Adverse effects with long-term cyclosporin for severe psoriasis. Clin Exp Dermatol 2002; 27: 111–4. 47 Lorber MI, Van Buren CT, Flechner SM et al. Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients. Transplantation 1987; 43: 35–40. 48 Ballantyne CM, Podet EJ, Patsch WP et al. Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 1989; 262: 53–6. 49 Arellano F, Krupp P. Muscular disorders associated with cyclosporin. Lancet 1991; 337: 915. 50 Penn I, First MR. Development and incidence of cancer following cyclosporin therapy. Transplant Proc 1986; 18 (Suppl. 1): 210–3. 51 Wright S, Glover M, Baker H. Psoriasis, cyclosporine, and pregnancy. Arch Dermatol 1991; 127: 426. 52 Imal N, Tatanabe R, Fujiwara H et al. Successful treatment of impetigo herpetiformis with oral cyclosporine during pregnancy. Arch Dermatol 2002; 138: 128–9. 53 Cockburn I, Krupp P, Monka C. Present experience of Sandimmune in pregnancy. Transplant Proc 1989; 21: 3730–2. 54 Yee GC, McGuire TR. Pharmacokinetic drug interactions with cyclosporin (Part I). Clin Pharmacokinet 1990; 19: 319–32. 55 Abel EA. Isotretinoin treatment of severe cystic acne in a heart transplant patient receiving cyclosporine: consideration of drug interactions. J Am Acad Dermatol 1991; 24: 511. 56 Anonymous. Drug interactions with grapefruit. Curr Probl Pharmacovig 1997; 23: 2.

Leflunomide This immunomodulating agent, recently introduced to treat rheumatoid and psoriatic arthritis, is reported to cause a drug hypersensitivity syndrome comprising fever, widespread and long lasting rash, generalized weakness and internal organ involvement [1]. A blistering eruption in SLE patients [2], an erythema multiforme-like drug eruption [3], and a photodistributed lichenoid drug eruption with rhabdomyolysis [4] have all been recorded.

PUVA therapy See Chapter 74.

Immunotherapy Sera Animal immune sera can produce any type of early or late hypersensitivity reactions, from urticaria, asthma or fatal anaphylaxis to serum sickness. Clinical manifestations of serum sickness include fever, arthritis, nephritis, neuritis, myocarditis, uveitis, oedema and an urticarial or papular rash. A characteristic serpiginous, erythematous and purpuric eruption developed on the hands and feet, at the borders of palmar and plantar skin, in patients treated with equine antithymocyte globulin [1,2]. Low serum C4 and C3 levels, elevated plasma C3a anaphylatoxin levels, and circulating immune complexes were found. Immunoreactants, including IgM, C3, IgE and IgA, were deposited in the walls of dermal blood vessels on direct immunofluorescence [1,2]. Patients with autoimmune disease may have a particular liability to react to antilymphocyte globulin.

Intravenous immunoglobulin Human intravenous immunoglobulin (IVIG) preparations are used to treat a number of autoimmune and inflammatory disorders [1]. Common and mild side effects include headache, malaise, nausea, low-grade fever, urticaria [2], arthralgias, and myalgia; these typically resolve within a few days. Rare, serious and potentially fatal side effects include anaphylactic reactions, aseptic meningitis, acute renal failure, stroke, myocardial infarction and other thrombotic complications [3]. Angio-oedema-like hypersensitivity eruptions and eczematous, purpuric, petechial/purpuric, lichenoid and vasculitic reactions are recorded [4–6]. A severe, extensive eczematous reaction characterized by dyshidrotic lesions on the palms, rapidly followed by pruriginous maculopapular lesions involving the whole body, occurred 10 days after high-dose IVIG infusion [7].

This macrolide immunosuppressant, which impairs lymphocyte activation by IL-2, IL-4 and IL-12, has caused a capillary leak syndrome [1].

References 1 Prins C, Gelfand EW, French LE. Intravenous immunoglobulin: properties, mode of action and practical use in dermatology. Acta Derm Venereol 2007; 87: 206–18. 2 Gürcan HM, Ahmed AR. Frequency of adverse events associated with intravenous immunoglobulin therapy in patients with pemphigus or pemphigoid. Ann Pharmacother 2007; 41: 1604–10. 3 Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharmacol 2006; 6: 535–42. 4 Lawley TJ, Bielory L, Gascon P et al. A prospective clinical and immunologic analysis of patients with serum sickness. N Engl J Med 1984; 311: 1407–13. 5 Bielory L, Yancey KB, Young NS et al. Cutaneous manifestations of serum sickness in patients receiving antithymocyte globulin. J Am Acad Dermatol 1985; 13: 411–7. 6 Smith KJ, Dutka AL, Skelton HG. Lichenoid/interface cutaneous eruptions to IVIg with the primary infusion may be related to the re-regulation of anti-idiotype network. J Cutan Med Surg 1998; 3: 96–101. 7 Vecchietti G, Kerl K, Prins C et al. Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: report of 4 cases and review of the literature. Arch Dermatol 2006; 142: 213–7.

Reference 1 Kaplan MJ, Ellis CN, Bata-Csorgo Z et al. Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis. Association of capillary leak syndrome with apoptosis of lesional lymphocytes. Arch Dermatol 1999; 135: 553–7.

Vaccines Overall, the incidence of significant side effects is very low [1]. In Canada during 1990, from more than 12 million doses of vaccines there were 2832 reports of adverse events associated with immu-

References 1 Shastri V, Betkerur J, Kushalappa PA et al. Severe cutaneous adverse drug reaction to leflunomide: a report of five cases. Indian J Dermatol Venereol Leprol 2006; 72: 286–9. 2 Jian X, Guo G, Ruan Y et al. Severe cutaneous adverse drug reaction to leflunomide: a report of two cases. Cutan Ocul Toxicol 2008; 27: 5–9. 3 Fischer TW, Bauer HI, Graefe T et al. Erythema multiforme-like drug eruption with oral involvement after intake of leflunomide. Dermatology 2003; 207: 386–9. 4 Rivarola de Gutierrez E, Abaca H. Photodistributed lichenoid drug eruption with rhabdomyolysis occurring during leflunomide therapy. Dermatology 2004; 208: 232–3.

Sirolimus

Important or widely prescribed drugs

nizing agents received by the Childhood Immunization Division of the Laboratory Centre for Disease Control [2]. Hepatitis B and bacille Calmette-Guérin vaccines are the most frequently incriminated products, whereas cutaneous adverse effects are less frequent following vaccination against varicella, diphtheria/ tetanus/ pertussis (primary and booster doses), measles, poliomyelitis, rubella, pneumococcus, tick-borne encephalitis, smallpox, Meningococcus and influenza [3]. Adverse effects may occur at the site of injection or at a distance, and involve predominantly non-specific lymphoid or granulomatous reactions. Local allergic reactions may develop to the vaccine strain, egg, gelatine, antibiotics such as neomycin, adjuvants, preservatives or other components including aluminium, thimerosal (merthiolate), 2-phenoxyethanol and formaldehyde [1,3,4]; needle gauge and length may affect the incidence of local reactions [5]. Systemic reactions may involve immediate-type or immune complex-related allergic reactions to toxoid-, ovalbumin-, gelatine- or pneumococcal-containing vaccines, and are sometimes related to a specific vaccine strain. Erythema multiforme minor is a recognized complication [6]. Local reactions include erythema, swelling and tenderness, which may result from an Arthus reaction [7–9]. Keloid scarring may develop. Local inflammatory reactions, fever, lymphadenopathy, urticaria and lichenoid rashes have been observed following vaccination in patients sensitive to the preservative merthiolate; patch testing and intradermal testing may be positive [10,11]. Inflammatory nodular reactions may occur as a result of aluminium sensitization, as with hepatitis B, diphtheria and tetanus vaccination [12–14]; patch testing to aluminium may be positive [12]. Itching, eczema and circumscribed hypertrichosis developed over nodules following immunization with vaccines adsorbed on aluminium hydroxide in three children [13]. Vaccination may result in development of an autoimmune state; dermatomyositis has been provoked. Fatalities have rarely occurred following vaccination as a result of anaphylaxis [15,16]. Urticaria and systemic symptoms including malaise and fever, or Stevens–Johnson syndrome may follow tetanus toxoid vaccination [17,18]. Urticaria, angio-oedema or anaphylaxis may occur in patients allergic to egg protein who are vaccinated with live measles vaccine. However, in a series of children with egg allergy and a positive skin-prick test to egg white, 0.98% developed a mild reaction not requiring therapy following immunization with a full dose of vaccine [19]. Measles and measles–mumps–rubella vaccine, hepatitis B vaccine, and diphtheria and tetanus toxoids have been statistically associated with anaphylaxis [20], and measles– mumps–rubella vaccine with thrombocytopenia and purpura [20,21], erythema multiforme [22], and Gianotti–Crosti syndrome [23]. Only 39 of 43 618 Alaskan natives who received 101 360 doses of hepatitis B plasma-derived vaccine developed side effects, including myalgia/arthralgia lasting longer than 3 days, rashes (eight patients) and dizziness [24]. A variety of other reactions have been documented following hepatitis B vaccination [25], including urticaria/angio-oedema [26], erythema multiforme [27], erythema nodosum [28], polyarteritis nodosa and pityriasis rosea [29], lichenoid eruptions [30–32] and granuloma annulare [32]. Influenza vaccination in the elderly was reported to cause no more systemic side effects than placebo [33]. In contrast, another study found local reactions in 17.5% of patients, including swell-

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ing, itching and pain [34]. Leukocytoclastic vasculitis has been reported with influenza vaccination [35]. An association with vaccination for influenza and with tetanus toxoid and induction of bullous pemphigoid has been noted rarely [36–38]. Erythema multiforme has been recorded with meningitis vaccine [39]. Transient subcutaneous nodule formation at the injection site, and increased regional adenopathy, have been rarely noted in patients with HIV infection treated with gp160 vaccination [40]. Of 98 patients with a history of previous inoculations with human diploid cell rabies vaccine, 3% developed generalized urticaria or wheezing within 1 day, and a further 3% developed urticaria within 6–14 days, after booster vaccination [41]. Hypersensitivity to smallpox vaccine provoked exanthematous, urticarial and erythema multiformelike reactions [42,43]. Vaccination against Japanese encephalitis caused serious adverse reactions, including urticaria, angiooedema, hypotension and collapse [44]. References 1 Georgitis JW, Fasano MB. Allergenic components of vaccines and avoidance of vaccination-related adverse events. Curr Allergy Rep 2001; 1: 11–7. 2 Duclos P, Pless R, Koch J, Hardy M. Adverse events temporally associated with immunizing agents. Can Fam Physician 1993; 39: 1907–13. 3 Nikkels AF, Nikkels-Tassoudji N, Piérard GE. Cutaneous adverse reactions following anti-infective vaccinations. Am J Clin Dermatol 2005; 6: 79–87. 4 Heidary N, Cohen DE. Hypersensitivity reactions to vaccine components. Dermatitis 2005; 16: 115–20. 5 Watson M. Needle length and incidence of local reactions to immunization. Needle gauge is more important than needle length. BMJ 2001; 322: 492. 6 Frederiksen MS, Brenøe E, Trier J. Erythema multiforme minor following vaccination with paediatric vaccines. Scand J Infect Dis 2004; 36: 154–5. 7 Jacobs RL, Lowe RS, Lanier BQ. Adverse reactions to tetanus toxoid. JAMA 1982; 247: 40–2. 8 Sutter RW. Adverse reactions to tetanus toxoid. JAMA 1994; 271: 1629. 9 Marrinan LM, Andrews G, Alsop-Shields L, Dugdale AE. Side effects of rubella immunisation in teenage girls. Med J Aust 1990; 153: 631–2. 10 Noel I, Galloway A, Ive FA. Hypersensitivity to thiomersal in hepatitis B vaccine. Lancet 1991; 338: 705. 11 Rueff F. Nebenwirkungen durch Thiomersal und Huhnereiweiss bei Impfungen. Hautarzt 1994; 45: 879–81. 12 Cosnes A, Flechet M-L, Revuz J. Inflammatory nodular reactions after hepatitis B vaccination due to aluminium sensitization. Contact Dermatitis 1990; 23: 65–7. 13 Pembroke AC, Marten RH. Unusual cutaneous reactions following diphtheria and tetanus immunization. Clin Exp Dermatol 1979; 4: 345–8. 14 Bergfors E, Björkelund C, Trollfors B. Nineteen cases of persistent pruritic nodules and contact allergy to aluminium after injection of commonly used aluminium-adsorbed vaccines. Eur J Pediatr 2005; 164: 691–7. 15 Boston Collaborative Drug Surveillance Program. Drug-induced anaphylaxis. A cooperative study. JAMA 1973; 224: 613–5. 16 Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987; 79: 660–77. 17 Kuhlwein A, Bleyl A. Tetanusantitoxintiter und Reaktionen nach Tetanusimpfungen. Hautarzt 1985; 36: 462–4. 18 Weisse ME, Bass JW. Tetanus toxoid allergy. JAMA 1990; 264: 2448. 19 Aickin R, Hill D, Kemp A. Measles immunisation in children with allergy to egg. BMJ 1994; 309: 223–5. 20 Stratton KR, Howe CJ, Johnson RB Jr. Adverse events associated with childhood vaccines other than pertussis and rubella. Summary of a report from the Institute of Medicine. JAMA 1994; 271: 1602–5. 21 Farrington P, Pugh S, Colville A et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 1995; 345: 567–9. 22 Bernardini ML, D’Angelo G, Oggiano N et al. Erythema multiforme following live attenuated trivalent measles-mumps-rubella vaccine. Acta Derm Venereol 2006; 86: 359–60.

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23 Velangi SS, Tidman MJ. Gianotti–Crosti syndrome after measles, mumps and rubella vaccination. Br J Dermatol 1998; 139: 1122–3. 24 McMahon BJ, Helminiak C, Wainwright RB et al. Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons. Am J Med 1992; 92: 254–6. 25 Drago F, Rebora A. Cutaneous immunologic reactions to hepatitis B virus vaccine. Ann Intern Med 2002; 136: 780. 26 Barbaud A, Trechot P, Reichert-Pénétrat S et al. Allergic mechanisms and urticaria/angioedema after hepatitis B immunization. Br J Dermatol 1998; 139: 925–6. 27 Loche F, Schwarze HP, Thedenat B et al. Erythema multiforme associated with hepatitis B immunization. Clin Exp Dermatol 2002; 25: 167–8. 28 Rogerson S, Nye F. Hepatitis B vaccine associated with erythema nodosum and polyarthritis. BMJ 1990; 301: 345. 29 De Heyser F, Naeyaert JM, Hindryckz P et al. Immune-mediated pathology following hepatitis B vaccination. Two cases of polyarteritis nodosa and one case of pityriasis-rosea-like drug eruption. Clin Exp Rheumatol 2000; 18: 81–5. 30 Saywell CA, Wittal RA, Kossard S. Lichenoid reaction to hepatitis B vaccination. Australas J Dermatol 1997; 38: 152–4. 31 Ferrando MF, Doutre MS, Beylot-Barry M et al. Lichen planus following hepatitis B vaccination. Br J Dermatol 1998; 139: 350. 32 Criado PR, de Oliveira Ramos R, Vasconcellos C et al. Two case reports of cutaneous adverse reactions following hepatitis B vaccine: lichen planus and granuloma annulare. J Eur Acad Dermatol Venereol 2004; 18: 603–6. 33 Margolis KL, Nichol KL, Poland GA, Pluhar RE. Frequency of adverse reactions to influenza vaccine in the elderly. A randomized, placebo-controlled trial. JAMA 1990; 264: 1139–41. 34 Govaert TME, Dinant GJ, Aretz K et al. Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial. BMJ 1993; 307: 988–90. 35 Tavadia S, Drummond A, Evans CD, Wainwright NJ. Leucocytoclastic vasculitis and influenza vaccination. Clin Exp Dermatol 2003; 28: 154–6. 36 Bodokh I, Lacour JP, Bourdet JF et al. Réactivation de pemphigoïde bulleuse apres vaccination antigrippale. Thérapie 1994; 49: 154. 37 Venning VA, Wojnarowska F. Induced bullous pemphigoid. Br J Dermatol 1995; 132: 831–2. 38 Fournier B, Descamps V, Bouscarat F et al. Bullous pemphigoid induced by vaccination. Br J Dermatol 1996; 135: 153–4. 39 Studdiford J, Oppenheim L, McCann E, Altshuler M. Erythema multiforme after meningitis vaccine: patient safety concerns with repeat immunization. Pharmacotherapy 2006; 26: 1658–61. 40 Redfield RR, Birx DL, Ketter N et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. N Engl J Med 1991; 324: 1677–84. 41 Fishbein DB, Yenne KM, Dreesen DW et al. Risk factors for systemic hypersensitivity reactions after booster vaccinations with human diploid cell rabies vaccine: a nationwide prospective study. Vaccine 1993; 11: 1390–4. 42 Greenberg RN, Schosser RH, Plummer EA et al. Urticaria, exanthems, and other benign dermatologic reactions to smallpox vaccination in adults. Clin Infect Dis 2004; 38: 958–65. 43 Bessinger GT, Smith SB, Olivere JW, James BL. Benign hypersensitivity reactions to smallpox vaccine. Int J Dermatol 2007; 46: 460–5. 44 Ruff TA, Eisen D, Fuller A, Kass R. Adverse reactions to Japanese encephalitis vaccine. Lancet 1991; 338: 881–2.

Hyposensitization immunotherapy Hyposensitization immunotherapy is a standard treatment for recalcitrant hay fever and bee or wasp stings in many countries in the world, including the USA, Scandinavia and the continent of Europe [1]. However, in the UK, allergen-injection immunotherapy for IgE-mediated diseases has been largely discontinued, following the recommendations of the Committee on Safety of Medicines in 1986 [2], because of concern about deaths related to bronchospasm and anaphylaxis. The Committee recommended that immunotherapy be given only where full facilities for cardiopulmonary resuscitation are available and that patients be kept under medical observation for at least 2 h. The necessity for the

latter recommendation has been questioned, as serious reactions occur within minutes [1]. The British Society for Allergy and Clinical Immunology Working Party concluded that specific allergen immunotherapy for summer hay fever uncontrolled by conventional medication and for wasp and bee venom hypersensitivity has an acceptable risk/benefit ratio, provided that treatment is given by experienced practitioners in a clinic where full resuscitative facilities are immediately available; a symptom-free observation period of 60 min after injection is sufficient [3,4]. Rush immunotherapy (rapid desensitization ) of 893 patients to multiple aeroallergens using a modified schedule involving premedication with corticosteroids and antihistamines resulted in 2.0% experiencing a mild systemic reaction, responding to subcutaneous epinephrine and/or nebulized albuterol, with only one patient (0.1%) experiencing true anaphylaxis [5]. Patients with asthma should be excluded, however, in view of an increased frequency of reactions [4,6]. Fatalities from allergen immunotherapy are extremely rare [7]. In one series, β-blocker drugs did not increase the frequency of systemic reactions in patients receiving allergen immunotherapy, but patients developed more severe systemic reactions that were more refractory to therapy [8]. In contrast, local urticarial reactions are common [1]. Desensitization injections for hay fever have resulted in occasional tender nodules lasting for several months or years [9,10]; these are thought to develop as a result of allergy to aluminium, as it is present in the lesions and patch tests may be positive [10,11]. Inflammatory nodules at injection sites, first developing several years later, have also been described [12]. Injections of mixtures of grass pollens, cereal pollens and dust-mite allergens have resulted in multiple cutaneous B-cell pseudolymphomas [13]. Polyarteritis nodosa [14], vasculitis [15,16] and serum sickness [17,18] have been described following hyposensitization therapy for allergy to pollen, house-dust mite and wasp venom. Cold urticaria developed during the course of hyposensitization to wasp venom [19]. References 1 Varney VA, Gaga M, Frew AJ et al. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ 1991; 302: 265–9. 2 Anonymous. CSM update. Desensitising vaccines. BMJ 1986; 293: 948. 3 Anonymous. Position paper on allergen immunotherapy. Report of a BSACI working party, January–October 1992. Clin Exp Allergy 1993; 23 (Suppl. 3): 1–44. 4 British Society for Allergy and Clinical Immunology Working Party. Injection immunotherapy. BMJ 1993; 307: 919–23. 5 Smits WL, Giese JK, Letz KL et al. Safety of rush immunotherapy using a modified schedule: a cumulative experience of 893 patients receiving multiple aeroallergens. Allergy Asthma Proc 2007; 28: 305–12. 6 Bousquet J, Michel FB. Safety considerations in assessing the role of immunotherapy in allergic disorders. Drug Saf 1994; 10: 5–17. 7 Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy and skin testing. J Allergy Clin Immunol 1987; 79: 660–77. 8 Hepner MJ, Ownby DR, Anderson JA et al. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 1990; 86: 407–11. 9 Osterballe O. Side effects during immunotherapy with purified grass pollen extracts. Allergy 1982; 37: 553–62. 10 Frost L, Johansen S, Pedersen S et al. Persistent subcutaneous nodules in children hyposensitised with aluminium-containing allergen extracts. Allergy 1985; 40: 368–72.

Important or widely prescribed drugs 11 Nagore E, Martinez-Escribano JA, Tato A et al. Subcutaneous nodules following treatment with aluminium-containing allergen extracts. Eur J Dermatol 2001; 11: 138–40. 12 Jones SK, Lovell CR, Peachey RDG. Delayed onset of inflammatory nodules following hay fever desensitization injections. Clin Exp Dermatol 1988; 13: 376–8. 13 Goerdt S, Spieker T, Wölffer L-U et al. Multiple cutaneous B-cell pseudolymphomas after allergen injections. J Am Acad Dermatol 1996; 35: 1072–4. 14 Phanuphak P, Kohler PF. Onset of polyarteritis nodosa during allergic hyposensitisation treatment. Am J Med 1980; 68: 479–85. 15 Merk H, Kober ML. Vasculitis nach spezifischer Hyposensibilisierung. Z Hautkr 1982; 57: 1682–5. 16 Berbis P, Carena MC, Auffranc JC, Privat Y. Vascularite nécrosante cutanéosystémique survenue en cours de désensibilisation. Ann Dermatol Vénéréol 1986; 113: 805–9. 17 Umetsu DT, Hahn JS, Perez-Atayde AR, Geha RS. Serum sickness triggered by anaphylaxis: a complication of immunotherapy. J Allergy Clin Immunol 1985; 76: 713–6. 18 De Bandt M, Atassi-Dumont M, Kahn MF, Herman D. Serum sickness after wasp venom immunotherapy: clinical and biological study. J Rheumatol 1997; 24: 1195–7. 19 Anfosso-Capra F, Philip-Joet F, Reynaud-Gaubert M, Arnaud A. Occurrence of cold urticaria during venom desensitization. Dermatologica 1990; 181: 276–7.

Bacille Calmette-Guérin (BCG) vaccination Vaccination with BCG causes a benign self-limiting lesion consisting of a small papule, pustule or ulcer, which heals to leave a small scar within weeks. Axillary lymphadenitis and abscesses occurred after vaccination of rural Haitian children [1], and disseminated BCG infection in children born to HIV-1-infected women [2]. Occasionally, local abscess formation may follow vaccination of strongly tuberculin-positive individuals, administration of too much vaccine, or injection of vaccine too deeply [3–5]. BCG abscesses may also rarely arise following needlestick injury in health-care professionals [6]. In Austria, where the Ministry of Health’s recommendation is for all neonates to be vaccinated, the normal complication rate is 0.3–0.6%, with suppurative lymphadenitis, generalized lymphadenopathy and osteitis [7]. Following a change to a more virulent vaccine strain, this rate temporarily increased substantially, with 5% of 659 children vaccinated at the University Hospital, Innsbruck requiring surgical excision of suppurating lymph nodes [7]. Anaphylactoid reactions to BCG vaccine, probably as a result of immune complex reactions mediated by antibodies to dextran in the vaccine, have been reported [8]. A papulonecrotic type of vasculitis has been documented [9]. Dermatomyositis may occasionally be a complication [10]. BCG immunotherapy for malignant melanoma [11] has been associated with local ulceration [11,12], local recurrent erysipelas, keloid formation, influenza-like symptoms, lymphadenopathy, urticaria and angio-oedema, granulomatous hepatitis, arthritis [13] and reactivation of pulmonary tuberculosis. Widespread miliary granulomas were present in a patient with fatal disseminated infection following intralesional immunotherapy of cutaneous malignant melanoma [14]. Cryoglobulinaemic vasculitis has followed intravesical instillation of bacille Calmette-Guérin [15]. References 1 Bonnlander H, Rossignol AM. Complications of BCG vaccinations in rural Haiti. Am J Public Health 1993; 83: 583–5. 2 O’Brien KL, Andrae JR, Marie AL et al. Bacillus Calmette-Guérin complications in children born to HIV-1-infected women, with a review of literature. Pediatrics 1995; 95: 414–7.

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3 Lotte A, Wasz-Hockert O, Poisson N et al. BCG complications. Adv Tuberculosis Res 1984; 21: 107–93, 194–245. 4 de Souza GRM, Sant’anna CC, Lapa e Silva JR et al. Intradermal BCG complications: analysis of 51 cases. Tubercle 1983; 64: 23–7. 5 Puliyel JM, Hughes A, Chiswick ML, Mughal MZ. Adverse local reactions from accidental BCG overdose in infants. BMJ 1996; 313: 528–9. 6 Warren JP, Nairn DS, Robertson MH. Cold abscess after accidental BCG inoculation. Lancet 1984; ii: 289. 7 Hengster P, Fille M, Menardi G. Suppurative lymphadenitis in newborn babies after change of BCG vaccine. Lancet 1991; 337: 1168–9. 8 Rudin C, Amacher A, Berglund A. Anaphylactoid reactions to BCG vaccination. Lancet 1991; 337: 377. 9 Lübbe D. Vasculitis allergica vom papulonekrotischen Typ nach BCG-Impfung. Dermatol Monatsschr 1982; 168: 186–92. 10 Kass E, Staume S, Mellbye OJ et al. Dermatomyositis associated with BCG vaccination. Scand J Rheumatol 1979; 8: 187–91. 11 Schult C. Nebenwirkungen der BCG-Immuntherapie bei 511 Patienten mit malignen Melanom. Hautarzt 1984; 35: 78–83. 12 Korting HC, Strasser S, Konz B. Multiple BCG-Ulzera nach subkutaner Impfstoffapplikation im Rahmen der Immunochemotherapie des malignen Melanoms. Hautarzt 1988; 39: 170–3. 13 Torisu M, Miyahara T, Shinohara A et al. A new side effect of BCG immunotherapy: BCG-induced arthritis in man. Cancer Immunol Immunother 1978; 5: 77–83. 14 de la Monte SM, Hutchins GM. Fatal disseminated bacillus Calmette-Guérin infection and arrested growth of cutaneous malignant melanoma following intralesional immunotherapy. Am J Dermatopathol 1986; 8: 331–5. 15 Granel B, Serratrice J, Morange PE et al. Cryoglobulinemia vasculitis following intravesical instillations of bacillus Calmette-Guerin. Clin Exp Rheumatol 2004; 22: 481–2.

Cytokines Cytokines are being increasingly used in the management of neoplastic and haematological disorders and AIDS, and in addition are starting to be used for the therapy of specific dermatological disorders; side effects have been reviewed [1]. Reactions range from minor injection-site reactions, pruritus and flushing to lifethreatening autoimmune disorders, severe erythroderma or bullous skin reactions [2]. References 1 Luger TA, Schwarz T. Therapeutic use of cytokines in dermatology. J Am Acad Dermatol 1991; 24: 915–26. 2 Asnis LA, Gaspari AA. Cutaneous reactions to recombinant cytokine therapy. J Am Acad Dermatol 1995; 33: 393–410.

Colony-stimulating factors Recombinant haematopoietic colony-stimulating factors used in the treatment of haematological disorders are usually well tolerated, but may induce itching and erythema or lichenoid reactions [1] at the site of injection, thrombophlebitis with intravenous infusion, facial flushing and a transient maculopapular eruption, fever, chills, myalgias, arthralgia and bone pain, transient leukopenia, decreased appetite, nausea and mild elevation of transaminase levels [2]. Neutrophilic dermatoses have been recorded in children [3]. Two types of recombinant human granulocyte colonystimulating factor are in use for neutropenia: one is a glycosylated natural product from mammalian cells, and the other a nonglycosylated form from Escherichia coli. A drug eruption may occur with either type without detectable antibodies; intradermal tests may be useful and there may not be cross-reactivity [4]. Both local reactions at the site of injection and diffuse maculopapular eruptions may be seen [4–7]. Local pustular reactions [8] or subcorneal

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pustular dermatosis [9] are documented. Intravenous recombinant granulocyte–macrophage colony-stimulating factor (GMCSF) therapy for leukaemia resulted in a widespread, confluent maculopapular eruption in three patients, associated with a dermal lymphocyte, macrophage and granulocyte infiltration, exocytosis, and keratinocyte ICAM-1 expression [10]. Of 23 patients with advanced malignancy treated with GM-CSF, nine had a cutaneous eruption characterized by local erythema and pruritus at the injection site, recall erythema at previous injection sites or a generalized maculopapular rash [11]. Other studies have reported widespread rashes [12,13], in one series manifested as annular erythematous papules and plaques on the extremities, becoming generalized and clearing with fine desquamation [13]. Recurrent exacerbation of acne [14], widespread folliculitis [15], toxic folliculitis [16] and a Sweet’s syndrome-like rash [17–19] have been recorded. A capillary leak syndrome with pleural and pericardial effusions, ascites and large-vessel thrombosis has been noted only with high-dose GM-CSF therapy [20]. Necrotizing vasculitis developed at GM-CSF injection sites in one patient with white cell aplasia, but not in over 150 other neutropenic patients who received the drug [21]. However, vasculitis was reported in a large series [22]. Thrombotic and necrotizing panniculitis has been documented [23]. Psoriasis [24], and arthritis in Felty’s syndrome with rheumatoid arthritis [25], have been reported to deteriorate. References 1 Viallard AM, Lavenue A, Balme B et al. Lichenoid cutaneous drug reaction at injection sites of granulocyte colony-stimulating factor (Filgrastim). Dermatology 1999; 198: 301–3. 2 Wakefield PE, James WD, Samlaska CP, Meltzer MS. Colony-stimulating factors. J Am Acad Dermatol 1990; 23: 903–12. 3 Prendiville J, Thiessen P, Mallory SB. Neutrophilic dermatoses in two children with idiopathic neutropenia: association with granulocyte colony-stimulating factor (G-CSF) therapy. Pediatr Dermatol 2001; 18: 417–21. 4 Sasaki O, Yokoyama A, Uemura S et al. Drug eruption caused by recombinant human G-CSF. Intern Med 1994; 33: 641–3. 5 Schiro JA, Kupper TS. Cutaneous eruptions during GM-CSF infusion. Clues for cytokine biology. Arch Dermatol 1991; 127: 110–2. 6 Samlaska CP, Noyes DK. Localized cutaneous reactions to granulocyte colonystimulating factor. Arch Dermatol 1993; 129: 645–6. 7 Scott GA. Report of three cases of cutaneous reactions to granulocyte– macrophage colony-stimulating factor and a review of the literature. Am J Dermatopathol 1995; 17: 107–14. 8 Passweg J, Buser U, Tichelli A et al. Pustular eruption at the site of subcutaneous injection of recombinant human granulocyte–macrophage colony-stimulating factor. Ann Hematol 1991; 63: 326–7. 9 Lautenschlager S, Itin PH, Hirsbrunner P, Büchner SA. Subcorneal pustular dermatosis at the injection site of recombinant human granulocyte–macrophage colony-stimulating factor in a patient with IgA myeloma. J Am Acad Dermatol 1994; 30: 783–9. 10 Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte–macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol 1991; 127: 49–52. 11 Lieschke GJ, Maher D, Cebon J et al. Effects of bacterially synthesized recombinant human granulocyte–macrophage colony-stimulating factor in patients with advanced malignancy. Ann Intern Med 1989; 110: 357–64. 12 Yamashita N, Natsuaki M, Morita H et al. Cutaneous eruptions induced by granulocyte colony-stimulating factor in two cases of acute myelogenous leukemia. J Dermatol 1993; 20: 473–7. 13 Glass LF, Fotopoulos T, Messina JL. A generalized cutaneous reaction induced by granulocyte colony-stimulating factor. J Am Acad Dermatol 1996; 34: 455–9. 14 Lee PK, Dover JS. Recurrent exacerbation of acne by granulocyte colonystimulating factor administration. J Am Acad Dermatol 1996; 34: 855–6.

15 Ostlere LS, Harris D, Prentice HG, Rustin MH. Widespread folliculitis induced by human granulocyte-colony-stimulating factor therapy. Br J Dermatol 1992; 127: 193–4. 16 Paul C, Giachetti S, Pinquier L et al. Cutaneous effects of granuloycte colonystimulating factor in healthy volunteers. Arch Dermatol 1998; 134: 111–2. 17 Karp DL. The Sweet syndrome or G-CSF reaction? Ann Intern Med 1992; 117: 875–6. 18 Richard MA, Grob JJ, Laurans R et al. Sweet’s syndrome induced by granulocyte colony-stimulating factor in a woman with congenital neutropenia. J Am Acad Dermatol 1996; 35: 629–31. 19 Prevost-Blank PL, Shwayder AT. Sweet’s syndrome secondary to granulocyte colony-stimulating factor. J Am Acad Dermatol 1996; 35: 995–7. 20 Antman KS, Griffin JD, Elias A et al. Effect of recombinant human granulocyte– macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 1988; 319: 593–8. 21 Farmer KL, Kurzrock R, Duvic M. Necrotizing vasculitis at granulocyte– macrophage-colony-stimulating factor injection sites. Arch Dermatol 1990; 126: 1243–4. 22 Jain KK. Cutaneous vasculitis associated with granulocyte colony-stimulating factor. J Am Acad Dermatol 1994; 31: 213–5. 23 Dereure O, Bessis D, Lavabre-Bertrand T et al. Thrombotic and necrotizing panniculitis associated with recombinant human granulocyte colony stimulating factor treatment. Br J Dermatol 2000; 142: 834–6. 24 Kelly RI, Marsden RA. Granulocyte–macrophage colony-stimulating factor and psoriasis. J Am Acad Dermatol 1994; 30: 144. 25 McMullin MF, Finch MB. Felty’s syndrome treated with rhG-CSF associated with flare of arthritis and skin rash. Clin Rheumatol 1995; 14: 204–8.

Interferon Cutaneous reactions to recombinant IFN [1–12] given to patients with chronic hepatitis C, cancer or AIDS are frequent (5–10%) but usually of moderate degree. No adverse cutaneous side effects resulted from intralesional injection of IFN-γ in 10 patients treated for keloid scarring [13]. Most patients experience influenza-like symptoms following systemic therapy; reversible leukopenia and thrombocytopenia are recorded with higher dosage. Local reactions [14,15] consist of erythema, eczema, epilation, or induration at injection sites or urticaria. Pegylated IFN-α-2b plus ribavirin combination therapy for chronic hepatitis C virus infection was associated with vesicular erythematous eruptions at injection sites, and pruritic papular erythematous eruptions on the face, neck, distal limbs, dorsa of the hands, trunk and buttocks away from the injection sites, in one case [15]. More serious reactions include vesiculobullous reactions, vasculitis, necrosis, ulceration, alopecia and exacerbation of psoriasis. Skin ulceration or necrosis may be a serious problem with both IFN-α and IFN-β [7–12,16]. Raynaud’s phenomenon and digital necrosis induced by IFN-α is recorded [17]. Of 63 patients treated with IFN-γ for prophylaxis of infection in chronic granulomatous disease, one had a severe cutaneous reaction (unspecified), and rashes or injection-site erythema or tenderness occurred in 17% and 14% of cases, respectively [1]. Diffuse inflammatory lesions have occurred with IFN-α and ribavirin therapy for hepatitis C [18]. Transient, localized or disseminated oedematous, erythematous and/or papular changes, vesicles or petechiae were seen in six patients during intravenous IFN-α for chronic active hepatitis C, 5–14 days after starting therapy [2]. Eruptions disappeared in 10–14 days despite continuation of IFNα; histology revealed upper dermal perivascular CD4+ lymphoid infiltration and oedema, with endothelial cell but not keratinocyte ICAM-1 and E-selectin expression, suggesting a non-allergic mechanism.

Important or widely prescribed drugs

Capillaritis is recorded with IFN-α [19], as is lichen planus [3,20]. Reactivation of oral herpes simplex and enhanced radiation toxicity have been recorded. IFN-α-2a for the treatment of cutaneous T-cell lymphoma has induced temporary alopecia [21]. In contrast, IFN-α therapy has caused increased eyelash and eyebrow growth [22], as well as straight hair [23]. Severe urticaria has been documented with IFN-α-1a [24] and mucinoses with IFN-α-1b [25]. Both IFN-α and IFN-α-1b have been associated with granulomatous or sarcoidal reactions [26–29]. IFN-α has caused hypertriglyceridaemia [30] and IFN-β has been related to squamous cell cancer following ulceration [31]. IFN-α used in the treatment of disseminated carcinoma [32,33] or intralesionally for viral warts [34], and IFN-β therapy for multiple sclerosis [11,35], have been reported to exacerbate or trigger onset of psoriasis; psoriatic arthritis has also been triggered by IFN-α [36] and IFN-γ [37], and Reiter’s syndrome by IFN-α [38]. Psoriasis appeared at the site of subcutaneous injection of recombinant IFN-γ in patients with psoriatic arthritis [39], and at the site of intralesional injection in a patient receiving recombinant IFN-β for a basal cell carcinoma [40]. Exacerbation of underlying autoimmune disease is documented with IFN-α [41]. Neutralizing antibodies to recombinant IFN-α may be produced [42]. Systemic sclerosis has been associated with IFN-α [43]. Systemic LE has been recorded following IFN therapy of myelogenous leukaemia [44], and pemphigus vulgaris after IFN-β and IL-2 therapy for lymphoma [45]. References 1 International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 1991; 324: 509–16. 2 Toyofuku K, Imayama S, Yasumoto S et al. Clinical and immunohistochemical studies of skin eruptions: relationship to administration of interferon-alpha. J Dermatol 1994; 21: 732–7. 3 Papini M, Bruni PL. Cutaneous reactions to recombinant cytokine therapy. J Am Acad Dermatol 1996; 35: 1021. 4 Elgart GW, Sheremata W, Ahn YS. Cutaneous reactions to recombinant human interferon beta-1b: the clinical and histologic spectrum. J Am Acad Dermatol 1997; 37: 553–8. 5 Paquet P, Pierard-Franchimont C, Arrese JE, Pierard GE. Cutaneous side effects of interferons. Rev Med Liege 2001; 56: 699–702. 6 Manjon-Haces JA, Vazquez-Lopez F, Gomez-Diez S et al. Adverse cutaneous reactions to interferon alfa-2b plus ribavirin therapy in patients with chronic hepatitis C virus. Acta Derm Venereol (Stockh) 2001; 81: 223. 7 Charron A, Bessis D, Dereure O et al. Local cutaneous side effects of interferons. Presse Med 2001; 30: 1555–60. 8 Garcia-F-Villalta M, Dauden E, Sanchez J et al. Local reactions associated with subcutaneous injections of both beta-interferon 1a and 1b. Acta Derm Venereol (Stockh) 2001; 81: 152. 9 Weinberg JM. Cutaneous necrosis associated with recombinant interferon injection. J Am Acad Dermatol 1998; 39: 807. 10 Sheremata WA, Taylor JR, Elgart GW. Severe necrotizing cutaneous lesions complicating treatment with interferon beta-1b. N Engl J Med 1995; 332: 1584. 11 Webster GF, Knobler RL, Lublin FD et al. Cutaneous ulcerations and pustular psoriasis flare caused by recombinant interferon beta injections in patients with multiple sclerosis. J Am Acad Dermatol 1996; 34: 365–7. 12 Levesque H, Cailleux N, Moore N et al. Autoimmune phenomena associated with cutaneous aseptic necrosis during interferon-alpha treatment for chronic myelogenous leukaemia. Br J Rheumatol 1995; 34: 582–3. 13 Granstein RD, Rook A, Flotte RJ et al. A controlled trial of intralesional recombinant interferon-γ in the treatment of keloidal scarring. Arch Dermatol 1990; 126: 1295–302.

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14 Samuel L, Lowenstein EJ. Recurrent injection site reactions from interferon beta 1-b. J Drugs Dermatol 2006; 5: 366–7. 15 Hashimoto Y, Kanto H, Itoh M. Adverse skin reactions due to pegylated interferon alpha 2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus. J Dermatol 2007; 34: 577–82. 16 Ozden MG, Erel A, Erdem O, Oztas MO. Dermal fibrosis and cutaneous necrosis after recombinant interferon-beta1a injection in a multiple sclerosis patient. J Eur Acad Dermatol Venereol 2005; 19: 112–3. 17 Bachmeyer C, Farge D, Gluckman E et al. Raynaud’s phenomenon and digital necrosis induced by interferon-alpha. Br J Dermatol 1996; 135: 481–3. 18 Dereure O, Faison-Peyron N, Larrey D et al. Diffuse inflammatory lesions in patients treated with interferon alfa and ribavirin for hepatitis C: a series of 20 patients. Br J Dermatol 2003; 147: 1142–6. 19 Gupta G, Holmes SC, Spence E, Mills PR. Capillaritis associated with interferonalfa treatment of chronic hepatitis C infection. J Am Acad Dermatol 2000; 43: 937–8. 20 Schlesinger TE, Camisa C, Gay D, Bergfeld WF. Oral erosive lichen planus with epidermolytic hyperkeratosis during interferon alfa-2b therapy for chronic hepatitis C virus infection. J Am Acad Dermatol 1997; 36: 1023–5. 21 Olsen EA, Rosen ST, Vollmer RT et al. Inteferon alfa-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol 1989; 20: 395–407. 22 Foon KA, Dougher G. Increased growth of eyelashes in a patient given leukocyte A interferon. N Engl J Med 1984; 311: 1259. 23 Bessis D, Luong MS, Blanc P et al. Straight hair associated with inteferon-alfa plus ribavirin in hepatitis C infection. Br J Dermatol 2002; 147: 392–3. 24 Mazzeo L, Ricciardi L, Fazio MC et al. Severe urticaria due to recombinant interferon beta-1a. Br J Dermatol 2003; 148: 172–3. 25 Benito-Leon J, Borbujo J, Cortes L. Cutaneous mucinoses complicating interferon beta-1b therapy. Eur Neurol 2002; 47: 123–4. 26 Sanders S, Busam K, Tahan SR et al. Granulomatous and suppurative dermatitis at interferon alfa injection sites: report of 2 cases. J Am Acad Dermatol 2002; 46: 611–6. 27 Cogrel O, Doutre MS, Marliere V et al. Cutaneous sarcoidosis during interferon alfa and ribavirin treatment of hepatitis C virus infection: two cases. Br J Dermatol 2002; 146: 320–4. 28 Mehta CL, Tyler RJ, Cripps DJ. Granulomatous dermatitis with focal sarcoidal features associated with recombinant interferon β-1b injections. J Am Acad Dermatol 1998; 39: 1024–8. 29 Pelletier F, Manzoni P, Jacoulet P et al. Pulmonary and cutaneous sarcoidosis associated with interferon therapy for melanoma. Cutis 2007; 80: 441–5. 30 Junghans V, Rünger TM. Hypertriglyceridaemia following adjuvant inteferon-α treatment in two patients with malignant melanoma. Br J Dermatol 1999; 140: 183–4. 31 Fruland JE, Sandermann S, Snow SN et al. Skin necrosis with subsequent formation of squamous cell carcinoma after subcutaneous interferon beta injection. J Am Acad Dermatol 1997; 37: 488–9. 32 Quesada JR, Gutterman JU. Psoriasis and alpha-interferon. Lancet 1986; i: 1466–8. 33 Hartmann F, von Wussow P, Deicher H. Psoriasis: exacerbation bei therapie mit alpha-Interferon. Dtsch Med Wochenschr 1989; 114: 96–8. 34 Shiohara T, Kobayashi M, Abe K, Nagashima M. Psoriasis occurring predominantly on warts. Possible involvement of interferon alpha. Arch Dermatol 1988; 124: 1816–21. 35 Kowalzick L. Psoriasis flare caused by recombinant interferon beta injections. J Am Acad Dermatol 1997; 36: 501. 36 Jucgla A, Marcoval J, Curco N, Servitje O. Psoriasis with articular involvement induced by interferon alfa. Arch Dermatol 1991; 127: 910–1. 37 O’Connell PG, Gerber LH, Digiovanna JJ, Peck GL. Arthritis in patients with psoriasis treated with gamma-interferon. J Rheumatol 1992; 19: 80–2. 38 Cleveland MG, Mallory SB. Incomplete Reiter’s syndrome induced by systemic interferon alpha treatment. J Am Acad Dermatol 1993; 29: 788–9. 39 Fierlbeck G, Rassner G, Müller C. Psoriasis induced at the injection site of recombinant interferon gamma. Arch Dermatol 1990; 126: 351–5. 40 Kowalzick L, Weyer U. Psoriasis induced at the injection site of recombinant interferons. Arch Dermatol 1990; 126: 1515–6. 41 Conlon KC, Urba WJ, Smith JW II et al. Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer 1990; 65: 2237–42.

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42 Steis RG, Smith JW, Urba WJ. Resistance to recombinant interferon alfa-2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies. N Engl J Med 1988; 318: 1409–13. 43 Beretta L, Caronni M, Vanoli M, Scorza R. Systemic sclerosis after interferon-alfa therapy for myeloproliferative disorders. Br J Dermatol 2002; 147: 385–6. 44 Shilling PJ, Kurzrock P, Kantarijian H et al. Development of systemic lupus erythematosus after interferon therapy for chronic myelogenous leukemia. Cancer 1991; 68: 1536–7. 45 Ramseur WL, Richards F, Duggan DB. A case of fatal pemphigus vulgaris in association with beta interferon and interleukin-2 therapy. Cancer 1989; 63: 2005–7.

Interleukins IL-1. Mucositis and an erythematous eruption with erosions in intertriginous areas and under occlusive tape have been documented [1]. IL-2. Immunotherapy with IL-2, either alone or in conjunction with lymphokine-activated killer cells, is used in the treatment of metastatic cancer; mild, influenza-like symptoms are common. Cutaneous complications [2–8] include mucositis, macular erythema (principally restricted to the head, neck and upper chest), burning and pruritus (which resolves with mild desquamation), erythroderma and petechiae. Transient urticaria, necrotic lesions and blisters may be seen [8]. Type I hypersensitivity reactions, ranging from pruritus, erythema and oedema to hypotension, within hours of chemotherapy in patients previously treated with high-dose IL-2, have occurred [9]. A generalized capillary leak syndrome, with non-pitting oedema and diffuse pulmonary infiltrate on chest X-ray, is recorded [6], and is also documented with denileukin diftitox, formed from the fusion of human IL-2 with diphtheria toxin [10]. Exacerbation of psoriasis (including erythroderma) has been described [2–6]. IL-2 treatment predisposes to acute hypersensitivity reactions to iodine-containing contrast media [6]. Glossitis, telogen effluvium, punctate superficial ulcers and erosions in scars may be seen. Erythema nodosum has been documented [11]. Local inflammatory painful nodules with a central multiloculated vesicle have occurred at the site of subcutaneous injections of IL-2 and IFN-α [12]. Linear IgA bullous dermatosis has been associated with IL-2 therapy [13]. TEN is a rare complication [14]. It is of interest that lymphocytes activated by IL-2 can non-specifically destroy keratinocytes in vitro [15]. Other side effects include hypothyroidism (antithyroid antibodies are present in 50% of patients), neurological and psychiatric disturbances, musculoskeletal disorders, impaired renal function, cardiovascular injuries, cholestasis, pancreatitis, anaemia, thrombocytopenia, lymphocytopenia and eosinophilia [6]. IL-3. Erythema and purpura at the site of injection, and urticaria [16] may be induced. IL-4. Transient acantholytic dermatosis is recorded [17]. IL-6. Coalescent, erythematous, scaling macules and papules occurred [18]. References 1 Prussick R, Horn TD, Wilson WH, Turner MC. A characteristic eruption associated with ifosfamide, carboplatin, and etoposide chemotherapy after pretreatment with recombinant interleukin-1α. J Am Acad Dermatol 1996; 35: 705–9.

2 Rosenberg SA, Lotze MT, Muul LM et al. Clinical experience with the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high dose interleukin 2 alone. N Engl J Med 1987; 316: 889–97. 3 Gaspari A, Lotze MT, Rosenberg SA et al. Dermatologic changes associated with interleukin-2 administration. JAMA 1987; 258: 1624–9. 4 Rosenberg SA. Immunotherapy of cancer using interleukin 2: current status and future prospects. Immunol Today 1988; 9: 58–62. 5 Lee RE, Gaspari AA, Lotze MT et al. Interleukin 2 and psoriasis. Arch Dermatol 1988; 124: 1811–5. 6 Vial T, Descotes J. Clinical toxicity of interleukin-2. Drug Saf 1992; 7: 417–33. 7 Larbre B, Nicolas JF, Sarret Y et al. Immunotherapie par interleukine 2 et manifestations cutanées. Ann Dermatol Vénéréol 1993; 120: 528–33. 8 Wolkenstein P, Chosidow O, Wechster J et al. Cutaneous side effects associated with interleukin 2 administration for metastatic melanoma. J Am Acad Dermatol 1993; 28: 66–70. 9 Heywood GR, Rosenberg SA, Weber JS. Hypersensitivity reactions to chemotherapy agents in patients receiving chemoimmunotherapy with high-dose interleukin 2. J Natl Cancer Inst 1995; 87: 915–22. 10 Railan D, Fivenson DP, Wittenberg G. Capillary leak syndrome in a patient treated with interleukin 2 fusion toxin for cutaneous T-cell lymphoma. J Am Acad Dermatol 2000; 43: 323–4. 11 Weinstein A, Bujak D, Mittelman A et al. Erythema nodosum in a patient with renal cell carcinoma treated with interleukin 2 and lymphokine activated killer cells. JAMA 1987; 258: 3120–1. 12 Klapholz L, Ackerstein A, Goldenhersh MA et al. Local cutaneous reaction induced by subcutaneous interleukin-2 and interferon alpha-2a immunotherapy following ABMT. Bone Marrow Transplant 1993; 11: 443–6. 13 Tranvan A, Pezen DS, Medenica M et al. Interleukin-2 associated linear IgA bullous dermatosis. J Am Acad Dermatol 1996; 35: 865–7. 14 Wiener JS, Tucker JA Jr, Walther PJ. Interleukin-2-induced dermatotoxicity resembling toxic epidermal necrolysis. South Med J 1992; 82: 656–9. 15 Kalish RS. Non-specifically activated human peripheral blood mononuclear cells are cytotoxic for human keratinocytes in vitro. J Immunol 1989; 142: 74–80. 16 Bridges AG, Helm TN, Bergfeld WF et al. Interleukin-3-induced urticaria-like eruption. J Am Acad Dermatol 1996; 34: 1076–8. 17 Mahler SJ, De Villez RL, Pulitzer DR. Transient acantholytic dermatosis induced by recombinant human interleukin 4. J Am Acad Dermatol 1993; 29: 206–9. 18 Fleming TE, Mirando WS, Soohoo LF et al. An inflammatory eruption associated with recombinant human IL-6. Br J Dermatol 1994; 130: 534–6.

Stem cell factor Human recombinant stem cell factor, a cytokine that acts on haematopoietic progenitor cells and which is used for human anaemic disorders and for speeding haematological recovery after chemotherapy, causes reversible hyperpigmentation at sites of injection; there are increases in melanocyte numbers, dendrite extension and melanin [1]. Reference 1 Grichnik JM, Crawford J, Jimenez F et al. Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients. J Am Acad Dermatol 1995; 33: 577–83.

Tumour necrosis factor Subcutaneous or intramuscular administration of TNF for advanced malignancy was limited by local pain, erythema and swelling or frank ulceration, and intravenous infusion may cause hypotension [1]. Reference 1 Wakefield PE, James WD, Samlaska CP, Meltzer MS. Tumor necrosis factor. J Am Acad Dermatol 1991; 24: 675–85.

Important or widely prescribed drugs

Inhibitors of tumour necrosis factor (Anti-TNF-a therapy) These include adalimumab (a recombinant human IgG1 anti-TNFα monoclonal antibody), etanercept (a recombinant human fusion protein, comprising the extracellular ligand-binding domain of the 75-kDa receptor for TNF-α (TNFR-2) and the Fc fragment of the constant domain of human IgG1), and infliximab (a mouse/ human chimeric anti-TNF-α antibody comprising the constant domain of human IgG1 and a murine variable region). They are indicated in the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn’s disease and ulcerative colitis [1,2]. Adverse reactions associated with these drugs have been extensively reviewed. There is evidence of an increased risk of serious infections [2–6], especially in the skin and soft tissues, and including with Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Listeria monocytogenes, and histoplasmosis [7]; there is also concern about a possible increased risk of malignancies [2], particularly lymphoma. Use of anti-TNF agents has been associated with an increase in autoimmune disease, principally lupus-like syndrome with positive antinuclear factor, SLE and interstitial lung disease [8–10]. Cutaneous vasculitis is well recognized [11–13]. Caution is recommended in the use of etanercept in patients with a current or past history of demyelinating disease, and in patients with heart failure [4,14], because of several reports indicating a worsening or de novo occurrence of congestive heart failure [15,16]. Injection site reactions are the commonest cutaneous manifestation [4,14,17–22]. Cutaneous infections caused by viral, bacterial and fungal agents may be seen, and chronic inflammatory skin diseases such as psoriasis and eczema-like manifestations also occur [6,23]. The appearance of psoriasis, either palmoplantar pustulosis, guttate or plaque type, as a potential side effect of a drug usually used to treat the condition is paradoxical [24] yet widely reported [25–32]. The mean time to appearance of this cutaneous adverse effect for all TNF-α inhibitors was 9.5 months [32]. There is controversy as to whether the psoriatic eruption is ‘true’ or not [33]. Annular plaques on the trunk and extremities with diffuse interstitial granulomatous infiltrates on histology have been associated separately with lenalidomide, infliximab, etanercept and adalimumab [34]. Adalimumab. Urticaria and angio-oedema-like skin reactions were recorded in one patient [35]. Etanercept. This drug has in addition been associated with follicular hyperkeratosis at distant sites and necrotic and purpuric reactions [20], urticaria [36], recall injection-site reactions [37], an eosinophilic cellulitis-like reaction [38], and onset of cutaneous squamous cell cancer [39]. Infliximab. Various other dermatological complications are recorded, including an eczematid-like purpura [40], erythema multiforme and lichenoid reactions [41], necrotizing fasciitis and sepsis [42], and serum sickness [43]. In the main, the drug is well tolerated, although thrombocytopenia and hepatitis [44] and occasional infusion reactions [45] are recorded.

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References 1 Woolacott N, Hawkins N, Mason A et al. Etanercept and efalizumab for the treatment of psoriasis: a systematic review. Health Technol Assess 2006; 10: 1–233, i–iv. 2 Bongartz T, Sutton AJ, Sweeting MJ et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 2275–85. 3 Dixon WG, Watson K, Lunt M et al. Rates of serious infection, including sitespecific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006; 54: 2368–76. 4 Sánchez Carazo JL, Mahiques Santos L, Oliver Martinez V. Safety of etanercept in psoriasis: a critical review. Drug Saf 2006; 29: 675–85. 5 Curtis JR, Patkar N, Xie A et al. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007; 56: 1125–33. 6 Lee HH, Song IH, Friedrich M et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol 2007; 156: 486–91. 7 Lee JH, Slifman NR, Gershon SK et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002; 46: 2565–70. 8 Brion PH, Mittal-Henkle A, Kalunian KC. Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med 1999; 131: 634. 9 Ramos-Casals M, Brito-Zerón P, Muñoz S et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86: 242–51. 10 Poulalhon N, Begon E, Lebbé C et al. A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity. Br J Dermatol 2007; 156: 329–36. 11 Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000; 27: 2041–4. 12 Mohan N, Edwards ET, Cupps TR et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004; 31: 1955–8. 13 Saint Marcoux B, De Bandt M; CRI (Club Rhumatismes et Inflammation). Vasculitides induced by TNF alpha antagonists: a study in 39 patients in France. Joint Bone Spine 2006; 73: 710–3. 14 Romero-Maté A, García-Donoso C, Córdoba-Guijarro S. Efficacy and safety of etanercept in psoriasis/psoriatic arthritis: an updated review. Am J Clin Dermatol 2007; 8: 143–55. 15 Curtis JR, Kramer JM, Martin C et al. Heart failure among younger rheumatoid arthritis and Crohn’s patients exposed to TNF-alpha antagonists. Rheumatology (Oxford) 2007; 46: 1688–93. 16 Listing J, Strangfeld A, Kekow J et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum 2008; 58: 667–77. 17 Zeltser R, Valle L, Tanck C et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol 2001; 137: 893–9. 18 Werth VP, Levinson AI. Etanercept-induced injection site reactions: mechanistic insights from clinical findings and immunohistochemistry. Arch Dermatol 2001; 137: 953–5. 19 Zeltser R, Valle L, Tanck C et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept. Arch Dermatol 2001; 137: 893–9. 20 Misery L, Perrot JL, Gentil-Perret A et al. Dermatological complications of etanercept therapy for rheumatoid arthritis. Br J Dermatol 2002; 146: 334–5. 21 Scheinfeld N. The medical uses and side effects of etanercept with a focus on cutaneous disease. J Drugs Dermatol 2004; 3: 653–9. 22 Davis JC Jr, van der Heijde DM, Braun J et al. Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis 2008; 67: 346–52. 23 Wright RC. Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol 2003; 49: 160–1.

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24 Aslanidis S, Pyrpasopoulou A, Douma S, Triantafyllou A. Tumor necrosis factorα antagonist-induced psoriasis: yet another paradox in medicine. Clin Rheumatol 2008; 27: 377–80. 25 Verea MM, Del Pozo J, Yebra-Pimentel MT et al. Psoriasiform eruption induced by infliximab. Ann Pharmacother 2004; 38: 54–7. 26 Pirard D, Arco D, Debrouckere V, Heenen M. Anti-tumor necrosis factor alpha-induced psoriasiform eruptions: three further cases and current overview. Dermatology 2006; 213: 182–6. 27 de Gannes GC, Ghoreishi M, Pope J et al. Psoriasis and pustular dermatitis triggered by TNF-α inhibitors in patients with rheumatologic conditions. Arch Dermatol 2007; 14: 223–31. 28 Cohen JD, Bournerias I, Buffard V et al. Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series. J Rheumatol 2007; 34: 380–5. 29 Ubriani R, Van Voorhees AS. Onset of psoriasis during treatment with TNF-α antagonists: a report of 3 cases. Arch Dermatol 2007; 143: 270–1. 30 Severs GA, Lawlor TH, Purcell SM et al. Cutaneous adverse reaction to infliximab: report of psoriasis developing in 3 patients. Cutis 2007; 80: 231–7. 31 Roux CH, Brocq O, Leccia N et al. New-onset psoriatic palmoplantaris pustulosis following infliximab therapy: a class effect? J Rheumatol 2007; 34: 434–7. 32 Wollina U, Hansel G, Koch A et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008; 9: 1–14. 33 Seneschal J, Lepreux S, Bouyssou-Gauthier ML et al. Psoriasiform drug eruptions under anti-TNF treatment of arthritis are not true psoriasis. Acta Derm Venereol 2007; 87: 77–80. 34 Deng A, Harvey V, Sina B et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006; 142: 198–202. 35 Nikas SN, Voulgari PV, Drosos AA. Urticaria and angioedema-like skin reactions in a patient treated with adalimumab. Clin Rheumatol 2007; 26: 787–8. 36 Skytta E, Pohjankoski H, Savolainen A. Etanercept and urticaria in patients with juvenile idiopathic arthritis. Clin Exp Rheumatol 2001; 18: 533–4. 37 González-López MA, Martínez-Taboada VM, González-Vela MC et al. Recall injection-site reactions associated with etanercept therapy: report of two new cases with immunohistochemical analysis. Clin Exp Dermatol 2007; 32: 672–4. 38 Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cellulitis like reaction to subcutaneous etanercept injection. Arch Dermatol 2006; 142: 218–20. 39 Smith KJ, Skelton HG. Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor α receptor IgG1-Fc fusion complex therapy. J Am Acad Dermatol 2002; 45: 953–6. 40 Wang LC, Medenica MM, Shea CR, Busbey S. Infliximab-induced eczematid-like purpura of Doucas and Kapetenakis. J Am Acad Dermatol 2003; 49: 157–8. 41 Vegara G, Sivestre JF, Betlloch I et al. Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol 2002; 138: 1258–9. 42 Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J 2002; 78: 47–8. 43 Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med 2006; 30: 41–4. 44 Smith CH, Jackson K, Bashir SJ et al. Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study. Br J Dermatol 2006; 155: 160–9. 45 Vultaggio A, Matucci A, Parronchi P et al. Safety and tolerability of infliximab therapy: suggestions and criticisms based on wide clinical experience. Int J Immunopathol Pharmacol 2008; 21: 367–74.

Monoclonal antibodies—miscellaneous Anakinra. This recombinant human IL-1 receptor antagonist used in the treatment of rheumatoid arthritis, familial Mediterranean fever and the Muckle Wells syndrome, caused erythema and oedema at injection sites within the first month of treatment, with marked dermal oedema and a lichenoid dermal infiltrate [1]. Basiliximab. This IL-2 receptor monoclonal antibody has caused myalgia [2].

Efalizumab [3]. This recombinant humanized IgG1 kappa isotype monoclonal antibody against the CD11a molecule was used as a weekly injection in the treatment of moderate to severe psoriasis. Headache, chills, fever, nausea and myalgia followed the first two injections within 2 days. Arthralgia, asthenia, peripheral oedema and psoriasis occured in up to 2%, and a rebound flare reaction on cessation of therapy in approximately 5%, of patients [3,4]. Immune-mediated thrombocytopenia and haemolytic anaemia were recorded. Severe arthritis events, including psoriatic arthritis events, were reported in clinical trials and post-marketing surveillance. However, the incidence of arthropathy adverse events in efalizumab-treated patients was more recently judged similar to placebo [5]. The drug has recently been withdrawn due to associated onset of multifocal leukoencephalopathy [6]. OKT3. Orthoclone OKT3, a murine monoclonal antibody directed against the CD3 subset of T lymphocytes, has been used as an immunosuppressive agent in renal transplant recipients, and was anecdotally associated with anaphylaxis [7]. Omalizumab. Therapy for asthma was associated with anaphylactoid reactions; polysorbate, an excipient in omalizumab, may have been responsible [8]. Rituximab. This murine–human chimeric anti-CD20 antibody for patients with CD20-expressing B-cell lymphoma, currently under investigation for other indications including autoimmune diseases, in particular rheumatoid arthritis, is usually well tolerated [9], but has caused vasculitis and serum sickness [10,11]. References 1 Vila AT, Puig L, Fernández-Figueras MT et al. Adverse cutaneous reactions to anakinra in patients with rheumatoid arthritis: clinicopathological study of five patients. Br J Dermatol 2005; 153: 417–23. 2 Bell HK, Parslew RAG. Use of basiliximab as a cyclosporin-sparing agent in palmopustular psoriasis with myalgia as an adverse effect. Br J Dermatol 2002; 147: 606–7. 3 Scheinfeld N. Efalizumab: a review of events reported during clinical trials and side effects. Expert Opin Drug Saf 2006; 5: 197–209. 4 Hassan AS, Simon D, Sumon H-U et al. Efalizumab-associated papular psoriasis. Arch Dermatol 2007; 143: 900–6. 5 Pincelli C, Henninger E, Casset-Semanaz F. The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab. Arch Dermatol Res 2006; 298: 329–38. 6 Korman BD, Tyler KL, Korman NJ. Progressive multifocal leukoencephalopathy, efalizumab and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 2009; 145: 937–42. 7 Werier J, Cheung AHS, Matas AJ. Anaphylactic hypersensitivity reaction after repeat OKT3 treatment. Lancet 1991; 337: 1351. 8 Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 2007; 28: 313–9. 9 Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005; 31: 456–73. 10 Dereure O, Navarro R, Rossi JF, Guilhou JJ. Rituximab-induced vasculitis. Dermatology 2001; 203: 83–4. 11 D’Arcy CA, Mannik M. Serum sickness secondary to treatment with the murine– human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum 2001; 44: 1717–8.

Important or widely prescribed drugs

Miscellaneous drugs affecting the immune response Topical calcineurin inhibitors Both pimecrolimus [1–9] and tacrolimus [9–14] are well tolerated. Transient application site reactions, including burning or pruritus, are related to disease severity, and decrease over time; skin infections, flu-like symptoms and headache occur, but no more frequently than with placebo. Focal hypertrichosis [15] and acne [16] are recorded with tacrolimus, and rosacea with both tacrolimus and pimecrolimus [17,18]. References 1 Shah Meurer M, Fölster-Holst R, Wozel G et al. Pimecrolimus cream in the longterm management of atopic dermatitis in adults: a six-month study. Dermatology 2002; 205: 271–7. 2 Kapp A, Papp K, Bingham A et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002; 110: 277–84. 3 Wahn U, Bos JD, Goodfield M et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002; 110: e2. 4 Meurer M, Fartasch M, Albrecht G et al. Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis. Dermatology 2004; 208: 365–72. 5 Hebert AA. Review of pimecrolimus cream 1% for the treatment of mild to moderate atopic dermatitis. Clin Ther 2006; 28: 1972–82. 6 Langley RG, Luger TA, Cork MJ et al. An update on the safety and tolerability of pimecrolimus cream 1%: evidence from clinical trials and post-marketing surveillance. Dermatology 2007; 215 (Suppl. 1): 27–44. 7 Gollnick H, Kaufmann R, Stough D et al. Pimecrolimus cream 1% in the longterm management of adult atopic dermatitis: prevention of flare progression. A randomized controlled trial. Br J Dermatol 2008; 158: 1083–93. 8 Zuberbier T, Bräutigam M. Long-term management of facial atopic eczema with pimecrolimus cream 1% in paediatric patients with mild to moderate disease. J Eur Acad Dermatol Venereol 2008; 22: 718–21. 9 Draelos ZD. Use of topical corticosteroids and topical calcineurin inhibitors for the treatment of atopic dermatitis in thin and sensitive skin areas. Curr Med Res Opin 2008; 24: 985–94. 10 Won CH, Seo PG, Park YM et al. A multicenter trial of the efficacy and safety of 0.03% tacrolimus ointment for atopic dermatitis in Korea. J Dermatolog Treat 2004; 15: 30–4. 11 Schachner LA, Lamerson C, Sheehan MP et al. Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study. Pediatrics 2005; 116: e334–42. 12 Paller AS, Lebwohl M, Fleischer AB Jr et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005; 52: 810–22. 13 Remitz A, Harper J, Rustin M et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Acta Derm Venereol 2007; 87: 54–61. 14 Rustin MH. The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br J Dermatol 2007; 157: 861–73. 15 Prats Caelles I, Pinto PH, Casado ELA, Laguna RL. Focal hypertrichosis during topical tacrolimus therapy for childhood vitiligo. Pediatr Dermatol 2005; 22: 86–7. 16 Bakos L, Marchiori Bakos R. Focal acne during topical tacrolimus therapy for vitiligo. Arch Dermatol 2007; 143: 123–4. 17 Antille C, Saurat JH, Lübbe J. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140: 457–60. 18 El Sayed F, Ammoury A, Dhaybi R et al. Rosaceiform eruption to pimecrolimus. J Am Acad Dermatol 2006; 54: 548–9.

Diphencyprone Diphencyprone [1] used for alopecia areata has resulted in urticaria [2,3] and erythema multiforme [4], and has been linked to

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the development of vitiligo [5–7]. Severe contact dermatitis reactions may be induced. References 1 Shah M, Lewis FM, Messenger AG. Hazards in the use of diphencyprone. Br J Dermatol 1996; 134: 1153. 2 van der Steen PHM, van Baar HMJ, Perret CM, Happle R. Treatment of alopecia areata with diphenylcyclopropenone. J Am Acad Dermatol 1991; 24: 253–7. 3 Alam M, Gross EA, Savin RC. Severe urticarial reaction to diphenylcyclopropenone therapy for alopecia areata. J Am Acad Dermatol 1999; 40: 110–2. 4 Perret CM, Steijlen PM, Zaun H, Happle R. Erythema multiforme-like eruptions: a rare side effect of topical immunotherapy with diphenylcyclopropenone. Dermatologica 1990; 180: 5–7. 5 Hatzis J, Gourgiotou K, Tosca A et al. Vitiligo as a reaction to topical treatment with diphencyprone. Dermatologica 1988; 177: 146–8. 6 Duhra P, Foulds IS. Persistent vitiligo induced by diphencyprone. Br J Dermatol 1990; 123: 415–6. 7 Henderson CA, Ilchyshyn A. Vitiligo complicating diphencyprone sensitization therapy for alopecia universalis. Br J Dermatol 1995; 133: 496–7.

Erythropoietin This drug has caused a generalized eczematous reaction [1]. Reference 1 Hardwick N, King CM. Generalized eczematous reaction to erythropoietin. Contact Dermatitis 1993; 28: 123.

Topical imiquimod This topical imidazoquinoline immunodulator drug, a toll-like receptor agonist, which induces cytokine production and stimulates the innate and cellular immune responses, is currently used in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions, including lentigo maligna [1]. It is broadly well tolerated; local application-site reactions, including pruritus, erythema, oedema and bleeding are common, usually mild, and do not necessitate discontinuation of therapy [2–9]. Inflammatory papules in the surrounding skin have been recorded [10]. There is evidence that the more severe the local reaction, the higher the clearance rate [3], without compromising the eventual cosmetic result [9]. Imiquimod appears safe to use in transplant patients [11]. Rarely, headache, influenza-like symptoms, myalgia, angio-oedema [12], Stevens–Johnson syndrome, and cutaneous lupus erythematosus-like reactions are seen. Erosive cheilitis [13] and aphthous ulceration [14], localized multiple comedones and epidermoid cysts [15,16], multiple keratoacanthomas [17], lymphocytic vasculitis [18], and chronic neuropathic pain [19] are documented. There are a number of published reports on vitiligo-like hypopigmentation [20–25], permanent on the face [25], and occasionally hyperpigmentation. Severe exacerbation of eczema [26], triggering of local or generalized psoriasis [27–30], or pemphigus [31–33] may occur rarely. Concerns about the possible risks of immunostimulation have been expressed [34]; exacerbation of HLA-B27 spondyloarthropathy [34] and exacerbation of myasthenia gravis [35] are recorded. References 1 Hardwick Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs 2007; 67: 2187–210.

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2 Micali G, De Pasquale R, Caltabiano R et al. Topical imiquimod treatment of superficial and nodular basal cell carcinomas in patients affected by basal cell nevus syndrome: a preliminary report. J Dermatolog Treat 2002; 13: 123–7. 3 Geisse J, Caro I, Lindholm J et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehiclecontrolled studies. J Am Acad Dermatol 2004; 50: 722–33. 4 Lebwohl M, Dinehart S, Whiting D et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004; 50: 714–21. 5 Schulze HJ, Cribier B, Requena L et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol 2005; 152: 939–47. 6 Ferrándiz C. Update on actinic keratosis in clinical trial experience with imiquimod. Br J Dermatol 2007; 157 (Suppl. 2): 32–3. 7 Rivers JK, Rosoph L, Provost N, Bissonnette R. Open-label study to assess the safety and efficacy of imiquimod 5% cream applied once daily three times per week in cycles for treatment of actinic keratoses on the head. J Cutan Med Surg 2008; 12: 97–101. 8 Jacobs AA, Snavely N, Markus J, Rosen T. Vasodilatory adverse events associated with topical imiquimod 5 percent cream. Dermatol Online J 2008; 14: 4. 9 Greenberg HL, Cohen JL, Rosen T, Orengo I. Severe reaction to 5% imiquimod cream with excellent clinical and cosmetic outcomes. J Drugs Dermatol 2007; 6: 452–8. 10 Stinco G, Frattasio A, Forcione M et al. The appearance of inflammatory papules in the skin surrounding areas treated with imiquimod cream for basal cell carcinoma. Br J Dermatol 2008; 158: 408–9. 11 Ulrich C, Bichel J, Euvrard S et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007; 157 (Suppl. 2): 25–31. 12 Barton JC. Angioedema associated with imiquimod. J Am Acad Dermatol 2004; 51: 477–8. 13 Campanelli A, Lübbe J. Erosive cheilitis after facial application of imiquimod 5% cream. J Eur Acad Dermatol Venereol 2007; 21: 1429–30. 14 Chakrabarty AK, Mraz S, Geisse JK, Anderson NJ. Aphthous ulcers associated with imiquimod and the treatment of actinic cheilitis. J Am Acad Dermatol 2005; 52 (2 Suppl. 1): 35–7. 15 Marty CL, Randle HW, Walsh JS. Eruptive epidermoid cysts resulting from treatment with imiquimod. Dermatol Surg 2005; 31: 780–2. 16 Nasca MR, De Pasquale R, Micali G. Multiple and clustered eruptive epidermoid cysts following treatment with topical imiquimod. Dermatology 2007; 215: 352–3. 17 D’Addario S, Carrington PR. Multiple keratoacanthomas as an untoward response to imiquimod therapy for actinic keratoses. Acta Derm Venereol 2006; 86: 366–7. 18 Treviño J, Prieto VG, Hearne R et al. Atypical lymphocytic reaction with epidermotropism and lymphocytic vasculopathic reaction (lymphocytic vasculitis) after treatment with imiquimod. J Am Acad Dermatol 2006; 55 (5 Suppl.): S123–5. 19 Yi BA, Nirenberg MJ, Goldstein SM, Berger TG. Chronic neuropathic pain associated with imiquimod: report of 2 cases. J Am Acad Dermatol 2005; 52 (2 Suppl. 1): 57–8. 20 Brown T, Zirvi M, Cotsarelis G, Gelfand JM. Vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts. J Am Acad Dermatol 2005; 52: 715–6. 21 Stefanaki C, Nicolaidou E, Hadjivassiliou M et al. Imiquimod-induced vitiligo in a patient with genital warts. J Eur Acad Dermatol Venereol 2006; 20: 755–6. 22 Serrão VV, Páris FR, Feio AB. Genital vitiligo-like depigmentation following use of imiquimod 5% cream. Eur J Dermatol 2008; 18: 342–3. 23 Mashiah J, Brenner S. Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod. Clin Exp Dermatol 2008; 33: 74–6. 24 Jacob SE, Blyumin M. Vitiligo-like hypopigmentation with poliosis following treatment of superficial basal cell carcinoma with imiquimod. Dermatol Surg 2008; 34: 844–5. 25 Mendonça CO, Yates VM. Permanent facial hypopigmentation following treatment with imiquimod cream. Clin Exp Dermatol 2006; 31: 721–2. 26 Taylor CL, Maslen M, Kapembwa M. A case of severe eczema following use of imiquimod 5% cream. Sex Transm Infect 2006; 82: 227–8.

27 Gilliet M, Conrad C, Geiges M et al. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol 2004; 140: 1490–5. 28 Wu JK, Siller G, Strutton G. Psoriasis induced by topical imiquimod. Australas J Dermatol 2004; 45: 47–50. 29 Fanti PA, Dika E, Vaccari S et al. Generalized psoriasis induced by topical treatment of actinic keratosis with imiquimod. Int J Dermatol 2006; 45: 1464–5. 30 Rajan N, Langtry JA. Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas. Clin Exp Dermatol 2006; 31: 140–1. 31 Lin R, Ladd DJ Jr, Powell DJ, Way BV. Localized pemphigus foliaceus induced by topical imiquimod treatment. Arch Dermatol 2004; 140: 889–90. 32 Ruocco E, Baroni A, Rossiello L, Ruocco V. Imiquimod contact pemphigus: a comment. Eur J Obstet Gynecol Reprod Biol 2004; 115: 242–3. 33 Mashiah J, Brenner S. Possible mechanisms in the induction of pemphigus foliaceus by topical imiquimod treatment. Arch Dermatol 2005; 141: 908–9. 34 Benson E. Imiquimod: potential risk of an immunostimulant. Australas J Dermatol 2004; 45: 123–4. 35 Wolfe CM, Tafuri N, Hatfield K. Exacerbation of myasthenia gravis during imiquimod treatment. J Drugs Dermatol 2007; 6: 745–6.

Roquinimex The incidence of graft-versus-host reactions is enhanced in patients treated with the cytokine inducer carboxamide–quinoline immunotherapeutic agent roquinimex (Linomide), used for posttransplantation immunotherapy in autologous bone marrow transplantation for acute and chronic myelogenous leukaemia [1,2]. Cutaneous graft-versus-host reactions were associated with eccrine sweat gland necrosis. References 1 Gaspari AA, Cheng SF, DiPersio JF, Rowe JM. Roquinimex-induced graftversus-host reaction after autologous bone marrow transplantation. J Am Acad Dermatol 1995; 33: 711–7. 2 Ohsuga Y, Rowe JM, Liesveld J et al. Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant. J Am Acad Dermatol 2000; 43: 437–41.

Antihistamines H1 antihistamines All traditional H1 antagonists cause side effects [1–4], especially sedation, most marked with the aminoalkylether and phenothiazine groups. Dizziness, poor coordination, blurred vision and diplopia, as well as nervousness, insomnia and tremor may occur. In addition, atropine-like anticholinergic effects, including dryness of mucous membranes, urinary retention, palpitations, agitation, increased intraocular pressure and gastrointestinal upset are seen. Phenothiazine-derived drugs may cause photosensitivity or cholestatic jaundice. The effects of nervous system depressants, such as alcohol, hypnotics, sedatives, analgesics and anxiolytics, may be potentiated. Decreased efficacy of drugs metabolized by the liver microsomal enzyme system, including oral anticoagulants, phenytoin and griseofulvin, may occur as a result of liver-enzyme induction by antihistamines. The newer antihistamines (e.g. terfenadine, astemizole, loratadine, cetirizine) are much less likely to cause sedation [1–4]. Terfenadine and astemizole rarely cause QT interval prolongation and torsade de pointes. Arrhythmias occur when metabolism of terfenadine is impaired, as with inhibition of the cytochrome P-450 isoform CYP 3A4 by ketoconazole, itraconazole and related imidazole antifungals, erythromycin, clarithromycin and related

Important or widely prescribed drugs

macrolide antibiotics, grapefruit juice, or liver disease [5–7]. Patients on terfenadine or astemizole should be instructed accordingly. The UK Committee on Safety of Medicines withdrew terfenadine from over-the-counter sale, as did the US FDA. However, in one study, there was no increased risk of life-threatening ventricular arrhythmic events or cardiac arrest with terfenadine compared with over-the-counter antihistamines, ibuprofen or clemastine [8]. True hypersensitivity reactions are rare. Fixed eruptions have been caused by thonzylamine and cyclizine [9], cetirizine [10,11], levocetirizine [12], hydroxyzine [13] and loratadine [14]. Skin eruptions have been documented with terfenadine [15,16], including possible exacerbation of psoriasis [17]; alopecia has been reported rarely [18]. Cetirizine has been linked to maculopapular morbilliform eruptions, with cross-reactivity to other piperazine (ethylenediamine) derivatives hydroxyzine and azelastine, and precipitation of urticaria [19–23]. Mizolastine has been reported to cause immediate hypersensitivity [24]. Lichenoid and subacute LE-like dermatoses are recorded with antihistamine therapy [25]. Hydroxyzine caused a systemic contact dermatitis in one case [26]. A pityriasis lichenoides et varioliformis acuta-like drug exanthem was reportedly caused by astemizole, with a positive challenge test [27]. Antihistamines are associated with atypical lymphoid hyperplasia, presenting as solitary or multiple nodules and plaques, or multiple papules, in some patients [28]. Urticaria was induced by different families of antihistamines—piperazines and piperidines—in one patient [29]. References 1 Woodward JK. Pharmacology and toxicology of nonclassical antihistamines. Cutis 1988; 42: 5–9. 2 Lichtenstein LM, Simons FER, eds. Advancements in antiallergic therapy: beyond conventional antihistamines. J Allergy Clin Immunol 1990; 86 (Suppl.): 995–1046. 3 Kennard CD, Ellis CN. Pharmacologic therapy for urticaria. J Am Acad Dermatol 1991; 25: 176–89. 4 Soter NA. Treatment of urticaria and angioedema: low-sedating H1-type antihistamines. J Am Acad Dermatol 1991; 24: 1084–7. 5 Thomas SHL. Drugs, QT interval abnormalities and ventricular arrhythmias. Adverse Drug React Acute Toxicol Rev 1994; 13: 77–102. 6 Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996; 36: 233–52. 7 Thomas SHL. Drugs and the QT interval. Adverse Drug React Bull 1997; 182: 691–4. 8 Pratt CM, Hertz RP, Ellis BE et al. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1994; 73: 346–52. 9 Griffiths WAD, Peachey RDG. Fixed drug eruption due to cyclizine. Br J Dermatol 1970; 82: 616–7. 10 Inamadar AC, Palit A, Athanikar SB et al. Multiple fixed drug eruptions due to cetirizine. Br J Dermatol 2002; 147: 1025–6. 11 Cravo M, Gonçalo M, Figueiredo A. Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives. Int J Dermatol 2007; 46: 760–2. 12 Mahajan VK, Sharma NL, Sharma VC. Fixed drug eruption: a novel side-effect of levocetirizine. Int J Dermatol 2005; 44: 796–8. 13 Cohen HA, Barzilai A, Matalon A, Harel L, Gross S. Fixed drug eruption of the penis due to hydroxyzine hydrochloride. Ann Pharmacother 1997; 31: 327–9. 14 Ruiz-Genao DP, Hernández-Nünez A, Sánchez-Pérez J, García-Díez A. Fixed drug eruption due to loratadine. Br J Dermatol 2002; 146: 528–9. 15 Stricker BHCH, Van Dijke CHP, Isaacs AJ, Lindquist M. Skin reactions to terfenadine. BMJ 1986; 293: 536.

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16 McClintock AD, Ching DW, Hutchinson C. Skin reactions and terfenadine. NZ Med J 1995; 108: 208. 17 Harrison PV, Stones RN. Severe exacerbation of psoriasis due to terfenadine. Clin Exp Dermatol 1988; 13: 275. 18 Jones S, Morley W. Terfenadine causing hair loss (unreviewed report). BMJ 1985; 291: 940. 19 Stingeni L, Caraffini S, Agostinelli D et al. Maculopapular and urticarial eruption from cetirizine. Contact Dermatitis 1997; 37: 249–50. 20 Lew BL, Haw CR, Lee MH. Cutaneous drug eruption from cetirizine and hydroxyzine. J Am Acad Dermatol 2004; 50: 953–6. 21 Karamfilov T, Wilmer A, Hipler UC, Wollina U. Cetirizine-induced urticarial reaction. Br J Dermatol 1999; 140: 979–80. 22 Calista D, Schianchi S, Morri M. Urticaria induced by cetirizine. Br J Dermatol 2001; 144: 196. 23 Schröter S, Damveld B, Marsch WC. Urticarial intolerance reaction to cetirizine. Clin Exp Dermatol 2002; 27: 185–7. 24 Gonzalo-Garijo MA, Jiménez-Ferrera G, Bobadilla-González P, Cordobés-Durán C. Hypersensitivity reaction to mizolastine: study of cross reactions. J Investig Allergol Clin Immunol 2006; 16: 391–3. 25 Crowson AN, Magro CM. Lichenoid and subacute cutaneous lupus erythematosus-like dermatitis associated with antihistamine therapy. J Cutan Pathol 1999; 26: 95–9. 26 Menne T. Systemic contact dermatitis to hydroxyzine. Am J Contact Dermatitis 1997; 8: 2–5. 27 Stosiek N, Peters KP, von den Driesch P. Pityriasis-lichenoides-et-varioliformisacuta-ähnliches Arzneiexanthem durch Astemizol. Hautarzt 1993; 44: 235–7. 28 Magro CM, Crowson AN. Drugs with antihistaminic properties as a cause of atypical cutaneous lymphoid hyperplasia. J Am Acad Dermatol 1995; 32: 419–28. 29 González de Olano D, Roán Roán J, de la Hoz Caballer B et al. Urticaria induced by antihistamines. J Investig Allergol Clin Immunol 2006; 16: 144–6.

H2 antihistamines Severe adverse reactions are rare with cimetidine, ranitidine, nizatidine and famotidine [1]. Gastrointestinal upset, headache, drowsiness, fatigue or muscular pain occur in fewer than 3% of patients. Confusion, dizziness, somnolence, gynaecomastia or galactorrhoea with increased prolactin levels (cimetidine and ranitidine only), impotence and loss of libido (with cimetidine), bone marrow depression, hepatitis, abnormal renal function or nephritis, arthralgia, myalgia, cardiac abnormalities, and minor or severe skin reactions occur in fewer than 1% of patients. Cimetidine. Mucocutaneous reactions are rare in relation to the enormous, worldwide use of this drug. Reported reactions include a seborrhoeic dermatitis-like rash [2] and asteatotic dermatitis [3], erythema annulare centrifugum [4], erythrosis [5], giant urticaria [6], transitory alopecia [7], erythema multiforme [8] and exfoliative dermatitis [9]. Other effects have included thrombocytopenia [10] and leukocytoclastic vasculitis [11]. Exacerbation of cutaneous LE [12] and SLE with granulocytopenia [13] are documented. Cimetidine binds to androgen receptors, thereby blocking the binding of dihydrotestosterone, and gynaecomastia and hypogonadism are now well-known side effects [14]. The drug augments cell-mediated immunity in vitro by blockade of H2 receptors on T lymphocytes [15]. References 1 Feldman M, Burton ME. Histamine2-receptor antagonists. Standard therapy for acid-peptic diseases. N Engl J Med 1990; 323: 1672–80. 2 Kanwar A, Majid A, Garg MP, Singh G. Seborrheic dermatitis-like eruption caused by cimetidine. Arch Dermatol 1981; 117: 65–6.

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3 Greist MC, Epinette WW. Cimetidine-induced xerosis and asteatotic dermatitis. Arch Dermatol 1982; 118: 253–4. 4 Merrett AC, Marks R, Dudley FJ. Cimetidine-induced erythema annulare centrifugum: no cross-sensitivity with ranitidine. BMJ 1981; 283: 698. 5 Angelini G, Bovo P, Vaona B, Cavallini G. Cimetidine and erythrosis-like lesions. BMJ 1979; i: 1147–8. 6 Hadfield WA Jr. Cimetidine and giant urticaria. Ann Intern Med 1979; 91: 128–9. 7 Vircburger MI, Prelevic GM, Brkic S et al. Transitory alopecia and hypergonadotrophic hypogonadism during cimetidine treatment. Lancet 1981; i: 1160–1. 8 Ahmed AH, McLarly DG, Sharma SK, Masawe AEJ. Stevens–Johnson syndrome during treatment with cimetidine. Lancet 1979; ii: 433. 9 Yantis PL, Bridges ME, Pittman FE. Cimetidine-induced exfoliative dermatitis. Dig Dis Sci 1980; 25: 73–4. 10 Rate R, Bonnell M, Chervenak C, Pavinich G. Cimetidine and hematologic effects. Ann Intern Med 1979; 91: 795. 11 Dernbach WK, Taylor G. Leukocytoclastic vasculitis from cimetidine. JAMA 1981; 246: 331. 12 Davidson BL, Gilliam JN, Lipsky PE. Cimetidine-associated exacerbation of cutaneous lupus erythematosus. Arch Intern Med 1982; 142: 166–7. 13 Littlejohn GO, Urowitz MB. Cimetidine, lupus erythematosus, and granulocytopenia. Ann Intern Med 1979; 91: 317–8. 14 Jensen RT, Collen MJ, Pandol SJ et al. Cimetidine-induced impotence and breast changes in patients with gastric hypersecretory states. N Engl J Med 1983; 308: 883–7. 15 Mavligit GM. Immunologic effects of cimetidine: potential uses. Pharmacotherapy 1987; 7 (Suppl. 2): S120–S124.

Famotidine. This drug has been associated with the development of symptomatic dermographism [1], pruritic exanthem [2–4], contact eczema [4], leukocytoclastic vasculitis [5] and TEN. References 1 McCarley Warner D, Ramos-Caro FA, Flowers FP. Famotidine (Pepcid)-induced symptomatic dermatographism. J Am Acad Dermatol 1994; 31: 677–8. 2 Reynolds JC. Famotidine in the management of duodenal ulcer: an analysis of multicenter findings worldwide. Clin Ther 1988; 10: 436–49. 3 Dragosics B, Weiss W, Okulski G. Zur Therapie peptischer Ulzera mit Famotidin. Erfahrungsbericht einer offenen klinischen Studie. Wien Med Wochenschr 1992; 142: 408–13. 4 Monteseirin J, Conde J. Contact eczema from famotidine. Contact Dermatitis 1990; 22: 290. 5 Andreo JA, Vivancos F, Lopez VM et al. Vasculitis leucocitoclastica y famotidina. Med Clin (Barc) 1990; 95: 234–5.

Ranitidine. Urticaria [1] and anaphylaxis [2] are recorded, as are allergic dermatitis and allergic contact dermatitis [3,4]. Immune complex-mediated rashes [5], lichenoid eruptions [6] and photosensitivity with UVA sensitivity on monochromator light testing [7] have been documented, as has cholestatic hepatitis [8]. This drug has a less marked effect on androgen receptors than cimetidine, but gynaecomastia has occurred [9]. References 1 Picardo M, Santucci B. Urticaria from ranitidine. Contact Dermatitis 1983; 9: 327. 2 Lazaro M, Compaired JA, De La Hoz B et al. Anaphylactic reaction to ranitidine. Allergy 1993; 48: 385–7. 3 Juste S, Blanco J, Garces M, Rodriguez G. Allergic dermatitis due to oral ranitidine. Contact Dermatitis 1992; 27: 339–40. 4 Alomar A, Puig L, Vilaltella I. Allergic contact dermatitis due to ranitidine. Contact Dermatitis 1987; 17: 54–5. 5 Haboub N. Rash mediated by immune complexes associated with ranitidine treatment. BMJ 1988; 296: 897.

6 Horiuchi Y, Katagiri T. Lichenoid eruptions due to the H2-receptor antagonists roxatidine and ranitidine. J Dermatol 1996; 23: 510–2. 7 Todd P, Norris P, Hawk JLM, du Vivier AWP. Ranitidine-induced photosensitivity. Clin Exp Dermatol 1995; 20: 146–8. 8 Devuyst O, Lefebvre C, Geubel A, Coche E. Acute cholestatic hepatitis with rash and hypereosinophilia associated with ranitidine treatment. Acta Clin Belg 1993; 48: 109–14. 9 Tosti S, Cagnoli M. Painful gynaecomastia with ranitidine. Lancet 1982; ii: 160.

Leukotriene receptor antagonists Montelukast. This drug for asthma, occasionally used in urticaria, has been associated with urticaria [1] and cutaneous lesions of Churg–Strauss syndrome [2]. References 1 Minciullo PL, Saija A, Bonanno D et al. Montelukast-induced generalized urticaria. Ann Pharmacother 2004; 38: 999–1001. 2 Gal AA, Morris RJ, Pine JR, Spraker MK. Cutaneous lesions of Churg–Strauss syndrome associated with montelukast therapy. Br J Dermatol 2002; 147: 618–9.

Injections, infusions and procedures Radiographic contrast media and radiopharmaceuticals Radiographic contrast media Reactions to radiographic contrast media were previously reported to occur in about 4–8% of cases; severe reactions occurred in 1 in 1000 administrations, and occasionally fatal anaphylactoid reactions developed (1 in 3000 for intravenous cholangiograms and between 1 in 10 000 and 1 in 100 000 for intravenous urography) [1–3]. Although IgE-mediated mechanisms may be involved [4], the vast majority of contrast reactions are not due to iodine allergy but rather to non-immunological release of mast cell mediators or to direct complement activation [5,6]. The risk of severe reactions is increased in atopics, asthmatics, those taking β-blockers, and with higher doses of contrast media; up to 40% of patients with a previous reaction may develop a recurrence [7,8]. Newer, low-osmolality radiocontrast media are associated with fewer reactions [8–14]. For example, administration of iohexol in 50 660 patients undergoing excretory urography resulted in a frequency of adverse reactions of any type of 2.1% [9]. In another series, there was a 7.0% incidence of mild adverse reactions to low-osmolar iodine contrast medium in 4550 radiological procedures, including computed tomography (CT), intravenous urography, arteriography, venography and myelography [10]. There were only two cases of severe anaphylactoid reactions during 783 consecutive cases undergoing voiding cystourethrography or retrograde pyelography [11]. The incidence of contrast media complications in the catheterization laboratory is 0.23%, with one death per 55 000 [12]. Non-serious and transient acute adverse events occurred in 0.9% of 49 975 patients undergoing intravenous urography using the intravenous contrast medium iobitridol; only one patient developed anaphylactic shock [13]. In another series involving iobitridol, 0.96% of 52 057 patients had an adverse event, and 0.044% of all patients (and 0.057% of at-risk patients) had a serious adverse event [14]. Low-osmolality radiocontrast media (e.g. iohexol or iopamidol) should be the contrast media of choice for patients with a prior immediate generalized reaction to conventional contrast media. In

Important or widely prescribed drugs

addition, patients should receive H1 antihistamines and corticosteroid prophylaxis [8,11,15], although a large number of patients need to receive premedication to prevent one potentially serious reaction [16]. However, although in one study the relative risk for all adverse drug reactions was three to six times higher for ionic versus non-ionic contrast media [17], in another study mortality was not lower with the newer, low-osmolar media than with the older high-osmolar media [18]. In this latter large study, the overall mortality was 13 per million intravenous injections of radiocontrast media, rising to 35 per million in those over 65 years of age. A further study in the USA found that in a clinical trial comparing the safety of low- versus high-osmolality radiologic contrast media in patients who underwent either cardiac angiography or contrast-enhanced body CT, 19% of 1004 patients had at least one adverse reaction [19]. The mean cost per patient of treating adverse reactions was $459 (range $0–39 057). Allergic reactions to intravenous gadolinium-based magnetic resonance imaging (MRI) contrast agents may occur despite premedication with corticosteroids and antihistamines [20]. In addition to immediate reactions, widespread erythema and oedema at 6 h, reaching a maximum at 9–12 h, followed intravenous injection of a CT contrast medium (iotrolan) [21]. Mild to moderate, delayed allergy-like reactions to contrast media of the maculopapular exanthematous and urticarial/angio-oedematous types were reported in 0.5–2% of recipients [22]. In more recent series, late adverse reactions to iodinated contrast media, including generalized maculopapular eruptions with fever, dress syndrome, lateonset urticaria with loss of consciousness, and facial oedema and respiratory distress, occurred in 2% to 5% of patients [23,24]. Fixed drug eruptions have been recorded with iopamidol and iomeprol [25,26]. Isolated cases of reticulate purpura [27], bullous lichen planus [28], iododerma [29], vasculitis [30] and erythrodermic psoriasis [31] have been documented. There has been a single case report of fatal TEN following second exposure to diatrizoate solution for excretory pyelography [32].

Nephrogenic systemic fibrosis Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, a fibromucinous scleromyxoedemalike disorder associated with renal dysfunction, has been linked to administration of gadolinium-based MRI contrast agents, including gadodiamide [33–39]. Symptom onset is from 3 weeks to 18 months after gadolinium exposure [36]. Skin involvement may take the form of papules and plaques with peau d’orange surface changes, especially on the legs and trunk. In other patients, it presents as grossly thickened, indurated, tight skin that is woody hard on palpation. In one case the fibrosis involved the breasts, clinically mimicking inflammatory breast carcinoma [34]. Histologically, the dermis contains thickened collagen bundles, numerous plump fibroblast-like cells and elevated hyaluronan expression [36]. Patient fibroblasts appear activated to synthesize elevated levels of hyaluronic acid and collagen in response to a serum factor [35,37]. Gadolinium has been detected in patients’ skin biopsies [36,38] and may be mobilized over time from bone stores, explaining the variably delayed onset and increasing skin concentration over time in patients with NSF. Gadodiamide stimulates control fibroblast growth, matrix synthesis and differentiation into

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myofibroblasts, suggesting a possible role for the agent in the pathophysiology of NSF [38]. Photophoresis has been advocated for the treatment of fibrosis [39]. References 1 Lieberman P, Siegle RL, Treadwell G. Radiocontrast reactions. Clin Rev Allergy 1986; 4: 229–45. 2 Grammer LC, Patterson R. Adverse reactions to radiographic contrast material. Clin Dermatol 1986; 4: 149–54. 3 Katayama H, Tanaka T. Clinical survey of adverse reactions to contrast media. Invest Radiol 1988; 23 (Suppl.): S88–S89. 4 Kanny G, Maria Y, Mentre B, Moneret-Vautrin DA. Case report: recurrent anaphylactic shock to radiographic contrast media. Evidence supporting an exceptional IgE-mediated reaction. Allerg Immunol 1993; 25: 425–30. 5 Arroyave CM, Bhatt KN, Crown NR. Activation of the alternative pathway of the complement system by radiocontrast media. J Immunol 1976; 117: 1866–9. 6 Rice MC, Lieberman P, Siegle RL, Mason J. In vitro histamine release induced by radiocontrast media and various chemical analogs in reactor and control subjects. J Allergy Clin Immunol 1983; 72: 180–6. 7 Enright T, Chua-Lim A, Duda E, Lim DT. The role of a documented allergic profile as a risk factor for radiographic contrast media reaction. Ann Allergy 1989; 62: 302–5. 8 Porri F, Vervloet D. Les reactions aux produits de contraste iodes. Allerg Immunol 1994; 26: 374–6. 9 Schrott KM, Behrends B, Clauss W et al. Iohexol in excretory urography: results of the drug monitoring programs. Fortschr Med 1986; 104: 153–6. 10 Kuwatsuru R, Katayama H, Tomita T et al. Adverse reactions to low osmolar iodine contrast media (second report) (in Japanese). Nippon Acta Radiologica 1992; 52: 1233–46. 11 Weese DL, Greenberg HM, Zimmern PE. Contrast media reactions during voiding cystourethrography or retrograde pyelography. Urology 1993; 41: 81–4. 12 Guéant-Rodriguez RM, Romano A, Barbaud A et al. Hypersensitivity reactions to iodinated contrast media. Curr Pharm Des 2006; 12: 3359–72. 13 Wendt-Nordahl G, Rotert H, Trojan L et al. Intravenous contrast media in uroradiology: evaluation of safety and tolerability in almost 50,000 patients. Med Princ Pract 2006; 15: 358–61. 14 Vogl TJ, Honold E, Wolf M et al. Safety of iobitridol in the general population and at-risk patients. Eur Radiol 2006; 16: 1288–97. 15 Goss JE, Chambers CE, Heupler FA Jr. Systemic anaphylactoid reactions to iodinated contrast media during cardiac catheterization procedures: guidelines for prevention, diagnosis, and treatment. Laboratory Performance Standards Committee of the Society for Cardiac Angiography and Interventions. Cathet Cardiovasc Diagn 1995; 34: 99–105. 16 Tramèr MR, von Elm E, Loubeyre P, Hauser C. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review. BMJ 2006; 333: 675. 17 Andrew E, Haider T. Incidence of roentgen contrast medium reactions after intravenous injection in pre-registration trials and post-marketing surveillances. Acta Radiol 1993; 34: 210–3. 18 Cashman JD, McCredie J, Henry DA. Intravenous contrast media: use and associated mortality. Med J Aust 1991; 155: 618–23. 19 Powe NR, Moore RD, Steinberg EP. Adverse reactions to contrast media: factors that determine the cost of treatment. Am J Roentgenol 1993; 161: 1089–95. 20 Dillman JR, Ellis JH, Cohan RH et al. Allergic-like breakthrough reactions to gadolinium contrast agents after corticosteroid and antihistamine premedication. Am J Roentgenol 2008; 190: 187–90. 21 Kanzaki T, Sakagami H. Late phase allergic reaction to a CT contrast medium (iotrolan). J Dermatol 1991; 18: 528–31. 22 Christiansen C, Pichler WJ, Skotland T. Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations. Eur Radiol 2000; 10: 1965–75. 23 Kanny G, Pichler W, Morisset M et al. T cell-mediated reactions to iodinated contrast media: evaluation by skin and lymphocyte activation tests. J Allergy Clin Immunol 2005; 115: 179–85. 24 Torres MJ, Mayorga C, Cornejo-Garcia JA et al. Monitoring non-immediate allergic reactions to iodine contrast media. Clin Exp Immunol 2008; 152: 233–8. 25 Yamauchi R, Morita A, Tsuji T. Fixed drug eruption caused by iopamidol, a contrast medium. J Dermatol 1997; 24: 243–5.

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26 Watanabe H, Sueki H, Nakada T et al. Multiple fixed drug eruption caused by iomeprol (Iomeron), a nonionic contrast medium. Dermatology 1999; 198: 291–4. 27 Rinker MH, Sangueza OP, Davis LS. Reticulated purpura occurring with contrast medium after hysterosalpingography. Br J Dermatol 1998; 138: 919–20. 28 Grunwald MH, Halevy S, Livni E, Feuerman EJ. Bullous lichen planus after intravenous pyelography. J Am Acad Dermatol 1985; 13: 512–3. 29 Chang MW, Miner JE, Moiin A, Hashimoto K. Iododerma after computed tomographic scan with intravenous radiopaque contrast media. J Am Acad Dermatol 1997; 36: 1014–6. 30 Kerdel FA, Fraker DL, Haynes HA. Necrotizing vasculitis from radiographic contrast media. J Am Acad Dermatol 1984; 10: 25–9. 31 Evans AV, Parker JC, Russell-Jones R. Erythrodermic psoriasis precipitated by radiologic contrast media. J Am Acad Dermatol 2002; 46: 960–1. 32 Kaftori JK, Abraham Z, Gilhar A. Toxic epidermal necrolysis after excretory pyelography. Immunologic-mediated contrast medium reaction? Int J Dermatol 1988; 27: 346–7. 33 Khurana A, Runge VM, Narayanan M et al. Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan). Invest Radiol 2007; 42: 139–45. 34 Solomon GJ, Wu E, Rosen PP. Nephrogenic systemic fibrosis mimicking inflammatory breast carcinoma. Arch Pathol Lab Med 2007; 131: 145–8. 35 Edward M, Fitzgerald L, Thind C et al. Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: fibroblast hyaluronan synthesis and the effect of patient serum. Br J Dermatol 2007; 156: 473–9. 36 Wiginton CD, Kelly B, Oto A et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. Am J Roentgenol 2008; 190: 1060–8. 37 Edward M, Quinn JA, Mukherjee S et al. Gadodiamide contrast agent ‘activates’ fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol 2008; 214: 584–93. 38 Abraham JL, Thakral C, Skov L et al. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008; 158: 273–80. 39 Richmond H, Zwerner J, Kim Y, Fiorentino D. Nephrogenic systemic fibrosis. Relationship to gadolinium and response to photophoresis. Arch Dermatol 2007; 143: 1025–30.

Radiopharmaceuticals The reported incidence of reactions to agents used in nuclear medicine is low; these usually take the form of immediate urticaria or angio-oedema [1–3]. Urticarial or anaphylactic reactions to technetium (99mTc) sulphur colloid and 99mTc human albumin microspheres together accounted for 50% of reported reactions [2]. The bone-scanning agent 99mTc methylene diphosphonate produces a delayed-onset erythematous pruritic eruption within 4–24 h [4]. References 1 Rhodes BA, Cordova MA. Adverse reactions to radio-pharmaceuticals: incidence in 1978, and associated symptoms. J Nucl Med 1980; 2: 1107. 2 Cordova MA, Hladik WB III, Rhodes BA. Validation and characterization of adverse reactions to radiopharmaceuticals. Noninvasive Med Imaging 1984; 1: 17–24. 3 Keeling D, Sampson CB. Adverse reactions to radiopharmaceuticals: incidence, reporting, symptoms, treatment. Nuklearmedizin 1986; 23 (Suppl.): 478–82. 4 Collins MRL, James WD, Rodman OG. Adverse cutaneous reaction to technetium Tc 99m methylene diphosphonate. Arch Dermatol 1988; 124: 180–1.

Halides Bromides Bromides have a long half-life and are excreted slowly by the kidney; bromism may develop in patients with impaired renal function, and eruptions may not develop until as much as 2 months after the drug has been discontinued. Acneiform and vegetating lesions occur more often, and bullae less frequently, than

with iodism [1,2]. Vegetating bromoderma presents as single or multiple papillomatous nodules or plaques, studded with small pustules, on the face or limbs. Bromoderma tuberosum has been caused by anticonvulsive treatment with potassium bromide [3]. Bromism is also characterized by weakness, restlessness, headache, ataxia and personality changes [2].

Iodides Serious and even fatal reactions of anaphylactic type have been caused by radiographic contrast media containing organic iodine [4]. Iodism, nasal congestion and conjunctivitis, often accompanied by an exanthematic eruption, may be associated with a wide variety of systemic symptoms [5,6]. Prolonged administration of small doses of iodide, as in many cough mixtures, may provoke eruptions with or without mucosal or systemic symptoms. Lesions may first develop some days after the drug is discontinued. The following may occur: urticaria, an acneiform rash, papulopustular lesions, nodules, anthracoid or carbuncular lesions, or clear or haemorrhagic bullae on the face, forearms, neck and flexures or on the buccal mucosa [6]. If the iodine is continued, the bullae may be replaced by vegetating masses, which simulate pemphigus vegetans or a granulomatous infection [7]. Iododerma has developed after administration of oral [8] and intravenous [9,10] radiographic contrast media, and during thyroid protection treatment [11]. Iododerma seems more frequent in patients with renal failure, and may be accompanied by leukocytoclastic vasculitis [2]. The eruption recurs within days of readministration in a sensitized individual [12]. Cell-mediated [5] and ‘hyperinflammatory’ [13] mechanisms have been postulated. Vegetating iododerma may be an idiosyncratic response that is commoner in patients with polyarteritis nodosa or paraproteinaemia [14]. Fixed eruptions occur rarely [15]. Generalized pustular psoriasis has been reportedly provoked by potassium iodide [16]. Histology of bromoderma and iododerma In bromoderma, verrucous pseudoepitheliomatous hyperplasia is associated with abscesses containing neutrophils and eosinophils in the epidermis, and with a dense dermal infiltrate initially consisting mainly of neutrophils and eosinophils and later containing many lymphocytes, plasma cells and histiocytes. The abundant dilated blood vessels may show endothelial proliferation. In iododermas, ulceration is more marked, but there is usually less epithelial hyperplasia. Both conditions must be differentiated from blastomycosis and coccidioidomycosis, and from pemphigus vegetans [17]. References 1 Blasik LG, Spencer SK. Fluoroderma. Arch Dermatol 1979; 115: 1334–5. 2 Carney MWP. Five cases of bromism. Lancet 1971; ii: 523–4. 3 Pfeifle J, Grieben U, Bork K. Bromoderma tuberosum durch antikonvulsive Behandlung mit Kaliumbromid. Hautarzt 1992; 43: 792–4. 4 Vaillant L, Pengloan J, Blanchier D et al. Iododerma and acute respiratory distress with leucocytoclastic vasculitis following the intravenous injection of contrast medium. Clin Exp Dermatol 1990; 15: 232–3. 5 Kincaid MC, Green WR, Hoover RE, Farmer ER. Iododerma of the conjunctiva and skin. Ophthalmology 1981; 88: 1216–20. 6 O’Brien TJ. Iodic eruptions. Australas J Dermatol 1987; 28: 119–22. 7 Rosenberg FR, Einbinder J, Walzer RA, Nelson CT. Vegetating iododerma. An immunologic mechanism. Arch Dermatol 1972; 105: 900–5.

Important or widely prescribed drugs 8 Boudoulas O, Siegle RJ, Grinwood RE. Iododerma occurring after orally administered iopanoic acid. Arch Dermatol 1987; 123: 387–8. 9 Heydenreich G, Larsen PO. Iododerma after high dose urography in an oliguric patient. Br J Dermatol 1977; 97: 567–9. 10 Lauret P, Godin M, Bravard P. Vegetating iodides after an intravenous pyelogram. Dermatologica 1985; 71: 463–8. 11 Wilkin JK, Strobel D. Iododerma during thyroid protection treatment. Cutis 1985; 36: 335–7. 12 Jones LE, Pariser H, Murray PF. Recurrent iododerma. Arch Dermatol 1958; 28: 353–8. 13 Stone OJ. Proliferative iododerma: a possible mechanism. Int J Dermatol 1985; 24: 565–6. 14 Soria C, Allegue F, España A et al. Vegetating iododerma with underlying systemic diseases: report of three cases. J Am Acad Dermatol 1990; 22: 418–22. 15 Baker H. Fixed drug eruption due to iodide and antipyrine. Br J Dermatol 1962; 74: 310–6. 16 Shelley WB. Generalized pustular psoriasis induced by potassium iodide. JAMA 1967; 201: 1009–14. 17 Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, et al. eds. Lever’s Histopathology of the Skin, 10th edn. Philadelphia: Lippincott, 2009.

Agents used in general anaesthesia Neuromuscular blocking agents, skeletal muscle relaxants and general anaesthetics The incidence of life-threatening anaphylactic or anaphylactoid reactions during anaesthesia has been variously reported to occur in 1 in 1000 to 1 in 20 000, and minor reactions probably occur in more than 1% of cases; neuromuscular blocking agents are the triggering agents in 50–69% of these reactions, with latex being less frequently incriminated (about 12%) [1–10]. The mortality rate in anaphylactic reactions to drugs used in general anaesthesia is between 4 and 6% [8]. Reactions were most likely with suxamethonium and gallamine, then d-tubocurarine and alcuronium, and least likely with pancuronium and vecuronium [3,6,9]; in another study, succinylcholine and rocuronium were most frequently incriminated [10]. Mucocutaneous manifestations including erythema, urticaria and angio-oedema are reported in up to 80% of reactions, but may only be recognized after the acute phase has passed. Reactions are more frequent in women and in atopic patients. Proposed mechanisms for anaphylactic reactions include type I (IgE antibody-mediated) hypersensitivity [9,11–13], with antibodies persisting for up to 29 years [12], and direct histamine release. Only one reaction in three is likely to be IgE-mediated (type I) anaphylaxis, but non-immune reactions are no less hazardous than type I reactions [9]. Cross-reactivity is widespread with most of the drugs but is least with pancuronium. It has been suggested that pancuronium should be used where muscle relaxation during anaesthesia is essential but sensitivity to another relaxant exists [3], although others have questioned the safety of this procedure [7]. IgE-dependent sensitivity to thiopental may result in anaphylactic reactions [5]. References 1 Fisher MMcD. Intradermal testing in the diagnosis of acute anaphylaxis during anaesthesia: results of five years experience. Anaesth Intensive Care 1979; 7: 58–61. 2 Fisher MMcD. The diagnosis of acute anaphylactoid reactions to neuromuscular blocking agents: a commonly undiagnosed condition. Anaesth Intensive Care 1981; 9: 235–41. 3 Galletly DC, Treuren BC. Anaphylactoid reactions during anaesthesia. Seven years’ experience of intradermal testing. Anaesthesia 1985; 40: 329–33. 4 Leynadier F, Sansarricq M, Didier JM, Dry J. Prick tests in the diagnosis of anaphylaxis to general anaesthetics. Br J Anaesth 1987; 59: 683–9.

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5 Cheema AL, Sussman GL, Jancelewicz Z et al. Update: pentothal-induced anaphylaxis. J Allergy Clin Immunol 1988; 81: 220. 6 Fisher MM, Baldo BA. The incidence and clinical features of anaphylactic reactions during anesthesia in Australia. Ann Fr Anesth Reanim 1993; 12: 97–104. 7 Moneret-Vautrin DA, Laxenaire MC. Anaphylaxis to muscle relaxants: predictive tests. Anaesthesia 1990; 45: 246–7. 8 Moscicki RA, Sockin SM, Corsello BF et al. Anaphylaxis during induction of general anesthesia: subsequent evaluation and management. J Allergy Clin Immunol 1990; 86: 325–32. 9 Watkins J. Adverse reaction to neuromuscular blockers: frequency, investigation, and epidemiology. Acta Anaesthesiol Scand 1994; 102 (Suppl.): 6–10. 10 Laxenaire MC, Mertes PM, Groupe d’Etudes des Reactions Anaphylactoides Peranesthesiques. Anaphylaxis during anaesthesia. Results of a two-year survey in France. Br J Anaesth 2001; 87: 549–58. 11 Baldo BA, Fisher MM. Mechanisms in IgE-dependent anaphylaxis to anesthetic drugs. Ann Fr Anesth Reanim 1993; 12: 131–40. 12 Fisher MM, Baldo BA. Persistence of allergy to anaesthetic drugs. Anaesth Intensive Care 1992; 20: 143–6. 13 Assem ES. Anaphylactoid reactions to neuromuscular blockers: major role of IgE antibodies and possible contribution of IgE-independent mechanisms. Monogr Allergy 1992; 30: 24–53.

Local anaesthetic agents Local anaesthetics may cause both immediate anaphylactic reactions and contact dermatitis [1–10]. In a large series of 236 patients with suspected allergy to local anaesthetics, allergic reactions were not reproduced during prick and intradermal skin testing or challenge with preparations that contained preservatives or preservatives with adrenaline [11]. True allergic reactions caused by local anaesthetics are extremely rare [9,12]; more often, the allergic response is caused by a metabolite, preservative or unrelated substance. Acute anaphylactic reactions are uncommon, but are probably less likely to occur when amide linkage agents are used [4,5]. Necrosis of the fingertip has followed local injection for nail extraction [13]. Dizziness and confusion due to systemic absorption followed repeated application of topical lidocaine (lignocaine) [14]. Severe lidocaine intoxication with progressive neurological and psychiatric abnormalities and cardiorespiratory arrest occurred following topical application to painful ulcerated areas in a patient with cutaneous T-cell lymphoma [15]. Amethocaine (tetracaine). Tetracaine in the form of a selfadhesive patch caused slight or moderate erythema at the site of application in 26% of patients, and slight oedema in 5% [16]. Bupivacaine (Marcain). A delayed hypersensitivity rash may occur after injection of arthroscopy portals with bupivacaine [17]. Prilocaine/lidocaine (EMLA). A eutectic mixture of prilocaine and lidocaine in a cream base (EMLA cream) has been associated with methaemoglobinaemia [18–20]; two metabolites of prilocaine, namely 4-hydroxy-2-methylaniline and 2-methylaniline (o-toluidine), have been incriminated. A 3-month-old infant became cyanosed after application of 5 g, but concomitant sulphonamide therapy may have made a contribution [18]. Small but significant increases in methaemoglobin levels have been reported in children aged 1–6 years following routine administration of 5 g before surgery, and these may persist for at least 24 h [19], so it is recommended that the minimum effective dose be used in children requiring daily application. Blanching following application of EMLA cream is common [21]. Hyperpigmentation is recorded

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[22]. Contact dermatitis can arise to both lidocaine and prilocaine [23–25]. References 1 Schatz M. Skin testing and incremental challenge in the evaluation of adverse reactions of local anesthetics. J Allergy Clin Immunol 1984; 74: 606–16. 2 Fisher MMcD, Graham R. Adverse responses to local anaesthetics. Anaesth Intensive Care 1984; 12: 325–7. 3 Ruzicka T, Gerstmeier M, Przybilla B, Ring J. Allergy to local anesthetics: comparison of patch test with prick and intradermal test results. J Am Acad Dermatol 1987; 16: 1202–8. 4 Christie JL. Fatal consequences of local anesthesia: report of five cases and a review of the literature. J Forensic Sci 1975; 21: 671–9. 5 Haugen RN, Brown CW. Case reports: type I hypersensitivity to lidocaine. J Drugs Dermatol 2007; 6: 1222–3. 6 Glinert RJ, Zachary CB. Local anesthetic allergy. Its recognition and avoidance. J Dermatol Surg Oncol 1991; 17: 491–6. 7 Grognard C. Complications des anesthesiques locaux. Ann Dermatol Vénéréol 1993; 120: 172–4. 8 Skidmore RA, Patterson JD, Tomsick RS. Local anesthetics. Dermatol Surg 1996; 22: 511–22. 9 Gall H, Kaufmann R, Kalveram CM. Adverse reactions to local anesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996; 97: 933–7. 10 Kajimoto Y, Rosenberg ME, Kytta J et al. Anaphylactoid skin reactions after intravenous regional anaesthesia using 0.5% prilocaine with or without preservative: a double-blind study. Acta Anaesthesiol Scand 1995; 39: 782–4. 11 Berkun Y, Ben-Zvi A, Levy Y et al. Evaluation of adverse reactions to local anesthetics: experience with 236 patients. Ann Allergy Asthma Immunol 2003; 91: 342–5. 12 Jackson D, Chen AH, Bennett CR. Identifying true lidocaine allergy. J Am Dent Assoc 1994; 125: 1362–6. 13 Roser-Maass E. Nekrosen an Fingerendgliedern nach Lokalanästhesie bei Nagelextraktion. Hautarzt 1981; 32: 39–41. 14 Goodwin DP, McMeekin TO. A case of lidocaine absorption from topical administration of 40% lidocaine cream. J Am Acad Dermatol 1999; 41: 280–1. 15 Lie RL, Vermeer BJ, Edelbroek PM. Severe lidocaine intoxication by cutaneous absorption. J Am Acad Dermatol 1990; 23: 1026–8. 16 Doyle E, Freeman J, Im NT, Morton NS. An evaluation of a new selfadhesive patch preparation of amethocaine for topical anaesthesia prior to venous cannulation in children. Anaesthesia 1993; 48: 1050–2. 17 Magsamen BF. Delayed hypersensitivity rash to the knee after injection of arthroscopy portals with bupivacaine (Marcain). Arthroscopy 1995; 11: 512–3. 18 Jakobson B, Nilsson A. Methaemoglobinaemia associated with a prilocaine– lidocaine cream and trimethoprim–sulphamethoxazole. A case report. Acta Anaesthesiol Scand 1985; 29: 453–5. 19 Frayling IM, Addison GM, Chattergee K, Meakin G. Methaemoglobinaemia in children treated with prilocaine–lignocaine cream. BMJ 1990; 301: 153–4. 20 Nilsson A, Engberg G, Henneberg S et al. Inverse relationship between agedependent erythrocyte activity of methaemoglobin reductase and prilocaineinduced methaemoglobinaemia during infancy. Br J Anaesth 1990; 64: 72–6. 21 Villada G, Zetlaoui J, Revuz J. Local blanching after epicutaneous application of EMLA cream. Dermatologica 1990; 181: 38–40. 22 Godwin Y, Brotherston M. Hyperpigmentation following the use of EMLA cream. Br J Plast Surg 2001; 54: 82–3. 23 Duggan M, Burns D, Henry M, Mitchell T. Reaction to topical lignocaine in a patient with contact dermatitis. Contact Dermatitis 1993; 28: 190–1. 24 van den Hove J, Decroix J, Tennstedt D, Lachapelle JM. Allergic contact dermatitis from prilocaine, one of the local anaesthetics in EMLA cream. Contact Dermatitis 1994; 30: 239. 25 Thakur BK, Murali MR. EMLA cream-induced allergic contact dermatitis: a role for prilocaine as an immunogen. J Allergy Clin Immunol 1995; 95: 776–8.

Infusions and injections Intravenous infusion Pain, oedema, induration and thrombophlebitis are wellrecognized complications [1–4]. Localized bullous eruptions

following infusion of commonly used non-vesicant fluids, such as saline, have been described [5]. Extravasation was reported to occur in 11% of 16 380 administrations to children monitored over a 6month period [6]. Skin necrosis following intravenous infusion of chemotherapeutic agents occurs in up to 6% of patients [1,3,5–9]. References 1 Barton A. Adverse reactions to intravenous catheters and other devices. Lancet 1993; 342: 683. 2 Dufresne RG. Skin necrosis from intravenously infused materials. Cutis 1987; 39: 197–8. 3 MacCara E. Extravasation: a hazard of intravenous therapy. Drug Intel Clin Phar 1987; 17: 713–7. 4 Rudolph R, Larson DL. Etiology and treatment of chemotherapeutic agent extravasation injuries. A review. J Clin Oncol 1987; 5: 1116–26. 5 Robijns BJL, de Wit WM, Bosma NJ, van Vloten WA. Localized bullous eruptions caused by extravasation of commonly used intravenous infusion fluids. Dermatologica 1991; 182: 39–42. 6 Brown AS, Hoelzer DJ, Piercy SA. Skin necrosis from extravasation of intravenous fluids in children. Plast Reconstr Surg 1979; 64: 145–50. 7 Ignoffo RJ, Friedman MA. Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7: 17–27. 8 Harwood KV, Aisner J. Treatment of chemotherapeutic extravasation: current status. Cancer Treat Rep 1984; 68: 939–45. 9 Banerjee A, Brotherston TM, Lamberty BGH et al. Cancer chemotherapy agentinduced perivenous extravasation injury. J Postgrad Med 1987; 63: 5–9.

Blood transfusion Urticaria occurs in about 1% of transfusions [1], and may be the result of allergy to soluble proteins in donor plasma. Posttransfusion purpura may rarely occur as a result of profound thrombocytopenia about 1 week after transfusion, and is associated with antiplatelet alloantibodies. Other potential side effects include transmission of infectious diseases, including syphilis, hepatitis B and HIV-related syndromes (AIDS). Graft-versus-host disease may develop following transfusion of unirradiated blood in immunosuppressed patients [2–8], including those with malignancies [2], and infants with severe congenital immunodeficiency [3]. Isolated reports of fatal transfusionassociated graft-versus-host disease in presumed immunocompetent hosts receiving fresh unirradiated blood have been reported [9–11]. This paradoxical situation may be partly explained by situations in which recipients heterozygous for a given MHC haplotype receive a transfusion from a donor homozygous for this haplotype, as the recipient would not react to the donor haplotype but the donor lymphocytes would react to the non-identical recipient haplotype [8]. Thus, some recipients of non-irradiated blood from their offspring may be at risk of developing graft-versus-host disease. An acute fatal illness, characterized by fever, diffuse erythematous rash and progressive leukopenia, has been described in Japanese patients 10 days after surgical operation and has been termed ‘postoperative erythroderma’ [12]. Histologically, scattered single cell epidermal cell eosinophilic necrosis, satellite cell necrosis, basal cell liquefaction degeneration and a scanty dermal infiltrate may be seen; the reaction is compatible with an acute graft-versus-host reaction following blood transfusion [12]. References 1 Shulman IA. Adverse reactions to blood transfusion. Texas Med 1990; 85: 35–42.

Important or widely prescribed drugs 2 Decoste SD, Boudreaux C, Dover JS. Transfusion-associated graft-vs-host disease in patients with malignancies. Report of two cases and review of the literature. Arch Dermatol 1990; 126: 1324–9. 3 Hathaway WE, Githens JH, Blackburn WR et al. Aplastic anemia, histiocytosis and erythrodermia in immunologically deficient children. N Engl J Med 1965; 273: 953–8. 4 Brubaker DB. Human posttransfusion graft-versus-host disease. Vox Sang 1983; 45: 401–20. 5 Leitman SF, Holland PV. Irradiation of blood products: indications and guidelines. Transfusion 1985; 25: 292–300. 6 Anderson KC, Weinstein HJ. Transfusion-associated graft-versus-host disease. N Engl J Med 1990; 323: 315–21. 7 Ray TL. Blood transfusions and graft-vs-host disease. Arch Dermatol 1990; 126: 1347–50. 8 Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991; 324: 667–74. 9 Arsura EL, Bertelle A, Minkowitz S et al. Transfusion-associated graft-vs-host disease in a presumed immunocompetent patient. Arch Intern Med 1988; 148: 1941–4. 10 Capond SM, DePond WD, Tyan DB et al. Transfusion-associated graftversus-host disease in an immunocompetent patient. Ann Intern Med 1991; 114: 1025–6. 11 Juji T, Takahashi K, Shibata Y et al. Post-transfusion graft-versus-host disease in immunocompetent patients after cardiac surgery in Japan. N Engl J Med 1989; 321: 56. 12 Hidano A, Yamashita N, Mizuguchi M, Toyoda H. Clinical, histological, and immunohistological studies of postoperative erythroderma. J Dermatol 1989; 16: 20–30.

Hydroxyethyl starch Hydroxyethyl starch (hetastarch) is used as a plasma expander for hypovolaemia, to prime cardiopulmonary bypass machines, as a sedimenting agent to increase the yield of granulocytes during leukapheresis and to improve microcirculation as in the treatment of sudden deafness. It has been implicated in the development of lichen planus [1], and severe generalized pruritus in up to 32% of recipients, beginning 2 weeks after exposure and taking up to 2 years to settle [2–6]. References 1 Bode U, Deisseroth AB. Donor toxicity in granulocyte collections: association of lichen planus with the use of hydroxyethyl starch leukapheresis. Transfusion 1981; 21: 83–5. 2 Parker NE, Porter JB, Williams HJM, Leftley N. Pruritus after administration of hetastarch. BMJ 1982; 284: 385–6. 3 Gall H, Kaufmann R, von Ehr M et al. Persistierender Pruritus nach Hydroxyathylstarke-Infusionen. Retrospektive Langzeitstudie an 266 Fallen. Hautarzt 1993; 44: 713–6. 4 Cox NH, Popple AW. Persistent erythema and pruritus, with a confluent histiocytic skin infiltrate, following the use of a hydroxyethylstarch plasma expander. Br J Dermatol 1996; 134: 353–7. 5 Speight EL, MacSween RM, Stevens A. Persistent itching due to etherified starch plasma expander. BMJ 1997; 314: 1466–7. 6 Murphy M, Carmichael AJ, Lawler PG et al. The incidence of hydroxyethyl starchassociated pruritus. Br J Dermatol 2001; 144: 973–6.

Fluorescein A psoriasiform eruption followed parenteral administration for fluorescein angiography [1]. Reference 1 Mayama M, Hirayama K, Nakano H et al. Psoriasiform drug eruption induced by fluorescein sodium used for fluorescein angiography. Br J Dermatol 1999; 140: 982–4.

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Renal dialysis Dermatological complications of renal dialysis have been reviewed [1,2]. These include marked premature ageing, hyperpigmentation, xeroderma, decreased sebaceous and sweat gland secretion, Raynaud’s syndrome, generalized pruritus and carpal tunnel syndrome due to amyloid β deposition [1]. Extravasation, phlebitis and bacterial infection of the cannula, with resulting septicaemia, may occur and are related to the site of insertion of the cannula into the arteriovenous fistula. A bullous dermatosis of haemodialysis has been described [2,3]. This resembles porphyria clinically and histologically, and porphyrins may be elevated [3], although cases with pseudoporphyria in which there are no abnormalities of porphyrin metabolism have also been documented [2]. Twothirds of patients with dialysis-associated anaphylaxis have IgE antibodies to ethylene oxide/human serum albumin [4]. Allergic contact dermatitis due to rubber chemicals in the haemodialysis equipment may be seen around the arteriovenous shunt [5]. Porokeratosis localized to the access region for haemodialysis has also been reported [6]. References 1 Altmeyer P, Kachel H-G, Jünger M et al. Hautveränderungen bei Langzeitdialysepatienten. Hautarzt 1982; 33: 303–9. 2 Gupta AK, Gupta MA, Cardella CJ, Haberman HF. Cutaneous complications of chronic renal failure and dialysis. Int J Dermatol 1986; 25: 498–504. 3 Poh-Fitzpatrick MB, Bellet N, DeLeo VA et al. Porphyria cutanea tarda in two patients treated with hemodialysis for chronic renal failure. N Engl J Med 1978; 299: 292–4. 4 Grammer LC, Roberts M, Wiggins CA et al. A comparison of cutaneous testing and ELISA testing for assessing reactivity to ethylene oxide–human serum albumin in hemodialysis patients with anaphylactic reactions. J Allergy Clin Immunol 1991; 87: 674–6. 5 Kruis-De Vries M, Coenraads P, Nater J. Allergic contact dermatitis due to rubber chemicals in haemodialysis equipment. Contact Dermatitis 1987; 17: 303–5. 6 Nakazawa A, Matsuo I, Ohkido M. Porokeratosis localized to the access region for hemodialysis. J Am Acad Dermatol 1991; 25: 338–40.

Necrosis from intramuscular injections Severe painful local necrosis at the site of an injected medicament (embolia cutis medicamentosa; also known as Nicolau’s syndrome) may follow intramuscular therapeutic injections and was originally described with bismuth. It occurs particularly with preparations containing corticosteroids, local anaesthetics, antirheumatic drugs and antihistamines; more rarely, chlorpromazine, penicillin, phenobarbital and sulphonamides have been implicated [1,2]. The condition has also followed sclerotherapy [3]. Clinically, stellate erythema and infiltration are followed by central deep necrosis that heals with scarring. References 1 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: Saunders, 1988. 2 Faucher L, Marcoux D. What syndrome is this? Nicolau syndrome. Pediatr Dermatol 1995; 12: 187–90. 3 Geukens J, Rabe E, Bieber T. Embolia cutis medicamentosa of the foot after sclerotherapy. Eur J Dermatol 1999; 9: 132–3.

Glatiramer acetate This drug administered for the treatment of relapsing-remitting multiple sclerosis caused lobular panniculitis at the site of injection [1].

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Polidocanol The sclerosing solution polidocanol is said to cause allergic reactions in up to 0.06% of cases; systemic allergic reactions may be more common than previously recognized [2].

Glibenclamide. Bullae and cholestasis have occurred together [14].

References 1 Ball NJ, Cowan BJ, Moore GR, Hashimoto SA. Lobular panniculitis at the site of glatiramer acetate injections for the treatment of relapsing-remitting multiple sclerosis. A report of two cases. J Cutan Pathol 2008; 35: 407–10. 2 Feied CF, Jackson JJ, Bren TS et al. Allergic reactions to polidocanol for vein sclerosis. Two case reports. J Dermatol Surg Oncol 1994; 20: 466–8.

Glyburide. A generalized lichenoid dermatitis has been reported [16].

Soft tissue fillers Continuing pain, erythema, swelling, nodules, pigmentation and abscess formation have been reported [1]. Cutaneous reactions may occur at sites distant from injected sites, due to secondary migration of the filler substance. A lapse of months to years may occur prior to the development of a cutaneous reaction [2]. Granulomatous reactions to injectable hyaluronic acid gel have been documented [3]. References 1 Zielke H, Wölber L, Wiest L, Rzany B. Risk profiles of different injectable fillers: results from the Injectable Filler Safety Study (IFS Study). Dermatol Surg 2008; 34: 326–35. 2 Dadzie OE, Mahalingam M, Parada M et al. Adverse cutaneous reactions to soft tissue fillers—a review of the histological features. J Cutan Pathol 2008; 35: 536–48. 3 Ghislanzoni M, Bianchi F, Barbareschi M, Alessi E. Cutaneous granulomatous reaction to injectable hyaluronic acid gel. Br J Dermatol 2006; 154: 755–8.

Drugs affecting metabolism or gastrointestinal function Hypoglycaemic drugs Dermatological aspects of the oral hypoglycaemic drugs have been reviewed [1–4].

Biguanides Rashes are much less frequent with metformin and phenformin than with sulphonylureas. Transient erythemas, pruritus and urticaria have been noted. Sulphonylureas Chlorpropamide and tolbutamide are most often prescribed, and both can give rise to toxic or allergic reactions. Angio-oedema with glibornuride, urticaria with glibenclamide and a bullous dermatitis with carbutamide have been described [5]; there was no crossreactivity between first- and second-generation sulphonylureas. Chlorpropamide. Eruptions occur in 2–3% of patients on chlorpropamide [2]. These include maculopapular rashes, photosensitivity [6], erythema annulare, Stevens–Johnson syndrome [7], erythema nodosum [1], lichenoid eruptions [8,9], purpura and exfoliative dermatitis [10]. Porphyria has been provoked [11]. A disulfiram-like effect, with flushing of the face, headache and palpitations after taking alcohol, occurs in up to 30% of patients [12,13]. The fact that the flush is blocked by naloxone suggests that opioids may be involved in the response.

Glipizide. Pigmented purpuric eruption is documented [15].

References 1 Beurey J, Jeandidier P, Bermont A. Les complications dermatologiques des traitements antidiabétiques. Ann Dermatol Syphiligr 1966; 93: 13–42. 2 Almeyda J, Baker H. Drug reactions. X. Adverse cutaneous reactions to hypoglycaemic agents. Br J Dermatol 1970; 82: 634–6. 3 Harris EL. Adverse reactions to oral antidiabetic agents. BMJ 1971; 3: 29–30. 4 Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994; 30: 519–31. 5 Chichmanian RM, Papasseudi G, Hieronimus S et al. Allergies aux sulfonylurees hypoglycemiantes. Les reactions croisées existent-elles? Thérapie 1991; 46: 163–7. 6 Hitselberger JF, Fosnaugh RP. Photosensitivity due to chlorpropamide. JAMA 1962; 180: 62–3. 7 Yaffee HS. Stevens–Johnson syndrome caused by chlorpropamide: report of a case. Arch Dermatol 1960; 82: 636–7. 8 Dinsdale RCW, Ormerod TP, Walker AE. Lichenoid eruption due to chlorpropamide. BMJ 1968; i: 100. 9 Barnett JH, Barnett SM. Lichenoid drug reactions to chlorpropamide and tolazamide. Cutis 1984; 34: 542–4. 10 Rothfeld EL, Goldman J, Goldberg HH, Einhorn S. Severe chlorpropamide toxicity. JAMA 1960; 172: 54–6. 11 Zarowitz H, Newhouse S. Coproporphyrinuria with a cutaneous reaction induced by chlorpropamide. NY State J Med 1965; 65: 2385–7. 12 Stakosch CR, Jefferys DB, Keen H. Blockade of chlorpropamide alcohol flush by aspirin. Lancet 1980; i: 394–6. 13 Medback S, Wass JAH, Clement-Jones V et al. Chlorpropamide alcohol flush and circulating met-enkephalin: a positive link. BMJ 1981; 283: 937–9. 14 Wongpaitoon V, Mills PR, Russell RI, Patrick RS. Intra-hepatic cholestasis and cutaneous bullae associated with glibenclamide therapy. Postgrad Med J 1981; 57: 244–6. 15 Adams BB, Gadenne AS. Glipizide-induced pigmented purpuric dermatosis. J Am Acad Dermatol 1999; 41: 827–9. 16 Fox GN, Harrell CC, Mehregan DR. Extensive lichenoid drug eruption due to glyburide: a case report and review of the literature. Cutis 2005; 76: 41–5.

Lipid-lowering drugs Acipimox This nicotinic acid analogue causes less prostaglandin-mediated flushing and itching than nicotinic acid [1].

Clofibrate Erythema multiforme and a variety of other erythematous rashes have been described [2]. Gemfibrozil This lipid-lowering drug, which mainly lowers triglycerides, has been associated with exacerbation of psoriasis [3,4]. Statins The lipid-lowering drugs lovastatin, simvastatin and pravastatin can cause eczema [4,5]; these drugs block an early step in cholesterol biosynthesis by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin has caused a lichenoid eruption with skin and mucosal involvement

Important or widely prescribed drugs

[6,7], and chronic actinic dermatitis [8]. Pravastatin has also been associated with a lichenoid rash [9]. Atorvastatin has caused linear IgA bullous dermatosis [10] and TEN [11]. A recent review documented 28 cases of autoimmune disease linked to therapy with statins [12]; systemic lupus erythematosus in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and one case of lichen planus pemphigoides. The mean time of exposure before disease onset was 12.8 ± 18 months; range 1 month–6 years. The majority of cases required systemic immunosuppressive therapy; there were nonetheless two fatalities. Antinuclear antibodies were still positive many months after clinical recovery in some patients.

Triparanol and diazacholesterol These drugs inhibit a late step in cholesterol biosynthesis (Δ24 sterol reductase) and can induce ichthyosis or palmoplantar hyperkeratosis [4]. References 1 Anonymous. Acipimox: a nicotinic acid analogue for hyperlipidaemia. Drug Ther Bull 1991; 29: 57–9. 2 Murata Y, Tani M, Amano M. Erythema multiforme due to clofibrate. J Am Acad Dermatol 1988; 18: 381–2. 3 Fisher DA, Elias PM, LeBoit PL. Exacerbation of psoriasis by the hypolipidemic agent, gemfibrozil. Arch Dermatol 1988; 124: 854–5. 4 Proksch E. Lipidsenker-induzierte Nebenwirkungen an der Haut. Hautarzt 1995; 46: 76–80. 5 Krasovec M, Elsner P, Burg G. Generalized eczematous skin rash possibly due to HMG-CoA reductase inhibitors. Dermatology 1993; 186: 248–52. 6 Feldmann R, Mainetti C, Saurat JH. Skin lesions due to treatment with simvastatin (Zocor). Dermatology 1993; 186: 272. 7 Roger D, Rolle F, Labrousse F et al. Simvastatin-induced lichenoid drug eruption. Clin Exp Dermatol 1994; 19: 88–9. 8 Granados MT, de la Torre C, Cruces MJ, Pineiro G. Chronic actinic dermatitis due to simvastatin. Contact Dermatitis 1998; 38: 294–5. 9 Keough GC, Richardson TT, Grabski WJ. Pravastatin-induced lichenoid drug eruption. Cutis 1998; 61: 98–100. 10 Konig C, Eickert A, Scharfetter-Kochanek K et al. Linear IgA bullous dermatosis induced by atorvastatin. J Am Acad Dermatol 2001; 44: 689–92. 11 Pfeiffer CM, Kazenoff S, Rothberg HD. Toxic epidermal necrolysis from atorvastatin. JAMA 1998; 279: 1613–4. 12 Noël B. Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review. J Eur Acad Dermatol Venereol 2007; 21: 17–24.

Drugs for gastrointestinal ulceration Proton pump inhibitors Esomeprazole. dress syndrome is recorded [1]. Lansoprazole. Anaphylactic reactions have been documented [2]. Omeprazole. This proton pump inhibitor, a substituted benzimidazole, has gained widespread use in the treatment of gastric and duodenal ulceration and reflux oesophagitis. Adverse events with the drug are rare and involve mainly the gastrointestinal and central nervous systems, with diarrhoea, headache and dizziness, and confusion in the elderly, moderate elevation of aminotransferases and possible leukopenia [1,3,4]. The prevalence of cutaneous reactions to omeprazole is approximately 0.5–1.5% [3–6]. A variety of eruptions are recorded, including angio-oedema and urticaria [6,7], anaphylaxis [8,9], maculopapular rashes, hyperpig-

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mentation mimicking ashy dermatosis [10], lichen planus [11,12], pityriasiform eruption [13], erythema multiforme and erythroderma [14], exfoliative dermatitis [15,16], bullous eruption [17], vasculitis [18] and photosensitivity. Gynaecomastia is recorded [19].

Tripotassium dicitratobismuthate (De-Nol) The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has received several reports of skin reactions, on average 2 days after starting treatment, including maculopapular exanthema, angio-oedema and erythema [20]. Bismuth subsalicylate (PeptoBismol) Black granules at follicular orifices have been reported [21]. Blue linear pigmentation of the soft palate, oral mucosa and vagina, ulcerative stomatitis, generalized pigmentation, dermatitis and erythroderma are recorded. References 1 Caboni S, Gunera-Saad N, Ktiouet-Abassi S et al. Esomeprazole-induced DRESS syndrome. Studies of cross-reactivity among proton-pump inhibitor drugs. Allergy 2007; 62: 1342–3. 2 Demirkan K, Bozkurt B, Karakaya G, Kalyoncu AF. Anaphylactic reaction to drugs commonly used for gastrointestinal system diseases: 3 case reports and review of the literature. J Investig Allergol Clin Immunol 2006; 16: 203–9. 3 McTavish D, Buckley MM, Heel RC. Omeprazole: an update review of its pharmacology and therapeutic use in acid related disorders. Drugs 1991; 42: 138–70. 4 Castot A, Bidault I, Dahan R, Efthymiou ML. Bilan des effects inattendus et toxiques de l’omeprazole (Mopral) rapportés aux centres regionaux de pharmacovigilance, au cours des 22 premiers mois de commercialisation. Thérapie 1993; 48: 469–74. 5 Yeomans ND. Omeprazole: short- and long-term safety. Adverse Drug React Acute Toxicol Rev 1994; 13: 145–56. 6 Bowlby HA, Dickens GR. Angioedema and urticaria associated with omeprazole confirmed by drug rechallenge. Pharmacotherapy 1994; 14: 119–22. 7 Haeney MR. Angio-oedema and urticaria associated with omeprazole. BMJ 1992; 305: 870. 8 Ottervanger JP, Phaff RA, Vermeulen EG, Stricker BH. Anaphylaxis to omeprazole. J Allergy Clin Immunol 1996; 97: 1413–4. 9 González P, Soriano V, López P, Niveiro E. Anaphylaxis to proton pump inhibitors. Allergol Immunopathol (Madr) 2002; 30: 342–3. 10 Ramírez-Hernández M, Martínez-Escribano JA, Martínez-Barba E et al. Cutaneous hyperpigmentation induced by omeprazole mimicking ashy dermatosis. J Eur Acad Dermatol Venereol 2006; 20: 584–7. 11 Sharma BK, Walt RP, Pounder RE et al. Optimal dose of oral omeprazole for maximal 24 hour decrease of intragastric acidity. Gut 1984; 25: 957–64. 12 Bong JL, Lucke TW, Douglas WS. Lichenoid drug eruption with proton pump inhibitors. BMJ 2000; 320: 283. 13 Buckley C. Pityriasis rosea-like eruption in a patient receiving omeprazole. Br J Dermatol 1996; 135: 660–1. 14 Cockayne SE, Glet RJ, Gawkrodger DJ, McDonagh AJ. Severe erythrodermic reactions to the proton pump inhibitors omeprazole and lansoprazole. Br J Dermatol 1999; 141: 173–5. 15 Epelde Gonzalo FD, Boada Montagut L, Thomas Vecina S. Exfoliative dermatitis related to omeprazole. Ann Pharmacother 1995; 29: 82–3. 16 Borrás-Blasco J, Navarro-Ruiz A, Navarro-Blasco F et al. Erythrodermia induced by omeprazole. Int J Clin Pharmacol Ther 2001; 39: 219–23. 17 Stenier C, Fiasse R, Bourlond J et al. Bullous skin reaction induced by omeprazole. Br J Dermatol 1995; 133: 343–4. 18 Odeh M, Lurie M, Oliven A. Cutaneous leucocytoclastic vasculitis associated with omeprazole. Postgrad Med J 2002; 78: 114–5. 19 Lindquist M, Edwards IR. Endocrine effects of omeprazole. BMJ 1992; 305: 451–2.

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20 Ottervanger JP, Stricker BH. Huidafwijkingen door bismutoxide (De-Nol). Ned Tijdschr Geneeskd 1994; 138: 152–3. 21 Ruiz-Maldonado R, Contreras-Ruiz J, Sierra-Santoyo A et al. Black granules on the skin after bismuth subsalicylate ingestion. J Am Acad Dermatol 1997; 37: 489–90.

Laxatives Side effects of laxatives have been reviewed [1].

Dantron (danthron) A highly characteristic irritant erythema of the buttocks and thighs has been observed in patients who are partially incontinent. The erythema results from skin soiling by faecal matter containing an anthralin (dithranol)-like breakdown product [2]. Phenolphthalein Fixed eruptions are well known [3–5]. Bullous erythema multiforme and an LE-like reaction are documented. References 1 Ruoff H-J. Unerwünschte Wirkungen und Wechselwirkungen von Abführmitteln. Med Klin 1980; 75: 214–8. 2 Barth JH, Reshad H, Darley CR, Gibson JRA. A cutaneous complication of Dorbanex therapy. Clin Exp Dermatol 1984; 9: 95–6. 3 Shelley WB, Schlappner OL, Heiss HB. Demonstration of intercellular immunofluorescence and epidermal hysteresis in bullous fixed drug eruption due to phenolphthalein. Br J Dermatol 1972; 6: 118–25. 4 Wyatt E, Greaves M, Sondergaard J. Fixed drug eruption (phenolphthalein). Evidence for a blood-borne mediator. Arch Dermatol 1972; 106: 671–3. 5 Zanolli MD, McAlvany J, Krowchuk DP. Phenolphthalein-induced fixed drug eruption: a cutaneous complication of laxative use in a child. Pediatrics 1993; 91: 1199–201.

Miscellaneous drugs Food and drug additives Dermatological complications of food and drug additives have been reviewed [1–14]. These substances have been implicated in the causation of urticaria [4–7], anaphylaxis, purpura and vasculitis [8–12]. However, one study suggested that common food additives are seldom if ever of significance in urticaria [11]. In another study, only 0.63% of food additive provocation tests resulted in exacerbation in 1110 patients with urticaria; tests were again not positive on re-provocation [13]. The prevalence of adverse reactions to food additives is estimated to be 0.03–0.23% [15]. The necessity for double-blind, placebo-controlled testing to substantiate alleged food additive allergy has been emphasized [16]. Information about excipients (‘inert ingredients’) has been reported in a study that examined the sweeteners, flavourings, dyes and preservatives present in chewable and liquid preparations of 102 over-the-counter and prescription brands of antidiarrhoeal, cough and cold, antihistamine/decongestant, analgesic/ antipyretic and liquid theophylline medications [17]. An average preparation contained two sweeteners, primarily saccharin and sucrose, followed by sorbitol, glucose, fructose and others. The type of flavouring was not specified in 36 of the 102 preparations; cherry was the most common flavouring, followed by vanilla and lemon. Twenty-one different dyes and colouring agents were used; red dye no. 40 was the most common, followed by yellow no. 6.

Sodium benzoate and methylparabens were the commonest of eight preservatives used. Mandatory labelling of excipients in all pharmaceutical preparations is the only way that physicians and patients can be fully informed [17]. It is important to appreciate that peanut oil, to which patients may be strongly allergic, is found in certain medications [18]. Caffeine in coffee and cola beverages caused urticaria in a 10-year-old child, confirmed by prick test and oral challenge test with caffeine [19]. References 1 Levantine AJ, Almeyda J. Cutaneous reactions to food and drug additives. Br J Dermatol 1977; 91: 359–62. 2 Simon RA. Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623–30. 3 Ruzicka T. Diagnostik von Nahrungsmittelallergien. Hautarzt 1987; 38: 10–5. 4 Juhlin LG, Michäelsson G, Zetterström O. Urticaria and asthma induced by food-and-drug additives in patients with aspirin hypersensitivity. J Allergy 1972; 50: 92–8. 5 Doeglas HMG. Reactions to aspirin and food additives in patients with chronic urticaria, including the physical urticarias. Br J Dermatol 1975; 93: 135–44. 6 Supramaniam G, Warner JO. Artificial food additive intolerance in patients with angio-oedema and urticaria. Lancet 1986; ii: 907–9. 7 Juhlin L. Additives and chronic urticaria. Ann Allergy 1987; 59: 119–23. 8 Michäelsson G, Petterson L, Juhlin L. Purpura caused by food and drug additives. Arch Dermatol 1974; 109: 49–52. 9 Kubba R, Champion RI. Anaphylactoid purpura caused by tartrazine and benzoates. Br J Dermatol 1975; 93 (Suppl. 2): 61–2. 10 Eisenmann A, Ring J, von der Helm D et al. Vasculitis allergica durch Nahrungsmittelallergie. Hautarzt 1988; 39: 319–21. 11 Veien NK, Krogdahl A. Cutaneous vasculitis induced by food additives. Acta Derm Venereol (Stockh) 1991; 71: 73–4. 12 Lowry MD, Hudson CF, Callen FP. Leukocytoclastic vasculitis caused by drug additives. J Am Acad Dermatol 1994; 30: 854–5. 13 Hernandez Garcia J, Garcia Selles J, Negro Alvarez JM et al. Incidencias de reacciones adversas con aditivos. Nuestra experiencia de 10 anos. Allergol Immunopathol 1994; 22: 233–42. 14 Barbaud A. Place of excipients in drug-related allergy. Clin Rev Allergy Immunol 1995; 13: 253–63. 15 Wuthrich B. Adverse reactions to food additives. Ann Allergy 1993; 71: 379–84. 16 Goodman DL, McDonnell JT, Nelson HS et al. Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). J Allergy Clin Immunol 1990; 86: 570–5. 17 Kumar A, Rawlings RD, Beaman DC. The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/ decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations. Pediatrics 1993; 91: 927–33. 18 Weeks R. Peanut oil in medications. Lancet 1996; 348: 759–60. 19 Caballero T, Garcia-Ara C, Pascual C et al. Urticaria induced by caffeine. J Invest Allergol Clin Immunol 1993; 3: 160–2.

Colouring agents Colourings in food and medications (including some antihistamines), such as tartrazine, sunset yellow and other azo dyes, have been reported to cause adverse reactions [1,2], including urticaria [3,4] or vasculitis [5,6]. References 1 Vandelle C, Belegaud D, Bidault I, Castol A. Allergie aux colorants des medicaments. Confrontation des cas publiés et de l’experience du Centre Regional de Pharmacovigilance. Thérapie 1993; 48: 484–5. 2 Gracey-Whitman L, Ell S. Artificial colourings and adverse reactions. BMJ 1995; 311: 1204. 3 Neuman I, Elian R, Nahum H et al. The danger of ‘yellow dyes’ (tartrazine) to allergic subjects. J Allergy 1972; 50: 92–8.

Important or widely prescribed drugs 4 Miller K. Sensitivity to tartrazine. BMJ 1982; 285: 1597–8. 5 Lowry MD, Hudson CF, Callen FP. Leukocytoclastic vasculitis caused by drug additives. J Am Acad Dermatol 1994; 30: 854–5. 6 Wuthrich B. Adverse reactions to food additives. Ann Allergy 1993; 71: 379–84.

Flavouring agents Aspartame. Aspartame, a synthetic dipeptide composed of aspartic acid and the methyl ester of phenylalanine and used under the trade name of NutraSweet (G.D. Searle & Co., Skokie, Illinois, USA) as a low-calorie artificial sweetener, has been associated with relatively few adverse side effects despite its widespread use [1]. Cutaneous side effects reported include urticaria, angiooedema and other non-descript ‘rashes’ [2], granulomatous septal panniculitis [3] and lobular panniculitis [4]. However, in a recent study of patients with a history of aspartame sensitivity, it was not possible to identify any subject with a clearly reproducible adverse reaction [5]. Similarly, a multicentre, placebo-controlled, challenge study showed that aspartame and its conversion products are no more likely than placebo to cause urticaria and/or angio-oedema reactions in subjects with a history consistent with hypersensitivity to aspartame [6]. Cyclamates. Cyclamates, used as sweeteners in soft drinks, have caused photosensitivity [7]. Quinine. Quinine in tonic water and other bitter drinks may cause fixed eruptions [8]. References 1 US Food and Drug Administration. Food additives permitted for direct addition to food for human consumption: aspartame. Federal Register 1983; 48: 31376–82. 2 Kulczycki A Jr. Aspartame-induced urticaria. Ann Intern Med 1986; 104: 207–8. 3 Novick NL. Aspartame-induced granulomatous panniculitis. Ann Intern Med 1985; 102: 206–7. 4 McCauliffe DP, Poitras K. Aspartame-induced lobular panniculitis. J Am Acad Dermatol 1991; 24: 298–300. 5 Garriga MM, Berkebile C, Metcalfe DD. A combined single-blind, double-blind, placebo-controlled study to determine the reproducibility of hypersensitivity reactions to aspartame. J Allergy Clin Immunol 1991; 87: 821–7. 6 Geha R, Buckley CE, Greenberger P et al. Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebo-controlled, crossover study. J Allergy Clin Immunol 1993; 92: 513–20. 7 Lambert SI. A new photosensitizer. The artificial sweetener cyclamate. JAMA 1967; 201: 747–50. 8 Commens C. Fixed drug eruption. Aust J Dermatol 1983; 24: 1–8.

Preservatives The antioxidant food preservatives butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) have been reported to exacerbate chronic urticaria [1]. Sodium benzoate has been associated with urticaria, angio-oedema, asthma and, rarely, anaphylaxis [2]. Parabens used as preservatives may also cause urticaria [3]. Sulphiting agents are commonly used in parenteral emergency drugs, including epinephrine (adrenaline), dexamethasone, dobutamine, dopamine, norepinephrine (noradrenaline), phenylephrine, procainamide and physostigmine [4]. Published anaphylactic or asthmatic reactions have been associated with sulphited local anaesthetics, gentamicin, metoclopramide, doxycycline and

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vitamin B complex. The reactions have a rapid onset and do not always coincide with a positive oral challenge, although patients with a history of positive oral challenge to 5–10 mg of sulphite may be at increased risk of developing a reaction to parenteral sulphites. Sulphites added as antioxidant preservatives may provoke urticaria, asthma, anaphylaxis and shock [4–10], as well as urticarial vasculitis [11]. Intolerance due to metabisulphite as an antioxidant in a dental anaesthetic has led to angio-oedema; patch tests were positive [12]. Basophil activation induced by sulphites may be IgE dependent [13]. It has been claimed that there is a high specificity of patch testing in the diagnosis of patients with sulphite sensitivity [14]. References 1 Goodman DL, McDonnell JT, Nelson HS et al. Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). J Allergy Clin Immunol 1990; 86: 570–5. 2 Michils A, Vandermoten G, Duchateau J, Yernault J-C. Anaphylaxis with sodium benzoate. Lancet 1991; 337: 1424–5. 3 Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy. JAMA 1977; 237: 1594–5. 4 Smolinske SC. Review of parenteral sulfite reactions. J Toxicol Clin Toxicol 1992; 30: 597–606. 5 Habenicht HA, Preuss L, Lovell RG. Sensitivity to ingested metabisulfites: cause of bronchospasm and urticaria. Immunol Allergy Pract 1983; 5: 243–5. 6 Settipane GA. Adverse reactions to sulfites in drugs and foods. J Am Acad Dermatol 1984; 10: 1077–80. 7 Belchi-Hernandez J, Florido-Lopez JF, Estrada-Rodriguez JL et al. Sulfite-induced urticaria. Ann Allergy 1993; 71: 230–2. 8 Twarog FJ, Leung DYM. Anaphylaxis to a component of isoetharine (sodium bisulfite). JAMA 1982; 248: 2030–1. 9 Przybilla B, Ring J. Sulfit-Überempfindlichkeit. Hautarzt 1987; 38: 445–8. 10 Hassoun S, Bonneau JC, Drouet M, Sabbah A. Enquete sur pathologies induites par les sulfites en allergologie. Allerg Immunol 1994; 26: 184, 187–8. 11 Wuthrich B. Adverse reactions to food additives. Ann Allergy 1993; 71: 379– 84. 12 Dooms-Goosens A, Gidi de Alan A, Degreef H, Kochuyt A. Local anaesthetic intolerance due to metabisulfite. Contact Dermatitis 1989; 20: 124–6. 13 Sainte-Laudy J, Vallon C, Guerin JC. Mise en evidence des IgE specifiques du groupe des sulfites chez les intolerants à ces conservateurs. Allerg Immunol 1994; 26: 132–4, 137–8. 14 Gay G, Sabbah A, Drouet M. Valeur diagnostique de l’epidermotest aux sulfites. Allerg Immunol 1994; 26: 139–40.

Miscellaneous food additives Agricultural or veterinary chemicals may leave residues in animals and plants used as human food, for example penicillin in milk or meat, with resultant urticaria [1,2]. The exposure of a rural Turkish population to flour contaminated with hexachlorobenzene induced an outbreak of cutaneous porphyria [3]. Contaminated rapeseed cooking oil containing acetanilide resulted in the Spanish ‘toxic oil syndrome’; the central feature of the illness was a toxic pneumonitis, but fixed rashes and scleroderma-like changes in survivors were seen [4–6]. Outbreaks of atypical erythema multiforme and other exanthems in the Netherlands were attributed to an additive in margarine [7,8]. The high arsenic content of a rural water supply in Taiwan caused arsenicism [9]. Chemicals added to tobacco, for example menthol in cigarettes, have caused urticaria [10]. NNitroso compounds, which are known to be carcinogenic in animals, occur in food products and certain alcoholic drinks, but there is no direct proof as yet of a causal role in human disease [11].

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References 1 Boonk WJ, Van Ketel WG. The role of penicillin in the pathogenesis of chronic urticaria. Br J Dermatol 1982; 106: 183–90. 2 Kanny G, Puygrenier J, Beaudoin E, Moneret-Vautrin DA. Choc anaphylactique alimentaire: implication des residus de penicilline. Allerg Immunol 1994; 26: 181–3. 3 Peters HA, Gocmen A, Cripps DJ et al. Epidemiology of hexachlorobenzeneinduced porphyria in Turkey. Arch Neurol 1982; 39: 744–9. 4 Martinez-Tello FJ, Navas-Palacios JJ, Ricoy JR et al. Pathology of a new toxic syndrome caused by ingestion of adulterated oil in Spain. Virchows Arch A 1982; 397: 261–85. 5 Anonymous. Toxic oil syndrome. Lancet 1983; i: 1257–8. 6 Rush PJ, Bell MJ, Fam AG. Toxic oil syndrome (Spanish oil disease) and chemically induced scleroderma-like conditions. J Rheumatol 1984; 11: 262–4. 7 Sternberg TH, Bierman SM. Unique syndromes involving the skin induced by drugs, food additives, and environmental contaminants. Arch Dermatol 1963; 88: 779–88. 8 Mali JW, Malten KE. The epidemic of polymorphic toxic erythema in the Netherlands in 1960. The so-called margarine disease. Acta Derm Venereol (Stockh) 1966; 46: 123–35. 9 Yeh S. Skin cancer in chronic arsenicism. Hum Pathol 1973; 4: 469–85. 10 McGowan EM. Menthol urticaria. Arch Dermatol 1966; 94: 62–3. 11 Tannenbaum SR. N-nitroso compounds: a perspective on human exposure. Lancet 1983; i: 628–30.

Herbal remedies, homeopathy and naturopathy (alternative therapy) Adverse cutaneous effects of herbal drugs have been reviewed [1–5]. Virtually all alternative remedies may cause allergic or hypersensitivity reactions; the most frequently involved are tea tree oil, members of the Compositae family, propolis, oils used in aromatherapy, substances responsible for photosensitization and metal-containing compounds [5]. Skin manifestations range from contact dermatitis (the most common) to urticaria–angio-oedema, anaphylaxis, maculopapular eruptions, photosensitivity reactions and the Stevens–Johnson syndrome. Some herbal medicines, particularly Ayurvedic remedies, contain arsenic or mercury that may produce typical skin lesions. Other popular remedies that can cause dermatological side effects include St John’s wort (Hypericum perforatum), kava, aloe vera, eucalyptus, camphor, henna and yohimbine. St John’s wort may interact with certain drugs, resulting in a decrease in the concentration or effect of the drug, due to induction of cytochrome P-450s and the key drug transporter P-glycoprotein [6]. In addition, pharmacodynamic interactions of St John’s wort with some drugs (e.g. selective serotonin re-uptake inhibitors) have been identified, which are associated with an increased risk of adverse reactions. Some herbal treatments used specifically for dermatological conditions, for example Chinese oral herbal remedies for atopic eczema, have been reported to cause systemic adverse effects. There is concern that some agents, notably Chinese herbal creams, have been shown repeatedly to be adulterated with corticosteroids [7,8]. References 1 Monk B. Severe cutaneous reactions to alternative remedies. BMJ 1986; 293: 665–6. 2 Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000; 143: 923–9. 3 Ernst E. The usage of complementary therapies by dermatological patients: a systematic review. Br J Dermatol 2000; 143: 857–61.

4 Bedi MK, Shenefelt PD. Herbal therapy in dermatology. Arch Dermatol 2002; 138: 232–42. 5 Ventura MT, Viola M, Calogiuri G et al. Hypersensitivity reactions to complementary and alternative medicine products. Curr Pharm Des 2006; 12: 3393–9. 6 Zhou SF, Lai X. An update on clinical drug interactions with the herbal antidepressant St. John’s wort. Curr Drug Metab 2008; 9: 394–409. 7 But PPH. Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 1994; 97: 371–4. 8 Bircher AJ, Hauri U, Niederer M et al. Stealth triamcinolone acetonide in a phytocosmetic cream. Br J Dermatol 2002; 146: 531–2.

Chinese herbal medicine Adverse effects of Chinese herbal medicines, including lifethreatening ‘dazao’-induced angio-oedema and liquorice-induced hypokalaemic periodic paralysis, accounted for 0.2% of medical admissions to a hospital in Hong Kong over an 8-month period [1]. Herbal poisoning in Hong Kong, Taipei and Kuala Lumpur has occurred as a result of addition of adulterants (Podophyllum emodi) or erroneous substitutes (Datura metel) [2]. A fatality due to total liver necrosis associated with ingestion of Chinese herbal medicines is believed to have occurred because the patient prepared a decoction from a herbal mixture containing Eurysolen gracilis Prain (Labiatae), a herb not used in Chinese medicine [3]. A multisystem illness developed in a patient after ingestion of Chinese herbal medicines containing the potentially toxic compounds benzaldehyde, cinnamoyl alcohol and ephedrine [4]. Toxic epidermal necrolysis from traditional Chinese medicine, acute generalized exanthematous pustulosis from piroxicam and salicylate-contaminated traditional Chinese medicine, and dress from traditional Chinese medicine and from phenylbutazoneadulterated traditional Chinese medicine have been recorded [5]. Some Chinese patent medicines contain mercurial ingredients— cinnabar (red mercuric sulphide) and calomel (mercurous chloride) [6]. Alopecia and sensory polyneuropathy from thallium in a Chinese herbal medication has been reported [7]. Cutaneous aspects of thallium poisoning include palmar and plantar scaling, acneiform lesions on the face and diffuse alopecia, accompanied by acute nervous system and gastrointestinal symptoms [8]. Chinese herbal medicine may contain camouflaged prescription anti-inflammatory drugs, corticosteroids and lead [9], and some practitioners of Chinese medicine supply ‘herbal creams’ that actually contain potent topical steroid ointments [10,11]. Fixed drug eruption has been documented with use of a Chinese traditional herbal medicine containing mainly pseudoephedrine and ephedrine [12]. There are major concerns about hepatotoxicity [13–17] and nephrotoxicity [18–24] with Chinese herbal medicine. In one case, hepatotoxicity was associated with ingestion of the Chinese herbal product jin bu huan anodyne tablets (Lycopodium serratum) [15]. A rapidly progressive fibrosing interstitial nephritis developed in young women who followed the same slimming regimen containing two Chinese herbs (Stephania tetrandra and Magnolia officinalis) [18–20]. The known carcinogen, aristolochic acid, has been suspected in some cases of nephropathy [21,22]. Urothelial malignancy has supervened [23]. Acquired Fanconi’s syndrome was induced by a mixture of Chinese crude drugs [24]. The need for correct identification of herbs in herbal poisoning [25], and for monitoring of the safety of herbal medicines [26], has been emphasized. Greater awareness of their toxicity is required

Important or widely prescribed drugs

[27,28]. Special licensing of herbal remedies exists in Germany, France and Australia, and has been advocated in the UK [29]. Analgesic and anti-inflammatory Chinese medicinal materials, especially those containing fragrance, may cause contact sensitization and can cause systemic contact dermatitis [29,30]. Erythema multiforme [31,32], exanthem [33] and erythroderma [34] are described. Fever with oedematous erythema was caused by a decoction of the crude drug Boi of Kampo (Sino-Japanese traditional) medicine for the alleviation of arthralgia; oral ingestion tests incriminated the constituent sinomenine [35]. A ‘tea’ prepared from a decoction of herbs has been reported to be of benefit in eczema [36,37]. The decoction contains paenol (2′hydroxy-4′-methoxyacetophenone), which is known to have platelet antiaggregatory, analgesic and antipyretic properties [38]. Hepatotoxicity was described in a 9-year-old girl who consumed a Chinese herbal tea for 6 months [39], and was reported in a further patient [40]. Reversible abnormal liver function tests have been reported in two children receiving Chinese herbal therapy (Zemaphyte) [41]. Toxicology screening in a group of adults on Zemaphyte for 1 year revealed no abnormalities in haematological or biochemical parameters; transient nausea and abdominal distension, with a mild laxative effect, was noted in about one-third of patients [42]. Dilated cardiomyopathy followed therapy of atopic eczema with Chinese herbal medicine [43]. References 1 Chan TY, Chan AY, Critchley JA. Hospital admissions due to adverse reactions to Chinese herbal medicines. J Trop Med Hyg 1992; 95: 296–8. 2 But PP. Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 1994; 947: 371–4. 3 Perharic-Walton L, Murray V. Toxicity of Chinese herbal remedies. Lancet 1992; 340: 674. 4 Gorey JD, Wahlqvist ML, Boyce NW. Adverse reaction to a Chinese herbal remedy. Med J Aust 1992; 157: 484–6. 5 Lim YL, Thirumoorthy T. Serious cutaneous adverse reactions to traditional Chinese medicines. Singapore Med J 2005; 46: 714–7. 6 Kang-Yum E, Oransky SH. Chinese patent medicine as a potential source of mercury poisoning. Vet Hum Toxicol 1992; 34: 235–8. 7 Schaumburg HH, Berger A. Alopecia and sensory polyneuropathy from thallium in a Chinese herbal medication. JAMA 1992; 268: 3430–1. 8 Tromme I, Van Neste D, Dobbelaere F et al. Skin signs in the diagnosis of thallium poisoning. Br J Dermatol 1998; 138: 321–5. 9 Goldman JA, Myerson G. Chinese herbal medicine: camouflaged prescription anti-inflammatory drugs, corticosteroids, and lead. Arthritis Rheum 1991; 34: 1207. 10 Allen BR, Parkinson R. Chinese herbs for eczema. Lancet 1990; 336: 177. 11 O’Driscoll J, Burden AD, Kingston TP. Potent topical steroid obtained from a Chinese herbalist. Br J Dermatol 1992; 127: 543–4. 12 Matsumoto K, Mikoshiba H, Saida T. Nonpigmenting solitary fixed drug eruption caused by a Chinese traditional herbal medicine, ma huang (Ephedra hebra), mainly containing pseudoephedrine and ephedrine. J Am Acad Dermatol 2003; 48: 628–30. 13 Mostefa-Kara N, Pauwels A, Pinus E et al. Fatal hepatitis after herbal tea. Lancet 1992; 340: 674. 14 Graham-Brown R. Toxicity of Chinese herbal remedies. Lancet 1992; 340: 673. 15 Woolf GM, Petrovic LM, Rojter SE et al. Acute hepatitis associated with the Chinese herbal product jin bu huan. Ann Intern Med 1994; 121: 729–35. 16 Pillans PI. Toxicity of herbal products. NZ Med J 1995; 108: 469–71. 17 Larrey D, Pageaux GP. Hepatotoxicity of herbal remedies and mushrooms. Semin Liver Dis 1995; 15: 183–8. 18 Vanherweghem JL, Depierreux M, Tielemans C et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341: 387–91.

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19 Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994; 24: 172–80. 20 Cosyns JP, Jadoul M, Squifflet JP et al. Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994; 45: 1680–8. 21 Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL. Identification of aristolochic acid in Chinese herbs. Lancet 1994; 343: 174. 22 Diamond JR, Pallone TL. Acute interstitial nephritis following use of tung shueh pills. Am J Kidney Dis 1994; 24: 219–21. 23 Cosyns JP, Jadoul M, Squifflet JP et al. Urothelial malignancy in nephropathy due to Chinese herbs. Lancet 1994; 344: 188. 24 Izumotani T, Ishimura E, Tsumura K et al. An adult case of Fanconi syndrome due to a mixture of Chinese crude drugs. Nephron 1993; 65: 137–40. 25 But PP. Need for correct identification of herbs in herbal poisoning. Lancet 1993; 341: 637. 26 Mills SY. Monitoring the safety of herbal remedies. European pilot studies are under way. BMJ 1995; 311: 1570. 27 Atherton DJ. Towards the safer use of traditional remedies. Greater awareness of toxicity is needed. BMJ 1994; 308: 673–4. 28 Harper J. Traditional Chinese medicine for eczema. Seemingly effective, but caution must prevail. BMJ 1994; 308: 489–90. 29 De Smet PAGM. Should herbal medicine-like products be licensed as medicines? Special licensing seems the best way forward. BMJ 1995; 310: 1023–4. 30 Li LF. A clinical and patch test study of contact dermatitis from traditional Chinese medicinal materials. Contact Dermatitis 1995; 33: 392–5. 31 Mateo MP, Velasco M, Miquel FJ, de la Cuadra J. Erythema-multiforme-like eruption following allergic contact dermatitis from sesquiterpene lactones in herbal medicine. Contact Dermatitis 1995; 33: 449–50. 32 Tan WP, Goh BK, Tan SH. Extensive erythema multiforme-like eruption due to traditional Chinese herbal drug ‘Dong Ling Hou Tong Pian’. Clin Exp Dermatol 2006; 31: 291–3. 33 Li LF, Zhao J, Li SY. Exanthematous drug eruption due to Chinese herbal medicines sanjieling capsule and huoxuexiaoyan pill. Contact Dermatitis 1994; 30: 252–3. 34 Catlin DH, Sekera M, Adelman DC. Erythroderma associated with ingestion of an herbal product. West J Med 1993; 159: 491–3. 35 Okuda T, Umezawa Y, Ichikawa M et al. A case of drug eruption caused by the crude drug Boi (Sinomenium stem/Sinomeni caulis et Rhizoma). J Dermatol 1995; 22: 795–800. 36 Atherton D, Sheehan M, Rustin MHA et al. Chinese herbs for eczema. Lancet 1990; 336: 1254. 37 Sheehan MP, Atherton DJ, Luo HD. Controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema (abstract). Br J Dermatol 1991; 125 (Suppl. 38): 17. 38 Galloway JH, Marsh ID, Bittiner SB et al. Chinese herbs for eczema, the active compound? Lancet 1991; 337: 566. 39 Davies EG, Pollock I, Steel HM. Chinese herbs for eczema. Lancet 1990; 336: 177. 40 Carlsson C. Herbs and hepatitis. Lancet 1990; 336: 1068. 41 Sheehan MP, Atherton DJ. One year follow-up of children with atopic eczema treated with traditional Chinese medicinal plants. Br J Dermatol 1992; 127 (Suppl. 40): 13. 42 Sheehan MP, Stevens H, Ostlere LS et al. Follow-up of adult patients with atopic eczema treated with Chinese herbal therapy for 1 year. Clin Exp Dermatol 1995; 20: 136–40. 43 Ferguson JE, Chalmers RJG, Rowlands DJ. Reversible dilated cardiomyopathy following treatment of atopic eczema with Chinese herbal medicine. Br J Dermatol 1997; 136: 592–3.

Kava dermopathy The kava plant, a member of the black-pepper family, is used ceremonially by many traditional societies of the southern Pacific in the form of an intoxicant beverage prepared from roots to induce relaxation and sociability and promote sleep. Herbal drugs containing kava have been used for insomnia, nervousness and depression. A reversible ichthyosiform kava dermopathy resulted

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from excessive use of kava [1,2]. Systemic contact-type dermatitis occurred after oral administration of kava extract [2]. References 1 Norton SA, Ruze P. Kava dermopathy. J Am Acad Dermatol 1994; 31: 89–97. 2 Suss R, Lehmann P. Hamatogenes Kontaktekzem durch pflanzliche Medikamente am Beispiel des Kavawurzel-extraktes. Hautarzt 1996; 47: 459–61.

Homeopathic drugs Cases of erythroderma, confluent urticaria and anaphylaxis have been reported following homeopathic medication [1]. Treatment of a diaper dermatitis and mild respiratory and enteral infections with the homeopathic mercurial medicine Mercurius 6a (cinnabar dilute 1 × 10(6)) was followed by dissemination of the dermatitis, irritability and albuminuria [2]. Baboon syndrome was associated with use of a homeopathic medicine containing mercury [3]. References 1 Aberer W, Strohal R. Homeopathic preparations: severe adverse effects, unproven benefits. Dermatologica 1991; 182: 253. 2 Montoya-Cabrera MA, Rubio-Rodriguez S, Velazquez-Gonzalez E, Avila Montoya S. Intoxicacion mercurial causada por un medicamento homeopatico. Gaceta Med Mex 1991; 127: 267–70. 3 Audicana M, Bernedo N, Gonzalez I et al. An unusual case of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001; 45: 185.

Naturopathy Bizarre and unpredictable cutaneous reactions may follow topical application or ingestion of naturally occurring substances. A curious gyrate erythematous eruption was seen in a patient following local application of onion rings as a home remedy for arthralgia [1]. Substantial amounts of psoralen may be absorbed from vegetables; a patient who consumed a large quantity of celery root (Apium graveolens) 1 h before a visit to a suntan parlour developed a severe generalized phototoxic reaction [2]. A bullous phototoxic reaction developed after exposure to aerosolized bergamot aromatherapy oil in a sauna and subsequent UVA radiation in a tanning salon [3]. Phytophotodermatitis followed application of Citrus hystrix as a mosquito repellent [4]. Phototoxicity has been reported from herbal remedies for vitiligo incorporating powdered seeds of Psoralea corylifolia, which contains psoralen, isopsoralen and psoralidin [5]. Contact sensitization has been caused by alternative topical medicaments containing plant extracts [6–10], including tea-tree oil, the extracted oil of Melaleuca alternifolia [7–9]. Tea-tree oil has also caused systemic contact dermatitis [7], linear immunoglobulin A disease [11], erythema multiforme-like id reactions, and systemic hypersensitivity reactions [9]. Allergic airborne contact dermatitis has been caused by benzaldehyde, eucalyptus oil, laurel oil, pomerance flower oil, lavender oil, rosewood oil and jasmine oil used for aromatherapy [12]. Application of henna as a decoration may cause allergic contact eczema [13]. A diffuse morbilliform eruption and other skin reactions occurred with a Gingko biloba supplement [14,15], recurrent erythema nodosum, other rashes and gastrointestinal upset with Echinacea therapy [16,17], and erythroderma with intake of St John’s wort (Hypericum perforatum) [18].

References 1 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 2 Ljunggren B. Severe phototoxic burn following celery ingestion. Arch Dermatol 1990; 126: 1334–6. 3 Kaddu S, Kerl H, Wolf P. Accidental bullous phototoxic reactions to bergamot aromatherapy oil. J Am Acad Dermatol 2001; 45: 458–61. 4 Koh D, Ong C-N. Phytophotodermatitis due to the application of Citrus hystrix as a folk remedy. Br J Dermatol 1999; 140: 737–8. 5 Maurice PDL, Cream JJ. The dangers of herbalism. BMJ 1989; 299: 1204. 6 Bruynzeel DP, van Ketel WG, Young E et al. Contact sensitization by alternative topical medicaments containing plant extracts. The Dutch Contact Dermatoses Group. Contact Dermatitis 1992; 27: 278–9. 7 de Groot AC, Weyland JW. Systemic contact dermatitis from tea tree oil. Contact Dermatitis 1992; 27: 279–80. 8 Knight TE, Hausen BM. Melaleuca oil (tea tree oil) dermatitis. J Am Acad Dermatol 1994; 30: 423–7. 9 Crawford GH, Sciacca JR, James WD. Tea tree oil: cutaneous effects of the extracted oil of Melaleuca alternifolia. Dermatitis 2004; 15: 59–66. 10 Hong SJ, Chang CH. Erythema multiforme-like generalized allergic contact dermatitis caused by Alpinia galanga. Contact Dermatitis 2006; 54: 118–20. 11 Perett CM, Evans AV, Russell-Jones R. Tea tree oil dermatitis associated with linear IgA disease. Clin Exp Dermatol 2003; 28: 167–70. 12 Schaller M, Korting HC. Allergic airborne contact dermatitis from essential oils used in aromatherapy. Clin Exp Dermatol 1995; 20: 143–5. 13 Lestringant GG, Bener A, Frossard PM. Cutaneous reactions to henna and associated additives. Br J Dermatol 1999; 141: 598–600. 14 Chiu AE, Lane AT, Kimball AB. Diffuse morbilliform eruption after consumption of Ginkgo biloba supplement. J Am Acad Dermatol 2002; 46: 145–6. 15 Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. J Food Sci 2008; 73: R14–9. 16 Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001; 44: 298–9. 17 Huntley AL, Thompson Coon J, Ernst E. The safety of herbal medicinal products derived from Echinacea species: a systematic review. Drug Saf 2005; 28: 387–400. 18 Holme SA, Roberts DL. Erythroderma associated with St John’s wort. Br J Dermatol 2000; 143: 1127–8.

Miscellaneous Canthaxanthin, a synthetic non-provitamin A carotenoid deposited in epidermis and subcutaneous fat, caused fatal aplastic anaemia when ingested to promote tanning [1]. Reference 1 Bluhm R, Branch R, Johnston P, Stein R. Aplastic anemia associated with canthaxanthin ingested for ‘tanning’ purposes. JAMA 1990; 264: 1141–2.

Industrial and other exposure to chemicals For a discussion of sclerodermatous reactions to environmental agents, see p. 75.43. A form of fluoride toxicity occurred due to industrial poisoning in the Italian town of Chizzolo, resulting in pinkish brown, round or oval macules seen in hundreds of the local population [1]. Similar small outbreaks have occurred in North America [2]. Exfoliative dermatitis has been recorded with trichloroethylene [3]. Occupational exposure to trichloroethylene has also caused Stevens–Johnson syndrome [4]. Patients exposed to dioxin after an industrial accident at Seveso, Italy developed early irritative lesions, comprising erythema and oedema of exposed areas, vesicobullous and necrotic lesions of the palms and fingertips, and papulonodular lesions; later lesions were those of chloracne [5]. Contamination of rice-bran cooking oil with polychlorinated biphenyls in Taiwan resulted in chloracne, and congenital abnormalities in offspring [6].

Important or widely prescribed drugs

Pruritus, urticaria, and discoid and diffuse eczema may occur following the use of brominated disinfectant compounds such as 1-bromo-3-chlor-5,5-dimethylhydantoin (Di-halo, Aquabrome) in public swimming pools [7]. Accidental occupational exposure to high concentrations of methyl bromide during a fumigation procedure resulted in erythema with multiple vesicles and large bullae, with predilection for moist flexures and pressure areas [8]. Idiopathic thrombocytopenic purpura has been associated with industrial exposure to wood preservatives [9], turpentine [10], and to insecticides such as chlordane and heptachlor [11]. Reversible alopecia occurred with occupational exposure to borax-containing solutions [12]. References 1 Waldbott GC, Cecilioni VA. ‘Chizzolo’ maculae. Cutis 1970; 6: 331–4. 2 Tabuenca JM. Toxic–allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 1981; ii: 567–8. 3 Nakayama H, Kobayashi M, Takahashi M et al. Generalized eruption with severe liver dysfunction associated with occupational exposure to trichloroethylene. Contact Dermatitis 1988; 19: 48–51. 4 Phoon WH, Chan MOY, Rahan VS et al. Stevens–Johnson syndrome associated with occupational exposure to trichloroethylene. Contact Dermatitis 1984; 10: 270–6. 5 Caputo R, Monti M, Ermacora E et al. Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. J Am Acad Dermatol 1988; 19: 812–9. 6 Gladen BC, Taylor JS, Wu Y-C et al. Dermatological findings in children exposed transplacentally to heat-degraded polychlorinated biphenyls in Taiwan. Br J Dermatol 1990; 122: 799–808. 7 Rycroft RJG, Penny PT. Dermatoses associated with brominated swimming pools. BMJ 1983; 28: 462. 8 Hezemans-Boer M, Toonstra J, Meulenbelt J et al. Skin lesions due to exposure to methyl bromide. Arch Dermatol 1988; 124: 917–21. 9 Hay A, Singer CRJ. Wood preservatives, solvents, and thrombocytopenic purpura. Lancet 1991; 338: 766. 10 Wahlberg P, Nyman D. Turpentine and thrombocytopenic purpura. Lancet 1969; ii: 215–6. 11 Epstein SS, Ozonoff D. Leukemias and blood dyscrasias following exposure to chloradone and heptachlor. Carcinogen Mutagen Teratogen 1987; 7: 527–40. 12 Beckett WS, Oskvig R, Gaynor ME, Goldgeier MH. Association of reversible alopecia with occupational topical exposure to common borax-containing solutions. J Am Acad Dermatol 2001; 44: 599–602.

Local and systemic effects of topical applications Many topical therapeutic agents may cause serious or even dangerous systemic side effects if absorbed in sufficient quantity; such absorption may be facilitated through diseased skin, and with use of newer vehicles or occlusive polythene dressings. The risk of serious systemic effects is greatest in infancy and in the old and frail. The quantity absorbed in relation to body weight is greatest in infancy, when the surface area is relatively greater; moreover, neonatal skin is more permeable. Most dangerous or fatal reactions have occurred because either the physician was unaware of the potential hazard or the patient continued self-treatment without medical supervision.

Topical therapy Anthralin (dithranol) Topical anthralin, used in the therapy of stable plaque psoriasis, is well known for causing erythema, irritation and a sensation of burning in normal skin; it stains the skin and clothing [1]. Application of 10% triethanolamine following short-contact anthralin

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treatment has been reported to inhibit anthralin-induced inflammation without preventing the therapeutic effect [2]. Allergic contact dermatitis to anthralin is very rare. The natural and synthetic anthranols have toxic effects on liver, intestines and the central nervous system, but systemic toxicity in humans under therapeutic conditions has not been established [3]. References 1 Paramsothy Y, Lawrence CM. Time course and intensity of anthralin inflammation on involved and uninvolved psoriatic skin. Br J Dermatol 1987; 116: 517–9. 2 Ramsay B, Lawrence CM, Bruce JM, Shuster S. The effect of triethanolamine application on anthralin-induced inflammation and therapeutic effect in psoriasis. J Am Acad Dermatol 1990; 23: 73–6. 3 Ippen H. Basic questions on toxicology and pharmacology of anthralin. Br J Dermatol 1981; 105 (Suppl. 20): 72–6.

Boric acid Poisoning has usually occurred in infants treated for napkin eruptions. Almost all cases have been caused by the use of boric ointments or lotions. However, use of borated talc proved fatal in one infant [1]. Wet boric dressings caused the death of an adult woman [2]. References 1 Brooke C, Boggs T. Boric-acid poisoning: report of a case and review of the literature. Am J Dis Child 1951; 82: 465–72. 2 Jordan JW, Crissey JT. Boric acid poisoning: report of fatal adult case from cutaneous use. A critical evaluation of this drug in dermatologic practice. Arch Dermatol 1957; 75: 720–8.

Calcineurin inhibitors (pimecrolimus and tacrolimus) (see pp. 75.146–147) Calcipotriol This vitamin D3 analogue has been reported to cause transient local irritation, and facial or perioral dermatitis [1]. Contact allergy is recorded [2]. Topical application of calcipotriol for 5 weeks to a mean of 16% of the body surface of psoriatic patients did not result in detectable systemic alteration of calcium metabolism [3]. The manufacturer’s data sheet (Leo Laboratories) states that increased serum calcium may occur with application in daily doses of 50– 100 g of the 50 μg/g ointment. Severe symptomatic hypercalcaemia developed after application of about 200 g of the ointment over 1 week to exfoliative psoriasis covering 40% of the body surface [4]. It is recommended that treatment be confined to stable mild to moderate psoriasis, and that the recommended dose of 100 g/week should not be exceeded. Hyperpigmentation occurred at the site of topical calcipotriol application in two patients receiving photochemotherapy [5]. References 1 Kragballe K, Gjertsen BT, De Hoop D et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337: 193–6. 2 de Groot AC. Contact allergy to calcipotriol. Contact Dermatitis 1994; 30: 242–3. 3 Saurat J-H, Gumowski Sunek D, Rizzoli R. Topical calcipotriol and hypercalcaemia. Lancet 1991; 337: 1287. 4 Dwyer C, Chapman RS. Calcipotriol and hypercalcaemia. Lancet 1991; 338: 764–5. 5 Gläser R, Röwert J, Mrowietz U. Hyperpigmentation due to topical calcipotriol and photochemotherapy in two psoriatic patients. Br J Dermatol 1998; 139: 148–51.

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Coal tar Coal tar vapour inhalation precipitated severe symptomatic bronchoconstriction in an atopic asthmatic subject following application of coal-tar bandages for treatment of eczema, confirmed by challenge [1]. Reference 1 Ibbotson SH, Stenton SC, Simpson NB. Acute severe bronchoconstriction precipitated by coal tar bandages. Clin Exp Dermatol 1995; 20: 58–9.

Chlorhexidine gluconate (Hibitane) Urticaria, dyspnoea and anaphylactic shock have occurred following topical application as a disinfectant [1,2], as have contact urticaria, photosensitive dermatitis [3] and deafness. References 1 Okano M, Nomura M, Hata S et al. Anaphylactic symptoms due to chlorhexidine gluconate. Arch Dermatol 1989; 125: 50–2. 2 Snellman E, Rantanen T. Severe anaphylaxis after a chlorhexidine bath. J Am Acad Dermatol 1999; 40: 771–2. 3 Wahlberg JE, Wennersten G. Hypersensitivity and photosensitivity to chlorhexidine. Dermatologica 1971; 143: 376–9.

Dequalinium chloride Necrotic lesions have occurred following its use in the treatment of balanitis [1]. Reference 1 Coles RB, Simpson WT, Wilkinson DS. Dequalinium: a possible complication of its use in balanitis. Lancet 1964; ii: 531.

Dimethylsulfoxide Topical application can cause erythema, pruritus and urticaria, but systemic reactions are very rare; a generalized contact dermatitis-like reaction followed intravesical instillation in a sensitized individual [1]. Reference 1 Nishimura M, Takano Y, Toshitani Y. Systemic contact dermatitis medicamentosa occurring after intravesical dimethyl sulfoxide treatment for interstitial cystitis. Arch Dermatol 1988; 124: 182–3.

Diphencyprone (see p. 75.147) Doxepin Doxepin cream causes allergic contact dermatitis and systemic contact dermatitis [1,2]. References 1 Taylor JS, Praditsuwan P, Handel D, Kuffner G. Allergic contact dermatitis from doxepin cream. One-year patch test clinic experience. Arch Dermatol 1996; 132: 515–8. 2 Shelley W, Shelley ED, Talanin NY. Self-potentiating allergic contact dermatitis caused by doxepin hydrochloride cream. J Am Acad Dermatol 1996; 34: 143–4.

EMLA cream (see pp. 75.153–154) 5-Fluorouracil (see p. 75.129) Formaldehyde Industrial exposure is recognized to be a health hazard, and a threshold limit of 2 ppm is allowed in the UK and the USA [1]. Irritant or allergic dermatitis is common in exposed workers [2].

Systemic symptoms including breathlessness, headache and drowsiness have been attributed to prolonged exposure to very low levels in the home [3]. References 1 Anonymous. The health hazards of formaldehyde. Lancet 1981; i: 926–7. 2 Glass WI. An outbreak of formaldehyde dermatitis. NZ Med J 1961; 60: 423. 3 Harris JC, Rumack BH, Aldrich FD. Toxicology of urea formaldehyde and polyurethane foam insulation. JAMA 1981; 245: 243–6.

Lindane (gamma benzene hexachloride) Lindane therapy for scabies has potential toxicity, which includes neurotoxicity with convulsions, especially in children [1–7]. Most reports have occurred with overexposure or misuse, although side effects have followed single applications, particularly when the epidermal barrier has been compromised. Whether this constitutes a significant problem in normal individuals is doubtful [6]. Nevertheless, it has been suggested that permethrin may be a safer and less toxic alternative [8]. References 1 Lee B, Groth P. Scabies: transcutaneous poisoning during treatment. Arch Dermatol 1979; 115: 124–5. 2 Pramanik AK, Hansen RC. Transcutaneous gamma benzene hexachloride absorption and toxicity in infants and children. Arch Dermatol 1979; 115: 124–5. 3 Matsuoka LY. Convulsions following application of gamma benzene hexachloride. J Am Acad Dermatol 1981; 5: 98–9. 4 Rasmussen JE. The problem of lindane. J Am Acad Dermatol 1981; 5: 507–16. 5 Davies JE, Dehdia HV, Morgade C et al. Lindane poisonings. Arch Dermatol 1983; 119: 142–4. 6 Rasmussen J. Lindane: a prudent approach. Arch Dermatol 1987; 123: 1008–10. 7 Friedman SJ. Lindane neurotoxic reaction in nonbullous ichthyosiform erythroderma. Arch Dermatol 1987; 123: 1056–8. 8 Schultz MW, Gomez M, Hansen RC et al. Comparative study of 5% permethrin cream and 1% lindane lotion for the treatment of scabies. Arch Dermatol 1990; 126: 167–70.

Hexachlorophene (hexachlorophane) This substance has potential neurotoxicity. Exposure of babies to a talc containing 6.3% hexachlorophene due to a manufacturing error resulted in deaths, with ulceration, skin lesions and a characteristic demyelinating encephalopathy [1]. A 3% emulsion has produced milder neurological changes, but a 0.33% concentration in talc is apparently safe. Encephalopathy has occurred in burns patients [2]. References 1 Martin-Bouyer G, Lebreton R, Toga M et al. Outbreak of accidental hexachlorophene poisoning in France. Lancet 1982; i: 91–5. 2 Larson DL. Studies show hexachlorophene causes burn syndrome. J Am Hosp Assoc 1968; 42: 63–4.

Hydroquinone Depigmenting creams containing 6–8% hydroquinone, used especially by black South African women, have caused rebound hyperpigmentation and coarsening of the skin, with ochronotic changes in the dermis, colloid degeneration and colloid milium [1–6]. Collagen degeneration may be seen histologically [2]. Similar changes have been seen in black women in the USA [3] and in a MexicanAmerican woman [4]. Interestingly, ochronosis does not develop in areas of vitiligo [7]. The Q-switched ruby laser may be helpful in treating exogenous ochronosis [8]. The nails may be pigmented [9].

Important or widely prescribed drugs References 1 Findlay GH, Morrison JGL, Simson IW. Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams. Br J Dermatol 1975; 93: 613–22. 2 Phillips JI, Isaacson C, Carman H. Ochronosis in Black South Africans who used skin lighteners. Am J Dermatopathol 1986; 8: 14–21. 3 Lawrence N, Bligard CA, Reed R, Perret WJ. Exogenous ochronosis in the United States. J Am Acad Dermatol 1988; 18: 1207–11. 4 Howard KL, Furner BB. Exogenous ochronosis in a Mexican-American woman. Cutis 1990; 45: 180–2. 5 Camarasa JG, Serra-Baldrich E. Exogenous ochronosis with allergic contact dermatitis from hydroquinone. Contact Dermatitis 1994; 31: 57–8. 6 Snider RL, Thiers BH. Exogenous ochronosis. J Am Acad Dermatol 1993; 28: 662–4. 7 Hull PR, Procter PR. The melanocyte: an essential link in hydroquinone-induced ochronosis. J Am Acad Dermatol 1990; 22: 529–31. 8 Kramer KE, Lopez A, Stefanato CM, Phillips TJ. Exogenous ochronosis. J Am Acad Dermatol 2000; 42: 869–71. 9 Garcia RL, White JW, Willis WF. Hydroquinone nail pigmentation. Arch Dermatol 1978; 114: 1402–3.

Imiquimod (see pp. 75.147–148) Iodine Povidone-iodine scrub for acne (Betadine) induced hyperthyroidism [1]. Reference 1 Smit E, Whiting DA, Feld S. Iodine-induced hyperthyroidism caused by acne treatment. J Am Acad Dermatol 1994; 31: 115–7.

Latanoprost Topical latanoprost for glaucoma may induce eyelash hypertrichosis [1]. Reference 1 Demitsu T, Manabe M, Harima N et al. Hypertrichosis induced by latanoprost. J Am Acad Dermatol 2001; 44: 721–3.

Lead lotions The continued use of wet dressings of lead subacetate in the treatment of exfoliative dermatitis caused lead poisoning, with punctate basophilia and an elevated urinary lead level [1]. Reference 1 Kennedy CC, Lynas HA. Lead poisoning by cutaneous absorption from lead dressings. Lancet 1949; i: 650–2.

Mercury Poisoning is now fortunately rare, but was seen from continued application of large amounts of a topical application, as for psoriasis [1,2]. Idiosyncratic poisoning after much smaller doses is also recognized [3]. Intoxication has followed the use of a mercury dusting powder [4] and poisoning of a suckling infant has followed the use of perchloride of mercury lotion for cracked nipples [5]. Fever, a generalized morbilliform rash and oedema of the extremities have been the usual clinical features. Exfoliative dermatitis and encephalopathy have developed; permanent damage to the renal tubules is manifest as persistent albuminuria or frank nephrotic syndrome [6]. Rarely, gross symptoms, such as loose teeth [7], swollen bleeding gums and weight loss, may be observed.

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Application of a mercury-containing cream to the face over many years can produce slate-grey pigmentation, especially on the eyelids, nasolabial folds and neck folds (exogenous ochronosis) [8–10]; mercury granules lie free in the dermis or within macrophages [11]. Mercury is a moderate sensitizer and leads to contact sensitivity. References 1 Inman PM, Gordon B, Trinder P. Mercury absorption and psoriasis. BMJ 1956; ii: 1202–6. 2 Young E. Ammoniated mercury poisoning. Br J Dermatol 1960; 72: 449–55. 3 Williams BH, Beach WC. Idiosyncrasy to ammoniated mercury: treatment with 2,3-dimercapto-propanol (BAL). JAMA 1950; 142: 1286–8. 4 MacGregor ME, Rayner PHW. Pink disease and primary renal tubular acidosis: a common cause. Lancet 1964; ii: 1083–5. 5 Hunt GM. Mercury poisoning in infancy. BMJ 1966; i: 1482. 6 Silverberg DS, McCall JT, Hunt JC. Nephrotic syndrome with use of ammoniated mercury. Arch Intern Med 1967; 20: 581–6. 7 Bourgeois M, Dooms-Goossens A, Knockaert D et al. Mercury intoxication after topical application of a metallic mercury ointment. Dermatologica 1986; 172: 48–51. 8 Lamar LM, Bliss BO. Localized pigmentation of the skin due to topical mercury. Arch Dermatol 1966; 93: 450–3. 9 Prigent F, Cohen J, Civatte J. Pigmentation des paupieres probablement secondaire l’application prolongée d’une pomade ophtalmologique contenant du mercure. Ann Dermatol Vénéréol 1986; 113: 357–8. 10 Aberer W. Topical mercury should be banned: dangerous, outmoded but still popular. J Am Acad Dermatol 1991; 24: 150–1. 11 Burge KM, Winkelmann RK. Mercury pigmentation. An electron microscopic study. Arch Dermatol 1970; 102: 51–61.

Methyl salicylate (oil of wintergreen) Topical application of methyl salicylate and menthol as a rubefacient, with use of a heating pad, resulted in local skin necrosis and interstitial nephritis [1]. Reference 1 Heng MCY. Local necrosis and interstitial nephritis due to topical methyl salicylate and menthol. Cutis 1987; 39: 442–4.

Mexiletine Mexiletine hydrochloride induced contact urticaria in a patient receiving iontophoresis [1]. A generalized drug eruption followed topical provocation on previously involved skin [2]. References 1 Yamazaki S, Katayama I, Kurumaji Y et al. Contact urticaria induced by mexiletine hydrochloride in a patient receiving iontophoresis. Br J Dermatol 1994; 130: 538–40. 2 Kikuchi K, Tsunoda T, Tagami H. Generalized drug eruption due to mexiletine hydrochloride: topical provocation on previously involved skin. Contact Dermatitis 1991; 25: 70–2.

Minoxidil Topical minoxidil, as used for androgenetic alopecia, is associated with cutaneous problems in up to 10% of patients, with allergic contact dermatitis occurring in 4% of individuals [1]. The contact allergen is often propylene glycol [2]. Diffuse hypertrichosis occurred during treatment with 5% topical minoxidil in female patients [3]. Acute non-allergic eruptions of the scalp resulted from combined use of minoxidil and retinoic acid [4].

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References 1 Wilson C, Walkden V, Powell S et al. Contact dermatitis in reaction to 2% topical minoxidil solution. J Am Acad Dermatol 1991; 24: 661–2. 2 Friedman ES, Friedman PM, Cohen DE, Washenik K. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol 2002; 46: 309–12. 3 Peluso AM, Misciali C, Vincenzi C, Tosti A. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol 1997; 136: 118–20. 4 Fisher AA. Unusual acute, nonallergic eruptions of the scalp from combined use of minoxidil and retinoic acid. Cutis 1993; 51: 17–8.

Non-steroidal anti-inflammatory drugs Allergic and photoallergic contact dermatitis and phototoxicity have resulted from topical NSAIDs [1–3]. An erythema multiforme-like reaction followed acute contact dermatitis from two different bufexamac-containing topical preparations [4]. References 1 Ophaswongse S, Maibach H. Topical nonsteroidal antiinflammatory drugs: allergic and photoallergic contact dermatitis and phototoxicity. Contact Dermatitis 1993; 29: 57–64. 2 Oh VM. Ketoprofen gel and delayed hypersensitivity dermatitis. BMJ 1994; 309: 512. 3 Valsecchi R, Pansera B, Leghissa P, Reseghetti A. Allergic contact dermatitis of the eyelids and conjunctivitis from diclofenac. Contact Dermatitis 1996; 34: 150–1. 4 Koch P, Bahmer FA. Erythema-multiforme-like, urticarial papular and plaque eruptions from bufexamac: report of 4 cases. Contact Dermatitis 1994; 31: 97–101.

Phenol Severe systemic reactions, such as abdominal pain, dizziness, haemoglobinuria, cyanosis and sometimes fatal coma, have followed the application of phenol to extensive wounds. Accidental application of pure phenol to a small area of skin in an infant has proved fatal. The prolonged use of phenol as a dressing for a large ulcer may give rise to exogenous ochronosis, with darkening of the cornea and of the skin of face and hands. Podophyllin Excessive application may lead to severe local irritation or ulceration [1]. There have been occasional reports of confusional states, coma, peripheral neuropathy, vomiting and even death following the application of this resin to large areas of genital warts, especially in pregnancy [2,3]. However, careful review of the reports suggests that in the majority the effects could not be attributed with certainty to podophyllin [2]. Animal experiments suggest teratogenicity; although teratogenicity is controversial in humans, the drug is best avoided in pregnancy. References 1 Higgins SP, Stedman YF, Chandiok P. Severe genital ulceration in two females following self-treatment with podophyllin solutions. Genitourin Med 1994; 70: 146–7. 2 Bargman H. Is podophyllin a safe drug to use and can it be used in pregnancy? Arch Dermatol 1988; 124: 1718–20. 3 Sundharam JA, Bargman H. Is podophyllin safe for use in pregnancy? Arch Dermatol 1989; 125: 1000–1.

Resorcinol Acute resorcinol poisoning is very rare, but an ointment containing 12.5% resorcinol applied to the napkin area produced dusky cyanosis, a maculopapular eruption, haemolytic anaemia and

haemoglobinuria in an infant [1]. The continued application to large leg ulcers of ointments containing resorcinol has caused myxoedema and widespread blue-grey pigmentation mimicking ochronosis [2]. Application for warts caused generalized urticaria with angio-oedema, pompholyx of palms and soles, or papulovesicular eczema with pompholyx [3]. References 1 Cunningham AA. Resorcin poisoning. Arch Dis Child 1956; 31: 173–6. 2 Thomas AE, Gisburn MA. Exogenous ochronosis and myxoedema from resorcinol. Br J Dermatol 1961; 73: 378–81. 3 Barbaud A, Modiano P, Cocciale M et al. The topical application of resorcinol can provoke a systemic allergic reaction. Br J Dermatol 1996; 135: 1014–5.

Salicylic acid and salicylates The frequent application of salicylic acid ointments to extensive lesions will produce symptoms of salicylism even in adults [1–7]. Most cases of poisoning have occurred in children with psoriasis or ichthyosis [1,2]; fatal cases have been recorded [4]. Drowsiness and delusions are followed by acidosis, coma and death from respiratory failure. References 1 Young CJ. Salicylate intoxication from cutaneous absorption of salicylate acid: review of the literature and report of a case. South Med J 1952; 45: 1075–7. 2 Cawley EP, Peterson NT, Wheeler CE. Salicylic acid poisoning in dermatological therapy. JAMA 1953; 151: 372–4. 3 Von Weiss JF, Lever WF. Percutaneous salicylic acid intoxication in psoriasis. Arch Dermatol 1964; 90: 614–9. 4 Lindsey LP. Two cases of fatal salicylate poisoning after topical application of an anti-fungal solution. Med J Aust 1969; 1: 353–4. 5 Davies MG, Vella Briffa D, Greaves MW. Systemic toxicity from topically applied salicylic acid. BMJ 1979; i: 661. 6 Anderson JAR, Ead RD. Percutaneous salicylate poisoning. Clin Exp Dermatol 1979; 4: 349–51. 7 Pec J, Strmenova M, Palencarova E et al. Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis. Cutis 1992; 50: 307–9.

Silver sulfadiazine Topical application has caused hyperpigmentation [1], contact sensitivity [2], dermatitis [3] and scar-localized argyria [4]. References 1 Dupuis LL, Shear NH, Zucker RM. Hyperpigmentation due to topical application of silver sulfadiazine cream. J Am Acad Dermatol 1985; 12: 1112–4. 2 Fraser-Moodie A. Sensitivity to silver in a patient treated with silver sulphadiazine (Flamazine). Burns 1992; 18: 74–5. 3 McKenna SR, Latenser BA, Jones LM et al. Serious silver sulphadiazine and mafenide acetate dermatitis. Burns 1995; 21: 310–2. 4 Fisher NM, Marsh E, Lazova R. Scar-localized argyria secondary to silver sulfadiazine cream. J Am Acad Dermatol 2003; 49: 730–2.

Tretinoin Topical tretinoin, used for the management of photo-aged skin, may cause erythema, peeling, burning and itching of the skin within days [1,2]. Pink discoloration without other signs may also develop, as may inflammation in solar keratoses. References 1 Weiss JS, Ellis CN, Headington JT et al. Topical tretinoin improves photoaged skin: a double-blind, vehicle-controlled study. JAMA 1988; 259: 527–32. 2 Weinstein GD, Nigra TP, Pochi PE et al. Topical tretinoin for treatment of photodamaged skin. Arch Dermatol 1991; 127: 659–65.

Management of drug reactions

Vitamin E Vitamin E in deodorants has caused contact dermatitis [1]. Reference 1 Minkin W, Cohen HJ, Frank SB. Contact dermatitis from deodorants. Arch Dermatol 1973; 107: 774–5.

Warfarin An epidemic of haemorrhagic disease with fatalities occurred due to warfarin-contaminated talcs [1]. Poisoning has also been attributed to preparation of rodent baits [2]. References 1 Martin-Bouyer G, Linh PD, Tuan LC et al. Epidemic of haemorrhagic disease in Vietnamese infants caused by warfarin-contaminated talcs. Lancet 1983; i: 230–2. 2 Fristedt B, Sterner N. Warfarin intoxication from percutaneous absorption. Arch Environ Health 1965; 11: 205–8.

Transdermal drug-delivery systems Cutaneous reactions to transdermal therapeutic systems have been reviewed [1]. Transdermal delivery systems are available for clonidine, estradiol (oestradiol), glyceryl trinitrate, scopolamine, nicotine, and methylphenidate, and systems for other drugs are being developed. Erythema, irritancy, scaling, vesiculation, excoriation, induration, pigmentary changes and contact sensitization are not uncommon; the occlusive element may lead to miliaria rubra [2–14]. Systemic reactions may occur. Allergic skin reactions occur in up to 50% of patients with clonidine, but with glyceryl trinitrate, scopolamine, estradiol and testosterone [3] and methylphenidate [15] they are much less frequent. Reactivation of an area of contact dermatitis may develop via oral medication rarely [3]. Transdermal compared with oral metoprolol had comparable efficacy, and systemic side effects were comparable; 69% of patients had local side effects at the patch site (erythema, papular exanthem, pruritus, localized urticarial exanthem) [5]. Allergic contact dermatitis is recorded with nicotine [9–12], glyceryl trinitrate and estradiol [13], and methylphenidate [15]. Use of transdermal oestrogen patches resulted in systemic sensitization to ethanol [16]. Transdermal fentanyl patches have been associated with a diffuse rash [17]. References 1 Musel AL, Warshaw EM. Cutaneous reactions to transdermal therapeutic systems. Dermatitis 2006; 17: 109–22. 2 Hogan DJ, Maibach HI. Adverse dermatologic reactions to transdermal drug delivery systems. J Am Acad Dermatol 1990; 22: 811–4. 3 Holdiness MR. A review of contact dermatitis associated with transdermal therapeutic systems. Contact Dermatitis 1989; 20: 3–9. 4 Berti JJ, Lipsky JJ. Transcutaneous drug delivery: a practical review. Mayo Clin Proc 1995; 70: 581–6. 5 Jeck T, Edmonds D, Mengden T et al. Betablocking drugs in essential hypertension: transdermal bupranolol compared with oral metoprolol. Int J Clin Pharmacol Res 1992; 12: 139–48. 6 Kolloch RE, Mehlburger L, Schumacher H, Gobel BO. Efficacy and safety of two different galenic formulations of a transdermal clonidine system in the treatment of hypertension. Clin Auton Res 1993; 3: 373–8. 7 Antihypertensive Patch Italian Study (APIS) Investigators. One year efficacy and tolerability of clonidine administered by the transdermal route in patients with mild to moderate essential hypertension: a multicentre open label study. Clin Auton Res 1993; 3: 379–83.

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8 Breidthardt J, Schumacher H, Mehlburger L. Long-term (5 year) experience with transdermal clonidine in the treatment of mild to moderate hypertension. Clin Auton Res 1993; 3: 385–90. 9 Bircher AJ, Howard H, Rufli T. Adverse skin reactions to nicotine in a transdermal therapeutic system. Contact Dermatitis 1991; 25: 230–6. 10 Farm G. Contact allergy to nicotine from a nicotine patch. Contact Dermatitis 1993; 29: 214–5. 11 Dwyer CM, Forsyth A. Allergic contact dermatitis from methacrylates in a nicotine transdermal patch. Contact Dermatitis 1994; 30: 309–10. 12 Sudan BJ. Nicotine skin patch treatment and adverse reactions: skin irritation, skin sensitization, and nicotine as a hapten. J Clin Psychopharmacol 1995; 15: 145–6. 13 Torres V, Lopes JC, Leite L. Allergic contact dermatitis from nitroglycerin and estradiol transdermal therapeutic systems. Contact Dermatitis 1992; 26: 53–4. 14 Prisant LM. Transdermal clonidine skin reactions. J Clin Hypertens 2002; 4: 136–8. 15 Warshaw EM, Paller AS, Fowler JF, Zirwas MJ. Practical management of cutaneous reactions to the methylphenidate transdermal system: recommendations from a dermatology expert panel consensus meeting. Clin Ther 2008; 30: 326–37. 16 Grebe SK, Adams JD, Feek CM. Systemic sensitization to ethanol by transdermal estrogen patches. Arch Dermatol 1993; 129: 379–80. 17 Stoukides CA, Stegman M. Diffuse rash associated with transdermal fentanyl. Clin Pharm 1992; 11: 222.

Management of drug reactions Diagnosis Drug reactions, apart from fixed drug eruption, have non-specific clinical features, and it is often impossible to identify the offending chemical with certainty, especially when a patient with a suspected reaction is receiving many drugs simultaneously. Drug reactions may be mistaken for naturally occurring conditions and may therefore be overlooked. By the same token, it may on occasion be very difficult to state that a given eruption is drug induced. Experience with the type of reaction most commonly caused by particular drugs may enable the range of suspects to be narrowed, but familiar drugs may occasionally produce unfamiliar reactions and new drugs may mimic the reactions of the familiar. The assessment of a potential adverse drug reaction always necessitates taking a careful history, and may involve a trial of drug elimination, skin tests, in vitro tests and challenge by re-exposure [1–8]. A drug reaction may first become evident after the offending medication has been stopped, and depot injections may have delayed effects. Interpretation of elimination tests should be tempered by the knowledge that drug reactions may take weeks to settle. In vivo and in vitro tests are only applicable to truly allergic reactions. The success of drug skin testing, including prick and intradermal testing and patch testing, varies with the drug tested, with a high percentage of positive results on delayed readings of intradermal tests with beta-lactam antibiotics and heparins, or on patch testing with beta-lactam antibiotics, pristinamycin, carbamazepine and tetrazepam. The results of skin tests also depend on the clinical features of the adverse drug reaction. Regrettably, drug skin tests are as yet unreliable overall, even when apparently appropriate antigens are used; they may be hazardous [9–11]. In vitro tests are not widely available and are essentially research tools. All too frequently, therefore, the diagnosis is no more than an assessment of probability. The fact that major disagreements

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occurred between clinical pharmacologists asked to assess the likelihood of adverse drug reaction in two series confirms that identification of a responsible drug is often a subjective judgement [12,13]. An algorithm has been reported that provides detailed criteria for ranking the probability of whether a given drug is responsible for a reaction, based on (i) previous experience, (ii) the alternative aetiological candidates, (iii) timing of events, (iv) drug level and (v) the results of drug withdrawal and rechallenge [14,15]. A number of other algorithms have been developed to assist in the diagnosis of which, if any, drug is the cause of a given eruption [16–19]. In a recent review, 34 different methods for causality assessment of adverse drug reactions were identified, falling into three broad categories: expert judgement based on experience alone, algorithms for calculating the likelihood of a cause–effect relationship, and probabilistic methods (Bayesian approaches) using epidemiological information modified by the specific findings in a case to achieve a mathematical estimate of likely causation [20]. As a result of problems of reproducibility and validity, and because assessment methods are inevitably not entirely devoid of individual judgements, inter-rater reliability can be low. In conclusion, there is still no method universally accepted for causality assessment of ADRs [21]. References 1 Ring J. Diagnostik von Arzneimittel-bedingten Unverträglichkeitsreaktionz. Hautarzt 1987; 38: S16–S22. 2 Shear NH. Diagnosing cutaneous adverse reactions to drugs. Arch Dermatol 1990; 126: 94–7. 3 Nigen S, Knowles SR, Shear NH. Drug eruptions: approaching the diagnosis of drug-induced skin diseases. J Drugs Dermatol 2003; 2: 278–99. 4 Romano A, Demoly P. Recent advances in the diagnosis of drug allergy. Curr Opin Allergy Clin Immunol 2007; 7: 299–303. 5 Cotliar J. Approach to the patient with a suspected drug eruption. Semin Cutan Med Surg 2007; 26: 147–54. 6 Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin 2007; 25: 245–53, viii. 7 Sachs B, Al Masaoudi T, Merk HF, Erdmann S. Combined in vivo and in vitro approach for the characterization of penicillin-specific polyclonal lymphocyte reactivity: tolerance tests with safe penicillins instead of challenge with culprit drugs. Br J Dermatol 2004; 151: 809–16. 8 Bousquet PJ, Kvedariene V, Co-Minh HB et al. Clinical presentation and time course in hypersensitivity reactions to beta-lactams. Allergy 2007; 62: 872–6. 9 Bruynzeel D, van Ketel W. Skin tests in the diagnosis of maculopapular drug eruptions. Semin Dermatol 1987; 6: 119–24. 10 Vaillant L, Camenen I, Lorette G. Patch testing with carbamazepine: reinduction of an exfoliative dermatitis. Arch Dermatol 1989; 125: 299. 11 Machet L, Vaillant L, Dardaine V, Lorette G. Patch testing with clobazam: relapse of generalized drug eruption. Contact Dermatitis 1992; 26: 347–8. 12 Karch FE, Smith CL, Kerzner B et al. Adverse drug reactions: a matter of opinion. Clin Pharmacol Ther 1976; 19: 489–92. 13 Koch-Weser J, Sellers EM, Zacest R. The ambiguity of adverse drug reactions. Eur J Clin Pharmacol 1977; 11: 75–8. 14 Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. JAMA 1979; 242: 623–32. 15 Leventhal JM, Hutchinson TA, Kramer MS, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions. III. Results of tests among clinicians. JAMA 1979; 242: 1991–4. 16 Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 27: 239–45. 17 Louick C, Lacouture P, Mitchell A et al. A study of adverse reaction algorithms in a drug surveillance program. Clin Pharmacol Ther 1985; 38: 183–7.

18 Pere J, Begaud B, Harramburu F, Albin H. Computerized comparison of six adverse drug reaction assessment procedures. Clin Pharmacol Ther 1986; 40: 451–61. 19 Ghajar BM, Lanctôt KL, Shear NH, Naranjo CA. Bayesian differential diagnosis of a cutaneous reaction associated with the administration of sulfonamides. Semin Dermatol 1989; 8: 213–8. 20 Agbabiaka TB, Savovic´ J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf 2008; 31: 21–37. 21 Macedo AF, Marques FB, Ribeiro CF. Can decisional algorithms replace global introspection in the individual causality assessment of spontaneously reported ADRs? Drug Saf 2006; 29: 697–702.

Drug history Patients should be specifically questioned about laxatives, oral contraceptives, vaccines, homeopathic medicines, etc. as these may not be volunteered as medications. The case of a patient who developed dress after taking a dietary supplement containing phenobarbital purchased over the Internet illustrates this point [1]. They should be asked when they last took a tablet for any reason. The history should include information on when each drug was first taken relative to the onset of the reaction, whether the same or a related drug has been administered previously, and whether there is a prior history of drug sensitivity or contact dermatitis. Allergic drug reactions do not usually develop for at least 4 days, more commonly 7–10 days, after initial drug administration in a previously unsensitized individual. However, this time relationship cannot be relied on to differentiate between allergic and nonallergic reactions, as a previous sensitizing exposure may not have produced a clinically evident reaction.

Drug elimination Resolution of a reaction on withdrawal of a drug is supportive incriminatory evidence but not diagnostic. Failure of a rash to subside on drug withdrawal does not necessarily exonerate it, as traces of the drug may persist for long periods and some reactions, once initiated, continue for many days without re-exposure to the drug. The unwitting substitution of a drug that is chemically closely related may perpetuate a reaction, as when an antihistamine of phenothiazine structure is prescribed to alleviate the symptoms of a reaction caused by another phenothiazine. Elimination diets have been advocated for diagnosis of food additive intolerance leading to urticaria [2,3]. References 1 Kubota Y, Yoneda K, Nakai K et al. DRESS in a patient taking a dietary supplement containing phenobarbital purchased over the internet. Eur J Dermatol 2008; 18: 209–10. 2 Rudzki E, Czubalski K, Grzywa Z. Detection of urticaria with food additives intolerance by means of diet. Dermatologica 1980; 161: 57–62. 3 Metcalfe DD, Sampson HA, eds. Workshop on experimental methodology for clinical studies of adverse reactions to foods and food additives. J Allergy Clin Immunol 1990; 86 (Suppl.): 421–42.

Skin testing Skin testing has been extensively reviewed [1–16]. Drug skin tests are of three types: prick tests for immediate hypersensitivity, patch tests for delayed cellular hypersensitivity, and intradermal tests for both immediate and delayed hypersensitivity. Drug skin tests should be performed 6 weeks to 6 months after complete resolution of the reaction, as it is unknown whether positive results will

Management of drug reactions

persist. Appropriate controls are essential to avoid false-positive results. Drug prick tests are performed on the volar forearm skin with the commercialized form of the drug, but with sequential dilutions in cases of urticaria. Intradermal tests are performed with sequential dilutions (10–4, 10–3, 10–2, 10–1) of 0.04 mL of a pure sterile or injectable form of the drug. Prick tests and intradermal tests should be read at 20 min and at 24 h. For patch tests, the commercial form of the drug should be tested diluted at 30% in petrolatum and/or water; the pure drug should be tested diluted at 10%. Lower concentrations should be used in severe drug reactions such as dress. It is useful to carry out the test on the site most affected in the initial reaction [17]. Patch tests are read at day 2 and day 4 and preferably also at 1 week. The quick patch test (application under a Finn chamber for 30 min) can be used in patients with severe hypersensitivity [18]. Prick tests and intradermal tests performed with sequential dilutions may be useful in the identification of patients who present with immediate IgE-related hypersensitivity reactions to certain drugs, such as penicillin and other beta-lactam antibiotics, agents used in general anaesthesia, tetanus toxoid, streptokinase, chymopapain, heterologous sera or insulin, and may thus aid in the prevention of anaphylaxis [8] (see also following sections). Older series suggested that positive patch tests were found in about 15% of patients with drug eruptions [2,3] and 25% of patients with penicillin allergy [1–3]. More recent reviews have indicated that drug patch tests are positive in 32–50% of patients with a drug eruption, being of potential value in generalized eczema, systemic contact dermatitis, photosensitivity (photopatch testing), maculopapular rashes, acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption [12,13]. Significantly higher numbers of positive patch tests are seen in maculopapular than in urticarial reactions [11]. Drug skin tests are of occasional value in investigating Stevens–Johnson syndrome or TEN; relevant positive patch tests were seen in only 9% of 22 patients with Stevens– Johnson syndrome/TEN compared with 50% of 14 patients with AGEP [19]. Vasculitis related to circulating immune complexes is not amenable to investigation by skin testing. Unfortunately, the usefulness of skin testing is limited by the fact that the significant antigenic determinants are unknown for most drugs. False-negative skin testing may occur because of poor absorption through the skin, because a metabolite rather than the substance administered in the test is the sensitizing antigen, or because testing is performed either too soon after a reaction, in a refractory period, or too late, so that the patient no longer demonstrates skin-test reactivity. False-positive reactions may also occur in drug allergy skin testing. Sodium lauryl sulphate in the commercial form of some drugs can induce irritation when they are patch tested as such, and positive patch tests to drugs can be related to an excipient [11,20], such as the surfactant polysorbate or the emulsion stabilizer carboxymethylcellulose, or even to sensitization to petrolatum [21] rather than the drug itself. Moreover, intradermal testing is not always safe. A patch test with a solution of the drug will sometimes induce a generalized petechial reaction in patients with purpura caused by drug sensitivity, for example in carbromal or apronalide (Sedormid) purpura. Anaphylactoid responses may occur even in response to the small amounts of drug absorbed from a patch test. Re-elicitation of an

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exfoliative dermatitis [19,22] and relapse of a generalized drug eruption [23] have followed patch testing. The results of skin-test reactions, including intradermal testing and patch testing, were evaluated in 242 patients with delayedtype (non-immediate) drug eruptions [14]. Intradermal testing was positive in 89.7% of patients, and patch tests were positive in 31.5% of cases; overall, 62% of patients had either a positive intradermal or patch test. Intradermal testing was more frequently positive in maculopapular rashes, erythema multiforme and erythrodermic rashes than in eczematous reactions, whereas positive patch tests were comparatively frequent in erythroderma, eczematous reactions and anticonvulsant-induced reactions. It was concluded that a combination of patch testing and intradermal testing is useful in the demonstration of causative agents in delayed-type drug eruptions. Skin tests, including patch tests and skin prick tests, were examined in 947 patients with a history of suspected cutaneous adverse drug reaction [16]. Positive patch test reactions to one or more drugs were seen in 10.8%, most often to beta-lactams, clindamycin and trimethoprim, whereas positive prick test reactions were seen in only 1.1% of patients. Eighty-one per cent of patch test-positive patients who underwent drug challenge developed exanthema, whereas only 9.6% of challenges in skin test-negative individuals resulted in a drug eruption, either exanthema, fixed drug eruption or urticaria. It was again concluded that skin testing, especially patch testing, was a useful screening method to find a cause of exanthematous adverse drug reactions. References 1 Bruynzeel DP, von Blomberg-van der Flier M, Scheper RJ et al. Allergy for penicillin and the relevance of epicutaneous tests. Dermatologica 1985; 171: 429–34. 2 Bruynzeel DP, van Ketel WG. Skin tests in the diagnosis of maculo-papular drug eruptions. Semin Dermatol 1987; 6: 119–24. 3 Bruynzeel DP, van Ketel WG. Patch testing in drug eruptions. Semin Dermatol 1989; 8: 196–203. 4 Calkin JM, Maibach HI. Delayed hypersensitivity drug reactions diagnosed by patch testing. Contact Dermatitis 1993; 29: 223–33. 5 Alanko K, Stubb S, Reitamo S. Topical provocation of fixed drug eruption. Br J Dermatol 1987; 116: 561–7. 6 Alanko K. Topical provocation of fixed drug eruption. A study of 30 patients. Contact Dermatitis 1994; 31: 25–7. 7 Lee A-Y. Topical provocation in 31 cases of fixed drug eruption: change of causative drugs in 10 years. Contact Dermatitis 1998; 38: 258–60. 8 Sussman GL, Dolovich J. Prevention of anaphylaxis. Semin Dermatol 1989; 8: 158–65. 9 Deleo VA. Skin testing in systemic cutaneous drug reactions. Lancet 1998; 352: 1488–90. 10 Barbaud A, Goncalo M, Bruynzeel D, Bircher A. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis 2001; 45: 321–8. 11 Barbaud A, Trechot P, Reichert-Penetrat S et al. Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions. Contact Dermatitis 2001; 45: 265–8. 12 Barbaud A. The use of skin testing in the investigation of toxidermia: from pathophysiology to the results of skin testing. Therapie 2002; 57: 258– 62. 13 Barbaud A. Drug patch testing in systemic cutaneous drug allergy. Toxicology 2005; 209: 209–16. 14 Osawa J, Naito S, Aihara M et al. Evaluation of skin test reactions in patients with non-immediate type drug eruptions. J Dermatol 1990; 17: 235–9. 15 Bruynzeel DP, Maibach HI. Patch testing in systemic drug eruptions. Clin Dermatol 1997; 15: 479–84.

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16 Lammintausta K, Kortekangas-Savolainen O. The usefulness of skin tests to prove drug hypersensitivity. Br J Dermatol 2005; 152: 968–74. 17 Barbaud A, Trechot P, Reichert-Penetrat S et al. The usefulness of patch testing on the previously most severely affected site in a cutaneous adverse drug reaction to tetrazepam. Contact Dermatitis 2001; 44: 259–60. 18 Oi M, Satoh T, Yokozeki H, Nishioka K. Detection of immediate-type reaction to the epitope of β-lactam antibiotics by the quick patch test. Br J Dermatol 2003; 148: 182–3. 19 Wolkenstein P, Chosidow O, Fléchet ML et al. Patch testing in severe cutaneous adverse drug reactions including Stevens–Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis 1996; 35: 234–6. 20 Grims RH, Kränke B, Aberer W. Pitfalls in drug allergy skin testing: false-positive reactions due to (hidden) additives. Contact Dermatitis 2006; 54: 290–4. 21 Ulrich G, Schmutz JL, Trechot P et al. Sensitization to petrolatum: an unusual cause of false-positive drug patch-tests. Allergy 2004; 59: 1006–9. 22 Vaillant L, Camenen I, Lorette G. Patch testing with carbamazepine: reinduction of an exfoliative dermatitis. Arch Dermatol 1989; 125: 299. 23 Machet L, Vaillant L, Dardaine V, Lorette G. Patch testing with clobazam: relapse of generalized drug eruption. Contact Dermatitis 1992; 26: 347–8.

Patch testing Patch testing in a previously involved site, but not in normal skin, yielded a positive response in a proportion of cases of fixed drug eruption, especially with phenazone (pyrazolone) derivatives (e.g. phenylbutazone), but also with a sulphonamide, doxycycline, trimethoprim, chlormezanone, a barbiturate and carbamazepine [1]. In a series of 30 patients [2], positive reactions were always seen with phenazone salicylate and carbamazepine, and in one case with chlormezanone. Both positive and negative reactions were seen with trimethoprim, doxycycline and sulfadiazine. The vehicle used as a diluent for the drug may be important in determining whether a reaction is seen; use of dimethylsulfoxide as the vehicle may increase the number of positive patch tests [1,3,4]. Topical provocation of fixed drug eruption has also been reported with sulfamethoxazole [5], dimenhydrinate [6] and metronidazole [7]. However, other reports in the literature do not suggest that patch testing is helpful in fixed drug eruption [8]. Patch testing has supported a diagnosis of allergy, in the absence of topical sensitization, to diazepam, meprobamate and practolol [9], anticonvulsants including hydantoin derivatives and carbamazepine [10–12] (but only in patients with exfoliative dermatitis and maculopapular exanthem and not with fixed drug eruption, erythema multiforme or urticaria [11]), tartrazine dyes [13], chloramphenicol [14], diclofenac-induced maculopapular eruption [15], and in TEN induced by ampicillin [16]. Antibiotics (especially penicillin, ampicillin and other beta-lactam antibiotics [17,18], cephalosporins [19] and aminoglycosides), NSAIDs (pyrazolone derivatives and occasionally aspirin), neuroleptics (phenothiazines, barbiturates, meprobamate, benzodiazepines), β-blockers, gold salts, carbimazole, amantadine, corticosteroids, mitomycin, heparin and amide anaesthetics have all been associated with positive drug patch tests in allergic subjects. Positive patch tests to the following drugs have been found in patients with acute generalized exanthematous pustulosis: diltiazem [20,21], metronidazole [22], nystatin [23] and terbinafine [24]. References 1 Alanko K, Stubb S, Reitamo S. Topical provocation of fixed drug eruption. Br J Dermatol 1987; 116: 561–7. 2 Alanko K. Topical provocation of fixed drug eruption. A study of 30 patients. Contact Dermatitis 1994; 31: 25–7.

3 Özkaya-Bayazit E, Güngör H. Trimethoprim-induced fixed drug eruption: positive topical provocation on previously involved and uninvolved skin. Contact Dermatitis 1997; 39: 87–8. 4 Özkaya-Bayazit H, Ozarmagan G. Topical provocation in 27 cases of cotrimoxazole-induced fixed drug eruption. Contact Dermatitis 1999; 41: 185–9. 5 Oleaga JM, Aguirre A, Gonzalez M, Diaz-Perez JL. Topical provocation of fixed drug eruption due to sulphamethoxazole. Contact Dermatitis 1993; 29: 155. 6 Smola H, Kruppa A, Hunzelmann N et al. Identification of dimenhydrinate as the causative agent in fixed drug eruption using patch-testing in previously affected skin. Br J Dermatol 1998; 138: 920–1. 7 Short KA, Salisbury JR, Fuller LC. Fixed drug eruption following metronidazole therapy and the use of topical provocation testing in diagnosis. Clin Exp Dermatol 2002; 27: 464–6. 8 Sehgal VN, Gangwani OP. Fixed drug eruption. Current concepts. Int J Dermatol 1987; 26: 67–74. 9 Felix RE, Comaish JS. The value of patch and other skin tests in drug eruptions. Lancet 1984; i: 1017–9. 10 Houwerzijl J, de Gast GC, Nater JP. Patch test in drug eruptions. Contact Dermatitis 1982; 8: 155–8. 11 Alanko K. Patch testing in cutaneous reactions caused by carbamazepine. Contact Dermatitis 1993; 29: 254–7. 12 Jones M, Fernandez-Herrera J, Dorado JM et al. Epicutaneous test in carbamazepine cutaneous reactions. Dermatology 1994; 188: 18–20. 13 Roeleveld CG, Van Ketel WG. Positive patch tests to the azo dye tartrazine. Contact Dermatitis 1976; 2: 180. 14 Rudzki E, Grzywa Z, Maciejowska E. Drug reaction with positive patch tests to chloramphenicol. Contact Dermatitis 1976; 2: 181. 15 Romano A, Pietrantonio F, Di Fonso M et al. Positivity of patch tests in cutaneous reaction to diclofenac. Two case reports. Allergy 1994; 49: 57–9. 16 Tagami H, Tatsuda K, Iwatski K, Yamada M. Delayed hypersensitivity in ampicillin-induced toxic epidermal necrolysis. Arch Dermatol 1983; 119: 910–3. 17 Galindo Bonilla PA, Garcia Rodriguez R, Feo Brito F et al. Patch testing for allergy to beta-lactam antibiotics. Contact Dermatitis 1994; 31: 319–20. 18 Romano A, Di Fonso M, Pietrantonio F et al. Repeated patch testing in delayed hypersensitivity to beta-lactam antibiotics. Contact Dermatitis 1993; 28: 190. 19 Gonzalo-Garijo MA, Rodríguez-Nevado I, de Argila D. Patch tests for diagnosis of delayed hypersensitivity to cephalosporins. Allergol Immunopathol (Madr) 2006; 34: 39–41. 20 Vincente-Calleja JM, Aguirre A, Landa N et al. Acute generalized exanthematous pustulosis due to diltiazem: confirmation by patch testing. Br J Dermatol 1997; 137: 837–9. 21 January V, Machet L, Gironet N et al. Acute generalized exanthematous pustulosis induced by diltiazem: value of patch testing. Dermatology 1998; 197: 274–5. 22 Watsky KL. Acute generalised exanthematous pustulosis induced by metronidazole: the role of patch testing. Arch Dermatol 1999; 135: 93–4. 23 Kuchler A, Hamm H, Weidenthaler-Barth B et al. Acute generalized exanthematous pustulosis following oral nystatin therapy: a report of three cases. Br J Dermatol 1997; 137: 808–11. 24 Kempinaire A, De Raeve L, Merckx M et al. Terbinafine-induced acute generalized exanthematous pustulosis confirmed by positive patch-test result. J Am Acad Dermatol 1997; 37: 653–5.

Penicillin It is clearly important to exclude from treatment with penicillin those patients truly at risk of developing hypotensive episodes or fatal anaphylaxis. The role of skin testing in this situation has been reviewed [1–11]. Skin tests should be carried out using majordeterminant antigens (benzylpenicilloyl polylysine, PPL) and minor-determinant mixture (benzylpenicillin, benzylpenicilloate and benzylpenilloate) antigens [12]. Allergopharma and HollisterStier stopped production of penicillin reagents around 2005, but new reagents from Diater (DAP) are a safe alternative [13,14]. Procedures have been published, and the reader is referred to the

Management of drug reactions

original articles for details about methodology [12,15,16]. Epicutaneous testing should precede intradermal testing, and positive (histamine or opiate) and negative (diluent) controls should be included. False-negative results may be found after a systemic allergic reaction, as a result of a refractory period or temporary desensitization, so that skin testing should be postponed for at least 4–6 weeks [12]. There is a high incidence of wrongly diagnosed penicillin allergy on the basis of history, and a considerable proportion of patients who have had proven allergic reactions to penicillins eventually stop producing the IgE antibody responsible. A recent study in fact reported that even positive penicillin skin test results for patients with a remote history of non-life-threatening allergic reaction to penicillin were not associated with a greater prevalence of adverse reactions to oral challenge with penicillin than negative results [17]. In a large study, only 1% of 566 patients with a history of penicillin allergy, and negative skin tests to major determinant (PPL) and minor-determinant mixture and its components (potassium benzylpenicillin, benzylpenicilloate and benzylpenicilloylN-propylamine), had possibly IgE-mediated reactions [3]. Similarly, only 1.7% of 290 patients with a history of beta-lactam allergy and negative penicillin skin test results had urticarial adverse reactions [18]. In another study [6], 7.1% of 776 individuals with a previous history of penicillin allergy, and 1.7% of 4287 subjects negative by history, had positive skin tests to major determinant (PPL) and/or a minor-determinant mixture. Positive skin tests were seen in 17% and 12% of patients with a history of anaphylaxis or urticaria, respectively, but in only 4% with a history of an exanthem. Mild adverse reactions to skin tests occurred in 1% of patients positive by history and 9% of those with positive skin tests. In patients with negative skin tests who received benzylpenicillin or ampicillin, mild acute allergic reactions occurred in 0.5% of subjects negative by history and 2.9% of subjects positive by history. Thus, routine penicillin skin testing can facilitate the safe use of penicillin in 90% of individuals with a previous history of allergy [6]. Positive skin tests, an average of 5 years later, to major and minor determinants of benzylpenicillin and/or minor-determinant mixtures of ampicillin, amoxicillin or cloxacillin were found in 19% of 112 patients with a history of urticaria and angio-oedema or exanthem to penicillins and other semi-synthetic penicillins (most frequently ampicillin and amoxicillin) [7]. Skin-test reactivity was limited in about half to the semi-synthetic penicillin reagents derived from ampicillin, amoxicillin or cloxacillin. The existence of isolated skin-test positivity to reagents specific for ampicillin or amoxicillin, with good tolerance of major and minor penicillin determinants, has been confirmed in other reports [8,19,20], emphasizing the necessity for using reagents specific for the side-chains of these aminopenicillin drugs to exclude possible immediate hypersensitivity in patients who reacted to these antibiotics clinically [7–10,19,20]. Thus, 7% of 288 patients with a history of penicillin allergy reacted only to skin testing with amoxicillin and not to benzylpenicillin or phenoxymethylpenicillin diagnostic reagent determinants [21]; these would have been missed if the latter agents had been used alone. Patients treated with penicillin after a negative skin test to PPL and to minor-determinant mixture develop IgE-mediated reactions only very rarely, and these are almost always mild and

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self-limited [1,3,6]. Thus, when adequately performed, negative skin tests indicate that the risk of a life-threatening reaction is almost negligible, and that any beta-lactam antibiotic may be safely given. In contrast, the risk of an acute allergic reaction, including respiratory obstruction or hypotension, with a positive history and positive skin test is 50–70%; the risk in a patient with a negative history but a positive skin test is about 10% [1,12,21]. Both patch testing and intradermal testing appeared valuable for the diagnosis of non-immediate reactions to aminopenicillins, but intradermal testing diagnosed more patients than patch testing [22]. Intradermal skin testing is generally safe, with few reactions, and although skin testing may rarely cause sensitization [23], it does not usually do so [12]. However, there is a risk, albeit very small, of fatality from skin testing [24]. A more major problem with skin testing is that use of the major determinant (PPL) alone misses about 10–25% of all positive subjects, and that even addition of benzylpenicillin G as the sole minor-determinant antigen misses 5–10% of positive subjects [25,26]. This is significant because patients with reactivity to minor antigenic determinants are thought to be at a higher risk for anaphylaxis [12,27]. In addition, as detailed above, reagents for detecting sensitivity to aminopenicillins (ampicillin and amoxicillin) should be used [16]. Comprehensive skin testing is therefore only practicable in specialized centres. Skin tests can give both false-positive and false-negative reactions [21]. Thus, it has been argued that a positive or negative result in an individual patient cannot be used to entirely reliably predict outcome [28]. Further difficulties are that skin prick tests have no predictive value in non-IgE-mediated reactions such as serum sickness, haemolytic anaemia, drug fever, interstitial nephritis, contact dermatitis, maculopapular exanthems or exfoliative dermatitis. Accelerated or late IgE-mediated reactions may occur despite a negative pretreatment skin test [1,12]. Positive intradermal skintest reactions occurred in only 87% of patients with a history of delayed-type rashes induced by penicillins and cephalosporins, and who had positive oral provocation tests [29]. Oral challenge was positive in 18 of 33 patients with positive delayed skin testing and patch testing to ampicillin or amoxicillin, but also in 16 of 27 patients with negative allergy tests [30]. Skin testing is contraindicated where there is a history of exfoliative dermatitis, Stevens–Johnson syndrome or TEN. There is clearly individual variation in the approach to the diagnosis and management of beta-lactam allergy [11], based on a survey of 3500 physician members and fellows of the American Academy of Allergy and Immunology and of allergy training programme directors in the USA. PPL and fresh penicillin G were used for skin testing by more than 86% of both respondent groups, whereas minor-determinant mixtures were used by only 40%. Epicutaneous followed by intradermal injection was the skin-test technique used by 86% of these allergists. References 1 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 2 Shepherd G, Mendelson L. The role of skin testing for penicillin allergy. Arch Intern Med 1992; 152: 2505. 3 Sogn DD, Evans R III, Shepherd GM et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive

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value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992; 152: 1025–32. Lin RY. A perspective on penicillin allergy. Arch Intern Med 1992; 152: 930–7. Weiss ME. Evaluation and treatment of patients with prior reactions to beta-lactam antibiotics. Curr Clin Top Infect Dis 1993; 3: 131–45. Gadde J, Spence M, Wheeler B, Adkinson NF Jr. Clinical experience with penicillin skin testing in a large inner-city STD clinic. JAMA 1993; 270: 2456–63. Silviu-Dan F, McPhillips S, Warrington RJ. The frequency of skin test reactions to side-chain penicillin determinants. J Allergy Clin Immunol 1993; 91: 694–701. Audicana M, Bernaola G, Urrutia I et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin. Allergy 1994; 49: 108–13. Blanca M. The contribution of the side chain of penicillins in the induction of allergic reactions. J Allergy Clin Immunol 1994; 94: 562–3. Warrington RJ. The contribution of the side chain of penicillins in the induction of allergic reactions. J Allergy Clin Immunol 1995; 95: 640. Wickern GM, Nish WA, Bitner AS, Freeman TM. Allergy to beta-lactams: a survey of current practices. J Allergy Clin Immunol 1994; 94: 725–31. Weber EA, Knight A. Testing for allergy to antibiotics. Semin Dermatol 1989; 8: 204–12. Romano A, Viola M, Bousquet PJ et al. A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity. Allergy 2007; 62: 53–8. Matheu V, Pérez E, González R et al. Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy. J Investig Allergol Clin Immunol 2007; 17: 257–60. Adkinson NF Jr. Tests for immunoglobulin drug reactions. In: Rose NF, Friedman H, eds. Manual of Clinical Immunology. Washington, DC: American Society for Microbiology, 1986: 692–7. Lisi P, Lapomarda V, Stingeni L et al. Skin tests in the diagnosis of eruptions caused by betalactams. Contact Dermatitis 1997; 37: 151–4. Goldberg A, Confino-Cohen R. Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy. Ann Allergy Asthma Immunol 2008; 100: 37–43. del Real GA, Rose ME, Ramirez-Atamoros MT et al. Penicillin skin testing in patients with a history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007; 98: 355–9. Blanca M, Vega JM, Garcia J et al. Allergy to penicillin with good tolerance to other penicillins: study of the incidence in subjects allergic to betalactams. Clin Exp Allergy 1990; 20: 475–81. Vega JM, Blanca M, Garcia JJ et al. Immediate allergic reactions to amoxicillin. Allergy 1994; 49: 317–22. Green GR, Rosenblum AH, Sweet LC. Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. A cooperative prospective study of the penicillin Study Group of the American Academy of Allergy. J Allergy Clin Immunol 1977; 60: 339–45. Torres MJ, Sánchez-Sabaté E, Alvarez J et al. Skin test evaluation in nonimmediate allergic reactions to penicillins. Allergy 2004; 59: 219–24. Nugent JS, Quinn JM, McGrath CM et al. Determination of the incidence of sensitization after penicillin skin testing. Ann Allergy Asthma Immunol 2003; 90: 398–403. Dogliotti M. An instance of fatal reaction to the penicillin scratch test. Dermatologica 1968; 136: 489–96. Gorevic PD, Levine BB. Desensitization of anaphylactic hypersensitivity specific for the penicilloate minor determinant of penicillin and carbenicillin. J Allergy Clin Immunol 1981; 68: 267–72. Sogn DD. Penicillin allergy. J Allergy Clin Immunol 1984; 74: 589–93. Adkinson NF Jr. Risk factors for drug allergy. J Allergy Clin Immunol 1984; 74: 567–72. Ewan P. Allergy to penicillin. BMJ 1991; 302: 1462. Aihara M, Ikezawa Z. Evaluation of the skin test reactions in patients with delayed type rash induced by penicillins and cephalosporins. J Dermatol 1987; 14: 440–8. Romano A, Di Fonso M, Papa G et al. Evaluation of adverse cutaneous reactions to aminopenicillins with emphasis on those manifested by maculopapular rashes. Allergy 1995; 50: 113–8.

Iodinated contrast media Diagnostic measures have been reviewed [1]. Reference 1 Kvedariene V, Martins P, Rouanet L, Demoly P. Diagnosis of iodinated contrast media hypersensitivity: results of a 6-year period. Clin Exp Allergy 2006; 36: 1072–7.

Agents used in general anaesthesia Intradermal [1–4] or prick [5,6] testing may be helpful in identifying the causative drug [7], and is essential in confirming lack of sensitivity to pancuronium before use in cases of documented sensitivity to other relaxants [3]. In one series of patients with a history of anaphylaxis during induction of general anaesthesia, skin testing was performed by the prick and intracutaneous methods with dilutions of thiobarbiturates, muscle relaxants or beta-lactam antibiotics [8]. No patient experienced a recurrence of anaphylaxis during subsequent general anaesthesia when agents producing positive skin tests were avoided, provided a premedication regimen of prednisone and diphenhydramine was given [8]. However, there is controversy over the diagnostic value of intradermal tests for the diagnosis of anaphylaxis during anaesthesia with the newer aminosteroidal neuromuscular blocking agents pancuronium, vecuronium and rocuronium and the benzylisoquinoline cisatracurium, as these all may induce nonspecific skin reactivity [9]. Strategies for prevention of reactions have been recently reviewed [10]. References 1 Fisher MMcD. Intradermal testing in the diagnosis of acute anaphylaxis during anaesthesia: results of five years experience. Anaesth Intensive Care 1979; 7: 58–61. 2 Fisher MMcD. The diagnosis of acute anaphylactoid reactions to neuromuscular blocking agents: a commonly undiagnosed condition. Anaesth Intensive Care 1981; 9: 235–41. 3 Galletly DC, Treuren BC. Anaphylactoid reactions during anaesthesia. Seven years’ experience of intradermal testing. Anaesthesia 1985; 40: 329–33. 4 Soetens FM, Smolders FJ, Meeuwis HC et al. Intradermal skin testing in the investigation of suspected anaphylactic reactions during anaesthesia: a retrospective survey. Acta Anaesthesiol Belg 2003; 54: 59–63. 5 Leynadier F, Sansarricq M, Didier JM, Dry J. Prick tests in the diagnosis of anaphylaxis to general anaesthetics. Br J Anaesth 1987; 59: 683–9. 6 Moneret-Vautrin DA, Laxenaire MC. Anaphylaxis to muscle relaxants: predictive tests. Anaesthesia 1990; 45: 246–7. 7 Moneret-Vautrin DA, Laxenaire MC. Skin tests in diagnosis of allergy to muscle relaxants and other anesthetic drugs. Monogr Allergy 1992; 30: 145–55. 8 Moscicki RA, Sockin SM, Corsello BF et al. Anaphylaxis during induction of general anesthesia: subsequent evaluation and management. J Allergy Clin Immunol 1990; 86: 325–32. 9 Mertes PM, Moneret-Vautrin DA, Leynadier F, Laxenaire MC. Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers. Anesthesiology 2007; 107: 245–52. 10 Liccardi G, Lobefalo G, Di Florio E et al. Strategies for the prevention of asthmatic, anaphylactic and anaphylactoid reactions during the administration of anesthetics and/or contrast media. J Investig Allergol Clin Immunol 2008; 18: 1–11.

Local anaesthetics Avoidance of local anaesthetics on the basis of a vague or equivocal history of a prior adverse reaction may result in substantial increased pain and risk. True allergic reactions probably constitute no more than 1% of all adverse reactions to these drugs, some, but

Management of drug reactions

not the majority, of which are due to preservatives, especially parabens. Skin testing and/or incremental challenge beginning with diluted drug is a safe and effective method for identifying a drug that a patient with a history of an adverse reaction can tolerate [1–8]. Patients with positive patch tests to local anaesthetics and a negative history of anaphylactoid reactions rarely have positive intradermal skin tests. The risk of anaphylactic reactions with amide local anaesthetics (except butanilicaine) is therefore low in such patients [3]. Conversely, patients with anaphylactic reactions to local anaesthetics are usually patch-test negative [3]. Skin testing may produce systemic adverse reactions, especially with undiluted drug. False-positive reactions occur, but false-negative reactions have not been reported, and most skin-tested patients who tolerate a local anaesthetic are skin-test negative to the drug. The choice of a drug for use in skin testing and incremental challenge may be facilitated by current concepts of non-cross-reacting groups of local anaesthetics. Thus, benzoic acid esters, both those with and without p-aminobenzoyl groups, do not cross-react with amide local anaesthetic agents. References 1 Schatz M. Skin testing and incremental challenge in the evaluation of adverse reactions of local anesthetics. J Allergy Clin Immunol 1984; 74: 606–16. 2 Fisher MMcD, Graham R. Adverse responses to local anaesthetics. Anaesth Intensive Care 1984; 12: 325–7. 3 Ruzicka T, Gerstmeier M, Przybilla B, Ring J. Allergy to local anesthetics: comparison of patch test with prick and intradermal test results. J Am Acad Dermatol 1987; 16: 1202–8. 4 Glinert RJ, Zachary CB. Local anesthetic allergy. Its recognition and avoidance. J Dermatol Surg Oncol 1991; 17: 491–6. 5 Hodgson TA, Shirlaw PJ, Challacombe SJ. Skin testing after anaphylactoid reactions to dental local anesthetics. A comparison with controls. Oral Surg Oral Med Oral Pathol 1993; 75: 706–11. 6 Wasserfallen JB, Frei PC. Long-term evaluation of usefulness of skin and incremental challenge tests in patients with history of adverse reaction to local anesthetics. Allergy 1995; 50: 162–5. 7 Gall H, Kaufmann R, Kalveram CM. Adverse reactions to local anesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996; 97: 933–7. 8 Phillips JF, Yates AB, Deshazo RD. Approach to patients with suspected hypersensitivity to local anesthetics. Am J Med Sci 2007; 334: 190–6.

Analgesics and NSAIDs Prick tests were positive in only 13% of 117 patients with a history suggestive of anaphylactoid reactions to a variety of mild analgesics, including NSAIDs [1]. Delayed-reading intradermal tests were more sensitive than patch tests in the diagnosis of nonimmediate reactions to pyrazolones [2]. References 1 Przybilla B, Ring J, Harle R, Galosi A. Hauttestung mit Schmerzmittelinhaltsstoffen bei Patienten mit anaphylaktoiden Unverträgli-chkeitsreaktionen auf ‘leichte’ Analgetika. Hautarzt 1985; 36: 682–7. 2 Macías E, Ruiz A, Moreno E et al. Usefulness of intradermal test and patch test in the diagnosis of nonimmediate reactions to metamizol. Allergy 2007; 62: 1462–4.

Heparin Provocation testing may be a useful diagnostic measure [1–7]. Low-molecular-weight heparin analogues may be satisfactorily substituted in some patients with this reaction, but are not always tolerated [2]. Subcutaneous testing of a panel of heparins, danaparoid and desirudin (hirudin) is recommended for determining

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acceptable treatment options for patients allergic to specific heparins [3,6]. In type I reactions, or in the presence of skin necrosis with or without heparin-induced thrombocytopenia, a lowmolecular-weight heparin should be replaced by danaparoid sodium or hirudin. In the presence of a negative subcutaneous provocation test, the compound can be used with little risk. If all types of low-molecular-weight heparin and danaparoid sodium show positive skin tests, oral anticoagulants should be used, and intravenous injections of any kind of heparin should be avoided because of the potential for anaphylactic shock. References 1 Zimmermann R, Harenberg J, Weber E et al. Behandlung bei heparin-induzierter kutaner Reaktion mit einem niedermolekularen Heparin-Analog. Dtsch Med Wochenschr 1984; 109: 1326–8. 2 Klein GF, Kofler H, Wol H, Fritsch PO. Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989; 21: 703–7. 3 Wutschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 1999; 20: 515–25. 4 Koch P, Münßinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612–9. 5 Szolar-Platzer C, Aberer W, Kranke B. Delayed-type skin reaction to the heparinalternative danaparoid. J Am Acad Dermatol 2000; 43: 920–2. 6 Grassegger A, Fritsch P, Reider N. Delayed-type hypersensitivity and crossreactivity to heparins and danaparoid: a prospective study. Dermatol Surg 2001; 27: 47–52. 7 Ludwig RJ, Schindewolf M, Utikal J et al. Management of cutaneous type IV hypersensitivity reactions induced by heparin. Thromb Haemost 2006; 96: 611–7.

Skin testing in urticaria Skin tests have been advocated as useful in the investigation of chronic urticaria [1,2]. Patch testing with a series of penicillins was positive in 6.9% of patients in one study [1], and there were positive intracutaneous tests to cilligen and/or penicillin G in 21.5% of patients. Avoidance of dietary dairy produce, which potentially might have contained penicillin, alleviated the urticaria in 50% of the penicillin-allergic patients. The reported prevalence of positive intracutaneous tests to penicillin was much higher in this study than in other reported series in the literature. References 1 Boonk WJ, van Ketel WG. Skin testing in chronic urticaria. Dermatologica 1981; 163: 151–9. 2 Antony SJ, Fisher RH. Association of penicillin allergy with idiopathic anaphylaxis. J Fam Pract 1993; 37: 499–502.

In vitro tests Tests for IgE antibody The detection of drug-specific circulating antibodies does not prove an allergy. It is important to record when a blood test is taken in relation to the evolution of a drug reaction, as the antibody response to a drug has a finite duration. For example, antipenicillin IgE antibodies begin to disappear within 10–30 days. Radioallergosorbent tests (RASTs) for drug-specific IgE class antibody are available for penicillin, insulin and ACTH. RAST detects specific IgE antibody to the penicilloyl determinant, and is positive in 60–90% of patients with a positive skin test to PPL [1,2];

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however, there is no in vitro test for minor-determinant antigens, and therefore in practice this test is of very limited use [2,3]. The specificity of beta-lactam-specific IgE measurement is good but sensitivity is low [4]. Investigation of cross-reactivity of antibodies to penicillin in 123 patients with a history of penicillin allergy, using enzyme-linked immunosorbent assay, detected IgE antibodies specific to amoxicillin, ampicillin or flucloxacillin, respectively, in three patients [5]. These antibodies did not cross-react with other penicillin antigens, and would have been missed had testing involved only the use of benzylpenicillin. Thus, allergy to semisynthetic penicillins can occur without allergy to benzylpenicillin, negative tests specific for benzylpenicillin or phenoxymethylpenicillin cannot be generalized to other penicillins, and exclusive reliance on benzylpenicilloyl RAST to detect allergy to semisynthetic penicillins could lead to serious adverse consequences [6]. The Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl test is beneficial for evaluating patients allergic to beta-lactams [7]. IgE antibodies specific for 1-phenyl-2,3-dimethyl3-pyrazoline-5-one were found in 17 of 19 serum samples from individuals sensitive to pyrazoline drugs with 4-aminoantipyrine discs by RAST [8]. References 1 Wide L, Juhlin L. Detection of penicillin allergy of the immediate type by radioimmunoassay of reagins (IgE) to penicilloyl conjugates. Clin Allergy 1971; 1: 171–7. 2 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 3 Ewan P. Allergy to penicillin. BMJ 1991; 302: 1462. 4 Fontaine C, Mayorga C, Bousquet PJ et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy. Allergy 2007; 62: 47–52. 5 Christie G, Coleman J, Newby S et al. A survey of the prevalence of penicillin specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition in patients with suspected penicillin allergy and in healthy volunteers. Br J Clin Pharmacol 1988; 25: 381–6. 6 Walley T, Coleman J. Allergy to penicillin. BMJ 1991; 302: 1462–3. 7 Blanca M, Mayorga C, Torres MJ et al. Clinical evaluation of Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy. Allergy 2001; 56: 862–70. 8 Zhu D, Becker WM, Schulz KH et al. Detection of IgE antibodies specific for 1-phenyl-2,3-dimethyl-3-pyrazoline-5-one by RAST: a serological diagnostic method for sensitivity to pyrazoline drugs. Asian Pac J Allergy Immunol 1992; 10: 95–101.

Miscellaneous in vitro tests The histamine-release test [1], basophil degranulation test [2–6] and passive haemagglutination test [7] are of limited use. A positive basophil degranulation assay, which involves binding of drug to specific IgE on the basophil surface, has been reported with penicillin, erythromycin, sulphonamides, non-steroidals and aspirin, but false-negative results are common. The leukocyte and macrophage migration inhibition tests [8–11], platelet-activating factor release from white blood cells after antigenic challenge as tested by platelet aggregation [12], and the lymphocyte toxicity assay [13–16] have essentially been research tools. A number of drugs have been reported to induce lymphocyte proliferation, as determined by incorporation of 3H-thymidine, in patients with drug eruptions, including penicillin, carbamazepine, phenytoin, furosemide, sulfamethoxazole and hydrochlorothiazide [17–22]. Positive lymphocyte transformation test reactions were obtained when the test was performed at the acute stage

(within 1 week after the onset of the rash) but not the recovery stage in maculopapular eruptions and SJS/TEN, and in the recovery stage (5–8 weeks after the rash) but not the acute stage in dress [23]. However, in general, only low levels of stimulation are observed, perhaps because the antigen responsible for the reaction is a drug metabolite rather than the parent compound, and the significance of the test is difficult to interpret. Addition of human liver microsomes containing cytochrome P-450 enzymes to the reaction medium of the lymphocyte transformation test, in order to aid generation of potentially reactive drug metabolites, may increase the sensitivity of in vitro detection of T-cell reactivity [24,25]. Upregulation of CD69 expression on T cells after 48 h of drug-stimulation [26] and in vitro drug-induced IFN-γ release from peripheral blood lymphocytes [27] have been claimed to be promising diagnostic tools in cutaneous adverse drug reactions. References 1 Perelmutter L, Eisen AH. Studies on histamine release from leukocytes of penicillin-sensitive individuals. Int Arch Allergy 1970; 38: 104–12. 2 Shelley WB. Indirect basophil degranulation test for allergy to penicillin and other drugs. JAMA 1963; 184: 171–8. 3 Sastre Dominguez J, Sastre Castillo A. Human basophil degranulation test in drug allergy. Allergol Immunopathol 1986; 14: 221–8. 4 Harrabi S, Loiseau P, Dehenry J. A technic for human basophil degranulation. Allerg Immunol 1987; 19: 287–9. 5 Sanz ML, Gamboa PM, Antépara I et al. Flow cytometric basophil activation test by detection of CD63 expression in patients with immediate-type reactions to betalactam antibiotics. Clin Exp Allergy 2002; 32: 277–86. 6 Rodríguez-Trabado A, Cámara-Hijón C, Ramos-Cantariño A et al. Basophil activation test for the in vitro diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity. Allergy Asthma Proc 2008; 29: 241–9. 7 Thiel JA, Mitchell S, Parker CW. The specificity of hemagglutination reactions in human and experimental penicillin hypersensitivity. J Allergy 1964; 35: 399–424. 8 David JR, al-Askari S, Lawrence HS, Thomas L. Delayed hypersensitivity in vitro. I. The specificity of inhibition of cell migration by antigens. J Immunol 1964; 93: 264–73. 9 Halevy S, Grunwald MH, Sandbank M et al. Macrophage migration inhibition factor (MIF) in drug eruption. Arch Dermatol 1990; 126: 48–51. 10 Lazarov A, Livni E, Halevy S. Generalised pustular drug eruptions: confirmation by in vitro tests. J Eur Acad Dermatol Venereol 1998; 10: 36–41. 11 Kivity S. Fixed drug eruption to multiple drugs: clinical and laboratory investigation. Int J Dermatol 1991; 30: 149–51. 12 Dunoyer-Geindre S, Ludi F et al. PAF acether release on antigenic challenge. A method for the investigation of drug allergic reactions. Allergy 1992; 47: 50–4. 13 Shear N, Spielberg S, Grant D et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105: 179–84. 14 Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1989; 82: 1826–32. 15 Rieder MJ, Uetrecht J, Shear NH et al. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9. 16 Shear NH. Diagnosing cutaneous adverse reactions to drugs. Arch Dermatol 1990; 126: 94–7. 17 Rocklin RE, David JR. Detection in vitro of cellular hypersensitivity to drugs. J Allergy Clin Immunol 1971; 48: 276–82. 18 Gimenez-Camarasa JM, Garcia-Calderon P, de Moragas JM. Lymphocyte transformation test in fixed drug eruption. N Engl J Med 1975; 292: 819–21. 19 Dobozy A, Hunyadi J, Kenderessy AS, Simon N. Lymphocyte transformation test in detection of drug hypersensitivity. Clin Exp Dermatol 1981; 6: 367–72. 20 Sarkany I. Role of lymphocyte transformation in drug allergy. Int J Dermatol 1981; 8: 544–5. 21 Roujeau JC, Albengres E, Moritz S et al. Lymphocyte transformation test in druginduced toxic epidermal necrolysis. Int Arch Allergy Appl Immunol 1985; 78: 22–4.

Management of drug reactions 22 Zakrzewska JM, Ivanyi L. In vitro lymphocyte proliferation by carbamazepine, carbamazepine-10,11-epoxide, and oxcarbazepine in the diagnosis of druginduced hypersensitivity. J Allergy Clin Immunol 1988; 82: 1826–32. 23 Kano Y, Hirahara K, Mitsuyama Y et al. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy 2007; 62: 1439–44. 24 Merk HF, Baron J, Kawadubo Y et al. Metabolites and allergic drug reactions. Clin Exp Allergy 1998; 28 (Suppl. 4): 21–4. 25 Sachs B, Erdmann S, Al-Masaoudi T, Merk HF. In vitro drug allergy detection system incorporating human liver microsomes in chlorazepate-induced skin rash: drug-specific proliferation associated with interleukin-5 secretion. Br J Dermatol 2001; 144: 316–20. 26 Beeler A, Zaccaria L, Kawabata T. CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity. Allergy 2008; 63: 181–8. 27 Halevy S, Cohen AD, Grossman N. Clinical implications of in vitro drug-induced interferon gamma release from peripheral blood lymphocytes in cutaneous adverse drug reactions. J Am Acad Dermatol 2005; 52: 254–61.

Challenge tests A drug suspected of causing a drug eruption may be reliably incriminated by the reaction in response to a test dose administered after recovery. However, fatal reactions have occurred to test doses, for example penicillin and quinine, and provocation tests should only be performed in exceptional circumstances [1–6]. A history of Stevens–Johnson syndrome or TEN constitutes an absolute contraindication to drug challenge, and test dosing in reactions of anaphylactic type, blood dyscrasia or SLE-like reaction is seldom advisable. Sensitization to two antibiotics without shared chemical structures can occur during the same episode of a cutaneous adverse drug reaction; thus, reintroduction of any drug suspected should be performed under hospital surveillance, even if skin tests with other drugs taken simultaneously were positive [7]. Challenge tests are open to misinterpretation [6], because a very small challenge dose may fail to elicit a reaction that a therapeutic dose would provoke, because of false positives, and because false negatives may occur as a result of a refractory period following a reaction [8]. Of 1001 challenges in 784 patients carried out from 1975 to 2000, 13% of patients developed a positive challenge reaction; antimicrobial drugs were most commonly suspected, accounting for 67% of challenges and 66% of the positive reactions, and exanthema was the most common skin reaction (72%), followed by fixed drug eruption (16%) and urticaria (12%), with a single serious challenge reaction to salazosulfapyridine [9]. Test dosing in patients with drug reactions such as fixed drug eruption, which are not potentially fatal, may be helpful [5]. Topical challenge in the form of patch testing in a previously involved site may yield a positive response in a high proportion of such cases [10]. Oral provocation tests using tartrazine, and other food additives such as sodium benzoate, have been advocated for the investigation of chronic urticaria or food intolerance [11–14]. Protocols for the analysis of adverse reactions to foods and food additives have been published [15]. References 1 Kauppinen K. Cutaneous reactions to drugs. With special reference to severe mucocutaneous bullous eruptions and sulphonamides. Acta Derm Venereol Suppl (Stockh) 1972; 68: 1–89. 2 Kauppinen K. Rational performance of drug challenge in cutaneous hypersensitivity. Semin Dermatol 1983; 2: 117–230. 3 Kauppinen K, Stubb S. Drug eruptions. Causative agents and clinical types. Acta Derm Venereol (Stockh) 1984; 64: 320–4.

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4 Girard M. Conclusiveness of rechallenge in the interpretation of adverse drug reactions. Br J Clin Pharmacol 1987; 23: 73–9. 5 Kauppinen K, Alanko K. Oral provocation: uses. Semin Dermatol 1989; 8: 187–91. 6 Girard M. Oral provocation: limitations. Semin Dermatol 1989; 8: 192–5. 7 Dellestable P, Weber-Muller F, Tréchot P et al. Co-sensitization to drugs belonging to different chemical classes during the same episode of cutaneous adverse drug reaction: two cases. Ann Dermatol Venereol 2007; 134: 655–8. 8 Stevenson DD, Simon RA, Mathison DA. Aspirin-sensitive asthma: tolerance to aspirin after positive oral aspirin challenges. J Allergy Clin Immunol 1980; 66: 82–8. 9 Lammintausta K, Kortekangas-Savolainen O. Oral challenge in patients with suspected cutaneous adverse drug reactions: findings in 784 patients during a 25-year-period. Acta Derm Venereol 2005; 85: 491–6. 10 Alanko K, Stubb S, Reitamo S. Topical provocation of fixed drug eruption. Br J Dermatol 1987; 116: 561–7. 11 Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J Dermatol 1976; 94: 401–6. 12 Supramaniam G, Warner JO. Artificial food additive intolerance in patients with angio-oedema and urticaria. Lancet 1986; ii: 907–9. 13 Wilson N, Scott A. A double blind assessment of additive intolerance in children using a 12 day challenge period at home. Clin Exp Allergy 1989; 19: 267–72. 14 Michils A, Vandermoten G, Duchateau J, Yemault J-C. Anaphylaxis with sodium benzoate. Lancet 1991; 337: 1424–5. 15 Metcalfe DD, Sampson HA, eds. Workshop on experimental methodology for clinical studies of adverse reactions to foods and food additives. J Allergy Clin Immunol 1990; 86 (Suppl.): 421–42.

Treatment Clearly, prevention is better than cure [1,2]. Drugs implicated in a previous reaction should be avoided; the patient should be asked about allergies, and hypersensitivity records in the notes and on prescription charts should be checked. In the case of suspected penicillin allergy, an alternative antibiotic, preferably with a nonbeta-lactam structure such as erythromycin, should be substituted; use of griseofulvin should be avoided as it has a 5–10% crossreactivity based on non-structural mechanisms [2]. However, lack of a positive history does not eliminate the possibility of an allergic reaction, as in the case of penicillin hypersensitivity [3]. Where it is essential to readminister one of a group of drugs to a patient with a previous history of an adverse reaction to a related medication, as with radiographic contrast media and agents used in general anaesthesia, then if possible preliminary skin testing should be carried out to enable identification of safe alternative therapy. In addition, the procedure should be covered by premedication with oral corticosteroids and antihistamines, with or without epinephrine, in order to obtund the onset of an anaphylactic reaction. In the situation where there is no acceptable alternative for an essential drug, then rapid desensitization therapy should be considered. The approach to treatment of an established presumed drug eruption obviously depends on the severity of the reaction. For many minor conditions, withdrawal of the suspected drug, and symptomatic therapy with emollients, mild to moderately potent topical corticosteroids and systemic antihistamines where indicated, is all that is necessary. When a patient is receiving multiple drugs, it is wise to withdraw all but the essential medications, and to consider substituting alternative, non-cross-reacting drugs for the remainder. Because of the wide variety of patterns of drug reaction, it is only possible to summarize the therapy of individual

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reactions here. The reader is referred to the discussion of the more serious conditions in this book and elsewhere [1–9]. References 1 Sheffer AL, Pennoyer MD. Management of adverse drug reactions. J Allergy Clin Immunol 1984; 74: 580–8. 2 Fellner MJ, Ledesma GN. Current comments on cutaneous allergy. Management of antibiotic allergies. Int J Dermatol 1991; 30: 184–5. 3 Weber EA, Knight A. Testing for allergy to antibiotics. Semin Dermatol 1989; 8: 204–12. 4 Braun-Falco O, Plewig G, Wolff HH, Winkelmann RK. Dermatology. Berlin: Springer, 1991. 5 Breathnach SM, Hintner H. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific Publications, 1992. 6 Breathnach SM. Management of drug eruptions. Part II. Diagnosis and treatment. Australas J Dermatol 1995; 36: 187–91. 7 Drake LA, Dinehart SM, Farmer ER et al. Guidelines of care for cutaneous adverse drug reactions. American Academy of Dermatology. J Am Acad Dermatol 1996; 35: 458–61. 8 Ellis AK, Day JH. Diagnosis and management of anaphylaxis. Can Med Assoc J 2003; 169: 307–11. 9 Bahna SL, Khalili B. New concepts in the management of adverse drug reactions. Allergy Asthma Proc 2007; 28: 517–24.

Anaphylaxis The management of severe acute urticaria and anaphylaxis is detailed in Table 75.21.

Exfoliative dermatitis/erythroderma The complications of this potentially serious drug-induced condition include hypothermia, fluid and electrolyte loss, infection, high-output cardiac failure, stress ulceration and gastrointestinal haemorrhage, malabsorption and venous thrombosis. The management [1,2] includes maintenance of body temperature and fluid and electrolyte balance, treatment of cardiac failure by use of digitalization and diuretics (avoiding vasodilator drugs), and administration of intravenous albumin for hypoalbuminaemia. If the patient does not respond rapidly to potent topical corticosteroids, prednisolone 40–60 mg/day should be given. This approach also applies to the anticonvulsant hypersensitivity syndrome (dress); oral corticosteroid therapy has been helpful [3,4]. Table 75.21 Management of anaphlyaxis. Stop drug administration Give 0.5–1 mL epinephrine (adrenaline) 1 in 1000 i.m. immediately Check airway and give oxygen Antihistamines Chlorpheniramine maleate 10–20 mg i.v. or Hydroxyzine 25–50 mg i.m. and four times daily orally or H1 and H2 antagonists or Cimetidine 300 mg i.v. 6 hourly Corticosteroids Hydrocortisone 250 mg i.v. and 100 mg 6 hourly Prednisolone 40 mg/day for 3 days Give i.v. 0.9% NaCl or 5% glucose Monitor blood pressure and pulse For bronchospasm Aminophylline 250 mg i.v. over 5 min and 250 mg in 500 mL 0.9% NaCl over 6 h or Nebulized terbutaline, salbutamol or metaproterenol

References 1 Marks J. Erythroderma and its management. Clin Exp Dermatol 1982; 7: 415–22. 2 Roujeau JC, Revuz J. Intensive care in dermatology. In: Champion RH, Pye RJ, eds. Recent Advances in Dermatology, Vol. 8. Edinburgh: Churchill Livingstone, 1990: 85–99. 3 Murphy JM, Mashman J, Miller JD, Bell JB. Suppression of carbamazepineinduced rash with prednisone. Neurology 1991; 41: 144–5. 4 Chopra S, Levell NJ, Cowley G, Gilkes JJ. Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol 1996; 134: 1109–12.

Toxic epidermal necrolysis See Chapter 76.

Desensitization It is possible to induce a state of antigen-specific mast cell unresponsiveness, in patients with type I IgE-mediated reactions, if a drug is essential for a patient’s well-being and no alternative is available. Desensitization markedly diminishes the risk of anaphylactic reactions but not of non-IgE-mediated reactions; it should only be carried out in an intensive care setting. Mechanisms proposed to explain the development of tolerance following desensitization procedures include mediator depletion, tachyphylaxis, production of blocking antibodies, or change in the level of specific IgE antibodies. Desensitization is most frequently carried out for patients with penicillin allergy, with increasing doses of penicillin being administered over 3–5 h [1–4]. The drug is usually given orally; increasing doses are given, starting with a very weak concentration (e.g. one millionth of the therapeutic dose) and working up to a full dose. There have been no severe allergic reactions recorded in patients who completed oral desensitization to penicillin; about 35% experience minor cutaneous reactions including pruritus or urticaria. Although the protection is usually short-lived, tolerance can be maintained by long-term administration of low doses of oral penicillin. Patients with sensitivity to vancomycin [5], 5aminosalicylic acid [6] and allopurinol [7] have been successfully desensitized. Intravenous and oral rapid desensitization protocols are available for taxenes, platinums, doxorubicin and monoclonal antibodies [8]. Patients with HIV infection with previous cutaneous reactions to sulphonamides [9–13] or antituberculous medication [14] have also been desensitized. A 10-day oral desensitization regimen was described for trimethoprim–sulfamethoxazole in 28 HIVinfected patients [10]; 82% were successfully desensitized, and four of the 28 patients had relatively severe rashes (three maculopapular, one erythroderma) during the desensitization phase. Four patients subsequently had rashes 12–33 weeks after desensitization [10]. References 1 Wendel GD, Stark BJ, Jamison RB et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985; 312: 1229–32. 2 Stark BJ, Earl HS, Gross GN et al. Acute and chronic desensitization of pencillin-allergic patients using oral penicillin. J Allergy Clin Immunol 1987; 79: 523–32. 3 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40. 4 Castells M. Desensitization for drug allergy. Curr Opin Allergy Clin Immunol 2006; 6: 476–81.

Management of drug reactions 5 Wong JT, Ripple RE, MacLean JA et al. Vancomycin hypersensitivity: synergism with narcotics and ‘desensitization’ by a rapid continuous intravenous protocol. J Allergy Clin Immunol 1994; 94: 189–94. 6 Stelzle RC, Squire EN. Oral desensitization to 5-aminosalicylic acid medications. Ann Allergy Asthma Immunol 1999; 83: 23–4. 7 Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum 2001; 44: 231–8. 8 Castells M. Rapid desensitization for hypersensitivity reactions to chemotherapy agents. Curr Opin Allergy Clin Immunol 2006; 6: 271–7. 9 Torgovnick J. Desensitization to sulfonamides in patients with HIV infection. Am J Med 1990; 88: 548–9. 10 Absar N, Daneshvar H, Beall G. Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients. J Allergy Clin Immunol 1994; 93: 1001–5.

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11 Belchi-Hernandez J, Espinosa-Parra FJ. Management of adverse reactions to prophylactic trimethoprim–sulfamethoxazole in patients with human immunodeficiency virus infection. Ann Allergy Asthma Immunol 1996; 76: 355–8. 12 Douglas R, Spelman D, Czarny D, O’Hehir RE. Successful desensitization of two patients who previously developed Stevens–Johnson syndrome while receiving trimethoprim-sulfamethoxazole. Clin Infect Dis 1997; 25: 1480. 13 Caumes E, Guermonprez G, Lecomte C et al. Efficacy and safety of desensitization with sulfamethoxazole and trimethoprim in 48 previously hypersensitive patients infected with human immunodeficiency virus. Arch Dermatol 1997; 133: 465–9. 14 Kura MM, Hira SK. Reintroducing antituberculosis therapy after Stevens– Johnson syndrome in human immunodeficiency virus-infected patients with tuberculosis: role of desensitization. Int J Dermatol 2001; 40: 481–4.