Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?
Content
DOI: 10.1111/j.1468-3083.2011.04412.x
JEADV
REVIEW ARTICL ARTICLE E
Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data? R.G. Langley* Queen Elizabeth II Health Sciences Centre, Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, Canada Correspondence: R. R. Langley. E-mail: [email protected] *Correspondence:
Abstract The introd introductio uction n of the biologic agents, adalimumab, adalimumab, etane etanercep rcept, t, inflixi infliximab mab and usteki ustekinumab numab,, has provid provided ed more options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and maintain mainta in effec effective tive disease control in more patients patients using biologic therapies. therapies. Newly published published clinica clinicall data support the introduction introduction of novel optim optimizatio ization n strat strategies egies to furthe furtherr impro improve ve outco outcomes mes in patie patients nts with psoria psoriasis. sis. Recent randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic agents age nts,, and bio biolog logics ics at spe specifi cific c tim time e poi points. nts. Swi Switch tching ing fro from m met methot hotrex rexate ate to a tum tumour our nec necros rosis is fac factor tor (TN (TNF)F)-a antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-tosevere psoriasis, psoriasis, while the benefit of long-t long-term erm methotrexate methotrexate use remai remains ns unclea unclear. r. In a separ separate ate study, psoria psoriasis sis area and severity index (PASI) ‡75 response rates were maintained over time (>3 years for adalimumab), suggesting that long-term biologic biologic therapy is an effe effective ctive and sustai sustainable nable treatment treatment option for psoriasis. For each individ individual ual patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions. Howeve How ever, r, a ben benefit efit–ris –risk k ass assess essmen mentt of TNF TNF--a antagonist antagonists s calcu calculated lated from an integr integrated ated analysis of publis published hed literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number needed to harm and number of patient years of observation to detect an adverse event have been determined for adalimumab, etanercept and infliximab. The benefit–risk profiles generated demonstrated that, during the initial year of tre treatm atment ent,, lik likeli elihoo hood d of suc succes cess s wit with h TNF TNF--a antagon antagonist ists s was sev severa erall ord orders ers of mag magnitu nitude de gre greate aterr tha than n the likelihood of serious toxicity. Received: Recei ved: 22 Novem November ber 2011; Accep Accepted: ted: 28 Nove November mber 2011
Conflicts of interest R.G.L. has served as consultant and ⁄ or or paid speaker for and ⁄ or or parti participate cipated d in clinica clinicall trials sponsored sponsored by companies that manufacture drugs used for the treatment of psoriasis including Abbott, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Genentech, Merck, Novartis and Pfizer.
Funding statement The writing of this supplement article was sponsored by an educational grant from Abbott Immunology.
Introduction The development of biologic therapies has provided dermatologistss with an incr gist increasi easing ng repe repertoi rtoire re of treat treatment mentss with which to treat psoriasis, in both the short- and long-term. Biologic therapies fall into two main categories: the tumour necrosis factor- a (TNF-a) antagonists and interleukin (IL)-12 ⁄ 23 23 monoclonal antibodies (mAbs). TNF-a antagonists (adalimumab, etanercept and infliximab) block the binding of TNF- a to its receptor, interrupting the subsequent signalling and inflammatory pathways driven by TNF-a. This suppresses inflammation and the increased activation of T cells that are characteristic of psoriasis. IL-12 ⁄ 23 23 mAbs
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(ustekinumab) inhibit the activity of IL-12 and IL-23, cytokines that drive the inflammatory processes which can cause psoriatic lesions. Several randomized controlled clinical trials have demonstrated the effi efficac cacyy of bio biolog logic ic the therap rapie iess in the firs firstt ye year ar of pso psoria riasis sis 1–11 treatment. A summary of the key outcomes of these trials is provided in Table 1. The TNF- a antagonists (adalimumab, etanercept and infliximab) and ustekinumab provide efficacious therapy, with wit h hi high gh rat rates es of pso psoria riasis sis are areaa and sev severi erity ty ind index ex (P (PASI ASI)) 75 response being achieved by patients in all trials. These trials also illust ill ustrat rated ed th thee saf safety ety and tol toler erabi abilit lityy of bio biolog logic ic the therap rapies ies,,
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Table 1 Results of pivotal randomized controlled clinical trials of biologic therapies for the treatment of psoriasis Treatment schedule
Number of patients receiving biologic therapy
PASI 75 response rate (%) at 10–16 weeks*
Complete or near-complete clearance (%)
80 mg at week 0 then 40 mg e.o.w. from week 1
108
79.6
16.7 (PASI 100)
80 mg at week 0 then 40 mg e.o.w. from week 1
814
80 mg at week 0 then 40 mg e.o.w. from week 1
364
Adalimumab
CHAMPION 1
51.3 (PASI 90) 73.1 (PGA 0 ⁄ 1)
REVEAL2
71
20 (PASI 100) 45 (PASI 90) 60 (PGA 0 ⁄ 1)
BELIEVE3
70.9
24.2 (PASI 100) 50.8 (PASI 90) 64.4 (PGA 0 ⁄ 1)
7
Gordon et al.
80 mg at weeks 0, 1; then 40 mg q.w.
50
80
26 (PASI 100) 33 (PASI 90) 76 (PGA 0 ⁄ 1)
Etanercept
Leonardi et al.4
50 mg b.i.w.
164
49
22 (PASI 90)
Papp et al.5
50 mg b.i.w.
194
49
21 (PASI 90)
49 (PGA 0 ⁄ 1) 57 (PGA 0 ⁄ 1) Tyring et al.
45
Gottlieb et al.46 47
van de Kerkhof et al.
50 mg b.i.w.
311
47
21 (PASI 90)
25 mg b.i.w.
57
30
>50 (PGA 0 ⁄ 1)
37.5
64 (PGA 0 ⁄ 1)
80
57 (PASI 90)
50 mg q.w.
Infliximab
EXPRESS 18
5 mg ⁄ kg at weeks 0, 2, 6; then every 8 weeks
301
83 (PGA 0 ⁄ 1) 9
EXPRESS 2
5 mg ⁄ kg at weeks 0, 2, 6
314
75.5
45.2 (PASI 90) 76.0 (PGA 0 ⁄ 1)
Ustekinumab
PHOENIX 110
45 mg at weeks 0, 4; then every 12 weeks
255
67.1
12.5 (PASI 100) 41.6 (PASI 90) 60.4 (PGA 0 ⁄ 1)
90 mg at weeks 0, 4; then every 12 weeks
256
66.4
10.9 (PASI 100) 36.7 (PASI 90) 61.7 (PGA 0 ⁄ 1)
PHOENIX 211
45 mg at weeks 0, 4; then every 12 weeks
409
66.7
18.1 (PASI 100) 42.3 (PASI 90) 68.0 (PGA 0 ⁄ 1)
90 mg at weeks 0, 4; then every 12 weeks
411
75.5
18.2 (PASI 100) 50.9 (PASI 90) 73.5 (PGA 0 ⁄ 1)
*These trials were not conducted in a head-to-head fashion and differing methods of statistical anaysis and study designs do not make comparisons possible. b.i.w., twice per week; e.o.w., every other week; PASI, psoriasis area and severity index; PGA, physicians global assessment; q.w., once per week.
during these periods, an important concept when considering treatment decisions. Role of conventional systemic therapies
Despite the encouraging results seen in response to biologic therapies, conventional treatments continue to play a major role in dermatology and should still be considered for use in patients with
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psoriasis. As psoriasis is a chronic disease, long-term maintenance requires continued use of therapy. Systemic therapies have been in use for decades and are well established in treatment regimens, and dermatologists are better positioned to make long-term decisions on the use of such conventional therapies. For example, methotrexate has been successfully used for the treatment of psoriasis since the 1950s.12,13 Methotrexate has been combined with
ª 2012 The Author Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
Effective, sustainable biologic treatment of psoriasis
psoralen and ultraviolet A (PUVA), ultraviolet B (UVB), etretinate and cyclosporine with the aim of improving efficacy, reducing dosage and limiting associated toxicity.14–21 Methotrexate and cyclosporine have been particularly successful in achieving this, although long-term use has not been reported. 21 The efficacy of cyclosporine in the treatment of psoriasis has been investigated and established in randomized controlled trials (RCTs). These studies have been of short duration and the approved use of this agent in most countries is for a limited period due to concerns over toxicity.22–27 However, short intermittent courses of cyclosporine are effective and have been adopted in clinical practice. 25,26 Retinoids are a group of natural and synthetic therapies closely related to vitamin A. They are also well established in the treatment of dermatological conditions: acitretin, an oral retinoid, is currently used for moderate-to-severe psoriasis.28 Despite these agents being in use for over 50 years, there are few RCTs that address the dosing and treatment regimen of retinoids. 29–32 The combination of retinoids with topical or phototherapies has proved effective for psoriasis treatment and can be more successful than retinoid monotherapy.33–38 Conventional systemic agents remain important therapies in the management of patients with psoriasis. The use of conventional therapies, however, must be monitored regularly and modified if the treatment goal is not reached. 39 For treatment to achieve maximal benefit and optimal patient outcomes, it must be initiated and modified in a timely and appropriate manner. Although RCTs continue to demonstrate the efficacy and safety of biologic therapies, there has been less systematic investigation regarding conventional therapies. Despite the proven efficacy and safety of biologic agents in the treatment of psoriasis, there appears to be a general reluctance among dermatologists to prescribe them. 40 This article aims to address this discrepancy and provide evidence for the effective and sustainable use of biologics in psoriasis. Optimization strategies for systemic and biologic therapies Optimizing results with systemic or biologic agents may enhance the efficacy achieved with these agents. It is important to be aware of what responses may be expected and when efficacy may be observed. Specific guidelines have been developed which summarize this information and can assist clinicians in the decision to switch or modify treatment regimens, as appropriate.39 As new treatments are introduced, it is important that dermatologists are aware of the best use of therapies through the analysis of evidencebased clinical data. Recent clinical studies have investigated optimization strategies to define such areas, and these are reviewed below. Optimization of conventional therapies
Conventional therapies range in their probability of achieving an adequate clinical response and in the level of efficacy attained. 41,42 Methotrexate provides an example of a drug that is well estab-
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lished in the treatment of psoriasis, but lacks an evidence-based approach to optimizing dose. The lack of evidence-based strategies has, in part, led to an ‘experience-based’ approach, with a subsequent lack of standardized, evidence-based treatment guidelines, which has contributed to a large variety of treatment regimens. Three recent Phase 3 clinical trials have been performed in which methotrexate was compared with biologic agents. 1,43,44 The initial trial, CHAMPION, randomized 271 patients to receive adalimumab, methotrexate or placebo for 16 weeks. 1 RESTORE randomized 868 patients to receive infliximab or methotrexate for 16 weeks, after which treatment switch was permitted. 44 A third Phase 3 trial randomized 317 patients to receive briakinumab or methotrexate over 52 weeks (M10-255).43 RESTORE and M10255 indicated that if a PASI 75 response is not achieved by week 16, then it is not likely to occur and treatment discontinuation or modification should be considered. 43,44 Switching from methotrexate to a TNF-a antagonist after 16 weeks can improve the response.44 In CHAMPION, the methotrexate dose was started at 7.5 mg orally and sequentially increased in subsequent weeks, depending on clinical response and the presence of adverse events.1 The methotrexate dose was increased to 20 mg ⁄ week if PASI 50 response had not been reached by week 8 and it was further increased to 25 mg ⁄ week if PASI 50 had not been reached by week 12. Results at week 16 showed that PASI 75 was achieved by 79.6% of patients who received adalimumab, compared with 35.5% of patients who received methotrexate. Conclusions drawn from this information are limited because methotrexate was started and maintained at a relatively low dose compared with clinical practice and dose increases were not appropriate in the achievement of a high PASI response (only increased if response was <PASI 50). In addition, insufficient follow-up time for patients on methotrexate may have limited them in achieving maximal response. In RESTORE, there was a higher starting dose of methotrexate at 15 mg ⁄ week.44 At week 16, 77.8% of patients receiving infliximab achieved PASI 75 compared with 41.9% of patients receiving methotrexate. This study was also limited by the slow rate of methotrexate escalation. The dose was only increased in the case of a response lower than PASI 25, which would limit dose escalation and optimization of results. The important M10-255 trial was recently published. 43 This trial determined a more appropriate schedule of methotrexate dose by examining different regimens. Patients receiving methotrexate were started on 15 mg ⁄ week and increased to 20 mg ⁄ week if a PASI 75 response was not reached by 8 weeks of treatment. This was raised further to 25 mg ⁄ week if PASI 75 was still not achieved (Fig. 1). This schedule showed that a substantial proportion of patients who received methotrexate achieved a PASI 75 response on a dose of 15 mg ⁄ week. As the methotrexate dose was increased to 20 mg ⁄ week and then 25 mg ⁄ week, the number of patients with a PASI 75 response rate began to plateau. After 24 weeks of treatment, 39.9% of patients receiving methotrexate had achieved PASI 75; but by week 52, only 23.9% of patients receiving metho-
ª 2012 The Author Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
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Figure 1 Methotrexate titration schedule in a 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. Methotrexate weekly doses are indicated in mg in light grey panels. Dose was titrated according to clinical responses at weeks 10 and 16.43
trexate had a PASI 75 response. The results from this trial demonstrate the benefit of appropriate dose escalation of oral methotrexate until 20 mg ⁄ week. Patients with a sub-optimal response at this stage receive little further benefit from increasing the dose to 25 mg.43 This ‘response-guided’ therapeutic approach increasingly reflects current practice, as depicted by the European Consensus Programme on goals for the treatment of psoriasis, and shows the importance of regular monitoring. 39 Optimization of biologic therapies
The expected short-term efficacy of different biologic agents has been described in several RCTs 1–5,7–11,45–47 and the European goals were recently set out by the European Consensus Programme. 39 Patients who have not achieved an adequate response by a defined endpoint may be considered primary failures. Patients who reach a specified endpoint but who then lose response are considered secondary failures.48 Following primary or secondary failure, it is important to clinically address why these patients failed to respond or lost response. Factors which may be considered include adherence ⁄ compliance, confounding factors (infection, natural variation in disease, exogenous stress) or inadequate drug levels. Before dose optimization, it is crucial to determine whether any of these confounding factors led to primary or secondary failure. In the absence of a confounding variable that would explain failure to achieve an immediate response (primary) or later response (secondary), clinicians can attempt to optimize therapy. The long-term use of biologic therapy was addressed in the Phase 3 REVEAL trial, which examined the extended efficacy and safety of adalimumab. Following the initial 52-week trial period,
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patients were able to enter an open-label extension trial to receive adalimumab for a total of 3 years. The PASI response rates achieved by patients treated with adalimumab were compared with patients who received placebo. 49 During the initial Phase 3 trial, 71% patients who received adalimumab achieved PASI 75 response. Approximately 60% of patients who entered the adalimumab arm became sustained responders, achieving a PASI 75 response at weeks 16 and 33. At 100 weeks and 160 weeks of continuous therapy, PASI 75 was retained by 83% and 76% of these initial responders, respectively. Some patients with <PASI 75 responses in the initial trial went on to reach long-term PASI 75. The trial demonstrated that the efficacy of continuous adalimumab was well maintained by patients who achieved the initial PASI 75 responses. Adverse events were similar across the arms in REVEAL and the open-label extension phase.49 Dose optimization of biologics
Optimization depends on the approval and guidelines of each country and the information provided herein is a summary of clinical trial data that is intended to facilitate such decisions within the guidelines appropriate to each country. When the treatment goal is not reached with a biologic agent, dose optimization may be carried out by increasing dosage or altering the interval between dosages depending on the molecule being utilized. Patients on low dose etanercept (50 mg ⁄ week) may have their drug increased to 50 mg twice per week (b.i.w.). Similarly, patients receiving ustekinumab can increase their dose from 45 mg every 12 weeks to 90 mg every 12 weeks. Changes in dose intervals can be made for patients receiving adalimumab (40 mg every other week to
ª 2012 The Author Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
Effective, sustainable biologic treatment of psoriasis
40 mg ⁄ week), infliximab (from a dose every 8 weeks to a dose every 6 weeks) and ustekinumab (45 or 90 mg every 12 weeks to 45 or 90 mg every 8 weeks). To ensure the optimal efficacy of adalimumab, it is important to include an induction dose of 80 mg at baseline. A recent study has shown that failing to provide this loading dose can result in inferior efficacy and is less cost-effective.50 A small study has shown that increasing infliximab dose beyond 5 mg does not improve the efficacy; rather, shortening the time between dose intervals may be a more appropriate modification.51 Weight is an important factor for consideration when making therapeutic decisions in the use of biologic agents. A study that examined the effect of weight on the efficacy of biologic therapy showed that weight-based regimens do not result in reduced efficacy in heavier patients.52 An analysis of the PHOENIX trials investigated how the optimal dose of ustekinumab is affected by weight. The study analysed weight in 10 kg increments and found that weight-based fixed dosing gives improved efficacy to patients. This study is potentially limited by a cut-off of 100 kg, which may not be reflected in clinical practice. 53 A comparison of week 12 data by weight was carried out using data from two clinical trials of adalimumab and one of etanercept. Patients were divided into <100 kg and >100 kg groups. The adjusted outcome showed that both drugs have a reduced efficacy in heavier patients. 54
25
Modification and transitioning of therapies
tively. This demonstrated that a rapid and higher efficacy was achieved with the combination therapy within the first 4 weeks of treatment. This was not sustained: by 16 weeks, 64.8% and 70.9% of patients receiving combination treatment compared with adalimumab + vehicle, respectively, had achieved a PASI 75 response.3 However, after 4 weeks of treatment, the use of topical therapy changed from once daily to ‘as required’, and this may have introduced adherence as a confounding factor in the interpretation of these data. Methotrexate has been utilized in combination with TNF-a antagonists routinely in the management of psoriatic arthritis and rheumatoid arthritis.59–61 More recently, the systemic agent has been combined with biologics in the treatment of psoriasis. The NORDIC study compared a combination of etanercept with continuous methotrexate versus etanercept with tapered and discontinued methotrexate in patients with psoriasis. Significantly more patients achieved a physicians global assessment score of ‘clear ⁄ almost clear’ in the continuous therapy group compared with the methotrexate tapered group (66.7% versus 37.0%, respectively). 62 This was supported by data from a more recent larger, randomized, double-blind, placebo-controlled Phase 3b study that compared the responses of patients who received methotrexate and etanercept compared with etanercept alone. After 24 weeks of treatment, significantly more patients receiving combination treatment achieved PASI 50, 75 and 90 responses compared with those receiving etanercept monotherapy. 55
Novel optimization strategies can provide a standardized basis for the development of patient treatment, ensuring that the most beneficial outcomes can be reached. The modification of treatment is crucial to achieving the treatment goal following initial failure. The transitioning of treatments may take a number of forms, including direct switching to a new therapy and the overlap or temporary ⁄ permanent addition of a new therapy. The successful transitioning from methotrexate to biologic therapy has been demonstrated in other clinical trials.44,55 Efficacy may also be achieved with the use of concomitant therapy. Topicals such as corticosteroids, calcipotriene and other agents (i.e. coal tar, anthralin) may be used as monotherapy or combination therapy [for example, betamethasone and calcipotriol (Dovobet)] in psoriasis treatment. Topical therapy is usually the initial therapy used in psoriasis treatment and can be added to biologic therapies to optimize results. 56 Acitretin is a retinoid that may be combined with biologic agents to increase efficacy and reduce side-effects compared with retinoid monotherapy, including a possible reduction in the risk of skin cancer. 57,58 Combined treatment with topical therapies and biologic agents can be used in clinical practice and may serve to maximize therapeutic outcome. The BELIEVE study compared the efficacy of adalimumab in combination with a topical versus adalimumab with vehicle only. After 4 weeks of therapy, PASI 75 rate was achieved by 40.7% versus 32.4% in the adalimumab + topical group compared with the adalimumab + vehicle group, respec-
Benefit–risk profiles of biologic therapies In making treatment decisions, there may be a tendency for personal experiences or perception of risk–benefit to positively or negatively influence the use of therapies. There may be some conflict between evidence-based data and the personal preferences of the dermatologist and ⁄ or patient. Treatment guidelines and goals are designed to facilitate such decisions, and the benefit–risk profiles of therapies provide dermatologists with important and accessible information regarding therapy options and outcomes. In the absence of head-to-head trials comparing the safety and efficacy of different TNF-a antagonists, a benefit–risk assessment of agents based on published data can be used to aid clinical decisions. This may come from RCTs, postmarketing data or registry data. Clinical trials provide high quality data but are often based on short-term use of treatments and may not reflect clinical practice. There can be caveats to consider when analysing longer-term studies with methodological shortcomings, the optimization of treatments and criteria for patient inclusion, as well as methods of statistical analysis. Postmarketing data can provide access to large numbers of patients, but may not be high quality and do not include controls. Registries are an important source of data, providing long-term information on large numbers of patients, although information from psoriasis-specific registries is limited. When assessing benefit–risk profiles, one approach considers the number of patients needed to treat (NNT) and number of
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patients needed to harm (NNH), together with the number of patient years of observation required before the detection of an adverse outcome. The NNT is a measure used to determine the efficacy of a given therapy defining the number of patients who need to receive the assessed treatment for one benefit to be observed, compared with a control group. The NNH is a measure of how many patients need to be exposed to a risk factor over a specified time frame in order for one patient to experience harm that would not otherwise have occurred. Such analyses are based on published data from trials of psoriatic treatments (Table 2).63,64 A meta-analysis and literature review of 22 trials that compared the efficacy of psoriasis treatments showed that TNF- a antagonists were most likely to achieve a PASI 75 response. The relative risk of achieving a PASI 75 response for TNF- a antagonists was 15.57, compared with 9.24 and 5.65 for systemic and T-cell therapies, respectively. 41 A comparison of the benefits and risks of TNF- a antagonists is shown in Table 3. Another meta-analysis comparing TNF- a antagonists and systemic therapies used in the treatment of moderate-to-severe psoriasis also demonstrated the high efficacy and tolerability of TNF- a antagonists. Low rates of adverse events were seen in patients receiving TNF-a antagonists, and these were comparable to equivalent rates observed in patients on systemic therapies (Table 4). 63 Due to their mode of action, there is concern that patients receiving TNF-a antagonists may become more susceptible to infection. This is an issue that may restrict the use of biologic therapy but, in so doing, limit the potential for optimal patient outcome. The meta-analysis of trial data of TNF-a antagonists showed low serious infection rates among patients on biologic therapy (Fig. 2). The rates of infection ranged from 0.1 to 1.0% of patients across the trials, compared with 0 to 0.9% of patients in the placebo groups.64 An analysis comparing serious adverse events across different indications of adalimumab indicated that these are particularly low when compared with the equivalent infection rates exhibited by patients who received adalimumab for rheumatoid arthritis. The rates of serious infection in this analysis were nearly three times greater in patients being treated for rheumatoid arthritis than in those treated for psoriasis (4.65 versus 1.32, respectively).65 Although such data may have raised concerns among dermatologists regarding the use of biologics, these patient groups cannot be compared directly because patients with rheu-
Langley
matoid arthritis may have different co-morbidities, and commonly receive multiple therapies, including steroids, which have an impact on their susceptibility to infection. The best predictors of serious infection events for patients with rheumatoid arthritis can include the severity of rheumatoid arthritis or the disease activity, the use of corticosteroid therapy, the presence of co-morbidities and the presence of skin infection and joint surgery. 66,67 The use of biologics should also be taken into consideration. These predictors are useful indicators for physicians in controlling infection, and similar parameters may prove useful for the treatment of psoriasis with biologic therapies. Essentially, the benefit–risk profiles generated for anti–TNF-a therapies demonstrate a benefit to patients in the first year of treatment that greatly outweighs the risk of serious toxicity. 64 This is an important message that must be appropriately conveyed to patients when discussing treatment options. The risk of developing adverse events, including infection, is low. Conclusions Conventional therapies remain important treatment options for patients with psoriasis. They continue to play a central role in developing therapy regimens, whether alone or in combination with biologic treatments. The advent of biologics has provided new options for dermatologists and patients with psoriasis. These therapies have been extensively studied in RCTs and show high efficacy rates as monotherapy in the majority of patients. 64 Although biologic therapies have shown high efficacy, in certain patients, optimization of therapy may be required to achieve an initial response or regain disease control when response has been lost. To optimize patient outcomes, it is vital to monitor the effectiveness of treatment and modify the dose or therapy as appropriate. Before optimizing treatment, it is important that any confounding factors are addressed and that patients are assessed with a careful history and clinical exam. Understanding new clinical data and guidelines may facilitate optimal patient management, in addition to enabling timely and appropriate decisions to be made with regard to treatment modification and switching. Optimization strategies can include an increase of dose, a decrease in dose interval, or modification of the treatment regimen to include a conventional topical or systemic agent. The rates of adverse events are low for conventional psoriatic treatments, including those for biologic therapies. The high effi-
Table 2 An evidence-based comparison from clinical trials: number of patients needed to treat with a specified biologic agent to see a benefit compared with patients in a control group.64 Drug
Dose
Treated patients who achieved PASI 75 (%)
Placebo patients who achieved PASI 75 (%)
Number needed to treat (95% confidence interval)
Adalimumab
80 mg at week 0 then 40 mg e.o.w. for 16 weeks
72.1
8.0
1.6 (1.5–1.7)
Etanercept
50 mg b.i.w. for 12 weeks
48.4
4.1
2.3 (2.1–2.5)
Infliximab
5 mg ⁄ kg at weeks 0, 2, 6; then every 8 weeks to 24 weeks
75.4
3.9
1.4 (1.3–1.5)
b.i.w., twice per week; e.o.w., every other week.
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ª 2012 The Author Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
Effective, sustainable biologic treatment of psoriasis
) o 8 b 0 e 2 c = a l n P ( § b ) a 4 1 m i x 3 i fl = n ( n I
o ) b 7 e 7 c = a l n P ( 9 , 8
b a m i x i fl n I
9 . 5 . A 1 0 ⁄ N
4 6
t
s p t s e c i n r o e g n a a t t n E a a F N T f 7 , o 2 , s 1 e b l fi a o r m p u m i k l s a i r d – A t fi e n e b f o n o s i r a p m o c A
5 . 2 . A 5 5 ⁄ 7 4 N
9 . 3 . A 3 1 ⁄ N
§ b ) a 1 0 m i x 3 i fl = n ( n I
4 . 5 . A 5 3 ⁄ 7 5 N
) o 5 b 6 e 6 c = a l n P (
1 . 9 . A 4 0 ⁄ N
3 e l b a T
t p e ) 9 c r 6 e 6 n = a t n E (
4 . 1 . A 8 1 ⁄ 4 2 N
) o 0 b 6 e 4 c = a l n P (
0 . 7 . A 3 0 ⁄ N
†
t p ) e 1 c r 1 e 5 n = a t n E ( ) o 1 b 5 e 4 c = a l n P ( * b a m ) u 1 2 m i 9 l a = d n A (
Table 4 Adverse event rates from a meta-analysis of 16 double-blind, placebo-controlled trials that were reviewed for treatment efficacy and tolerability 63
Drug
‡
9 6 , 8 6 , 7 4 – 5 4 , 5 , 4
) 7 0 2 = n ( 0 . 4 . 4 . A A 6 2 2 ⁄ ⁄ 5 N N
27
8 . 1 . 9 . A A 8 5 2 ⁄ ⁄ 6 N N ) 6 7 = n ( 0 . 6 . 6 . A 0 1 6 2 ⁄ 7 N ) 8 9 2 = n ( 0 . 1 . 7 . A 0 . 2 9 5 ⁄ 1 N 8 ) 0 7 2 = n ( 3 . 1 . A 0 . 7 . 8 2 ⁄ 1 0 4 N ) 0 7 6 = n ( 5 . 2 . A 5 . 1 . 7 1 ⁄ 1 0 4 N ) 4 ) 1 6 4 4 = = n n ( ( 0 . 8 . 5 . 5 . 9 . 1 2 6 1 0 5 ) 5 ) 1 6 4 9 = = n n ( ( 0 . 3 . 1 . 6 . 2 . 6 2 2 1 0 5
. x e d n i y t i r 2 A . 5 . ⁄ e 4 1 v 3 1 N e s d n a a 5 0 9 9 2 8 9 9 e . . . . . . . . r 8 2 1 0 0 8 2 0 a 5 s i s a i . r s o k s e p , e I w S A 1 6 8 P . 8 . 7 . . 6 . 8 . 3 . 5 . 2 5 9 3 1 1 1 0 ; y r e 7 4 1 6 e l v b a e l i % n a , v e n a h % e o t t i l , t , o fi E a . 6 n o e u A % k , , l r e n 2 A i fi p , s e t , ⁄ . o u E t n r y 0 N o A w l n o i r p k s t e ; c e e k t c s v s y i u h e e n e t e c f . e d o a y w w e n i v t o l e o % i c - c y e t e s t r k , fi c a e e i n % r e f % % , e e f E e g o n v e , , 0 v w g s r n A n i e w t k i – 5 0 0 d e t d s s s g g ⁄ v g fi 7 9 1 a a u u u g d m m e I I I – m e o i o i o a l i n S S S k r r 0 0 m , s E E r e A A A i e e e 0 4 5 5 5 E B P P P R A A S S S * † ‡ § A
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Adverse Number of Number of events*, studies patients %
Serious adverse events*, %
Cyclosporine 2.5–5 mg ⁄ kg
3
318
16.1 ( n = 503) 2.3
Methotrexate 15 mg q.w.
1
43
17.7
0
Infliximab 5 mg ⁄ kg
3
711
17.8
1.1
Etanercept 50 mg b.i.w.
1
311
17.6
0.6
Adalimumab 1 80 mg at week 0 then 40 mg e.o.w.
814
16.6
0.5
*Average monthly incidence rate. b.i.w., twice per week; e.o.w., every other week; q.w., once per week.
Figure 2 A comparison of serious infection rates from a metaanalysis of patients with psoriasis who received different TNF-a antagonist therapies. Point estimates for the NNHs, with 95% CI lower (NNH 2.5) and upper (NNH 97.5) bounds are provided.64 b.i.w., twice per week; e.o.w., every other week; NNH, number needed to harm; q.w., once per week.
cacy demonstrated by biologic therapies greatly outweighs the low risk of experiencing adverse events. The risks and side effects associated with treatment are an important consideration and should be taken into account when defining therapeutic strategies. The benefit–risk profile of biologic therapies favours the appropriate use of biologics for the treatment of moderate-to-severe psoriasis, and effective disease control can now be achieved and maintained through the appropriate use of such therapies. Acknowledgements The author would like to thank Facilitate Ltd, funded by Abbott Immunology, for editorial assistance in the production of this manuscript. References 1 Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs.
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5
6
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Effective, sustainable biologic treatment of psoriasis
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