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Polymyalgia Rheumatica Diagnosis and Treatment

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Joint Bone Spine 73 (2006) 599–605 http://france.elsevier.com/direct/BONSOI/


Polymyalgia rheumatica: diagnosis and treatment
Martin Soubrier*, Jean-Jacques Dubost, Jen-Michel Ristori
Service de Rhumatologie, CHU de Clermont-Ferrand, place Henri-Dunant, BP 69, 63003 Clermont-Ferrand cedex 1, France Received 1 August 2006; accepted 6 September 2006 Available online 12 October 2006

Abstract Polymyalgia rheumatica (PMR) typically manifests as inflammatory pain in the shoulder and/or pelvic girdles in a patient over 50 years of age. This condition was long underrecognized and therefore underdiagnosed. Today, however, overdiagnosis may occur. Physicians must be aware that many conditions may simulate PMR, including diseases that carry a grim prognosis or require urgent treatment. PMR may be the first manifestation of giant cell arteritis, and a painstaking search for other signs is mandatory. PMR may inaugurate other rheumatologic diseases such as rheumatoid arthritis, RS3PE syndrome, spondyloarthropathy, systemic lupus erythematosus (SLE), myopathy, vasculitis, and chondrocalcinosis. Finally, PMR may be the first manifestation of an endocrine disorder, a malignancy, or an infection. Failure to respond to glucocorticoid therapy should suggest giant cell arteritis, malignant disease, or infection. Ultrasonography may assist in the diagnosis by showing bilateral subdeltoid bursitis. Glucocorticoids are the mainstay of the treatment of PMR. Although the optimal starting dosage and tapering schedule are not agreed on, a low starting dosage and slow tapering may decrease the relapse rate. Methotrexate is probably useful when glucocorticoid dependency develops. In contrast, TNF-α antagonists are probably ineffective. © 2006 Elsevier Masson SAS. All rights reserved.
Keywords: PMR; Giant cell arteritis; RS3PE; Rheumatoid arthritis; Methotrexate

1. Introduction Polymyalgia rheumatica (PMR) is characterized by inflammatory pain and stiffness of the shoulder and/or pelvic girdles accompanied with laboratory evidence of severe inflammation in a patient older than 50 years of age [1–4]. Although this independent entity carries a good prognosis, it can occur as a manifestation of a number of diseases, some of which are serious or require immediate treatment [1–4]. The distinction is often impossible to achieve given the absence of pathognomonic signs, and nosological confusion probably contributes substantially to the differences in reported manifestations and treatments of PMR. 2. Epidemiology The lack of universally accepted classification criteria for PMR complicates the interpretation of epidemiological data.
* Corresponding

The disease is exceedingly rare before 50 years of age. Its prevalence after 50 years of age has been estimated at 1 case per 133 population [5]. The incidence increases with age [3,6]. PMR is more common in women than in men in all affected age groups, although the difference may be smaller in older populations [6]. A North-to-South gradient has been reported. In Norway, the annual rate after 50 years of age was 11.2/10,000 between 1987 and 1994 [7]. Annual rates of 8.4/10,000 in the UK and 1.9/10,000 in Spain have been reported [6,8]. These geographic variations may be ascribable to genetic factors. Supporting this hypothesis is the high incidence of PMR in Minnesota, where a large proportion of the population is of North European descent [9]. Until recently, the incidence of PMR was thought to be stable [9]. However, a recent study from the UK showed an increase in the incidence of the disease from 6.9/10,000 patient-years in 1990 to 9.3/10,000 patient-years in 2001 [6]. 3. Etiology Seasonal variations in the incidence of PMR have been reported, suggesting a role for an infectious agent [6,10–13].

author. E-mail address: [email protected] (M. Soubrier).

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M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605

Several organisms have been incriminated, including adenovirus, respiratory syncytial virus, type 1 parainfluenza virus, parvovirus B19, Mycoplasma pneumoniae, and Chlamydia pneumoniae [10–13]. Other studies found no evidence of seasonal variations or associations with infectious agents [14,15]. The ethnic distribution and reports of familial cases suggest a role for genetic factors. The HLA DRB1*04 and DRB1*01 alleles are associated with PMR and perhaps also with greater severity of the disease [16,17]. Genetic polymorphisms for intercellular adhesion molecules (ICAM-1), TNF-α, and the IL-1 receptor antagonist may influence the susceptibility to PMR [3]. Inappropriate secretion of serum cortisol, ACTH, and dehydroepiandrosterone sulfate has been documented, suggesting a pathogenic role for adrenal gland dysfunction [18– 20]. 4. Clinical manifestations Inflammatory pain with morning stiffness for longer than 1 hour in the shoulder girdle (70–95% of patients) and/or pelvic girdle (50–70%) is the typical presentation. Pain for at least 1 month is required for the diagnosis. The cervical or lumbar spine may be affected also. The pain may be confined to one side at first but rapidly becomes bilateral. One-third of patients have constitutional symptoms such as low-grade fever, asthenia, anorexia, and weight loss. The marked functional impairment contrasts with the paucity of the physical findings. Examination of the shoulders fails to disclose objective evidence of inflammation. The active range of motion of the shoulders may be diminished, most notably in the morning. Passive range of motion is occasionally reduced. Muscle strength is normal. Peripheral manifestations seem common [21]. Thus, 79 (45%) of 177 patients followed up prospectively in Italy exhibited peripheral manifestations [21]. Asymmetric polyarthritis without joint erosions was noted in 45 patients (25%), carpal tunnel syndrome in 24 (14%), and swelling of the hands in (12%). These peripheral manifestations coincided with girdle involvement in 69% of cases and occurred during follow-up in the absence of girdle symptoms in 30% of cases, indicating a relapse. Peripheral arthritis may develop, most notably in women with a history of multiple relapses over several years of treatment. Peripheral edema predominantly affects older patients treated with low-dose glucocorticoid therapy for a short period. 5. Laboratory tests Erythrocyte sedimentation rate (ESR) elevation to more than 40 mm/h is a major diagnostic criterion for PMR. However, the value is normal in 7–20% of patients [22–25]. C-reactive protein (CRP) elevation with a normal ESR has been reported [22]. IL-6 elevation is common [26,27], and presence of this abnormality despite treatment indicates an increased risk of relapse [26,27]. However, the IL-6 assay is not widely available. Cholestasis without jaundice is found in 20–30% of cases

[3]. Tests are negative for rheumatoid factors and antinuclear antibodies. Muscle enzyme levels are normal. 6. Imaging studies Studies using ultrasonography and magnetic imaging resonance (MRI) have established that bursitis and synovitis are very common in patients with PMR [28,29]. Acromiodeltoid bursitis and subdeltoid bursitis were present in 55 of 57 patients in one study [29], compared to only 25 of 114 controls (46 with rheumatoid arthritis, 21 with spondyloarthropathies, six with connective tissue diseases, 35 with osteoarthritis, and six with fibromyalgia). Bursitis was present in 12 of the 46 patients with rheumatoid arthritis and 7 of the 21 patients with spondyloarthropathies. Of the 55 patients with bursitis and PMR, 53 had bilateral bursitis, compared to only 1 of the 25 controls with bursitis. Bilateral bursitis had 92.9% sensitivity, 99.1% specificity, and 98.1% positive predictive value for PMR [29]. In another study [30], however, bilateral bursitis was noted in only 35 (70%) of 50 patients with PMR, compared to 22 (44%) of 50 patients with rheumatoid arthritis. MRI studies have shown tenosynovitis in patients with peripheral edema [31]. 7. Diagnostic criteria Diagnostic criteria for the diagnosis of PMR are empirical. The first criteria were developed by Bird et al. in 1979 (Table 1) [32]. However, they fail to include pelvic girdle involvement, a prompt response to glucocorticoid therapy, or exclusion of other diagnoses. Among the many other criteria sets [33], those developed by Hunder and Healey are widely used in the US and UK (Table 1) [34,35]. The only difference between them is that a prompt response to glucocorticoid therapy is included in the Healey set [3]. Not surprisingly, sensitivity is highest for the Bird criteria set (99.5%), followed by the Hunder set [33].
Table 1 A: Criteria for PMR developed by Bird and colleagues: three of the following seven features are required; B: criteria for PMR developed by Healey and colleagues: all six criteria are required A 1° 2° 3° 4° 5° 6° 7° Bilateral shoulder pain and/or stiffness Bilateral upper arm tenderness Onset of illness within 2 weeks ESR >40 mm/h Morning stiffness >1 hour Age >65 years Depression or weight loss or both

B 1° Pain for at least 1 month at two or more of the following sites: shoulders, pelvic girdle, and cervical spine 2° Morning stiffness >1 hour 3° Age >50 years 4° ESR >40 mm/h 5° Exclusion of other diagnoses 6° Prompt and marked response to glucocorticoid therapy in a dosage <20 mg/day

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8. Differential diagnosis Inflammation of the girdles is a common but misleading inaugural manifestation in many conditions that are far more severe than PMR. In a recent study of 208 patients who had manifestations consistent with PMR, 23 patients were found to have another disease [36]. Among these other diagnoses, 10 were malignancies (five solid cancers and five hematological malignancies) and 10 were rheumatologic diseases (seronegative polyarthritis in five cases, lupus in two cases, polymyositis in one case, and ankylosing spondylitis in one case). The remaining three patients had infective endocarditis, hypothyroidism, and Parkinson disease, respectively. 8.1. Giant cell arteritis The most common differentials discussed in everyday practice are giant cell arteritis and late-onset rheumatoid arthritis. The association between PMR and giant cell arteritis is firmly established. Several arguments suggest that these two conditions may belong to the same disease spectrum. Thus, 50% of patients with giant cell arteritis have symptoms of PMR, and 15–20% of patients with PMR have temporal arteritis. The two diseases share the same genetic susceptibility factors [2]. Increased fluorodeoxyglucose uptake by affected arteries has been reported in patients with giant cell arteritis [37–39]. Blockmans et al. [37,38] were the first to document increased arterial uptake in PMR, supporting the existence of vascular lesions in this disease. However, recent work by the same group seems to contradict the first studies, at least in part. Thus, proximal limb pain in patients with giant cell arteritis correlated with increased uptake by the shoulders but not by the subclavian and axillary arteries [38]. Among the 35 patients with PMR, only 11 had increased uptake by the subclavian arteries, and the increase was modest; uptake was high at the shoulders in 33 patients and at the hips in 31 [39]. In a study of gallium scintigraphy, uptake by the temporal arteries was increased in patients with giant cell arteritis [40]. An increase, albeit of smaller magnitude, was also found in nine patients meeting Healey’s criteria for PMR, compared to controls [41]. In practice, when PMR is suspected, a painstaking search must be undertaken for symptoms and signs of giant cell arteritis, such as headaches, intermittent claudication of the jaw, hyperesthesia of the scalp, and abnormal temporal artery to palpation. If giant cell arteritis is suspected, a temporal artery biopsy should be obtained and appropriate glucocorticoid therapy initiated. A temporal artery biopsy is also in order in patients who fail to respond to low-dose glucocorticoid therapy and in those whose tests for inflammation worsen despite treatment [2,3]. The place for Doppler ultrasonography of the temporal artery remains to be determined. Findings suggestive of giant cell arteritis include vessel wall thickening due to inflammatory edema. However, in 102 patients with apparently pure PMR, only 8% had a positive halo sign [42].

8.2. Rheumatoid arthritis Symptom onset after 60 years of age is usually taken to define late-onset rheumatoid arthritis. The sex distribution was balanced in some studies and biased toward females in others [43–45]. The onset is often abrupt, with arthritis developing within 24 hours in 40% of cases. Symmetric joint involvement is noted in 70% of cases. The small and medium-sized joints are affected in 90% of cases and the large joints (most notably the shoulders) in 40%. The symptoms are often interpreted as indicating PMR in this age group. Anti-CCP assays may help to establish the diagnosis of rheumatoid arthritis with initial involvement of the proximal limb joints [46,47]. In one study [46], anti-CCP assays were negative in 49 patients with PMR but were positive in 35 of 57 patients with late-onset rheumatoid arthritis; in this last subgroup, of the 10 patients who had proximal limb joint involvement, two tested positive for anti-CCP antibodies. Of 41 patients in this study who had typical rheumatoid arthritis, 38 (92.7%) had anti-CCP antibodies. Finally, none of the 24 healthy controls tested positive for anti-CCP antibodies. Anti-CCP was 61.4% sensitive and 100% specific for the diagnosis of late-onset rheumatoid arthritis [46]. In another study, 1 of 13 patients with PMR tested positive for anti-CCP, in low titers, compared to 9 of 16 patients with late-onset rheumatoid arthritis; sensitivity was 56% and specificity 92% for rheumatoid arthritis [47]. In many cases, only time can distinguish between PMR and late-onset rheumatoid arthritis. In a prospective follow-up study [48] of 349 patients with suspected late-onset rheumatoid arthritis (N =141), PMR (N =171), or giant cell arteritis (N =37) [48], nine initial diagnoses of PMR were corrected to rheumatoid arthritis, and the opposite occurred in five patients. In 29 patients with giant cell arteritis, proximal limb manifestations inaugurated the disease. Overall, the first diagnosis was wrong in 10% of patients [48]. 8.3. RS3PE The relationship between remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and PMR is controversial [49]. These two conditions share many features, including occurrence in older individuals, an abrupt onset, symmetric manifestations, a response to low-dose glucocorticoid therapy, and absence of relapses after 2 years of treatment. Peripheral manifestations may occur in PMR, and shoulder pain is common in RS3PE. Furthermore, RS3PE may develop before or after PMR. The numerous similarities suggest that these two conditions may belong to the same entity, with RS3PE being a distinctive clinical pattern of PMR characterized by the development of edema. 8.4. Late-onset peripheral spondyloarthropathy (LOPS) Patients with LOPS may present with inflammatory neck and shoulder pain, constitutional symptoms, and marked ESR elevation. Asymmetric oligoarthritis is suggestive, as well as


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asymmetric pitting edema predominating in the lower limbs. Even more suggestive is a weaker than expected response to glucocorticoid therapy. A family history of LOPS and presence of HLA B27 support the diagnosis. [50]. 8.5. Systemic lupus erythematosus (SLE) SLE may mimic PMR at presentation [51]. Serositis is more common in elderly patients and suggests SLE [52]. A positive test for anti-dsDNA confirms the diagnosis. Induced lupus is common in older individuals and should be painstakingly looked for, without omitting to ask for a history of betablocker eye drop use [52]. 8.6. Vasculitides The clinical features of micropolyangeiitis may mimic PMR. Consequently, a urine dipstick test should be done to look for blood or proteins. A test for antineutrophil cytoplasmic antibody should be obtained at the slightest doubt [4]. 8.7. Chondrocalcinosis Articular chondrocalcinosis may manifest as proximal limb pain [53]. Patients with chondrocalcinosis are older and more likely to have arthritis, compared to patients with PMR. In patients with manifestations that are consistent with PMR, features that suggest chondrocalcinosis include femorotibial osteoarthritis, ankle arthritis, and tendon calcifications (rotator cuff and quadricipital tendon) [53]. Ultrasonography of the shoulders may show bursitis, suggesting PMR, or chondrocalcinosis (calcifications without bursitis) [53]. However, linear calcifications denoting chondrocalcinosis are common in individuals older than 80 years and may coexist with PMR. 8.8. Polymyositis Inflammatory muscle disease usually results in weakness of the shoulder and pelvic girdles, without pain [4]. Routine measurement of muscle enzyme levels rules out this diagnosis. 8.9. Endocrine disorders Thyroid dysfunction, hyperparathyroidism, and osteomalacia should be ruled out routinely [54]. 8.10. Drugs Clinical manifestations suggesting PMR have been reported to occur with statins, conversion enzyme inhibitors, betablockers, and dipyridamole [55–58].

8.11. Infective endocarditis Rheumatologic manifestations are common in patients with infective endocarditis [59] and may mimic PMR [36]. Blood cultures should be obtained routinely in patients with valve disease. Infective endocarditis should also be considered in patients with muscle pain, a fever, and general malaise [59], as well as in those who fail to respond to glucocorticoid therapy [36]. 8.12. Malignant disease and amyloidosis The presentation in myelodysplasia may simulate PMR [60], and the manifestations usually respond to glucocorticoid therapy. Therefore, caution is in order when the initial blood counts show cytopenia [60]. Multiple myeloma, lymphoma, and leukemia may also resemble PMR at presentation [36]. A few cases of amyloidosis with gammopathy presenting as PMR have been reported [61]. Many malignancies can present as PMR (e.g. renal carcinoma, gastric adenocarcinoma, colon cancer, pancreatic cancer, prostate cancer, uterine cancer, and ovarian cancer) [36]. However, a thorough work-up for cancer should be reserved for patients who fail to respond to glucocorticoid therapy. Patients with PMR are not at increased risk for hematological malignancies or solid tumors, compared to controls [62]. PMR is a syndrome, and many differential diagnoses must be considered. The initial evaluation should rule out the most common among them (Table 2). In patients who have no laboratory evidence of inflammation or who fail to respond dramatically to glucocorticoid therapy, clinicians should be prepared to reappraise the diagnosis (Tables 3 and 4).
Table 2 Suggested investigations for patients with PMR Full blood cell counts, platelet count ESR, CRP Serum protein electrophoresis Creatinine Urine dipstick test Chest radiograph Anteroposterior radiographs of the hands and wrists on the same plate Anteroposterior radiographs of the forefeet on the same plate Ultrasonography of the shoulders

Serum calcium and phosphate ASAT, ALAT, alkaline phosphatase CPK Rheumatoid factors, Anti-CCP ANF ESR: erythrocyte sedimentation rate; CRP: C-reactive protein level in serum; ASAT: aspartate aminotransferase; ALAT: alanine aminotransferase; CPK: creatine phosphokinase; ANF: antinuclear factor. Table 3 Differential diagnoses in patients with PMR and a normal ESR Myositis, myopathy Endocrine disorders: thyroid gland dysfunction, hyperparathyroidism, osteomalacia Drugs: lipid-lowering agents, angiotensin-conversion enzyme inhibitors, beta-blockers, dipyridamole…

M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605 Table 4 Differential diagnoses in patients with PMR that fails to respond to glucocorticoid therapy Giant cell arteritis Spondyloarthropathy Malignancy Amyloidosis Infective endocarditis


9. Treatment Nonsteroidal antiinflammatory drugs have been suggested to treat mild forms of PMR. In the elderly population targeted by this disease, however, they carry a high risk of gastrointestinal, renal, and cardiovascular side effects [63]. Glucocorticoid therapy is the mainstay of the treatment of PMR. The optimal starting dosage is not agreed on and varies across studies from 15–25 mg/day. A dramatic response with complete symptom resolution within 48–72 hours can be expected and supports the diagnosis of PMR. Although lower dosages (e.g. 10 mg) have been suggested, they induce a less conclusive response. The starting dosage should be given for 3–6 weeks on average, until the laboratory tests for inflammation return to normal. No studies designed to determine the optimal tapering schedule are available. In practice, relapses rarely occur when the dosage is decreased by 10% every 10– 15 days down to 10 mg/day. A slower rate of decrease of about 1 mg every month or 2 months is then used to taper the patient off the drug. Total treatment duration is usually 2–3 years [3]. Glucocorticoid therapy induces side effects in older patients. In a prospective cohort study, nearly 65% of patients with PMR treated with a glucocorticoid alone experienced side effects [63]. Bone loss prevention requires calcium and vitamin D supplementation, as well as bisphosphonate therapy. The main prophylactic measure, however, is use of the lowest possible glucocorticoid dose. A higher starting dose and a faster tapering rate are associated with a greater risk of relapse [64]. Therefore, a low starting dose and slow tapering are recommended. Isolated ESR elevation does not warrant an increase in the glucocorticoid dosage. The CRP level is a better parameter for monitoring the course of the disease. The need for a dosage increase should be considered only if the CRP level rises or the symptoms recur. The recently developed disease activity score for PMR (PMR-DAS) [65] is obtained by summing the CRP level (mg/dl), the patient-assessed visual-analogscale score for disease activity, the duration of morning stiffness (min · 0.1), and the ability to lift the arms (3, impossible; 2, below the shoulder; 1, to the shoulder; 3, above the shoulder). PMR-DAS values lower than 7 indicate inactive disease, between 7 and 17 moderately active disease, and greater than 17 highly active disease. If studies succeed in determining a cutoff that defines a relapse, the PMR-DAS may prove useful for monitoring disease activity under treatment and for avoiding unnecessary exposure to glucocorticoid therapy. Intramuscular methylprednisolone 120 mg every 3 weeks has been evaluated in patients with PMR. Efficacy and safety were good, but bone loss was not diminished [66]. Methylprednisolone acetate

injections into the glenohumeral joints (40 mg four times at 1week intervals) may be a valid alternative to systemic glucocorticoid therapy [67]. Drugs used in an effort to reduce glucocorticoid requirements include hydroxychloroquine, methotrexate, and TNF-α antagonists. No prospective data on hydroxychloroquine are available. A 1983 retrospective study of 176 patients showed that only five patients given a nonsteroidal antiinflammatory drug combined with an antimalarial drug experienced relapses, one of which was associated with giant cell arteritis [68]. Double-blind placebo-controlled studies would be of great interest. Methotrexate as a glucocorticoid-sparing agent was evaluated in two open-label studies and three placebocontrolled studies, with conflicting results. An open-label study in 27 patients showed a beneficial effect with a mean time to remission of 6 months [69]. No benefits were noted in the other open-label study [70], which was conducted in 108 patients given a diagnosis of PMR between 1989 and 1993. All patients took prednisone 10 mg/day. Patients who required more than 20 mg/day of prednisone were given methotrexate 7.5 mg/week for 3 months. Adding methotrexate was associated neither with a glucocorticoid-sparing effect nor with control of the clinical and laboratory test abnormalities at the end of the 3-month period. In a placebo-controlled study done between November 1989 and November 1991, 40 patients with PMR (including six with giant cell arteritis) were randomized to prednisone 20 mg/day plus methotrexate 7.5 mg orally per week or to prednisone 20 mg/day plus a placebo [71]. When the symptoms abated and the laboratory tests showed resolution of the inflammatory syndrome (ESR <15 mm/h and CRP <6 mg/l), the prednisone dosage was reduced by 2.5 mg every 3 weeks down to 7.5 mg/day then by 2.5 mg every 6 weeks. Only 21 patients completed the 2-year follow-up, 11 in the methotrexate group and 10 in the placebo group. The remission rate, time to remission, and duration of remission were not significantly different in the two groups. Neither was the cumulative glucocorticoid dosage significantly different between the two groups (2.4 g with methotrexate and 2.9 g with the placebo). The number of relapses was similar in the two groups (18 in 10 patients with methotrexate and 15 in 9 patients with the placebo). In contrast, two other randomized placebocontrolled studies found a decrease in glucocorticoid exposure in patients given methotrexate [72,73]. The earliest study was an open-label randomized evaluation of 27 patients [72]. Methotrexate was given intramuscularly in a dosage of 10 mg/week. Prednisone was started in a dosage of 25 mg/day and tapered rapidly (25 mg during the first month then 12.5, 10, 6.25, 5, and 2.5 mg for 1 month each). After 1 year, all patients were in clinical remission and six patients in the methotrexate group were off glucocorticoid therapy, compared to none in the placebo group. The mean cumulative glucocorticoid dosage was significantly lower in the methotrexate group (1.84 g) than in the placebo group (3.2 g). The other study used a randomized double-blind placebo-controlled design to evaluate 72 patients, who were followed up for 18 months [73]. Methotrexate was given orally in a dosage of 10 mg/week. Patients took 7.5 mg


M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605 [11] Elling P, Olsson AT, Elling H. Synchronous variations of the incidence of temporal arteritis and PMR in different regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection. J Rheumatol 1996;23:112–9. [12] Cimmino MA, Grazi G, Balistreri M, Accardo S. Increased prevalence of antibodies to adenovirus and respiratory syncytial virus in PMR. Clin Exp Rheumatol 1993;11:309–13. [13] Duhaut P, Bosshard S, Calvet A, Pinede L, Demolombe-Rague S, Dumontet C, et al. Giant cell arteritis, PMR, and viral hypotheses: a multicenter, prospective case-control study. Groupe de Recherche sur l’Arterite a Cellules Geantes. J Rheumatol 1999;26:361–9. [14] Narvaez J, Clavaguera MT, Nolla-Sole JM, Valverde-Garcia J, RoigEscofet D. Lack of association between infection and onset of PMR. J Rheumatol 2000;27:953–7. [15] Peris P. PMR is not seasonal in pattern and is unrelated to parvovirus 19 infection. J Rheumatol 2003;30:2624–6. [16] Haworth S, Ridgeway J, Stewart I, Dyer PA, Pepper L, Ollier W. PMR is associated with both HLA-DRB1*0401 and DRB1*0404. Br J Rheumatol 1996;35:632–5. [17] Salvarani C, Boiardi L, Mantovani V, Ranzi A, Cantini F, Olivieri I, et al. HLA-DRB1 alleles associated with PMR in northern Italy: correlation with disease severity. Ann Rheum Dis 1999;58:303–8. [18] Cutolo M, Straub RH, Foppiani L, Prete C, Pulsatelli L, Sulli A, et al. Adrenal gland hypofunction in active PMR. effect of glucocorticoid treatment on adrenal hormones and interleukin 6. J Rheumatol 2002;29:748– 56. [19] Straub RH, Cutolo M. Further evidence for insufficient hypothalamicpituitary-glandular axes in PMR. J Rheumatol 2006;33:1219–23. [20] Narvaez J, Bernad B, Torne CD, Momplet JV, Montpel JZ, Nolla JM, et al. Low Serum Levels of DHEAS in Untreated PMR/Giant Cell Arteritis. J Rheumatol 2006;33:1293–8. [21] Salvarani C, Cantini F, Macchioni P, Olivieri I, Nicoli L, Padula A, et al. Distal musculoskeletal manifestations in PMR: a prospective followup study. Arthritis Rheum 1998;41:1221–6. [22] Cantini F, Salvarani C, Olivieri I, Macchioni L, Ranzi A, Niccoli L, et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in PMR: a prospective follow-up study. Semin Arthritis Rheum 2000;30:17–24. [23] Proven A, Gabriel SE, O’Fallon WM, Hunder GG. PMR with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 1999;26:1333–7. [24] Helfgott SM, Kieval RI. PMR in patients with a normal erythrocyte sedimentation rate. Arthritis Rheum 1996;39:304–7. [25] Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, Fernandez-Sueiro JL, Armona J, Figueroa M, et al. PMR without significantly increased erythrocyte sedimentation rate. A more benign syndrome. Arch Intern Med 1997;157:317–20. [26] Weyand CM, Fulbright JW, Evans JM, Hunder GG, Goronzy JJ. Corticosteroid requirements in PMR. Arch Intern Med 1999;159:577–84. [27] Salvarani C, Cantini F, Niccoli L, Macchioni P, Consonni D, Bajocchi G, et al. Acute-phase reactants and the risk of relapse/recurrence in PMR: a prospective followup study. Arthritis Rheum 2005;53:33–8. [28] Salvarani C, Cantini F, Olivieri I, Barozzi L, Macchioni L, Niccoli L, et al. Proximal bursitis in active PMR. Ann Intern Med 1997;127:27–31. [29] Cantini F, Salvarani C, Olivieri I, Niccoli L, Padula A, Macchioni L, et al. Shoulder ultrasonography in the diagnosis of PMR: a case-control study. J Rheumatol 2001;28:1049–55. [30] Falsetti P, Fredniani B, Storri L, Bisogno S, Baldi F, Campanella V, et al. Evidence for synovitis in active PMR: sonographic study in a large seriesof patients. J Rheumatol 2002;29:123–30. [31] Cantini F, Salvarani C, Olivieri I, Barozzi L, Macchioni L, Niccoli L, et al. Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study. Ann Rheum Dis 1999;58:230–6. [32] Bird HA, Esselinckx W, Dixon AS, Mowat AG, Wood PH. An evaluation of criteria for PMR. Ann Rheum Dis 1979;38:434–9.

of folinic acid orally on the day after each methotrexate dose. All patients in both groups were treated with prednisone 25 mg/day tapered each month (17.5, 12.5, 7.5, and 5 mg). Of the 72 patients, 10 (14%) discontinued treatment or were lost to follow-up. After 76 weeks, 28 (87.5%) of the 32 methotrexate patients compared to only 16 (53%) of the 30 placebo patients were no longer on prednisone (P =0.003). The relapse rate was 47% (15/32) in the methotrexate group and 73% (22/30) in the placebo group. The total number of relapses was 27 with methotrexate compared to 50 with the placebo (P =0.009). The mean cumulative prednisone dose was significantly lower in the methotrexate group (2.1 vs. 2.97 g, P =0.003). In practice, we believe that first-line use of methotrexate, as investigated in these clinical trials, is inappropriate but that methotrexate may be helpful in patients who are dependent on or refractory to glucocorticoid therapy. Finally, a limited amount of data suggests that TNF-α antagonists may be useful in refractory PMR [74,75]. However, the results of a randomized double-blind placebo-controlled study of infliximab have tempered the enthusiasm generated by early studies [76]. The 49 study patients met Healey’s criteria for PMR and were given 15 mg/day of prednisone. After 16 weeks, the prednisone was stopped and the patients were given either a placebo or infliximab 3 mg/kg at weeks 0, 2, 6, 14, and 22. Evaluations were conducted after 22 and 54 weeks. After 22 weeks, 26 patients were evaluated in the placebo group and 21 in the infliximab group. No significant differences were found regarding the remission rate (58% with the placebo and 48% with infliximab), the duration of prednisone therapy (18.3 vs. 18.2 weeks), or the glucocorticoid discontinuation rate (62% vs. 45%). References
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