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Review
Current diagnosis and treatment of polymyalgia rheumatica Michel De Bandt ∗ Service de Rhumatologie, Hôpital Pierre Zobda Quitman, CHU de la Martinique, route de Chateauboeuf, CS 90632, 97261 Fort-de-France, Martinique
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Article history: Accepted 13 December 2013 Available online xxx Keywords: Polymyalgia rheumatica Polymyalgic syndrome Diagnostic criteria Glucocorticoid therapy PMR-DAS
a b s t r a c t The diagnostic and therapeutic strategies for polymyalgia rheumatica (PMR) have changed substantially in recent years. Rather than a single disease entity, PMR has emerged as a syndrome produced by a variety of conditions. The diagnostic criteria that have been used for several decades are inadequate. These facts support a new and broader pathological concept, polymyalgic syndrome, and a standardized diagnostic and therapeutic approach designed to rule out diseases with misleading presentations and to identify the limited number of patients with polymyalgic syndrome who have PMR. Criteria for both polymyalgic syndrome and PMR were developed recently but remain to be validated. These criteria are discussed, as well as the suggested diagnostic approach and treatment strategy. In contrast, studies on pathophysiological models, inflammatory mechanisms, and genetic factors are not considered herein, as they were conducted in heterogeneous populations of patients who did not meet the new criteria. Current data indicate that polymyalgic syndrome is a mode of onset of inflammatory joint disease in individuals older than 50 years of age and not (in most cases) a disease entity. © 2014 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
1. Introduction
2. Background
In 1953, Forestier and Certonciny [1] described an apparently inflammatory condition involving only the limb girdles and affecting older individuals, which they designated “pseudo-polyarthrite rhizomélique” “polymyalgia rheumatica” (PMR). Links were then recognized between PMR and giant-cell arteritis (GCA), and the term polymyalgia arteritica was suggested in the 1960s to designate both diseases [2,3]. The main flaw of this concept is that it views PMR and GCA as two expressions of the same disease entity, whereas most patients who present with symptoms suggesting PMR, i.e., with polymyalgic syndrome, do not have GCA. Recent studies support the view that PMR and GCA are two distinct conditions that overlap to some extent [4,5]. The misconception that PMR and GCA are the same disease has led to the inclusion in several clinical and therapeutic studies of patients with either condition. Recent work supports the polymyalgic syndrome concept and indicates a pressing need to look for the cause of polymyalgic syndrome elsewhere than in GCA. Advances in the field of PMR can be credited to an ACR-EULAR task force [6] that has been working for 15 years to dissect the clinical, diagnostic, and therapeutic aspects of PMR and to develop management guidelines, as well as criteria sets for diagnosing polymyalgic syndrome and PMR. Their work does not presume to resolve all the issues raised by PMR but has nevertheless resulted in substantial progress.
PMR is a clinical condition defined as the presence of inflammatory pain in the limb girdles [6]. Range of motion is decreased at the shoulder and pelvic girdles, and the pain radiates to the buttocks and cervical spine. By definition, these symptoms persist for at least 1 month and are combined with incapacitating morning stiffness, a decline in general health, and an elevated acute-phase response. PMR affects individuals older than 50 years of age and is the most common inflammatory rheumatic disease of the elderly. According to the new concept, PMR is a benign and highly steroid-sensitive disease that should resolve fully with low-dose glucocorticoid therapy for 12–24 months, although one or two relapses may occur. By definition, conditions that fail to meet this description constitute polymyalgic syndrome and not PMR. Thus, polymyalgic syndrome is a set of manifestations that mimic PMR at presentation but are ascribed based on subsequent information to another disease. In contrast, PMR is the condition described by Forestier, whose evaluation may benefit from the new diagnostic criteria. However, PMR continues to raise many unresolved issues.
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3. Unresolved issues At present, the management of PMR is affected by six unresolved issues [6–9]: (a) the definition of PMR rests only on clinical criteria; (b) no specific diagnostic test is available; (c) no treatment objective has been defined; (d) the clinical course is highly variable; (e) no definitions exist for PMR flare or relapse; and (f) no consensus has been developed regarding the treatment of PMR.
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The absence of specific markers for PMR and extraordinary variability in the clinical manifestations mandates the use of diagnostic criteria in clinical practice [6,7]. The disparate criteria suggested in the past had good sensitivity but low specificity for PMR. As discussed below, even in experienced hands these criteria produce the wrong diagnosis in half the cases. In other terms, they allow the diagnosis of polymyalgic syndrome but not of PMR. PMR is the leading reason for long-term glucocorticoid therapy in individuals older than 60 years of age. Some patients remain on glucocorticoid therapy for years (and probably have polymyalgic syndrome), whereas current data indicate that patients with PMR can be taken off glucocorticoid therapy after 1 or 2 years [6–9]. In rheumatoid arthritis (RA), the treatment objective is to obtain a remission. No treatment objective has been clearly defined in PMR [6,7,9]. Possible objectives include absence of pain, weaning off glucocorticoid therapy, functional recovery, absence of relapses, and resolution of the systemic inflammation. The treatment of PMR is not standardized [6–9]. A nonsteroidal antiinflammatory drug or low-dose glucocorticoid therapy (< 0.3 mg/kg/day) has been suggested. Studies found no benefits from the use of hydroxychloroquine, azathioprine, methotrexate, or TNF␣ antagonists, although these negative results may be ascribable to the heterogeneity of the patient populations. Finally, when used as a diagnostic criterion, a rapid and dramatic response to glucocorticoid therapy results in an erroneous diagnosis in half the cases (for the same reason). In several studies [6,9], after 3 weeks of glucocorticoid therapy, 35% of patients on average had persistent systemic inflammation (22% with an ESR > 30 mm/h and 32% with CRP > 10 mg/L), 45% a complete clinical response, 44% a partial clinical response, and 11% no response. A poor response was associated with a higher risk of relapse within the first year (27%, 33%, and 37%, respectively). After 3 weeks, one-third of patients still reported limb girdle pain and morning stiffness. 4. Suggested broadened definition of polymyalgic syndrome The ACR/EULAR task force has suggested the concept of polymyalgic syndrome, which can indicate PMR or other diseases [6]. According to this concept, the diagnostic strategy must be expanded considerably. Then, exclusion criteria must be ruled out. Finally, standardized treatment with 15 mg/day of prednisone is given. Thus, the definite diagnosis of PMR can be established only at the end of follow-up, usually after 12–18 months of treatment, when the patient is fully recovered and off glucocorticoid therapy. This strategy can be likened to an obstacle course during which the patient and rheumatologist rule out conditions that mimic PMR. As shown in Table 1, these criteria are considerably simpler than the previous ones and allow the inclusion of a larger number of patients. The task force suggests the following stepped diagnostic process: • evaluate for inclusion criteria; • evaluate for exclusion criteria; • prescribe standardized low- or moderate-dose glucocorticoid therapy; Table 1 Core criteria for polymyalgic syndrome. Core inclusion criteria Age > 50 years Bilateral shoulder or pelvic girdle aching, or both Morning stiffness duration of > 45 minutes Evidence of an acute-phase response (e.g., raised ESR or CRP)
Table 2 Categories of diseases that may present as polymyalgic syndrome. Common diagnoses (strong similarities with PMR) Active infection Cancer Giant-cell arteritis (temporal headache, visual disturbances, jaw, tongue, or limb claudication. . .) Rare diagnoses (limited similarities with PMR) Chronic inflammatory joint diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, lupus. . .) Crystal deposition disease Chronic multifocal pain syndromes Myopathies (metabolic, inflammatory, drug-induced. . .) Endocrinopathies Neurological conditions (e.g., Parkinson’s disease)
• evaluate the response; • and confirm the diagnosis on follow-up and treatment discontinuation. 5. Exclusion criteria The criteria used for years to diagnose PMR were neither selective nor specific [10–14]. By giving clinicians a false sense of confidence in the diagnosis, they carried a risk of unnecessary and/or prolonged exposure of patients to glucocorticoids. The diagnostic error was often discovered only late in the course of the disease. The new criteria expand the diagnostic field (Table 1), thereby inducing a risk of poor specificity. To improve specificity, the new approach involves a list of exclusion criteria and a standardized treatment regimen [6]. The exclusion criteria are divided into frequent and rare conditions, depending on the likelihood that their presentation may mimic PMR (Table 2). An exhaustive list of conditions that must be sought is provided (Table 3). The conditions at the top of Table 2 are considered closely similar to PMR in terms of the clinical picture, and those in the lower part of the table as less likely to mimic PMR. This classification is partly subjective, as no detailed epidemiological studies are available. My own experience suggests that polymyalgic syndrome is more likely to result from elderly-onset RA or spondyloarthritis than from infective endocarditis [15–18]. However, rather than the contents of the list, the important point is the emphasis on looking for possible causes to polymyalgic syndrome other than PMR (Table 3) [17,19–28]. The usefulness of looking for exclusion criteria is well illustrated by a prospective study of 249 patients with suspected PMR (mean age, 71 years; 60% of women) seen at eight rheumatology clinics in England [29]. Although the patients were evaluated by experienced rheumatologists, diagnostic errors were common. Fulfilment of Jones and Hazelman criteria for PMR was an inclusion criterion, but no exclusion criteria were applied routinely and all patients received 15 mg/day of oral prednisolone tapered according to a predefined schedule. Six months later, 120/249 patients had incontrovertible evidence of another disease and after 1 year 10 additional patients received other diagnoses (e.g., cancer or RA). Thus, overall, 130/249 (52.2%) patients were initially given a mistaken diagnosis of PMR. 6. Routine laboratory tests To facilitate the initial workup and follow-up, the task force recommends a minimal set of laboratory investigations (Table 4). These investigations contribute to the initial diagnostic strategy and serve as a reference data set in the event the initial diagnosis is subsequently called into question. This list of investigations is
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Table 3 Exhaustive list of conditions that can present as polymyalgic syndrome. Differential diagnosis approach. Presenting symptoms
Type of pain
Other clinical findings
Laboratory findings
Diagnosis
Pain/stiffness of the girdles persisting for 2 weeks
Inflammatory pain
Acute-phase response
PMR with or without GCA
id
id
Age > 50 years Morning stiffness > 45 min Shoulders predominantly involved Bilateral symmetric involvement Concomitant peripheral joint involvement
Radiological lesions Anti-CCP Latex and Waaler-Rose Acute-phase response
id
id
Edema of the hands and/or feet
RA Late-onset SpA Other chronic inflammatory joint disease. . . Articular chondrocalcinosis RS3PE syndrome
id
id
Concomitant multiorgan involvement
id
id
Muscle pain and/or fatigability
id
id
id
Mechanical or mixed pain
id
id
Decline in general health Prolonged fever Heart murmur Marked acute-phase response Decline in general health Concomitant signs. . . In some cases, marked inflammatory symptoms Mechanical symptoms
id
id
id
id
id
id
Id
id
More or less marked acute-phase response Laboratory evidence of organ dysfunction (e.g., proteinuria) Auto-antibodies. . . Muscle enzymes Auto-antibodies Hematuria Positive blood cultures. . . Bacterial serological tests
Normal laboratory tests Usefulness of radiographs
Shoulder osteoarthritis Frozen shoulder Capsulitis Mechanical low back and buttock pain Fibromyalgia
Diffuse pain Arthralgia and myalgia. . . Diffuse pain
Drug toxicities
by no means exhaustive, and any tests deemed appropriate by the rheumatologist should be performed. 7. Special points Two points deserve discussion. 7.1. Can polymyalgia rheumatica (PMR) cause peripheral arthritis? Many authors have suggested that synovitis is among the possible manifestations of PMR. Forestier and Certonciny described PMR
Deep infection Diskitis Endocarditis Brucellosis
Osteophilic cancer (prostate, breast. . .), myeloma
Criteria for diffuse idiopathic pain syndrome Endocrine disorders
Blood cell and platelet counts, CRP, ESR, Fibrin Blood and urine electrolytes, serum urea and creatinine Full battery of liver function tests Phosphate and calcium in blood and urine, alkaline phosphatases, 25 OH Vit D ± parathyroid hormone Serum protein electrophoresis, free light chains (blood and urine) Thyroid function tests CPK, LDH, transaminases, aldolase if appropriate Antinuclear antibody, latex and Waaler-Rose, anti-CCP Urinary dipstick (proteinuria) Radiographs of painful joints, chest radiograph, radionuclide bone scan Plus any investigations deemed necessary by the clinician. For instance, computed tomography of the chest and abdomen in patients with a decline in general health, temporal artery biopsy in those with headache
Inflammatory muscle disease
PSA Serum protein electrophoresis Tumor markers
Mechanical symptoms, sleep disturbances, tender points. . . Diffuse pain Arthralgia and myalgia. . .
Table 4 Minimal laboratory tests to perform before starting treatment for polymyalgia rheumatica.
Connective tissue disease, lupus vasculitis. . .
Rigidity Gait disturbances Tremor
Vitamin D deficiency Hypothyroidism Hyperthyroidism Hyperparathyroidism Statins, Proton-pump inhibitors, H2 receptor antagonists. . . Extrapyramidal syndromes
as a disease of the limb girdles that spares the peripheral joints. In several case-series, 5% to 40% of patients had distal synovitis (e.g., wrists and metacarpophalangeal joints) [30–34]. Synovitis is not among the items of any of the early criteria sets for PMR [7–14]. Recent case-series studies [7–9] indicate that patients with peripheral synovitis have polymyalgic syndrome and not PMR. Thus, synovitis may be a feature of joint diseases whose initial presentation mimics PMR, and the presence of peripheral arthritis rules out PMR. In a case-series from the Mayo Clinic, 50% of patients believed to have PMR had peripheral synovitis, usually manifesting as transient oligoarthritis, and this manifestation was most common among patients who subsequently developed a well-defined joint disease. In contrast, no cases of synovitis were noted among patients with PMR. The most specific feature of PMR (by magnetic resonance imaging or ultrasonography) is subacromial or trochanteric bursitis and not peripheral synovitis [2,35]. These two items will be incorporated into the new criteria set (see below). Positron emission tomography has not been fully evaluated as a diagnostic tool for PMR but may hold promise for the future [36].
7.2. Should a temporal artery biopsy be obtained routinely in patients with polymyalgic syndrome? True GCA can occur concomitantly with PMR. Nevertheless, the most recent data do not support routine temporal artery biopsy in patients without symptoms suggesting temporal artery inflammation [3–5].
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Table 5 Warning signs suggesting polymyalgic syndrome rather than polymyalgia rheumatica. Warning signals before treatment Age < 60 years Slow gradual onset No involvement of the shoulders No pain And/or no stiffness Predominant systemic manifestations CRP/ESR normal or very markedly elevated Peripheral arthritis Warning signals during follow-up Incomplete response to glucocorticoid therapy Steroid dependency Multiple relapses Treatment > 2 years
8. Therapeutic approach Glucocorticoid therapy remains the first-line treatment for PMR [6,9,37]. Current recommendations support an initial dosage in all patients of 15 mg/day for 3 weeks (regardless of body weight). The usual schedule involves 15 mg/day for 3 weeks, 12.5 mg/day for the next 3 weeks, 10 mg/day for the next 4–8 weeks, then tapering by 1 mg every 4–8 weeks. This schedule results in a total treatment duration of 1–2 years. Instead of a good initial response, the absence of relapse after glucocorticoid therapy discontinuation is now the diagnostic criterion for PMR. Thus, in my opinion, a patient treated for PMR who is still on glucocorticoid therapy 2 years later probably has another disease. An acute-phase response is among the main features of PMR. It may be absent (10% of patients) or subtle [29,37–39]. The ESR is often greater than 50 mm/h and the acute-phase proteins (e.g., CRP and haptoglobin) more or less elevated. Glucocorticoid therapy corrects these abnormalities. As a rule of thumb, the ESR can be expected to return to normal within 3–5 weeks and the CRP level within 2–4 weeks. Complete absence of a decrease in the acutephase response after 1 month of treatment defines early steroid resistance and occurs in about 10% of patients. 9. Red flags Red flags have been identified (Table 5), although the appropriate response to their presence has been defined so far [6]. In practice, these red flags identify patients whose initial diagnosis of PMR will prove erroneous. The first red flags should be sought at presentation: onset before 60 years of age, chronic onset, lack of shoulder involvement, prominent systemic features, peripheral arthritis, and normal or very high acute-phase response. Presence of these features before treatment initiation cast doubt on the diagnosis of PMR and should prompt a search for other conditions, even in patients with an apparently unremarkable complaint of inflammatory limb-girdle pain. Four other red flags pertain to the treatment: incomplete response to 1 month of glucocorticoid therapy, dependency on glucocorticoid therapy, multiple relapses, and need for glucocorticoid therapy for longer than 2 years. The presence of one or more of these red flags warrants a high level of alertness, as the probability that the patient has a diagnosis other than PMR is very high. That the presence of peripheral arthritis is viewed as a red flag before treatment initiation is, in my opinion, a major advance, as peripheral arthritis was long considered a common manifestation of PMR. This misconception led to the inclusion of patients with peripheral arthritis into studies of PMR, whereas symptoms confined to the limb girdles are part of the definition of PMR.
Table 6 The PMR-DAS. The PMR-DAS is obtained by summing the CRP level (mg/dL), VAS p (0–10), VASph (0–10), MST (min) 0.1, and EUL (3–0) VAS indicates a 0-to-10 visual analog scale for disease activity assessed by the patient (VASp) or physician (VASph) MST indicates the duration of morning stiffness in minutes 0.1 (e.g., morning stiffness of 60 minutes contributes 6 points) EUL (Elevation of Upper Limb) is the ability to lift the arms above the head, rated from 0 (normal) to 3 (cannot lift the arms) Values < 7 indicate a disease remission A score increase ≥ 7 points between two visits indicates a relapse
In some patients with red flags, although the diagnosis of PMR is strongly in doubt, no other disease can be identified despite careful history taking, a thorough physical evaluation, and extensive investigations. In this situation, every effort must be made during follow-up to identify additional red flags or signs suggesting another diagnosis. Red flags present before treatment initiation should in no case be viewed as a reason to increase the glucocorticoid dose above the recommended value. Risks associated with this approach include delaying the diagnosis of another disease by masking its symptoms and exposing the patients to adverse effects of glucocorticoids. The recommended glucocorticoid dose should be given and the patient monitored very closely. An incomplete or absent response to glucocorticoid therapy is associated with a high risk of relapse. However, relapses do not occur in all non-responders or poor responders. On the other hand, about one-fourth of patients with a complete response after 1 month experience a relapse. Steroid dependency is probably the red flag of greatest concern to the clinician. PMR responds fully to limited-dose glucocorticoid therapy, which can be stopped according to the recommended tapering schedule. When glucocorticoid therapy is needed for more than 2 years, in my opinion, the patient has a disease other than PMR that manifests as limb-girdle symptoms. Multiple relapses occurring spontaneously or at each decrease in the glucocorticoid dosage deserves careful attention as a sign that strongly suggests an underlying undiagnosed inflammatory joint disease. The recommendations indicate that patients with PMR may experience one or two relapses over the 12 to 24 months of follow-up and that a relapse warrants the temporary administration of a higher glucocorticoid dosage. This approach has been found valid, provided the glucocorticoid taper and weaning can subsequently be conducted within the usual time frame. When red flags accumulate over time, the diagnosis of PMR should be reappraised. However, after 12 or 18 months of followup, few differential diagnoses remain possible. At that point, the probability of having missed a malignancy (metastatic disease) or infection (infective endocarditis) is small. The main possibilities are chronic inflammatory joint diseases such as delayed reactivation of juvenile idiopathic arthritis, delayed onset or reactivation of spondyloarthritis, proximal-onset RA, crystal deposition disease, or late-onset lupus. 10. Response criteria The PMR-DAS is a validated tool for measuring the activity of PMR [39–44] (Table 6). A PMR-DAS < 7 indicates inactive disease, of 7 to 17 moderately active disease, and of > 17 highly active disease. Studies have established that a PMR-DAS increase by more than 7 points between two visits indicates a relapse with 100% sensitivity and 97.1% specificity. The same group showed that the PMR-DAS is a good tool when used by primary-care physicians to modulate the glucocorticoid regimen.
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11. Patient follow-up The minimal frequency of follow-up visits is weeks 1, 3, and 6 then every 3 months, with additional visits as needed. The recommendations define a relapse only as the recurrence of the initial manifestations. In this situation, the suggested treatment strategy consists in returning to the previous glucocorticoid dosage. After two “relapses”, the choice of the best drug (e.g., methotrexate) is at the discretion of the physician. 12. Polymyalgia rheumatica Clearly, the diagnosis of PMR is extremely challenging and must be established over time using a stepped approach. The definite diagnosis can be given only after several months when the patient is fully recovered, with no relapse, recurrence, or clinical signs, despite discontinuation of the glucocorticoid therapy. Thus, much work remains to be done: the characteristics of this small proportion of patients with a definite diagnosis of PMR must be investigated in detail. The task force used the Delphi method to identify candidate criteria based on the above-described approach. These criteria were applied to two prospective patient cohorts then reevaluated [45,46]. The suggested criteria are as follows: in a patient older than 50 years of age with bilateral shoulder pain for at least 2 weeks and an acute-phase response (polymyalgic syndrome), morning stiffness of at least 45 minutes’ duration contributes 2 points, hip pain/limited range of motion 1 point, absence of peripheral joint pain 1 point, and absence of rheumatoid factor or anti-citrullinated peptide antibodies 2 points. Thus, the maximal total score is 6 points. A score of 4 points has 62% sensitivity and 77% specificity with a positive predictive value of 80%. Adding ultrasound criteria contributes 2 points: involvement of at least one hip or shoulder (subacromial bursitis and/or long biceps tenosynovitis and/or glenohumeral synovitis; trochanteric bursitis and/or hip synovitis) adds 1 point and involvement of both shoulders 1 point. Thus, the total number of points is 8. A score of 5 or more indicates PMR. Adding ultrasound improves specificity to 86%. 13. Usefulness of these criteria The new classification criteria for PMR have two main flaws and one objective. They are intended for classification and not for diagnosis. Although they will be used as diagnostic tools, they were not designed for this purpose. In addition, prospective validation studies in other cohorts are needed to better evaluate their sensitivity and specificity. These criteria emerged from a careful analysis performed by an international task force seeking to standardize patient management and follow-up in order to improve practice uniformity and to refine diagnostic approaches with the ultimate goal of obtaining uniform patient populations for detailed studies (e.g., of genetic and immunological features) designed to identify a specific disease marker. 14. Future prospects Two points pertaining to the diagnosis and treatment, respectively, deserve discussion. Anti-ferritin antibodies have been reported as markers for both PMR and GCA [47]. These IgG antibodies are directed against the human ferritin heavy chain (27 N-terminal amino acids) or the homologous peptide from Staphylococcus epidermidis. Sera from patients with GCA and no PMR (n = 64), PMR and no GCA (n = 47), or both PMR and GCA (n = 31) were studied. With an ELISA using the
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human ferritin peptide as the substrate, sensitivity was 92% in the patients with PMR and/or GCA before treatment, 69% in patients with disease flares, and 55% in the overall cohort of treated and untreated patients. In controls, the false-positive rates were 29% in lupus, 3% in RA, 0% in elderly-onset RA, 6.5% in B-cell lymphoma, and 1% in blood donors. The ELISA using the staphylococcal homologous protein was positive in 89% of patients with PMR and/or GCA before treatment initiation. Despite the high quality of this study, a major flaw, also found in many other investigations, is the inclusion of both patients with PMR and patients with GCA. The new criteria can be expected to improve patient selection, thus providing better information on the diagnostic value of this test. Some patients have poor disease control by glucocorticoid therapy, with an incomplete response and/or multiple relapses. Furthermore, upregulation of IL-6 signaling pathways has been demonstrated in patients with temporal arteritis, Takayasu disease, or PMR [48–51]. Consequently, the use of IL-6 antagonists to treat PMR has been suggested [52–55]. The preliminary results are promising but difficult to interpret given the heterogeneity of the patient population. Studies involving the prospective inclusion of patients selected based on the new criteria – such as the ongoing TENOR study conducted in Brest and Nantes, France – are needed to obtain reliable information on IL-6 antagonist therapy in PMR. Disclosure of interest The author declares that he has no conflicts of interest concerning this article References [1] Forestier J, Certonciny A. Pseudo-polyarthrite rhizomélique. Rev Rhum Mal Osteoartic 1953;20:854–62. [2] Cantini F, Niccoli L, Storri L, et al. Are polymyalgia rheumatica and giant cell arteritis the same disease? Semin Arthritis Rheum 2004;33:294–301. [3] Gonzalez-Gay MA. Giant cell arteritis and polymyalgia rheumatica: two different but often overlapping conditions. Semin Arthritis Rheum 2004;33:289–93. [4] Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom, 1990–2001. Ann Rheum Dis 2006;65:1093–8. [5] Kobayashi S, Yano T, Matsumoto Y, et al. Clinical and epidemiologic analysis of giant cell (temporal) arteritis from a nationwide survey in 1998 in Japan: the first government-supported nationwide survey. Arthritis Rheum 2003;49:594–8. [6] Dasgupta B, Borg FA, Hassan N, et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology 2010;49:186–90. [7] Dasgupta B, Hutchings A, Matteson EL. Polymyalgia rheumatica: the mess we are now in and what we need to do about it. Arthritis Rheum 2006;55:518–20. [8] Subrahmanyan P, Dasgupta B. Polymyalgia rheumatica and giant cell arteritis. Br J Hosp Med (Lond) 2006;67:240–3. [9] Michet CJ, Matteson EL. Polymyalgia rheumatica. BMJ 2008;336:765–9. [10] Bird HA, Leeb BF, Montecucco CM, et al. A comparison of the sensitivity of diagnostic criteria for polymyalgia rheumatica. Ann Rheum Dis 2005;64:626–9. [11] Bird HA, Esselinckx W, Dixon AS, et al. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 1979;38:434–9. [12] Healey LA. Polymyalgia rheumatica and the American Rheumatism Association criteria for rheumatoid arthritis. Arthritis Rheum 1983;26:1417–8. [13] Chuang TY, Hunder GG, Ilstrup DM, et al. Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 1982;97:672–80. [14] Jones JG, Hazleman BL. Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis 1981;40:1–5. [15] Auzary C, Le Thi Huong D, Delarbre X, et al. Subacute bacterial endocarditis presenting as polymyalgia rheumatica or giant cell arteritis. Clin Exp Rheumatol 2006;24:S38–40. [16] Toussirot E, Wendling D. Late-onset ankylosing spondylitis and related spondylarthropathies: clinical and radiological characteristics and pharmacological treatment options. Drugs Aging 2005;22:451–69. [17] Ponce A, Sanmarti R, Orellana C, et al. Spondyloarthropathy presenting as a polymyalgia rheumatica-like syndrome. Clin Rheumatol 1997;16:614–6. [18] Ceccato F, Roverano S, Barrionuevo A, et al. The role of anticyclic citrullinated peptide antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Clin Rheumatol 2006;25:854–7. [19] Aouba A, Vuillemin-Bodaghi V, Mutschler C, et al. Crowned dens syndrome misdiagnosed as polymyalgia rheumatica, giant cell arteritis,
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[39] Proven A, Gabriel SE, O’Fallon WM, et al. Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 1999;26:1333–7. [40] Leeb BF, Bird HA, Nesher G, et al. EULAR response criteria for polymyalgia rheumatica: results of an initiative on the European collaborative PMR group. Ann Rheum Dis 2003;62:1189–94. [41] Leeb BF, Bird HA. A disease activity score for polymyalgia rheumatica. Ann Rheum Dis 2004;63:1279–83. [42] Binard A, De Bandt M, Berthelot JM, et al. Usefulness of the disease activity scores for polymyalgia rheumatica for predicting glucocorticoid dose changes: a study of 243 scenarios. Arthritis Rheum 2007;57:481–6. [43] Binard A, Lefebvre B, De Bandt M, et al. Validity of the polymyalgia rheumatica activity score in primary care practice. Ann Rheum Dis 2009;68:541–5. [44] Cleuziou C, Binard A, De Bandt M, et al. Contribution of the polymyalgia rheumatica activity score to glucocorticoid dosage adjustment in everyday practice. J Rheumatol 2012;39:310–3. [45] Dasgupta B, Matesson E. Development of classification criteria for polymyalgia rheumatica: results from a consensus conference and extended Delphi survey. Arthritis Rheum 2006;54:S345 [abstract 767]. [46] Dasgupta B, Cimmino M, Kremers M, et al. Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum 2012;64:943–54. [47] Baerlecken NT, Linnemann A, Gross WL, et al. Association of ferritin autoantibodies with giant cell arteritis/polymyalgia rheumatica. Ann Rheum Dis 2012;6:943–7. [48] Boiardi L, Casali B, Farnetti E, et al. Relationship between interleukin 6 promoter polymorphism at position -174, IL-6 serum levels, and the risk of relapse/recurrence in polymyalgia rheumatica. J Rheumatol 2006;33:703–8. [49] Salvarani C, Casali B, Farnetti E, et al. Interleukin-6 promoter polymorphism at position -174 in giant cell arteritis. J Rheumatol 2005;32:2173–7. [50] Gonzalez-Gay MA, Hajeer AH, Dababneh A, et al. IL-6 promoter polymorphism at position -174 modulates the phenotypic expression of polymyalgia rheumatica in biopsy-proven giant cell arteritis. Clin Exp Rheumatol 2002;20: 179–84. [51] Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36:1286–94. [52] Macchioni P, Boiardi L, Catanoso M, et al. Tocilizumab for polymyalgia rheumatica: report of two cases and review of the literature. Semin Arthritis Rheum 2013;43:113–8. [53] Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res 2012;64:1720–9. [54] Masson C. Therapeutic approach to giant cell arteritis. Joint Bone Spine 2012;79:219–27. [55] Vinit J, Bielefeld P, Muller G, et al. Efficacy of tocilizumab in refractory giant cell arteritis. Joint Bone Spine 2012;79:317–8.
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Current diagnosis and treatment of polymyalgia rheumatica Michel De Bandt ∗ Service de Rhumatologie, Hôpital Pierre Zobda Quitman, CHU de la Martinique, route de Chateauboeuf, CS 90632, 97261 Fort-de-France, Martinique
a r t i c l e
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Article history: Accepted 13 December 2013 Available online xxx Keywords: Polymyalgia rheumatica Polymyalgic syndrome Diagnostic criteria Glucocorticoid therapy PMR-DAS
a b s t r a c t The diagnostic and therapeutic strategies for polymyalgia rheumatica (PMR) have changed substantially in recent years. Rather than a single disease entity, PMR has emerged as a syndrome produced by a variety of conditions. The diagnostic criteria that have been used for several decades are inadequate. These facts support a new and broader pathological concept, polymyalgic syndrome, and a standardized diagnostic and therapeutic approach designed to rule out diseases with misleading presentations and to identify the limited number of patients with polymyalgic syndrome who have PMR. Criteria for both polymyalgic syndrome and PMR were developed recently but remain to be validated. These criteria are discussed, as well as the suggested diagnostic approach and treatment strategy. In contrast, studies on pathophysiological models, inflammatory mechanisms, and genetic factors are not considered herein, as they were conducted in heterogeneous populations of patients who did not meet the new criteria. Current data indicate that polymyalgic syndrome is a mode of onset of inflammatory joint disease in individuals older than 50 years of age and not (in most cases) a disease entity. © 2014 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
1. Introduction
2. Background
In 1953, Forestier and Certonciny [1] described an apparently inflammatory condition involving only the limb girdles and affecting older individuals, which they designated “pseudo-polyarthrite rhizomélique” “polymyalgia rheumatica” (PMR). Links were then recognized between PMR and giant-cell arteritis (GCA), and the term polymyalgia arteritica was suggested in the 1960s to designate both diseases [2,3]. The main flaw of this concept is that it views PMR and GCA as two expressions of the same disease entity, whereas most patients who present with symptoms suggesting PMR, i.e., with polymyalgic syndrome, do not have GCA. Recent studies support the view that PMR and GCA are two distinct conditions that overlap to some extent [4,5]. The misconception that PMR and GCA are the same disease has led to the inclusion in several clinical and therapeutic studies of patients with either condition. Recent work supports the polymyalgic syndrome concept and indicates a pressing need to look for the cause of polymyalgic syndrome elsewhere than in GCA. Advances in the field of PMR can be credited to an ACR-EULAR task force [6] that has been working for 15 years to dissect the clinical, diagnostic, and therapeutic aspects of PMR and to develop management guidelines, as well as criteria sets for diagnosing polymyalgic syndrome and PMR. Their work does not presume to resolve all the issues raised by PMR but has nevertheless resulted in substantial progress.
PMR is a clinical condition defined as the presence of inflammatory pain in the limb girdles [6]. Range of motion is decreased at the shoulder and pelvic girdles, and the pain radiates to the buttocks and cervical spine. By definition, these symptoms persist for at least 1 month and are combined with incapacitating morning stiffness, a decline in general health, and an elevated acute-phase response. PMR affects individuals older than 50 years of age and is the most common inflammatory rheumatic disease of the elderly. According to the new concept, PMR is a benign and highly steroid-sensitive disease that should resolve fully with low-dose glucocorticoid therapy for 12–24 months, although one or two relapses may occur. By definition, conditions that fail to meet this description constitute polymyalgic syndrome and not PMR. Thus, polymyalgic syndrome is a set of manifestations that mimic PMR at presentation but are ascribed based on subsequent information to another disease. In contrast, PMR is the condition described by Forestier, whose evaluation may benefit from the new diagnostic criteria. However, PMR continues to raise many unresolved issues.
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3. Unresolved issues At present, the management of PMR is affected by six unresolved issues [6–9]: (a) the definition of PMR rests only on clinical criteria; (b) no specific diagnostic test is available; (c) no treatment objective has been defined; (d) the clinical course is highly variable; (e) no definitions exist for PMR flare or relapse; and (f) no consensus has been developed regarding the treatment of PMR.
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The absence of specific markers for PMR and extraordinary variability in the clinical manifestations mandates the use of diagnostic criteria in clinical practice [6,7]. The disparate criteria suggested in the past had good sensitivity but low specificity for PMR. As discussed below, even in experienced hands these criteria produce the wrong diagnosis in half the cases. In other terms, they allow the diagnosis of polymyalgic syndrome but not of PMR. PMR is the leading reason for long-term glucocorticoid therapy in individuals older than 60 years of age. Some patients remain on glucocorticoid therapy for years (and probably have polymyalgic syndrome), whereas current data indicate that patients with PMR can be taken off glucocorticoid therapy after 1 or 2 years [6–9]. In rheumatoid arthritis (RA), the treatment objective is to obtain a remission. No treatment objective has been clearly defined in PMR [6,7,9]. Possible objectives include absence of pain, weaning off glucocorticoid therapy, functional recovery, absence of relapses, and resolution of the systemic inflammation. The treatment of PMR is not standardized [6–9]. A nonsteroidal antiinflammatory drug or low-dose glucocorticoid therapy (< 0.3 mg/kg/day) has been suggested. Studies found no benefits from the use of hydroxychloroquine, azathioprine, methotrexate, or TNF␣ antagonists, although these negative results may be ascribable to the heterogeneity of the patient populations. Finally, when used as a diagnostic criterion, a rapid and dramatic response to glucocorticoid therapy results in an erroneous diagnosis in half the cases (for the same reason). In several studies [6,9], after 3 weeks of glucocorticoid therapy, 35% of patients on average had persistent systemic inflammation (22% with an ESR > 30 mm/h and 32% with CRP > 10 mg/L), 45% a complete clinical response, 44% a partial clinical response, and 11% no response. A poor response was associated with a higher risk of relapse within the first year (27%, 33%, and 37%, respectively). After 3 weeks, one-third of patients still reported limb girdle pain and morning stiffness. 4. Suggested broadened definition of polymyalgic syndrome The ACR/EULAR task force has suggested the concept of polymyalgic syndrome, which can indicate PMR or other diseases [6]. According to this concept, the diagnostic strategy must be expanded considerably. Then, exclusion criteria must be ruled out. Finally, standardized treatment with 15 mg/day of prednisone is given. Thus, the definite diagnosis of PMR can be established only at the end of follow-up, usually after 12–18 months of treatment, when the patient is fully recovered and off glucocorticoid therapy. This strategy can be likened to an obstacle course during which the patient and rheumatologist rule out conditions that mimic PMR. As shown in Table 1, these criteria are considerably simpler than the previous ones and allow the inclusion of a larger number of patients. The task force suggests the following stepped diagnostic process: • evaluate for inclusion criteria; • evaluate for exclusion criteria; • prescribe standardized low- or moderate-dose glucocorticoid therapy; Table 1 Core criteria for polymyalgic syndrome. Core inclusion criteria Age > 50 years Bilateral shoulder or pelvic girdle aching, or both Morning stiffness duration of > 45 minutes Evidence of an acute-phase response (e.g., raised ESR or CRP)
Table 2 Categories of diseases that may present as polymyalgic syndrome. Common diagnoses (strong similarities with PMR) Active infection Cancer Giant-cell arteritis (temporal headache, visual disturbances, jaw, tongue, or limb claudication. . .) Rare diagnoses (limited similarities with PMR) Chronic inflammatory joint diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, lupus. . .) Crystal deposition disease Chronic multifocal pain syndromes Myopathies (metabolic, inflammatory, drug-induced. . .) Endocrinopathies Neurological conditions (e.g., Parkinson’s disease)
• evaluate the response; • and confirm the diagnosis on follow-up and treatment discontinuation. 5. Exclusion criteria The criteria used for years to diagnose PMR were neither selective nor specific [10–14]. By giving clinicians a false sense of confidence in the diagnosis, they carried a risk of unnecessary and/or prolonged exposure of patients to glucocorticoids. The diagnostic error was often discovered only late in the course of the disease. The new criteria expand the diagnostic field (Table 1), thereby inducing a risk of poor specificity. To improve specificity, the new approach involves a list of exclusion criteria and a standardized treatment regimen [6]. The exclusion criteria are divided into frequent and rare conditions, depending on the likelihood that their presentation may mimic PMR (Table 2). An exhaustive list of conditions that must be sought is provided (Table 3). The conditions at the top of Table 2 are considered closely similar to PMR in terms of the clinical picture, and those in the lower part of the table as less likely to mimic PMR. This classification is partly subjective, as no detailed epidemiological studies are available. My own experience suggests that polymyalgic syndrome is more likely to result from elderly-onset RA or spondyloarthritis than from infective endocarditis [15–18]. However, rather than the contents of the list, the important point is the emphasis on looking for possible causes to polymyalgic syndrome other than PMR (Table 3) [17,19–28]. The usefulness of looking for exclusion criteria is well illustrated by a prospective study of 249 patients with suspected PMR (mean age, 71 years; 60% of women) seen at eight rheumatology clinics in England [29]. Although the patients were evaluated by experienced rheumatologists, diagnostic errors were common. Fulfilment of Jones and Hazelman criteria for PMR was an inclusion criterion, but no exclusion criteria were applied routinely and all patients received 15 mg/day of oral prednisolone tapered according to a predefined schedule. Six months later, 120/249 patients had incontrovertible evidence of another disease and after 1 year 10 additional patients received other diagnoses (e.g., cancer or RA). Thus, overall, 130/249 (52.2%) patients were initially given a mistaken diagnosis of PMR. 6. Routine laboratory tests To facilitate the initial workup and follow-up, the task force recommends a minimal set of laboratory investigations (Table 4). These investigations contribute to the initial diagnostic strategy and serve as a reference data set in the event the initial diagnosis is subsequently called into question. This list of investigations is
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Table 3 Exhaustive list of conditions that can present as polymyalgic syndrome. Differential diagnosis approach. Presenting symptoms
Type of pain
Other clinical findings
Laboratory findings
Diagnosis
Pain/stiffness of the girdles persisting for 2 weeks
Inflammatory pain
Acute-phase response
PMR with or without GCA
id
id
Age > 50 years Morning stiffness > 45 min Shoulders predominantly involved Bilateral symmetric involvement Concomitant peripheral joint involvement
Radiological lesions Anti-CCP Latex and Waaler-Rose Acute-phase response
id
id
Edema of the hands and/or feet
RA Late-onset SpA Other chronic inflammatory joint disease. . . Articular chondrocalcinosis RS3PE syndrome
id
id
Concomitant multiorgan involvement
id
id
Muscle pain and/or fatigability
id
id
id
Mechanical or mixed pain
id
id
Decline in general health Prolonged fever Heart murmur Marked acute-phase response Decline in general health Concomitant signs. . . In some cases, marked inflammatory symptoms Mechanical symptoms
id
id
id
id
id
id
Id
id
More or less marked acute-phase response Laboratory evidence of organ dysfunction (e.g., proteinuria) Auto-antibodies. . . Muscle enzymes Auto-antibodies Hematuria Positive blood cultures. . . Bacterial serological tests
Normal laboratory tests Usefulness of radiographs
Shoulder osteoarthritis Frozen shoulder Capsulitis Mechanical low back and buttock pain Fibromyalgia
Diffuse pain Arthralgia and myalgia. . . Diffuse pain
Drug toxicities
by no means exhaustive, and any tests deemed appropriate by the rheumatologist should be performed. 7. Special points Two points deserve discussion. 7.1. Can polymyalgia rheumatica (PMR) cause peripheral arthritis? Many authors have suggested that synovitis is among the possible manifestations of PMR. Forestier and Certonciny described PMR
Deep infection Diskitis Endocarditis Brucellosis
Osteophilic cancer (prostate, breast. . .), myeloma
Criteria for diffuse idiopathic pain syndrome Endocrine disorders
Blood cell and platelet counts, CRP, ESR, Fibrin Blood and urine electrolytes, serum urea and creatinine Full battery of liver function tests Phosphate and calcium in blood and urine, alkaline phosphatases, 25 OH Vit D ± parathyroid hormone Serum protein electrophoresis, free light chains (blood and urine) Thyroid function tests CPK, LDH, transaminases, aldolase if appropriate Antinuclear antibody, latex and Waaler-Rose, anti-CCP Urinary dipstick (proteinuria) Radiographs of painful joints, chest radiograph, radionuclide bone scan Plus any investigations deemed necessary by the clinician. For instance, computed tomography of the chest and abdomen in patients with a decline in general health, temporal artery biopsy in those with headache
Inflammatory muscle disease
PSA Serum protein electrophoresis Tumor markers
Mechanical symptoms, sleep disturbances, tender points. . . Diffuse pain Arthralgia and myalgia. . .
Table 4 Minimal laboratory tests to perform before starting treatment for polymyalgia rheumatica.
Connective tissue disease, lupus vasculitis. . .
Rigidity Gait disturbances Tremor
Vitamin D deficiency Hypothyroidism Hyperthyroidism Hyperparathyroidism Statins, Proton-pump inhibitors, H2 receptor antagonists. . . Extrapyramidal syndromes
as a disease of the limb girdles that spares the peripheral joints. In several case-series, 5% to 40% of patients had distal synovitis (e.g., wrists and metacarpophalangeal joints) [30–34]. Synovitis is not among the items of any of the early criteria sets for PMR [7–14]. Recent case-series studies [7–9] indicate that patients with peripheral synovitis have polymyalgic syndrome and not PMR. Thus, synovitis may be a feature of joint diseases whose initial presentation mimics PMR, and the presence of peripheral arthritis rules out PMR. In a case-series from the Mayo Clinic, 50% of patients believed to have PMR had peripheral synovitis, usually manifesting as transient oligoarthritis, and this manifestation was most common among patients who subsequently developed a well-defined joint disease. In contrast, no cases of synovitis were noted among patients with PMR. The most specific feature of PMR (by magnetic resonance imaging or ultrasonography) is subacromial or trochanteric bursitis and not peripheral synovitis [2,35]. These two items will be incorporated into the new criteria set (see below). Positron emission tomography has not been fully evaluated as a diagnostic tool for PMR but may hold promise for the future [36].
7.2. Should a temporal artery biopsy be obtained routinely in patients with polymyalgic syndrome? True GCA can occur concomitantly with PMR. Nevertheless, the most recent data do not support routine temporal artery biopsy in patients without symptoms suggesting temporal artery inflammation [3–5].
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Table 5 Warning signs suggesting polymyalgic syndrome rather than polymyalgia rheumatica. Warning signals before treatment Age < 60 years Slow gradual onset No involvement of the shoulders No pain And/or no stiffness Predominant systemic manifestations CRP/ESR normal or very markedly elevated Peripheral arthritis Warning signals during follow-up Incomplete response to glucocorticoid therapy Steroid dependency Multiple relapses Treatment > 2 years
8. Therapeutic approach Glucocorticoid therapy remains the first-line treatment for PMR [6,9,37]. Current recommendations support an initial dosage in all patients of 15 mg/day for 3 weeks (regardless of body weight). The usual schedule involves 15 mg/day for 3 weeks, 12.5 mg/day for the next 3 weeks, 10 mg/day for the next 4–8 weeks, then tapering by 1 mg every 4–8 weeks. This schedule results in a total treatment duration of 1–2 years. Instead of a good initial response, the absence of relapse after glucocorticoid therapy discontinuation is now the diagnostic criterion for PMR. Thus, in my opinion, a patient treated for PMR who is still on glucocorticoid therapy 2 years later probably has another disease. An acute-phase response is among the main features of PMR. It may be absent (10% of patients) or subtle [29,37–39]. The ESR is often greater than 50 mm/h and the acute-phase proteins (e.g., CRP and haptoglobin) more or less elevated. Glucocorticoid therapy corrects these abnormalities. As a rule of thumb, the ESR can be expected to return to normal within 3–5 weeks and the CRP level within 2–4 weeks. Complete absence of a decrease in the acutephase response after 1 month of treatment defines early steroid resistance and occurs in about 10% of patients. 9. Red flags Red flags have been identified (Table 5), although the appropriate response to their presence has been defined so far [6]. In practice, these red flags identify patients whose initial diagnosis of PMR will prove erroneous. The first red flags should be sought at presentation: onset before 60 years of age, chronic onset, lack of shoulder involvement, prominent systemic features, peripheral arthritis, and normal or very high acute-phase response. Presence of these features before treatment initiation cast doubt on the diagnosis of PMR and should prompt a search for other conditions, even in patients with an apparently unremarkable complaint of inflammatory limb-girdle pain. Four other red flags pertain to the treatment: incomplete response to 1 month of glucocorticoid therapy, dependency on glucocorticoid therapy, multiple relapses, and need for glucocorticoid therapy for longer than 2 years. The presence of one or more of these red flags warrants a high level of alertness, as the probability that the patient has a diagnosis other than PMR is very high. That the presence of peripheral arthritis is viewed as a red flag before treatment initiation is, in my opinion, a major advance, as peripheral arthritis was long considered a common manifestation of PMR. This misconception led to the inclusion of patients with peripheral arthritis into studies of PMR, whereas symptoms confined to the limb girdles are part of the definition of PMR.
Table 6 The PMR-DAS. The PMR-DAS is obtained by summing the CRP level (mg/dL), VAS p (0–10), VASph (0–10), MST (min) 0.1, and EUL (3–0) VAS indicates a 0-to-10 visual analog scale for disease activity assessed by the patient (VASp) or physician (VASph) MST indicates the duration of morning stiffness in minutes 0.1 (e.g., morning stiffness of 60 minutes contributes 6 points) EUL (Elevation of Upper Limb) is the ability to lift the arms above the head, rated from 0 (normal) to 3 (cannot lift the arms) Values < 7 indicate a disease remission A score increase ≥ 7 points between two visits indicates a relapse
In some patients with red flags, although the diagnosis of PMR is strongly in doubt, no other disease can be identified despite careful history taking, a thorough physical evaluation, and extensive investigations. In this situation, every effort must be made during follow-up to identify additional red flags or signs suggesting another diagnosis. Red flags present before treatment initiation should in no case be viewed as a reason to increase the glucocorticoid dose above the recommended value. Risks associated with this approach include delaying the diagnosis of another disease by masking its symptoms and exposing the patients to adverse effects of glucocorticoids. The recommended glucocorticoid dose should be given and the patient monitored very closely. An incomplete or absent response to glucocorticoid therapy is associated with a high risk of relapse. However, relapses do not occur in all non-responders or poor responders. On the other hand, about one-fourth of patients with a complete response after 1 month experience a relapse. Steroid dependency is probably the red flag of greatest concern to the clinician. PMR responds fully to limited-dose glucocorticoid therapy, which can be stopped according to the recommended tapering schedule. When glucocorticoid therapy is needed for more than 2 years, in my opinion, the patient has a disease other than PMR that manifests as limb-girdle symptoms. Multiple relapses occurring spontaneously or at each decrease in the glucocorticoid dosage deserves careful attention as a sign that strongly suggests an underlying undiagnosed inflammatory joint disease. The recommendations indicate that patients with PMR may experience one or two relapses over the 12 to 24 months of follow-up and that a relapse warrants the temporary administration of a higher glucocorticoid dosage. This approach has been found valid, provided the glucocorticoid taper and weaning can subsequently be conducted within the usual time frame. When red flags accumulate over time, the diagnosis of PMR should be reappraised. However, after 12 or 18 months of followup, few differential diagnoses remain possible. At that point, the probability of having missed a malignancy (metastatic disease) or infection (infective endocarditis) is small. The main possibilities are chronic inflammatory joint diseases such as delayed reactivation of juvenile idiopathic arthritis, delayed onset or reactivation of spondyloarthritis, proximal-onset RA, crystal deposition disease, or late-onset lupus. 10. Response criteria The PMR-DAS is a validated tool for measuring the activity of PMR [39–44] (Table 6). A PMR-DAS < 7 indicates inactive disease, of 7 to 17 moderately active disease, and of > 17 highly active disease. Studies have established that a PMR-DAS increase by more than 7 points between two visits indicates a relapse with 100% sensitivity and 97.1% specificity. The same group showed that the PMR-DAS is a good tool when used by primary-care physicians to modulate the glucocorticoid regimen.
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11. Patient follow-up The minimal frequency of follow-up visits is weeks 1, 3, and 6 then every 3 months, with additional visits as needed. The recommendations define a relapse only as the recurrence of the initial manifestations. In this situation, the suggested treatment strategy consists in returning to the previous glucocorticoid dosage. After two “relapses”, the choice of the best drug (e.g., methotrexate) is at the discretion of the physician. 12. Polymyalgia rheumatica Clearly, the diagnosis of PMR is extremely challenging and must be established over time using a stepped approach. The definite diagnosis can be given only after several months when the patient is fully recovered, with no relapse, recurrence, or clinical signs, despite discontinuation of the glucocorticoid therapy. Thus, much work remains to be done: the characteristics of this small proportion of patients with a definite diagnosis of PMR must be investigated in detail. The task force used the Delphi method to identify candidate criteria based on the above-described approach. These criteria were applied to two prospective patient cohorts then reevaluated [45,46]. The suggested criteria are as follows: in a patient older than 50 years of age with bilateral shoulder pain for at least 2 weeks and an acute-phase response (polymyalgic syndrome), morning stiffness of at least 45 minutes’ duration contributes 2 points, hip pain/limited range of motion 1 point, absence of peripheral joint pain 1 point, and absence of rheumatoid factor or anti-citrullinated peptide antibodies 2 points. Thus, the maximal total score is 6 points. A score of 4 points has 62% sensitivity and 77% specificity with a positive predictive value of 80%. Adding ultrasound criteria contributes 2 points: involvement of at least one hip or shoulder (subacromial bursitis and/or long biceps tenosynovitis and/or glenohumeral synovitis; trochanteric bursitis and/or hip synovitis) adds 1 point and involvement of both shoulders 1 point. Thus, the total number of points is 8. A score of 5 or more indicates PMR. Adding ultrasound improves specificity to 86%. 13. Usefulness of these criteria The new classification criteria for PMR have two main flaws and one objective. They are intended for classification and not for diagnosis. Although they will be used as diagnostic tools, they were not designed for this purpose. In addition, prospective validation studies in other cohorts are needed to better evaluate their sensitivity and specificity. These criteria emerged from a careful analysis performed by an international task force seeking to standardize patient management and follow-up in order to improve practice uniformity and to refine diagnostic approaches with the ultimate goal of obtaining uniform patient populations for detailed studies (e.g., of genetic and immunological features) designed to identify a specific disease marker. 14. Future prospects Two points pertaining to the diagnosis and treatment, respectively, deserve discussion. Anti-ferritin antibodies have been reported as markers for both PMR and GCA [47]. These IgG antibodies are directed against the human ferritin heavy chain (27 N-terminal amino acids) or the homologous peptide from Staphylococcus epidermidis. Sera from patients with GCA and no PMR (n = 64), PMR and no GCA (n = 47), or both PMR and GCA (n = 31) were studied. With an ELISA using the
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human ferritin peptide as the substrate, sensitivity was 92% in the patients with PMR and/or GCA before treatment, 69% in patients with disease flares, and 55% in the overall cohort of treated and untreated patients. In controls, the false-positive rates were 29% in lupus, 3% in RA, 0% in elderly-onset RA, 6.5% in B-cell lymphoma, and 1% in blood donors. The ELISA using the staphylococcal homologous protein was positive in 89% of patients with PMR and/or GCA before treatment initiation. Despite the high quality of this study, a major flaw, also found in many other investigations, is the inclusion of both patients with PMR and patients with GCA. The new criteria can be expected to improve patient selection, thus providing better information on the diagnostic value of this test. Some patients have poor disease control by glucocorticoid therapy, with an incomplete response and/or multiple relapses. Furthermore, upregulation of IL-6 signaling pathways has been demonstrated in patients with temporal arteritis, Takayasu disease, or PMR [48–51]. Consequently, the use of IL-6 antagonists to treat PMR has been suggested [52–55]. The preliminary results are promising but difficult to interpret given the heterogeneity of the patient population. Studies involving the prospective inclusion of patients selected based on the new criteria – such as the ongoing TENOR study conducted in Brest and Nantes, France – are needed to obtain reliable information on IL-6 antagonist therapy in PMR. Disclosure of interest The author declares that he has no conflicts of interest concerning this article References [1] Forestier J, Certonciny A. Pseudo-polyarthrite rhizomélique. Rev Rhum Mal Osteoartic 1953;20:854–62. [2] Cantini F, Niccoli L, Storri L, et al. Are polymyalgia rheumatica and giant cell arteritis the same disease? Semin Arthritis Rheum 2004;33:294–301. [3] Gonzalez-Gay MA. Giant cell arteritis and polymyalgia rheumatica: two different but often overlapping conditions. Semin Arthritis Rheum 2004;33:289–93. [4] Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom, 1990–2001. Ann Rheum Dis 2006;65:1093–8. [5] Kobayashi S, Yano T, Matsumoto Y, et al. Clinical and epidemiologic analysis of giant cell (temporal) arteritis from a nationwide survey in 1998 in Japan: the first government-supported nationwide survey. Arthritis Rheum 2003;49:594–8. [6] Dasgupta B, Borg FA, Hassan N, et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology 2010;49:186–90. [7] Dasgupta B, Hutchings A, Matteson EL. Polymyalgia rheumatica: the mess we are now in and what we need to do about it. Arthritis Rheum 2006;55:518–20. [8] Subrahmanyan P, Dasgupta B. Polymyalgia rheumatica and giant cell arteritis. Br J Hosp Med (Lond) 2006;67:240–3. [9] Michet CJ, Matteson EL. Polymyalgia rheumatica. BMJ 2008;336:765–9. [10] Bird HA, Leeb BF, Montecucco CM, et al. A comparison of the sensitivity of diagnostic criteria for polymyalgia rheumatica. Ann Rheum Dis 2005;64:626–9. [11] Bird HA, Esselinckx W, Dixon AS, et al. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 1979;38:434–9. [12] Healey LA. Polymyalgia rheumatica and the American Rheumatism Association criteria for rheumatoid arthritis. Arthritis Rheum 1983;26:1417–8. [13] Chuang TY, Hunder GG, Ilstrup DM, et al. Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 1982;97:672–80. [14] Jones JG, Hazleman BL. Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis 1981;40:1–5. [15] Auzary C, Le Thi Huong D, Delarbre X, et al. Subacute bacterial endocarditis presenting as polymyalgia rheumatica or giant cell arteritis. Clin Exp Rheumatol 2006;24:S38–40. [16] Toussirot E, Wendling D. Late-onset ankylosing spondylitis and related spondylarthropathies: clinical and radiological characteristics and pharmacological treatment options. Drugs Aging 2005;22:451–69. [17] Ponce A, Sanmarti R, Orellana C, et al. Spondyloarthropathy presenting as a polymyalgia rheumatica-like syndrome. Clin Rheumatol 1997;16:614–6. [18] Ceccato F, Roverano S, Barrionuevo A, et al. The role of anticyclic citrullinated peptide antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Clin Rheumatol 2006;25:854–7. [19] Aouba A, Vuillemin-Bodaghi V, Mutschler C, et al. Crowned dens syndrome misdiagnosed as polymyalgia rheumatica, giant cell arteritis,
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