Polymyalgia Rheumatica and Giant Cell Arteritis
Eamonn Molloy, MD
Curry L. Koening, MD
Gary S. Hoffman, MD
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two related, immune-mediated, inflammatory conditions that occur in the elderly. PMR coexists in 40% of patients with GCA. Similarly, 10% of PMR patients develop GCA at some point during their disease course. The relation between PMR and GCA is further demonstrated by their preference for similar patient populations, linkage to the same HLA haplotypes, similar cytokine patterns in temporal artery biopsies, and similarities in anatomic involvement on PET imaging.1-3 PMR and GCA represent two extremes of a disease spectrum.
Bruce is credited with the first description in 1888 of PMR, which he described as “senile rheumatic gout.”4 However, Barber coined the term polymyalgia rheumatica in 1957, and it has become the universally accepted name for this condition.5
PMR is characterized by proximal, symmetrical musculoskeletal pain and stiffness. Symptoms of systemic inflammation are also common. A dramatic response to low-dose corticosteroids can be a valuable diagnostic tool in patients for whom the diagnosis is uncertain. The lack of response to prednisone raises the possibility of a paraneoplastic process manifesting with proximal pain and stiffness. In patients who have a dramatic response to treatment there is still a need for caution because some patients (~11%) with an initial PMR-like presentation evolve into a phenotype that is more that of rheumatoid arthritis and, less often, other systemic rheumatic illnesses.6
PMR has a predilection for patients older than 50 years. The mean age at onset is 73 years, and women are affected more often than men. Its annual incidence in Olmstead County, Minnesota, a population with mostly Scandinavian heritage, is 59 per 100,000. The annual incidence of the disease increases with age.7 Whites of northern European descent have a higher incidence of disease than people of African American or Latin American descent.8,9
Much has been learned about PMR and GCA, but their cause remains unknown. Their cause is likely multifactorial, resulting in the interplay of age, environment, and genetic susceptibility. The suggestion that PMR may be a forme fruste of GCA was first advanced in the 1950s and 1960s.5 The pathophysiology for both diseases is similar, with abnormalities of cellular immunity leading to vessel and systemic inflammation. Sixteen percent to at least 20% or more of PMR patients demonstrate arteritis on histologic examination, requiring the diagnosis to be changed to GCA.10 Cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α are important in the development of inflammation in GCA.11 Messenger RNA (mRNA) for interferon-gamma (IFN-γ) and IFN-γ protein, a product of Th1 lymphocytes, is found in the arterial wall of GCA patients. This suggests that IFN-γ may be a necessary element in the development of vasculitis. The classic histologic features of GCA, which include inflammatory cells involving the adventitia of a muscular artery and migrating toward the media and intima, consist of Th1 cells, dendritic cells, and macrophages.9
Signs and Symptoms
Most patients describe subacute onset of symptoms that remain persistent over time. Seventy percent to 95% of patients report symmetrical shoulder girdle pain and stiffness. Fifty percent to 70% report neck and pelvic girdle pain. Concurrent pain in the upper arms and thighs is common and is usually worse in the morning. Shoulder and leg discomfort can lead to difficulty dressing, hair grooming, and rising from a chair. One third of patients have flulike symptoms described as fever, malaise, anorexia, or weight loss.12
Physical examination findings may reveal pain that limits active range of motion in the shoulders and hips. Passive range of motion should be normal. Despite subjective symptoms of muscle weakness, muscle strength testing should be normal unless it is affected by examination discomfort or by another condition.12 Approximately 50% of patients have been said to present with distal extremity abnormalities including swelling of the knees, wrists, or metacarpophalangeal joints. Other reported findings include soft-tissue swelling; pitting edema of the hands, ankles, and feet; and median nerve compression. However, these findings are typical of inflammatory joint disease and not PMR. The examiner should direct the evaluation along other lines in attempting to define another diagnosis. Frank synovitis of the hands or feet should suggest rheumatoid arthritis or another inflammatory arthropathy. Thus, further laboratory and imaging may be needed to differentiate the two. (See the chapter “Rheumatoid Arthritis”).
The diagnosis of PMR is based primarily on clinical features. Elevated acute phase reactants provide secondary support for the diagnosis. The erythrocyte sedimentation rate (ESR) is greater than 40 mm/hr in 90% of cases. Other laboratory findings include an elevated C-reactive protein (CRP), normocytic normochromic anemia, thrombocytosis, and elevated alkaline phosphatase. Elevation of muscle enzymes, such as creatine kinase and aldolase, is not a feature of PMR and should prompt consideration of an alternative diagnosis.
In 1979, Bird and colleagues proposed diagnostic criteria for PMR (Table 1). Patients who fulfilled any three criteria or had one criterion along with vasculitis on a temporal artery biopsy were considered to have PMR.13 In 1984, Healy proposed that patients older than 50 years, seronegative for rheumatoid factor, and any three clinical features (neck, shoulder, or pelvic girdle pain, morning stiffness, elevated ESR, or rapid response to low-dose steroids) have PMR.14 Although these criteria should serve as guidelines for the diagnosis of PMR, most authorities agree that no single feature is necessary to diagnose it in all cases. The features noted in these criteria are common enough that if patients present without these symptoms or have a suboptimal response to corticosteroids, the diagnosis should be reconsidered. Conditions that can mimic PMR include malignancies, chronic infections, drug reactions, and other rheumatic conditions such as seronegative rheumatoid arthritis or polymyositis.6
Table 1: Often-Cited Diagnostic Criteria for Polymyalgia Rheumatica
|Authors and Year Proposed||Proposed Criteria||Requirement for Making Diagnosis|
|Bird et al. (1979)||
||Any three of these criteria, or any one plus positive temporal artery biopsy|
|Jones and Hazelman (1981)||
||All criteria must be met|
|Chuang et al. (1982)||
||All criteria must be met|
||All criteria must be met|
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
© 2004 The Cleveland Clinic Foundation.
The first successful use of corticosteroids in patients with PMR was reported by Kersley in 1951.5 Since that time, it has remained the cornerstone of therapy for PMR. Prednisone or prednisolone is the most commonly used corticosteroids. Starting doses range from 15 to 20 mg per day. A dramatic response to therapy with near-total relief of symptoms should occur within 1 to 5 days. Lack of a dramatic response to corticosteroids should prompt physicians to reconsider the diagnosis. A gradual decline of the acute phase reactants should be expected but should never be the sole gauge of therapy. After an adequate response to corticosteroids has been achieved, the initial dose should be maintained for 1 month before beginning a slow taper to the lowest effective dose. One to 2 years of treatment with corticosteroids should be expected, and a few patients require low-dose prednisone for several years.15
Disease flares during the corticosteroid taper are common and often require temporary increases in therapy. Disease flares can occur in the presence of normal acute-phase reactants. Increases in acute phase reactants mandate an evaluation to be sure that comorbid conditions are not responsible for such changes. Isolated increases in acute-phase reactants should lead to more careful monitoring and not to reflexive increases in corticosteroids doses.16
Corticosteroids are the cornerstone of therapy, but they are not without side effects. Most patients have at least one relapse as corticosteroids are tapered, and adverse events occur in almost every patient. The role of immunosuppressive agents other than corticosteroids in PMR is controversial. Methotrexate has been studied in two randomized, double-blind, controlled trials. Van der Veen and colleagues reported that patients randomized to take oral methotrexate (10 mg/week) had the same number of relapses and received the same total cumulative prednisone dose compared with patients who received placebo.17 Caporali and colleagues reported that patients randomized to oral methotrexate (10 mg/week) for 48 weeks had fewer relapses and required lower cumulative prednisone doses than patients who took placebo.18 However, further review of the patients who received methotrexate revealed that they had the same number of relapses while they were taking prednisone as did patients who received placebo. Furthermore, the number of corticosteroid-related adverse events was equal in both treatment groups and the total cumulative prednisone dose reduction achieved by taking methotrexate in place of placebo equaled only about 1 mg/day.19
TNF-α, a cytokine produced by macrophages and T-lymphocytes, appears to play a significant role in the inflammatory process of PMR and GCA. In one pilot study, 3 mg/kg of intravenous infliximab was administered as adjunctive therapy to patients on corticosteroids. This therapy allowed 12 months of remission in three out of four patients treated with the drug.20 These results were not seen in a recent double-blind, randomized, placebo-controlled study by the same author. Patients who received 3 mg/kg of infliximab at the same dosing intervals as used for rheumatoid arthritis over 22 weeks experienced the same number of weeks in remission as those who received placebo. No difference was seen in the duration of corticosteroid therapy or in the total number of patients who were able to discontinue corticosteroids between the groups.21
Adequate treatment with corticosteroids allows most patients to remain symptom free. Patients who have PMR need continued follow-up to monitor for drug-related toxicities and for possible progression to GCA. The development of a new headache or visual changes should prompt immediate medical evaluation and institution of higher doses of corticosteroids. Bilateral upper- and lower-extremity blood pressures should be obtained periodically. Differences between contralateral extremity pressures of 10 mm Hg or more should be considered abnormal. Bruits over carotid, subclavian, or femoral arteries may be due to either atheromatous disease or GCA and require further evaluation by vascular imaging.Continue