Polymyalgia rheumatica (PMR) is a rheumatic disorder characterized by pain and stiffness around the neck, shoulder and hip area. This disorder is more common in white adults over 50 years of age. It is an inflammatory condition associated with an elevation of erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) being the common findings. PMR patients can have coexisting and/or develop giant cell arteritis (GCA). Some authors consider Giant-cell arteritis (GCA) to be an extreme entity of the same spectrum of disorders as PMR. Challenges in managing PMR lie in correctly diagnosing the condition and appropriate treatment which would involve a long period of follow-up.
The etiology of polymyalgia rheumatica is not well understood.
Familial aggregation of PMR has suggested a genetic predisposition.[1] HLA class II alleles are found to be associated with PMR and among these, the HLA-DRB1*04 allele correlates most frequently, seen in up to 67% of cases.[2] Genetic polymorphisms for ICAM-1, RANTES and IL-1 receptor also appear to play a role in the pathogenesis of PMR in some populations.[3]
There were reports of increased incidence of PMR along with GCA were reported during epidemics of mycoplasma pneumonia and parvovirus B19 in Denmark suggesting a possible role of infection in etiopathogenesis.[4] The Epstein-Barr virus has also been proposed as a possible trigger for PMR.[5] However, several other studies have not supported an infectious etiology hypothesis.[6][7]
There are also reports of an association between PMR and diverticulitis, which could suggest a role of change in microbiota and chronic bowel inflammation in the immunopathogenesis of disease.[8]
A case series of previously healthy subjects developing GCA/PMR after influenza vaccination also exists.[9] Vaccine adjuvants can trigger autoimmunity causing "ASIA" syndrome which can have clinical features similar to PMR.
The annual incidence of polymyalgia rheumatica per 100,000 population of age more or equal to 50 years was found to be between 58 to 96 in the populations of predominantly white. Incidence rates increase with age until 80 years.[10][11] PMR has been reported as the second most common inflammatory autoimmune rheumatic disease after rheumatoid arthritis in some predominantly white population. PMR is much less common in African American, Asian, and Hispanic populations.
Polymyalgia rheumatica is an immune-mediated disorder, and elevated inflammatory markers are one of the most common features. IL-6 appears to have a central role in mediating inflammation.[12] IFN may be present in temporal artery biopsy in patients with GCA but not in patients with PMR, suggesting its role in the development of arteritis.[13] Elevated IGG4 level was found in PMR patients but less frequently so in GCA patients.[14] The same study discovered an increased number of patients with PMR features and without elevation of IgG4 disease to have simultaneous GCA.
Patients with PMR have a decreased number of circulating B cells compared to healthy adults. The circulating B cells number inversely correlate with ESR and CRP. This altered distribution of B cells possibly contributes to IL-6 response in PMR.[15] Autoantibodies with a significant role in pathogenesis are not a feature in PMR. Patients with PMR have decreased Treg cells and Th1 cells and an increased TH 17 cells.[16] Increased expression of toll-like receptor 7 and 9 in peripheral blood monocytes suggests the role of innate immunity in pathogenesis as well.[17]
Polymyalgia rheumatica (PMR) characteristically demonstrates symmetrical pain and stiffness in and around shoulders, neck and hip girdle. Pain and stiffness are the worst in the morning and also worsen after rest or prolonged inactivity. Restricted range of motion of shoulder is common. Patients often complain of pain and stiffness in the upper arms, hips, thighs, upper and lower back. The onset of symptoms is rapid, usually from a day up to 2 weeks. It affects the quality of life as pain may impair sleep at nighttime and daytime routine activities like getting out of bed or chair, taking a shower, making own hair, driving, etc.[18]
The pain and stiffness associated with PMR are most probably related to inflammation of the glenohumeral and hip joints and in the upper extremity the subacromial, subdeltoid, and trochanteric bursae.[19] Almost up to half of the patients experience systemic symptoms like fatigue, malaise, anorexia, weight loss or low-grade fever.[20] Persistent high fever is uncommon in PMR and should alert suspicion of GCA.[18]
Peripheral involvement is also frequent with arthritis in a fourth of patients. Other peripheral features like carpal tunnel syndrome, distal extremity swelling with pitting edema, and distal tenosynovitis can be present. Arthritis does not lead to erosions or deformities or development of rheumatoid arthritis.[21] Distal extremity swelling with pitting edema responds promptly to glucocorticoids.[22]
On physical examination, diffuse tenderness is usually in evidence over the shoulder without localization to specific structures. Pain usually restricts the active shoulder range of motion, and passive range of motion could be normal when carefully examined. Restriction of neck and hip movements because of pain is also common. Muscle tenderness of neck, arms and thigh may be present. Even though the patient might complain of non-specific weakness, muscle strength is usually intact on a more thorough examination.[18]
Laboratory studies:
Elevated ESR is a common feature in polymyalgia rheumatica. ESR higher than 40mm has been considered significant by the majority of authors.[23][24][25] ESR lower than 40 mm/h is present in 7% to 20% of patients. Patients with low ESR usually have a lower frequency of systemic features like fever, weight loss, and anemia. Response to therapy, the frequency of relapses and the risk of developing GCA among these patients appear to be comparable with high ESR patients.[26][27] CRP is also typically elevated. CRP was found to be a more sensitive indicator of disease activity in one study while ESR found to be a superior predictor of relapse.[28]
Normocytic anemia and thrombocytosis can occur. Liver enzymes and especially alkaline phosphatase are occasionally elevated. Serologic tests, such as ANA, RF, and Anti-CCP Ab are negative. CPK value is within the normal range.
Imaging studies:
Ultrasound:
Ultrasound is useful in diagnosis and monitoring of treatment by assessing degrees of subacromial/subdeltoid bursitis, long head biceps tenosynovitis, and glenohumeral synovitis. In one study power Doppler (PD) signal at subacromial/subdeltoid bursae was observed in a third of PMR patients. The positive PD signal at diagnosis correlated with the increased frequency of relapses but the persistence of PD findings did not correlate with relapses/recurrences.[29] The 2012 ACR/EULAR PMR classification criteria include ultrasound.[30]
MRI:
MRI helps depict bursitis, synovitis and tenosynovitis similar way the ultrasound does, however, it is more sensitive for hip and pelvic girdle findings.[31] Pelvic MRI frequently shows often bilateral, peri-tendinous enhancement of pelvic girdle tendons and occasional low-grade hip synovitis. An enhancement of the proximal origin of rectus femoris appears to be highly specific and sensitive finding.[32]
PET:
PET scan shows FDG uptake in shoulders, ischial tuberosities, greater trochanters, glenohumeral and sternoclavicular joints in PMR patients.[33] Role of PET in diagnosing large vessel vasculitis is described in a discussion below with GCA.
2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative[30]
Patients aged 50 years or older with bilateral shoulder aching and abnormal C-reactive protein concentrations or ESR, plus at least four points (without ultrasonography) or five points or more (with ultrasonography) from
"A score=4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score=5 had increased sensitivity to 66% and specificity to 81%. These criteria are not meant for diagnostic purposes."[30]
PMR and GCA
PMR and GCA frequently overlap, and 20% of patients with PMR will get diagnosed with GCA later. In biopsy-proven GCA, PMR features are present in up to 50% of cases.[18]
In a study, among PMR patients with persistence of classic symptoms but no cranial GCA like symptoms, a PET/CT scan was positive for large vessel vasculitis in 60.7%. Inflammatory low back pain, pelvic girdle, and diffuse lower limb pain were also predictors of positive PET/CT scan these patients.[34] In another study among patients who required higher doses of steroids or those who had atypical features like low-grade fever and weight loss among others, 48% had large vessel vasculitis in PET/CT. Elevated CRP values were found to correlate with large vessel vasculitis.[35]
In a study where a random sample of 68 patients with "pure' PMR, histological examinations of biopsy specimens of the temporal artery revealed inflammatory changes in three patients only (4.4%).[36]
PMR patients should undergo evaluation for features suggestive of GCA at every visit. Routine biopsy of the temporal artery is not a recommendation. Features like the development of a new headache, vision and jaw symptoms, tenderness and lack of pulses in temporal artery, lack of pulses in the periphery, the persistence of inflammatory markers, high-grade fever and refractoriness of classic symptoms are the red flags that should prompt an urgent evaluation for GCA.
Oral glucocorticoid is a well-proven treatment. The following summarizes the essential points of EULAR-ACR 2015 recommendations for management[37]
Clinical trials used oral MTX at oral doses of 7.5 to 10 mg/week.[37] A study shows leflunomide is an effective steroid-sparing agent can be used in PMR as well.[38] It could be an alternative if the patient is not able to take MTX for various reasons. Sparse data for azathioprine exist for treatment of PMR, and its use may be an option in cases with contraindications for methotrexate.[39]. EULAR-ACR 2015 recommendations advise against the use of anti-TNF agents.[37]
Most of the data for the use of tocilizumab (TCZ) in PMR come from PMR coexisting with GCA. Case series and open-label studies have shown TCZ is useful in PMR with relapse or insufficient response to GC.[40] An open-label study suggested that when used in newly diagnosed PMR patients, relapse-free remission without GC treatment at 6 months was achievable.[41] Randomized controlled trials are needed to evaluate if TCZ is routinely beneficial in certain PMR patients.
Vitamin D and calcium supplementation are routine recommendations for patients on long-term steroid. Bisphosphonate prophylaxis is a recommended option for patients in moderate to high fracture risk categories that would include patients over 40 years with FRAX score of >1% and 10% risk of hip and major osteoporotic fracture respectively.[42]
Close follow up is recommended. Guidelines published by BSR and BHPR recommends follow up at weeks 0, 1 to 3, and 6, then months 3, 6, 9, and 12 in the first year (with extra visits for relapses or adverse events).[43] It seems prudent to follow up patient every 3 months till remission and after that every 6 months to annually to monitor recurrence. Relapses often entail an increase in ESR and CRP and the return of symptoms. Increased risk of relapse is found to correlate with a higher initial dose of steroid used, rapid steroid tapering, HLA-DRB1*0401, and persistently high inflammatory markers.[12][44][45]
Polymyalgia rheumatica has nonspecific features that many other entities could mimic. Other entities need to be excluded with the investigations, as deemed needed by clinical suspicion, before diagnosing PMR. Some important differentials are listed below[20][46]
Mortality among individuals with polymyalgia rheumatica is not significantly increased compared to the general population.
Discussion of Giant-cell arteritis was under the evaluation heading.
Polymyalgia rheumatica patients have an increased risk of cardiovascular diseases by 1.15 to 2.70 as per different studies. Premature atherosclerosis resulting from chronic inflammation is the most likely cause if premature CAD.[47]
Cancer association with PMR is not entirely clear.[48] In a study increased the risk of lymphoplasmacytic lymphoma - Waldenstrom macroglobulinemia correlated with PMR with OR of 2.9.[49]
PMR patients have higher chances of developing inflammatory arthritis. Features of small joint synovitis, younger age and positive anti-CCP positivity in PMR patients were found to have an association with risk of developing inflammatory arthritis.[50]
Patients with polymyalgia rheumatica usually receive an initial evaluation by primary care doctors or nurse practitioners. Low threshold for suspicion, timely referral to rheumatology and excluding giant cell arteritis are important aspects in the initial care of these patients. PMR has a long list of differentials and mimickers and diagnosis may be even more challenging if the patient already has one of those as a coexisting condition. Essential aspects of long-term management are the need for frequent follow-up, vigilance in detecting developing GCA, and the management of relapse or refractory disease.
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