Polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a rheumatic disease characterized by pain and stiffness in the neck, shoulders and hips. This disease is more common in adults over 50 years of age. It is an inflammatory condition associated with increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Patients with polymyalgia rheumatica may coexist and / or develop giant cell arteritis (GCA). Some authors believe that giant cell arteritis is an extreme manifestation of the same spectrum of diseases as polymyalgia rheumatica. Challenges in PMR management lie in the correct diagnosis of the condition and appropriate treatment, which requires a long follow-up period. This article examines the causes, pathophysiology, and manifestations of polymyalgia rheumatica. [1]

Epidemiology

It has been found that the annual incidence of polymyalgia rheumatica per 100,000 population over or equal to 50 years of age ranges from 58 to 96 in a predominantly white population. Incidence rates increase with age up to 80 years. [2],  [3]  PMR is considered the second most common autoimmune inflammatory rheumatic disease after rheumatoid arthritis in some predominantly white populations. Polymyalgia rheumatica is much less common in blacks, Asians, and Hispanics.

Causes of the polymyalgia rheumatica

The etiology of polymyalgia rheumatica is not well understood.

Familial PMR aggregation suggests a genetic predisposition. [4]HLA class II alleles are associated with PMR, and among them the most frequently correlated allele is HLA-DRB1 * 04, observed up to 67% of cases. [5]Genetic polymorphism of ICAM-1, RANTES and IL-1 receptors also appears to play a role in the pathogenesis of PMR in some populations. [6]

There have been reports of increased incidence of PMR along with GCA during epidemics of mycoplasma pneumonia and parvovirus B19 in Denmark, indicating a possible role for infection in etiopathogenesis. [7] Epstein-Barr virus (EBV) has also been suggested as a possible trigger for polymyalgia rheumatica. [8]However, several other studies have failed to support the infectious etiology hypothesis.[9], [10]

There are also reports of an association between PMR and diverticulitis , which may indicate a role for microbiota changes and chronic intestinal inflammation in the immunopathogenesis of the disease. [11]

There is also a series of cases in previously healthy patients who developed GCA / PMR after influenza vaccination . [12]Vaccine adjuvants can induce autoimmune reactions resulting in an Autoimmune / Inflammatory Adjuvant Induced Syndrome (ASIA), which may have clinical features similar to polymyalgia rheumatica.

Pathogenesis

Polymyalgia rheumatica is an immune-mediated disease, and elevated markers of inflammation are one of the most common features. IL-6 appears to play a central role in mediating inflammation. [13]Interferon (IFN) may be present on temporal artery biopsies in GCA patients but not in PMR patients, suggesting a role in the development of arteritis. [14]Elevated IgG4 levels have been found in PMR patients, but less frequently in GCA patients. [15]The same study found an increase in the number of patients with features of polymyalgia rheumatica and without an increase in IgG4 levels who were simultaneously observed with GCA. 

Patients with polymyalgia rheumatica have fewer circulating B cells compared to healthy adults. The number of circulating B cells is inversely correlated with ESR and CRP. This altered B cell distribution may contribute to the IL-6 response in the PMR. [16]  Autoantibodies, which play an important role in pathogenesis, are not a sign of polymyalgia rheumatica. PMR patients have decreased Treg and Th1 cells and increased TH 17 cells.  [17]Increased expression of toll-like receptors 7 and 9 in peripheral blood monocytes also suggests a role of innate immunity in pathogenesis. [18]

Symptoms of the polymyalgia rheumatica

Polymyalgia rheumatica is characterized by symmetrical pain and stiffness in and around the shoulders, neck, and hip girdle. Pain and stiffness are worse in the morning and also worse after rest or prolonged inactivity. Limited shoulder range of motion is common. Patients often complain of pain and stiffness in the forearms, hips, thighs, upper and lower back. Symptoms appear quickly, usually from one day to 2 weeks. This affects quality of life, as pain can impair sleep at night and daily routines such as getting out of bed or stool, showering, brushing your hair, driving, etc.

Pain and stiffness associated with polymyalgia rheumatica are most likely associated with inflammation of the shoulder and hip joints, and in the upper limb, the subacromial, subdeltoid, and trochanteric bursa. [19]  Nearly half of patients experience systemic symptoms such as fatigue, malaise, anorexia, weight loss, or low-grade fever. [20]Persistent fever is rare in polymyalgia rheumatica and should indicate suspicion of giant cell arteritis.[21]

Peripheral involvement is also common in arthritis in a quarter of patients. Other peripheral features such as carpal tunnel syndrome, distal limb edema with pinpoint edema, and distal tenosynovitis may be present. Arthritis does not erode, deform, or develop rheumatoid arthritis. [22]Swelling of the distal limb with punctate edema responds quickly to glucocorticoids.[23]

On physical examination, diffuse tenderness usually appears over the shoulder without localization to specific structures. Pain usually limits the range of active movement of the shoulder, and range of passive movement may be normal on close examination. Restriction of neck and hip movements due to pain is also common. Muscle soreness in the neck, arms, and thighs may be present. Even though the patient may complain of nonspecific weakness, muscle strength usually remains unchanged upon closer examination.

Giant cell arteritis and polymyalgia rheumatica

PMR and GCA are common comorbidities, and GCA will be diagnosed later in 20% of PMR patients. In giant cell arteritis confirmed by biopsy, signs of polymyalgia rheumatica are present in up to 50% of cases.

In a study of patients with polymyalgia rheumatica with persistence of classic symptoms but no cranial GCA-like symptoms, PET / CT scans were positive for large vessel vasculitis in 60.7%. Inflammatory pain in the lower back, pelvic girdle and diffuse pain in the lower extremities were also predictors of a positive PET / CT scan in these patients. [24]In another study, among patients requiring higher steroid doses, or patients with atypical features such as low-grade fever and weight loss, among others, 48% had large vessel vasculitis on PET / CT. Elevated CRP values have been found to correlate with large vessel vasculitis. [25]

In a study that selected a random sample of 68 patients with "pure" polymyalgia rheumatica, histological examination of temporal artery biopsies revealed inflammatory changes in only three patients (4.4%). [26]

Patients with polymyalgia rheumatica should be screened for signs suggestive of giant cell arteritis at each visit. Routine temporal artery biopsy is not recommended. Signs such as the appearance of a new headache, visual and jaw symptoms, soreness and absence of pulse in the temporal artery, absence of pulse in the periphery, persistence of inflammatory markers, high fever and refractoriness of classic symptoms are alarming symptoms that should require urgent diagnosis of giant cell arteritis.

Forms

2012 Preliminary criteria for the classification of polymyalgia rheumatica: a joint initiative of the European League Against Rheumatism / American College of Rheumatology [30]

Patients aged 50 years or older with bilateral shoulder pain and abnormal C-reactive protein or ESR concentrations plus at least four points (without ultrasound) or five or more points (with ultrasounds):

• Morning stiffness lasting more than 45 minutes (two points).
• Hip pain or limited range of motion (one point).
• Absence of rheumatoid factor or antibodies to citrullinated protein (two points).
• No other concomitant disease (one point).
• If ultrasound is available, at least one shoulder with subdeltoid bursitis, biceps tenosynovitis, or brachial synovitis (posterior or axillary); and at least one femur with synovitis or trochanteric bursitis (one point).
• If ultrasound is available, both shoulders with subdeltoid bursitis, biceps tendosynovitis, or brachial synovitis (one point).

“Score = 4 had 68% sensitivity and 78% specificity for discriminating all compared subjects from polymyalgia rheumatica. The specificity was higher (88%) for distinguishing shoulder conditions from PMR and lower (65%) for differentiating rheumatoid arthritis from polymyalgia rheumatica. The addition of ultrasound, score = 5 increased the sensitivity to 66% and the specificity to 81%. These criteria are not intended for diagnostic purposes. "[27]

Complications and consequences

Patients with polymyalgia rheumatica have an increased risk of cardiovascular disease from 1.15 to 2.70 according to various studies. Premature atherosclerosis resulting from chronic inflammation is the most likely cause of premature coronary artery disease.[28]

The link between cancer and polymyalgia rheumatica is not entirely clear. [29]In a study of an increased risk of lymphoplasmacytic lymphoma, Waldenstrom 's macroglobulinemia was correlated with polymyalgia rheumatica with an OR of 2.9.[30]

Patients with polymyalgia rheumatica have a higher chance of developing inflammatory arthritis . Features of small joint synovitis, younger age, and positive anti-CCP positivity in PMR patients were found to be associated with the risk of developing inflammatory arthritis. [31]

Diagnostics of the polymyalgia rheumatica

The diagnosis of polymyalgia rheumatica is possible only after excluding other diseases occurring with similar clinical and laboratory signs (oncopathology, rheumatoid arthritis, etc.).

Laboratory research

Elevated ESR is a common symptom of polymyalgia rheumatica. ESR above 40 mm is considered by a significant majority of authors. [32],  [33]  ESR below 40 mm / h is present in 7-20% of patients. Patients with low ESR generally have less systemic symptoms such as fever, weight loss, and anemia. The response to therapy, the recurrence rate, and the risk of developing giant cell arteritis in these patients are comparable to those with high ESR. [34], [35]C-reactive protein is also usually elevated. One study found that CRP is a more sensitive indicator of disease activity, and ESR is a better predictor of relapse.[36]

Possible normocytic anemia and thrombocytosis. Sometimes the level of liver enzymes and especially alkaline phosphatase increases. Serologic tests such as antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (Anti-CCP AB) are negative. The value of creatine phosphokinase (CPK) is within the normal range. 

Visual research

• Ultrasound

Ultrasound is useful in diagnosing and monitoring treatment by assessing the extent of subacromial / subdeltoid bursitis, biceps long head tendosynovitis, and brachial synovitis. In one study, a Power Doppler (PD) signal in the subacromial / subdeltoid bursa was observed in a third of patients with polymyalgia rheumatica. A positive PD signal on diagnosis correlated with an increased relapse rate, but the persistence of PD results did not correlate with relapse / relapse. [37]The ACR / EULAR PMR 2012 classification criteria include ultrasound.

• Magnetic resonance imaging (MRI)

MRI can help diagnose bursitis, synovitis, and tendosynovitis in the same way as ultrasound, but it is more sensitive to the results of examinations of the hip and pelvic girdle. [38]Pelvic MRI often reveals bilateral periapical lesions of the pelvic girdle tendons and sometimes low-severity hip synovitis. An increase in the proximal origin of the rectus femoris appears to be a highly specific and sensitive finding.[39]

• Positron Emission Tomography (PET)

PET scans show FDG uptake by the shoulders, ischial tubercles, greater trochanters, shoulder and sternoclavicular joints in patients with polymyalgia rheumatica. [40]  The role of PET in the diagnosis of large vessel vasculitis is described below in the discussion of giant cell arteritis.

Differential diagnosis

Polymyalgia rheumatica has nonspecific features that can mimic many other diseases. Other entities should be excluded from the study, if clinically suspected, prior to diagnosis of PMR. Some important differences are listed below:[41]

• Rheumatoid arthritis.
• Giant cell arteritis.
• Vasculitis associated with antineutrophilic cytoplasmic antibodies (ANCA).
• Inflammatory myositis and statin-induced myopathy.
• Gout and calcium pyrophosphate dihydrate (CPPD) crystal deposition disease.
• Fibromyalgia
• Overuse or degenerative shoulder abnormalities such as osteoarthritis, rotator cuff tendonitis and tendon rupture, adhesive capsulitis.
• Diseases of the cervical spine, for example, osteoarthritis, radiculopathy.
• Hypothyroidism
• Obstructive sleep apnea.
• Depression.
• Viral infections such as EBV, hepatitis, human immunodeficiency virus, parvovirus B19.
• Systemic bacterial infections, septic arthritis.
• Cancer.
• Diabetes.

Treatment of the polymyalgia rheumatica

Oral glucocorticoids (GCs) are a well-established treatment. The main points of the EULAR-ACR 2015 guidelines for treatment are summarized below:[42]

• 12.5 to 25 mg daily prednisone equivalent as initial therapy.
• Glucocorticoid levels should be reduced gradually.
• Reduce dose to 10 mg prednisone equivalent daily for 4 to 8 weeks.
• Once remission is achieved, reduce your daily oral prednisone by 1 mg every 4 weeks until you stop taking it. 
• Minimum 12 months of treatment
• In case of relapse, increase oral prednisone to the pre-relapse dose and gradually decrease (over 4 to 8 weeks) to the dose at which the relapse occurred.
• Make a personalized dose reduction schedule based on regular monitoring of the patient's disease activity, laboratory markers and adverse events.
• Consider early administration of methotrexate (MT) in addition to glucocorticoids, especially in patients at high risk of relapse and / or long-term therapy, as well as in cases with risk factors, concomitant diseases and / or concomitant medications, when side effects associated with GC are more pronounced. Can happen

In clinical trials, methotrexate has been used in oral doses of 7.5 to 10 mg per week. Research shows that leflunomide is an effective steroid-sparing agent that can also be used for polymyalgia rheumatica. [43]This can be an alternative if the patient is unable to take methotrexate for various reasons. There are scant data on azathioprine for the treatment of polymyalgia rheumatica, and its use may be an option in cases where methotrexate is contraindicated. [44]The EULAR-ACR 2015 guidelines do not recommend the use of anti-TNF agents.

A series of observational studies and open-label studies have shown that tocilizumab (TCZ) is beneficial in polymyalgia rheumatica with recurrent or insufficient response to HA. [45]An open-label study showed that when used in newly diagnosed patients with polymyalgia rheumatica, relapse-free remission without HA treatment was achievable after 6 months. [46]Randomized controlled trials are needed to assess whether TCZ is of routine benefit in some PMR patients. 

Vitamin D and calcium supplements are common recommendations for long-term steroid users. Bisphosphonate prophylaxis is the recommended option for patients at moderate to high risk of fracture, which includes patients over 40 years of age with a FRAX score> 1% and a 10% risk of hip fracture and major osteoporotic fracture, respectively.[47]

Close observation is recommended. Guidelines published by BSR and BHPR recommend follow-up at weeks 0.1–3 and 6, then at 3, 6, 9 and 12 months of the first year of life (with additional visits for relapse or side effects). [48]It seems prudent to monitor patients every 3 months until remission and then every 6 months annually to monitor for relapse. Relapses often lead to increased ESR and CRP and recurrence of symptoms. The increased risk of relapse was found to correlate with a higher initial dose of steroids used, a rapid decrease in steroid dose, HLA-DRB1 * 0401, and persistently high markers of inflammation. [49], [50]

Forecast

When the diagnosis is made on time and appropriate treatment is started, polymyalgia rheumatica has a favorable prognosis. The mortality rate among people with polymyalgia rheumatica does not increase significantly compared to the general population.