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Polymyalgia Rheumatica
Introduction
Polymyalgia rheumatica (PMR) is a rheumatic disorder characterized by pain and stiffness around the neck, shoulder, and hip area that significantly impacts quality of life. 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 typical findings. Patients with PMR can develop or have concomitant giant cell arteritis (GCA), also known as Horton disease. Some authors consider GCA an extreme entity of the same spectrum of disorders as PMR.
Understanding the intricacies of PMR is essential for clinicians, as it requires a nuanced approach to management, including careful consideration of the potential long-term complications and the crucial interplay with GCA. This review aims to highlight the key aspects of PMR, including the etiology, clinical features, and optimal management strategies.
Etiology
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Etiology
The etiology of PMR 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 receptors 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 during epidemics of mycoplasma pneumonia and parvovirus B19 in Denmark, suggesting a possible role of infection in etiopathogenesis.[4] The Epstein-Barr virus (EBV) 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 a change in microbiota and chronic bowel inflammation in the immunopathogenesis of the disease.[8]
A case series of previously healthy subjects developing GCA/PMR after influenza vaccination also exists.[9] Vaccine adjuvants can trigger autoimmunity-causing autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which can have clinical features similar to PMR.
Epidemiology
The annual incidence of PMR in individuals aged 50 years or older was found to be between 58 to 96 per 100,000 population, specifically predominantly White populations. 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 populations. It is at least twice as common as GCA and is found in approximately 50% of patients with GCA.[12] PMR is much less common in Black, Asian, and Hispanic populations.
Pathophysiology
PMR is an immune-mediated disorder, and elevated inflammatory markers are common. IL-6 is key in mediating inflammation and is elevated in both PMR and GCA.[13] Interferon (IFN) may be present in temporal artery biopsies in patients with GCA but not in patients with PMR, suggesting its role in the development of arteritis.[14]
An elevated IgG4 level was found in patients with PMR but less frequently in patients with GCA.[15] The same study discovered an increased number of patients with PMR features 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 cell number inversely correlates with ESR and CRP. This altered distribution of B cells possibly contributes to the IL-6 response in PMR.[16]
Autoantibodies with a significant role in pathogenesis are not a feature of PMR. Like GCA, patients with PMR also have decreased regulatory T (Treg) cells and T helper (Th)1 cells and increased Th17 cells.[17] Some studies have suggested a cyclical pattern of GCA and PMR in seasonal variation and incidence, implying possible environmental triggers.[18] Increased expression of toll-like receptors 7 and 9 in peripheral blood monocytes suggests the role of innate immunity in pathogenesis as well.[19]
History and Physical
PMR characteristically demonstrates symmetrical pain and stiffness in and around the shoulders, neck, and hip girdle. Pain and stiffness (lasting longer than 45 minutes) are the worst in the morning and worsen after rest or prolonged inactivity. Restricted range of motion of the shoulders is common. Patients often complain of pain and stiffness in the upper arms, hips, thighs, and 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 the pain may impair sleep at nighttime and daytime routine activities like getting out of bed or a chair, hooking a bra in the back, donning socks and shoes, taking a shower, hair brushing, driving, etc.[20]
The pain and stiffness associated with PMR are most probably related to inflammation of the glenohumeral and hip joints and the subacromial, subdeltoid, and trochanteric bursae in the upper extremities.[21] Almost up to half of the patients experience systemic symptoms like fatigue, malaise, anorexia, weight loss, and/or low-grade fever.[22] Persistent high fever is uncommon in PMR and should alert suspicion of GCA.[23]
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, deformities, or the development of rheumatoid arthritis.[24] Distal extremity swelling with pitting edema responds promptly to glucocorticoids.[25] An unusual distal manifestation is puffy edematous hand syndrome or remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, comprised of explosive and abrupt clinical symptoms.
On physical examination, diffuse tenderness is usually present over the shoulder without localization to specific structures. The pain usually restricts the shoulder's active range of motion, while the passive range of motion can be normal when carefully examined. Restriction of neck and hip movements because of pain is also common. Muscle tenderness of the neck, arms, and thighs may be present. Although the patient might complain of nonspecific weakness, muscle strength is usually intact on a more thorough examination.[20] Tenderness to muscle palpation is a nonspecific sign and usually relates to articular or bursal involvement.
Evaluation
Laboratory Studies
Elevated ESR is a common feature in PMR. The majority of authors consider ESR >40 mm/h significant.[26][27][28] ESR <40 mm/h is present in 5 to 20% of patients.[29] One study revealed ESR values >104 mm/h in 20% of patients.[29] 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.[30][31] CRP is also typically elevated. CRP was found to be a more sensitive indicator of disease activity in 1 study, while ESR was found to be a superior predictor of relapse.[29]
Normocytic anemia and thrombocytosis can occur. Liver enzymes, especially alkaline phosphatase, are occasionally elevated. Serologic tests, such as an antinuclear antibody (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (Anti-CCP AB), are negative. The creatine phosphokinase (CPK) value is within the normal range.
Imaging Studies
Ultrasound
Ultrasound is useful in diagnosing and monitoring treatment by assessing degrees of subacromial/subdeltoid bursitis, long-head biceps tenosynovitis, and glenohumeral synovitis. In 1 study, a power Doppler (PD) signal at subacromial/subdeltoid bursae was observed in a third of PMR patients. The positive PD signal at diagnosis correlated with an increased frequency of relapses, but the persistence of PD findings did not correlate with relapses/recurrences.[32] The 2012 ACR/EULAR PMR classification criteria include ultrasound.[33]
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) helps depict bursitis, synovitis, and tenosynovitis in a similar way as ultrasound does. However, it is more sensitive for hip and pelvic girdle findings.[34] Pelvic MRI frequently shows 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 a highly specific and sensitive finding.[35]
Positron Emission Tomography
A positron emission tomography (PET) scan shows 18 F-fluorodeoxyglucose (FDG) uptake in shoulders, ischial tuberosities, greater trochanters, and glenohumeral and sternoclavicular joints in patients with PMR.[36] The 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
Patients aged 50 years or older with bilateral shoulder aching and abnormal C-reactive protein concentrations or ESR, plus at least 4 points (without ultrasonography) or 5 points or more (with ultrasonography) from
- Morning stiffness in excess of 45 minutes duration (2 points)
- Hip pain or restricted range of motion (1 point)
- Absence of rheumatoid factor or anti-citrullinated protein antibodies (2 points)
- Absence of other joint involvement (1 point)
- If ultrasonography is available, at least 1 shoulder with subdeltoid bursitis, biceps tenosynovitis or glenohumeral synovitis (either posterior or axillary), and at least 1 hip with synovitis or trochanteric bursitis (1 point)
- If ultrasonography is available, both shoulders with subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis (1 point)[33]
"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."[33]
Polymyalgia Rheumatica and Giant Cell Arteritis
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.[20]
In a study, among patients with PMR with the 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 scans in these patients.[37] 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 on PET/CT. Elevated CRP values were found to correlate with large vessel vasculitis.[38]
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 only 3 patients (4.4%).[39]
Patients with PMR should undergo evaluation for features suggestive of GCA at every visit. A routine biopsy of the temporal artery is not recommended. Features like the development of a new headache, vision and jaw symptoms, tenderness and lack of pulses in the 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 with imaging (chest/abdomen) such as CT angiography (CTA), magnetic resonance angiography (MRA), or PET.
Treatment / Management
Oral glucocorticoid (GC) therapy is a well-proven treatment.[40][41] The essential points of EULAR-ACR 2015 recommendations for management are summarized as follows:(B3)
- Administer 12.5 to 25 mg daily prednisone equivalent as an initial therapy.
- Taper GCs gradually.
- Taper to an oral dose of 10 mg daily prednisone equivalent within 4 to 8 weeks.
- Once remission is achieved, taper daily oral prednisone by 1 mg every 4 weeks until discontinuation
- Treat for a minimum of 12 months.
- For relapse, increase oral prednisone to the pre-relapse dose and decrease it gradually (within 4 to 8 weeks) to the dose at which the relapse occurred.
- Individualize dose-tapering schedules based on regularly monitoring patient disease activity, laboratory markers, and adverse events.
- Administer lower doses of 7.5 to 10 mg daily for smaller patients with mild symptoms or brittle diabetes.
- Consider early introduction of methotrexate (MTX) in addition to GCs, particularly in patients at high risk of relapse and/or prolonged therapy, as well as in cases with risk factors, comorbidities, and/or concomitant medications where GC-related adverse events are more likely to occur.
Clinical trials used MTX at oral doses of 7.5 to 10 mg/week.[40] A study shows leflunomide is an effective steroid-sparing agent that can also be used in PMR.[42] It can be an alternative if the patient is not able to take MTX for various reasons. Sparse data for azathioprine exist for treating PMR, and its use may be an option in cases with contraindications for methotrexate.[43] EULAR-ACR 2015 recommendations advise against the use of anti-TNF agents.[40](A1)
Most data for using 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.[44] An open-label study suggested that relapse-free remission without GC treatment at 6 months was achievable in newly diagnosed patients with PMR.[45] Randomized controlled trials are needed to evaluate if TCZ is routinely beneficial in certain patients with PMR.
Vitamin D and calcium supplementation are routine recommendations for patients on long-term steroids. Bisphosphonate prophylaxis is recommended for patients in moderate to high fracture risk categories, including patients older than 40 years with a fracture risk assessment (FRAX) score of >1% and >10% risk of hip and major osteoporotic fracture, respectively.[46]
Close follow-up is recommended. Guidelines published by BSR and BHPR recommend 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).[47] It seems prudent to follow up with patients every 3 months until remission and, after that, every 6 months to 1 year to monitor for recurrence. CRP and ESR help monitor disease activity, and some data indicate CRP as a more sensitive marker.[29]
Relapses often entail increased 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.[13][48][49](A1)
Managing relapses can be challenging. The usual approach is as follows:
- For patients with recurrent symptoms developing following discontinuation of GCs and accompanied by an elevation in the CRP and/or ESR, GCs can be restarted at the original dose that managed symptoms.
- For patients who relapse several times, it is reasonable to lengthen the interval between dose reductions to 6 to 8 weeks.
Differential Diagnosis
PMR has nonspecific features that many other entities can mimic. Other entities should be excluded from investigations before diagnosing PMR, as deemed necessary by clinical suspicion.[22][50] Differential diagnoses are as follows:
- Crown dens syndrome [51]
- Hypothyroidism
- Obstructive sleep apnea
- Depression
- Viral infections such as EBV, hepatitis, human immunodeficiency virus, parvovirus B19
- Systemic bacterial infections, septic arthritis
- Cancer
- Diabetes
- Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome [52]
Prognosis
PMR has an excellent prognosis when the diagnosis is made promptly, and appropriate treatment is initiated. Mortality among individuals with PMR is not significantly increased compared to the general population.[53]
Complications
According to different studies, PMR patients have an increased risk of cardiovascular diseases by 1.15 to 2.70. Premature atherosclerosis resulting from chronic inflammation is the most likely cause of premature CAD.[54]
A cancer association with PMR is not entirely clear.[55] In a study of the increased risk of lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia correlated with PMR with an odds ratio (OR) of 2.9.[56]
PMR patients have a higher chance of developing inflammatory arthritis. Features of small joint synovitis, younger age, and positive anti-CCP positivity in patients with PMR were associated with the risk of developing inflammatory arthritis.[57]
Consultations
Referral to a rheumatologist is suggested if there are atypical features (eg, presenting fever, younger patients), an inadequate response to initial GC treatment, prominent peripheral arthritis, or difficulties with GC tapering.
Deterrence and Patient Education
Deterrence and prevention strategies for PMR primarily revolve around early recognition, accurate diagnosis, and timely initiation of appropriate treatment. Since PMR predominantly affects individuals older than 50 years, proactive screening and awareness campaigns among this age group may facilitate early identification of symptoms, enabling prompt medical intervention. Additionally, raising awareness among healthcare professionals about the clinical features and diagnostic criteria for PMR can improve detection rates.
Implementing routine monitoring of inflammatory markers, such as ESR and CRP, in older populations with musculoskeletal complaints can aid in early detection. Moreover, educating the public on lifestyle factors that may impact inflammatory conditions and promoting regular physical activity and a healthy diet may play a role in preventing or mitigating the severity of PMR.
Patients should be thoroughly counseled regarding the risks and benefits of GC treatment. Patients should also be encouraged to adhere to their medication regimens and long-term follow-up to minimize the risk of disease recurrence and potential side effects of medications. Patients should also be made aware of the importance of taking calcium and vitamin D supplements.
Overall, a multifaceted approach that combines public awareness, healthcare provider education, and proactive screening holds promise for enhancing deterrence and prevention efforts against the impact of PMR.
Pearls and Other Issues
Key facts to keep in mind regarding polymyalgia rheumatica are as follows:
- Asymptomatic patients with elevations in the ESR and/or CRP do not require increased doses of GCs.
- Fibromyalgia-like symptoms, such as widespread muscle pain associated with fatigue and stiffness, have been reported during the tapering phase of longstanding GC therapy in PMR patients and can be managed by chronic low doses of GCs.
- Physical therapy can benefit an older adult who has become deconditioned but has no role in initial management.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) have no therapeutic role in the initial management of PMR.
Enhancing Healthcare Team Outcomes
The management of PMR is best accomplished using an interprofessional team approach. Patients with PMR usually receive an initial evaluation by primary care clinicians. A low threshold for suspicion, timely referral to rheumatology, and excluding giant cell arteritis are essential 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 1 of those as a coexisting condition.
Once PMR is diagnosed, the pharmacist should be consulted regarding dosing and potential interactions with the patient's drug regimen. The pharmacist can also counsel patients regarding their medications and warn them of possible adverse effects. If the pharmacist notes any concerns, he should inform the prescriber immediately for therapeutic changes.
Nursing likewise plays a crucial role in these cases, as they will have more patient contact, can counsel the patient about their condition, and must report any concerns or changes in the patient's condition to the clinicians immediately, noting the changes and reasons for concern, so the clinicians can follow-up and make any therapeutic changes necessary.
Essential aspects of long-term management include frequent follow-up, vigilance in detecting developing GCA, and managing relapse or refractory disease. Strong coordination and peer-to-peer communication within the interprofessional team are essential for good outcomes and an optimal care model.
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