In focus: Polymyalgia rheumatica

Polymyalgia rheumatica is a chronic inflammatory disease affecting the connective vascular tissue.
Pain, along with morning stiffness, are the two main characteristic features

Polymyalgia rheumatica (PMR) is considered the second commonest widespread inflammatory rheumatological disease following rheumatoid arthritis (RA), and has an estimated overall prevalence of 0.7 per cent. PMR usually affects adults over the age of 50 years and becomes more frequent with advancing age, peaking between 70-to-80 years. Additionally, women are affected 1.5-to-two-times more often than men.

Patients diagnosed at a younger age than 60 have been noted to have a lower risk of relapse, but similar outcomes in terms of the continuous need for treatment of disease.

As the incidence of PMR increases with age and with the ongoing trend of increased population ageing, it is therefore expected to keep increasing even further in the near future.

PMR particularly affects individuals of Caucasian ethnicity in comparison with Latin-American, African-American, and Asian populations. A geographical variation is noted, with an increased incidence seen in Scandinavian countries. The incidence in northern Europeans is 0.04-to-0.113 per cent in those over 50 years of age.

A diagnosis of PMR does not seem to increase the risk of premature death. It does, however, have a notable impact on the patient’s quality-of-life.

Clinical presentation

Classical symptoms of PMR include stiffness, pain, and impaired activities of daily living. The stiffness and pain commonly occur in the arms, neck, pelvic girdle, and thighs, and are usually bilateral. This occurrence lasts typically more than 45 minutes in the affected areas and improves progressively from early morning throughout the day. However, symptoms worsen after a period of rest. Constitutional symptoms including fever, fatigue, and weight loss are common. A prevalence of extra-articular involvement (tendons, bursae, and entheses) has also been identified.

Causes/risk factors

There is evidence that there is a variety of exogenous and endogenous factors which favour the development of PMR and these include:

• Age over 50: A strong influence of age is assumed in the pathogenesis of PMR.

• Immunosenescence, that is, ageing of the immune system, also has a role in increased susceptibility to infections and autoimmune processes.

• History of infections: Mycoplasma pneumoniae, Chlamydia pneumoniae, and parainfluenza viruses are considered triggers for development of PMR in patients with a genetic predisposition.

• Female sex: The disease affects females more than males.

• Genetic factors: Polymorphisms of the human leucocyte antigen (HLA)-DRB1 gene appear to have an influence on the severity and relapse rate of PMR.

Pathophysiology

The exact pathophysiology of PMR is not fully understood, but it is believed to involve a combination of genetic predisposition and environmental factors, such as infections, that trigger an abnormal immune response. This response leads to widespread inflammation of the synovial membranes and bursae, particularly in proximal large joints and periarticular structures. The inflammatory process is marked by elevated levels of cytokines, such as interleukin-6 (IL-6), which play a critical role in the clinical manifestations of the disease. Additionally, there is a close association between PMR and giant cell arteritis (GCA), suggesting overlapping pathogenic mechanisms involving vascular inflammation.

Diagnosis

Classification/scoring systems

The most commonly used classification criteria are those of the European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR).

For the diagnosis of PMR, the following criteria must be met:

• Age over 50;

• Bilateral shoulder pain;

• Increased ESR and/or CRP.

In addition, according to the EULAR/ACR secondary criteria, PMR is present if there is a score of at least four-out-of-six points apart from the criteria mentioned above.

Diagnostic approach

The diagnosis of PMR is commonly defined by clinical diagnosis based on information gathered from medical records, along with clinical evaluation. Laboratory tests and imaging studies are essential tools in order to exclude differential diagnoses.

Typical laboratory tests for PMR include an elevated ESR and/or CRP. However, the finding of normal levels of inflammatory markers does not exclude the diagnosis of PMR, although other conditions should be considered in such circumstances. Other laboratory tests which should be performed in order to exclude differential diagnoses include rheumatoid factor, antibodies to cyclic citrullinated peptides (anti-CCP), creatine kinase (CK), antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), serum electrophoresis, and tuberculosis testing, amongst others.

The importance of imaging as a diagnostic tool in PMR above clinical and laboratory tests has been described. There are many imaging techniques which can be used to study PMR and its possible complications and/or associations. These include x-rays, scintigraphy, ultrasound (US), MRI, and PET-CT.

US has become the preferred technique in the assessment and monitoring of PMR owing to its ability to evaluate both articular and extra-articular anatomy, along with its relative low cost and wide availability. The commonest findings include glenohumeral joint inflammation, inflammation and effusion of the subacromial-subdeltoid bursa, biceps tenosynovitis, and hip trochanteritis and synovitis. Additionally, the use of colour- and power-Doppler US has gained importance in the assessment of joint inflammation.

Biomarkers of PMR

IL-6, IL-8, and CXCL9 levels have been found to be significantly increased during the acute onset of PMR. Plasma fibrinogen, which is closely related to IL-6 production, is a biomarker which may accurately identify patients with quiescent PMR.

This biomarker is considered as useful as CRP and ESR in the diagnosis of active PMR and in the confirmation of response to treatment. Angiopoeitin-2, a protein involved in angiogenesis, along with metalloproteinase 3 (MMP-3) and ESR, are strong predictors of GCA in PMR patients.

Differential diagnoses

Diagnosing PMR is a challenge for clinicians, particularly in patients with an atypical presentation. Therefore, differential diagnosis of PMR should be taken into consideration.

Relevant differential diagnoses would include:

• Rheumatological conditions including EORA, spondyloarthritis, calcium pyrophosphate dehydrate deposition disease, systemic lupus erythematosus (SLE), and vasculitis;

• Non-inflammatory musculoskeletal conditions including fibromyalgia, rotator cuff pathologies, osteomalacia, and osteoarthritis, amongst others;

• Remitting symmetrical seronegative oedematous synovitis;

• Viral or bacterial infections and infectious endocarditis;

• Endocrinopathies, particularly thyroid and parathyroid pathologies;

• Solid or haematological malignancy;

• Other conditions including depression, low vitamin D, Parkinson’s disease, and medication-induced myopathy.

Management: Drug therapy

The mainstay of treatment of PMR is glucocorticoids, which should be initiated immediately after diagnosis. The recommended initial dose for most patients is 12.5-to-25mg/day prednisolone (or equivalent). The dose should not fall below 7.5mg/day and should not exceed 30mg/day. The drug should ideally be taken orally and in the morning, if possible.

If the patient has other comorbidities, such as diabetes or osteoporosis, the initial dosage may be changed. In most cases, symptoms cease immediately once glucocorticoid treatment is initiated and this is considered an important element in establishing a diagnosis of PMR. Glucocorticoids are usually tapered after achieving remission in order to decrease the occurrence of adverse events. However, if a relapse occurs, the dose of glucocorticoid can be increased once again for a short period of time before another attempt is made to decrease it. Some patients need long-term therapy with glucocorticoids for more than four years and a history of relapse within six months is considered a strong predictor of the need for long-term glucocorticoid therapy.

Adverse effects are commonly encountered with the use of glucocorticoids and therefore, appropriate monitoring of treatment is required. If such effects are observed, or significant comorbidities are present, disease activity remains persistently high, or there are contraindications to the use of glucocorticoids, then glucocorticoids may be combined with methotrexate (MTX), which is an immunosuppressant. This allows for a lower dose of glucocorticoids to be used, hence, the early use of MTX is suggested in patients with diabetes mellitus, osteoporosis, or glaucoma. A starting dose of 7.5-to-10mg/week is usually recommended for MTX.

Biologics are also being tested for the treatment of PMR in trials. These include IL receptor blockers, tumour necrosis factor alpha (TNF-α) inhibitors, and selective immunosuppressants. The use of anti-TNF-α is not recommended in the treatment of PMR as evidence to date shows that it is not beneficial to this patient group.

The use of tocilizumab, an antagonist of the receptor for IL-6, has been proven to be an efficient, well-tolerated medication with a great steroid-sparing effect and a good safety profile. Tocilizumab has been proven to reduce inflammatory markers and imaging findings in patients with PMR.

The use of tofacitinib, a Janus tyrosine kinase (Jak) inhibitor, has also been found to effectively treat patients with PMR just as glucocorticoids do.

Rituximab, a monoclonal anti-CD20 antibody, has also been shown to be a potential valuable glucocorticoid-sparing agent for patients with PMR.

In 2023, the US Food and Drug Administration (FDA) approved sarilumab, an injectable IL-6 receptor blocker, as the first biologic to treat adult patients with PMR who had inadequate response to corticosteroids or could not tolerate a corticosteroid taper.

Non-drug therapy

Certain patients, particularly older patients with an impaired physical function, should be offered exercise programmes together with drug treatment in order to maintain muscle mass and function and for prevention of falls, especially in patients on long-term glucocorticoid therapy. Hygiene and dietary advice also have a role to play.

Specialised care

Prompt referral to a rheumatologist or other medical specialist for management is recommended for those patients with a complicated disease course, those with frequent relapses, or in cases in which glucocorticoid therapy is contraindicated or gives rise to adverse side-effects.

Comorbidities associated with PMR

Patients with PMR have been proven to suffer from a higher burden of comorbidities when compared to patients without the disease. These comorbidities can be grouped as follows:

• Vascular disease is the most frequently reported comorbidity after diagnosis of PMR and includes myocardial infarction, stroke, and peripheral vascular disease;

• Malignancy;

• Other diseases such as diverticular disease, depression, and hypothyroidism.

Patients with PMR also suffer from comorbidities and an unhealthier metabolic profile relating to glucocorticoid treatment including hypertension infections, glaucoma and cataracts, osteoporosis, and vertebral fractures.

PMR and GCA

PMR is closely related to GCA, also known as Horton’s disease or temporal arteritis, and the two can be concurrent diseases. GCA is a granulomatous vasculitis affecting large size arteries and is considered to be the most common vasculitis occurring in the over-50s age group. Two GCA phenotypes can be differentiated: Cranial GCA (C-GCA) and large vessel-GCA (LV-GCA).

Around 10-to-30 per cent of patients with PMR develop GCA, resulting in severe vascular complications. On the other hand, PMR occurs in 40-to-60 per cent of patients with GCA during the disease course. A subset of patients suffering from PMR may develop subclinical GCA, with research reporting occurrences in 9-to-25 per cent of PMR patients.

The close relationship between PMR and GCA suggests a common ground between the two, that is, similar immunogenetic mechanisms. Similar patterns of HLA association have been noted in PMR and GCA, resulting from HLA-DRB1 being one of the strongest genetic factors predisposing to autoimmune diseases.

GCA is commonly underdiagnosed in patients with PMR, and may therefore, be the cause of therapy-resistant PMR.

Hence, all patients with PMR should be thoroughly assessed for signs and symptoms of C-GCA, including recent headache, jaw claudication, abrupt onset of visual disturbances (particularly monocular visual loss), temporal artery tenderness, or decrease in temporal artery pulsations. It is more challenging to diagnose isolated LV-GCA due to the lack of specific clinical features which may be limited to constitutional features and/or fever of unknown origin.

Both PMR and GCA are also characterised by a fast, even if sometimes only partial, response to glucocorticoids. For patients with GCA, high doses of glucocorticoids (40-to-60mg/day of prednisolone or equivalent) are started in order to provide symptom relief and to prevent irreversible visual loss. In patients with visual symptoms, intravenous methylprednisolone at a dose of 1g/day for three days would be the initial treatment, followed by a three-to-four-week course of oral prednisolone at a dose of 80-to-100mg/day.

The clinician should keep in mind that PMR and GCA are treated with different doses of glucocorticoids and that treating GCA is considered a medical emergency, whereas the priority with PMR is to exclude differential diagnoses prior to starting treatment.

Covid-19 and PMR

Research has confirmed infection with SARS-CoV-2 can trigger onset or relapse of PMR, and also that Covid-19 vaccines can be a potential rare trigger of onset or relapse of PMR.

Also of interest is that research has shown that patients with concomitant PMR and GCA were more likely to have severe Covid-19 infection and higher mortality rates when compared to other rheumatological diseases, specifically RA.

Immune checkpoint inhibitor mediated PMR

Immune checkpoint inhibitors (ICI), as used in cancer therapy, particularly in metastatic cancers, have been associated with the emergence of various autoimmune disorders, with PMR and PMR-like syndromes being among the most common. In spite of the fact that ICI-PMR and primary PMR share a set of symptoms, mainly related to inflammation in the shoulders and hips, ICI-PMR is associated with a lesser degree of intense inflammation and therefore requires less treatment than primary PMR.

References on request

Authors: Dr Fancesca Briffa MD (Melit), BSc (Hons) Pod, Letterkenny University Hospital; and Dr Mark Emanuel Debono MD (Melit), PGDip Endo (USW), Letterkenny University Hospital