In focus: Polymyalgia rheumatica

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Reference: June 2024 | Issue 6 | Vol 10 | Page 47

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Polymyalgia rheumatica (PMR) is a chronic inflammatory disease affecting the connective vascular tissue. Pain, along with morning stiffness, predominantly of neck muscles, hip, and shoulders, are the two main characteristic features.

Epidemiology

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. It usually affects the elderly population and the median age of disease onset is 73 years. Although individuals between the age of 70 and 80 are primarily affected, those aged 50 years and upwards are also prone to PMR.

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. The incidence of PMR increases with age and with population ageing, and is therefore, is 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) have also been identified.

Causes/risk factors

There is evidence to suggest 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 leading to 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 three times as much as 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

Innate immune responses
The inflammation in PMR has been demonstrated to take place at the level of the bursae and synovium involved in the anatomy of the shoulder and hip girdles, where there is a recognition of an unknown antigen by macrophages or dendritic cells. The synovitis present in PMR is characterised by leukocytic infiltration, mainly by T-lymphocytes and macrophages, along with vascular proliferation.

An intense HLA class II expression has been found in macrophages and lymphocytes, as well as in the lining layer cells. In patients with PMR, adventitial dendritic cells have been demonstrated to be mature and to produce C-C motif chemokine ligand (CCL)19 and CCL21, both ligands of CCR7, and this occurs even in the absence of vasculitic infiltrates. Apart from the presence of macrophages in the arterial and synovial samples of patients of PMR, there is also evidence of a systemic activation of circulating monocytes, mainly by increased beta production of interleukin (IL)-1 and IL-6.

Toll-like receptors (TLRs) are expressed on various cell types, including dendritic cells and macrophages, and these are considered to play a major role in the activation and regulation of innate immune responses via recognition of specific pathogen-associated molecular patterns and endogenous peptides.

In the healthy immune system, abnormal immune stimulation is avoided by the means of negative co-stimulatory signals which serve as protection of tissue tolerance. Programmed cell death protein, also known as PD-1 or cluster of differentiation 279 (CD279), is a cell surface receptor which plays a prominent role in the regulation of immune system homeostasis through suppression of T-cell inflammatory processes.

PD-1 acts by the promotion of apoptosis in antigen specific T-cells in lymph nodes while simultaneously downregulating apoptosis in regulatory T-cells. Giant cell arteritis (GCA)-affected temporal arteries have been demonstrated to have a low expression of the co-inhibitory ligand programmed death ligand-1 (PDL-1) along with an increase in PD-1 receptor.

Adaptive immune responses
IL-6 is a cytokine which induces formation of acute phase proteins such as C-reactive protein (CRP), fibrinogen, serum amyloid A, and hepcidin in hepatocytes. It plays an imperative role in the acquired immune response via the stimulation of antibody production and of development of T-cells such as Th17 cells.

Patients with PMR often display elevated levels of IL-6, IL-1 receptor antagonist (IL-1Ra), and B-cell activating factor (BAFF), which are closely related to clinical symptoms. Corticosteroids act by rapid suppression of IL-6 production; however, they do not correct the underlying mechanism. This is evidenced by an increase in IL-6 production once there is a short-term withdrawal of corticosteroids, even within several months of treatment, after which there is an immediate increase in the plasma concentrations of IL-6.

Additionally, studies in PMR have shown that a decrease in the level of IL-6 in the circulation correlates with remission of clinical symptoms. A high serum level of IL-6 receptor (IL6R) in combination with a low haemoglobin has been shown to result in a 10-fold increased risk of relapse of PMR.

In view of the important role that IL-6 plays in modulating the function of effector regulator T-cells (Treg) and Th17 cells, the disturbed production of IL-6 seen in PMR should be correlated with a disturbed effector T-cell distribution. Patients with PMR have been shown to have a decreased frequency of Treg cells and a significantly increased Th17 cell population.

In spite of the fact that the frequency of CD161+CD4+ T-cells, considered precursors of Th17 cell, is similar in patients with and without PMR, their ability to produce IL-17 is prominently increased in patients with PMR. Apart from the changes in distribution of Treg/Th17 cells, a decrease in the activated cytotoxic/suppressor T-cells has also been noted in PMR patients, along with an increase in circulating Th1 and Tc1 cells.

B-lymphocytes play a crucial role in both innate and adaptive immune responses. A decreased frequency of circulating B-cells has been demonstrated in PMR – this is quickly recovered after treatment with corticosteroids. Interestingly, there has been evidence that there is an inverse correlation between the number of B cells and the levels of erythrocyte sedimentation rate (ESR), CRP, and serum BAFF.

Endothelial dysfunction
There is evidence that systemic inflammation in many diseases has been associated with an imbalance between endothelial injury and repair which is characterised by a decreased number of endothelial progenitor cells (EPCs).

This concept has also been studied in patients with PMR and the levels of CRP were associated with an increased level of circulating endothelial microparticles (EMP) EMP:EPC ratio, irrespective of any existing cardiovascular risk factors.

Treatment with steroids has been shown to lead to a significant reduction in CRP along with a concomitant decrease in the EMP:EPC ratio. The existence of endothelial dysfunction in PMR is also implied by a significantly higher level of vascular endothelial growth factor (VEGF) serum concentration in untreated PMR.

Diagnosis

Classification/scoring systems
The most commonly used classification criteria being used in the last few years have been 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 test results 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), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET-CT).

Radiography: Conventional radiology does not show any abnormalities in PMR due to the non-erosive arthritis and the inflammatory features of joint and periarticular structures characteristic of the disease. Hence, the use of this imaging modality for diagnosis of PMR is considered outdated. However, it could be used in order to differentiate PMR from associated conditions and differential diagnoses which may mimic the disease and in such cases may be useful.

Scintigraphy: The high sensitivity of this imaging modality has been described since O’Duffy et al in 1976. However, there is no recent research regarding the use of scintigraphy, which is most likely as a result of more modern imaging modalities.

US: This imaging modality 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.

MRI: Similar to US, MRI is safe; however, it is more expensive and may sometimes not be accepted by patients. It is still considered an important imaging modality because it visualises articular bursitis, synovitis, and tenosynovitis and is also considered more sensitive for pelvic and hip findings than US.

PET-CT: PET-CT scans using an analogue of glucose called 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18-F-FDG-PET/CT), are a type of imaging which uses a radioactive isotope, often used in diagnosis and treatment monitoring in oncological and haematological patients.

However, the clinical applications of this imaging modality goes beyond that specialty as FDG accumulates not only in malignant tissues, but also in inflamed tissues. The reason behind this is due to the presence of increased activity of inflammatory cells such as neutrophils, lymphocytes, and macrophages inside inflamed tissues.

The typical findings in patients with active PMR include increased tracer uptake in sternoclavicular joints, glenohumeral joints, ischial tuberosities, vertebral spinous processes, and greater trochanters. Several FDG-PET/CT scores, such as the Leuven score, and algorithms have been developed, and these assess the level of FDG uptake in the most typical sites around the shoulders, hips, and spine.

This imaging tool is also especially useful in diagnosing vascular involvement, including GCA, and for identification of possible complications (such as organ ischaemia, aneurysm, and dissection) that other imaging modalities may falsely report as negative. 18-F-FDG-PET/CT also aids to differentiate between PMR and RA, particularly elderly-onset RA (EORA), and to identify PM-like paraneoplastic syndrome.

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 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 immunosuppresant. 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.

Biologicals 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 there is evidence 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.

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. Other non-pharmacological means include hygiene and diet advice, and reduce/avoid sarcopenia.

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 50 age group. Two GCA phenotypes can be differentiated: Cranial GCA (C-GCA) and large vessel-GCA (LV-GCA). Diagnosis of GCA is based upon 1) a range of clinical and biological features, and 2) ‘proof’ of vasculitis via vascular imaging.

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 (vaccination) and PMR

During the Covid-19 pandemic, vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a great role in its management. The high efficacy in prevention of Covid-19 and the lack of safety concerns regarding the mRNA-1273 SARS-CoV-2 vaccine, aside from transient reactions, have indeed been confirmed.

However, research has confirmed the possibility of Covid-19 vaccination being a potential trigger of onset or relapse of PMR. There have been various reports of development of PMR and PMR-like syndromes after Covid-19 vaccination.

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 polymyalgia rheumatica

Immune checkpoint inhibitors (ICI) are progressively used in cancer therapy, particularly in metastatic cancers, with the aim to upregulate the anti-tumour immune response. Currently, the most commonly used ICI therapies include durvalumab, nivolumab, pembrolizumab, atezolizumab, and ipilimumab.

Treatment with monoclonal antibodies blocking the PD-1, its ligand PD-L1, or the cytotoxic lymphocyte-associated protein 4 (CTLA-4), has been associated with the emergence of various autoimmune disorders, with PMR and PMR-like syndromes being amongst 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.

Conclusion

PMR places a significant burden on patients and their quality-of-life. Improved understanding of disease pathophysiology has resulted in new biomarkers and novel treatments to aid diagnosis and optimise treatment strategies. Research investigating the connections between PMR and Covid-19 may provide further insights as data emerges.

References on request