Management and Treatment of Polymyalgia Rheumatica

Management and Treatment of Polymyalgia Rheumatica

AUTHOR:

Dr Richard Conway, Consultant Rheumatologist, St. James Hospital; Clinical Associate Professor, Trinity College Dublin

Richard Conway graduated from the Royal College of Surgeons in Ireland in 2006. He completed rheumatology and general internal medicine training in Ireland in 2014, and a PhD in giant cell arteritis at University College Dublin in 2017. He is currently a consultant rheumatologist and physician at St. James’s Hospital and a clinical associate professor at Trinity College Dublin. He is the author of more than 150 peer-reviewed publications and 3 book chapters. His research interests include interstitial lung disease in systemic rheumatic diseases, vasculitis, and polymyalgia rheumatica.

60 Second Summary

Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease which demonstrates a strong association with aging. In Ireland, 2% of the population will experience the condition at some time during their life. Characteristic symptoms constitute bilateral hip and shoulder stiffness with an early morning predominance. Inflammatory markers (ESR and CRP) are generally elevated, but not always markedly so. Many other conditions can present with polymyalgia-like symptoms, with potential negative consequences if missed, therefore a thorough clinical assessment at initial presentation is crucial.

Symptom response to relatively modest doses of glucocorticoids, for example 15mg prednisolone, is usually dramatic. Long-term glucocorticoids are needed however, with a minimum of one year duration. Difficulties therefore arise due to the challenge of maintaining a good clinical response while minimising glucocorticoid related adverse events.

Careful navigation of these challenges has the potential to improve long term outcomes for people with PMR and close clinical monitoring is essential. There are several treatment options which now have evidence of efficacy for relapsing or refractory disease, including methotrexate, tocilizumab, and rituximab. Adjunctive treatment for bone and gastro protection is crucial, as are patient education and careful management of emergent treatment or disease related complications.

Introduction

Polymyalgia Rheumatica (PMR) is an inflammatory rheumatic condition. It has a striking age predilection, virtually never occurring prior to age 50 and becoming more common until a peak in the 70’s with a plateau thereafter. PMR is a common disease, with an incidence equivalent to rheumatoid arthritis (RA). It demonstrates a marked geographic preponderance being strikingly more common in Northern European populations than in other parts of the world. This association seems to be genetically based rather than due to physical location with emigrant populations maintaining the risk of their ancestral origin. The lifetime risk of PMR in Ireland (extrapolated from similar populations) is 2.5% for women and 1.5% for men. 1 The cause of PMR is unknown; the marked age association suggests a key role for immunosenescence. It is hypothesised that a particular individual’s immune system may be primed, by aging and/or other factors, to develop PMR, and then a subsequent second hit triggers the disease. The nature of this trigger has been elusive, and this may reflect the fact that there is no specific trigger; rather it may be the case that anything that stimulates the immune system can act in this role, this would correlate with the wide variety of infectious agents mooted as triggers, and indeed with the more controversial association with vaccines.

Clinical Presentation

PMR is very much a disease defined by the word “usually”. While there is a classic presentation, the individual components of which are seen in the majority of patients, the absence of these features does not rule out the diagnosis. By virtue of how common PMR is, it becomes relatively frequent to see patients with atypical presentations, where we run the risk of erroneously ruling out PMR.

PMR typically presents with a sudden onset of symptoms. This can be dramatic; a patient can go to bed perfectly well and wake the subsequent morning unable to move. Patients will often report that “I became an old woman/ man overnight”. The symptoms are most often described as an ache or stiffness but may be referred to as pain. The typical sites affected are the proximal limb muscles – the shoulders and hips, and the neck. However, it is a myth that distal involvement rules out PMR, up to 50% of patients will have involvement of the hands, wrists, or knees; frequently this is mild but can occasionally predominate. PMR is classically a bilateral and symmetric condition. At initial onset one side may be affected in isolation, however it rapidly progresses to involve both sides. While most patients will present with both shoulders and hips affected, they may not be equally involved, and a substantial minority of patients will report only shoulder or hip involvement in isolation. Early morning predominance of symptoms is characteristic, this is described as early morning stiffness – a shared feature of all inflammatory arthritis conditions. Patients will often also become stiff to a lesser degree after sitting for prolonged periods – not infrequently on the car journey to their clinic appointment or sitting in the waiting room! Patients with more severe symptoms will often not manifest the characteristic improvement during the day, they will wake with early morning stiffness which will then continue until they go to bed again. Systemic symptoms such as weight loss, malaise, and anorexia are common. Fever however is unusual in isolated PMR and should prompt a search for one of the PMR mimics.

PMR Mimics

It is perhaps more appropriate to consider PMR as a clinical syndrome rather than a specific disease, at least at initial presentation. This reflects the limitations of our nosological framework of disease categorisation. The entity we consider as PMR is likely composed of a number of different “diseases” which present in similar ways, sometimes this will differentiate into other defined conditions over time. It is likely however that even in those who remain in the PMR diagnostic category that several different disease subsets and pathogeneses are represented.

This being the case, when a patient presents with a polymyalgic syndrome there are a number of important differentials to consider. PMR is frequently considered an easy diagnosis to make, I would argue that it is easy to mis-diagnose PMR given the many different conditions which can present with similar symptom complexes.

Probably the most frequent and important of these to consider is giant cell arteritis (GCA). While it is still debated, PMR and GCA are likely two ends of the spectrum of a single disease process. This is supported by shared pathogenic mechanisms, demographic associations, treatment responses, and particularly by the frequent co-occurrence of the two – 50% of GCA patients have polymyalgic symptoms, while 10-30% of people with PMR will ultimately develop GCA. All patients presenting with PMR should have a clinical assessment for GCA including examination of the temporal arteries and for large vessel arterial bruits. If the history or examination raise concern for GCA, further investigation with imaging and/or temporal artery biopsy should be pursued.

The second classic mimic of PMR is rheumatoid arthritis (RA). RA can present initially with proximal joint symptoms in the same distribution as PMR. This is particularly the case in elderly patients, the very group in whom PMR classically presents. Clues to the presence of RA can include synovitis in the hands and feet, and of course positive rheumatoid factor or anti-cyclic citrullinated peptide antibodies (these are only present in 70% of rheumatoid arthritis patients however). Marked foot involvement in particular is almost never seen in true PMR.

A number of other conditions can present with initial polymyalgic symptoms. These include ANCAassociated vasculitis (which can subsequently manifest severe organ damage) and idiopathic inflammatory myopathies (which more commonly present with muscle weakness rather than stiffness or pain). Non-rheumatic diseases are important mimics, these include hypothyroidism, Parkinson’s disease, myasthenia gravis, and non-inflammatory myopathies – all of these should particularly be considered in patients with no elevation in inflammatory markers.

The final mimics are those which are drilled into the minds of medical students and trainees the world over – paraneoplastic and infections (particularly infective endocarditis). It is of course vital not to miss these, however, it is unusual that these would present with symptoms of PMR in the absence of other consistent features.

Clinical Examination

Given the predominant symptoms, the clinical examination in PMR will often be dominated by pain and restricted range of motion in the shoulders and hips. It is important to assess for synovitis clinically as this may be a clue as to the presence of rheumatoid arthritis. Palpation of the temporal artery for tenderness, swelling, hardening, or loss of pulsation is important to assess for cranial GCA. Auscultation of the carotid, subclavian, and axillary arteries to assess for vascular bruits may be a clue to large vessel GCA but can also be seen in atherosclerosis. Stigmata of infective endocarditis or signs of an underlying malignancy should not be missed.

It is important in patients with known PMR to assess for clinical signs of GCA at each visit due to the high rate (10-30%) of development of GCA in patients with PMR. As diseases may evolve over time, it is also prudent to reassess the peripheral joints for synovitis at each visit, as a diagnosis of rheumatoid arthritis would change management.

Laboratory Investigations

PMR is a systemic inflammatory rheumatic disease. As such acute phase reactants / inflammatory markers are characteristically but not invariably elevated. Erythrocyte sedimentation rate (ESR) is the traditional diagnostic test in PMR but actually, C-reactive protein (CRP) is the more useful test overall. CRP is elevated in 98-99% of patients with PMR. ESR can be normal in up to 20% of patients with untreated PMR. While having both a normal ESR and CRP does occur in PMR, this is distinctly unusual and should prompt reconsideration of the diagnosis. An important pitfall to avoid is being misled by the extent of the inflammatory marker elevation. While it sometimes occurs, PMR does not necessarily need to be associated with very high inflammatory markers, lesser elevations are also significant in the appropriate clinical scenario.

Fibrinogen is another potentially useful acute phase reactant and biomarker in PMR, however its widespread utilisation is limited due to cost implications. 2 Patients can also have elevated platelets as an acute phase response, as well as reduced haemoglobin and albumin as negative acute phase reactants.

In terms of monitoring, while all of the above acute phase reactants may be elevated, for the individual patient it is likely that one or the other more closely reflects their disease activity. This will most frequently be the CRP, but for some patients ESR, fibrinogen, or even platelets may be more closely related to their symptoms. It is useful to check all available and practical markers at first presentation, and then to choose to monitor the best marker of the patient’s disease longitudinally.

Imaging

Imaging is rarely required to make the diagnosis of PMR. It sometimes reveals the disease when done for other reasons, either incidentally or when investigating unexplained inflammatory marker elevations. Ultrasound, MRI, and PET scan can all demonstrate evidence of inflammation in periarticular structures. This typically consists of subdeltoid/subacromial bursitis and long head of biceps tenosynovitis in the shoulders, and trochanteric bursitis and hamstring tendinitis in the hips. Capsular inflammation can also be seen.

Treatment

It is a misconception that PMR is an easy disease to treat. It is relatively easy to get a rapid benefit in these patients, but longer-term management and maintenance of initial good responses is much trickier. Negotiation of treatment related adverse events is also a significant challenge.

Our treatment paradigm in PMR continues to be largely glucocorticoid based. In Ireland this will utilise prednisolone as the glucocorticoid of choice. Enteric coated formulations may be associated with less adverse events in individual patients but there is little objective evidence they are beneficial for the wider group of people with PMR and dose tapering is complicated by the absence of lower strength doses of these formulations. I recommend a starting dose of prednisolone 15mg daily in PMR; this will be sufficient for complete symptom resolution in most patients. There are a small percentage of PMR patients who will require a higher initial dose of 20mg or even 25mg; glucocorticoids are a weightbased medication, and this is more commonly seen in higher weight individuals. There are two benefits to starting with this relatively low glucocorticoid dose, the lower cumulative glucocorticoid exposure is self-evident. The second benefit is a diagnostic one; 15mg of prednisolone will generally completely resolve “true” PMR but will frequently be less effective in many of the mimics. The glucocorticoid response is typically dramatic in PMR, some individuals will have symptom resolution in hours, and most will in 1-2 days; there are however a smaller percentage of patients where this may take 1-2 weeks, and the absence of a rapid response does not exclude PMR.

Once glucocorticoids have commenced, it is prudent to review the response, either in person or by telehealth, at 2-4 weeks. This again helps to provide diagnostic confirmation. If a response is absent or suboptimal, the diagnostic process should be revisited. If a good response has been achieved, this is now the time to formulate a long-term treatment plan. There are many ways in which the glucocorticoid dose can be tapered. My practice is to reduce glucocorticoids at monthly intervals; this obviates the need for the patient to change doses between pharmacy prescriptions – they receive 1 month supply at a time and stay at the same dose until they return for the next dispensing. After 1 month on 15mg, the dose reduces to 12.5mg for 1 month, then 10mg for 1 month, thereafter, reducing by 1mg a month until stopped. If a higher starting dose is needed (20 or 25mg), then this extra reduction should be added initially as extra months, I generally reduce by 5mg a month above 20mg, by 2.5mg a month between 20mg and 10mg, and 1mg a month under 10mg. It is absolutely vital during this process that the patient both knows to, and has the facility, to contact the treating physician if there is a recrudescence of their symptoms.

Relapse is common on glucocorticoid tapering, occurring in up to 50% of patients. 3 Many relapses, particularly if addressed promptly will respond to an increase to the last prednisolone dose at which there were no symptoms, while further delay will often lead to a necessity to return to the initial prednisolone dose. Subsequent tapering as per the original protocol, will generally be successful. If patients continually relapse at a particular glucocorticoid dose, alternative tapering strategies such as alternate day tapering (eg reduce from 5mg to 4mg/5mg on alternate days instead of directly to 4mg) or reducing the dose every two months rather than monthly, may be successful. Even with these strategies many patients will reach a “threshold” glucocorticoid dose below which relapse inevitably and persistently occurs. At this point consideration should be given to the alternative options of long-term maintenance glucocorticoids or addition of a second agent. This decision may be dependent on what the threshold glucocorticoid dose is; glucocorticoids have a multitude of adverse events related to dose and cumulative dose. Generally, anything above 5mg daily of prednisolone is probably inadvisable, but even at lower doses there are increased rates of adverse events. 4, 5

Methotrexate has been our traditional second line medication in PMR. There is randomised controlled trial evidence for a steroid sparing effect. 6 However, in clinical practice this is often quite modest, and the efficacy of methotrexate in PMR does not approach its efficacy in rheumatoid arthritis. For some patients this modest steroid effect, even if it only results in a reduction of a few milligrams in the daily dose, may be clinically meaningful, however. Within the last year we now have evidence from three randomised controlled trials of biologic disease modifying antirheumatic drugs (bDMARDs) to treat PMR. The IL-6 inhibitors tocilizumab and sarilumab, the latter not available in Ireland, appear to have excellent efficacy, mirroring their known effect in GCA. 7 More surprisingly perhaps, a single dose of rituximab at treatment initiation has been shown to have long term benefits in PMR. 8 The place of these bDMARDs in the PMR treatment algorithm is still under consideration. While it would be intuitively appealing to administer them up front to all patients with the aim to minimise cumulative glucocorticoid exposure as much as possible, this would undoubtedly lead to the overtreatment of many patients who would have done just fine with glucocorticoid monotherapy. The disadvantage of waiting until relapses occur, is that by that time a significant accumulation of glucocorticoid adverse events has already occurred. We need better predictive prognostic markers in order to properly risk stratify patients. The role of shared decision making is also crucial, and the input of people with PMR on the risks and benefits of various treatment strategies is crucial given that they will be the ones ultimately experiencing them.

Adjunctive managements are important in all patients with PMR. These are largely directed at minimising glucocorticoid adverse events. Long term glucocorticoids, even at relatively modest doses, have a profound negative effect on bone, leading to glucocorticoid induced osteoporosis. All patients should be assessed for the need for calcium and vitamin D supplementation, and have it provided to those who have dietary calcium deficiency and low serum vitamin D respectively. All patients receiving long-term glucocorticoids should receive an anti-resorptive agent, generally a bisphosphonate while on glucocorticoids. People with PMR are generally also in the age range where DXA screening for osteoporosis is recommended, but many will have not had this performed, if this is the case, it should be performed to guide the need for long-term bone protection after glucocorticoids have finished. Those receiving the initial glucocorticoid doses will generally also receive gastroprotection with a proton pump inhibitor, this can usually be ceased as the glucocorticoid dose reduces. It is important to encourage people with PMR to maintain activity in order to limit glucocorticoid adverse events, particularly myopathy. Patients who have more significant myopathy, either due to disease or glucocorticoid related effects may benefit from physiotherapy. Patient education is important both in terms of the management plan and as there are many pervasive myths around PMR.

Summary

PMR is a common and disabling condition. Dramatic initial treatment responses are tempered by longer term struggles with relapses and treatment related adverse events. Focused optimum management of PMR leads to dramatically improved patient outcomes.