Polymyalgia rheumatica (PMR) is an inflammatory disorder that occurs almost entirely in people over the age of 50. Its name is somewhat misleading: although it literally means “rheumatic pain in many muscles,” the muscles themselves are not primarily diseased. Much of the inflammation appears to involve structures around the joints, including bursae and tendons, particularly around the shoulders and hips.
The illness can begin abruptly. A person who has been well may develop severe aching and stiffness in both shoulders, the neck, hips, or thighs over a period of days, or occasionally overnight. Morning stiffness is especially characteristic and may make such ordinary activities as getting out of bed, putting on a shirt, rising from a chair, or getting into a car difficult. Symptoms often improve as the day progresses, only to return after prolonged inactivity.
There is no test specific to PMR. The diagnosis rests on the characteristic symptoms, the patient’s age, physical examination, and laboratory evidence of inflammation. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated, though they are not invariably so. Other illnesses – particularly rheumatoid arthritis, infections, malignancy, and several other inflammatory disorders – may produce a similar picture.
One of the striking features of PMR is its response to glucocorticoids, usually prednisone. Relatively modest doses often produce dramatic improvement within a few days. Steroids are then gradually reduced, or tapered. The difficulty is that the disease frequently returns as prednisone is reduced, and some patients require treatment for several years. Prolonged steroid therapy is itself troublesome, particularly in older people. It may cause osteoporosis and fractures, hypertension, diabetes, cataracts, weight gain, skin thinning, and an increased susceptibility to infection.
An important associated condition is giant-cell arteritis (GCA), an inflammation of medium- and large-sized arteries that can occur in patients with PMR. A new persistent headache, pain in the jaw while chewing, or especially a change in vision requires prompt medical attention. Untreated GCA can suddenly and permanently damage eyesight or cause a stroke. Roughly 40% to 50% of people with GCA also suffer from PMR.
For decades, prednisone has been the standard treatment of PMR. A therapeutic challenge has been to find drugs that control the inflammation while reducing the amount and duration of steroid treatment. Methotrexate is sometimes used for this purpose. More recently, biologic agents targeting specific components of the immune system have emerged. Sarilumab, which blocks the interleukin-6 receptor, is FDA-approved for adults with PMR who have responded inadequately to corticosteroids or cannot tolerate a steroid taper.
PMR is generally very responsive to treatment and does not ordinarily destroy joints or muscles. Yet relapse is common, and prolonged treatment with the glucocorticoids traditionally used to control it can itself cause substantial morbidity. The search for effective steroid-sparing therapy is consequently one of the most important efforts in the management of PMR.
A study just published in the New England Journal of Medicine, Phase 3 Trial of Secukinumab in Polymyalgia Rheumatica, studied 381 patients with recently relapsed PMR. They received a weekly dose of 300 mg of secukinumab, 150 mg of secukinumab, or placebo over 52 weeks. Secukinumab blocks interleukin-17A, a different inflammatory pathway from the IL-6 pathway blocked by sarilumab. All three groups underwent the same 24-week prednisone taper. Sustained remission at one year occurred in 41.2% with 300 mg, 40.6% with 150 mg, and only 20.4% with placebo. Thus, adding secukinumab approximately doubled the probability of remaining in remission through the year. Both comparisons were highly statistically significant.
Secukinumab also reduced steroid exposure. Mean adjusted cumulative glucocorticoid use was about 1604 mg with 300 mg secukinumab and 1683 mg with 150 mg, compared with 2093 mg in the placebo group – a reduction of roughly 20–23%. The investigators also found less measured glucocorticoid toxicity, less fatigue, and better physical function in the treated patients.
The two secukinumab doses performed almost identically. The trial does not prove that 150 mg and 300 mg are therapeutically equivalent; it was not designed primarily to establish that, but it suggests that doubling the dose will not double the benefit. That will be important when an eventual dose is selected for clinical use.
The trial should not be interpreted as showing that every patient with PMR ought to receive secukinumab. The patients studied had already relapsed while being treated with prednisone. The results therefore apply most directly to patients with relapsing PMR despite glucocorticoid treatment. Nor does the study tell us whether secukinumab is better than sarilumab, the biologic already FDA-approved for patients with an inadequate response to corticosteroids or who cannot tolerate a corticosteroid taper. There was no head-to-head comparison. Sarilumab is FDA- approved for PMR, while secukinumab has yet to gain FDA approval.
There are several other qualifications. Follow-up extended only to one year, so we do not know whether the advantage persists after secukinumab is stopped. More placebo patients discontinued treatment, potentially making some safety comparisons less certain. Overall, serious adverse-event rates were similar among the three groups, although nasopharyngitis, urinary tract infections, fungal infections, and hypersensitivity reactions were more frequent with secukinumab. There was also one death from cryptococcal meningitis in the 150-mg group that the investigator regarded as potentially related to secukinumab, although that patient had additional risk factors, including prolonged previous glucocorticoid exposure.
Perhaps the most striking observation in the paper is that fewer than half the patients achieved a sustained remission at one year. The improvement from about 20% to about 41% is clinically meaningful, but PMR has by no means been solved.
The etiology of polymyalgia rheumatica remains unknown, but its pathogenesis is becoming much clearer. Current thinking is that PMR results from an age-dependent dysregulation of the immune system in a genetically susceptible person, possibly initiated by an environmental stimulus. There is no single demonstrated cause.
The paper discussed above is available below.
