How to Treat Refractory Polymyalgia Rheumatica

Patients with polymyalgia rheumatica (PMR) who had relapsed while tapering glucocorticoid therapy were more likely to achieve sustained remission at one year and have a lower glucocorticoid exposure if they were treated with sarilumab (Kevzara) plus a rapid, 14-week glucocorticoid taper than if they received placebo plus a standard, 52-week glucocorticoid taper. This is according to a study published in The New England Journal of Medicine that supported the U.S. Food & Drug Administration’s (FDA) approval of the interleukin (IL) 6 receptor antagonist for the treatment of adults with PMR who have had an inadequate response to glucocorticoids or who cannot tolerate a glucocorticoid taper.^1-3

“PMR is among the most common inflammatory diseases, and although corticosteroids are extremely effective in controlling disease activity, flares, which generally necessitate raising the corticosteroid dose, are common, meaning that most patients have a prolonged course of treatment,” explains Robert Spiera, MD, professor of clinical medicine at Weill Cornell Medical College and director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery, New York City. “This results in many corticosteroid-related complications in this vulnerable group of patients. There is a major unmet need for an effective corticosteroid-sparing strategy in this disease, particularly in refractory patients.” Previous studies have implicated IL-6 in the pathophysiology of PMR and suggested that IL-6 inhibition may be clinically useful in treating the condition.^4,5

“It is exciting to see an understanding of disease pathophysiology ultimately result in the demonstration of a targeted therapy being effective in a rheumatic disease,” says Dr. Spiera. “This is truly a bench-to-bedside journey, as it has been for many of the other biologics and targeted therapies that have led to improved outcomes for patients with inflammatory and autoimmune diseases. Our improved sophistication in clinical trial design and execution also contributed enormously to the ability to prove this strategy as effective.”

The SAPHYR Trial

Dr. Spiera

The randomized, double-blind, placebo-controlled phase 3 SAPHYR trial was designed to assess the efficacy and safety of the IL-6 antagonist sarilumab in patients with PMR who had a disease flare while tapering glucocorticoid therapy.¹

The study, which had lower enrollment than planned because of the COVID-19 pandemic, included 118 patients with active PMR who had a disease flare while taking at least 7.5 mg prednisone or the equivalent daily within three months of screening. The patients’ median age was 69 years, 70% were women, and 83% were white. From October 2018 through July 2020, 60 patients were randomized to receive 200 mg of sarilumab subcutaneously every two weeks with a 14-week glucocorticoid taper and 58 patients were assigned to placebo plus a 52-week glucocorticoid taper.

The primary end point was the proportion of patients at 52 weeks who achieved sustained remission, defined as being in disease remission by week 12, along with the absence of disease flare, sustained C-reactive protein (CRP) normalization and adherence to the glucocorticoid taper, all from weeks 12 to 52. Key secondary end points included each component of the sustained remission outcome, the time until the first disease flare after remission, the cumulative glucocorticoid dose over 52 weeks and safety.

Results

“Patients treated with sarilumab were three times more likely to achieve the primary outcome at 52 weeks, despite being treated with a very rapid corticosteroid taper,” says Dr. Spiera.

At 52 weeks, 28% of patients who received sarilumab and 10% of patients who received placebo achieved the primary end point (P=0.02). Patients who received sarilumab (47%) were more likely than those on placebo (38%) to achieve clinical remission at 12 weeks and avoid disease flare after this (55% vs. 33%). The remaining components of the sustained remission outcome also favored sarilumab over placebo. The respective rates for sustained CRP normalization were 67% and 45%, and for glucocorticoid taper adherence were 50% and 24%.

At all follow-up visits, the proportion of patients without signs and symptoms of PMR was higher with sarilumab than with placebo. The respective rates were 57% and 49% at 16 weeks and 81% and 57% at 52 weeks. Despite a faster glucocorticoid taper, a lower proportion of patients who received sarilumab (32%) required additional rescue therapy with glucocorticoids during the study than those who received placebo (59%). At week 52, the median cumulative glucocorticoid dose was lower in the sarilumab group, at 777 mg, vs. 2,044 mg in the placebo group (P<0.001).

Despite a rapid corticosteroid taper, “we found that sarilumab patients were much more likely to remain in remission. There was also a significantly smaller amount of steroid exposure in the sarilumab-treated patients. And importantly, patient-reported outcomes assessing quality of life and function all favored treatment with sarilumab,” says Dr. Spiera.

The results suggested that patients who received sarilumab fared better than those who received placebo in patient-reported quality of life and function measures, including the Short Form-36 Mental Component and Physical Component Scores, the EuroQol-5 Dimension (EQ-5D) scale, the Functional Assessment of Chronic Illness Therapy (FACITfatigue) score and the Health Assessment Questionnaire-Disability Index (HAQ-DI).

No new safety signals were found during the study. The most common adverse events with sarilumab were neutropenia (15%), arthralgia (15%), diarrhea (12%) and hypertension (10%). More treatment-related discontinuations were reported in the patients on sarilumab (12%) than those on placebo (7%), driven primarily by a higher incidence of neutropenia with sarilumab use.

Clinical Implications

“The current practice is to treat patients with corticosteroids and try to taper the dose over nine to 12 months, treating flares when they occur by increasing the dose of corticosteroids. Often, patients are ultimately treated with two years of corticosteroids, and some observational studies [have reported] as long as six years of corticosteroid exposure. Although rheumatologists are vigilant regarding corticosteroid-related side effects and are good at monitoring and addressing those, this prolonged exposure nevertheless comes at a price in terms of side effects and impaired quality of life,” explains Dr. Spiera. “We now have an effective therapy specifically approved for treating patients who flare in the context of a corticosteroid taper. Previously these patients were offered methotrexate, with limited efficacy.

“I suspect that new-onset PMR patients will now be treated as before with corticosteroids, but with a planned taper over a shorter period (perhaps six months or less), recognizing that should a flare occur, there is an effective intervention that would be appropriate in most patients.

“It should be noted that this study did not address whether sarilumab should be used in new-onset PMR and indeed the FDA indication is for patients for whom corticosteroids were inadequate or who could not tolerate a corticosteroid taper,” continues Dr. Spiera. “What role, if any, sarilumab has in the treatment of new-onset PMR remains to be determined.”

Katie Robinson is a medical writer based in New York.

Disclosure

Sanofi and Regeneron Pharmaceuticals sponsored the trial and took part in its design, along with the collection and analysis of the data.

References

1. Spiera RF, Unizony S, Warrington KJ, et al. Sarilumab for relapse of polymyalgia rheumatica during glucocorticoid taper. N Engl J Med. 2023 Oct 5;389(14):1263–1272.
2. Highlights of prescribing information: Kevzara (sarilumab) injection for subcutaneous use. U.S. Food & Drug Administration. 2023 Feb 28.
3. News release: Kevzara (sarilumab) approved by FDA as first and only biologic indicated for patients with polymyalgia rheumatica. Regeneron. 2023 Feb 28. https://investor.regeneron.com/news-releases/news-release-details/kevzarar-sarilumab-approved-fda-first-and-only-biologic.
4. Jiemy WF, Zhang A, Boots AMH, et al. Expression of interleukin-6 in synovial tissue of patients with polymyalgia rheumatica. Ann Rheum Dis. Mar 2023;82(3):440–442.
5. Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, et al. Effect of tocilizumab on disease activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: A randomized clinical trial. JAMA. 2022 Sep 20;328(11):1053–1062.