Comparing IL-6 Inhibitors and Glucocorticoids in Treating PMR: SAPHYR Trial Results

Polymyalgia rheumatica (PMR) is an inflammatory condition affecting individuals over 50. It is characterized by pain and stiffness in the shoulder and pelvic girdles, significantly impacting their quality of life and functioning. Questions linger regarding the effectiveness of treatment options for PMR, like corticosteroid therapy (particularly glucocorticoids) and interleukin-6 (IL-6) inhibitors. These treatments yield diverse outcomes, making it crucial for health care professionals to comprehensively grasp these results when selecting the most suitable treatment strategies for their patients.

Traditionally, glucocorticoids have been the primary treatment for PMR, but tapering off glucocorticoid therapy is often challenging, leading to long-term use and associated side effects. Patients who experience relapses or side effects due to glucocorticoids have limited treatment options, making the need for alternative therapies crucial.¹

In a study published in Rheumatology, researchers aimed to explore glucocorticoid therapy's effectiveness in treating PMR. The study explored NET formation, a process of neutrophil cell death, and researchers discovered elevated levels of MPO-DNA complexes in PMR patients, indicating increased NET formation. Researchers confirmed these levels are not solely attributed to age, as older and younger patients had elevated NET levels. Treatment with glucocorticoids did not reduce these levels.² The study also revealed that calprotectin levels differed between PMR patients and healthy individuals and decreased after glucocorticoid treatment.² 

Although glucocorticoids appear to be generally effective, this treatment option can lead to various adverse events (AEs), according to a study published in Arthritis Care & Research.³ In the study, researchers explored the incidence of glucocorticoid-related AEs in PMR; AEs included diabetes mellitus, hypertension (requiring medical treatment), hyperlipidemia, cataracts, symptomatic vertebral fractures, Colles fracture, hip fractures, and avascular necrosis.³

The AEs were determined by reviewing patient medical records, and their presence was categorized as either preexisting or newly developed. Preexisting conditions were only monitored for hypertension, hyperlipidemia, cataracts, and diabetes mellitus because patients with these conditions were not at risk of developing them due to glucocorticoid therapy.³ Researchers found that patients have difficulty discontinuing glucocorticoid treatment due to medication withdrawal.³ As AEs worsened, researchers had to increase the glucocorticoid dose due to elevated ESR/CRP levels, or both, to help alleviate symptoms.³

Given the diverse complications linked to glucocorticoid usage in PMR, there is a noticeable research gap in exploring alternative treatment options that can either aid in glucocorticoid reduction or explore the utilization of IL-6 inhibitors and their overall effectiveness. To address this gap, researchers investigated the efficacy and safety of IL-6 inhibitors, particularly sarilumab, in patients with PMR through a clinical trial, comparing effectiveness of tapering glucocorticoid treatment with sarilumab to improve patient outcomes in a recent study published in The New England Journal of Medicine.¹ The goal of this study, known as the SAPHYR trial, was to investigate treatments that can alleviate symptoms, expedite disease remission, reduce the reliance on glucocorticoids and their associated harmful effects, and enhance the quality of life and functionality in PMR patients.¹

IL-6 has been implicated in the pathophysiology of PMR, as elevated levels of IL-6 have been found in affected patients. Sarilumab, a human monoclonal antibody, blocks the IL-6 pathway effectively. Therefore, the SAPHYR trial aimed to evaluate sarilumab's efficacy in patients with PMR experiencing disease flares during glucocorticoid tapering.¹

The trial involved a phase 3, multicenter, randomized, double-blind, placebo-controlled design and included patients who met the 2012 provisional classification criteria for PMR. They received sarilumab or a placebo in addition to glucocorticoid tapering. The primary outcome measured was sustained remission, defined as the resolution of PMR symptoms and normalization of CRP levels by week 12, along with no disease flare and adherence to the prednisone taper regimen from weeks 12 to 52.¹

At week 52, the sarilumab group had significantly higher sustained remission rates (28% vs 10%) than the placebo group. This effect was consistent in sensitivity analyses that excluded CRP and ESR values, suggesting that sarilumab's impact extended beyond its effect on CRP levels.¹

Sarilumab also substantially reduced the cumulative glucocorticoid dose over 52 weeks, with the median cumulative dose being significantly lower in the sarilumab group than in the placebo group.¹ This demonstrates potential in the treatment field due to its favorable outcomes.

Patients in the sarilumab group also experienced fewer disease flares and required less rescue therapy during the trial. Quality of life measurements indicated better outcomes for patients receiving sarilumab.¹ "The results suggested that patients in the sarilumab group had better scores than those in the placebo group concerning the least-squares mean change from baseline to week 52 in both the physical and mental components of the SF-36, on the single-unit utility scale of the EQ-5D-3L, and on FACIT-fatigue, HAQ-DI, and MD-VAS," according to researchers.

Safety assessments showed that the most common AEs in the sarilumab group included neutropenia, arthralgia, diarrhea, insomnia, hypertension, and osteoarthritis. However, no infections were associated with neutropenia, and only one patient required a reduced sarilumab dose due to mild neutropenia. In contrast to glucocorticoid therapy, the range of adverse events linked to sarilumab is less extensive.

The SAPHYR trial demonstrated that sarilumab, when combined with a prednisone taper, led to higher sustained remission rates, reduced glucocorticoid exposure, and improved quality of life in patients with PMR experiencing disease flares during glucocorticoid tapering.¹ The safety profile of sarilumab was consistent with its known safety profile. However, it's important to note that the trial was prematurely terminated due to the COVID-19 pandemic, resulting in a smaller sample size and potential limitations in statistical power. Further research and more extensive trials may be necessary to confirm these findings and better understand sarilumab's long-term effects and safety in PMR patients.¹

Other studies have reported similar remission rates with the use of IL-6 inhibitors. In a study published in Arthritis & Rheumatology, researchers investigated PMR treatment with tocilizumab (an IL-6 inhibitor). Tocilizumab-treated patients (n=9) remained free of relapses after 6 months without needing glucocorticoid treatment.⁴ These findings underscore the effectiveness of IL-6 inhibitors in PMR treatment. Furthermore, for the 9 patients who completed a 15-month trial with tocilizumab, the disease remained in a state of remission, even during the final study visit conducted 3 months after the last tocilizumab infusion, with no relapses or recurrences observed.⁴

Within the control group (n=10), none of the patients achieved remission without glucocorticoid treatment within the initial 6 months. Although remission or low disease activity was noted in these patients at 6 months, they were still on low-dose glucocorticoids. One patient experienced a relapse 4 months after the initial PMR diagnosis, and over a 12-month period, 6 patients in this group experienced seven relapses.⁴ Demonstrating similar outcomes as the SAPHYR trial.

Although the study published in Arthritis & Rheumatology helps to support IL-6 inhibitor effectiveness in the treatment of PMR, the SAPHYR trial has provided researchers with valuable insights into alternative treatment options for PMR due to its larger patient population. The effectiveness of sarilumab and the achieved rates of remission offer promise for enhancing the well-being of PMR patients.

According to researchers from the SAPHYR trial, “at the end of the 6-week post-treatment follow-up period, the proportion of patients who did not have active polymyalgia rheumatica among those who did not receive rescue therapy was higher in the sarilumab group than in the placebo group: 73% (22 of 30 patients) and 40% (6 of 15 patients), respectively.”

References

1. Spiera R, Unizony S, Warrington KJ, et al. Sarilumab for relapse of polymyalgia rheumatica during glucocorticoid taper. NEJM. 2023;389(14):1263-1272. doi:10.1056/nejmoa2303452
2. Michailidou D, Johansson L, Runa Kuley, et al. Immune complex-mediated neutrophil activation in patients with polymyalgia rheumatica. Rheumatology. 2022;62(8):2880-2886. doi:10.1093/rheumatology/keac722
3. Shbeeb I, Challah D, Raheel S, Crowson CS, Matteson EL. Comparable rates of glucocorticoid-associated adverse events in patients with polymyalgia rheumatica and comorbidities in the general population. Arthritis Care & Research. 2018;70(4):643-647. doi:10.1002/acr.23320
4. Lally L, Forbess L, Hatzis C, Spiera R. Brief report: A prospective open-label phase IIa trial of tocilizumab in the treatment of polymyalgia rheumatica. Arthritis & Rheumatology. 2016;68(10):2550-2554. doi:10.1002/art.39740