Clinical Pearls & Morning Reports
Published October 4, 2023
Spiera et al. conducted a phase 3, placebo-controlled trial, in which patients with polymyalgia rheumatica were randomized in a 1:1 ratio to receive subcutaneous injections every 2 weeks of either sarilumab plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Read the NEJM Review Article here.
Q: Why are new therapies for polymyalgia rheumatica needed?
A: Polymyalgia rheumatica is an inflammatory disease of unknown cause that affects persons over the age of 50 years and is characterized by pain and morning stiffness of the shoulder and pelvic girdles. Glucocorticoids have been the mainstay of treatment in patients with this condition. Although moderate doses of glucocorticoids (15 to 20 mg of prednisone) can control disease, more than half of patients cannot successfully taper glucocorticoid therapy. The resultant long-term treatment has been linked to substantial glucocorticoid-related side effects. Adjunctive treatments, including methotrexate, have been investigated without clear demonstration of benefit.
Q: Why is sarilumab a potentially effective therapy for polymyalgia rheumatica?
A: Interleukin-6 has been implicated in the pathophysiology of polymyalgia rheumatica because circulating elevated levels and increased tissue expression of interleukin-6 have been identified in patients with this condition. Studies have suggested that interleukin-6 blockade may be clinically useful in the treatment of polymyalgia rheumatica. Biologic pathways independent of interleukin-6 probably also contribute to disease pathogenesis. Sarilumab, a human monoclonal antibody, binds interleukin-6 receptor α and efficiently blocks the interleukin-6 pathway.
A: The primary outcome of the trial at 52 weeks was sustained remission, which was defined as clinical remission (i.e., the resolution of signs and symptoms of polymyalgia rheumatica and normalization of the C-reactive protein [CRP] level to <10 mg per liter) by week 12, along with the absence of disease flare, sustained CRP normalization, and adherence to the prednisone taper regimen from weeks 12 to 52. Patients who received sarilumab plus a 14-week glucocorticoid taper had a higher frequency of remission and lower glucocorticoid exposure than those who received placebo plus a 52-week prednisone taper. At week 52, sustained remission occurred in 28% of the patients (17 of 60) in the sarilumab group and in 10% (6 of 58) in the placebo group (difference, 18 percentage points; 95% confidence interval [CI], 4 to 32; P = 0.02). By week 52, the median cumulative glucocorticoid dose was 777 mg (interquartile range, 777 to 1018) in the sarilumab group and 2044 mg (interquartile range, 1950 to 2840) in the placebo group (P<0.001).
A: Safety data were consistent with the known safety profile of sarilumab. The most common adverse events during treatment (reported in ≥10% of the patients in the sarilumab group) were neutropenia (15% vs. 0 in the placebo group; unadjusted P<0.05), arthralgia (15% vs. 5.2%), diarrhea (12% vs. 2%), insomnia (10% vs. 16%), hypertension (10% vs. 3%), and osteoarthritis (10% vs. 9%). Adverse events that led to permanent treatment discontinuation — which occurred in 7 of 59 patients (12%) in the sarilumab group and in 4 of 58 patients (7%) in the placebo group — were driven primarily by a higher incidence of neutropenia in the sarilumab group. No infections were associated with neutropenia.