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Study Summary

RHAPSODY was a multicenter, double-blind, randomized-controlled-withdrawal trial designed to assess the safety and efficacy of rilonacept, an interleukin-1α and interleukin-1ꞵ inhibitor, as compared with placebo among patients with recurrent pericarditis. Patients with at least two episodes of recurrent pericarditis, as defined by the 2015 European Society of Cardiology criteria, and a C-reactive protein (CRP) level of at least 1mg per deciliter were included. After a run-in period, in which standard medications were discontinued and, after which, all patients received rilonacept monotherapy for 2 weeks, 61 patients who had shown a clinical response during the run-in period were randomized to receive subcutaneous rilonacept (N = 30) or placebo (N = 31). Among these patients, the median time to pain resolution was 5 days (95% CI 4-6) and the median time to normalization of CRP was 7 days (95% CI 5-8; see accompanying Hurst’s Central Illustration). By 16 weeks of follow-up, the primary outcome, first pericarditis recurrence, occurred in 7% (N = 2) of the rilonacept group and 74% (N = 23) of the placebo group (HR 0.04, 95% CI 0.01-0.18; P <0.001). Minor injection site reactions, upper respiratory tract infections, and higher low-density lipoprotein (LDL) cholesterol levels were more common in the rilonacept group.

Commentary

Study Strengths: This was the first study to show that subcutaneous rilonacept, a steroid-sparing therapy, prevented recurrence compared to placebo over 4 months. It also supports the concept that inhibition of both interleukin-1α and interleukin-1ꞵ is an important mediator of recurrent pericarditis in patients with systemic inflammation, as indicated by elevated CRP levels.

Study Limitations: The short follow-up duration means that the long-term benefit and safety profile of rilonacept is unknown. Only patients with recurrent pericarditis with associated elevated CRP levels were included in this study, thus it remains to be tested if rilonacept prevents recurrence of pericarditis in patients with normal inflammatory markers. The randomized-withdrawal design of this study restricts the findings only to patients who had a response to rilonacept during the 12-week run-in period. Standard medications, including colchicine and non-steroidal medications were discontinued in both the placebo and rilonacept groups during the run-in period; therefore, it remains unknown how continued use of these medications would have affected the primary outcome. The placebo arm received rilonacept during the run-in period, therefore it is unclear if rapid tapering of rilonacept affected the primary outcome in this group.

Next Steps/Clinical Perspective: Longer follow-up and a larger and more diverse population study of rilonacept is needed. Additionally, investigators may wish to study whether rilonacept prevents recurrence of pericarditis in patients with normal inflammatory markers as well as compare rilonacept to standard therapies, such as colchicine and NSAIDs.

Trial Reference

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Klein  AL, Imazio  M, Cremer  P,  et al Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis. N Engl J Med. doi:10.1056/NEJMoa2027892.

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