Interleukin-1 blockade: a paradigm shift in the treatment of patients with recurrent pericarditis?

Comment on “Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis”, which was presented at the American Heart Association 2020 Scientific Sessions and published in the New England Journal of Medicine (https://doi.org/10.1056/NEJMoa2027892) RHAPSODY is an industry-funded, multicentre, double-blind, randomized-withdrawal, phase III trial to test whether rilonacept—an interleukin (IL)-1α and IL-1β cytokine trap—can reduce the risk of recurrence in rilonacept-responder patients with acute symptoms of recurrent pericarditis (RP) and systemic inflammation [C-reactive protein (CRP) level ≥1 mg/dL].1 A total of 86 adults and adolescents (≥12 years of age) who had experienced at least a second RP episode despite treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, or corticosteroids, were enrolled. The predominant cause of pericarditis was idiopathic (85%). During a 12-week run-in phase, all patients received subcutaneous rilonacept therapy (loading dose 320 mg, followed by weekly maintenance doses of 160 mg), and standard pericarditis therapy was weaned over 9 weeks, prior to 2-week rilonacept monotherapy. Pain resolved or improved within 5 days, while CRP normalized by Day 7. Sixty-one patients who demonstrated a clinical response during the run-in phase entered the withdrawal phase and were randomly assigned to continue rilonacept monotherapy (160 mg) or replace it with placebo, once weekly. Two of 30 patients (7%) in the rilonacept group and 23/31 (74%) in the placebo group had a recurrence [return of pericarditis pain and increased CRP; hazard ratio for recurrence = 0.04, 95% confidence interval 0.01–0.18; log-rank P < 0.001]. All 23 patients in the placebo group who had pericarditis recurrence received bailout rilonacept. Three secondary endpoints were assessed at 16 weeks and supported a benefit of rilonacept monotherapy in providing a sustained clinical response. During the run-in phase, four patients (5%) developed adverse events leading to discontinuation of rilonacept. The most common adverse events were injection-site reactions (34%) and mild or moderate upper respiratory tract infections (23% with rilonacept vs. 0 with placebo, before bailout). At Week 24, 12% and 105% higher low-density lipoprotein cholesterol and triglyceride levels, respectively, were also observed in the rilonacept group. Recurrent pericarditis is a disabling chronic condition, occurring in 15–30% of patients following the first episode, despite standard treatment with NSAIDs, colchicine, and corticosteroids.2 Pericardial tissue damage, involving ab initio cytokines of the IL-1 family, triggers an abnormal inflammatory response that evokes further production of IL-1α and IL-1β, inducing a self-perpetuating cycle of pericardial inflammation.3 A small trial evaluated the efficacy of anakinra, a recombinant IL-1-receptor antagonist, in 21 patients with colchicine-resistant, idiopathic RP, and corticosteroid dependence, and reported promising results.4 Rilonacept, an engineered fusion protein approved in the USA for the treatment of cryopyrin-associated periodic syndromes, is a soluble decoy receptor or ‘trap’, which binds IL-1α or IL-1β and prevents their engagement with the cell-surface receptor for IL-1. A previous phase-2 open-label study investigated the therapeutic potential of rilonacept in 25 patients with idiopathic and postpericardiotomy RP, providing preliminary evidence of efficacy.5 Based on the findings of RHAPSODY, rilonacept not only provided a steroid-sparing option to half of the patients who were on steroids at study entry but potentially obviated the need for initiation of steroids in patients experiencing RP despite colchicine.1 However, this trial has major limitations: (i) its randomized-withdrawal design restricts the findings to patients who had already had a response to rilonacept; (ii) it does not provide a comparative assessment of efficacy vs. standard therapy; (iii) its limited size and duration (median drug exposure, 9 months) preclude a proper evaluation of safety. Although no deaths or drug-related serious adverse events were recorded, there are safety concerns with rilonacept other than injection-site reactions, including upper respiratory tract infections and unfavourable lipid changes. The randomized-withdrawal period of the trial provided confirmatory evidence that rilonacept monotherapy could be sufficient to maintain disease control; this therapeutic strategy would be best suited to replace corticosteroids that have important adverse effects as second-line therapy in the management of pericarditis, after NSAIDs and colchicine. If this is the case, its efficacy and safety would need to be directly compared to corticosteroids, both in the short-term and over the long-term. If these expectations are met by the results of larger studies with a different trial design, then IL-1 blockade could represent a real paradigm shift in how we treat RP. Supplementary material is available at European Heart Journal online. Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.