A Toolkit for Health Care Professionals Recurrent Pericarditis This approach reflects a shift toward personalized, inflammation-targeted therapy and accounts for regional differences in available therapies, rather than a universal second-line strategy. Clinicians should adhere to best practices based on current evidence and the therapeutics available in their region. Low- to medium-dose corticosteroids plus colchicine, or triple medical therapy with corticosteroids, NSAIDs and colchicine, should be considered for patients with pericarditis only in case of contraindication/failure of aspirin/NSAIDS and colchicine (Class IIa). However, patients may experience pericarditis recurrences as a consequence of serial tapering to mitigate the risk of iatrogenic consequences, resulting in periodic sub-therapeutic dosing and subsequent unmasking of the underlying disease. Long-term management of recurrent pericarditis with corticosteroids is associated with an increased risk of adverse effects. These may include immunosuppression, osteoporosis, weight gain, hyperglycemia, hypertension, fluid retention, gastrointestinal upset, adrenal suppression and mood changes.74 Therefore, minimizing prolonged corticosteroid exposure is a key therapeutic goal in managing patients with recurrent disease. Role of interleukin-1 In recurrent pericarditis, patients mount an abnormal innate inflammatory system response, which is mediated primarily by the IL-1 pathway and other cytokines. The two main isoforms of IL-1 pathway are IL-1α and IL-1β. Both isoforms exert their effects via the IL-1 receptor. Of the two, IL-1β is the more predominant isoform and contributes significantly to the pathophysiology of the pericarditis flare. Activation of the NLRP3 inflammasome, which can be initiated by IL-1α, stimulates the production of active IL-1β, which can then promote the activation of COX-2.75 IL-1α and β bind to IL-1 receptor type 1 on the pericardium and stimulate additional IL-1α and β, thereby creating a self-perpetuating cycle of autoinflammation. IL-1 pathway inhibitors not only rapidly reduce symptoms and signs of inflammation but also provide a corticosteroid sparing effect that allows patients to be tapered off corticosteroids safely without disease relapse, especially in the setting of multiple recurrences and persistently elevated CRP, or in second-line treatment, obviate the need to initiate steroids. The two main agents used in recurrent pericarditis that directly target IL-1 are anakinra and rilonacept. Rilonacept is the first and only FDA-approved treatment for the treatment of recurrent pericarditis and reduction in risk of recurrence in adults and children aged 12 years and older. It is an IL-1 trap protein that serves as a decoy IL-1 receptor that traps IL-1α and β cytokines. In the phase 3 RHAPSODY, 86 patients with a history of at least two recurrences, elevated CRP (≥1 mg/dL) and a pericarditis pain score of at least four were enrolled. All patients received rilonacept treatment for 12 weeks while being weaned off background therapies (run-in period [RI]). Rilonacept resolved or nearly resolved chest pain after only a median of five days and normalized CRP after a median of seven days. Time to rilonacept monotherapy was 7.9 weeks.77 In the run-in period, 97% of participants achieved a treatment response (NRS score ≤ 2 and CRP ≤ 0.5 mg/dL). After the 12-week run-in period, patients entered an event-driven randomized withdrawal (RW) period where 61 patients were randomly assigned to weekly rilonacept or placebo. In the RW period, the median time to pericarditis recurrence in the rilonacept arm could not be calculated because there were too few recurrence events; the median time to recurrence in the placebo arm was 8.6 weeks. Rilonacept treatment resulted in a 96% reduction in risk of recurrence (HR 0 .04 [95 % CI, 0.01 to 0.18], P <0.0001). At the time when the event-driven portion of the trial had 21
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