22 Recurrent Pericarditis Overview and epidemiology Recurrent pericarditis is defined by the 2015 ESC guidelines as a recurrence after an initial episode following a symptom-free interval of 4 to 6 weeks (or longer), and evidence of new pericardial inflammation. Up to 30% of patients with an acute pericarditis episode will experience a recurrence. History of recurrent episodes and nonidiopathic etiologies also increase the risk of future recurrences in up to 50% of patients.70,71 Corticosteroid use (especially long-term use or doses above 1 mg/kg/day), lack of response to anti-inflammatories and persistent elevations in hs-CRP are independent risk factors for recurrence.72 Management of the first recurrence The preferred regimen in recurrent pericarditis is similar to that of acute pericarditis, but with longer durations of therapy. (See Table 1: Treatment and Tapering of Initial Therapies for Acute and Recurrent Pericarditis on page 16.) For recurrent pericarditis, aspirin/NSAID therapy lasts weeks to months, while colchicine therapy should be continued for at least 6 months. Combination therapy with aspirin/ NSAIDs plus colchicine for recurrent pericarditis has been shown to significantly reduce further recurrence compared to standard therapy, with an absolute risk reduction of 26.6% at 18 months.73 Low-dose corticosteroids can be considered as a second-line option, as add-on to other preferred antiinflammatory therapies or if aspirin/NSAIDs and/ or colchicine cannot be used. However, patients may develop refractory recurrences and corticosteroiddependence, in which relapses occur when corticosteroid tapering is attempted. It is estimated that 20%-30% of patients with recurrent pericarditis develop corticosteroid dependence, which increases the risk of related adverse effects, such as immunosuppression, osteoporosis, weight gain, hyperglycemia, hypertension, fluid retention, gastrointestinal upset, adrenal suppression and mood changes.74 Downstream steroid-sparing immunosuppression strategies include interleukin-1 (IL-1) blockade, azathioprine and intravenous immunoglobulin, and are considered to be third-line in the treatment of recurrent pericarditis based on the 2015 ESC Guidelines for the Diagnosis and Management of Pericardial Diseases.1 Over the past decade, IL-1 blockade has been the primary emerging therapeutic strategy for patients with multiple recurrences. Role of interleukin-1 The two main isoforms of IL-1 are IL-1 alpha and IL-1 beta. Both isoforms exert their effects via the IL-1 receptor. Of the two, IL-1 beta is the more predominant isoform, and contributes significantly to the pathophysiology of pericarditis. Activation of the NLR-P3 inflammasome stimulates the production of IL-1 beta, which can then promote the activation of COX-2.75 IL-1 blockade not only rapidly reduces symptoms, but also provides a sparing effect that allows patients to be tapered off corticosteroids safely without disease relapse, especially in the setting of multiple recurrences and persistently elevated hs-CRP. The two main agents used in recurrent pericarditis that directly target IL-1 are anakinra and rilonacept. Anakinra is a recombinant human IL-1 receptor antagonist (IL-1RA) that competes with endogenous IL-1 and mimics the effects of a native human interleukin-1 receptor antagonist (IL-1RA), blunting the activity of both IL-1 alpha and beta. It has been used off-label in the treatment of recurrent pericarditis. The AIRTRIP trial randomized 21 corticosteroid-dependent patients with a history of 3 or more recurrences.76 After an open-label phase in which all patients received anakinra for 2 months, patients were randomized to anakinra or receive placebo. All patients in the 2-month, open-label phase experienced a complete response to anakinra after approximately 1 week of therapy. After 180 days, anakinra significantly reduced the risk of recurrence by 80%.76 Rilonacept is the first and only FDA-approved treatment for recurrent pericarditis in children and adults aged 12 years and older. It is an IL-1 trap protein that serves as a decoy IL-1 receptor that traps IL-1 alpha and beta cytokines. In the RHAPSODY trial, patients with a history of at least 2 recurrences, elevated hs-CRP and a pericarditis pain score of at least 4 were randomized to receive rilonacept or placebo
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