Rilonacept is a recombinant interleukin-1 (IL-1) antagonist which is used in the therapy of cryopyrin-associated periodic syndromes (CAPS) and other autoinflammatory conditions. Rilonacept has had limited clinical use and has yet to be linked to cases of clinically apparent, acute liver injury.
Rilonacept (ril on’ a sept) is a recombinant fusion protein which includes the extracellular portion of the human IL-1 receptor and the IL-1 receptor accessory protein fused with the Fc portion of human IgG1. Rilonacept binds and inactivates IL-1, acting as an “IL-1 trap”. IL-1 is a key proinflammatory cytokine that is a powerful inducer of fever and inflammation. Excessive production of IL-1 or lack of its inactivation is believed to play a major role in many autoinflammatory conditions and particularly in cold induced autoinflammatory conditions such as cryopyrin associated periodic syndromes (CAPS). IL-1 may also play an important role in inflammatory arthritidies and familial Mediterranean fever. In controlled trials and open label studies, rilonacept has been shown to improve symptoms and laboratory abnormalities associated CAPS and, to a lesser extent, in patients with gouty arthritis, juvenile idiopathic arthritis, familial Mediterranean fever and in rare forms of autoinflammatory conditions such as Schnitzler syndrome. Rilonacept was approved for use in the United States in 2010 to treat CAPS. Rilonacept is given by subcutaneous injection in a loading dose of 320 mg and a maintenance dose of 160 mg weekly. Rilonacept is available in vials of 20 mL containing 222 mg of rilonacept under the brand name Arcalyst. The most frequent side effects are injection site reactions, upper respiratory symptoms, headache, nausea and hypertension.
In clinical trials, ALT elevations were rarely mentioned as an adverse event in patients receiving rilonacept, but minor overall increases in both ALT and AST levels were described. The timing, severity and outcome of these elevations were not characterized, but there were no instances of jaundice or clinically apparent liver injury. Most ALT elevations were without symptoms or elevations in bilirubin or alkaline phosphatase and no long term hepatic effects were observed. In addition, rilonacept has not been linked to cases of reactivation of hepatitis B or exacerbation of chronic hepatitis C which can occur with other cytokines and anticytokines. Since its approval, there have been no published reports of hepatotoxicity due to rilonacept, although its use has been limited.
Mechanism of Injury
Rilonacept is a recombinant protein and has little hepatic metabolism. Any liver injury due to rilonacept is more likely due to its effect on the immune system or on IL-1 pathways rather than a direct toxic effect on the liver.
Outcome and Management
Agents that block the proinflammatory pathways of IL-1 and IL-6 share similar activity against autoinflammatory diseases and have little evidence for serious hepatotoxicity. There is no reason to suspect that there may be cross sensitivity to hepatic injury between rilonacept and other immune modulating biologic agents or anti-IL1 blockers such as anakinra, canakinumab and tocilizumab.
REPRESENTATIVE TRADE NAMES
Rilonacept – Arcalyst®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 24 August 2013
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Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 2008; 58: 2432-42. PubMed Citation (Among 5 patients with familial cold autoinflammatory syndrome treated with rilonacept [100-160 mg weekly], all had a clinical response to therapy and 3 had mild, transient elevations in ALT or AST).
Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, Weinstein SP, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58: 2443-52. PubMed Citation (Among 47 adults with CAPS enrolled in a controlled trial of rilonacept vs placebo for 6 weeks followed by a 9 weeks of open therapy and then continuation or withdrawal, "small increases in mean ALT and AST levels" were reported with rilonacept, but these changes were not clinically significant).
Church LD, McDermott MF. Rilonacept in cryopyrin-associated periodic syndromes: the beginning of longer-acting interleukin-1 antagonism. Nat Clin Pract Rheumatol 2009; 5: 14-5. PubMed Citation (Commentary on studies of rilonacept in CAPS [Hoffman and Goldbach-Mansky, 2008]; no mention of hepatotoxicity or ALT elevations during treatment).
Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2010; 39: 327-46. PubMed Citation (Review of the excess risk of infections during biologic therapy of rheumatoid arthritis mentions that the rate of infections was 2.1% in treated patients vs 0.4% in controls; infections were primarily pneumonia and skin infections, none were fatal and few were opportunistic infections).
Carroll MB. The impact of biologic response modifiers on hepatitis B virus infection. Expert Opin Biol Ther 2011; 11: 533-44. PubMed Citation (Review of reactivation of hepatitis B by biologic response modifiers; rilonacept has not been linked to reactivation of HBV, although the experience in treating patients with HBsAg has been limited).
Dubois EA, Rissmann R, Cohen AF. Rilonacept and canakinumab. Br J Clin Pharmacol 2011; 71: 639-41. PubMed Citation (Short review of mechanism of action, clinical efficacy and safety of rilonacept and canakinumab; no mention of ALT elevations or hepatotoxicity).
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Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10(117): 37-44. PubMed Citation (Concise summary on current therapies of rheumatoid arthritis discusses anakinra and tocilizumab, but not rilonacept or canakinumab).
Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11: 633-52. PubMed Citation (Review of the biologic actions of IL-1 and the clinical efficacy and safety of agents that block its activity including anakinra [IL-1Ra], canakinumab [monoclonal antibody to IL-1 beta] and rilonacept [recombinant soluble IL-1 receptor]).
Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, Barron KS, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med 2012; 157: 533-41. PubMed Citation (Among 14 patients with familial Mediterranean fever treated with sequential 3 month courses of rilonacept or placebo, attacks were less frequent during rilonacept therapy; no mention of ALT elevations or hepatotoxicity).
Hoffman HM, Throne ML, Amar NJ, Cartwright RC, Kivitz AJ, Soo Y, Weinstein SP. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin Ther 2012; 34: 2091-103. PubMed Citation (Analysis of long term efficacy and safety of rilonacept in 101 patients with CAPS treated in an open label study for up to 2 years; mean levels of ALT and AST occurred in patients receiving rilonacept [2-4 U/L], and therapy was temporarily discontinued in 2 patients because of ALT elevations).
Krause K, Weller K, Stefaniak R, Wittkowski H, Altrichter S, Siebenhaar F, Zuberbier T, Maurer M. Efficacy and safety of the interleukin-1 antagonist rilonacept in Schnitzler syndrome: an open-label study. Allergy 2012; 67: 943-50. PubMed Citation (Among 8 patients with Schnitzler syndrome treated with rilonacept for up to 1 year, symptoms and inflammatory markers improved and there were "no significant changes in safety laboratory values").
Lovell DJ, Giannini EH, Reiff AO, Kimura Y, Li S, Hashkes PJ, Wallace CA, et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis (sJIA). Arthritis Rheum 2013; 65: 2486-96. PubMed Citation (Among 24 children with juvenile idiopathic arthritis treated with rilonacept for up to 2 years, the most common adverse event was injection site reactions; no mention of ALT elevations or hepatotoxicity).
Mitha E, Schumacher HR, Fouche L, Luo SF, Weinstein SP, Yancopoulos GD, Wang J, et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial. Rheumatology (Oxford) 2013; 52: 1285-92. PubMed Citation (Among 248 patients with acute gouty arthritis treated with 2 doses of rilonacept or placebo once weekly for 16 weeks, acute flares were reduced with rilonacept therapy, but adverse events were similar in the two groups except for injection site reactions; no mention of ALT elevations or hepatotoxicity).
Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, King-Davis S, Weinstein SP. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther 2013; 15: R25. PubMed Citation (Among 225 patients with acute gouty arthritis treated with rilonacept versus indomethacin vs the combination, there were no differences in pain scores with addition of rilonacept; no mention of ALT elevations or hepatotoxicity).
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