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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: June 6, 2018.



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. Potential serious adverse events include life-threatening infections and hypersensitivity reactions


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 (1-4%). 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.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

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.

Drug Class: Antirheumatic Agents

Other Drugs in the Subclass, Interleukin Receptor Antagonists: Anakinira, Canakinumab, Sarilumab, Tocilizumab



Rilonacept – Arcalyst®


Antirheumatic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Rilonacept501081-76-1C9030-H13932-N2400-O2670-S74No Structure


References updated: 06 June 2018

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    (Expert review of hepatotoxicity published in 1999 before the availability of rilonacept and other recombinant proteins and anticytokines).
  • Krensky AM, Bennett WM, Vincenti F. Immunosuppressants, tolerogens, and immunostimulants. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1005-29.
    (Textbook of pharmacology and therapeutics).
  • 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. [PMC free article: PMC2875198] [PubMed: 18668591]
    (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: 18668535]
    (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: 19015646]
    (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: 19117595]
    (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: 21269234]
    (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. [PMC free article: PMC3093069] [PubMed: 21375570]
    (Short review of mechanism of action, clinical efficacy and safety of rilonacept and canakinumab; no mention of ALT elevations or hepatotoxicity).
  • Miyamae T. Cryopyrin-associated periodic syndromes: diagnosis and management. Paediatr Drugs 2012; 14: 109-17. [PubMed: 22335455]
    (Review of the clinical features and pathogenesis [mutation in NLRP3 gene] of cryopyrin associated periodic syndromes [CAPS] and currently available treatments including anakinra [recombinant IL-1Ra], rilonacept [recombinant IL-1 trap] and canakinumab [monoclonal antibody to IL-1 beta]; no mention of ALT elevations or hepatotoxicity).
  • Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10 (117): 37-44. [PubMed: 22538522]
    (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. [PMC free article: PMC3644509] [PubMed: 22850787]
    (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: 23070486]
    (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: 23031624]
    (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: 22583335]
    (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: 23754188]
    (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: 23485476]
    (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. [PMC free article: PMC3672764] [PubMed: 23375025]
    (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).
  • Ilowite NT, Prather K, Lokhnygina Y, Schanberg LE, Elder M, Milojevic D, Verbsky JW, et al. Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66: 2570-9. [PMC free article: PMC4314719] [PubMed: 24839206]
    (Among 50 children with juvenile idiopathic arthritis treated with rilonacept or placebo for 4 weeks and then with open label rilonacept for up to 24 weeks, response rates were higher with rilonacept, and 4 receiving rilonacept developed elevated ALT levels that were above 5 times ULN in 2 [4%]).
  • Sundy JS, Schumacher HR, Kivitz A, Weinstein SP, Wu R, King-Davis S, Evans RR. Rilonacept for gout flare prevention in patients receiving uric acid-lowering therapy: results of RESURGE, a phase III, international safety study. J Rheumatol 2014; 41: 1703-11. [PubMed: 25028379]
    (Among 1315 adults with gout treated with rilonacept or placebo for 16 weeks, rilonacept was associated with fewer gout flares but higher rates of ALT elevations [1.1% vs 0.6%]).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to rilonacept or other IL-1 antagonists).
  • Winthrop KL, Mariette X, Silva JT, Benamu E, Calabrese LH, Dumusc A, Smolen JS, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect 2018; 24 Suppl 2: S21-S40. [PubMed: 29447987]
    (Review of the risk of infections in patients receiving biologic therapies targeting interleukins and immunoglobulins concludes that patients taking IL-1 targeted agents have a moderate increased risk for infections, should be prescreened for tuberculosis and monitored for infections during therapy).


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