A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares

Kenneth G Saag, Puja P Khanna, Robert T Keenan, Sven Ohlman, Lisa Osterling Koskinen, Erik Sparve, Ann-Charlotte Åkerblad, Margareta Wikén, Alexander So, Michael H Pillinger, Robert Terkeltaub, Kenneth G Saag, Puja P Khanna, Robert T Keenan, Sven Ohlman, Lisa Osterling Koskinen, Erik Sparve, Ann-Charlotte Åkerblad, Margareta Wikén, Alexander So, Michael H Pillinger, Robert Terkeltaub

Abstract

Objective: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares.

Methods: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response.

Results: One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction.

Conclusion: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

Trial registration: ClinicalTrials.gov NCT03002974.

© 2021, American College of Rheumatology.

References

    1. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken) 2012;64:1447-61.
    1. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda J, et al. 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis 2020;79:31-8.
    1. Chen K, Fields T, Mancuso CA, Bass AR, Vasanth L. Anakinra’s efficacy is variable in refractory gout: report of ten cases. Semin Arthritis Rheum 2010;40:210-4.
    1. Gratton SB, Scalapino KJ, Fye KH. Case of anakinra as a steroid-sparing agent for gout inflammation. Arthritis Rheum 2009;61:1268-70.
    1. Keenan RT, O’Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 2011;124:155-63.
    1. Thueringer JT, Doll NK, Gertner E. Anakinra for the treatment of acute severe gout in critically ill patients. Semin Arthritis Rheum 2015;45:81-5.
    1. Tran AP, Edelman J. Interleukin-1 inhibition by anakinra in refractory chronic tophaceous gout. Int J Rheum Dis 2011;14:e33-7.
    1. Hirsch JD, Gnanasakthy A, Lale R, Choi K, Sarkin AJ. Efficacy of canakinumab vs. triamcinolone acetonide according to multiple gouty arthritis-related health outcomes measures. Int J Clin Pract 2014;68:1503-7.
    1. Schlesinger N, Alten RE, Bardin T, Schumacher HR, Bloch M, Gimona A, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 2012;71:1839-48.
    1. Schlesinger N, De Meulemeester M, Pikhlak A, Yucel AE, Richard D, Murphy V, et al. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat gouty arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res Ther 2011;13:R53.
    1. Schlesinger N, Mysler E, Lin HY, De Meulemeester M, Rovensky J, Arulmani U, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis 2011;70:1264-71.
    1. So A, De Meulemeester M, Pikhlak A, Yucel AE, Richard D, Murphy V, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum 2010;62:3064-76.
    1. Solomon DH, Glynn RJ, MacFadyen JG, Libby P, Thuren T, Everett BM, et al. Relationship of interleukin-1β blockade with incident gout and serum uric acid levels: exploratory analysis of a randomized controlled trial. Ann Intern Med 2018;169:535-42.
    1. Aouba A, Deshayes S, Frenzel L, Decottignies A, Pressiat C, Bienvenu B, et al. Efficacy of anakinra for various types of crystal-induced arthritis in complex hospitalized patients: a case series and review of the literature. Mediators Inflamm 2015;2015:792173.
    1. Ghosh P, Cho M, Rawat G, Simkin PA, Gardner GC. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken) 2013;65:1381-4.
    1. Ottaviani S, Molto A, Ea HK, Neveu S, Gill G, Brunier L, et al. Efficacy of anakinra in gouty arthritis: a retrospective study of 40 cases. Arthritis Res Ther 2013;15:R123.
    1. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28.
    1. Pascart T, Norberciak L, Ea HK, Graf S, Guggenbuhl P, Liote F. Difficult-to-treat gout flares: eligibility for interleukin-1 inhibition in private practice is uncommon according to current EMA approval. Rheumatology (Oxford) 2019;58:2181-7.
    1. FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Rheumatol 2020;72:879-95.
    1. Janssen CA, Oude Voshaar MA, Vonkeman HE, Jansen T, Janssen M, Kok MR, et al. Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-controlled, active-comparator, non-inferiority trial. Rheumatology (Oxford) 2019;58:1344-52.
    1. Mitha E, Schumacher HR, Fouche L, Luo SF, Weinstein SP, Yancopoulos GD, 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.
    1. Schumacher HR Jr, Evans RR, Saag KG, Clower J, Jennings W, Weinstein SP, et al. Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study. Arthritis Care Res (Hoboken) 2012;64:1462-70.
    1. Schumacher HR Jr, Sundy JS, Terkeltaub R, Knapp HR, Mellis SJ, Stahl N, et al. Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2012;64:876-84.
    1. Terkeltaub R, Sundy JS, Schumacher HR, Murphy F, Bookbinder S, Biedermann S, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009;68:1613-7.
    1. Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, et al. 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.
    1. Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative [published erratum appears in Arthritis Rheumatol 2016;68:515]. Arthritis Rheumatol 2015;67:2557-68.
    1. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614-24.
    1. Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:1006-12.
    1. Wiken M, Hallen B, Kullenberg T, Koskinen LO. Development and effect of antibodies to anakinra during treatment of severe CAPS: sub-analysis of a long-term safety and efficacy study. Clin Rheumatol 2018;37:3381-6.
    1. Kineret (anakinra) prescribing information. Stockholm (Sweden): Sobi; 2001. URL: https://wwwaccessdatafdagov/drugsatfda_docs/label/2012/103950s5136lblpdf.
    1. Singh JA, Taylor WJ, Dalbeth N, Simon LS, Sundy J, Grainger R, et al. OMERACT endorsement of measures of outcome for studies of acute gout. J Rheumatol 2014;41:569-73.
    1. Janssen CA, Voshaar MA, Klooster PM, Vonkeman HE, van de Laar M. Development and validation of a patient-reported gout attack intensity score for use in gout clinical studies. Rheumatology (Oxford) 2019;58:1928-34.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi