Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

Naomi Schlesinger, Eduardo Mysler, Hsiao-Yi Lin, Marc De Meulemeester, Jozef Rovensky, Udayasankar Arulmani, Alison Balfour, Gerhard Krammer, Peter Sallstig, Alexander So, Naomi Schlesinger, Eduardo Mysler, Hsiao-Yi Lin, Marc De Meulemeester, Jozef Rovensky, Udayasankar Arulmani, Alison Balfour, Gerhard Krammer, Peter Sallstig, Alexander So

Abstract

Objective: This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment.

Methods: In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks.

Results: A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p≤0.05). The incidence of adverse events was similar across treatment groups.

Conclusions: Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg.

Conflict of interest statement

Competing interests NS: grant, travel expenses and payment for advisory board membership from Novartis Pharma, payment for development of educational presentations from Takeda and payment for advisory board membership from Savient, URL Pharma and Enzyme Rx. H-YL, EM and JR report no conflicts of interest. MDeM: payment from Novartis for development of educational presentations. PS, UA, GK and AB are employees of Novartis and report having equity interests in Novartis. AS: payment from Novartis for board membership, consultancy and travel expenses.

Figures

Figure 1
Figure 1
Patient disposition. Patients were recruited from the following countries (number of centres): Argentina (1), Belgium (2), Columbia (5), Czech Republic (5), Germany (5), Guatemala (5), Hungary (4), Poland (2), Portugal (3), Russia (7), Singapore (1), Slovakia (6), South Africa (4), Spain (4), Taiwan (4), Turkey (8), UK (2) and USA (20).
Figure 2
Figure 2
Time to first acute gouty arthritis flare after randomisation (Kaplan–Meier estimate).
Figure 3
Figure 3
Median C reactive protein levels over time. CRP, C reactive protein; q4wk, every 4 weeks; ULN, upper limit of the normal range.

References

    1. Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Kidney Dis 2002;40:37–42
    1. Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: results from the UK General Practice Research Database, 1990-1999. Ann Rheum Dis 2005;64:267–72
    1. Schlesinger N. Diagnosis of gout. Minerva Med 2007;98:759–67
    1. Schlesinger N. Diagnosis of gout: clinical, laboratory, and radiologic findings. Am J Manag Care 2005;11(15 Suppl):S443–50; quiz S465–8
    1. Keenan RT, O'Brien WR, Lee KH, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 2011;124:155–63
    1. Schlesinger N, Thiele RG. The pathogenesis of bone erosions in gouty arthritis. Ann Rheum Dis 2010;69:1907–12
    1. Becker MA, Schumacher HR, Benjamin KL, et al. Quality of life and disability in patients with treatment-failure gout. J Rheumatol 2009;36:1041–8
    1. Lee SJ, Hirsch JD, Terkeltaub R, et al. Perceptions of disease and health-related quality of life among patients with gout. Rheumatology (Oxford) 2009;48:582–6
    1. Edwards N, Blume S, Pan F, et al. Work productivity loss due to flares in treatment-failure gout. Arthritis Rheum 2008;58:S673
    1. Schlesinger N. Diagnosing and treating gout: a review to aid primary care physicians. Postgrad Med 2010;122:157–61
    1. Schlesinger N, Dalbeth N, Perez-Ruiz F. Gout–what are the treatment options? Expert Opin Pharmacother 2009;10:1319–28
    1. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312–24
    1. Suresh E. Diagnosis and management of gout: a rational approach. Postgrad Med J 2005;81:572–9
    1. Yamanaka H, Togashi R, Hakoda M, et al. Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment. Adv Exp Med Biol 1998;431:13–18
    1. Becker MA, Schumacher HR, Jr, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 2005;52:916–23
    1. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51:321–5
    1. Schumacher HR, Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008;59:1540–8
    1. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:2429–32
    1. Paulus HE, Schlosstein LH, Godfrey RG, et al. Prophylactic colchicine therapy of intercritical gout. A placebo-controlled study of probenecid-treated patients. Arthritis Rheum 1974;17:609–14
    1. Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Prevention of recurrent gouty arthritis over a mean period of five years in 208 gouty subjects. Ann Intern Med 1961;55:179–92
    1. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63.
    1. Becker MA, Schumacher HR, Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450–61
    1. So A. Developments in the scientific and clinical understanding of gout. Arthritis Res Ther 2008;10:221.
    1. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41
    1. Kim JH, Jin HM, Kim K, et al. The mechanism of osteoclast differentiation induced by IL-1. J Immunol 2009;183:1862–70
    1. Tunyogi-Csapo M, Kis-Toth K, Radacs M, et al. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum 2008;58:2397–408
    1. Alten R, Gram H, Joosten LA, et al. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 2008;10:R67.
    1. So A, De Meulemeester M, Pikhlak A, 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. Wallace SL, Singer JZ, Duncan GJ, et al. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol 1991;18:264–9
    1. Schumacher HR, Sundy JS, Terkeltaub R, et al. Placebo-controlled study of rilonacept for gout flare prophylaxis during initiation of urate-lowering therapy. ACR 2009: Abstract 1096
    1. Neogi T. Interleukin-1 antagonism in acute gout: is targeting a single cytokine the answer? Arthritis Rheum 2010;62:2845–9
    1. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009;360:2416–25
    1. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46:1372–4
    1. Schumacher HR, Taylor W, Edwards L, et al. Outcome domains for studies of acute and chronic gout. J Rheumatol 2009;36:2342–5

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