Canakinumab for the treatment of acute flares in difficult‐to‐treat gouty arthritis: Results of a multicenter, phase II, dose‐ranging study

Abstract

Objective. To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1␤ monoclonal antibody, for the treatment of acute gouty arthritis.Methods. In this 8-week, single-blind, doubledummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n ‫؍‬ 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n ‫؍‬ 57). Patients assessed pain using a 100-mm visual analog scale.Results. Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of ؊11.5 mm [P ‫؍‬ 0.04], ؊18.2 mm [P ‫؍‬ 0.002], and ؊19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P < 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity.Conclusion. Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.Gout is a metabolic disease caused by monosodium urate monohydrate (MSU) crystal deposition and is one of the most common forms of inflammatory arthritis in adults (1,2). Its prevalence increases with age and is especially high in older men (2). Gouty arthritis commonly occurs in the lower extremities (3,4), and flares are characterized by rapid onset and build-up of pain, warmth, swelling, decreased range of motion, and redness of the involved joints (3,4). Initial flares last hours to weeks, whereas subsequent flares may be more prolonged. The frequency of flares often increases over time in patients who are inadequately treated (3,4).The goal of therapy in an acute gout flare is prompt and safe termination of pain and inflammation. Acute gouty arthritis is usually treated with nonsteroidal ClinicalTrials.gov identifier: NCT00798369.

Identifying Patient Candidates for IL-1 Inhibition: Lessons From Real-World Cases

“…In a phase III, randomized, controlled trial (RCT), canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvement in health-related quality of life occurred in both treatment groups but with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg [22], confirming the results of a phase II dose-finding, RCT, in which canakinumab 150 mg provided rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduced the risk of recurrent flares compared with triamcinolone acetonide [23].…”

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

“…Recently, IL-1 blockade also proved effective in crystal-mediated diseases, such as gout and pseudogout (44,45). The dramatic therapeutic effects seem to directly relate to the fact that NLRP3 translates crystal recognition into IL-1β secretion as a central element of crystal-induced tissue inflammation and pathology (24).…”

The Therapeutic Potential of Modifying Inflammasomes and NOD-Like Receptors

“…The molecular mechanism of inflammasome activation by MSU and CPPD has not been clarified, and it is possible that inflammasome stimulation requires an intermediate and as yet unknown step (Kingsbury et al, 2011). In support of the pathogenetic role of the inflammasome in acute and chronic gout, administration of IL1b blockers such as the recombinant IL-1Ra (IL-1 receptor antagonist) anakinra (McGonagle et al, 2007), the IL-1 Trap rilonacept (Terkeltaub et al, 2009), or the monoclonal anti-IL-1b antibody canakinumab (So et al, 2010) proved to be very effective. Recent reports suggest that activation of the inflammasome by 892 particulate agents might be a general paradigm for sterile inflammation.…”