Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1 beta (IL-1 beta) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1 beta inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (Clinical Trials.gov: NCT01327846) Setting: 1091 clinical sites in 39 countries. Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Limitation: Because the parent trial was not designed to examine the efficacy of IL-1 beta inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1 beta inhibition for treatment of large joint osteoarthritis.