Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement
Matthias Schieker, Philip G. Conaghan, Linda Mindeholm, Jens Præstgaard, Daniel H. Solomon, Celeste Scotti, Herman Gram, Tom Thurén, Ronenn Roubenoff, Paul M. Ridker
Abstract
Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (ClinicalTrials.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-1β 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-1β inhibition for treatment of large joint osteoarthritis. Primary Funding Source: Novartis Pharmaceuticals.