Advancing IL-1 inhibition for OA: Lessons learned from clinical trials and new approaches

Interleukin-1 (IL-1) inhibitors have failed to be clinically approved for osteoarthritis (OA) treatment, despite their success in treating other rheumatic diseases. Preclinical studies suggest that IL-1 inhibition can reduce cartilage degradation and synovitis, yet clinical outcomes have been limited to transient pain relief and modest functional improvement. This review critically evaluates the lessons learned from both preclinical and clinical studies of IL-1 inhibition in OA and identifies the contexts in which such therapies may be effective. We examine the conditions under which IL-1 is elevated in the synovial fluid, discuss routes of administration and pharmacokinetics, and highlight why IL-1 inhibitors fell short in clinical trials. Systemic administration carries risks of immunosuppression, while intra-articular (IA) delivery, although localized, is hindered by rapid clearance due to synovial fluid turnover and the avascular nature of cartilage. Without strategies to enhance tissue targeting and joint retention, current IL-1 inhibitors are unlikely to realize their full therapeutic potential. We also outline emerging approaches to improve joint bioavailability and reduce injection frequency, including recent viral, non-viral, and electrostatic drug delivery strategies. Ultimately, to maximize the potential for IL-1 inhibitors in OA, they must be administered within the correct intervention window and in an appropriate patient population able to respond to anti-IL-1 therapy.