Therapeutic Prospects for Modification of Interleukin-1 Activity in Arthritis

Abstract

Interleukin-1 (IL-1) is a major proinflammatory cytokine that is implicated in the pathogenesis of rheumatoid arthritis and osteoarthritis, together with other cytokines such as tumour necrosis factor-α. IL-1 is produced in the inflamed synovial tissue, where it contributes to synovial inflammation and proliferation, to bone and cartilage degradation and to systemic symptoms. Inhibition of IL-1 activity is a promising therapeutic approach in arthritis. Some existing antiarthritic agents, such as corticosteroids or methotrexate, are thought to exert part of their beneficial activity by interfering with IL-1 activity. However, IL-1 production may be specifically targeted by inhibiting the recently discovered IL-1β converting enzyme (ICE). Furthermore, it is possible to specifically block IL-1 at the effector level, using natural antagonists of IL-1 such as the soluble forms of the IL-1 receptor (IL-1sR) or the IL-1 receptor antagonist (IL-1Ra). In animal studies, IL-1Ra exerts antiarthritic effects in animal models following systemic administration or local gene transfer therapy to the joint. Phase I and phase II clinical trials have been completed in rheumatoid arthritis using IL-1Ra and IL-1sR. These agents were generally well tolerated and exhibited some beneficial effect. More studies are now being undertaken to fully investigate the clinical potential of these new therapeutic agents, either alone or in combination.