Combination cytokine therapy in rheumatoid arthritis: The next generation

Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the joints with concomitant destruction of cartilage and bone. The involvement of proinflammatory cytokines, particularly interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), in the pathogenesis of RA. is now well accepted. The IL-1 receptor antagonist (IL-1Ra) is a specific receptor antagonist that competitively inhibits binding of IL-1 beta and IL-1 alpha to human and animal IL-1 type I and II receptors. IL-1Ra, when administered chronically to patients with RA, has resulted in lower acute-phase protein levels and swollen joint counts as well as inhibition of radiographic disease progression. Soluble TNF receptors and antibodies to TNF have also been shown to be clinically efficacious in RA patients. Animal models of arthritis in which these agents were evaluated predicted the excellent human clinical, response. Several animal studies have focused on the efficacy of the high-affinity monomeric PEGylated type 1 TNF receptor administered alone or in combination with other agents such as methotrexate, dexamethasone, and indomethacin, where the potential for additive or synergistic effects was shown. Although there are no human trials to date, the combination of two anticytokines, such as IL-1Ra and a soluble TNF receptor, may offer greater efficacy than either agent alone.