Combination benefit of treatment with the cytokine inhibitors interleukin‐1 receptor antagonist and PEGylated soluble tumor necrosis factor receptor type I in animal models of rheumatoid arthritis

Objective To determine the potential for additive or synergistic effects of combination therapy with the recombinant anticytokine agents interleukin‐1 receptor antagonist (IL‐1Ra) and PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI) in established type II collagen–induced arthritis (CIA) and developing adjuvant‐induced arthritis (AIA) in rats. Methods Rats with established CIA or developing AIA were treated with various doses of IL‐1Ra in a slow‐release hyaluronic acid vehicle or with PEG sTNFRI, either alone or in combination with the IL‐1Ra. The effects of treatment were monitored by sequential caliper measurements of the ankle joints or hind paw volumes, final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. Results Combination therapy with IL‐1Ra and PEG sTNFRI in rats with CIA resulted in an additive effect on clinical and histologic parameters when moderately to highly efficacious doses of each protein were administered. Greater‐than‐additive effects were seen when an inactive dose of IL‐1Ra was given in combination with moderately to minimally active doses of PEG sTNFRI. Plasma levels associated with the latter effect (for both proteins) were similar to those seen in rheumatoid arthritis (RA) patients in clinical trials with these agents. Combination therapy in the AIA model generally resulted in additive effects, but some parameters showed a greater‐than‐additive benefit. Conclusion The results provide preclinical support for the hypothesis that IL‐1Ra administered in combination with PEG sTNFRI might provide substantially more clinical benefit to RA patients than either agent alone at blood levels that are currently achievable in patients.