Efficacy of sustained blood levels of interleukin-1 receptor antagonist inanimal models of arthritis - Comparison of efficacy in animal models with human clinical data

Objective, To determine the role of interleukin-1 receptor antagonist (IL-1 Ra) in rat adjuvant arthritis and rat type II collagen-induced arthritis, a nd to compare the efficacy in rat models with that seen in human clinical t rials of IL-1Ra. Methods. Rats with developing adjuvant arthritis or established collagen-in duced arthritis were treated with IL-1Ra by continuous infusion in order to determine and maintain efficacious blood levels of this IL-1 inhibitory pr otein in the rats for comparison with human clinical data. The effects of t reatment in the rats were monitored by sequential caliper measurement of th e ankle joints, determination of final paw weights, and histologic evaluati on with particular emphasis on bone and cartilage lesions. The effects of I L-1Ra on joint swelling and radiographic bone damage in patients with rheum atoid arthritis (RA) in a 6-month trial were compared with the findings in rats. Results. Dramatic differences in the profile of IL-1Ra activity were seen b etween the 2 groups of rats. Modest antiinflammatory effects were observed in the adjuvant arthritis rats treated with IL-1Ra. However, marked inhibit ion of bone resorption occurred, even at doses with which antiinflammatory activity was not seen. In contrast, IL-1Ra treatment of rats with establish ed collagen-induced arthritis resulted in nearly complete suppression of al l aspects of the disease when adequate blood levels of IL-1Ra were maintain ed. Treatment of RA patients with IL-1Ra (150 mg daily) resulted in modest inhibition of joint swelling and inhibition of radiographic progression of bone lesions. Conclusion. IL-1 appears to be of major importance in mediating the bone re sorption that occurs in rat adjuvant arthritis, but is less important in th e pathogenesis of periarticular inflammation in this disease. In contrast, IL-1 is of major importance in mediating all aspects of disease progression in rat collagen-induced arthritis. Similar to the response in adjuvant art hritic rats, RA patients treated with IL-1Ra showed only modest antiinflamm atory activity, but had evidence of inhibition of progression of bone resor ption. However, a comparison of the plasma levels of IL-1Ra in humans and r ats suggests that the optimal level of dosing for continuous saturation of IL-1 receptors may not have been achieved in humans, although this was achi eved in the rat studies.