Objective: To determine the role of interleukin-1 receptor antagonist (IL-1Ra) in rat adjuvant arthritis and rat type II collagen-induced arthritis, and to compare the efficacy in rat models with that seen in human clinical trials of IL-1Ra.
Methods: Rats with developing adjuvant arthritis or established collagen-induced arthritis were treated with IL-1Ra by continuous infusion in order to determine and maintain efficacious blood levels of this IL-1 inhibitory protein in the rats for comparison with human clinical data. The effects of treatment in the rats were monitored by sequential caliper measurement of the ankle joints, determination of final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. The effects of IL-1Ra on joint swelling and radiographic bone damage in patients with rheumatoid 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 between the 2 groups of rats. Modest antiinflammatory effects were observed in the adjuvant arthritis rats treated with IL-1Ra. However, marked inhibition of bone resorption occurred, even at doses with which antiinflammatory activity was not seen. In contrast, IL-1Ra treatment of rats with established collagen-induced arthritis resulted in nearly complete suppression of all aspects of the disease when adequate blood levels of IL-1Ra were maintained. 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 resorption that occurs in rat adjuvant arthritis, but is less important in the 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 arthritic rats, RA patients treated with IL-1Ra showed only modest antiinflammatory activity, but had evidence of inhibition of progression of bone resorption. However, a comparison of the plasma levels of IL-1Ra in humans and rats suggests that the optimal level of dosing for continuous saturation of IL-1 receptors may not have been achieved in humans, although this was achieved in the rat studies.