Synergistic Benefit of Combining Inhibitors of Interleukin-1 and Tumor Necrosis Factor in Animal Models of Rheumatoid Arthritis

Edwards, et al (Arthritis Rheum 43:2648, 2000) have published data presented at EULAR comparing the benefits of combination therapy with interleukin-1 receptor antagonist (IL-Ra) and PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI) in a rat model of rheumatoid arthritis.

Rats with established collagen-induced arthritis (CIA) or developing adjuvant-induced arthritis (AIA) were treated with 20 or 100 mg/kg IL-1R or with 0.3, 1. or 3 mg/ml sTNFRI, either alone or in combination. Paw and joint swelling, paw weights, and histology were monitored.

In rats with CIA, combination therapy with 100 mg/kg IL-1Ra and all doses of PEG sTNFRI resulted in additive beneficial effects on area under the curve (AUC) for paw swelling and weight, histologic parameters, and body weight gain when compared to placebo-treated control rats. However, combination therapy with IL-1Ra 20 mg/kg and all doses of PEG sTNFRI had greater-than-additive benefit for these same parameters. In rats with AIA, combination therapy with 100 mg/kg IL-1Ra and all doses of PEG sTNFRI resulted in additive beneficial effects on area under the curve (AUC) for ankle joint swelling, paw weight and swelling, and histologic evaluation. Body weight showed little change with either treatment alone and modest increased benefit with combination treatment. The blood levels of IL-1Ra are much higher in rats treated with 100 mg/kg than those seen in humans. However, in rats treated with 20 mg/kg, blood levels of IL-1Ra are similar to those in humans for the first 8 hours post dosing and much lower by 24 hours.

These data show that there is a beneficial synergistic effect of IL-1Ra and PEG sTNFRI given in combination therapy for CIA and AIA and that this effect is achieved with realistic blood levels, thereby supporting the need for further clinical investigation.

Editorial Comment: IL-1 and TNF-ahave been shown in vitro to have synergistic effects on inflammatory indices. THis study in rats suggests that inhibitors of IL-1 and TNF may act similarly to synergistically inhibit inflammation. THis means, theoretically, that lower doses of each agent may be able to be used in combination than when used alone. Studies are planned in RA patients to test thes findings.