Anti-interleukin-1 and anti-tumor necrosis factor-alpha synergistically inhibit adjuvant arthritis in Lewis rats

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play domin ant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mi ce and rats, and adjuvant arthritis in rats. Blockade of either cytokine pa rtially controls these diseases. The present study investigated the value o f combination anti-cytokine therapy in arthritis: the efficacy of IL-I rece ptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated so luble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewi s rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF -RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine tr eatments exhibited a synergistic capacity to inhibit these changes, even wh en combining doses of IL-lra and PEG sTNF-RI that did not affect lesion sev erity when used alone. Statistical analysis of these adjuvant arthritis dat a using the isobologram method proved that IL-lra and PEG sTNF-RI were clea rly synergistic in inhibiting inflammation, loss of bone mineral density, l oss of body weight, and histopathologic parameters of inflammation and join t destruction. These results suggest that treating autoimmune arthritic dis eases with combinations of anti-IL-l and anti-TNF molecules will achieve su perior efficacy compared to the use of a single class of anti-cytokine agen t and may allow for dose reductions that could prove useful in minimizing p otential side effects.