M Chabaud1, P Miossec. 1. INSERM U403, Hĵpital Edouart Herriot, Lyon, France.
Abstract
OBJECTIVE: Anti-tumor necrosis factor a (anti-TNFalpha) therapy has shown efficacy in the treatment of rheumatoid arthritis (RA). Since interleukin-1 (IL-1), TNFalpha, and IL-17 have many additive and/or synergistic effects in vitro, we tested whether their combined inhibition by soluble receptors would lead to an enhanced effect on ex vivo models of synovial inflammation and bone destruction. METHODS: RA synovium and bone explants were cultured for 7 days in the presence of 1 microg/ml soluble TNFalpha receptor (STNFR; as in current therapy), type II soluble IL-1 receptor (sIL-1RII), or sIL-17R either alone or in combination. Their effects on the production of IL-6 and the release of C-telopeptide of type I collagen (CTX), a marker of type I collagen destruction, were measured by enzyme-linked immunosorbent assay. RESULTS: In synovium, each soluble receptor alone decreased IL-6 production and CTX release by approximately 35% and approximately 55%, respectively. The combination of all 3 receptors was more effective, inhibiting IL-6 production and collagen degradation by up to 70%. Neither sIL-17R, sIL-1RII, or sTNFR alone had no effect (or an effect of <20% inhibition) on IL-6 production in 18%, 33%, and 22%, respectively, of the samples. In bone, sIL-17R, sIL-1RII, and sTNFR decreased IL-6 production by 23%, 50%, and 37%, respectively, while the combination decreased IL-6 production by 75%. A 50% inhibition of CTX release was obtained with sIL-1RII for 63% of the samples versus 38% of the samples with either sTNFR or sIL-17R. However, the combination of all 3 receptors was not more potent than sIL-1RII alone. CONCLUSION: The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients as well as the degree of individual patient response.
OBJECTIVE: Anti-tumor necrosis factor a (anti-TNFalpha) therapy has shown efficacy in the treatment of rheumatoid arthritis (RA). Since interleukin-1 (IL-1), TNFalpha, and IL-17 have many additive and/or synergistic effects in vitro, we tested whether their combined inhibition by soluble receptors would lead to an enhanced effect on ex vivo models of synovial inflammation and bone destruction. METHODS: RA synovium and bone explants were cultured for 7 days in the presence of 1 microg/ml soluble TNFalpha receptor (STNFR; as in current therapy), type II soluble IL-1 receptor (sIL-1RII), or sIL-17R either alone or in combination. Their effects on the production of IL-6 and the release of C-telopeptide of type I collagen (CTX), a marker of type I collagen destruction, were measured by enzyme-linked immunosorbent assay. RESULTS: In synovium, each soluble receptor alone decreased IL-6 production and CTX release by approximately 35% and approximately 55%, respectively. The combination of all 3 receptors was more effective, inhibiting IL-6 production and collagen degradation by up to 70%. Neither sIL-17R, sIL-1RII, or sTNFR alone had no effect (or an effect of <20% inhibition) on IL-6 production in 18%, 33%, and 22%, respectively, of the samples. In bone, sIL-17R, sIL-1RII, and sTNFR decreased IL-6 production by 23%, 50%, and 37%, respectively, while the combination decreased IL-6 production by 75%. A 50% inhibition of CTX release was obtained with sIL-1RII for 63% of the samples versus 38% of the samples with either sTNFR or sIL-17R. However, the combination of all 3 receptors was not more potent than sIL-1RII alone. CONCLUSION: The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients as well as the degree of individual patient response.
Authors: Sujata Sarkar; Laura A Cooney; Peter White; Deborah B Dunlop; Judith Endres; Julie M Jorns; Matthew J Wasco; David A Fox Journal: Arthritis Res Ther Date: 2009-10-26 Impact factor: 5.156