The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model.
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.


CONCLUSIONS
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.
Chabaud
M
M
INSERM U403, Hĵpital Edouart Herriot, Lyon, France.
Miossec
P
P
D000328:Adult; D000368:Aged; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D046508:Culture Techniques; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020381:Interleukin-17 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008875:Middle Aged; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D004338:Drug Combinations; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen