Development of novel therapeutics for rheumatoid arthritis utilizing the adenosine deaminase inhibition

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We previously reported that the elevated adenosine deaminase (ADA) activities in the joints of rheumatoid arthritis (RA) patients contribute to the pathogenesis of RA by neutralizing the anti-rheumatic properties of endogenous adenosine. In the present study, we examined the in vivo effects of ADA inhibitor on Lewis rats adjuvant-induced arthritis. The novel non-nucleoside ADA inhibitor FR242685 was daily injected into the right ankle of each rat. The development of arthritis was significantly suppressed on FR242685-treated rats in a concentration-dependent manner, while FR242685 alone did not induce arthritis. FR242685 treatment did not show any adverse effect. Radiographic analyses revealed that osteoporosis, joint space narrowing and bone destruction were all improved in arthritis rats treated with FR242685 compared with those in arthritis rats treated with saline. Histopathological analyses also revealed that FR242685 treatment improved the joint space narrowing, destruction of cartilage, proliferation of synoviocytes, infiltration of inflammatory cells, and formation of pannus. Decrease in blood and SF adenosine of arthritis rats were normalized, but not exceeded the normal level, by FR242685, which may explain the absence of adverse effects in FR242685 treatment. Concentration of IFNγ and TNF α in plasma as well as concentration of IL-6 in ankle tissue of arthritis rats treated with FR242685 were significantly lower than those of arthritis rats treated with saline. mRNA expression of IL-6 and RANKL in ankle tissue of arthritis rats treated with FR242685 was significantly lower than that of arthritis rats treated with saline. These data suggest that treatment with FR242685 improves the arthritis in vivo without any adverse effects, making the ADA inhibitor as a plausible candidate with which to develop novel therapeutics for RA.