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薬理と治療
Abstract
Rheumatoid arthritis(RA)is a chronic inflammatory autoimmune disease resulting in progressive joint destruction and polyarticular synovitis. A major cause of pathogenesis is thought to be TNF-α, IL-1, and IL-6 inducing activation and infiltration of inflammatory cells, proliferation of synovial lining cells, angiogenesis, and destruction of cartilage and bone. This review discusses the difference in the modes of action of IL-6 and JAK in the signaling cascade of inflammatory cytokines. Tocilizumab is an IL-6 receptor blocker that has been demonstrated in the actual clinical setting to be useful in preventing symptoms of RA, improving activities of daily living, and inhibiting structural damage of joints. Its mode of action involves blocking only IL-6R-gp130 signaling, resulting in the activation of intracellular JAK1 and JAK2, which has a variety of pathophysiological effects in RA pathogenesis. Tofacitinib, a JAK1 and JAK3 inhibitor with short plasma half-life(T1/2=3 h), shows high efficacy comparable to that of biologics such as TNF-α inhibitors, through inhibiting the intracellular signaling of various cytokine receptors, such as IFN-α/γ receptors, gp130, and common γ chain. JAK plays an important role in the immune system and hematopoietic system by modulating cell proliferation, survival, differentiation, and activation. At present, it is not clear whether FDA-approved doses of tofacitinib inhibit joint destruction in established RA. Possible complications, including anemia, myelosuppression, immunosuppression, NK cell depletion, and tumorigenesis, should be carefully examined, especially in Japanese patients. Its clinical use should be managed with caution until clinical evidence and tolerability has been established.
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