Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first ‘outside to in’ signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of interleukin 17 (IL-17) and interferon γ production and proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA animal model using SCID mice implanted with synovium and cartilage from patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice and also reduced synovial inflammation and invasion into the implanted cartilage. A phase 2 double-blind study using tofacitinib was carried out in Japanese patients with active RA and inadequate response to methotrexate (MTX). A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.
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Funding The clinical examination regarding tofacitinib (CP-690,550) was sponsored by Pfizer Inc and the compound CP-690,550 for in vitro studies was provided by Pfizer Inc. The series of studies were also supported in part by a research grant-in-aid for scientific research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and the University of Occupational and Environmental Health, Japan.
Competing interests YT has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma, Chugai Pharma, Eisai Pharma, Pfizer, Abbott Immunology Pharma, Daiichi-Sankyo, Janssen Pharma, Astra-Zeneca, Takeda Industrial Pharma, Astellas Pharma, Asahi-kasei Pharma and GlaxoSmithKline and has received research grant support from Mitsubishi-Tanabe Pharma, Bristol-Myers Squibb, Takeda Industrial Pharma, MSD, Astellas Pharma, Eisai Pharma, Chugai Pharma, Pfizer and Daiichi-Sankyo.
Provenance and peer review Commissioned; externally peer reviewed.
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