title: In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis.
abstract: 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.
authors.affiliation: The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Maeshima
authors.forename: Y
authors.initials: Y
authors.lastname: Maeshima
authors.forename: K
authors.initials: K
authors.lastname: Yamaoka
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D007527:Isoenzymes; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3