title: Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside.
abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. However, the combined use of synthetic disease-modifying anti-rheumatic drug (DMARD) such as methotrexate and a biological DMARD targeting tumour necrosis factor (TNF) has revolutionized treatment of RA. Clinical remission is a realistic target to treat and the maintenance of remission has produced significant improvements in structural and function outcomes. However, biological DMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. The multiple cytokines and cell surface molecules bind to receptors, resulting in the activation of various signalling, including phosphorylation of kinase proteins. Among multiple kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA. Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to efficient propagation of its anti-inflammatory effects for the treatment of RA. The primary targets of tofacitinib are dendritic cells, CD4(+) T cells such as Th1 and Th17 and activated B cells which leads to multi-cytokine targeting. Six global phase 3 studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly effective than placebo with or without methotrexate in active RA patients with methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors. Therapeutic efficacy of tofacitinib was observed in a short term after administration and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed adverse events were related to infection, hematologic, hepatic and renal disorders and association of tofacitinib with carcinogenicity and infections remains debated. Further investigation on post-marketing survey would help us understand the positioning of this drug.
authors.affiliation: The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu 807-8555, Japan tanaka@med.uoeh-u.ac.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008727:Methotrexate / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D057170:Translational Research, Biomedical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; C479163:tofacitinib; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008727:Methotrexate
keywords: DMARD; JAK inhibitor; remission; rheumatoid arthritis