JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical

Modern Rheumatology, Mar 2013

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4+ T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.

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JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical

Yoshiya Tanaka 0 Kunihiro Yamaoka 0 0 Y. Tanaka (&) K. Yamaoka The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health , Japan , 1-1 Iseigaoka, Kitakyushu 807-8555, Japan Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX nave or show inadequate response to methotrexate (MTX-IR), diseasemodifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-c production and proliferation of CD4? T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment. - Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by systemic, chronic, destructive inflammatory synovitis and multiple organ manifestations and causes severe disability and mortality rates. Conventional disease-modifying antirheumatic drugs (DMARDs), most commonly, methotrexate (MTX), remain the cornerstone of RA treatment. However, patients with active RA and an inadequate response to MTX (MTX-IR) are treated with biological agents targeting tumor necrosis factor (TNF) and interleukin (IL)-6, which play a pivotal role during the pathological processes of RA and that bring destructive inflammatory synovitis and multiple organ manifestations. The combinational application of TNF inhibitors and MTX has brought about a paradigm shift in RA management, and the RA treatment target has evolved to clinical, structural, and functional remission simply by reducing polyarthralgia [13]. On the other hand, orally available low molecular weight products targeting key molecules during the disease processes are attracting particular attention because they enter the cytoplasm and directly regulate intracellular signals, whereas high molecular weight biologics regulate intercellular signals by binding to cell-surface molecules or secreted protein. Among them, products targeting kinase proteins are emerging because multiple signaling kinases are involved in the pathological processes and can be designed to recognize particular conformations of target molecules, such as the relationships of a key and key hole, during the signaling cascade. For example, imatinib, which Druker and others reported in 1996, is the derivative designed to antagonize an adenosine triphosphatase (ATP) binding site of the tyrosine kinase of BCR-ABL protein peculiar to chronic myelogenous leukemia and induces apoptosis of leukemic cells [4]. The multiple cytokines and cell-surface molecules play a pivotal role in RA pathogenesis, and binding of these molecules to their ligands on the cell surface induces various signals, including phosphorylation of kinase proteins. Thus, similar trials as those in leukemia using low molecular weight products targeting kinase proteins have been undertaken in RA treatment. What is JAK, and why was JAK chosen as the target of treatment? Five hundred and eighteen genes encoding kinase proteins have been identified from human genome-wide studies, and [99 % of them are serine/threonine kinases in physiological and ordinary condition. On the other hand, tyrosine kinase is the first intracellular signaling molecules to be phosphorylated following receptor binding in a cytokine response and is involved in fundamental functions such as cell proliferation, differentiation, and adhesion in various pathological processes, including inflammation and cancer. Therefore, many investigators have shed light on tyrosine kinases as the target of treatment of various diseases. More than 90 genes encoding tyrosine kinases have been identified from human genome-wide studies, and 14 tyrosine kinases are known to be involved in synovial membrane in patients with RA compared with patients with osteoarthritis [5]. Among them, members of the Janus kinase (JAK) family are essential for the signal (...truncated)


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Yoshiya Tanaka, Kunihiro Yamaoka. JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical, Modern Rheumatology, 2013, pp. 415-424, Volume 23, Issue 3, DOI: 10.1007/s10165-012-0799-2