JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical
Yoshiya Tanaka
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Kunihiro Yamaoka
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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.
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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)