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      JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis

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          Abstract

          Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs—called JAK inhibitors or JAKinibs—that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.

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          Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis

          Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.
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            JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects

            The Janus kinase/signal transduction and activator of transcription (JAK–STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK–STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK–STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK–STAT signaling blockade.
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              Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

              Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors.
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                Author and article information

                Journal
                Rheumatology (Oxford)
                Rheumatology (Oxford)
                brheum
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                February 2019
                26 February 2019
                26 February 2019
                : 58
                : Suppl 1 , Can JAK inhibitors bring a paradigm shift for the treatment of autoimmune diseases?
                : i43-i54
                Affiliations
                Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
                Author notes
                Correspondence to: Iain B. McInnes, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK. E-mail: Iain.McInnes@ 123456glasgow.ac.uk
                Article
                key276
                10.1093/rheumatology/key276
                6390879
                30806709
                ffa3bcb5-fe0c-4315-b4ff-e42c77894763
                © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 March 2018
                : 03 August 2018
                Page count
                Pages: 12
                Funding
                Funded by: Gilead Sciences, Inc. 10.13039/100005564
                Funded by: AbbVie 10.13039/100006483
                Funded by: Celgene 10.13039/100006436
                Funded by: Bristol-Myers Squibb 10.13039/100002491
                Funded by: Pfizer 10.13039/100004319
                Funded by: Lilly 10.13039/100004312
                Funded by: Galapagos
                Funded by: Janssen
                Funded by: Novartis 10.13039/100004336
                Funded by: UCB 10.13039/100011110
                Funded by: Boehringer-Ingelheim
                Categories
                Reviews

                Rheumatology
                jak/stat pathway,jak inhibitors,immune-mediated diseases
                Rheumatology
                jak/stat pathway, jak inhibitors, immune-mediated diseases

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