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      Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

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          Abstract

          Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs.

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          Rheumatoid arthritis

          Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
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            Mechanisms and consequences of Jak–STAT signaling in the immune system

            O’Shea and colleagues review recent advances in Jak–STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent transcription factors.
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              JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

              The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                01 April 2021
                April 2021
                : 10
                : 7
                : 1431
                Affiliations
                [1 ]Institute of Molecular and Clinical Immunology, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; linda.voss@ 123456med.ovgu.de (L.V.); karina.guttek@ 123456med.ovgu.de (K.G.); dirk.reinhold@ 123456med.ovgu.de (D.R.)
                [2 ]Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany; dirk.roggenbuck@ 123456b-tu.de
                [3 ]Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, 01968 Senftenberg, Germany
                [4 ]Helios-Department of Rheumatology, Cooperation Partner of the Otto-Von-Guericke-University, 39245 Vogelsang-Gommern, Germany; eugen.feist@ 123456helios-gesundheit.de
                Author notes
                [* ]Correspondence: annika.reddig@ 123456med.ovgu.de ; Tel.: +49-391-67-17842
                Author information
                https://orcid.org/0000-0001-6587-206X
                https://orcid.org/0000-0002-6861-6827
                https://orcid.org/0000-0002-9872-5282
                https://orcid.org/0000-0002-6441-9631
                Article
                jcm-10-01431
                10.3390/jcm10071431
                8036268
                33916057
                eccf4302-dfd7-4e94-a4b1-079457ef7e56
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 02 February 2021
                : 29 March 2021
                Categories
                Article

                jak inhibitor,proliferation,dna damage repair,γh2ax,pbmcs,t lymphocytes

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