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      JAK Inhibition as a New Treatment Strategy for Patients with COVID-19

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          After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1–7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.

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          Most cited references 20

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          Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.

          Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.
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            Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial

            Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate.
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              Is Open Access

              The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells

              The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed.

                Author and article information

                Int Arch Allergy Immunol
                Int. Arch. Allergy Immunol
                International Archives of Allergy and Immunology
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, )
                11 May 2020
                : 181
                : 6
                : 467-475
                aDepartment of Immunology and Allergy, Academic Center for Education, Culture, and Research, Tehran, Iran
                bNeuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
                cEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
                dDepartment of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
                eRajaei Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
                fDepartment of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
                gDepartment of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, Academic Center for Education, Culture, and Research, Tehran, Iran
                hDepartment of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                iThe Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                jPediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                Author notes
                *Majid Pornour, Academic Center for Education, Culture, and Research, Enghelab St., Aboureyhan St., PO Box 14155-4364, Tehran (Iran),, Davood Mansouri, Masih Daneshvari Hospital, Darabad Avenue, Shahid Bahonar Roundabout, PO Box 19575154, Tehran (Iran), dmansouree@

                M.P. and D.M. contributed equally to this work as corresponding authors. Edited by: H.-U. Simon, Bern.

                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                Page count
                Figures: 3, References: 44, Pages: 9
                Clinical Immunology - Review Article


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