Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases
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TLDR
The ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.Abstract:
Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.read more
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Journal ArticleDOI
JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.
Daniella M. Schwartz,Yuka Kanno,Alejandro V. Villarino,Michael E. Ward,Massimo Gadina,John J. O'Shea +5 more
TL;DR: The biology of JAKs is discussed 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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Kinase inhibitors: the road ahead
TL;DR: An overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors are provided.
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Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch
Landon K. Oetjen,Madison R. Mack,Jing Feng,Timothy M. Whelan,Haixia Niu,Changxiong J. Guo,Sisi Chen,Anna M. Trier,Amy Z. Xu,Shivani V. Tripathi,Jialie Luo,Xiaofei Gao,Lihua Yang,Samantha L. Hamilton,Peter L. Wang,Jonathan R. Brestoff,Richard Brasington,Andras Schaffer,Frank Brombacher,Chyi-Song Hsieh,Robert W. Gereau,Mark J. Miller,Zhou-Feng Chen,Hongzhen Hu,Steve Davidson,Qin Liu,Brian S. Kim +26 more
TL;DR: An evolutionarily conserved paradigm is revealed in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior, including chronic itch.
Journal ArticleDOI
The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells
Farhad Seif,Majid Khoshmirsafa,Hossein Aazami,Monireh Mohsenzadegan,Gholam Reza Sedighi,Mohammad Ali Bahar +5 more
TL;DR: This review represents how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail and introduces novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders.
Journal ArticleDOI
Erratum to: JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects
TL;DR: The JAK–STAT pathway is described, its role in autoimmunity is outlined, and the rationale/pre-clinical evidence for targeting JAK-STAT signaling is explained, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation JakinIBs.
References
More filters
Journal ArticleDOI
Systematic review and meta-analysis
TL;DR: In this review the usual methods applied in systematic reviews and meta-analyses are outlined, and the most common procedures for combining studies with binary outcomes are described, illustrating how they can be done using Stata commands.
Journal ArticleDOI
The pathogenesis of rheumatoid arthritis.
Iain B. McInnes,Georg Schett +1 more
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
A Systematic Review and Meta-analysis
TL;DR: A systematic review of studies published from January 1, 1950, through November 31, 2008 using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews found that randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.
Journal ArticleDOI
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
Andre Franke,Dermot P.B. McGovern,Jeffrey C. Barrett,Kai Wang,Graham L. Radford-Smith,Tariq Ahmad,Charlie W. Lees,Tobias Balschun,James Lee,Rebecca L. Roberts,Carl A. Anderson,Joshua C. Bis,Suzanne Bumpstead,David Ellinghaus,Eleonora M. Festen,Michel Georges,Todd Green,Talin Haritunians,Luke Jostins,Anna Latiano,Christopher G. Mathew,Grant W. Montgomery,Natalie J. Prescott,Soumya Raychaudhuri,Jerome I. Rotter,Philip Schumm,Yashoda Sharma,Lisa A. Simms,Kent D. Taylor,David C. Whiteman,Cisca Wijmenga,Robert N. Baldassano,Murray L. Barclay,Theodore M. Bayless,Stephan Brand,Carsten Büning,Albert Cohen,Jean Frederick Colombel,Mario Cottone,Laura Stronati,Ted Denson,Martine De Vos,Renata D'Incà,Marla Dubinsky,Cathryn Edwards,Timothy H. Florin,Denis Franchimont,Richard B. Gearry,Jürgen Glas,Jürgen Glas,Jürgen Glas,André Van Gossum,Stephen L. Guthery,Jonas Halfvarson,Hein W. Verspaget,Jean-Pierre Hugot,Amir Karban,Debby Laukens,Ian C. Lawrance,Marc Lémann,Arie Levine,Cécile Libioulle,Edouard Louis,Craig Mowat,William G. Newman,Julián Panés,Anne M. Phillips,Deborah D. Proctor,Miguel Regueiro,Richard K Russell,Paul Rutgeerts,Jeremy D. Sanderson,Miquel Sans,Frank Seibold,A. Hillary Steinhart,Pieter C. F. Stokkers,Leif Törkvist,Gerd A. Kullak-Ublick,David C. Wilson,Thomas D. Walters,Stephan R. Targan,Steven R. Brant,John D. Rioux,Mauro D'Amato,Rinse K. Weersma,Subra Kugathasan,Anne M. Griffiths,John C. Mansfield,Severine Vermeire,Richard H. Duerr,Mark S. Silverberg,Jack Satsangi,Stefan Schreiber,Judy H. Cho,Vito Annese,Hakon Hakonarson,Mark J. Daly,Miles Parkes +97 more
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.