title: JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects.
abstract: 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.
authors.affiliation: Rheumatology Fellowship and Training Branch, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. shubhasree.banerjee@nih.gov.
authors.forename: Shubhasree
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Biehl
authors.affiliation: Translational Immunology Section, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Lupus Clinical Research Program, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sarfaraz
authors.initials: S
authors.lastname: Hasni
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Daniella M
authors.initials: DM
authors.lastname: Schwartz
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D053612:Janus Kinases