title: Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.
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.
authors.affiliation: Molecular Immunology &Inflammation Branch, and Translational Immunology Section, National Institute of Arthritis &Musculoskeletal and Skin Diseases, NIH, Building 10, 9000 Rockville Pike, Bethesda, Maryland 20892-1616, USA.
authors.forename: Daniella M
authors.initials: DM
authors.lastname: Schwartz
authors.affiliation: Medical University of Vienna, Department of Rheumatology, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonelli
authors.affiliation: Molecular Immunology &Inflammation Branch, and Translational Immunology Section, National Institute of Arthritis &Musculoskeletal and Skin Diseases, NIH, Building 10, 9000 Rockville Pike, Bethesda, Maryland 20892-1616, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Molecular Immunology &Inflammation Branch, and Translational Immunology Section, National Institute of Arthritis &Musculoskeletal and Skin Diseases, NIH, Building 10, 9000 Rockville Pike, Bethesda, Maryland 20892-1616, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053612:Janus Kinases / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D018121:Receptors, Cytokine / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D018121:Receptors, Cytokine; D053612:Janus Kinases