Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases

• Published in: Nature reviews. Rheumatology Vol. 12; no. 1; pp. 25 - 36
• Main Authors: Schwartz, Daniella M., Bonelli, Michael, Gadina, Massimo, O'Shea, John J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2016; Nature Publishing Group
• Subjects: 692/4017; 692/420/2780; 692/699/249/1313; Autoimmune diseases; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Autoimmunity; Cytokines; Cytokines - metabolism; Disease; Growth factors; Humans; Immune response; Immune system; Immunology; Immunosuppressive Agents - therapeutic use; Janus kinase; Janus Kinases - drug effects; Janus Kinases - metabolism; Medicine & Public Health; Mutation; Protein Kinase Inhibitors - therapeutic use; Receptors, Cytokine - drug effects; Receptors, Cytokine - metabolism; Remission (Medicine); review-article; Rheumatoid arthritis; Rheumatology; Signal Transduction
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/nrrheum.2015.167

Key Points
Cytokines are major drivers of autoimmunity, and targeting cytokines has revolutionized the treatment of rheumatologic diseases
Despite their success, biologic agents that target key cytokines are not completely effective in all patients
Type I and II cytokines signal through the JAK–STAT pathway, and pharmacological inhibition of this signal transduction pathway with small molecules can block the actions of these cytokines
JAK inhibitors, or Jakinibs, are effective for rheumatoid arthritis and other immune-mediated diseases
Many of the adverse effects of Jakinibs can be linked to action of the cytokines that are blocked
Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested
Cytokines that signal via the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway have diverse roles in normal immune responses as well as immune-mediated diseases. This Review provides an overview of these roles as well as the JAK–STAT pathway, and discusses emerging therapies that block JAKs and the cytokines that signal through them.
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.