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 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.
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The work of D.M.S., M.G. and J.J.O'S. is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH.
J.J.O'S. declares that he and the US Government receive royalties based on patents related to targeting Janus kinases. J.J.O'S. and M.G. and the US Government have had longstanding Cooperative Research and Development Agreements with Pfizer, which produces tofacitinib, a Janus kinase inhibitor.
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