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

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

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.

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Figure 1: Cytokines are grouped into superfamilies based on shared structural elements of the receptors they bind.
Figure 2: Type I and II cytokines (red), which are blocked by Jakinibs, are major drivers of autoimmune diseases such as rheumatoid arthritis.
Figure 3: JAKs are composed of several key domains including a tyrosine kinase domain, pseudokinase domain, FERM (band four-point-one, ezrin, radixin, moesin) domain, and SH2 (Src homology 2) domain.

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Acknowledgements

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.

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All authors researched the data, provided a substantial contribution to discussions of the content, contributed to writing the article, and reviewed/edited the manuscript before submission.

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Correspondence to Daniella M. Schwartz.

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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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Schwartz, D., Bonelli, M., Gadina, M. et al. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 12, 25–36 (2016). https://doi.org/10.1038/nrrheum.2015.167

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