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THERAPY IN 2018

Selective Janus kinase inhibitors come of age

Nature Reviews Rheumatology volume 15, pages 74–75 (2019)Cite this article

Subjects

Janus kinase (JAK) inhibitors (jakinibs) that target downstream signalling by a large range of cytokines are effective in treating autoimmune and rheumatic diseases. Newer jakinibs that selectively inhibit individual JAKs and a narrower spectrum of cytokines have now been developed, but how do these inhibitors compare with existing drugs?

Key advances

  • Filgotinib, a JAK1-selective inhibitor, demonstrates efficacy in psoriatic arthritis with no unexpected safety signals1.

  • Filgotinib is efficacious in patients with ankylosing spondylitis who did not respond to nonsteroidal anti-inflammatory drugs2.

  • Two phase III trials demonstrate efficacy of upadacitinib, a selective JAK1, in RA3,4.

JAKs are phosphotransferases that bind to the intracellular domains of cytokine receptors and transmit signals to activate immune responses. The family of cytokines that signal via JAKs includes many interleukins, interferons, colony stimulating factors and hormone-like cytokines (such as erythropoietin). The receptors for these cytokines signal via various combinations of four JAKs (JAK1, JAK2, JAK3 and TYK2). First-generation jakinibs, such as tofacitinib and baricitinib (and oclacitinib in dogs), block more than one JAK, and thereby can inhibit a large number of cytokines; these and other pan-jakinibs are being investigated as therapeutic agents for a wide variety of autoimmune diseases5. Common adverse effects include infection, anaemia, neutropenia, lymphopenia and hyperlipidaemia. These effects are expected owing to the inhibition of multiple JAKs and many cytokines5,6, and the rate of infections in patients treated with these drugs is similar to the rate with other immunosuppressive drugs and biologic agents. Venous thromboembolism occurred in clinical trials of baricitinib at a rate of ~5 events per 1000 patient-years, but whether this rate is significantly different from the background rate is not yet clear. Although the risk–benefit profile of jakinibs has been judged to be acceptable by regulatory agencies, new jakinibs that inhibit the function of fewer cytokines with greater specificity might have fewer adverse effects.

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Fig. 1: Selectivity of JAK inhibitors.

References

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Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institutes of Arthritis and Musculoskeletal and Skin diseases, Bethesda, MD, USA

    John J. O’Shea

  2. Translational Immunology Section, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA

    Massimo Gadina

Authors
  1. John J. O’Shea
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Correspondence to John J. O’Shea.

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Competing interests

J.J.O’S. declares that he and the NIH hold a patent related to JAK inhibition in autoimmune disease and receive royalties from this patent. Both authors declare that they have a Collaborative Research and Development Agreement related to JAK inhibitors with Pfizer.

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O’Shea, J.J., Gadina, M. Selective Janus kinase inhibitors come of age. Nat Rev Rheumatol 15, 74–75 (2019). https://doi.org/10.1038/s41584-018-0155-9

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