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  • Review Article
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JAK–STAT pathway targeting for the treatment of inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 17, pages 323–337 (2020)Cite this article

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Abstract

Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn’s disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK–STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.

Key points

  • Cytokines contribute to both normal intestinal homeostasis and pathological processes associated with the chronic and relapsing (acute) nature of inflammatory bowel disease (IBD).

  • Therapies targeting individual pro-inflammatory cytokines have revolutionized the treatment of IBD, although many patients are unresponsive or lose response to therapy.

  • The Janus kinase (JAK) tyrosine kinases and signal transducer and activator of transcription (STAT) DNA-binding proteins mediate the signalling and downstream biological effects in response to cytokine receptor binding, including several effects involved in IBD pathology.

  • Small-molecule JAK inhibitors, which have the potential to affect multiple cytokine-dependent pathways, have been shown to be efficacious in treating IBD.

  • However, the degeneracy of JAK-mediated signalling and the targeting of multiple cytokine pathways could increase the potential for unpredictable effects (including adverse effects).

  • New approaches such as selective or gut-specific JAK inhibitors, and a greater understanding of disease-specific mechanisms of action to facilitate personalized approaches to treatment, could improve the risk–benefit profiles of this class of therapy.

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Fig. 1: Distinct intracellular signalling pathways mediated by the JAK family of tyrosine kinases.
Fig. 2: Pleiotropic role of JAK-associated receptors in IBD.
Fig. 3: Management of potential adverse events associated with JAK inhibition.

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Acknowledgements

The authors thank L. M. Shackelton for technical review and editing, and M. Andic for editorial assistance.

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Authors and Affiliations

  1. Department of Gastroenterology, IDIBAPS, Barcelona, Spain

    Azucena Salas

  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

    Azucena Salas

  3. Zane Cohen Center for Digestive Diseases, Mount Sinai Hospital Inflammatory Bowel Disease Group, Toronto, Ontario, Canada

    Cristian Hernandez-Rocha

  4. Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Marjolijn Duijvestein

  5. Gastroenterology and Hepatology, Mayo Clinic, Rochester, MI, USA

    William Faubion

  6. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dermot McGovern

  7. Department of Gastroenterology, University Hospitals Leuven, KU Leuven, Leuven, Belgium

    Severine Vermeire

  8. Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Stefania Vetrano

  9. IBD Center, Laboratory of Immunology in Gastroenterology, Humanitas Clinical and Research Center IRCCS, Milan, Italy

    Stefania Vetrano

  10. Robarts Clinical Trials, London, ON, Canada

    Niels Vande Casteele

  11. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Niels Vande Casteele

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  1. Azucena Salas
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The authors contributed equally to all aspects of the article.

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Correspondence to Niels Vande Casteele.

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Competing interests

A.S. reports research grants from Roche, Genentech, Boehringer Ingelheim and AbbVie, lecture fees from Roche, Boehringer Ingelheim and Pfizer, and consultancy fees from Genentech and GSK; M.D. reports advisory fees from Echo Pharma and Robarts Clinical Trials, speaker fees from Janssen, Merck, Pfizer, Takeda and Tillotts Pharma, and nonfinancial support from Dr. Falk Pharma. W.F. reports consulting or advisory fees from AbbVie, Boehringer Ingelheim Pharma, MediBeacon, Celegene, Janssen Research and Development, Robarts Clinical Trials, Takeda Pharma, Eli Lily, Hire, Velocity Pharma, S&B Pharms and Connecticut Children’s Medical Center. D.M. reports consulting fees from Pfizer, Gilead, Janssen, Qu Biologics, Bridge Therapeutics, Precision IBD, and grant support from Janssen, and Second Genome. S.Vermeire reports grants/research support from MSD, AbbVie, Takeda, Janssen, and Pfizer, honoraria or consultation fees from AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, Progenity, Lilly, Arena, Gilead and Janssen, participation on speaker’s bureaus for AbbVie, MSD, Takeda, Ferring, Hospira, Pfizer, Janssen and Tillots, and employment of spouse by Biogen. N.V.C. reports research support from R-Biopharm and Takeda and consulting fees from Boehringer Ingelheim, Janssen, Pfizer, Progenity, Prometheus and Takeda, outside of the submitted work. C.H.-R. and S. Vetrano declare no competing interests.

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Salas, A., Hernandez-Rocha, C., Duijvestein, M. et al. JAK–STAT pathway targeting for the treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 17, 323–337 (2020). https://doi.org/10.1038/s41575-020-0273-0

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