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JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?
  1. Silvio Danese1,2,
  2. Marjorie Argollo2,3,
  3. Catherine Le Berre4,
  4. Laurent Peyrin-Biroulet5,6
  1. 1IBD Centre, Humanitas Clinical Research Centre, Rozzano, Milan, Italy
  2. 2Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
  3. 3Gastroenterology, Universidade Federal de São Paulo, São Paulo, Brazil
  4. 4Gastroenterology, Nancy-Universite, Nancy, Lorraine, France
  5. 5Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-lès-Nancy, France
  6. 6Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France
  1. Correspondence to Prof Silvio Danese, Istituto Clinico Humanitas, Rozzano 20089, Italy; sdanese{at}hotmail.com

Abstract

The two major forms of inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions characterised by an increased production of pro-inflammatory cytokines that act as critical drivers of intestinal inflammation. Anti-cytokine therapy has been shown to improve clinical outcomes in IBD. Janus kinases (JAKs) are tyrosine kinases that bind different intracellular cytokine receptors, leading to phosphorylation of signal transducer and activation of transcription molecules implicated on targeted gene transcription. Four isoforms of JAKs have been described: JAK1, JAK2, JAK3 and TYK2. Oral JAK inhibitors (JAKi) have been developed as synergic anti-cytokine therapy in IBD, showing different selectivity towards JAK isoforms. Tofacitinib, a pan-JAK inhibitor, has been recently approved for the treatment of moderate-to-severe UC. With the aim of improving the benefit: risk ratio of this drug class, several second-generation subtype-selective JAKi are under development. However, whether selective inhibition of JAK isoforms is associated with an increased clinical efficacy and/or a better safety profile remains debatable. The aim of this review is to critically review the preclinical and clinical data for the differential selectivity of JAK inhibitors and to summarise the potential clinical implications of the selective JAK inhibitors under development for UC and CD.

  • crohn’s disease
  • ulcerative colitis
  • inflammatory bowel disease
  • drug development
  • IBD clinical
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Footnotes

  • Contributors All authors contributed to this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The acknowledgement statement has been updated.

  • Patient consent for publication Not required.

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