User's guide to JAK inhibitors in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), are remitting and relapsing disorders of the gastrointestinal tract, highlighted by the dysregulation of pro- and anti-inflammatory mediators, which lead to mucosal damage. These conditions cause a significant burden worldwide as primary and secondary treatment failure rates remain high even with our current therapeutic options. This emphasizes the need for continued advancement in treatment efficacy with improved safety profiles. Novel disease-targeting therapeutics have been developed, most recently being the Janus kinase inhibitors (JAKi). JAKi serve as a promising new class of non-immunogenic small molecule inhibitors that modulate inflammatory pathways by blocking the critical role that Janus kinase (JAK) proteins play in mediating the innate and adaptive immune responses. Tofacitinib has been shown to be therapeutically efficacious, to have a tolerable safety profile, and to be available for adult patients with moderate-to-severe UC. This review was designed to serve as an overview and as practical guidance for medical practitioners. Author recommendations and appraisals of the quality of evidence throughout this article are based solely on personal opinion and are not the outcome of a formal methodology followed by a consensus group.

Keywords: Biologic; Efficacy; Janus kinase inhibitors; Safety; Tofacitinib; Ulcerative colitis.

Graphical abstract

Fig. 1

(Color) Overview of the steps involved in cytokine signaling via the Janus kinase pathway and the therapeutic target for JAK inhibitors. Cytokines bind to cell-surface receptors; after ligand stimulation, receptors undergo conformational changes, and JAKs become approximated. Paired JAKs and receptors undergo phosphorylation which allows STATs to bind to the receptor. Activated JAKs then phosphorylate docked STATs. Activated STATs then dimerize and migrate to the nucleus, where they act as transcription factors that bind DNA and regulate gene transcription. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)