Are All Janus Kinase Inhibitors for Inflammatory Bowel Disease the Same?

Abstract

Ulcerative colitis and Crohn's disease are chronic, progressive inflammatory bowel diseases (IBDs) and are without a known cure. Janus kinase (JAK) is a family of cytosolic tyrosine kinases that mediate signal transduction in response to extracellular stimuli. Abrogating the proinflammatory cytokine signaling cascades using JAK inhibitors (jakinibs) has been shown to be highly effective in the treatment of numerous inflammatory diseases, including IBD. Jakinibs currently licensed for moderate-to-severe IBD include the first-generation, nonselective tofacitinib and the second-generation JAK1-selective inhibitors filgotinib (licensed outside of the United States) and upadacitinib; several other jakinibs in the therapeutic pipeline are in various stages of clinical development. The jakinib class of small-molecule drugs share numerous commonalities such as their oral administration, nonimmunogenicity, short half-life, rapid onset of action, and the same class-wide regulatory restrictions owing to safety concerns. However, jakinibs differ on several fronts, translating into important clinical practice points for health care providers managing IBD patients. This article provides an overview of the jakinib class in IBD, examines how each drug differs in terms of pharmacology as well as efficacy and safety, and offers perspectives on challenges that remain and future opportunities.

Keywords: Crohn’s disease; Janus kinase inhibitors; inflammatory bowel disease; selectivity; ulcerative colitis.

Figure.

Activation of the JAK-STAT pathway and key cellular processes regulated. EPO, erythropoietin; G-CSF, granulocyte-colony stimulating factor; GH, growth hormone; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; OSM, oncostatin M; P, phosphate; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; Treg, regulatory T; TYK2, nonreceptor tyrosine-protein kinase 2.