Updated review of Janus kinase inhibitors for the management of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) management has evolved with the advent of Janus kinase inhibitors (JAKi), oral small molecules that modulate cytokine-driven inflammation via the Janus kinase-signal transducer and activator of transcription pathway. This narrative review synthesizes current evidence for JAKi in ulcerative colitis (UC) and Crohn’s disease (CD), detailing their efficacy, safety, positioning, and special contexts. Tofacitinib has demonstrated robust induction and maintenance efficacy in moderate-to-severe UC, including steroid-refractory and acute severe cases, while failing to meet endpoints in CD. Upadacitinib shows high rates of clinical, endoscopic, and durable remission in both UC and CD across pivotal trials, and emerging real-world data support its superiority in certain refractory settings. Filgotinib is effective in UC, with more limited but promising data in CD. Safety concerns span infectious complications (notably herpes zoster), cytopenias, dyslipidemia, thromboembolic risk, and potential impacts on pregnancy and lactation; long-term data remain largely extrapolated from rheumatologic cohorts. Combination regimens with other biologics have been explored but warrant caution due to additive immunosuppression. Data on pediatric IBD and extraintestinal manifestations are nascent. Limitations include sparse long-term safety data specific to IBD, unclear carcinogenesis implications, and reliance on indirect comparisons for positioning. Despite these gaps, JAKi - particularly tofacitinib and upadacitinib - offer effective alternatives in biologic-experienced and refractory IBD, with careful patient selection, screening, and monitoring essential to mitigate risks. Future prospective studies should clarify optimal sequencing, long-term safety, and gut-selective strategies.

Keywords: Janus kinase inhibitors; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease

Core Tip: Janus kinase inhibitors are reserved for moderate-to-severe inflammatory bowel disease (IBD) after biologic failure or steroid dependence. Carefully selecting patients based on their cardiovascular, thromboembolic, and infection-related risks is of paramount importance. Tofacitinib is an excellent choice for patients with moderate to severe ulcerative colitis (UC) and acute severe UC. Upadacitinib is currently approved for both refractory UC and Crohn’s disease (CD); however, emerging data suggest its beneficial role in acute severe UC. Limited evidence exists for the combination of small molecules and other biologicals in patients with difficult-to-treat IBD and peri-anal CD. Close monitoring of side effects is advocated in such patients. More data is warranted on their role in extraintestinal manifestations, pediatric and pregnant patients with IBD.