State-of-the-Art Evidence for Clinical Outcomes and Therapeutic Implications of Janus Kinase Inhibitors in Moderate-to-Severe Ulcerative Colitis: A Narrative Review

Abstract

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing inflammation and incomplete response to conventional therapies. Although biologics have advanced UC management, many patients with moderate-to-severe disease experience treatment failure, relapse, or adverse effects. This review evaluates the pharmacology, efficacy, and safety of oral Janus kinase (JAK) inhibitors-tofacitinib, upadacitinib, and filgotinib-to guide their clinical use in UC. Methods: A comprehensive literature review was conducted using the PubMed, Embase, Cochrane, and Web of Science databases to identify relevant studies on JAK inhibitors in UC. The review included Phase 3 randomized controlled trials (RCTs), real-world observational studies, and recent network meta-analyses. We assessed pharmacologic profiles, clinical efficacy, and safety data for tofacitinib, upadacitinib, and filgotinib. Additionally, we reviewed emerging pipeline agents and future directions in oral immunomodulatory therapy for UC. Results: All three agents demonstrated efficacy in the induction and maintenance of remission. Upadacitinib showed superior performance, including rapid symptom control, high clinical remission rates, and favorable long-term outcomes in both biologic-naïve and -experienced patients. Tofacitinib offered strong efficacy, particularly in early response, but was associated with higher risks of herpes zoster and thromboembolic events. Filgotinib provided moderate efficacy with a favorable safety profile, making it suitable for risk-averse populations. Meta-analyses consistently ranked upadacitinib highest in clinical efficacy and onset of action. Conclusions: JAK inhibitors offer effective and convenient oral treatment options for moderate-to-severe UC. Upadacitinib emerges as a high-efficacy agent; tofacitinib and filgotinib remain valuable based on patient-specific risk profiles. Future studies are needed to clarify optimal sequencing, long-term safety, and the role of emerging agents or combination therapies.

Keywords: Janus kinase inhibitors; filgotinib; narrative review; tofacitinib; ulcerative colitis; upadacitinib.

Figure 1

JAK-STAT pathway activation and intracellular signaling. Purple arrows represent the direction of intracellular signal transduction. Activation of the JAK-STAT signaling pathway: (1) A cytokine or growth factor binds to its specific cell surface receptor; (2) The receptor dimerizes and activates associated JAKs by phosphorylation; (3) JAKs phosphorylate tyrosine residues on the receptor, creating docking sites for STATs; (4) STATs are phosphorylated by JAKs, dissociate from the receptor, and form STAT dimers; (5) STAT dimers translocate to the nucleus, modulating gene transcription. Abbreviations: JAK, Janus kinase; STAT, signal transducer and activator of transcription; P, phosphorylation.