Authors: David I. Fudman, Ryan A. McConnell, Christina Ha, and Siddharth Singh
Journal: Clinical Gastroenterology and Hepatology
Year: 2025
Volume: 23
Pages: 454–468
DOI: https://doi.org/10.1016/j.cgh.2024.06.050
Study at a Glance
- Study type: Narrative review
- Participants: Not applicable
- Population studied: Patients with inflammatory bowel disease
- Intervention or approach studied: Janus kinase inhibitors, interleukin-23 antagonists, and sphingosine 1-phosphate receptor modulators
- Comparison group: Not applicable
- Follow-up duration: Not applicable
- Main outcome(s): Practical considerations for use, real-world effectiveness, safety, dosing, monitoring, and positioning of newer advanced therapies
Why was this study done?
Treatment options for inflammatory bowel disease (IBD) have expanded considerably over the past decade. Recent approvals include oral Janus kinase inhibitors (upadacitinib for both Crohn’s disease and ulcerative colitis, and tofacitinib for ulcerative colitis), sphingosine 1-phosphate receptor modulators (ozanimod and etrasimod for ulcerative colitis), and selective interleukin-23 antagonists (risankizumab for Crohn’s disease and mirikizumab for ulcerative colitis). The authors aimed to provide practical guidance on using these newer therapies, synthesising real-world effectiveness, safety, dosing, monitoring requirements, use in special situations, and approaches to selecting between therapies based on individual patient characteristics.
How was the study performed?
The authors conducted a narrative review drawing on clinical experience and published evidence from pivotal trials, real-world studies, and comparative studies. They examined three newer therapy classes, evaluating real-world effectiveness, dosing strategies, onset of action, safety profiles, and specific clinical situations. Treatment algorithms integrating comparative effectiveness and safety with individual patient characteristics were provided.
What did the researchers find?
Janus Kinase Inhibitors
For tofacitinib in ulcerative colitis, real-world effectiveness mirrored clinical trials. A combined analysis of 17 studies (1,162 patients) showed approximately two-thirds achieved response and one-third achieved remission within eight weeks. Real-world studies suggest tofacitinib may be more effective than vedolizumab and ustekinumab in patients with prior tumour necrosis factor antagonist failure.
For upadacitinib, real-world studies showed clinical response and remission rates exceeding 80% in ulcerative colitis and 64% response with 27% remission at three months in Crohn’s disease, despite highly treatment-experienced populations. Upadacitinib may be more effective than tofacitinib and can benefit patients who failed tofacitinib. Both drugs show rapid onset, with many patients improving within one to three days.
Regarding safety, whilst Janus kinase inhibitors carry black-box warnings based on rheumatoid arthritis trials showing increased cardiovascular events, blood clots, cancer, and serious infections, no such risks have been observed in IBD patients in long-term studies, possibly due to younger age and lower smoking rates. Both drugs increase herpes zoster risk in a dose-dependent manner, particularly with corticosteroids. Acne occurs in approximately 20% of patients, especially with higher-dose upadacitinib.
Interleukin-23 Antagonists
For risankizumab in Crohn’s disease, Belgian and French real-world studies of highly treatment-experienced patients showed 62% to 79% clinical response and 18% to 46% steroid-free remission. In head-to-head comparison with ustekinumab, risankizumab achieved superior clinical remission at week 24 (59% versus 40%) and endoscopic remission at week 48 (32% versus 16%). For ulcerative colitis, 21% achieved remission versus 6% with placebo at week 12.
For mirikizumab in ulcerative colitis, week 12 results showed clinical response (64% versus 42% placebo), clinical remission (24% versus 15%), and endoscopic remission (36% versus 21%). Among week 12 responders continuing treatment, 51% and 58% achieved clinical remission and endoscopic improvement at week 52. In Crohn’s disease, mirikizumab was superior to placebo (clinical remission 54% versus 20%) and similar to ustekinumab (54% versus 48%) at week 52.
Risankizumab showed early response, with 13% achieving symptomatic remission and 33% significant improvement within two weeks. Interleukin-23 antagonists appear safe with low rates of serious infection, major adverse cardiovascular events, and cancer. Common adverse events included upper respiratory infections, joint pain, injection site reactions, rash, headache, and urinary infections in approximately 3% to 14% across trials.
Sphingosine 1-Phosphate Receptor Modulators
For ozanimod in ulcerative colitis, week 10 results showed superiority over placebo for clinical remission (18% versus 6%), clinical response (48% versus 26%), endoscopic improvement (27% versus 12%), and mucosal healing (13% versus 4%). Effectiveness was higher in biologic-naive patients. Real-world study (45 patients) showed 53% clinical remission at week 10 and 25% at week 52.
For etrasimod, week 12 results showed clinical remission (25% to 27% versus 7% to 15% placebo), clinical response (62% versus 34% to 41%), and endoscopic improvement (31% to 35% versus 14% to 19%). Week 52 results showed clinical remission (32% versus 7%) and endoscopic improvement (39% versus 13%).
Absolute lymphocyte count decreases approximately 50% but remains stable. These medications may marginally increase blood pressure and decrease heart rate, though symptomatic bradycardia is rare. Ozanimod requires first-week dose titration to reduce bradycardia risk.
What did the authors conclude?
For Crohn’s disease, infliximab and adalimumab are probably most effective for biologic-naive patients, particularly with complicated disease. Ustekinumab and risankizumab are reasonable alternatives for moderate disease with superior safety profiles. After tumour necrosis factor antagonist failure, risankizumab and upadacitinib are likely most effective, with risankizumab superior to ustekinumab.
For ulcerative colitis, excluding upadacitinib (limited to use after tumour necrosis factor antagonist failure), infliximab and vedolizumab are probably most effective for biologic-naive patients. Vedolizumab is preferred for moderate, steroid-dependent disease without short-term hospitalisation risk; infliximab is preferred for severe disease requiring rapid onset. Ozanimod and etrasimod are effective first-line oral therapies after 5-aminosalicylic acid failure, though effectiveness reduces after other advanced therapy failure. After vedolizumab failure, infliximab is generally preferred. After infliximab failure in severe disease, upadacitinib is preferred for high effectiveness and rapid onset.
The authors acknowledged that future head-to-head trials and precision medicine initiatives will help more accurately select and position therapies.
Key Takeaways
- Real-world studies confirm newer advanced therapies for IBD are effective in patients who have failed previous treatments.
- Janus kinase inhibitors offer rapid onset (one to three days), though require monitoring for infections, particularly herpes zoster, and are associated with acne in approximately 20% of patients.
- In head-to-head trials, risankizumab was more effective than ustekinumab in Crohn’s disease, achieving clinical remission in 59% versus 40% at week 24.
- Safety concerns from rheumatoid arthritis patients (cardiovascular events, blood clots) have not been observed in IBD patients, possibly due to younger age and lower smoking rates.
- Selecting between newer therapies should integrate comparative effectiveness and safety evidence with individual patient characteristics, including disease severity, previous responses, coexisting conditions, and patient preferences.
This Scientific Publication Summary is an objective summary of the published study for personal and educational use. It does not constitute medical advice, endorsement of the intervention, or a recommendation to alter clinical practice.