The therapeutic landscape for moderately to severely active inflammatory bowel disease (IBD) has expanded significantly. It incorporates three novel mechanisms of action: Anti-interleukins, JAK inhibitors, and S1P receptor modulators.
Anti-interleukins
Selective IL23 antagonists—risankizumab (SKYRIZI), guselkumab (TREMFYA), and mirikizumab (OMVOH)—are FDA-approved for moderately to severely active IBD. Compared to ustekinumab (STELARA), which targets the p40 subunit shared by both IL12 and IL23 cytokines, these agents target the p19 subunit specific to IL23, which drives chronic inflammation through Th17 cells. Data suggests potential superiority over ustekinumab in Crohn’s disease (based on the GALAXI studies1,2), including in anti-TNF exposed patients (based on the SEQUENCE study3).
Administration of these agents involves induction via infusion(s) or subcutaneous injections, followed by subcutaneous maintenance injections. Patient assistance programs are available through manufacturers. Risankizumab and guselkumab are also approved for use with plaque psoriasis and psoriatic arthritis. Adverse events primarily include non-serious upper respiratory infections and rarely injection or infusion reactions.
JAK Inhibitors
Upadacitinib (RINVOQ), a second-generation JAK inhibitor, is approved for moderately to severely active IBD. In contrast to tofacitinib (a pan-JAK inhibitor), upadacitinib has more JAK1 selectivity to help mediate downstream cytokines driving chronic inflammation. Advantages include rapid onset, short half-life (beneficial for acute severe ulcerative colitis), lack of immunogenicity, and oral administration. Upadacitinib is also approved for rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.
As of 2025, FDA updated the use of upadacitinib for IBD after usage of at least one systemic therapy (not exclusively TNF antagonists). These agents are used with caution in older patients and those with cardiovascular risk factors, thromboembolic history, or malignancy risk factors. The ORAL Surveillance study showed increased cardiovascular events and malignancy with tofacitinib in high-risk rheumatoid arthritis patients4, though UC studies haven’t clearly demonstrated this risk. Additional concerns include herpes zoster, anemia, leukopenia, elevated lipids, and abnormal liver function. Safety in pregnancy is unknown and its use is not recommended.
S1P Modulators
Ozanimod (ZEPOSIA) and etrasimod (VELSIPITY) are oral agents approved for moderately to severely active ulcerative colitis and multiple sclerosis (ozanimod). They prevent lymphocyte migration by internalizing S1P receptors and lack immunogenicity.
Contraindications include recent myocardial infarction, stroke, severe obstructive sleep apnea, advanced heart failure, certain arrhythmias, and MAO inhibitor use. Risks include cardiac arrhythmias (bradyarrhythmia, AV conduction delays), respiratory infections, herpes zoster, liver injury, macular edema (especially with uveitis or diabetes history), cutaneous malignancies, and rarely neurologic complications. Safety in pregnancy is unknown and its use is not recommended.
References
- Sandborn WJ, et al. Guselkumab for the Treatment of Crohn’s Disease: Induction Results From the Phase 2 GALAXI-1 Study. Gastroenterology 2022; 162:1650-1664.
- Danese S et al. Efficacy and safety of 48 weeks of guselkumab for patients with Crohn’s disease: maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial. Lancet Gastro Hep 2024; 9:133-46.
- Peyrin-Biroulet L, et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. NEJM 2024;391:213-23.
- Ytterberg, SR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. NEJM 2022; 386: 315-326. https://www.nejm.org/doi/full/10.1056/NEJMoa2109927