Bridging the gap between guidelines and practice: comparative effectiveness of ustekinumab and vedolizumab in Crohn’s disease

Selecting the optimal biologic for patients with moderate to severe Crohn’s disease (CD) is one of the most consequential decisions in gastroenterology practice. The 2025 American Gastroenterological Association (AGA) Living Clinical Practice Guideline provides a tiered framework for treatment positioning.¹ In therapy-naive patients, ustekinumab and vedolizumab are both classified as higher-efficacy options. However, in patients previously exposed to advanced therapies, vedolizumab is reclassified as a lower-efficacy treatment alongside certolizumab pegol, while ustekinumab retains its intermediate-efficacy designation.¹

In this evolving guideline landscape, the study by Eldesouki et al provides timely real-world data that reinforce this positioning.² Using the TriNetX US Collaborative Network, the authors conducted a propensity score-matched retrospective cohort study comparing ustekinumab and vedolizumab in more than 8000 matched patients with CD, stratified by prior anti–tumor necrosis factor (TNF) exposure.² Their principal finding was that ustekinumab is associated with significantly lower corticosteroid exposure at 12 and 24 months in both anti-TNF–naive and anti-TNF–exposed populations, which addresses a clinically meaningful endpoint. Corticosteroid sparing is a cornerstone treatment goal in CD, as prolonged steroid use is associated with well-documented toxicities, and steroids are ineffective as maintenance therapy.^3,4 The consistency of the steroid-sparing signal across all four subgroup analyses with adjusted hazard ratios ranging from 0.71 to 0.73 strengthens the reliability of these findings. The secondary outcomes (fewer emergency department visits and, in the anti-TNF–exposed cohort, fewer hospitalizations) underscore the clinical relevance.

The study’s sample size is among the largest in the comparative effectiveness literature for these two agents, exceeding the total patient population across all 14 studies included in a recent systematic review.⁵ These results are consistent with the 2025 AGA evidence synthesis, in which a network meta-analysis of 28 induction and 22 maintenance trials ranked ustekinumab higher than vedolizumab for the induction of remission in biologic-naive patients.⁶ Prior real-world studies yielded largely concordant findings: Yang et al demonstrated higher steroid-free remission with ustekinumab at weeks 26 and 52 in both anti-TNF–naive and anti-TNF–exposed subgroups, and Kappelman et al reported lower hospitalization rates with ustekinumab in anti-TNF–experienced patients.^7,8 The present study extends this evidence with the largest matched cohort to date and 24-month follow-up.

For the practicing clinician, several aspects deserve attention. The stratification by anti-TNF exposure status is directly applicable to clinical decision-making, as the choice between these agents often arises at precisely this juncture. The 2025 AGA guideline’s classification of vedolizumab as lower efficacy in biologic-exposed patients may help clinicians prioritize ustekinumab or newer IL-23 inhibitors in this population.^1,6 The 60-day washout period before outcome assessment and the requirement of at least three medication refills are thoughtful methodological choices that make the results more reflective of real-world maintenance-phase effectiveness.

Limitations should be acknowledged. The analysis lacks granular data on disease phenotype, endoscopic outcomes, and validated disease activity indices. Confounding by indication remains a concern, as vedolizumab may be preferentially prescribed for colonic disease or patients at risk for infection, while ustekinumab may be selected for systemic inflammation. The corticosteroid outcome, while clinically relevant, does not capture mucosal healing. The authors appropriately frame their conclusions as associative rather than causal.

In summary, this large real-world study adds meaningful evidence consistent with the 2025 AGA guideline’s tiered positioning of these agents. The findings provide clinicians with additional data to support individualized biologic selection, particularly for patients in whom minimizing steroid exposure and reducing emergency healthcare encounters are prioritized treatment goals.

—Rajesh R. Shah, MD
Division of Gastroenterology, Baylor Scott & White
Medical Center–Buda, Buda, Texas, USA
Rajesh.shah@bswhealth.org
http://orcid.org/0000-0002-2318-3714