Dilemmas beyond p40: Risankizumab vs. Ustekinumab in Anti-TNF-Refractory Crohn's Disease – Which one to choose?
Review by Dr. Edyta Tulewicz-Marti (Poland)
Study Summary
Among the dilemmas we meet in daily practice is which agent targeting the IL-23 axis to choose, and where each belongs in the treatment sequence—a question that arises particularly often once anti-TNF therapy has been used, as it is first-line in many countries. SEQUENCE addressed this directly and remains the only head-to-head comparison of risankizumab and ustekinumab in Crohn's disease.
SEQUENCE (NCT04524611) was a phase 3b, multicenter, open-label, randomized controlled trial with blinded endpoint assessment. It enrolled 520 adults with moderate-to-severe Crohn's disease and inadequate response or intolerance to at least one anti-TNF agent, randomized 1:1 to risankizumab (600 mg intravenously at weeks 0, 4, and 8, followed by 360 mg subcutaneously every 8 weeks from week 12; n = 255) or ustekinumab (a single weight-based intravenous induction dose, followed by 90 mg subcutaneously every 8 weeks from week 8; n = 265), through week 48. Corticosteroids were tapered from week 2. Two primary endpoints were tested sequentially: clinical remission, defined as a Crohn's Disease Activity Index (CDAI) score below 150, at week 24, assessed for non-inferiority with a margin of 10 percentage points among the first 50% of patients who reached that visit; and endoscopic remission at week 48, defined as a Simple Endoscopic Score for Crohn's Disease of 4 or less with a reduction of at least 2 points from baseline and no individual sub-score above 1, tested for superiority in the full population.
The primary results, published initially in the New England Journal of Medicine in 2024, met both endpoints. Risankizumab was non-inferior to ustekinumab for clinical remission at week 24, achieved by 58.6% versus 39.5% of patients (adjusted difference 18.4 percentage points, 95% CI 6.6 to 30.3), and superior for endoscopic remission at week 48, achieved by 31.8% versus 16.2% (adjusted difference 15.6 percentage points, 95% CI 8.4 to 22.9).1 Treatment completion differed considerably between the arms: 90.2% of patients assigned to risankizumab completed all assigned treatment, compared with 72.8% of those assigned to ustekinumab.
Interestingly, a subsequent post hoc analysis examined corticosteroid-free outcomes among patients receiving corticosteroids at baseline and found the same direction of effect across every endpoint assessed.2 For corticosteroid-free clinical remission by CDAI, the difference favoring risankizumab was 10.5 percentage points at week 24 and 25.4 points at week 48 (p ≤ .01). Defined instead by stool frequency and abdominal pain score, the corresponding differences were 20.4 points at week 24 (p ≤ .001) and 29.2 points at week 48 (p ≤ .01). Corticosteroid-free endoscopic remission favored risankizumab by 23.0 percentage points at week 24 and 20.2 points at week 48 (both P ≤ .01). Moreover, clinical-plus-endoscopic endpoints and quality-of-life outcomes showed the same pattern.
The overall incidence of adverse events was similar between the two arms, and both agents were well tolerated. Notably, exposure-adjusted event rates for serious infection and hypersensitivity were numerically higher in association with concomitant corticosteroid use in both treatment groups.
Commentary
SEQUENCE answered a question clinicians face daily and that placebo-controlled trials cannot address: after anti-TNF failure, which agent next and which one should we use? Its practical importance is reflected in the 2025 ACG guideline, which now prefers risankizumab over ustekinumab in anti-TNF-exposed patients.3
Still, the choice is not that easy to make; in some refractory cases, steroid-free remission is as important as an endoscopic one, which we may not always achieve. In this study, the corticosteroid-sparing analysis is the more clinically persuasive of the two datasets. Steroid-free remission is a harder endpoint than either primary outcome, and the advantage widened between weeks 24 and 48 rather than eroding—the pattern one expects from a genuine maintenance effect rather than an induction artefact. The finding that steroid exposure carried higher serious infection rates regardless of assigned biologic is a useful reminder that steroid withdrawal is a therapeutic target in its own right, not merely a marker of response.
There are still some points which should be discussed. The open-label design is a real concern for CDAI, a symptom-based index susceptible to expectation effects, though endoscopic readings were blinded and the endoscopic result is correspondingly more robust. More importantly, completion rates differed markedly (90.2% vs 72.8%); combined with non-responder imputation, this asymmetry mathematically penalizes the comparator arm. A recent network meta-analysis adjusting for imbalanced discontinuation raised ustekinumab's estimated remission rates substantially and found comparable efficacy across the IL-23 class—a signal that the true gap may be narrower than the headline figures suggest. Finally, the steroid analysis is post hoc and confined to a baseline subgroup. However, due to the availability of biosimilars for ustekinumab in some countries, it may prove both more accessible and more cost-effective.
For an anti-TNF-experienced patient with endoscopically active, steroid-dependent disease, risankizumab is a well-supported first choice. Where cost is the binding constraint, a biosimilar of ustekinumab remains defensible—a decision that is now as much economic as immunological.
Citation
- Peyrin-Biroulet, L., Chapman, J. C., Colombel, J.-F., Caprioli, F., D’Haens, G., Ferrante, M., Schreiber, S., Atreya, R., Danese, S., Lindsay, J. O., Bossuyt, P., Siegmund, B., Irving, P. M., Panaccione, R., Cao, Q., Neimark, E., Wallace, K., Anschutz, T., Kligys, K., … Dubinsky, M. (2024). Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. The New England Journal of Medicine, 391(3), 213–223. https://doi.org/10.1056/NEJMOA2314585
- Peyrin-Biroulet, L., Chapman, J. C., Colombel, J.-F., Caprioli, F., D’Haens, G., Ferrante, M., Schreiber, S., Atreya, R., Danese, S., Lindsay, J. O., Bossuyt, P., Siegmund, B., Irving, P. M., Panaccione, R., Cao, Q., Neimark, E., Wallace, K., Anschutz, T., Kligys, K., … Dubinsky, M. (2024). Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. The New England Journal of Medicine, 391(3), 213–223. https://doi.org/10.1056/NEJMOA2314585
- Lichtenstein, G. R., Loftus, E. V., Afzali, A., Long, M. D., Barnes, E. L., Isaacs, K. L., & Ha, C. Y. (2025). ACG Clinical Guideline: Management of Crohn’s Disease in Adults. The American Journal of Gastroenterology, 120(6), 1225–1264. https://doi.org/10.14309/AJG.0000000000003465
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