Skyrizi and Stelara are two interleukin-pathway biologics for moderate-to-severe Crohn's disease, and until recently the choice between them was largely mechanistic speculation. That changed with the SEQUENCE trial, a rare head-to-head randomized study that directly compared risankizumab (Skyrizi) with ustekinumab (Stelara) in Crohn's patients who had failed an anti-TNF. The results have reshaped how many gastroenterologists think about IL-23 targeting and have moved Skyrizi toward the front of the line for biologic-experienced Crohn's disease. This guide walks through the SEQUENCE findings and the practical decisions patients need to make with their GI.
IL-23 p19 vs IL-12/23 p40
Skyrizi (risankizumab) binds the p19 subunit of interleukin-23, selectively blocking IL-23 signaling. Stelara (ustekinumab) binds the p40 subunit shared by IL-12 and IL-23, so it blocks both cytokines. The clinical rationale for p19 selectivity is that IL-23 is the dominant driver of pathogenic T-cell subsets in Crohn's, while IL-12 plays a broader immune role that may be unnecessary to block. By sparing IL-12 and narrowing the target to IL-23, p19-selective biologics theoretically deliver the efficacy of ustekinumab with a cleaner safety profile and potentially stronger endoscopic outcomes. SEQUENCE was designed to test that hypothesis directly.
The SEQUENCE Trial Results
SEQUENCE was a phase 3 head-to-head trial of 520 adults with moderate-to-severe Crohn's disease who had failed at least one anti-TNF. Patients were randomized to risankizumab or ustekinumab and followed for 48 weeks. At week 24, 59% of Skyrizi patients achieved clinical remission compared with 40% of Stelara patients, a statistically significant difference. At week 48, Skyrizi was superior on the key endoscopic endpoint, with 32% endoscopic remission versus 16% for Stelara. Biologic-defined remission (a composite of clinical and biomarker measures) was 46.3% on Skyrizi versus 27.5% on Stelara at week 48. SEQUENCE was the first head-to-head trial to show clear superiority of one IL-pathway biologic over another in Crohn's, and the endoscopic outcome gap was large enough to shift prescribing practice.
Who Benefits Most From Switching
The SEQUENCE population was anti-TNF experienced, so the trial directly applies to Crohn's patients who have lost response to Humira, Remicade, Cimzia, or another anti-TNF. For biologic-naive patients, head-to-head data is not yet available, though real-world cohorts suggest similar patterns with p19 selectivity outperforming older p40 blockade. Patients who have already been on Stelara with partial response face a more nuanced decision. Some of these patients do gain additional benefit by switching to Skyrizi because of the mechanistic shift, while others may have disease phenotypes that do not respond well to either IL-23 targeting. Your GI may consider therapeutic drug monitoring or endoscopic assessment before recommending a switch from Stelara to Skyrizi.
Safety Profiles
Both drugs have favorable safety profiles relative to anti-TNFs. In SEQUENCE, rates of serious adverse events were similar between the two arms, and no new safety signals emerged for either drug. Both carry boxed warnings related to serious infections, both require TB and hepatitis B screening before starting, and both are typically used as monotherapy without an immunomodulator. Long-term safety data for Skyrizi is shorter than for Stelara simply because Stelara has been on the market longer, but the psoriasis indication for both drugs has generated extensive safety data that supports their use in IBD. For skyrizi vs stelara side effects, the most notable practical difference tends to be injection-site reactions, which are comparable in frequency between the two drugs.
Dosing and Administration
Skyrizi for Crohn's uses IV induction at weeks 0, 4, and 8 (600 mg per infusion), followed by subcutaneous maintenance of 360 mg every 8 weeks. Stelara uses a single weight-based IV induction dose, then 90 mg subcutaneous every 8 weeks. For patients comparing long-term convenience, both drugs share an every-8-week SC maintenance cadence. Skyrizi's three-infusion induction is a bigger up-front commitment than Stelara's single infusion. Patients evaluating practical fit often weigh that early IV schedule against the later efficacy benefits demonstrated in SEQUENCE. Once patients are on maintenance SC dosing, administration is similar between the two drugs.
Cost and Access
Both drugs are branded biologics without US biosimilars, and both are expensive. Insurance coverage, manufacturer copay assistance, and formulary preference often determine which drug is easier to access. Skyrizi's relatively recent Crohn's approval (2022) and growing prescribing volume have brought manufacturer support programs into play, and many plans now cover it. Stelara has had biosimilars approved in the US starting in 2025, with several interchangeable ustekinumab biosimilars reaching market. That may shift the cost calculation in favor of Stelara for patients where insurance prefers the biosimilar. For patients prioritizing lowest out-of-pocket cost, a ustekinumab biosimilar may win. For patients prioritizing the superior endoscopic outcomes shown in SEQUENCE, Skyrizi often justifies the cost.
Choosing With Your GI
For a Crohn's patient who has failed an anti-TNF, SEQUENCE provides the strongest direct evidence yet for choosing between these two IL-pathway biologics, and the data favors Skyrizi on both clinical remission and endoscopic outcomes. For a biologic-naive patient, the choice rests on mechanistic reasoning, cost, and access rather than direct trial data. Ask your GI how response will be measured after induction, what to do if symptoms persist beyond the standard assessment window, and whether a ustekinumab biosimilar is an option if cost is a barrier. A log of stool frequency, urgency, abdominal pain, and any new extraintestinal symptoms between visits helps your care team recognize early loss of response so that switches or dose adjustments can happen before a full flare develops.
This article is for educational purposes and is not medical advice. It is researched against current AGA clinical guidelines and peer-reviewed sources. Always discuss treatment decisions with your care team.