Skyrizi vs Stelara for Crohn's Disease: A Patient Guide

In the SEQUENCE head-to-head trial, Skyrizi (risankizumab) was superior to Stelara (ustekinumab) for endoscopic remission at week 48, achieved by 31.8% of Skyrizi patients versus 16.2% of Stelara patients (1). Both drugs are effective biologics for moderate-to-severe Crohn's disease, but the first trial to compare them directly gives Skyrizi an edge on deep healing, especially for people who have already failed a TNF blocker.

Key Takeaways

• In the SEQUENCE trial, Skyrizi was noninferior to Stelara for clinical remission at week 24, with rates of 58.6% versus 39.5% (1)
• Skyrizi was superior to Stelara for endoscopic remission at week 48: 31.8% versus 16.2%, an adjusted difference of about 15.6 percentage points (1)
• At week 48, clinical remission favored Skyrizi over Stelara, 60.8% versus 40.8% (2)
• Skyrizi targets the IL-23 p19 subunit only, while Stelara blocks both IL-12 and IL-23 by binding the shared p40 subunit (3)(4)
• Skyrizi was FDA-approved for adult Crohn's disease in June 2022, and Stelara was approved for adult Crohn's disease in September 2016 (5)(6)
• SEQUENCE enrolled 520 patients who had all already had an inadequate response to or intolerance of at least one anti-TNF therapy (1)

How Skyrizi and Stelara Work

Both Skyrizi and Stelara are biologic medications that calm the overactive immune signaling that drives Crohn's inflammation. They do this by blocking interleukins, which are messenger proteins the immune system uses to ramp up inflammation. The key difference is which messengers each drug silences.

Skyrizi (risankizumab) is a selective interleukin-23 (IL-23) inhibitor. It binds the p19 subunit that is unique to IL-23, switching off that single pathway while leaving IL-12 alone (3). IL-23 is a central driver of the chronic gut inflammation seen in Crohn's, so targeting it narrowly is the appeal of this newer class.

Stelara (ustekinumab) is older and works more broadly. It binds the p40 subunit, which is shared by both IL-12 and IL-23, so it blocks two pathways at once (4). For years this dual blockade was considered an advantage, and Stelara has a long, reassuring safety record. The SEQUENCE trial was designed to test whether the more selective IL-23 approach actually performs better in practice.

Why the Difference Between IL-23 and IL-12/23 Matters

Researchers increasingly believe that in Crohn's disease, IL-23 is the more important inflammatory driver, while IL-12 may play a less central or even partly protective role. Blocking IL-23 alone, as Skyrizi does, is the theory behind the newer generation of biologics. The SEQUENCE results give that theory real-world support, though both drugs clearly help many patients.

Skyrizi vs Stelara: Side-by-Side Comparison

| Feature | Skyrizi (risankizumab) | Stelara (ustekinumab) | | --- | --- | --- | | Target | IL-23 p19 subunit only (3) | IL-12 and IL-23 shared p40 subunit (4) | | Induction route | Intravenous (IV) infusion (5) | Single weight-based IV infusion (6) | | Induction schedule | 600 mg IV at weeks 0, 4, and 8 (5) | One-time IV dose: 260, 390, or 520 mg by body weight (6) | | Maintenance route | Subcutaneous (SC) injection (5) | Subcutaneous (SC) injection (6) | | Maintenance dose and interval | 180 mg or 360 mg SC every 8 weeks (5) | 90 mg SC every 8 weeks (6) | | FDA approval for Crohn's | June 2022 (5) | September 2016 (6) | | Self-injection at home | Yes, after training (5) | Yes, after training (6) |

What the SEQUENCE Trial Found

SEQUENCE was a phase 3b, multicenter, randomized trial and the first head-to-head comparison of these two drugs in Crohn's disease, published in the New England Journal of Medicine in 2024 (1). It enrolled 520 adults with moderate-to-severe Crohn's disease who had all already had an inadequate response to, or could not tolerate, at least one anti-TNF therapy. Patients were assigned to receive either risankizumab (Skyrizi) or ustekinumab (Stelara) over 48 weeks.

The trial had two co-primary endpoints. The first was clinical remission at week 24, meaning a Crohn's Disease Activity Index score below 150. On this measure, Skyrizi was noninferior to Stelara, with clinical remission in 58.6% of the Skyrizi group versus 39.5% of the Stelara group (1).

The second primary endpoint was endoscopic remission at week 48, judged by looking directly at healing of the bowel lining. Here Skyrizi was superior: 31.8% of Skyrizi patients reached endoscopic remission versus 16.2% of Stelara patients, an adjusted difference of roughly 15.6 percentage points (1). In plain terms, nearly twice as many people on Skyrizi had healed bowel tissue.

The advantage carried through the secondary endpoints. At week 48, clinical remission was reached by 60.8% of Skyrizi patients versus 40.8% on Stelara (2). Skyrizi was also linked to significantly greater reductions in inflammatory blood and stool markers, including high-sensitivity CRP and fecal calprotectin, compared with Stelara (2).

How Should Patients Read These Numbers?

It is worth keeping perspective. SEQUENCE studied people who had already failed a TNF blocker, so these results apply most directly to that group, not necessarily to someone choosing a first biologic. Stelara still produced remission in a large share of patients and remains a strong option. The trial shows Skyrizi outperformed Stelara on bowel healing in this population, not that Stelara stopped working.

Are Skyrizi and Stelara Safe?

Both drugs have well-established safety profiles, and in SEQUENCE the overall safety was broadly consistent with what is already known for each medication, with no unexpected new risks reported (1). Like all biologics that quiet the immune system, both can raise the risk of infections, and both prescribing labels advise screening for tuberculosis and other infections before starting treatment.

Stelara has the longer track record, with use across Crohn's disease, psoriasis, and psoriatic arthritis since well before its 2016 Crohn's approval, which is reassuring to many patients and physicians (6). Skyrizi is newer for Crohn's but has accumulated substantial safety data across its approved uses. Your gastroenterologist will weigh your infection history, vaccinations, and other conditions when deciding which is the better fit. Always report fevers, persistent infections, or new symptoms promptly.

Can You Switch From Stelara to Skyrizi?

Many people in SEQUENCE had already been through other biologics, and switching biologics is common in Crohn's care when a drug stops working or never worked well enough. If your current treatment is not controlling your disease, your gastroenterologist may discuss moving from Stelara to Skyrizi or the reverse. Because they hit overlapping but not identical targets, a switch can sometimes succeed even after one of them has failed. This is a clinical decision that depends on your history, your endoscopy and lab results, and insurance coverage, so it should always be made with your IBD team rather than on your own.

Who Might Prefer Which Drug?

There is no universal winner, but a few patterns help frame the conversation. Someone who has already failed a TNF blocker and whose top priority is deep bowel healing has reason to consider Skyrizi, given the SEQUENCE endoscopic results (1). Someone who values the longest safety track record, or who is already doing well on Stelara, has good reason to stay the course (6). Dosing logistics also matter to some people: both require an IV induction phase and then move to at-home subcutaneous injections every 8 weeks (5)(6). The right answer comes from matching the evidence to your individual situation with your gastroenterologist.

What About Cost and Access?

Both medications are brand-name biologics and are expensive without insurance, so for most patients the practical question is what their plan covers and what step-therapy rules apply. Insurers often require trying certain drugs first, and prior authorization is common for both. Manufacturer patient-support and copay-assistance programs exist for each drug and can substantially lower out-of-pocket costs for eligible, commercially insured patients. Your GI clinic's prior-authorization staff and the manufacturer support programs are the best starting points for working out access and affordability.

Frequently Asked Questions

Is Skyrizi better than Stelara for Crohn's disease?

In the SEQUENCE head-to-head trial, Skyrizi was superior to Stelara for endoscopic remission at week 48, with 31.8% versus 16.2% of patients achieving healed bowel tissue (1). It was noninferior for clinical remission at week 24. Both work, but Skyrizi had the edge on deep healing in people who had already failed a TNF blocker.

How are Skyrizi and Stelara given?

Both start with an intravenous (IV) infusion induction phase, then switch to at-home subcutaneous (SC) injections every 8 weeks. Skyrizi uses 600 mg IV at weeks 0, 4, and 8, then 180 mg or 360 mg SC. Stelara uses one weight-based IV dose, then 90 mg SC every 8 weeks (5)(6).

What is the main difference in how they work?

Skyrizi blocks only interleukin-23 by targeting its p19 subunit, while Stelara blocks both interleukin-12 and interleukin-23 by binding the shared p40 subunit (3)(4). Skyrizi is the more selective, newer approach; Stelara is the broader, older one with a longer safety history.

Can I switch from Stelara to Skyrizi?

Yes, switching between biologics is common in Crohn's care when a medication is not controlling the disease. Because the two drugs hit overlapping but different targets, a switch can sometimes work even after one fails. This is a decision to make with your gastroenterologist based on your test results and insurance.

Which drug has been approved longer for Crohn's?

Stelara has been approved for adult Crohn's disease since September 2016, while Skyrizi received FDA approval for adult Crohn's disease in June 2022 (5)(6). Stelara therefore has the longer real-world track record, though Skyrizi has rapidly built a substantial evidence base.

Are these drugs safe long term?

Both have established safety profiles, and SEQUENCE reported no unexpected new safety concerns for either drug (1). As immune-modulating biologics, both can raise infection risk, so screening before starting and prompt reporting of infections is important. Discuss your personal risk factors with your doctor.

Do both drugs require infusions forever?

No. The IV infusions are only for the induction phase that starts treatment. After induction, both Skyrizi and Stelara move to subcutaneous injections every 8 weeks that you can give yourself at home after training (5)(6).

This article is for general educational purposes only and is not medical advice; always discuss treatment decisions, including any change to your biologic therapy, with your own gastroenterologist or qualified healthcare provider.

References

1. Peyrin-Biroulet L, et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn's Disease (SEQUENCE trial). New England Journal of Medicine, 2024. View study
2. Ferrante M, et al. Risankizumab Versus Ustekinumab for the Achievement of Clinical Remission and Reduction in Inflammatory Biomarkers in Patients With Moderate-to-Severe Crohn's Disease: Results From the Phase 3b SEQUENCE Trial. PubMed Central (PMC), 2024. View study
3. Skyrizi (risankizumab-rzaa) Prescribing Information. FDA / AbbVie, 2024. View label
4. FDA Approves STELARA (ustekinumab) for Treatment of Adults With Moderately to Severely Active Crohn's Disease. Johnson & Johnson, 2016. View release
5. SKYRIZI (risankizumab-rzaa) Receives FDA Approval to Treat Moderately to Severely Active Crohn's Disease in Adults. AbbVie News, 2022. View release
6. FDA Approves STELARA for Crohn's Treatment. Crohn's and Colitis Foundation, 2016. View release