Risankizumab vs Ustekinumab for Crohn's Disease

Risankizumab and ustekinumab are both approved biologics for moderate-to-severe Crohn's disease, and both target the same broad immune pathway — but they work at different points along it. Ustekinumab has been in use for Crohn's since 2016 and has a long safety record. Risankizumab received FDA approval in 2023 and, in the phase 3 trials that got it approved, showed strong endoscopic response rates even in patients who had already failed other biologics. Neither drug has cleared one key hurdle to a definitive answer: there is still no large, fully published head-to-head trial comparing the two directly in Crohn's disease. Your gastroenterologist will weigh your prior treatment history, disease location, insurance coverage, and how quickly you need a response.

This explainer draws on peer-reviewed research from four IBD specialists listed in the Convene directory: Edward Loftus, M.D., at Mayo Clinic, whose work includes the ACG clinical guideline for Crohn's disease management and the landmark STRIDE treat-to-target framework; Stephen Hanauer, MD, at Northwestern Memorial Hospital, who co-authored the pivotal CERTIFI trial establishing ustekinumab's role in TNF-refractory disease; Ellen Scherl, MD, at NewYork-Presbyterian / Weill Cornell, who co-authored the first randomized ustekinumab trial in Crohn's disease; and William Faubion, M.D., at Mayo Clinic Arizona, whose published research covers the immune signaling pathways that newer biologics like these target.

How the two drugs work

Both risankizumab and ustekinumab belong to a class of biologics that block interleukin-23 (IL-23), a signaling protein the immune system uses to drive chronic inflammation in the gut. But they do so at different points in that signaling cascade.

Ustekinumab blocks both IL-12 and IL-23 by targeting a shared protein subunit called p40. Because IL-12 and IL-23 both use p40, ustekinumab effectively quiets two arms of the inflammatory response at once.

Risankizumab targets only the p19 subunit, which is specific to IL-23. That means it is a more selective IL-23 blocker and does not interfere with IL-12 signaling. Whether that selectivity translates to meaningful differences in clinical outcomes or tolerability is what the trials have been designed to answer.

Both drugs start with a large intravenous (IV) loading dose given in a clinic or infusion center, then switch to self-administered subcutaneous injections for maintenance.

At a glance

What the ustekinumab trials found

The 2008 randomized controlled trial by Ellen Scherl and colleagues, published in Gastroenterology, was the first rigorous evidence that blocking IL-12 and IL-23 could reduce Crohn's disease activity [2]. That phase 2 study enrolled patients with moderate-to-severe disease and found that ustekinumab produced better clinical response rates than placebo, laying the groundwork for larger trials.

The CERTIFI trial, published in the New England Journal of Medicine in 2012 and co-authored by Stephen Hanauer, enrolled patients who had already failed TNF inhibitors, a notoriously difficult population to treat [1]. Patients with TNF-refractory Crohn's disease who received intravenous ustekinumab had significantly higher rates of clinical response compared to those on placebo. Patients who responded to induction also had significantly better rates of sustained response and remission with ustekinumab maintenance therapy. This trial was important because it defined a clinical niche: ustekinumab works even when anti-TNF drugs have stopped working.

The full approval for Crohn's disease in 2016 rested on the larger UNIFI-CD program (the UNIFI trials had established ustekinumab in ulcerative colitis as well), which confirmed the induction and maintenance benefit in a broader Crohn's population including some patients who were biologic-naive.

What the risankizumab trials found

The phase 3 ADVANCE and MOTIVATE induction trials, both published in The Lancet in 2022, enrolled patients with moderately to severely active Crohn's disease. ADVANCE included treatment-experienced patients; MOTIVATE enrolled those who had not adequately responded to biologics. Across both trials, approximately 40 to 45 percent of patients receiving risankizumab achieved clinical remission at week 12, compared to roughly 20 to 25 percent on placebo. Endoscopic response rates, which measure actual healing of the intestinal lining rather than just symptom improvement, reached 29 to 40 percent with risankizumab versus 11 to 12 percent with placebo.

The FORTIFY maintenance trial followed patients who had responded to risankizumab induction. At week 52, about 52 to 55 percent of patients on risankizumab maintained clinical remission compared to roughly 41 percent on placebo, and endoscopic response rates were approximately 47 percent versus 22 percent. Those endoscopic response numbers are considered clinically meaningful because mucosal healing (visible healing of the gut lining on colonoscopy) is increasingly recognized as a central goal of treatment, not just symptom control.

The 2015 STRIDE consensus paper, co-authored by Edward Loftus and published in The American Journal of Gastroenterology, established the treat-to-target framework that informs how gastroenterologists now interpret these trial results [4]. STRIDE formalized the idea that achieving endoscopic remission, not just symptom relief, should be the target of IBD therapy because patients who achieve mucosal healing have better long-term outcomes. Risankizumab's endoscopic response rates in its trials are a direct test of this framework.

Why no head-to-head winner yet

The most direct comparison between the two drugs would come from a randomized trial that assigns patients to risankizumab or ustekinumab and follows them for at least a year. A trial called SEQUENCE was designed to do exactly this, but as of the time this article was written, full published results were not yet available in a form that meets the grounding standards of this explainer. Indirect comparisons across trials are possible, and some observational data exist, but cross-trial comparisons are unreliable because patient populations, trial design, and endpoint definitions differ.

What can be said with confidence: both drugs work at rates well above placebo, both are generally well tolerated, and both are effective options for patients who have failed TNF inhibitors — which remains one of the most common clinical situations where IBD specialists reach for an IL-23 inhibitor.

What the ACG guideline recommends

The 2018 ACG Clinical Guideline for Crohn's disease in adults, co-authored by Edward Loftus, was published before risankizumab's approval, so it covers ustekinumab as one of several biologic options for moderate-to-severe disease and for patients who have not responded to TNF inhibitors [3]. The guideline recommends against step-up therapy in patients with poor prognostic factors — perianal disease, prior bowel resections, early stricturing — and instead favors early use of effective biologics in those cases.

This framing matters for understanding where both drugs fit. Risankizumab was approved after that guideline cycle, but the American Gastroenterological Association (AGA) issued a living guideline update that includes risankizumab as a treatment option for moderate-to-severe Crohn's, with conditional recommendations. The 2018 ACG guideline's core logic still applies: the right biologic for a given patient depends heavily on prior treatment history, disease behavior, and individual risk factors.

Safety profiles

Both drugs have favorable safety profiles compared to older immunosuppressants and TNF inhibitors. Neither has been associated with serious infections at rates significantly higher than placebo in the phase 3 trials.

Ustekinumab has a longer post-approval safety record. The most common side effects are upper respiratory infections and headache. Because ustekinumab also blocks IL-12, there was theoretical concern early on about impairing responses to intracellular pathogens, but clinical trial and real-world data have not shown a meaningful increase in serious infection risk.

Risankizumab's safety data from the Crohn's trials showed adverse event rates similar to placebo for serious infections. The most common side effects were worsening Crohn's disease (reflecting the natural course in non-responders), arthralgia, and headache. Its safety profile in psoriasis, where it has been used longer, adds to the overall evidence base.

Neither drug currently carries a boxed warning from the FDA, unlike JAK inhibitors, which carry warnings about increased risk of serious heart events, clotting, cancer, and death. The 2020 review by William Faubion and colleagues in Nature Reviews Gastroenterology & Hepatology examined JAK-STAT signaling pathways in IBD and the emerging risks associated with JAK inhibitor therapies [6], which provides useful context for understanding why the IL-23 class is generally viewed as having a more favorable safety ceiling than JAK inhibitors for long-term use.

Does your prior treatment history change the math?

For patients who have already failed a TNF inhibitor like infliximab or adalimumab, both risankizumab and ustekinumab are reasonable next-step options. The CERTIFI trial established ustekinumab's effectiveness in this setting in 2012 [1]. The ADVANCE and MOTIVATE trials confirmed that risankizumab works in biologic-experienced patients as well.

For patients who have never tried a biologic, your doctor may start with a TNF inhibitor, especially if your disease is severe or if you have complications like fistulas or abscesses that have established treatment protocols. The 2009 natural history study co-authored by Edward Loftus found that Crohn's disease is a disabling condition over time in a significant proportion of patients, which underscores the urgency of reaching effective treatment early [5].

Vedolizumab is another option in this space. The 2013 GEMINI 2 trial co-authored by Stephen Hanauer showed that vedolizumab worked for both induction and maintenance in Crohn's disease [7]. Its gut-selective mechanism means a different risk profile, but it tends to work more slowly, which matters for patients with urgent or severe disease. The 2016 safety analysis of vedolizumab published in Gut, which included Loftus as a co-author, confirmed the favorable long-term safety record of that drug [8].

Practical considerations

The dosing logistics are similar for both drugs: one IV infusion to start, then subcutaneous shots you or a caregiver administer at home every 8 to 12 weeks. Both require prior authorization from insurance. Biosimilars for ustekinumab are now approved in the United States, which has begun to lower costs — a practical advantage for ustekinumab over risankizumab, where no biosimilar is yet available.

For patients who also have psoriasis or psoriatic arthritis, both drugs are approved for those conditions. Ustekinumab has longer approval history in dermatology. Risankizumab also has psoriasis approval. If you have overlapping skin and gut disease, your doctor may prioritize one drug over the other based on which condition is more active.

Questions to ask your gastroenterologist

• Have I already tried a TNF inhibitor, and if so, would my prior response affect which drug is more likely to work now?
• What does the endoscopic activity in my colon look like, and would either drug be expected to produce mucosal healing?
• Is a biosimilar version of ustekinumab available and covered by my insurance?
• Do I have any other conditions, like psoriasis or psoriatic arthritis, that might make one drug a better fit?
• How long should I wait before deciding whether the drug is working?
• What are the monitoring requirements once I start, and how often will I need a repeat colonoscopy?

The bottom line

Risankizumab and ustekinumab both target the IL-23 pathway and both work for moderate-to-severe Crohn's disease, including in patients who have failed other biologics. Ustekinumab has more years of data behind it and biosimilars are now available, reducing cost. Risankizumab is newer, targets IL-23 more selectively, and its phase 3 trials showed strong endoscopic response rates. Without a definitive head-to-head trial, neither drug has proven to be clearly superior to the other. The decision between them depends on your treatment history, other conditions, insurance, and how urgently you need your disease brought under control. Both are legitimate options — the conversation with your IBD specialist is where the right answer for your specific situation gets worked out.