Gastroenterology · Medical Literature
Corticosteroid-sparing effects of risankizumab versus ustekinumab in patients with moderately to severely active Crohn's disease: post hoc results from the phase 3b SEQUENCE trial.
Abstract
This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) versus ustekinumab (UST) in patients with moderate to severe Crohn's disease (CD) with prior inadequate response or intolerance to ≥ 1 anti-tumor necrosis factor (TNF) therapy. SEQUENCE (NCT04524611) was an open-label, multicenter, randomized, efficacy assessment-blinded study. Patients were randomized 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, then a subcutaneous [SC] 360 mg maintenance dose every 8 weeks [Q8w] starting at week 12) or UST (single weight-based IV induction dose, then a SC 90 mg maintenance dose Q8w starting at week 8) up to week 48. Patients tapered corticosteroids beginning at week 2. Achievement of clinical, endoscopic, and quality of life outcomes without concomitant use of steroids ("corticosteroid-free") and safety were assessed. In patients taking corticosteroids at baseline, response rate differences by the week 24 and 48 timepoints with RZB versus UST were 10.5% and 25.4% (P ≤ .01) for corticosteroid-free clinical remission per CD activity index and 20.4% (P ≤ .001) and 29.2% (P ≤ .01) per stool frequency/abdominal pain score, and 23.0% and 20.2% (both P ≤ .01) for corticosteroid-free endoscopic remission. Similar results were also observed for additional corticosteroid-free endpoints, including endoscopic, composite (clinical + endoscopic), and quality of life outcomes. Numerically higher exposure-adjusted event rates of serious infections and hypersensitivity with RZB and UST were observed with corticosteroid use. In patients with CD refractory to anti-TNF therapy, higher rates of corticosteroid-free clinical, endoscopic, and quality of life outcomes were achieved with RZB versus UST. Both treatments were well-tolerated. NCT04524611.
Clinical relevance
This post hoc analysis of the phase 3b SEQUENCE trial addresses a critical clinical gap in the management of moderate-to-severe Crohn's disease (CD) in anti-TNF-refractory patients: the comparative corticosteroid-sparing efficacy of two IL-23p19 and IL-12/23p40 inhibitors, risankizumab (RZB) and ustekinumab (UST). Prolonged corticosteroid use in CD carries well-documented risks including infection, metabolic complications, and adrenal suppression, making steroid-free remission a high-priority therapeutic benchmark. As both biologics are now established options in this population, head-to-head data on corticosteroid-free outcomes directly inform sequencing and selection decisions for gastroenterologists managing refractory CD.
Key findings
1. Corticosteroid-free clinical remission by CDAI: RZB demonstrated a statistically significant response rate difference versus UST of +10.5% at week 24 and +25.4% at week 48 (both P ≤ .01) among patients using corticosteroids at baseline. 2. Corticosteroid-free clinical remission by SF/APS: RZB showed a response rate difference of +20.4% at week 24 (P ≤ .001) and +29.2% at week 48 (P ≤ .01) versus UST, consistent across both patient-reported symptom measures. 3. Corticosteroid-free endoscopic remission: RZB achieved response rate differences of +23.0% at week 24 and +20.2% at week 48 versus UST (both P ≤ .01), indicating a robust and durable endoscopic advantage. 4. Composite and quality-of-life endpoints: Corticosteroid-free composite (clinical + endoscopic) and quality-of-life outcomes similarly favored RZB over UST, though specific effect sizes for these endpoints were not individually quantified in the abstract. 5. Safety signal with concomitant corticosteroid use: Numerically higher exposure-adjusted event rates of serious infections and hypersensitivity reactions were observed in patients receiving corticosteroids alongside either biologic, underscoring the clinical importance of achieving steroid-free status irrespective of agent. 6. Study design context: SEQUENCE (NCT04524611) was an open-label, randomized, efficacy assessment-blinded, multicenter phase 3b trial with 1:1 randomization, a corticosteroid taper initiated at week 2, and outcomes assessed through week 48; this is a post hoc subgroup analysis and findings should be interpreted with the inherent limitations of post hoc analyses.
Practice implications
In anti-TNF-refractory patients with moderate-to-severe CD who require corticosteroids at treatment initiation, RZB (IV 600 mg induction at weeks 0, 4, and 8 followed by SC 360 mg Q8W) should be preferentially considered over UST given its significantly superior corticosteroid-free clinical and endoscopic remission rates at both 24 and 48 weeks. Clinicians should initiate a structured corticosteroid taper no later than week 2 of biologic induction — as per the SEQUENCE protocol — to minimize the additive infection and hypersensitivity risks associated with prolonged concomitant steroid use. Corticosteroid-free endoscopic remission should be used as a primary treatment target at follow-up endoscopy (approximately week 24–48), with escalation or reassessment warranted in patients failing to achieve steroid independence on UST, for whom a switch to RZB may offer meaningful additional benefit.