Highlight
This prospective randomized trial investigated dose intensification with ustekinumab in Crohn’s disease patients experiencing secondary loss of response. Two regimens – intravenous reinduction plus either every 4-week or every 8-week subcutaneous maintenance dosing – were compared over 48 weeks. Steroid-free clinical remission rates were low and statistically similar between groups, with comparable safety profiles.
Study Background
Crohn’s disease (CD) is a chronic inflammatory bowel disease marked by relapsing intestinal inflammation causing significant morbidity. Biological therapies such as ustekinumab, which targets interleukin-12 and interleukin-23, have improved management of moderate to severe CD. However, many patients experience secondary loss of response to ustekinumab during maintenance therapy, limiting its long-term effectiveness.
When secondary loss of response occurs, clinicians often consider dose intensification strategies to regain disease control, but evidence guiding the optimal approach to ustekinumab reinduction and maintenance dosing remains scarce. This knowledge gap prompted the REScUE study conducted across multiple Belgian centers, designed to compare two distinct dose intensification regimens after secondary loss of response.
Study Design
The REScUE study was a prospective, randomized, placebo-controlled, multicenter trial enrolling adults with established Crohn’s disease who were on maintenance ustekinumab dosing (90 mg subcutaneously every 8 weeks). Eligibility required objective evidence of secondary loss of response, defined by Patient-Reported Outcomes 2 (PRO2) criteria—abdominal pain score >1 and liquid/very soft stool frequency >3—plus biomarker or endoscopic evidence of active disease.
Participants (n=108) were randomized 1:1 to receive a single intravenous ustekinumab reinduction dose (~6 mg/kg), then either 90 mg subcutaneously every 4 weeks or continuation of every 8 weeks for 48 weeks. The primary endpoint was the proportion of patients achieving steroid-free clinical remission at week 48, stipulated as PRO2 remission (abdominal pain ≤1 and stool frequency ≤3), fecal calprotectin <250 μg/g, and no corticosteroids within 90 days before week 48.
Key Findings
At 48 weeks, steroid-free clinical remission was attained in 15% of patients in the every 4-week group versus 19% in the every 8-week group. This 4% absolute difference was not statistically significant (P=0.5), indicating no clear advantage to more frequent subcutaneous dosing following intravenous reinduction.
Safety profiles were comparable between the groups, with serious adverse events reported in 17% versus 13% respectively, without significant differences or new safety signals. The low remission rates underscore the challenge of recapturing sustained disease control after secondary loss of response to ustekinumab.
Secondary analyses were not detailed but the primary outcome suggests that increasing dosing frequency of maintenance ustekinumab after reinduction does not substantially improve long-term outcomes. This is an important finding, given the cost and patient burden implications of more frequent injections.
Expert Commentary
The REScUE study adds valuable prospective randomized data to the field, addressing an important clinical dilemma—how best to manage secondary loss of response to ustekinumab in Crohn’s disease. Prior evidence mainly arose from retrospective cohorts or uncontrolled studies.
The lack of superiority of the intensified maintenance dosing regimen suggests that other strategies beyond simple dose escalation may be necessary for patients who lose response. These could include therapeutic drug monitoring, switching to alternative biologic classes, or combination therapies.
Limitations include modest remission rates possibly influenced by eligibility criteria or patient heterogeneity, and the absence of biomarker or pharmacokinetic-guided adjustments. Moreover, all patients received an initial IV reinduction, potentially masking differences related to maintenance dosing frequencies.
Conclusion
In Crohn’s disease patients experiencing secondary loss of response to ustekinumab, dose intensification by increasing subcutaneous maintenance dosing frequency from every 8 weeks to every 4 weeks after a single intravenous reinduction does not enhance steroid-free clinical remission at 48 weeks. These findings suggest that routine escalation to more frequent dosing should be reconsidered, highlighting the need for further research into alternative strategies to optimize long-term disease control.
Funding and ClinicalTrials.gov
This investigator-initiated study was conducted in Belgium across 15 hospitals under the Belgian IBD Research and Development (BIRD) group.
Registry: ClinicalTrials.gov Identifier: NCT04245215.
References
Bossuyt P, Rahier JF, Baert F, et al. The Effect of Dose Intensification After Secondary Loss of Response to Ustekinumab in Crohn’s Disease: Results of the REScUE Study. Gastroenterology. 2026 Feb 24;171(1):99-109. PMID: 41747777.
Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375(20):1946-1960.
Danese S, Vuitton L, Peyrin-Biroulet L. Biologic agents for moderately to severely active Crohn’s disease: network meta-analysis. Gut. 2018;67(2):238-249.
