Ustekinumab Works Best in Crohn’s Disease Patients New to Biologics, Real-World Study Finds

Ustekinumab, a monoclonal antibody that blocks the interleukin-12 and interleukin-23 inflammatory pathway, has become a mainstay biologic therapy for moderate to severe Crohn’s disease. A new retrospective study from Wuhu First People’s Hospital in China, published in Frontiers in Gastroenterology, now offers one of the most detailed real-world comparisons yet between patients receiving the drug as their first biologic and those who had already failed a previous biologic agent. The findings suggest that while ustekinumab benefits both groups, patients who start it earlier in their treatment journey may experience deeper control of inflammation and better endoscopic healing.

The research team, led by Kaifei Yuan, Xianhong Hu, Qi Fang, Siyuan Li, Ping Lin, Baijing Ding, and Tongyuan Lin, analyzed 61 patients with Crohn’s disease treated between April 2022 and May 2025. Twenty-one patients were biologic-naïve, meaning ustekinumab was their first biologic therapy, while 40 were biologic-experienced, having previously failed treatment with agents such as infliximab, adalimumab, or vedolizumab. The investigators tracked clinical data, laboratory markers, disease activity scores, and endoscopic findings at baseline, week 8, and week 32, and separately assessed quality of life and psychological well-being at the start and end of the observation period.

Ustekinumab works by selectively binding the p40 subunit shared by interleukin-12 and interleukin-23, preventing these cytokines from engaging the IL-12Rβ1 receptor on immune cells. This disrupts downstream signaling that would otherwise activate natural killer cells and T cells, reducing the secretion of inflammatory mediators that drive chronic intestinal inflammation. The drug is recommended as a first-line biologic for induction and maintenance of remission in moderate to severe Crohn’s disease, yet questions have persisted about how prior biologic exposure shapes its real-world effectiveness.

At baseline, the two groups were statistically comparable in gender, age, disease duration, laboratory values, Crohn’s Disease Activity Index (CDAI) scores, and Simplified Endoscopic Score for Crohn’s Disease (SES-CD) scores. Most patients in the cohort were diagnosed between ages 17 and 40, and the majority had ileocolonic disease with non-stricturing, non-penetrating behavior. Dosing followed European Crohn’s and Colitis Organisation guidelines, with weight-based intravenous induction followed by 90 milligram subcutaneous injections every eight weeks.

Laboratory results revealed distinct response patterns between the groups. By week 8, erythrocyte sedimentation rate had fallen significantly in both cohorts, but the biologic-naïve group showed larger reductions in C-reactive protein and ESR than the biologic-experienced group. By week 32, the naïve group had achieved statistically significant improvements in CRP, platelet count, hemoglobin, and ESR, while the experienced group showed significant gains in albumin, platelets, red blood cells, hemoglobin, and ESR but no significant CRP improvement. The authors suggest that prior biologic exposure may alter ustekinumab trough concentrations, and that intestinal fibrosis or structural damage in previously treated patients may blunt the apparent decline in systemic inflammatory markers.

Clinical and endoscopic outcomes favored earlier intervention. At week 32, the biologic-naïve group achieved a mean CDAI reduction of 136.25 points compared with 102.28 points in the experienced group, and their mean SES-CD score fell by 5.48 points versus 3.80 points, both differences statistically significant. Despite these gaps, the overall clinical response rates were 61.9 percent in the naïve group and 52.5 percent in the experienced group, with remission rates of 42.9 percent and 40.0 percent respectively. The overlapping 95 percent confidence intervals indicate no statistically significant difference in short-term clinical efficacy between the two treatment strategies.

The study then reclassified all 61 patients into clinical responders and non-responders based on CDAI decline at week 32. Thirty-four patients achieved a clinical response, defined as a reduction of at least 100 points from baseline, while 27 did not. Quality of life, measured with the 32-item Inflammatory Bowel Disease Questionnaire, improved significantly in both groups, but the gain was markedly larger in responders, whose IBDQ scores rose by an average of 38.11 points compared with 20.56 points in non-responders. This finding underscores that effective control of intestinal inflammation remains the central driver of improved daily functioning in Crohn’s disease.

Psychological outcomes told a more nuanced story. Using the Hospital Anxiety and Depression Scale, the researchers found that anxiety scores fell significantly only in the clinical response group, dropping from a mean of 6.72 to 5.44, while depression scores showed no significant change in either group. The authors attribute the anxiety benefit to successful symptom control breaking the vicious cycle of gut-brain axis inflammation, in which persistent intestinal inflammation feeds back through neuroendocrine and autonomic pathways to sustain psychological distress. Depression, they note, is influenced by genetic and psychosocial factors beyond disease activity, and a 32-week follow-up may simply be too short to capture meaningful improvement.

The study has important limitations. As a single-center retrospective analysis with a modest sample size and unbalanced group allocation, it is vulnerable to selection bias and reduced statistical power. Only a subset of patients completed week-32 endoscopy, fecal calprotectin and therapeutic drug monitoring data were unavailable, and the investigators could not stratify outcomes by Montreal classification phenotype. Larger, multi-center prospective studies will be needed to confirm these findings and to identify which patients benefit most from early ustekinumab initiation.

Nevertheless, the results carry practical weight for clinicians managing a disease whose prevalence in China has climbed to an estimated 60 to 70 cases per 100,000 people and continues to rise. The data support a treatment philosophy already embedded in the 2023 Chinese national guidelines, which emphasize not only symptom control and normalization of inflammatory markers but also psychological health and overall quality of life. For patients with Crohn’s disease, the message is clear: ustekinumab can deliver meaningful benefit whether it is the first biologic tried or a rescue after failure of another agent, but the deepest and most durable improvements in inflammation, mucosal healing, and emotional well-being appear to belong to those who reach it earliest.

Subject of Research: Real-world comparative effectiveness of ustekinumab in biologic-naïve versus biologic-experienced Crohn's disease patients

Article Title: Retrospective analysis of ustekinumab in Crohn’s disease between biologic-naïve and biologic-experienced

Article References: Yuan, K., Hu, X., Fang, Q., Li, S., Lin, P., Ding, B., & Lin, T. (2026). Retrospective analysis of ustekinumab in Crohn’s disease between biologic-naïve and biologic-experienced. Frontiers in Gastroenterology, 5, Article 1926425. https://doi.org/10.3389/fgstr.2026.1926425

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1926425

Keywords: ustekinumab, Crohn's disease, biologic-naïve, biologic-experienced, inflammatory bowel disease, CDAI, SES-CD, quality of life, anxiety, depression, IL-12/23, retrospective study