Abstract Background Ustekinumab is an effective biologic for inflammatory bowel disease (IBD), but the added benefit of combining it with azathioprine remains uncertain. Thiopurine co-therapy may enhance immunosuppression but also increase complication risks. This study compared real-world clinical outcomes of ustekinumab monotherapy versus ustekinumab combined with azathioprine in patients with IBD. Methods A retrospective cohort analysis was performed using the TriNetX U.S. Collaborative Network. Adults (≥18 years) with Crohn’s disease or ulcerative colitis who initiated ustekinumab between 2020–2024 were categorized into ustekinumab monotherapy (Cohort 1) and ustekinumab + azathioprine therapy (Cohort 2). Patients with indeterminate colitis or positive pregnancy tests were excluded. Propensity score matching (1:1) produced 1,764 balanced patients per cohort. Outcomes assessed over 365 days included abdominal pain, diarrhea, fever, gastrointestinal bleeding, fistula, abscess, bowel obstruction, steroid use, pancytopenia, and infection. Measures of association and survival analyses were reported using odds ratios (OR), risk ratios, and hazard ratios (HR). Results Combination therapy demonstrated significantly higher risks of fistula formation (12.6% vs 8.6%; OR 0.652, 95% CI 0.524–0.810; p 0.001), bowel obstruction (7.8% vs 6.1%; OR 0.768, 95% CI 0.592–0.998; p = 0.047), and steroid use (41.6% vs 37.4%; OR 0.837, 95% CI 0.731–0.958; p = 0.010). Fever showed a borderline increase with azathioprine (4.8% vs 3.5%; p = 0.053). Rates of abscess, diarrhea, abdominal pain, pancytopenia, GI bleeding, and infection were similar between groups. Kaplan-Meier analysis confirmed worse survival free of fistula, bowel obstruction, and steroid exposure in the combination cohort. Conclusion Compared with ustekinumab monotherapy, ustekinumab combined with azathioprine was associated with higher risks of fistula, bowel obstruction, and steroid use, without clear improvement in gastrointestinal or infectious outcomes. These findings suggest limited clinical benefit and potential added risk with thiopurine co-therapy. Further evaluation is warranted to clarify the optimal role of combination immunosuppression in IBD management. Conflict of interest: Dr. Johal, Jashanveer: No conflict of interest Patel, Om: No conflict of interest Al-Bataineh, Mahmoud: No conflict of interest Hussein, Abdallah: No conflict of interest Schneider, Yecheskel: No conflict of interest Hyman, Jason: No conflict of interest
Johal et al. (Thu,) studied this question.