Abstract Background Ustekinumab is an established therapy for inflammatory bowel disease (IBD), yet the clinical value of adding thiopurines such as 6-mercaptopurine (6-MP) remains unclear. Combination therapy may enhance immunomodulation but could also introduce added toxicity. This study evaluated real-world differences in clinical outcomes between ustekinumab monotherapy and ustekinumab combined with 6-MP. Methods Using the TriNetX U.S. Collaborative Network, a retrospective cohort study was performed among adults (≥18 years) with Crohn’s disease or ulcerative colitis treated with ustekinumab between 2020–2024. Patients were categorized into ustekinumab monotherapy (Cohort 1) and ustekinumab + 6-MP combination therapy (Cohort 2). Individuals with indeterminate colitis or positive pregnancy tests were excluded. Propensity score matching (1:1) yielded 623 patients per cohort. Outcomes over 730 days included abdominal pain, diarrhea, fever, gastrointestinal bleeding, fistula, abscess, bowel obstruction, steroid use, and pancytopenia. Odds ratios (OR), risk ratios, and hazard ratios (HR) were reported. Results Combination therapy with 6-MP demonstrated significantly higher risks of fistula formation (21.0% vs 13.5%; OR 0.585, 95% CI 0.434–0.790; p 0.001) and pancytopenia (22.0% vs 16.1%; OR 0.678, 95% CI 0.510–0.903; p = 0.008). Additional nonsignificant trends suggested increased rates of abscess (6.1% vs 4.0%), bowel obstruction (12.5% vs 10.4%), fever (6.4% vs 5.6%), diarrhea (29.5% vs 27.4%), and steroid use (44.9% vs 41.7%). Abdominal pain and gastrointestinal bleeding rates were similar. Kaplan-Meier analyses confirmed significantly worse survival free of fistula and pancytopenia in the combination cohort. Conclusion Compared with ustekinumab monotherapy, combination therapy with 6-MP was associated with increased risks of fistula formation and pancytopenia without clear improvement in gastrointestinal symptom outcomes. These findings suggest that adding thiopurines to ustekinumab may offer limited therapeutic benefit while introducing additional risk. Further investigation is warranted to clarify the role of combination immunosuppression in IBD management. Conflict of interest: Dr. Patel, Om: No conflict of interest Johal, Jashanveer: 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
Patel et al. (Thu,) studied this question.