Towards Precision Medicine in Inflammatory Bowel Diseases: Pharmacogenetic Predictors of Ustekinumab Effectiveness and Persistence.

Background/Objectives: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), show substantial variability in response to biologic therapies. Ustekinumab, which targets the IL-12/23 pathway, is an established treatment for moderate-to-severe IBD; however, a proportion of patients fail to achieve sustained remission or discontinue treatment over time. This study aimed to evaluate the effectiveness and persistence of ustekinumab and to explore the potential role of pharmacogenetic markers in predicting treatment outcomes. Methods: In this observational cohort study, 98 IBD patients treated with ustekinumab, with or without corticosteroid bridge therapy, in routine clinical practice were enrolled. The primary endpoint was steroid-free remission (SFR) at 12 months, defined as clinical remission without concomitant corticosteroid use, whereas treatment discontinuation was evaluated during follow-up. Genomic DNA was extracted from peripheral blood samples, and four single-nucleotide polymorphisms (SNPs) in selected immune-related genes were analyzed: PTPN2 rs7234029, HLA-C rs10484554, IL23R rs11209026, and IL12B rs6887695. Results: Of the 98 patients included, 73 (74.5%) achieved SFR, whereas 25 (25.5%) did not. Carriers of IL12B rs6887695 variant genotypes showed higher odds of achieving SFR than wild-type patients after adjustment for disease type and baseline disease activity (OR = 4.77; 95% CI, 1.60-14.23; p = 0.005). During follow-up, 16 patients (16.3%) discontinued treatment. Carriers of IL12B rs6887695 variant genotypes also showed a significantly lower hazard of ustekinumab discontinuation than wild-type patients (HR = 0.29; 95% CI, 0.10-0.85; p = 0.024). Conclusions: This study provides real-world evidence supporting the effectiveness and persistence of ustekinumab in IBD patients. IL12B rs6887695 emerged as a potential pharmacogenetic marker associated with favorable ustekinumab outcomes; however, this exploratory and hypothesis-generating finding requires external validation in larger, independent cohorts before clinical application.