Prior Ustekinumab Exposure and Ulcerative Colitis Are Associated with Suboptimal Trough Levels in Patients Receiving Advanced-Line Vedolizumab or Ustekinumab for Inflammatory Bowel Disease: A Cross-Sectional Cohort Study

Background: Ustekinumab (UST) and vedolizumab (VDZ) are established therapies for Crohn’s disease (CD) and ulcerative colitis (UC), including in patients with prior tumour necrosis factor-alpha inhibitor (anti-TNF) failure. Trough levels (TRLs) and antidrug antibodies (ADAs) are among several factors associated with therapeutic response. The aim of this study was to retrospectively identify factors associated with suboptimal TRL and ADA presence in a large, multicentre, cross-sectional cohort. Methods: TRLs and ADAs for VDZ and UST were measured routinely during therapy. A Cox proportional hazards model was used to identify clinical and treatment-related factors associated with suboptimal TRLs. Results: A total of 184 patients (78 children and 106 adults) with inflammatory bowel disease (IBD) were included; 104 and 80 were treated with UST and VDZ, respectively. TRLs were measured as part of routine clinical care between 2022 and 2025. Of the 184 patients, 80 (43.48%) had previously received both infliximab and adalimumab. Overall, 103 patients (55.98%) had received at least two advanced therapies (infliximab, adalimumab, VDZ, UST or a small-molecule inhibitor (SMI)) before the current biologic therapy. In exploratory Cox analyses, prior UST exposure (HR = 4.13, 95% CI = 1.58–10.81, p = 0.004) and UC subtype (HR = 2.83, 95% CI = 1.39–5.76, p = 0.004) were associated with a higher hazard of suboptimal TRL, whereas longer duration of prior biologic therapy (HR = 0.89, 95% CI = 0.82–0.96, p = 0.003) and current VDZ treatment (HR = 0.36, 95% CI = 0.16–0.82, p = 0.014) were associated with a lower hazard. In a cross-sectional logistic model accounting for time on therapy, only longer duration of prior biologic therapy remained significantly associated with suboptimal TRL. Prior UST exposure was associated with ADA presence in the cross-sectional model, although the estimate was imprecise and sensitive to model specification. Conclusions: Prior UST exposure, UC subtype and current VDZ therapy were associated with suboptimal TRLs in exploratory Cox analyses; however, these associations were not reproduced in the cross-sectional logistic model and were sensitive to adjustment for inflammatory burden. Longer duration of prior biologic therapy remained associated with lower odds of suboptimal TRL in the cross-sectional analysis. The observed association between prior UST exposure and ADA presence was imprecise and model-dependent. Given the study’s retrospective design and limited sample size, these findings should be considered preliminary and require validation in larger prospective cohorts.