Higher Anti-Drug Antibody Levels to Anti-Tumor Necrosis Factor Therapies Are Associated with Treatment Failure in Patients with Inflammatory Bowel Disease

<b>Background/Objectives:</b> There is limited data regarding the association of anti-drug antibody (ADA) levels with the efficacy of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). We aimed to investigate the association between antibody to adalimumab (ATA) and antibody to infliximab (ATI) levels and treatment failure in IBD. <b>Methods:</b> This single-center, retrospective cohort study included consecutive IBD patients with ADA evaluated with a drug-tolerant assay between September 2012 and February 2023. A time-to-event analysis was performed for treatment failure, defined as the need for drug discontinuation due to primary non-response, loss of response, a serious adverse event, or an IBD-related surgery. Patients were followed from first positive ADA until treatment failure or the end of the follow-up (May 2024). <b>Results:</b> The study population consisted of 134 patients with IBD [n = 58 (43%) on adalimumab; n = 86, (64%) with Crohn's disease]. Multiple COX regression analysis identified higher ADA levels to be associated with treatment failure (HR: 1.034, 95%CI: 1.024-1.045, <i>p</i> < 0.001). A ROC analysis identified an ATA and ATI level threshold of 5.2 U/mL (AUC: 0.705; 95%CI: 0.569-0.841; <i>p</i> = 0.003; sensitivity: 64%; specificity: 82%) and 8.8 U/mL (AUC: 0.809; 95%CI: 0.713-0.906; <i>p</i> < 0.001; sensitivity: 69%; specificity: 93%), respectively, to distinguish patients with or without treatment failure. <b>Conclusions:</b> In this large retrospective cohort study, higher levels of ADA were associated with treatment failure to anti-TNF therapy in IBD. Moreover, we identified ATA and ATI level thresholds of 5.2 U/mL and 8.8 U/mL, respectively, to be associated with treatment failure.