Interaction of Clinical Factors Modestly Predict Anti-TNF-Alpha Antibody Formation in a Real-World Cohort of Inflammatory Bowel Disease Patients

<b>Background:</b> Biological therapy is frequently used for the treatment of inflammatory bowel disease (IBD); however, the long-term efficacy of anti-tumor necrosis factor-alpha (TNF-α) therapies, such as infliximab (IFX) and adalimumab (ADA), is often compromised by the development of antidrug antibodies (AIFX and AADA, respectively). While several individual factors are known to contribute to immunogenicity, the complex, interactive effects of various clinical variables have not been fully elucidated in a real-world setting. <b>Methods:</b> We conducted a hierarchical logistic regression analysis on a retrospective cohort of 153 pediatric and adult IBD patients receiving IFX or ADA therapy to identify clinical factors and their interactions associated with AIFX/AADA positivity. The analysis progressively incorporated demographic, disease-related, and treatment-related variables, culminating in a model that included two- and three-way interaction terms. <b>Results:</b> Our final model demonstrated modest predictive power, with a Nagelkerke R² of 0.287, explaining less than 30% of the variance in antibody positivity using readily available clinical data (AUC of 0.806, 71.0% sensitivity and 77.6% specificity). Key predictors included the type of biological therapy (IFX vs. ADA) and the duration of treatment, with IFX therapy being a significant independent predictor (OR = 6.940, <i>p</i> = 0.004) for antibody positivity. Importantly, we identified novel three-way interactions, revealing that the combined effect of age at disease onset, IBD subtype, and biological therapy type significantly influences antibody formation (<i>p</i> = 0.042), particularly in childhood-onset ulcerative colitis patients treated with IFX. A similar interaction was found for treatment duration, IBD subtype, and therapy type (<i>p</i> = 0.042), where the risk of antibody positivity with IFX increased significantly with treatment length, particularly in UC patients. <b>Conclusions:</b> This study highlights that the combination of routine clinical variables in IBD offers a data-driven, mechanistically insightful framework, supporting the prediction of AIFX/AADA positivity to a modest extent. This framework requires prospective and external validation before clinical implementation.