Factors Associated with the Immunogenicity of Anti-Tumor Necrosis Factor Agents in Pediatric Patients with Inflammatory Bowel Disease

Abstract

Background/Aims: Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods: Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this crosssectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results: A total of 76 patients (Crohn's disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%). Conclusions: IFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Optimization of a Quantitative Anti-Drug Antibodies against Infliximab Assay with the Liquid Chromatography-Tandem Mass Spectrometry: A Method Validation Study and Future Perspectives

“…Kim et al measured these transient ADAs in 30% of pediatric patients with IBD in which initial ADAs were found. Although both groups found ADAs during treatment, they did not show worsening of the treatment due to the transient nature of these antibodies, a phenomenon also shown by Steenholdt et al [27][28][29]. Ungar et al conducted a prospective observational study and showed that of the patients developing persistent ADAs against IFX, 90% do so within the first year after treatment initiation, while transient ADAs were detected during the entirety of the IFX therapy, having less implication for the loss of response to IFX or adverse events [30].…”