Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn’s disease patients with secondary loss of response

Abstract

Background: Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. Objectives: This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. Design: We performed a prospective, observational study including pediatric patients with Crohn’s disease (CD) receiving IFX maintenance therapy without dose intensification. Methods: We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Results: Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs ( p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31–151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590–0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Conclusion: Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.