Background: Anti-drug antibodies (ADA) may develop in up to 51% of patients treated with infliximab maintenance therapy and are associated with infusion reactions and impaired response. Drug-sensitive assays do not detect ADA in the presence of drug and underestimate ADA formation. Drug-tolerant assays have therefore been developed and markedly increased the detection of ADA, although their clinical relevance remains to be shown. Our goal was to evaluate the clinical relevance of anti-drug antibodies (ADA) measured using a drug-tolerant assay in comparison to a drug-sensitive assay in a post-hoc analysis of the Trough Concentration Adapted Infliximab Treatment (TAXIT) randomized controlled trial.
Methods: Patients who presented with an infliximab trough concentration (TC) <3 μg/mL at screening (n=76) underwent dose escalation to achieve therapeutic TCs between 3–7 μg/mL prior to randomization. Serum samples were re-analyzed at screening, after optimization and one year after randomization using a drug-tolerant ADA assay.
Results: Using a drug-tolerant assay, the immunogenicity detection rate increased from 21% (drug-sensitive assay) to 63% at screening, from 0% to 51% after optimization and from 3% to 42% one year after randomization. ADA concentration (median [interquartile range, IQR]) in ADA+ patients grouped into quartiles according to ADA concentration at screening, decreased throughout the study: from 220 [116–737] ng/mL eq at screening to 112 [78–180] ng/mL eq after optimization and to 95 [0–166] ng/mL eq at the end of the study. Patients in ADA Q4 required a higher cumulative infliximab dose (2390 [880–2998] mg) to achieve target TCs (Figure 1) compared to ADA negative patients (450 [365–680] mg, p<0.001) and patients in ADA Q1/Q2 (425 [344–863]/483 [398–719], p<0.001).
However, all but one patient belonging to ADA Q4 were also ADA positive using a drug-sensitive assay. Once dose optimized, patients have similar rates of clinical, biological and endoscopic remission after one year of treatment, regardless of ADA status in a drug-tolerant assay.
Conclusions: Upon dose intensification, low concentration ADA, not detectable using a drug-sensitive assay, disappear in more than half of the patients over time and are clinically non-relevant. In contrast, high concentration ADA which are typically also detected in a drug-sensitive assay, persist over time and necessitate a higher cumulative dose and drug cost. In the latter group, proactive drug switching may be more cost-efficient.