Abstract and Introduction
Background: Anti-drug antibodies develop mostly during the induction therapy with anti-tumour necrosis factor (TNF) drugs and can be revealed by means of a drug-tolerant assay.
Aim: To investigate whether the early detection of anti-drug antibodies during the induction therapy was predictive of treatment discontinuation.
Methods: In a prospective study, consecutive patients with inflammatory bowel disease (IBD), who should start an anti-TNF, were enrolled and followed regularly during 24 months or less in case of non- or loss of response (LOR) or adverse events requiring treatment discontinuation. Anti-TNF levels and anti-drug antibodies were measured at week 2 for adalimumab (ADA) and weeks 2 and 6 for infliximab (IFX) using a drug-tolerant assay.
Results: One hundred and eight patients were enrolled (54 under ADA). At week 2, antibodies to ADA and to IFX were detected in 76% and 67% of patients. Time to treatment discontinuation was significantly shorter (P < 0.001) in patients with antibodies to ADA ≥2.0 μg/mL-eq (6.0 vs 24 months, HR = 18.51, 95% CI [4.35–78.71]) or with antibodies to IFX ≥4.0 μg/mL-eq (5.5 vs >24 months, HR = 13.89, 95% CI [4.08–47.31]) at week 2 compared to patients without positive antibodies. Antibodies to ADA and to IFX were predictive of treatment failure within 24 months with a sensitivity of 79% and 62%, and specificities and positive predictive values of 100%. In multivariate analysis, antibodies to ADA or to IFX at week 2 were the only factors associated with treatment discontinuation.
Conclusions: The prevalence of antibodies to anti-TNF is high when detected early using a drug-tolerant assay, and their appearance predicts further treatment discontinuation.
Low trough levels of anti-tumour necrosis factor (TNF)—adalimumab (ADA) and infliximab (IFX)—and high levels of anti-drug antibodies have been associated with primary non-response (PNR) and secondary loss of response (LOR) to anti-TNF therapy in patients with inflammatory bowel disease (IBD).[1–4] However, a therapeutic threshold of anti-TNF concentrations has not yet been associated with treatment outcome and may vary with treatment target, disease type and state or phase of therapy.[1,5–8]
In contrast to the drug-sensitive assay, the drug-tolerant assay has been shown to allow reliable measurements of anti-drug antibodies even in the presence of detectable drug levels, which is the case, in particular, during the induction phase of anti-TNF therapy.[9,10] Using this drug-tolerant assay, it has been recently reported that anti-drug antibodies appeared mostly during anti-TNF induction therapy, as early as 2 weeks, highlighting the importance of tight therapeutic drug monitoring during the first months of therapy.[11–15]
We aimed to investigate whether the early detection of anti-drug antibodies revealed by means of a drug-tolerant assay during the induction phase of anti-TNF therapy was predictive of subsequent drug failure in IBD patients and to determine the optimal threshold of anti-drug antibodies associated with this outcome.
Aliment Pharmacol Ther. 2021;53(11):1190-1200. © 2021 Blackwell Publishing