The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

Abstract

Objective: Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab.

Design: In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission.

Results: Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 μg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission.

Conclusions: The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

Keywords: CROHN'S DISEASE; INFLIXIMAB; PHARMACOKINETICS; PHARMACOLOGY; TNF.

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Figures

Figure 1

XY plot of infliximab (IFX) and antibody to infliximab (ATI) concentration of all 1487 samples. Lower limit of quantitation (LLOQ) for IFX and ATI using the homogenous mobility shift assay was respectively 0.98 μg/mL and 3.13 U/mL. Seventeen data points were outside the axis limits: 4/17 samples had IFX >35 μg/mL (none were positive for ATI) and 13/17 samples had ATI >90 U/mL (none were positive for IFX). Positive (+) and negative (–) signs represent respectively samples with detectable and undetectable IFX or ATI.

Figure 2

Receiver operating characteristic curve analysis showing the infliximab threshold that best discriminated disease activity, as measured by C-reactive protein (concentration ≤5 mg/L was defined as inactive disease).

Figure 3

Median C-reactive protein (CRP) concentration (mg/L) per quartile of infliximab trough (IFX) concentration (A) and antibody to infliximab (ATI) concentration (B). IFX concentration (μg/mL) quartiles (Q) were Q1

Figure 4

Whiskers boxplot (5th–95th centile) representing the C-reactive protein concentration (mg/L) in samples with an infliximab (IFX) trough concentration above or below the threshold of 3 μg/mL, both for antibody to IFX (ATI) negative (