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

• Published in: Gut Vol. 64; no. 10; pp. 1539 - 1545
• Main Authors: Vande Casteele, Niels, Khanna, Reena, Levesque, Barrett G, Stitt, Larry, Zou, G Y, Singh, Sharat, Lockton, Steve, Hauenstein, Scott, Ohrmund, Linda, Greenberg, Gordon R, Rutgeerts, Paul J, Gils, Ann, Sandborn, William J, Vermeire, Séverine, Feagan, Brian G
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.10.2015; BMJ Publishing Group
• Series: Original article
• Subjects: Adult; Antibodies, Monoclonal - blood; Biomarkers - blood; Bowel disease; Crohn Disease - diagnosis; Crohn Disease - drug therapy; Crohn Disease - immunology; Crohn's disease; Dose-Response Relationship, Drug; Drug dosages; Female; Follow-Up Studies; Gastrointestinal Agents - administration & dosage; Gastrointestinal Agents - immunology; Gastrointestinal Agents - pharmacokinetics; Humans; Inflammatory Bowel Disease; Infliximab - administration & dosage; Infliximab - immunology; Infliximab - pharmacokinetics; Male; Predictive Value of Tests; Prognosis; Proteins; Remission Induction; ROC Curve; Severity of Illness Index; Studies; CROHN'S DISEASE; PHARMACOKINETICS; INFLIXIMAB; TNF; PHARMACOLOGY
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2014-307883

ObjectiveAlthough 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.DesignIn 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.ResultsBased 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.ConclusionsThe 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.