title: 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.
  
  
  METHODS
  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.
authors.affiliation: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium Division of Gastroenterology, University of California San Diego, La Jolla, California, USA Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: Niels
authors.identifier: http://orcid.org/0000-0003-0854-0274
authors.initials: N
authors.lastname: Vande Casteele
authors.affiliation: Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: Reena
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Division of Gastroenterology, University of California San Diego, La Jolla, California, USA Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: Barrett G
authors.initials: BG
authors.lastname: Levesque
authors.affiliation: Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: Larry
authors.initials: L
authors.lastname: Stitt
authors.affiliation: Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: G Y
authors.initials: GY
authors.lastname: Zou
authors.affiliation: Prometheus Laboratories, Inc., San Diego, California, USA.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: Prometheus Laboratories, Inc., San Diego, California, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Lockton
authors.affiliation: Prometheus Laboratories, Inc., San Diego, California, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hauenstein
authors.affiliation: Prometheus Laboratories, Inc., San Diego, California, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Ohrmund
authors.affiliation: University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Greenberg
authors.affiliation: KU Leuven Department of Clinical and Experimental Medicine, Leuven, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rutgeerts
authors.affiliation: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.affiliation: Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: KU Leuven Department of Clinical and Experimental Medicine, Leuven, Belgium.
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Robarts Clinical Trials, Western University, London, Ontario, Canada.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D006801:Humans; D000069285:Infliximab / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D012074:Remission Induction; D012720:Severity of Illness Index
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D005765:Gastrointestinal Agents; D000069285:Infliximab
keywords: CROHN'S DISEASE; INFLIXIMAB; PHARMACOKINETICS; PHARMACOLOGY; TNF