title: Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.
abstract: OBJECTIVE
  Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes.
  
  
  METHODS
  We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial.
  
  
  RESULTS
  Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable.
  
  
  CONCLUSIONS
  Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark steenholdt@brygge.dk.
authors.forename: Casper
authors.initials: C
authors.lastname: Steenholdt
authors.affiliation: Institute for Inflammation Research, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bendtzen
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Brynskov
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors.forename: Ole Ø
authors.initials: OØ
authors.lastname: Thomsen
authors.affiliation: Department of Medical Gastroenterology, Køge Hospital, Køge, Denmark.
authors.forename: Lars K
authors.initials: LK
authors.lastname: Munck
authors.affiliation: Department of Hepatology and Gastroenterology V, Aarhus Hospital, Aarhus, Denmark.
authors.forename: Lisbet A
authors.initials: LA
authors.lastname: Christensen
authors.affiliation: Department of Gastroenterology, Hvidovre Hospital, Hvidovre Denmark.
authors.forename: Gitte
authors.initials: G
authors.lastname: Pedersen
authors.affiliation: Department of Medical Gastroenterology S, Odense Hospital, Odense, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Kjeldsen
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ainsworth
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood*; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005765:Gastrointestinal Agents / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D000069285:Infliximab / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016014:Linear Models; D008297:Male; D011446:Prospective Studies; D012372:ROC Curve; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000906:Antibodies; D005765:Gastrointestinal Agents; D000069285:Infliximab
keywords: IBD; antibodies against IFX; dose intensification; dose optimization; infliximab; loss of response; therapeutic drug monitoring