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

Authors
  • Vande Casteele, Niels1
  • Khanna, Reena2
  • Levesque, Barrett G3
  • Stitt, Larry2
  • Zou, G Y2
  • Singh, Sharat4
  • Lockton, Steve4
  • Hauenstein, Scott4
  • Ohrmund, Linda4
  • Greenberg, Gordon R5
  • Rutgeerts, Paul J6
  • Gils, Ann7
  • Sandborn, William J8
  • Vermeire, Séverine6
  • Feagan, Brian G2
  • 1 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. , (Belgium)
  • 2 Robarts Clinical Trials, Western University, London, Ontario, Canada. , (Canada)
  • 3 Division of Gastroenterology, University of California San Diego, La Jolla, California, USA Robarts Clinical Trials, Western University, London, Ontario, Canada. , (Canada)
  • 4 Prometheus Laboratories, Inc., San Diego, California, USA.
  • 5 University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada. , (Canada)
  • 6 KU Leuven Department of Clinical and Experimental Medicine, Leuven, Belgium. , (Belgium)
  • 7 KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. , (Belgium)
  • 8 Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.
Type
Published Article
Journal
Gut
Publisher
BMJ
Publication Date
Oct 01, 2015
Volume
64
Issue
10
Pages
1539–1545
Identifiers
DOI: 10.1136/gutjnl-2014-307883
PMID: 25336114
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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