Abstract
Background: In adults, infliximab (IFX) levels correlate with disease activity, and antibodies to IFX (ATIs) predict treatment failure. We aimed to determine the association of IFX levels and ATIs with disease activity in a paediatric population. We prospectively collected blood, stool, and clinical data from 65 patients (age 10.5-15.1 years) with Crohn's disease (CD) before IFX administration, and measured IFX trough levels, ATIs, and faecal calprotectin levels (CPT). Samples were collected during maintenance therapy. We used multivariate analysis to identify the predictors of IFX levels. Summary: Lower levels of IFX were associated with ATIs positivity (OR 0.027, 95% CI 0.009-0.077). Higher C-reactive protein (CRP) level, erythrocyte sedimentation rate, and CPT levels were found in patients with lower IFX levels. The optimal combination of sensitivity (0.5) and specificity (0.74) for disease activity was calculated for IFX levels ≥1.1 µg/mL using CRP level <5 mg/L as a marker of laboratory remission. In a model that used CPT ≤100 µg/g as the definition of remission, the optimal IFX trough level was 3.5 µg/mL. No independent association between remission and ATIs was found in our study population. However, we found an independentz association between IFX levels and serum albumin levels (OR 1.364, 95% CI 1.169-1.593), p < 0.001. Key Messages: The paediatric population was similar to adult populations in terms of the association between IFX and ATIs as well as between IFX and disease activity.
References
1.
Rosen MJ, Dhawan A, Saeed SA: Inflammatory bowel disease in children and adolescents. JAMA Pediatr 2015;169:1053-1060.
2.
Ruemmele FM, Veres G, Kolho KL, et al: Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014;8:1179-1207.
3.
Steenholdt C, Brynskov J, Thomsen OØ, et al: Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919-927.
4.
Silva-Ferreira F, Afonso J, Pinto-Lopes P, Magro F: A systematic review on infliximab and adalimumab drug monitoring: levels, clinical outcomes and assays. Inflamm Bowel Dis 2016;22:2289-2301.
5.
Yarur AJ, Kanagala V, Stein DJ, Czul F, Quintero MA, Agrawal D, Patel A, Best K, Fox C, Idstein K, Abreu MT: Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn's disease. Aliment Pharmacol Ther 2017;45:933-940.
6.
Roblin X, Duru G, Williet N, Del Tedesco E, Cuilleron M, Jarlot C, Phelip JM, Boschetti G, Flourié B, Nancey S, Peyrin-Biroulet L, Paul S: Development and internal validation of a model using fecal calprotectin in combination with infliximab trough levels to predict clinical relapse in Crohn's disease. Inflamm Bowel Dis 2017;23:126-132.
7.
Hofmekler T, Bertha M, McCracken C, Martineau B, McKinnon E, Schoen BT, McElhanon BO, Tenjarla G, Kugathasan S, Sauer CG: Infliximab optimization based on therapeutic drug monitoring in pediatric inflammatory Bowel disease. J Pediatr Gastroenterol Nutr 2017;64:580-585.
8.
Strik AS, van den Brink GR, Ponsioen C, Mathot R, Löwenberg M, D'Haens GR: Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory Bowel disease. Aliment Pharmacol Ther 2017;45:1128-1134.
9.
Shakhnovich V, Van Haandel L, Becker M, Funk R: O-005 Combination therapy with methotrexate does not change infliximab pharmacokinetics in children with inflammatory Bowel disease. Inflamm Bowel Dis 2017;23(suppl 1):S2.
10.
Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, van den Brink GR, D'Haens GR: A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory Bowel disease. Inflamm Bowel Dis 2017;23:650-660.
11.
Strobe Checklist for Cohort, Case-Control, and Cross Sectional Studies. Strobe Statement Website. [Online, 20 May 2016].
12.
IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition: Inflammatory bowel disease in children and adolescents: recommendations for diagnosis-the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41:1-7.
13.
Levine A, Koletzko S, Turner D: ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806.
14.
Vande Casteele N, Feagan BG, Gils A: Therapeutic drug monitoring in inflammatory bowel disease: current state and future perspectives. Curr Gastroenterol Rep 2014;16:378.
15.
R Core Team: R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2013. http://www.R-project.org.
16.
R Core Team: R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2015. (Online, May 20, 2016).
17.
Robin X, Turck N, Hainard A, Tiberti N, et al: pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77.
18.
LeDell E, Petersen M, van der Laan M: cvAUC: Cross-Validated Area Under the ROC Curve Confidence Intervals. R package version 1.1.0., 2014.
19.
Bates D, Mächler M, Bolker B: Fitting linear mixed-effects models using lme4. J Stat Soft 2015;67:1-48.
20.
Kuznetsova A, Bruun Brockhoff P, Haubo Bojesen Christen R: lmertest: Tests in Linear Mixed Effects Models. R package version 2.0-29., 2015.
21.
van Buuren S, Groothuis-Oudshoorn K: Mice: multivariate imputation by chained equations in R. J Stat Soft 2011;45:1-67.
22.
Moore C, Corbett G, Moss AC: Systematic review and meta-analysis: serum infliximab levels during maintenance therapy and outcomes in inflammatory bowel disease. J Crohns Colitis 2016;10:619-625.
23.
Noemie, SensMice: Multivariate Imputation by Chained Equations (Iteration Step for Sensitivity Analysis). R package version 1.0., 2010.
24.
Guiotto C, Daperno M, Frigerio F, et al: Clinical relevance and inter-test reliability of anti-infliximab antibodies and infliximab trough levels in patients with inflammatory bowel disease. Dig Liver Dis 2015;48:138-143.
25.
Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC, Sandborn WJ, Cheifetz AS: Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis 2014;20:1996-2003.
26.
Marits P, Landucci L, Sundin U, et al: Trough s-infliximab and antibodies towards infliximab in a cohort of 79 IBD patients with maintenance infliximab treatment. J Crohns Colitis 2014;8:881-889.
27.
Vande Casteele N, Buurman DJ, Sturkenboom MG, et al: Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays. Aliment Pharmacol Ther 2012;36:765-771.
28.
Vande Casteele N, Khanna R, Levesque BG, et al: The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease. Gut 2015;64:1539-1545.
29.
Hämäläinen A, Sipponen T, Kolho KL: Serum infliximab concentrations in pediatric inflammatory bowel disease. Scand J Gastroenterol 2013;48:35-41.
30.
Vande Casteele N, Ferrante M, Van Assche G, et al: Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 2015;148:1320-1329.e3.
31.
Singh N, Rosenthal CJ, Melmed GY: Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2014;20:1708-1713.
32.
Cornillie F, Hanauer SB, Diamond RH, et al: Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut 2014;63:1721-1727.
33.
Zitomersky NL, Atkinson BJ, Fournier K, et al: Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD. Inflamm Bowel Dis 2015;21:307-314.
34.
Minar P, Saeed SA, Afreen M, et al: Practical use of infliximab concentration monitoring in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2016;62:715-722.
35.
Q-Inflixi Manual o Matriks Biotek Website. (Online, May 20, 2016).
36.
Q-ATI Manual o Matriks Biotek Website. (Online, May 20, 2016).
37.
Frymoyer A, Piester TL, Park KT: Infliximab dosing strategies and predicted trough exposure in children with Crohn disease. J Pediatr Gastroenterol Nutr 2016;62:723-727.
38.
Detection of Infliximab and Anti-Infliximab Antibodies with ELISA or High-Performance Liquid Chromatography Summary, CADTH Website. (Online, May 20, 2016).
39.
Fabian O, Hradsky O, Potuznikova K, Kalfusova A, Krskova L, Hornofova L, Zamecnik J, Bronsky J: Low predictive value of histopathological scoring system for complications development in children with Crohn's disease. Pathol Res Pract 2017;213:353-358.
40.
Dolinšek J, Rižnik P, Sabath L, Mičetić-Turk D: Fecal calprotectin as a marker of the severity of mucosal inflammation in children with inflammatory bowel disease. Wien Klin Wochenschr 2016;128:253-259.
41.
Turner D, Levine A, Walters TD, Focht G, Otley A, López VN, Koletzko S, Baldassano R, Mack D, Hyams J, Griffiths AM: Which PCDAI version best reflects intestinal inflammation in pediatric Crohn disease? J Pediatr Gastroenterol Nutr 2017;64:254-260.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
