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

Casper Steenholdt; Klaus Bendtzen; Jørn Brynskov; Ole Ø Thomsen; Lars K Munck; Lisbet A Christensen; Gitte Pedersen; Jens Kjeldsen; Mark A Ainsworth

doi:10.1093/ecco-jcc/jjv004

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

Casper Steenholdt, Klaus Bendtzen, Jørn Brynskov, Ole Ø Thomsen, Lars K Munck, Lisbet A Christensen, Gitte Pedersen, Jens Kjeldsen, Mark A Ainsworth

Institut for Klinisk Medicin

44 Citationer (Scopus)

Abstract

BACKGROUND AND AIMS: 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.

CONCLUSION: 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.

Originalsprog	Engelsk
Tidsskrift	Journal of Crohn's & colitis
Vol/bind	9
Udgave nummer	3
Sider (fra-til)	238-45
Antal sider	8
ISSN	1873-9946
DOI	https://doi.org/10.1093/ecco-jcc/jjv004
Status	Udgivet - 1 mar. 2015

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10.1093/ecco-jcc/jjv004

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Citationsformater

Steenholdt, C., Bendtzen, K., Brynskov, J., Thomsen, O. Ø., Munck, L. K., Christensen, L. A., Pedersen, G., Kjeldsen, J., & Ainsworth, M. A. (2015). 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. Journal of Crohn's & colitis, 9(3), 238-45. https://doi.org/10.1093/ecco-jcc/jjv004

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. / Steenholdt, Casper; Bendtzen, Klaus; Brynskov, Jørn et al.
I: Journal of Crohn's & colitis, Bind 9, Nr. 3, 01.03.2015, s. 238-45.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Steenholdt, C, Bendtzen, K, Brynskov, J, Thomsen, OØ, Munck, LK, Christensen, LA, Pedersen, G, Kjeldsen, J & Ainsworth, MA 2015, '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', Journal of Crohn's & colitis, bind 9, nr. 3, s. 238-45. https://doi.org/10.1093/ecco-jcc/jjv004

Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Munck LK, Christensen LA et al. 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. Journal of Crohn's & colitis. 2015 mar. 1;9(3):238-45. doi: 10.1093/ecco-jcc/jjv004

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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 = "BACKGROUND AND AIMS: 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.CONCLUSION: 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.",

keywords = "Adolescent, Adult, Antibodies, Crohn Disease, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Monitoring, Female, Gastrointestinal Agents, Humans, Infliximab, Linear Models, Male, Prospective Studies, ROC Curve, Treatment Failure, Young Adult",

author = "Casper Steenholdt and Klaus Bendtzen and J{\o}rn Brynskov and Thomsen, {Ole {\O}} and Munck, {Lars K} and Christensen, {Lisbet A} and Gitte Pedersen and Jens Kjeldsen and Ainsworth, {Mark A}",

note = "Copyright {\textcopyright} 2015 European Crohn{\textquoteright}s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].",

year = "2015",

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doi = "10.1093/ecco-jcc/jjv004",

language = "English",

volume = "9",

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journal = "Journal of Crohn's & colitis",

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TY - JOUR

T1 - 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

AU - Steenholdt, Casper

AU - Bendtzen, Klaus

AU - Brynskov, Jørn

AU - Thomsen, Ole Ø

AU - Munck, Lars K

AU - Christensen, Lisbet A

AU - Pedersen, Gitte

AU - Kjeldsen, Jens

AU - Ainsworth, Mark A

PY - 2015/3/1

Y1 - 2015/3/1

N2 - BACKGROUND AND AIMS: 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.CONCLUSION: 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.

AB - BACKGROUND AND AIMS: 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.CONCLUSION: 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.

KW - Adolescent

KW - Adult

KW - Antibodies

KW - Crohn Disease

KW - Dose-Response Relationship, Drug

KW - Drug Administration Schedule

KW - Drug Monitoring

KW - Female

KW - Gastrointestinal Agents

KW - Humans

KW - Infliximab

KW - Linear Models

KW - Male

KW - Prospective Studies

KW - ROC Curve

KW - Treatment Failure

KW - Young Adult

U2 - 10.1093/ecco-jcc/jjv004

DO - 10.1093/ecco-jcc/jjv004

M3 - Journal article

C2 - 25576753

SN - 1873-9946

VL - 9

SP - 238

EP - 245

JO - Journal of Crohn's & colitis

JF - Journal of Crohn's & colitis

IS - 3

ER -