Mucosal IL13RA2 expression predicts nonresponse to anti-TNF therapy in Crohn's disease.
Adalimumab
/ pharmacology
Adult
Antibodies, Monoclonal, Humanized
/ pharmacology
Biomarkers
/ metabolism
Cohort Studies
Crohn Disease
/ drug therapy
Female
Gastrointestinal Agents
/ pharmacology
Gene Expression
Humans
Immunotherapy
/ methods
Infliximab
/ pharmacology
Interleukin-13 Receptor alpha2 Subunit
/ biosynthesis
Male
Middle Aged
Mucous Membrane
/ drug effects
Predictive Value of Tests
Treatment Outcome
Tumor Necrosis Factor-alpha
/ antagonists & inhibitors
Journal
Alimentary pharmacology & therapeutics
ISSN: 1365-2036
Titre abrégé: Aliment Pharmacol Ther
Pays: England
ID NLM: 8707234
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
19
10
2018
revised:
04
11
2018
accepted:
13
12
2018
pubmed:
22
1
2019
medline:
4
3
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
Ileocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD). To validate the IL13RA2 biomarker, study its anti-TNF specificity and get a better understanding of the underlying biology driving its expression. IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti-TNF nonresponsiveness, weighted gene co-expression network analysis was applied on publicly available microarray data of IFX-treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers. Increased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti-TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti-TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF-driven pathways were significantly enriched in future anti-TNF nonhealers (P = 5.0 × 10 Increased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti-TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti-TNF drug dosing.
Sections du résumé
BACKGROUND
Ileocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD).
AIM
To validate the IL13RA2 biomarker, study its anti-TNF specificity and get a better understanding of the underlying biology driving its expression.
METHODS
IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti-TNF nonresponsiveness, weighted gene co-expression network analysis was applied on publicly available microarray data of IFX-treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers.
RESULTS
Increased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti-TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti-TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF-driven pathways were significantly enriched in future anti-TNF nonhealers (P = 5.0 × 10
CONCLUSIONS
Increased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti-TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti-TNF drug dosing.
Identifiants
pubmed: 30663072
doi: 10.1111/apt.15126
pmc: PMC6849553
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Biomarkers
0
Gastrointestinal Agents
0
IL13RA2 protein, human
0
Interleukin-13 Receptor alpha2 Subunit
0
Tumor Necrosis Factor-alpha
0
vedolizumab
9RV78Q2002
Infliximab
B72HH48FLU
Adalimumab
FYS6T7F842
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
572-581Subventions
Organisme : Clinical Research Fund KOF
Pays : International
Organisme : Advanced European Research Council
ID : ERC-2015-AdG
Pays : International
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2019 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.
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