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Gut. 2015 Feb;64(2):233-42. doi: 10.1136/gutjnl-2013-306518. Epub 2014 Apr 3.

Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy.

Author information

1
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Postdoctoral CAPES fellow, Brazil.
2
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Bioinformatics Platform, CIBERehd, Barcelona, Spain.
3
Hoffmann-La Roche, Nutley, New Jersey, USA Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
4
Bioinformatics Platform, CIBERehd, Barcelona, Spain.
5
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
6
Hoffmann-La Roche, Nutley, New Jersey, USA EMD Serono Research & Development Institute, Boston, Massachusetts, USA.

Abstract

BACKGROUND:

Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα.

OBJECTIVE:

To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy.

DESIGN:

An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7).

RESULTS:

We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19.

CONCLUSIONS:

Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.

KEYWORDS:

CROHN'S DISEASE; IBD BASIC RESEARCH; INFLAMMATORY MEDIATORS; TNF-ALPHA

PMID:
24700437
DOI:
10.1136/gutjnl-2013-306518
[Indexed for MEDLINE]

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