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Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy
- Source :
- Gut. 64:233-242
- Publication Year :
- 2014
- Publisher :
- BMJ, 2014.
-
Abstract
- Background Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn9s 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.
- Subjects :
- Adult
Male
Transcriptional Activation
Necrosis
Colon
Inflammation
Disease
Antibodies, Monoclonal, Humanized
S100A8
Young Adult
Crohn Disease
Gastrointestinal Agents
medicine
Humans
Treatment Failure
Intestinal Mucosa
Aged
Oligonucleotide Array Sequence Analysis
Crohn's disease
Interleukin-6
Tumor Necrosis Factor-alpha
business.industry
Gene Expression Profiling
Anti-Inflammatory Agents, Non-Steroidal
Adalimumab
Gastroenterology
Antibodies, Monoclonal
Middle Aged
medicine.disease
Infliximab
CXCL1
Gene Expression Regulation
Immunology
Female
Tumor necrosis factor alpha
IL17A
Inflammation Mediators
medicine.symptom
business
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....81b181e4e596f3bca265da81edd7af5f