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

Background Anti-tumour necrosis factor alpha (TNF alpha) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNF alpha. Objective To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNF alpha 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-TNF alpha therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNF alpha 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-TNF alpha and non-IBD controls (n=7). Results We confirmed that response to anti-TNF alpha 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-TNF alpha 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-TNF alpha 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.