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

<h3>Background</h3> 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. <h3>Objective</h3> To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy. <h3>Design</h3> 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). <h3>Results</h3> 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. <h3>Conclusions</h3> 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.