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Inflammatory mediators isolated in patients with Crohn’s disease unresponsive to anti-TNF-alpha
Anti-tumor necrosis factor-alpha was shown to downregulate a subset of inflammation-dependent genes, independent of response to treatment, according to new data suggesting that these genes may not be 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,” the study authors wrote.
Azucena Salas
Investigators analyzed whole-genome transcriptional data using intestinal biopsy specimens from Crohn’s disease (CD) patients who received (n=12) or did not receive (n=10) anti-TNF-alpha therapy. Seventeen controls with non-inflammatory bowel disease (non-IBD) were used for comparisons. Real-time RT-PCR was used to validate genes of interest in an independent cohort of patients with CD who received (n=17) or did not receive (n=16) anti-TNF-alpha, along with non-IBD controls (n=7).
Response to anti-TNF-alpha was accompanied by regulation of a large number of genes, including IL1B, S100A8, CXCL1, correlating with endoscopic activity.
The investigation showed that even patients who did not respond to anti-TNF-alpha presented a mixed signature and maintained increased expression of IL1B, IL17A and S100A8. But these patients also showed significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19.
“Modulation of TNF-alpha-dependent genes in non-responsive patients suggests that lack of response to anti-TNF-alpha does not result from the absence of biological activity of the administered antibody,” the study authors wrote. “Our new results may be instrumental in guiding the choice of treatments to be used in patients who fail to respond to anti-TNF-alpha treatment.”
Disclosure: Research was supported by Hoffmann-La Roche Pharmaceuticals.