P064. Identification of inflammatory mediators in Crohn's disease patients who are unresponsive to anti-TNF therapy - A transcriptional analysis of intestinal mucosa
R.F. Leal1, N. Planell2, R. Kajekar3, J.J. Lozano2, I. Ordás4, I. Dotti1, M. Esteller1, M.C. Masamunt1, H. Parmar3, E. Ricart4, J. Panés1, A. Salas1, 1IDIBAPS, Hospital Clínic, CIBERehd, Department of Gastroenterology, Barcelona, Spain, 2IDIBAPS, CIBERehd, Bioinformatics Platform, Barcelona, Spain, 3Hoffmann-La Roche, Nutley, New Jersey, United States, 4Hospital Clínic Barcelona, Department of Gastroenterology, Barcelona, Spain
Crohn's disease (CD) is a chronic inflammatory disease with a relapsing course. Its clinical treatment has greatly improved with the introduction of antibodies such as anti-tumor necrosis factor (TNF)-α. Nonetheless, over time up to 40% of patients become unresponsive to anti-TNF-α treatment.
Aim: To identify the molecular mechanisms underlying the persistence of mucosal lesions in patients who do not respond to anti-TNF-α therapy.
Whole genome-transcriptional analysis was carried out using intestinal biopsies from CD patients before and after anti-TNF-α therapy. The transcriptional signature of responders was compared to that of non-responders after anti-TNF-α therapy. Non-inflammatory bowel disease (non-IBD) controls were also used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of individuals. For statistical analysis, the non-parametric Wilcoxon test was performed and the Benjamini-Hochberg procedure was used for multiple testing corrections. A p-value of <0.05 was considered statistically significant. Pearson's product moment correlation was used to test for any associations between paired data. All analyses were performed using R statistical environment (V.2.15.0). The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the Hospital Clinic of Barcelona (Spain).
The response to anti-TNF-α was accompanied by significant regulation of a large number of genes. Expression of a subset of these genes (i.e. IL-1B, S100A8, CXCL1, etc.) correlated with endoscopic activity and C-reactive protein. Remarkably, patients that failed to respond to anti-TNF-α showed a mixed signature, maintaining up-regulation of IL-1B, IL-17 and S100A8, while exhibiting significant down-regulation of other genes commonly up-regulated in active CD, including IL-6 and IL-23p19.
Anti-TNF-α therapy significantly down-regulates a subset of inflammatory genes even in patients that do not achieve endoscopic remission, suggesting that these genes may not be responsible for driving inflammation in non-responders. On the other hand, IL-1B and IL-17 were identified as genes that remained altered in non-responders, which suggests the existence of more relevant targets to modulate mucosal damage in this set of refractory patients.