Project description:We used microarrays to identify mucosal gene signatures predictive of response to infliximab (IFX) in patients with inflammatory bowel disease (IBD) and to gain more insight into the pathogenesis of IBD. Keywords: drug response and treatment effect
Project description:To further explore predictors and targets of response to infliximab, differential gene expression was examined at baseline and after 6 and 24 hours and 2 weeks after the first infusion of infliximab in TRD patients who were infliximab responders versus nonresponders, and compared to placebo-treated patients. All subjects were administered either infliximab (5mg/kg, n=30) or placebo (n=30) through an indwelling catheter at the Emory Division of Digestive Diseases at 3 separate time points (baseline, 2 weeks and 6 weeks). Infliximab infusion dosing protocol and scheduling were matched to the standard intravenous induction routine for the treatment of inflammatory bowel disease.
Project description:We used microarrays to identify mucosal gene signatures predictive of response to infliximab (IFX) in patients with inflammatory bowel disease (IBD) and to gain more insight into the pathogenesis of IBD. Keywords: drug response and treatment effect Mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from 61 IBD patients (24 ulcerative colitis (UC), 19 Crohnâs colitis (CDc) and 18 Crohnâs ileitis (CDi)), refractory to corticosteroids and/or immunosuppression, before and 4-6 weeks after (except for 1 CDc patient) their first infliximab infusion and in normal mucosa from 12 control patients (6 colon and 6 ileum). The patients were classified for response to infliximab based on endoscopic and histologic findings at 4-6 weeks after first infliximab treatment. Total RNA was isolated from intestinal mucosal biopsies, labelled and hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays.
Project description:A gene expression profiling sub-study was conducted in which colonic biopsy samples were collected for RNA extraction and hybridization to microarrays from 48 patients with UC who were participating in ACT 1, a placebo-controlled study of infliximab. Gene expression profiles from infliximab responders were compared with those of baseline and infliximab non-responder samples. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Infliximab non-responders had a molecular phenotype that closely resembled that of untreated patients with UC. Unlike responders, non-responders do not effectively modulate TH1, TH2, and TH17 pathways. Gene expression can differentiate placebo and infliximab responders.
Project description:In this study we wanted to identify baseline predictors of successful vedolizumab therapy in patients with inflammatory bowel disease.
Project description:Background & Aims. As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently we showed T cell-mediated rejection of kidney and heart transplants share large scale molecular changes. We hypothesized that UC would manifest a similar disturbance, and that these features would correlate with response to infliximab. Results. UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance expressed as principal component 1 correlated with conventional assessments e.g. Mayo scores, serum albumin, and lymphoplasmacytic infiltrate. When assessed in published microarray studies, the disturbance predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was usually seen even in non-responders. Similar changes were seen in Crohn’s colitis (CDc). Conclusions. The molecular phenotype of UC manifests a large scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab.
Project description:A gene expression profiling sub-study was conducted in which colonic biopsy samples were collected for RNA extraction and hybridization to microarrays from 48 patients with UC who were participating in ACT 1, a placebo-controlled study of infliximab. Gene expression profiles from infliximab responders were compared with those of baseline and infliximab non-responder samples. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Infliximab non-responders had a molecular phenotype that closely resembled that of untreated patients with UC. Unlike responders, non-responders do not effectively modulate TH1, TH2, and TH17 pathways. Gene expression can differentiate placebo and infliximab responders. Patients with moderate-to-severe, active UC were treated with infliximab or placebo at weeks 0, 2, 6 and every 8 weeks thereafter. Biopsy samples (n=113) were collected from 48 patients at baseline, weeks 8 and 30 for RNA extraction and microarray analysis.
Project description:Objectives: We monitored the mRNA expression profiles of peripheral blood cells during treatment with a tumor necrosis factor-a inhibitor, infliximab, in patients with rheumatoid arthritis (RA). Using a DNA microarray analysis, we demonstrated a unique set of genes, with distinct baseline and post-treatment changes in expression between responders and non-responders to infliximab treatment.Methods: Using a customized low-density cDNA microarray and a reliable data collection system, we monitored the mRNA expression profiles of whole blood cells from 18 RA patients before and after the infusion of infliximab for up to 22 weeks. The clinical response to treatment with infliximab was determined using the American College of Rheumatology (ACR) response criteria, the disease activity score of 28 joints (DAS28), and individual clinical parameters. The patients were classified as responders or non-responders based on their ACR50% response at 22 weeks. Results: Approximately 15% of the total genes were found to exhibit a greater than 1.5-fold change, compared to their reference values, at one or more time points during the 22 weeks of infliximab therapy. The expression of inflammatory genes, such as interferon-related genes, was strongly correlated with the serum level of C-reactive protein and the DAS28. The increased expression of inflammatory genes in responders was normalized within 2 weeks and then remained at a normal level during the treatment period. In contrast, in the non-responders, the elevated expression at baseline, although it was significantly decreased at 2 weeks, returned to the baseline level after 14 weeks. In addition to inflammatory genes, we identified several groups of genes with distinct differences in expression between the responders and non-responders.Conclusions: Our results suggest that a customized low-density microarray is useful for monitoring mRNA expression profiles in peripheral blood cells, enabling us to identify a unique set of genes with differentially regulated expressions in responders and non-responders to a TNF inhibitor among patients with RA. Keywords: disease state analysis 18 RA Patients, We have collected blood samples into PAXgene tube systems for microarray measurement from patients as follows, just before first iv-injection of infliximab, 2 weeks, 14 weeks, and 22 weeks after first infliximab injection.