Microbial and metabolic features associating outcome of infliximab therapy in pediatric Crohn’s disease
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ABSTRACT:
PROVIDER: PRJEB38210 | ENA |
REPOSITORIES: ENA
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Project description:REMICADE (infliximab) is a drug used to treat active Crohn’s disease and is being tested in an experiment to see if it may be useful in preventing relapse of Crohn’s disease after surgical resection. This study will compare the effects (both good and bad) of REMICADE (infliximab) to those of placebo. Placebo looks like the drug being studied but has no active ingredients.
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Project description:This study will determine if the drug infliximab is safe for treating inflammatory bowel disease (IBD) in patients with chronic granulomatous disease (CGD). IBD is an inflammation or irritation of the gut that leads to symptoms such as diarrhea, bloating and stomach cramps. CGD is an inherited disease affecting white blood cells called neutrophils in which patients are susceptible to repeated bacterial and fungal infections. They also have a higher incidence of some autoimmune diseases, such as IBD. Infliximab is approved to treat Crohn’s disease, an IBD similar to that seen in patients with CGD.
Patients 10 years of age and older with CGD and IBD may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, electrocardiogram (EKG), tuberculosis skin test (PPD skin testing), and stool test for the presence of infections. Additional tests may be done, including colonoscopy (procedure using a flexible tube through the rectum to examine the lining of the gut) and imaging studies such as an x-ray, chest CT scan (test using a special x-ray machine), MRI (test using a magnetic field and radio waves), and barium studies (study using a drinkable solution of barium to help enhance the x-ray pictures of the gut).
Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures:
Group 1
Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below).
Group 2
Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years.
Group 3
Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.
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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.
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Project description: Not available
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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.
2011-07-22 | GSE23597 | GEO
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.
2013-04-01 | GSE45468 | GEO
Project description:We sought to find a gene-expression multigene predictor of response to infliximab therapy in Rheumatoid Arthritis patients. Using internal and external cross-validation systems we have built and validated an 8-gene predictor for response to infliximab.
2009-10-02 | GSE12051 | GEO
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.
2011-07-21 | E-GEOD-23597 | biostudies-arrayexpress
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. In a recent clinical trial, the TNF antagonist infliximab was found to reduce depressive symptoms compared to placebo but only in patients with increased inflammation as reflected by a CRP >5 mg/L. 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.
2013-04-01 | E-GEOD-45468 | biostudies-arrayexpress
Project description:Infliximab, an anti-TNFa monoclonal antibody, is an effective treatment for ulcerative colitis (UC) inducing over 60% of patients to respond to treatment. Consequently, about 40% of patients do not respond. This study analyzed mucosal gene expression from patients enrolled in ACT1 to provide a predictive response signature for infliximab treatment. Keywords: predictive response signature
2009-08-25 | GSE12251 | GEO