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Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to... Full description

Journal Title: Gut 2009, Vol.58 (12), p.1612-1619
Main Author: Arijs, I
Other Authors: Li, K , Toedter, G , Quintens, R , Van Lommel, L , Van Steen, K , Leemans, P , De Hertogh, G , Lemaire, K , Ferrante, M , Schnitzler, F , Thorrez, L , Ma, K , Song, X-Y R , Marano, C , Van Assche, G , Vermeire, S , Geboes, K , Schuit, F , Baribaud, F , Rutgeerts, P
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: BMJ Publishing Group Ltd and British Society of Gastroenterology
ID: ISSN: 0017-5749
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recordid: cdi_liege_orbi_v2_oai_orbi_ulg_ac_be_2268_38707
title: Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
format: Article
creator:
  • Arijs, I
  • Li, K
  • Toedter, G
  • Quintens, R
  • Van Lommel, L
  • Van Steen, K
  • Leemans, P
  • De Hertogh, G
  • Lemaire, K
  • Ferrante, M
  • Schnitzler, F
  • Thorrez, L
  • Ma, K
  • Song, X-Y R
  • Marano, C
  • Van Assche, G
  • Vermeire, S
  • Geboes, K
  • Schuit, F
  • Baribaud, F
  • Rutgeerts, P
subjects:
  • Abridged Index Medicus
  • Adult
  • Antibodies, Monoclonal - therapeutic use
  • Biological and medical sciences
  • Biopsy
  • Bones, joints and connective tissue. Antiinflammatory agents
  • Care and treatment
  • Cohort Studies
  • Colitis, Ulcerative - drug therapy
  • Colitis, Ulcerative - genetics
  • Colitis, Ulcerative - metabolism
  • Colitis, Ulcerative/drug therapy/genetics/metabolism
  • Colon - metabolism
  • Dosage and administration
  • Drug Resistance - genetics
  • Endoscopy
  • Enzymes
  • Female
  • Gastroenterology & hepatology
  • Gastroenterology. Liver. Pancreas. Abdomen
  • Gastroentérologie & hépatologie
  • Gastrointestinal Agents - therapeutic use
  • Gene expression
  • Gene Expression Profiling - methods
  • Genetic aspects
  • Human health sciences
  • Humans
  • Immune response
  • Immunomodulators
  • Inflammation
  • Inflammatory bowel disease
  • Infliximab
  • Intestinal Mucosa - metabolism
  • Ligands
  • Male
  • Medical sciences
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis - methods
  • Other diseases. Semiology
  • Pathogenesis
  • Pharmacology. Drug treatments
  • Prognosis
  • Proteins
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction - methods
  • Rodents
  • Sciences de la santé humaine
  • Smoking
  • Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
  • Studies
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha - immunology
  • Tumor necrosis factor-TNF
  • Ulcerative colitis
  • Young Adult
ispartof: Gut, 2009, Vol.58 (12), p.1612-1619
description: Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
language: eng
source:
identifier: ISSN: 0017-5749
fulltext: no_fulltext
issn:
  • 0017-5749
  • 1468-3288
  • 1468-3288
url: Link


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titleMucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
creatorArijs, I ; Li, K ; Toedter, G ; Quintens, R ; Van Lommel, L ; Van Steen, K ; Leemans, P ; De Hertogh, G ; Lemaire, K ; Ferrante, M ; Schnitzler, F ; Thorrez, L ; Ma, K ; Song, X-Y R ; Marano, C ; Van Assche, G ; Vermeire, S ; Geboes, K ; Schuit, F ; Baribaud, F ; Rutgeerts, P
creatorcontribArijs, I ; Li, K ; Toedter, G ; Quintens, R ; Van Lommel, L ; Van Steen, K ; Leemans, P ; De Hertogh, G ; Lemaire, K ; Ferrante, M ; Schnitzler, F ; Thorrez, L ; Ma, K ; Song, X-Y R ; Marano, C ; Van Assche, G ; Vermeire, S ; Geboes, K ; Schuit, F ; Baribaud, F ; Rutgeerts, P
descriptionBackground and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
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publisherLondon: BMJ Publishing Group Ltd and British Society of Gastroenterology
subjectAbridged Index Medicus ; Adult ; Antibodies, Monoclonal - therapeutic use ; Biological and medical sciences ; Biopsy ; Bones, joints and connective tissue. Antiinflammatory agents ; Care and treatment ; Cohort Studies ; Colitis, Ulcerative - drug therapy ; Colitis, Ulcerative - genetics ; Colitis, Ulcerative - metabolism ; Colitis, Ulcerative/drug therapy/genetics/metabolism ; Colon - metabolism ; Dosage and administration ; Drug Resistance - genetics ; Endoscopy ; Enzymes ; Female ; Gastroenterology & hepatology ; Gastroenterology. Liver. Pancreas. Abdomen ; Gastroentérologie & hépatologie ; Gastrointestinal Agents - therapeutic use ; Gene expression ; Gene Expression Profiling - methods ; Genetic aspects ; Human health sciences ; Humans ; Immune response ; Immunomodulators ; Inflammation ; Inflammatory bowel disease ; Infliximab ; Intestinal Mucosa - metabolism ; Ligands ; Male ; Medical sciences ; Middle Aged ; Oligonucleotide Array Sequence Analysis - methods ; Other diseases. Semiology ; Pathogenesis ; Pharmacology. Drug treatments ; Prognosis ; Proteins ; Reproducibility of Results ; Reverse Transcriptase Polymerase Chain Reaction - methods ; Rodents ; Sciences de la santé humaine ; Smoking ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Studies ; Treatment Outcome ; Tumor Necrosis Factor-alpha - immunology ; Tumor necrosis factor-TNF ; Ulcerative colitis ; Young Adult
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0Arijs, I
1Li, K
2Toedter, G
3Quintens, R
4Van Lommel, L
5Van Steen, K
6Leemans, P
7De Hertogh, G
8Lemaire, K
9Ferrante, M
10Schnitzler, F
11Thorrez, L
12Ma, K
13Song, X-Y R
14Marano, C
15Van Assche, G
16Vermeire, S
17Geboes, K
18Schuit, F
19Baribaud, F
20Rutgeerts, P
title
0Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
1Gut
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descriptionBackground and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
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1Adult
2Antibodies, Monoclonal - therapeutic use
3Biological and medical sciences
4Biopsy
5Bones, joints and connective tissue. Antiinflammatory agents
6Care and treatment
7Cohort Studies
8Colitis, Ulcerative - drug therapy
9Colitis, Ulcerative - genetics
10Colitis, Ulcerative - metabolism
11Colitis, Ulcerative/drug therapy/genetics/metabolism
12Colon - metabolism
13Dosage and administration
14Drug Resistance - genetics
15Endoscopy
16Enzymes
17Female
18Gastroenterology & hepatology
19Gastroenterology. Liver. Pancreas. Abdomen
20Gastroentérologie & hépatologie
21Gastrointestinal Agents - therapeutic use
22Gene expression
23Gene Expression Profiling - methods
24Genetic aspects
25Human health sciences
26Humans
27Immune response
28Immunomodulators
29Inflammation
30Inflammatory bowel disease
31Infliximab
32Intestinal Mucosa - metabolism
33Ligands
34Male
35Medical sciences
36Middle Aged
37Oligonucleotide Array Sequence Analysis - methods
38Other diseases. Semiology
39Pathogenesis
40Pharmacology. Drug treatments
41Prognosis
42Proteins
43Reproducibility of Results
44Reverse Transcriptase Polymerase Chain Reaction - methods
45Rodents
46Sciences de la santé humaine
47Smoking
48Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
49Studies
50Treatment Outcome
51Tumor Necrosis Factor-alpha - immunology
52Tumor necrosis factor-TNF
53Ulcerative colitis
54Young Adult
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7De Hertogh, G
8Lemaire, K
9Ferrante, M
10Schnitzler, F
11Thorrez, L
12Ma, K
13Song, X-Y R
14Marano, C
15Van Assche, G
16Vermeire, S
17Geboes, K
18Schuit, F
19Baribaud, F
20Rutgeerts, P
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titleMucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
authorArijs, I ; Li, K ; Toedter, G ; Quintens, R ; Van Lommel, L ; Van Steen, K ; Leemans, P ; De Hertogh, G ; Lemaire, K ; Ferrante, M ; Schnitzler, F ; Thorrez, L ; Ma, K ; Song, X-Y R ; Marano, C ; Van Assche, G ; Vermeire, S ; Geboes, K ; Schuit, F ; Baribaud, F ; Rutgeerts, P
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1Adult
2Antibodies, Monoclonal - therapeutic use
3Biological and medical sciences
4Biopsy
5Bones, joints and connective tissue. Antiinflammatory agents
6Care and treatment
7Cohort Studies
8Colitis, Ulcerative - drug therapy
9Colitis, Ulcerative - genetics
10Colitis, Ulcerative - metabolism
11Colitis, Ulcerative/drug therapy/genetics/metabolism
12Colon - metabolism
13Dosage and administration
14Drug Resistance - genetics
15Endoscopy
16Enzymes
17Female
18Gastroenterology & hepatology
19Gastroenterology. Liver. Pancreas. Abdomen
20Gastroentérologie & hépatologie
21Gastrointestinal Agents - therapeutic use
22Gene expression
23Gene Expression Profiling - methods
24Genetic aspects
25Human health sciences
26Humans
27Immune response
28Immunomodulators
29Inflammation
30Inflammatory bowel disease
31Infliximab
32Intestinal Mucosa - metabolism
33Ligands
34Male
35Medical sciences
36Middle Aged
37Oligonucleotide Array Sequence Analysis - methods
38Other diseases. Semiology
39Pathogenesis
40Pharmacology. Drug treatments
41Prognosis
42Proteins
43Reproducibility of Results
44Reverse Transcriptase Polymerase Chain Reaction - methods
45Rodents
46Sciences de la santé humaine
47Smoking
48Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
49Studies
50Treatment Outcome
51Tumor Necrosis Factor-alpha - immunology
52Tumor necrosis factor-TNF
53Ulcerative colitis
54Young Adult
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1Li, K
2Toedter, G
3Quintens, R
4Van Lommel, L
5Van Steen, K
6Leemans, P
7De Hertogh, G
8Lemaire, K
9Ferrante, M
10Schnitzler, F
11Thorrez, L
12Ma, K
13Song, X-Y R
14Marano, C
15Van Assche, G
16Vermeire, S
17Geboes, K
18Schuit, F
19Baribaud, F
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abstractBackground and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
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