Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
- I Arijs1,2,
- K Li3,
- G Toedter4,
- R Quintens2,
- L Van Lommel2,
- K Van Steen5,
- P Leemans6,
- G De Hertogh6,
- K Lemaire2,
- M Ferrante1,
- F Schnitzler1,
- L Thorrez2,
- K Ma4,
- X-Y R Song7,
- C Marano8,
- G Van Assche1,
- S Vermeire1,
- K Geboes6,
- F Schuit2,
- F Baribaud4,
- P Rutgeerts1,9
- 1Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
- 2Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium
- 3Bioinformatics, Centocor Research and Development, Inc., Radnor, Pennsylvania, USA
- 4Biomarker, Centocor Research and Development, Inc., Radnor, Pennsylvania, USA
- 5Department of Electrical Engineering and Computer Science (Montefiore Institute), University of Liege, Liege, Belgium
- 6Department of Morphology and Molecular Pathology, University Hospital Gasthuisberg, Leuven, Belgium
- 7Ethicon, Inc., Somerville, New Jersey, USA
- 8Clinical Immunology, Centocor Research and Development, Inc., Radnor, Pennsylvania, USA
- 9Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, Leuven, Belgium
- Correspondence to Professor P Rutgeerts, Department of Gastroenterology, University of Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; paul.rutgeerts{at}uz.kuleuven.be
- Revised 25 May 2009
- Accepted 23 June 2009
- Published Online First 20 August 2009
Abstract
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.
Footnotes
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Funding This work was supported by a grant from the Fund for Scientific Research – Flanders (FWO) Belgium (FWO project nr.G.0440.06) and by Centocor.
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Competing interests PR, SV, GvA and KG have received grant support, lecture fees and consulting fees from Centocor and Schering–Plough. GT, K Li, CM, KM and FB are employees of Centocor Research and Development, Inc. X-YRS is a former employee of Centocor Research and Development, Inc. and is currently an employee of Ethicon, Inc. The other authors have no competing interests.
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Provenance and peer review Not commissioned; externally peer reviewed.
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Ethics approval The ethics committee of the University Hospital Gasthuisberg, Leuven, approved the study on 3 March 2005.
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‣ Supplementary material (an appendix and four tables) is published online only at http://gut.bmj.com/content/vol58/issue12
