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Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
  1. Ingrid Arijs
  1. University Hospital Gasthuisberg, Leuven, Belgium
    1. Katherine Li
    1. Centocor Research and Development, Inc., Radnor, Pennsylvania, United States
      1. Gary Toedter
      1. Centocor Research and Development, Inc., Radnor, Pennsylvania, United States
        1. Roel Quintens
        1. Katholieke Universiteit Leuven, Leuven, Belgium
          1. Leentje Van Lommel
          1. Katholieke Universiteit Leuven, Leuven, Belgium
            1. Kristel Van Steen
            1. University of Liege, Liege, Belgium
              1. Peter Leemans
              1. University Hospital Gasthuisberg, Leuven, Belgium
                1. Gert De Hertogh
                1. University Hospital Gasthuisberg, Leuven, Belgium
                  1. Katleen Lemaire
                  1. Katholieke Universiteit Leuven, Leuven, Belgium
                    1. Marc Ferrante
                    1. University Hospital Gasthuisberg, Leuven, Belgium
                      1. Fabian Schnitzler
                      1. University Hospital Gasthuisberg, Leuven, Belgium
                        1. Lieven Thorrez
                        1. Katholieke Universiteit Leuven, Leuven, Belgium
                          1. Keying Ma
                          1. Centocor Research and Development, Inc., Radnor, Pennsylvania, United States
                            1. Xiao-Yu R Song
                            1. Ethicon, Inc., Somerville, NJ, United States
                              1. Colleen Marano
                              1. Centocor Research and Development, Inc., Radnor, Pennsylvania, United States
                                1. Gert Van Assche
                                1. University Hospital Gasthuisberg, Leuven, Belgium
                                  1. Séverine Vermeire
                                  1. University Hospital Gasthuisberg, Leuven, Belgium
                                    1. Karel Geboes
                                    1. University Hospital Gasthuisberg, Leuven, Belgium
                                      1. Frans Schuit
                                      1. Katholieke Universiteit Leuven, Leuven, Belgium
                                        1. Frédéric Baribaud
                                        1. Centocor Research and Development, Inc., Radnor, Pennsylvania, United States
                                          1. Paul Rutgeerts (paul.rutgeerts{at}uz.kuleuven.ac.be)
                                          1. University Hospital Gasthuisberg, Leuven, Belgium

                                            Abstract

                                            Background & Aims: Infliximab is an effective treatment for ulcerative colitis (UC) with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-TNF-alpha is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in UC.

                                            Methods: Two cohorts of patients who received their first treatment with infliximab for refractory UC were studied. Response to infliximab was defined as endoscopic and histologic healing. Total RNA from pre-treatment colonic mucosal biopsies was analyzed 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 5 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 UC 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 UC.

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