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Crohn's Disease Mucosal Transcriptomes Highlight JAK/STAT Pathway Involvement in Postoperative Recurrence

36 Pages Posted: 22 Aug 2019

See all articles by Marjolaine Ngollo

Marjolaine Ngollo

University of Paris - Institut de Recherche Saint-Louis

Kevin Perez

University of Paris - Institut de Recherche Saint-Louis

Nassim Hammoudi

University of Paris - Institut de Recherche Saint-Louis

Yuri Gorelik

Technion-Israel Institute of Technology

Marc Delord

University of Paris - Institut de Recherche Saint-Louis

Claire Auzolle

University of Paris - Institut de Recherche Saint-Louis

Hugo Bottois

University of Paris - Institut de Recherche Saint-Louis

Dominique Cazals-Hatem

Hospital Beaujon

Madeleine Bezault

Saint Louis Hospital - REMIND Group

Stéphane Nancey

Hospital Claude Huriez

Benjamin Pariente

Hospital Claude Huriez

Xavier Treton

Hospital Beaujon

Mathurin Fumery

University Hospital Center Amiens

Antony Buisson

University Hospital Center Clermont-Ferrand

Nicolas Barnich

Université Clermont Auvergne

Philippe Seksik

Sorbonne University

REMIND Study Group Invertigators

Shai S. Shen-Orr

Technion-Israel Institute of Technology

Lionel Le Bourhis

University of Paris - Institut de Recherche Saint-Louis

Matthieu Allez

University of Paris - Intestinal Immunity in Inflammation and Cancer; Saint Louis Hospital - Gastroenterology Department; Saint Louis Hospital - REMIND Group

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Abstract

Background: Crohn's disease displays heterogeneity in terms of disease location, progression and response to treatment. Most patients require an intestinal resection due to complicated disease, and a majority of them will experience disease recurrence. We aimed to characterize biological pathways driving postoperative recurrence and to identify predictors which could guide therapeutic management.

Methods: In this multicentre prospective study, we conducted transcriptome analysis on ileal mucosa of CD patients undergoing ileocolonic resection. Samples were collected from the most inflamed part of the ileum (n=200), from the ileal resection margin (n=149) and in the neo-terminal ileum 6 months after surgery (n=122). The primary endpoint was postoperative endoscopic recurrence at month 6. We applied a regression model to identify gene signatures predicting for endoscopic recurrence.

Findings: Molecular patterns of early endoscopic recurrence significantly differed from those observed in chronic inflammation. Gene expression analysis of the inflamed area of the surgical specimens identified clusters of CD patients. However, pathway gene signatures at the ileal margin were superior to those of the inflamed area to predict postoperative outcome. Several pathways, including JAK/STAT signalling, cell adhesion molecules and extracellular matrix protein were associated with a higher risk of endoscopic recurrence. JAK/STAT pathway activation at the ileal margin predicted early postoperative endoscopic recurrence (AUC of 0*74) and was associated with a higher of clinical relapse on the long term. A significant increase of p-STAT3 levels at the ileal margin was associated with severe endoscopic recurrence (i3, i4) compared to no recurrence (i0) (p=0*02) and moderate recurrence (i1, i2) (p=0*04).

Interpretation: Gene expression analysis at the ileal margin of the surgical specimen may strongly predict postoperative outcome. The inflammatory processes associated with postoperative recurrence differ from those engaged in chronic inflammation. Activation of JAK/STAT signalling at the ileal margin of the surgical specimen is predictive of postoperative recurrence and should be specifically targeted.

Trial Registration: ClinicalTrials.gov (NCT03458195).

Funding Statement: This work was supported by Helmsley Charitable Trust and the Institut national de santé et de la recherche biomedical (INSERM).

Declaration of Interests: SN received honoraria from MSD, Abbvie, Takeda, Janssen, HAC Pharma, Tillots, Ferring, and Novartis. BP received honoraria from AbbVie, MSD, Takeda, Janssen, Bioagaran, and Ferring. AB received honoraria from MSD, Abbvie, Ferring, Takeda, Vifor Pharma, Sanofi-Aventis, Hospira, and Janssen. XT received honoraria from Abbvie, MSD, Takeda, Ferring, Norgine, and Janssen. MF received honoraria from AbbVie, MSD, Takeda, Janssen, Pfizer, Ferring, and Boehringer. PS received honoraria from Takeda, MSD, Biocodex, Ferring and Abbvie and financial support from Takeda. MA received honoraria from Janssen, Takeda, Pfizer, MSD, Abbvie, Ferring, Amgen, Biogen, Celgene, and Genentech/Roche. All other authors have no conflict of interest regarding this study.

Ethics Approval Statement: All patients provided an informed written consent. The study was approved by AFFSAPS (IDRCB: 2009-A00205-52) and the French Ethic Committee (CPP 2009/17).

Suggested Citation

Ngollo, Marjolaine and Perez, Kevin and Hammoudi, Nassim and Gorelik, Yuri and Delord, Marc and Auzolle, Claire and Bottois, Hugo and Cazals-Hatem, Dominique and Bezault, Madeleine and Nancey, Stéphane and Pariente, Benjamin and Treton, Xavier and Fumery, Mathurin and Buisson, Antony and Barnich, Nicolas and Seksik, Philippe and Invertigators, REMIND Study Group and Shen-Orr, Shai S. and Bourhis, Lionel Le and Allez, Matthieu, Crohn's Disease Mucosal Transcriptomes Highlight JAK/STAT Pathway Involvement in Postoperative Recurrence (08/14/2019 12:49:19). Available at SSRN: https://ssrn.com/abstract=3439555

Marjolaine Ngollo

University of Paris - Institut de Recherche Saint-Louis

France

Kevin Perez

University of Paris - Institut de Recherche Saint-Louis

France

Nassim Hammoudi

University of Paris - Institut de Recherche Saint-Louis

France

Yuri Gorelik

Technion-Israel Institute of Technology

Technion City
Haifa 32000, Haifa 32000
Israel

Marc Delord

University of Paris - Institut de Recherche Saint-Louis

France

Claire Auzolle

University of Paris - Institut de Recherche Saint-Louis

France

Hugo Bottois

University of Paris - Institut de Recherche Saint-Louis

France

Dominique Cazals-Hatem

Hospital Beaujon

France

Madeleine Bezault

Saint Louis Hospital - REMIND Group

France

Stéphane Nancey

Hospital Claude Huriez

France

Benjamin Pariente

Hospital Claude Huriez

France

Xavier Treton

Hospital Beaujon

France

Mathurin Fumery

University Hospital Center Amiens

France

Antony Buisson

University Hospital Center Clermont-Ferrand

France

Nicolas Barnich

Université Clermont Auvergne

Clermont-Ferrand
France

Philippe Seksik

Sorbonne University

UFR 927, 4 Place Jussieu
Paris, F-75252
France

Shai S. Shen-Orr

Technion-Israel Institute of Technology

Technion City
Haifa 32000, Haifa 32000
Israel

Lionel Le Bourhis

University of Paris - Institut de Recherche Saint-Louis

France

Matthieu Allez (Contact Author)

University of Paris - Intestinal Immunity in Inflammation and Cancer ( email )

France

Saint Louis Hospital - Gastroenterology Department ( email )

France

Saint Louis Hospital - REMIND Group ( email )

France

No contact information is available for REMIND Study Group Invertigators

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