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Original research
Discovery of biomarker candidates associated with the risk of short-term and mid/long-term relapse after infliximab withdrawal in Crohn’s patients: a proteomics-based study
  1. Nicolas Pierre1,
  2. Dominique Baiwir2,
  3. Vân Anh Huynh-Thu3,
  4. Gabriel Mazzucchelli4,
  5. Nicolas Smargiasso4,
  6. Edwin De Pauw4,
  7. Yoram Bouhnik5,
  8. David Laharie6,
  9. Jean-Frédéric Colombel7,
  10. Marie-Alice Meuwis1,8,
  11. Edouard Louis1,8
  12. GETAID (Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif)
  1. 1 Laboratory of Translational Gastroenterology, GIGA-Institute, Liege University, Liege, Belgium
  2. 2 GIGA Proteomics Facility, Liege University, Liege, Belgium
  3. 3 Department of Electrical Engineering and Computer Science, Liege University, Liege, Belgium
  4. 4 Laboratory of Mass Spectrometry, MolSys Research Unit, Liege University, Liege, Belgium
  5. 5 Service de Gastroentérologie et Assistance Nutritive, Hôpital Beaujon, Clichy, France
  6. 6 Service d'Hépato-Gastroentérologie, CHU de Bordeaux, Bordeaux, France
  7. 7 Division of Gastroenterology, Icahn School of Medicine at Mount Sina, New York, New York, USA
  8. 8 Hepato-Gastroenterology and Digestive Oncology Department, Liege University, Liege, Belgium
  1. Correspondence to Dr Nicolas Pierre, Laboratory of Translational Gastroenterology, GIGA-institute, Liege University, 4000 Liege, Belgium; nicolas.pierre{at}uliege.be

Abstract

Objective A subset of Crohn’s disease (CD) patients experiences mid/long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients.

Design New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short-term (<6 months) or mid/long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs.

Results Distinct biomarker candidates were associated with the risk (HR) of short-term (15 proteins, 2.9<HR<16.1, p<0.05) and mid/long-term (17 proteins, 2.1<HR<4.7, p<0.05) relapse, they reflect different pathophysiological processes. In stratified and non-stratified datasets, novel marker combinations exhibited a high predicting capacity as shown by their higher Z-scores (false discovery rate <0.001) than C reactive protein and faecal calprotectin (current references in predicting relapse).

Conclusion We identified for the first time circulating biomarker candidates associated with the risk of mid/long-term relapse in CD patients stopping infliximab. We also highlight a sequence of pathophysiological processes leading to relapse, this could help to better understand the disease progression. Our findings may pave the way for a better non-invasive evaluation of the risk of relapse when contemplating antitumour necrosis factor α withdrawal in CD patients.

  • Crohn's disease
  • clinical decision making
  • IBD clinical
  • inflammatory bowel disease
  • infliximab

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All the raw data and results of the discovery step have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD019008. For the verification step, all the SRM raw files and the Skyline files (including those of the quality controls) are available on Panorama with the dataset identifier PXD019434 (https://panoramaweb.org/atQBcH.url).

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Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All the raw data and results of the discovery step have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD019008. For the verification step, all the SRM raw files and the Skyline files (including those of the quality controls) are available on Panorama with the dataset identifier PXD019434 (https://panoramaweb.org/atQBcH.url).

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Footnotes

  • DB and VAH-T contributed equally.

  • M-AM and EL contributed equally.

  • Contributors NP, M-AM, YB, DL, J-FC and EL designed the experiments. The GETAID provided the samples and the clinical information. M-AM performed the discovery study. M-AM, DB and NP developed the SRM method. NP and M-AM performed the sample preparation. NP, M-AM, DB, NS, GM and EDP managed the injection of the proteomic experiments and provided advises for the raw data analysis. VAH-T and NP performed the statistical analysis. NP, M-AM, VAH-T and EL interpreted the data. NP, M-AM and EL wrote the paper.

  • Funding This work was supported by the Walloon Region and the Fond européen de développement régional (FEDER) [Grant portfolio 2 46099-510388]. Financial support for the STORI trial was provided by the SNFGE and the association François Aupetit. M-AM received an ECCO research grant (2012) for the discovery study. Additional support was provided by internal funding from ULiège and CHU de Liège.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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