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  • External validation of serum biomarkers predicting short-term and mid/long-term relapse in patients with Crohn’s disease stopping infliximab

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Inflammatory bowel disease
Original research
External validation of serum biomarkers predicting short-term and mid/long-term relapse in patients with Crohn’s disease stopping infliximab
  1. Nicolas Pierre1,
  2. Vân Anh Huynh-Thu2,
  3. Dominique Baiwir3,
  4. Gabriel Mazzucchelli4,
  5. Maximilien Fléron3,
  6. Lisette Trzpiot4,
  7. Gauthier Eppe4,
  8. Edwin De Pauw4,
  9. David Laharie5,
  10. Jack Satsangi6,
  11. Peter Bossuyt7,
  12. Lucine Vuitton8,9,
  13. Sophie Vieujean1,10,
  14. Jean-Frédéric Colombel11,
  15. Marie-Alice Meuwis1,10,
  16. Edouard Louis1,10
  17. GETAID and the SPARE-Biocycle research group
    1. 1Laboratory of Translational Gastroenterology, GIGA-institute, Liège University, Liège, Belgium
    2. 2Department of Electrical Engineering and Computer Science, Liège University, Liège, Belgium
    3. 3GIGA Proteomics Facility, Liège University, Liège, Belgium
    4. 4Laboratory of Mass Spectrometry, MolSys Research Unit, Liège University, Liège, Belgium
    5. 5Service d’Hépato-gastroentérologie et oncologie digestive, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    6. 6Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
    7. 7Imelda GI Clinical Research Center, Imelda Hospital, Bonheiden, Belgium
    8. 8Department of Gastroenterology, Besançon University Hospital, Besancon, France
    9. 9UMR 1098, Franche-Comté University, Besancon, France
    10. 10Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
    11. 11Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    1. Correspondence to Dr Nicolas Pierre, Laboratory of Translational Gastroenterology, GIGA-institute, Liège University, Liège, Belgium; nicolas.pierre{at}uliege.be

    Abstract

    Objective In patients with Crohn’s disease (CD) on combination therapy (infliximab and immunosuppressant) and stopping infliximab (cohort from the study of infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI)), the risk of short-term (≤6 months) and mid/long-term relapse (>6 months) was associated with distinct blood protein profiles. Our aim was to test the external validity of this finding in the SPARE cohort (A proSpective Randomized Controlled Trial comParing infliximAb-antimetabolites Combination Therapy to Anti-metabolites monotheRapy and Infliximab monothErapy in Crohn's Disease Patients in Sustained Steroid-free Remission on Combination Therapy).

    Design In SPARE, patients with CD in sustained steroid-free clinical remission and on combination therapy were randomly allocated to three arms: continuing combination therapy, stopping infliximab or stopping immunosuppressant. In the baseline serum of the STORI and SPARE (arm stopping infliximab) cohorts, we studied 202 immune-related proteins. The proteins associated with time to relapse (univariable Cox model) were compared between STORI and SPARE. The discriminative ability of biomarkers (individually and combined in pairs) was evaluated by the c-statistic (concordance analysis) which was compared with C-reactive protein (CRP), faecal calprotectin and a previously validated model (CEASE).

    Results In STORI and SPARE, distinct blood protein profiles were associated with the risk of short-term (eg, high level: CRP, haptoglobin, interleukin-6, C-type lectin domain family 4 member C) and mid/long-term relapse (eg, low level: Fms-related tyrosine kinase 3 ligand, kallistatin, fibroblast growth factor 2). At external validation, the top 10 biomarker pairs showed a higher c-statistic than the CEASE model, CRP and faecal calprotectin in predicting short-term (0.76–0.80 vs 0.74 vs 0.71 vs 0.69, respectively) and mid/long-term relapse (0.66–0.68 vs 0.61 vs 0.52 vs 0.59, respectively).

    Conclusion In patients with CD stopping infliximab, we confirm that the risk of short-term and mid/long-term relapse is associated with distinct blood protein profiles showing the potential to guide infliximab withdrawal.

    Trial registration number NCT00571337 and NCT02177071.

    • CROHN'S DISEASE
    • 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 data (clinical, selected reaction monitoring (SRM) and proximity extension assay) supporting our findings are available at https://panoramaweb.org/7PNxFY.url. For the STORI study, SRM raw data are available at https://panoramaweb.org/atQBcH.url (dataset identifier: PXD019434). For the SPARE study, SRM raw data are available at https://panoramaweb.org/7PNxFY.url(dataset identifier: PXD051233). The Python codes used for data analysis are available at https://github.com/vahuynh/STORI_SPARE.

    https://doi.org/10.1136/gutjnl-2024-332648

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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 data (clinical, selected reaction monitoring (SRM) and proximity extension assay) supporting our findings are available at https://panoramaweb.org/7PNxFY.url. For the STORI study, SRM raw data are available at https://panoramaweb.org/atQBcH.url (dataset identifier: PXD019434). For the SPARE study, SRM raw data are available at https://panoramaweb.org/7PNxFY.url(dataset identifier: PXD051233). The Python codes used for data analysis are available at https://github.com/vahuynh/STORI_SPARE.

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      Footnotes

      • X @ibd_kliniek

      • M-AM and EL contributed equally.

      • Collaborators The following GETAID centres (investigators) participated in the STORI trial: Amiens (Jean-Louis Dupas), Bordeaux (David Laharie), Caen (Jean-Marie Reimund), Clichy-Beaujon (Yoram Bouhnik), Colombes-L Mourier (Pauline Jouet), Gent (Martine De Vos), Liège (Jacques Belaiche, Edouard Louis), Lille (Jean-Frédéric Colombel, Gwenola Vernier-Massouille), Lyon (Stéphane Nancey), Marseille (Jean Charles Grimaud), Montpellier (Michel Veyrac), Nantes (Arnaud Boureille, Mathurin Flamant), Paris-HEGP (Raymond Jian), Paris-Lariboisière (Philippe Marteau), Paris-St Louis (Marc Lemann, Matthieu Allez), Rouen (Guillaume Savoye), Strasbourg (Bernard Duclos) and Tours (Laurence Picon). Members of the SPARE Biocycle research group collaborative authorship: A Andrews, M Sparrow, R Leong, S Connor, G Radforth-Smith, P De Cruz, F Baert, E Louis, P Bossuyt, M Resche-Rignon, N Ding, S Almer, S Ben-Horin, JF Colombel,B Siegmund, J Preiss, A Stallmach, T Liceni, O Grip, J Halfvarson, D Durai, F Cummings, C Seilinger, M Parkes, J Lindsay, G Lambrecht, P VanHootegem, JF Rahier, M Dewitte, X Hebuterne, E Chanteloup, R Altwegg, S Nancey, G Bouguen, G Pineton de Chambrun, F Pollenot, Y Bouhnik, L Vuitton, M Nachury, D Laharie, S Nancey, M Fumery, G Bouguen, L Picon, C Gilletta, S Viennot, X Roblin, J Satsangi, J Lindsay, M Parkes, P Irving, C Lamb, D Durai, R Pollok, G D’haens, E Hertervig, O Grip, J Halfvarsson.

      • Contributors EL and J-FC conceived the STORI and SPARE trials. EL, DL, J-FC, PB, LV and JS were involved in the recruitment of patients and their follow-up. NP developed the selected reaction monitoring (SRM) method with the help of M-AM and DB. NP and LT performed the sample preparation for the SRM analysis. DB, GM, MF, LT, GE and EDP managed the instrumental set-up for the SRM analysis. NP, SV and VAH-T verified and curated the data. VAH-T and NP performed the statistical analysis. NP created the figures. NP wrote the manuscript. EL, M-AM, SV, VAH-T, PB, JS and J-FC critically reviewed the manuscript. NP is the guarantor.

      • Funding This work was supported by the European Union’s Horizon 2020 under the grant agreement N° 633168 — BIOCYCLE (PHC-13-2014), the Walloon Region and the Fond Européen de Développement Régional (FEDER) (Grant portfolio 246099-510388) and internal funding from the Liege University Hospital.

      • Competing interests PB has received research grants from AbbVie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly and Takeda; and consulting fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda and Tetrameros. LV has received fees from AbbVie, Amgen, Biogen, Mylan, Takeda, MSD, Janssen, Pfizer, Ferring and Galapagos. SV has received speaker’s fees from AbbVie, Ferring, Janssen and Takeda. J-FC has received grants from AbbVie, Janssen Pharmaceuticals, Prometheus, Takeda and Bristol Myers Squibb; receiving payment for lectures from AbbVie, and Takeda; receiving consulting fees from AbbVie, Amgen, AnaptysBio, Allergan, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Genentech (Roche), Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Invea, Iterative Scopes, Merck, Landos, Microba Life Science, Novartis, Otsuka Pharmaceutical, Pfizer, Protagonist Therapeutics, Prometheus, Sanofi, Seres, Takeda, Teva, TiGenix, Vifor; and hold stock options in Intestinal Biotech Development. EL has received educational and research grants from Janssen, Pfizer, AbbVie and Takeda, Fresenius-Kabi; speaker fees from AbbVie, Dr Falk Pharma, Ferring, Janssen, Pfizer, Celgene, Bristol Myers Squibb (BMS), Galapagos and Takeda; advisory board fees for AbbVie, Celgene, Ferring, Janssen, BMS, Pfizer, Takeda, Gilead-Galapagos, Arena and Elli Lilly; and consultancy fees from AbbVie.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • 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.