Gut. 2024 Nov 11;73(12):1965-1973.doi: 10.1136/gutjnl-2024-332648.

Nicolas Pierre ¹, Vân Anh Huynh-Thu ², Dominique Baiwir ³, Gabriel Mazzucchelli ⁴, Maximilien Fléron ³, Lisette Trzpiot ⁴, Gauthier Eppe ⁴, Edwin De Pauw ⁴, David Laharie ⁵, Jack Satsangi ⁶, Peter Bossuyt ⁷, Lucine Vuitton ^8 9, Sophie Vieujean ^10 11, Jean-Frédéric Colombel ¹², Marie-Alice Meuwis ^# 10 11, Edouard Louis ^# 10 11; GETAID and the SPARE-Biocycle research group

Collaborators

• GETAID and the SPARE-Biocycle research group: 

Jean-Louis Dupas, David Laharie, Jean-Marie Reimund, Yoram Bouhnik, Pauline Jouet, Martine De Vos, Jacques Belaiche, Edouard Louis, Jean-Frédéric Colombel, Gwenola Vernier-Massouille, Stéphane Nancey, Jean Charles Grimaud, Michel Veyrac, Arnaud Boureille, Mathurin Flamant, Raymond Jian, Philippe Marteau, Marc Lemann, Matthieu Allez, Guillaume Savoye, Bernard Duclos, Laurence Picon, 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, J F 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 Van Hootegem, J F 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

Author information

¹Laboratory of Translational Gastroenterology, GIGA-institute, Liège University, Liège, Belgium nicolas.pierre@uliege.be.

²Department of Electrical Engineering and Computer Science, Liège University, Liège, Belgium.

³GIGA Proteomics Facility, Liège University, Liège, Belgium.

⁴Laboratory of Mass Spectrometry, MolSys Research Unit, Liège University, Liège, Belgium.

⁵Service d'Hépato-gastroentérologie et oncologie digestive, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

⁶Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.

⁷Imelda GI Clinical Research Center, Imelda Hospital, Bonheiden, Belgium.

⁸Department of Gastroenterology, Besançon University Hospital, Besancon, France.

⁹UMR 1098, Franche-Comté University, Besancon, France.

¹⁰Laboratory of Translational Gastroenterology, GIGA-institute, Liège University, Liège, Belgium.

¹¹Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium.

¹²Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

^#Contributed equally.

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.