P0424A validated predictive biomarker for postoperative endoscopic recurrence in Crohn’s disease: intestinal epithelial GPX4

Abstract Background Postoperative recurrence in Crohn’s disease (CD) remains common, underscoring the need to identify patients at risk to guide postoperative management. We previously discovered that reduced intestinal epithelial Glutathione peroxidase 4 (GPX4), an antioxidant that protects against ileitis1, 2, correlates with postoperative endoscopic recurrence (ePOR) 3. Here, we evaluate intestinal epithelial GPX4 at the time of resection as a predictive biomarker for ePOR. Methods Three independent European ileocolonic (ICR) cohorts were included (n = 241 CD patients), with availability of ileocolonic resection specimens (Fig. 1A-1B). Intestinal epithelial GPX4 protein expression was quantified on formalin-fixed paraffin-embedded (FFPE) ileal tissue sections, using quantitative confocal microscopy. ePOR was defined as Rutgeerts score ≥i2b at 6 months after ICR, and was compared to complete absence of endoscopic activity (Rutgeerts score i0). Odds ratios for recurrence were estimated across GPX4 quintiles using logistic regression, and then pooled using a random-effects patient-level meta-analysis (R 4. 3. 2). Results Included patients had a mean (±SD) age of 36 (±13) years, 52% were female, 41% had penetrating disease, and 35% were current smokers (Fig. 1B). Reduced intestinal epithelial GPX4 expression predicted ePOR in a patient-level meta-analysis across the three ICR cohorts. In particular, lower GPX4 expression was inversely and approximately log-linearly associated with higher odds of ePOR (Fig. 1C). Each 1-SD decrease in GPX4 expression significantly increased ePOR risk, also after multivariable adjustment (OR 1. 78, 95%CI 1. 22–2. 58; P 0. 001) (Fig. 1D). Importantly, GPX4 expression was unrelated to GPX4 genetic variation (rs2024092, P = 0. 60), histologic severity of inflammation (Geboes Grade, P = 0. 792), or established clinical risk factors (sex: P = 0. 370, penetrating disease: P = 0. 646, or active smoking (P = 0. 532) ). Adding GPX4 to a model with established clinical risk factors significantly improved the prediction of ePOR (AUROC from 0. 638 to 0. 707; P = 0. 014) (Fig. 1E-1F). Conclusion Intestinal epithelial GPX4 expression independently predicts ePOR, and improves prediction beyond established clinical risk factors. As such, GPX4 may serve as a clinically valuable biomarker to guide patient-tailored postoperative management in CD. References: 1. Mayr L, Grabherr F, Schwärzler J, et al. Dietary lipids fuel gpx4-restricted enteritis resembling crohn’s disease. Nature communications 2020;11: 1775. 2. Schwärzler J, Mayr L, Vich Vila A, et al. Pufa-induced metabolic enteritis as a fuel for crohn’s disease. Gastroenterology 2022;162: 1690-704. 3. Verstockt S, Machiels K, Dehairs J, et al. OP01 sequencing-based gene network analysis reveals a profound role for ferroptosis key gene gpx4 in post-operative endoscopic recurrence in crohn’s disease (ecco conference). Journal of Crohn’s and Colitis 2023;17, Issue Supplement₁: i1-i3. Conflict of interest: Ms. Verstockt, Sare: No conflict of interest Schwärzler, Julian Peter: No conflict of interest Willeit, Peter: Peter Willeit receives consultancy fees from Novartis Pharmaceuticals. Bislenghi, Gabriele: No conflict of interest Meyer, Moritz: No conflict of interest Mayer, Lisa: No conflict of interest Machiels, Kathleen: postdoctoral fellow of the Fund for Scientific Research-Flanders, Belgium (FWO-Vlaanderen) until 5/01/2021. Pfizer Medical advisor employee in inflammation and immunology since 5/01/2021. De Hertogh, Gert: Other: Fees to my institution KULeuven for my activities as central pathology reviewer for: Centocor and Eli Lilly Lenfant, Matthias: None Scheffauer, Laura: No conflict of interest Grabherr, Felix: No conflict of interest Jans, Deborah: No conflict of interest Abdurahiman, Saeed: No conflict of interest Cleynen, Isabelle: No conflict of interest Jukic, Almina: No conflict of interest Zundel, Luis: No conflict of interest Moser, Patrizia: No conflict of interest Forer, Lukas: Lukas Forer received consultancy fees from Novartis Pharmaceuticals. Witsch-Baumgartner, Martina: No conflict of interest Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Guedelha Sabino, João: Speaker’s fees: Lilly, Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos. Consultancy fees: Takeda, Pfizer, Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia. Research support: Galapagos, Viatris, and Eurogenerics. JS is supported by a Senior Clinical researcher grant from the Research foundation – Flanders. D’Hoore, André Jan Louis: Personal Fees: Takeda, Janssens Hess, Michael: No conflict of interest Kaser, Arthur: Personal Fees: MiroBio, Merck, Janssen, GSK, Pfizer, ONO Pharmaceuticals, Ferring, Nimbus, Astrazeneca, Imhotex, Boehringer Ingelheim, Novartis, Applied Molecular Transport, Eli Lilly, Galapagos Blumberg, Richard S: No conflict of interest Koch, Robert: No conflict of interest Le Bourhis, Lionel: No conflict of interest Hammoudi, Nassim: Other: Honoraria from Janssen Cazals-Hatem, Dominique Louise: No conflict of interest Vermeire, Séverine: Grant: AbbVie, Pfizer, Takeda, J & J, Galapagos Personal Fees: AbbVie - AbolerIS Pharma - AgomAb - Alimentiv - Arena Pharmaceuticals - AstraZeneca - Avaxia- BMS - Boehringer Ingelheim - Celgene - CVasThera - Dr Falk Pharma - Ferring - Galapagos - Genentech-Roche - Gilead - GSK - Hospira - Imidomics - Janssen -J & J - Lilly - Materia Prima - MiroBio - Morphic - MrMHealth - Mundipharma - MSD - Pfizer - Prodigest - Progenity - Promakhos Therapeutics - Prometheus - Robarts Clinical Trials - Second Genome - Shire - Surrozen - Takeda - Theravance - Tillots Pharma AG - Zealand Pharma - Other: AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc, Galapagos, Mundipharma, Tilg, Herbert: No conflict of interest Allez, Matthieu: Grant: Janssen, Genentech/Roche, Takeda Personal Fees: Abbvie, Amgen, Astra-Zeneca, Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead, IQVIA, Janssen, Novartis, Pfizer, Spyre therapeutics, Roche, Takeda, Tillots Adolph, Timon: No conflict of interest Verstockt, Bram: Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. Stock options Vagustim and Thethis Pharma.