OBJECTIVES: There is a paucity of validated predictors of response to anti-tumor necrosis factor (TNF) in pediatric Crohn's disease (CD). We aimed to evaluate the predictive utility of intestinal gene expression to predict response to anti-TNF in children with CD. METHODS: We enrolled children with CD before initiating anti-TNF as part of the prospective biobank of the pediatric inflammatory bowel disease Porto group of ESPGHAN. Genes potentially associated with therapeutic response were first preselected from a systematic literature review. Ribonucleic acid was extracted and sequenced from inflamed ileal biopsies of 20 children before initiating anti-TNF (13 with steroid-free remission [SFR] at 12 months, and seven with primary nonresponse [PNR]). An external validation cohort including 22 children (21 SFR, 1 PNR) was enrolled from Germany and Canada. Using maximum relevance-minimum redundancy (mRMR) methods, we constructed a support vector machine-learning model evaluated via leave-one-out cross-validation and permutation testing. RESULTS: Of 1799 studies identified in the systematic review, 24 met the inclusion criteria, reporting on 150 genes possibly associated with anti-TNF response in children or adults. In the Porto group cohort, 30 genes were associated with treatment response, of which five (TREM1, IL23R, CCL7, IL17F, and YES1) were most frequently selected. A multivariable model of these genes achieved high predictive utility (area under receiver operating characteristic curve: 0.88 [95% confidence interval: 0.69-1.0], sensitivity/specificity/positive predictive value/negative predictive value: 92%/71%/86%/83%). The same genomic signature in external validation achieved accuracy of 82% (i.e., 18/22 samples were classified correctly, including the single PNR patient). CONCLUSION: Increased expression of five genes is associated with higher rate of anti-TNF response in pediatric CD. Prospective studies are now warranted to validate these genes as biomarkers for treatment selection.

Department of Developmental Biology and Cancer Research Institute for Medical Research Israel Canada Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel

Department of Immunology Trinity College Dublin Dublin Ireland

Department of Pediatrics Centre de Recherche du CHU Sainte Justine and University of Montreal Montréal Quebec Canada

Department of Pediatrics Dr von Hauner Children's Hospital University Hospital LMU Munich Germany

Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition The Eisenberg R and D Authority Shaare Zedek Medical Center The Hebrew University of Jerusalem Jerusalem Israel

Our Lady's Children's Hospital Crumlin Ireland

Paediatric Department Vittore Buzzi Children's Hospital University of Milan Milan Italy

Pediatric Gastroenterology and Liver Unit Sapienza University of Rome Rome Italy

Pediatric Gastroenterology Hepatology and Nutrition Unit University Hospital Motol Prague Czech Republic

Pediatric Hepatology Gastroenterology and Transplantation ASST Papa Giovanni XXIII Bergamo Italy

Zobrazit více v PubMed

Malmborg P, Grahnquist L, Ideström M, et al. Presentation and progression of childhood‐onset inflammatory bowel disease in Northern Stockholm County. Inflamm Bowel Dis. 2015;21:1098‐1108.

Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn's disease complicated by strictures: a systematic review. Gut. 2013;62:1072‐1084.

Atia O, Orlanski‐Meyer E, Lujan R, et al. Improved outcomes of paediatric and adult Crohn's disease and association with emerging use of biologics: a nationwide study from the Epi‐IIRN. J Crohn's Col. 2022;16:778‐785.

Atia O, Focht G, Lujan R, et al. Perianal Crohn disease is more common In children and is associated with complicated disease course despite higher utilization of biologics: a population‐based study from the epidemiology group of the Israeli IBD research nucleus (epiIIRN). J Pediatr Gastroenterol Nutr. 2022;74:788‐793.

Atia O, Friss C, Focht G, et al. Durability of adalimumab and infliximab in children with Crohn's disease: a nationwide comparison from the epi‐IIRN cohort. Inflamm Bowel Dis. 2024;30:2097‐2104.

Kennedy NA, Heap GA, Green HD, et al. Predictors of anti‐TNF treatment failure in anti‐TNF‐naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4:341‐353.

Fumery M, Dupont C, Ley D, et al. Long‐term effectiveness and safety of anti‐TNF in pediatric‐onset inflammatory bowel diseases: a population‐based study. Dig Liver Dis. 2024;56:21‐28.

Atia O, Kang B, Orlansky‐Meyer E, et al. Existing prediction models of disease course in paediatric Crohn's disease are poorly replicated in a prospective inception cohort. J Crohn's Col. 2022;16:1039‐1048.

Peters LA, Perrigoue J, Mortha A, et al. A functional genomics predictive network model identifies regulators of inflammatory bowel disease. Nat Genet. 2017;49:1437‐1449.

Gaujoux R, Starosvetsky E, Maimon N, et al. Cell‐centred meta‐analysis reveals baseline predictors of anti‐TNFα non‐response in biopsy and blood of patients with IBD. Gut. 2019;68:604‐614.

James JP, Nielsen BS, Langholz E, Malham M, Høgdall E, Riis LB. Estimating tissue‐specific TNF mRNA levels prior to anti‐TNFα treatment may support therapeutic optimisation in IBD patients. Scand J Gastroenterol. 2023;58:1237‐1245.

Ezirike Ladipo J, He Z, Chikwava K, Robbins K, Beri J, Molle‐Rios Z. Oncostatin‐M does not predict treatment response in inflammatory bowel disease in a pediatric cohort. J Pediatr Gastroenterol Nutr. 2021;73:352‐357.

Campbell GR, Rawat P, To RK, Spector SA. HIV‐1 tat upregulates TREM1 expression in human microglia. J Immunol. 2023;211:429‐442.

West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor‐neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23:579‐589.

Gole B, Potočnik U. Pre‐treatment biomarkers of anti‐tumour necrosis factor therapy response in Crohn's disease: a systematic review and gene ontology analysis. Cells. 2019;8:515.

Zhang X, Hu J, Suo L, Yang Z, Xu T, Zhang Y. [IL‐17 and IL23 expression as a predictor of response to infliximab treatment in Crohn's disease]. Zhonghua Nei Ke Za Zhi. 2015;54:940‐944.

Iacucci M, Jeffery L, Acharjee A, et al. Computer‐aided imaging analysis of probe‐based confocal laser endomicroscopy with molecular labeling and gene expression identifies markers of response to biological therapy in IBD patients: the endo‐omics study. Inflamm Bowel Dis. 2023;29:1409‐1420.

Noor NM, Lee JC, Bond S, et al. A biomarker‐stratified comparison of top‐down versus accelerated step‐up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open‐label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024;9:415‐427.

Thomas T, Friedrich M, Rich‐Griffin C, et al. A longitudinal single‐cell Atlas of anti‐tumour necrosis factor treatment in inflammatory bowel disease. Nat Immunol. 2024;25:2152‐2165.

Zheng HB. Application of single‐cell omics in inflammatory bowel disease. World J Gastroenterol. 2023;29:4397‐4404.

Garrido‐Trigo A, Corraliza AM, Veny M, et al. Macrophage and neutrophil heterogeneity at single‐cell spatial resolution in human inflammatory bowel disease. Nat Commun. 2023;14:4506.