BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

2nd Clinic of Pediatrics Iuliu Hatieganu University of Medicine and Pharmacy Emergency Clinical Hospital for Children Cluj Napoca Romania

Amsterdam UMC location VUMC Amsterdam Netherlands

Children's Hospital University of Helsinki Helsinki Finland

Children's Hospital Zagreb Faculty of Medicine Zagreb Croatia

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics Faculty of Medicine in Pilsen Charles University Prague Czech Republic

Department of Pediatrics University Hospital Charles University Hradec Kralove Czech Republic

Department of Probability and Mathematical Statistics Faculty of Mathematics and Physics Charles University Prague Czech Republic

Erasmus MC Sophia Children's Hospital Rotterdam Netherlands

Ghent University Hospital Ghent Belgium

Hospital S Joao do Porto Porto Portugal

Hvidovre Hospital Copenhagen Denmark

Pediatric Institute Clinic University of Debrecen Debrecen Hungary

Polish American Children's Hospital Jagiellonian University Cracow Poland

Zobrazit více v PubMed

Ruemmele, F. M. et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J. Crohns Colitis 8, 1179–1207 (2014). PubMed DOI

van Rheenen, P. F. et al. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN guideline update. J. Crohns Colitis 15, 171–194 (2020).

Bronsky, J. et al. Diagnostic and therapeutic approach in paediatric inflammatory bowel diseases: results from a clinical practice survey. J. Pediatr. Gastroenterol. Nutr. 68, 676–683 (2019). PubMed DOI

Markowitz, J., Grancher, K., Kohn, N., Lesser, M. & Daum, F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 119, 895–902 (2000). PubMed DOI

Hradsky, O., Copova, I., Zarubova, K., Nevoral, J. & Bronsky, J. Time to relapse in children with crohn’s disease treated with azathioprine and nutritional therapy or corticosteroids. Dig. Dis. Sci. 61, 2041–2050 (2016). PubMed DOI

Riello, L. et al. Tolerance and efficacy of azathioprine in pediatric Crohn’s disease. Inflamm. Bowel Dis. 17, 2138–2143 (2011). PubMed DOI

Jongsma, M. M. E. et al. First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn’s disease: an open-label multicentre randomised controlled trial. Gut 71, 34–42 (2020).

Hyams, J. et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: reach open-label extension. Curr. Med. Res. Opin. 27, 651–662 (2011). PubMed DOI

Ruemmele, F. M. et al. Efficacy of infliximab in pediatric Crohn’s disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm. Bowel Dis. 15, 388–394 (2009). PubMed DOI

Pariente, B. et al. Development of the Crohn’s disease digestive damage score, the Lemann Score. Inflamm. Bowel Dis. 17, 1415–1422 (2011). PubMed DOI

D’Haens, G. et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 371, 660–667 (2008). PubMed DOI

Peyrin-Biroulet, L., Bigard, M. A., Malesci, A. & Danese, S. Step-up and top-down approaches to the treatment of Crohn’s disease: early may already be too late. Gastroenterology 135, 1420–1422 (2008). PubMed DOI

Hindorf, U., Lindqvist, M., Hildebrand, H., Fagerberg, U. & Almer, S. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment. Pharm. Ther. 24, 331–342 (2006). DOI

Gearry, R. B., Barclay, M. L., Burt, M. J., Collett, J. A. & Chapman, B. A. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol. Drug Saf. 13, 563–567 (2004). PubMed DOI

Bonovas, S. et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis. Clin. Gastroenterol. Hepatol. 14, 1385.e10–1397.e10 (2016). DOI

de Bie, C. I., Escher, J. C. & de Ridder, L. Antitumor necrosis factor treatment for pediatric inflammatory bowel disease. Inflamm. Bowel Dis. 18, 985–1002 (2012). PubMed DOI

Subramaniam, K. et al. Hepatosplenic T-cell lymphoma, immunosuppressive agents and biologicals: what are the risks? Intern. Med. J. 44, 287–290 (2014). PubMed DOI

Siegel, C. A., Marden, S. M., Persing, S. M., Larson, R. J. & Sands, B. E. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin. Gastroenterol. Hepatol. 7, 874–881 (2009). PubMed DOI PMC

de Bie, C. I. et al. Disease phenotype at diagnosis in pediatric Crohn’s disease: 5-year analyses of the Eurokids Registry. Inflamm. Bowel Dis. 19, 378–385 (2013). PubMed DOI

Levine, A. et al. ESPGHAN revised Porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J. Pediatr. Gastroenterol. Nutr. 58, 795–806 (2014). PubMed DOI

Jaspers, G. J. et al. Azathioprine maintains first remission in newly diagnosed pediatric Crohn’s disease. Inflamm. Bowel Dis. 12, 831–836 (2006). PubMed DOI

Punati, J. et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm. Bowel Dis. 14, 949–954 (2008). PubMed DOI

Atia, O. et al. Role of thiopurines in pediatric inflammatory bowel diseases: a real-life prospective cohort study. J. Pediatr. Gastroenterol. Nutr. 70, 825–832 (2020). PubMed DOI

Gupta, N. et al. Risk factors for initial surgery in pediatric patients with Crohn’s disease. Gastroenterology 130, 1069–1077 (2006). PubMed DOI

Henderson, P. et al. Serum C-reactive protein and CRP genotype in pediatric inflammatory bowel disease: influence on phenotype, natural history, and response to therapy. Inflamm. Bowel Dis. 21, 596–605 (2015). PubMed DOI

Kugathasan, S. et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet 389, 1710–1718 (2017). PubMed DOI PMC

Levine, A. et al. Comparison of outcomes parameters for induction of remission in new onset pediatric Crohn’s disease: evaluation of the Porto IBD Group “Growth Relapse and Outcomes with Therapy” (Growth CD) Study. Inflamm. Bowel Dis. 20, 278–285 (2014). PubMed DOI

Siegel, C. A. et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm. Bowel Dis. 17, 30–38 (2011). PubMed DOI

Siegel, C. A. et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment. Pharm. Ther. 43, 262–271 (2016). DOI

Waljee, A. K. et al. Machine learning algorithms for objective remission and clinical outcomes with thiopurines. J. Crohns Colitis 11, 801–810 (2017). PubMed DOI PMC

Nguyen, T. V., Vu, D. H., Nguyen, T. M., Lachaux, A. & Boulieu, R. Exploring associations of 6-thioguanine nucleotide levels and other predictive factors with therapeutic response to azathioprine in pediatric patients with ibd using multilevel analysis. Inflamm. Bowel Dis. 19, 2404–2410 (2013). PubMed DOI

Dayharsh, G. A. et al. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 122, 72–77 (2002). PubMed DOI

Ford, L. T. & Berg, J. D. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J. Clin. Pathol. 63, 288–295 (2010). PubMed DOI

Kirschner, B. S. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 115, 813–821 (1998). PubMed DOI

Kreijne, J. E. et al. Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment. Aliment. Pharm. Ther. 50, 407–415 (2019). DOI

Mottet, C. et al. Experts opinion on the practical use of azathioprine and 6-mercaptopurine in inflammatory bowel disease. Inflamm. Bowel Dis. 22, 2733–2747 (2016). PubMed DOI

Weersma, R. K. et al. Increased incidence of azathioprine-induced pancreatitis in Crohn’s disease compared with other diseases. Aliment. Pharm. Ther. 20, 843–850 (2004). DOI

Fuentes, D. et al. High-dose azathioprine in children with inflammatory bowel disease. Aliment. Pharm. Ther. 17, 913–921 (2003). DOI

Papay, P. et al. The impact of thiopurines on the risk of surgical recurrence in patients with Crohn’s disease after first intestinal surgery. Am. J. Gastroenterol. 105, 1158–1164 (2010). PubMed DOI

Levine, A. et al. Crohn’s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial. Gastroenterology 157, 440.e8–450.e8 (2019). DOI

Svolos, V. et al. Treatment of active Crohn’s disease with an ordinary food-based diet that replicates exclusive enteral nutrition. Gastroenterology 156, 1354.e6–1367.e6 (2019). DOI

Lindberg, E., Jarnerot, G. & Huitfeldt, B. Smoking in Crohn’s disease: effect on localisation and clinical course. Gut 33, 779–782 (1992). PubMed DOI PMC

Preventing Recurrence of Crohn's Disease Post-Ileocaecal Surgery in Paediatric Patients: A Therapy Guide Based on Systematic Review of the Evidence

Sustainability of biologic treatment in paediatric patients with Crohn's disease: population-based registry analysis