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Risk stratification of pediatric IBD: What disease phenotype does your patient really have?

Ghassan Wahbeh MD Associate Professor, Director IBD Program Seattle Children’s Hospital University of Washington. Risk stratification of pediatric IBD: What disease phenotype does your patient really have?. Content. Background The natural history of pediatric IBD Phenotypes and behavior

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Risk stratification of pediatric IBD: What disease phenotype does your patient really have?

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  1. Ghassan Wahbeh MD Associate Professor, Director IBD Program Seattle Children’s Hospital University of Washington Risk stratification of pediatric IBD: What disease phenotype does your patient really have?

  2. Content • Background • The natural history of pediatric IBD • Phenotypes and behavior • Complications • Can we predict pediatric IBD course? • Impact of mucosal healing

  3. IBD: Age at presentation Years 0 10 20 30 40 50 80 60 70 25 20 Percent of Cases 15 10 5 0 Loftus, Gastroenterology 2003; 124:abstract 278

  4. Puberty

  5. Wahbeh G et al. Inflamm Bowel Dis. 2008 Dec;14(12):1753

  6. Challenges in Peds IBD • Early Diagnosis • Longer exposure to disease • Longer exposure to medication • Risk of adverse events • Medications • Testing • Presentation more severe than adult onset

  7. Pediatric IBD: burden & opportunity • Achieving treatment goals • Clinical remission • Restoring growth &development • Restoring bone health • Mucosal healing • IBD does not end at age 18-21 years • Response to therapy is different in early IBD • Changing the natural history • Can it be done?

  8. Natural History of Pediatric IBD Phenotypes, behavior & complications

  9. Defining Disease • Phenotype The observable properties of an organism that are produced by the interaction of the genotype and the environment • Phenotype evolution: Extent & Behavior Does the extent change and when? Does the behavior change and when?

  10. Crohn’s Disease: Initial Location EUROKIDS 2004-2009 0-18 years N = 582 L4:A+B: 4% De Bie CL et al. Inflamm Bowel Dis. 2013 Feb;19(2):378-385

  11. Crohn’s Disease: Location EPIMAD 1998-2002 0-17 years N = 281 Median f/u 84 months (52-124) Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113

  12. Crohn’s Disease: Behavior & Surgery 25 44% Perianal 9-27% first intestinal resection EPIMAD 1998-2002 0-17 years N = 404 Median f/u 84 months (52-124) 34% 5 years Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113

  13. Crohn’s disease Steroid therapy N= 109 84% complete or partial response 31% steroid dependent 8% surgery 3 months 1 year Markowitz J et a.l. Clin Gastroenterol Hepatol. 2006 Sep;4(9):1124-9.

  14. Crohn’s disease at younger age • 10% pediatric CD <5 years • IBDU more common • Perianal disease less common • Less aggressive behavior • IBD <2 years of age • IL10 & IL10 receptor dysfunction Gupta N et al. Am J Gastroenterol. 2008 August; 103(8): 2092–2098 Glocker E et al. N Engl J Med 2009;361 Kotlarz D et al. Gastroenterology. 2012 Aug;143(2):347-55

  15. IL10 & IL10 Receptor Mutations Pre transplant Day 108 post

  16. Ulcerative colitis: Initial Location 2004-2009 0-18 years N=670 Levine A et al. Inflamm Bowel Dis 2012;000:000–000)

  17. Ulcerative Colitis: Behavior • 28% hospitalized within 3 years • 36% with acute severe colitis steroid refractory • 61% needed colectomy within 1 year pre biologics Turner D et al. Am J Gastroenterol 2011; 106:574–588 Gower-Rousseau C et al. Am J Gastroenterol, 104(8), 2080-2088 (2009) Hyams JS et al . J Pediatr, 129(1), 81-88 (1996)

  18. UC Post surgical outcomes • Pouch complications • 50% children will have ≥ 1 complication • Crohn’s of the pouch 6-13% • IBDU: progression and surgery outcomes Ill defined in children Wahbeh G et al. Expert Rev Gastroenterol Hepatol. 2013 Mar;7(3):215-23

  19. Pediatric vs adult IBD • UC : • Pancolitis, steroid dependence more common • “atypical” features • Rectal Sparing • Fewer chronic architecture changes • CD: • More aggressive phenotypes • IBDU more common at younger age Van Limbergen et al. Gastroenterology. 2008;135:1114-1122 Kugathasan S et al. J Pediatr. 2003;143:525-531 Hyams J et al. J Pediatr. 1988;112:893-898 Hyams JS, et al. Clin Gastroenterol Hepatol 2006;4:1118-1123 Vernier-Massouille G et al. Gastroenterology. 2008;135:1106-1113

  20. Can we predict pediatric IBD course? Phenotype & behavior evolution Risk of complications

  21. Current risk assessment tools • Clinical picture at presentation • Labs & stool markers • Genetics • Serology • Microbiome?

  22. Clinical predictors: IBD surgery • ↑ Risk • Female gender • Poor growth • Abscess • Fistula • Stricture • ↓ Risk • Younger age • Fever • Azathioprine • Infliximab • 5-ASAs Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113 Gupta N, et al. Gastroenterology 2006;130:1069-1077

  23. Deep ulcers: activity at 1 year • 333 children with newly diagnosed CD • 169: deep ulcers on initial colonoscopy • 2.7 x active disease at 1 year • 10 x less likely active disease if Anti TNF in 3 mo Hyams et al. RISK CCFA study, DDW 2012

  24. Labs & stool markers • Not useful to predict behavior • Predictive of disease relapse • CRP (Crohn’s) • Calprotectin

  25. Genetics • Disease course • NOD 2 & IL23 R: limited predictive value • Steroid response • Infliximab response De Iudicibus SJ Clin Gastroenterol. 2011 Jan;45(1):e1-7 Dubinsky et al. Inflamm Bowel Dis. 2010 Aug;16(8):1357-66.

  26. Predictors of Phenotype & Complications Mow et al. Gastroenterology 2004; 126(2):414-424 Papadakis et al. Inflamm Bowel Dis 2007:13(5):524-530 Dubinsky M. World J Gastroenterol. 2010 June 7; 16(21): 2604–2608

  27. Antibody response sum & phenotype Dubinsky et al. Clin Gastr Hep 2008;6:1105-1111

  28. Serology & time to surgery

  29. Can mucosal healing predict phenotype change & complications?

  30. Impact of mucosal healing • ↑ Steroid-free remission • ↓ Hospitalization • ↓ Surgery • Children without mucosal healing: • more likely to receive treatment change • Deep mucosal healing predicts sustained clinical remission after stopping anti-TNF ab Allez M et al. World J Gastroenterol 2010;16:2626e32 Froslie et al. Gastroenterology 2007:133(2):412-422 van Assche G, et al . Curr Drug Targets 2010;11:227e33 Thakkar K et al. Am J Gastroenterol 2009;104:722e7 Louis E et al Gastroenterology 2012;142:63e70.e65

  31. Conclusions • Pediatric IBD includes a spectrum of phenotype severity • The burden of pediatric IBD is substantial with significant cumulative need for surgery • Evolving role for disease behavior predictors • Mucosal healing is a strong predictor of future course

  32. The end

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