Ghassan Wahbeh MDAssociate Professor, Director IBD ProgramSeattle Children’s HospitalUniversity of Washington

Content

Background The natural history of pediatric IBD

Phenotypes and behavior Complications

Can we predict pediatric IBD course? Impact of mucosal healing

IBD: Age at presentation

0 10 20 30 40 50 60 70 80

Per

cent

of

Cas

es

25

20

15

10

5

0

Loftus, Gastroenterology 2003; 124:abstract 278

Years

Puberty

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

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

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?

Phenotypes, behavior & complications

Natural History of Pediatric IBD

Defining Disease

PhenotypeThe observable properties of an

organism that are produced by the interaction of the genotype and the environment

Phenotype evolution:Does the extent change and

when?Does the behavior change and

when?

Extent &

Behavior

Crohn’s Disease: Initial Location

De Bie CL et al. Inflamm Bowel Dis. 2013 Feb;19(2):378-385

EUROKIDS2004-20090-18 yearsN = 582

L4:A+B: 4%

Crohn’s Disease: Location

Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113

EPIMAD1998-20020-17 yearsN = 281Median f/u 84 months (52-124)

Crohn’s Disease: Behavior & Surgery

Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113

first intestinal resection

34%5

years

Perianal 9-27%

25 44%

EPIMAD1998-20020-17 yearsN = 404Median f/u 84 months (52-124)

Crohn’s disease Steroid therapy

N= 109

Markowitz J et a.l. Clin Gastroenterol Hepatol. 2006 Sep;4(9):1124-9.

3 months

1 year

84% complete or partial response

31% steroid dependent 8% surgery

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): 2092–2098Glocker E et al. N Engl J Med 2009;361Kotlarz D et al. Gastroenterology. 2012 Aug;143(2):347-55

IL10 & IL10 Receptor Mutations

Pre transplant Day 108 post

Ulcerative colitis: Initial Location

Pancolitis 78%

Left sided colitis 18%

Extensive colitis 9%

Proctitis 5%

Levine A et al. Inflamm Bowel Dis 2012;000:000–000)

2004-20090-18

yearsN=670

Atypical features

Rectal Sparing 5%

Backwash ileitis 10%

UGI lesions 4%

• 28% hospitalized within 3 years• 36% with acute severe colitis steroid

refractory• 61% needed colectomy within 1 year pre

biologics

Ulcerative Colitis: Behavior

Turner D et al. Am J Gastroenterol 2011; 106:574–588Gower-Rousseau C et al. Am J Gastroenterol, 104(8), 2080-2088 (2009)Hyams JS et al . J Pediatr, 129(1), 81-88 (1996)

Colectomy

1 year 8%

5 years 26%

UC Post surgical outcomes Pouch complications

50% children will have ≥ 1 complication Crohn’s of the pouch 6-13%

Wahbeh G et al. Expert Rev Gastroenterol Hepatol. 2013 Mar;7(3):215-23

Ill defined in children

IBDU: progression and surgery outcomes

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 ageVan Limbergen et al. Gastroenterology. 2008;135:1114-1122Kugathasan S et al. J Pediatr. 2003;143:525-531Hyams J et al. J Pediatr. 1988;112:893-898Hyams JS, et al. Clin Gastroenterol Hepatol 2006;4:1118-1123 Vernier-Massouille G et al. Gastroenterology. 2008;135:1106-1113

Phenotype & behavior evolutionRisk of complications

Can we predict pediatric IBD course?

Current risk assessment tools

Clinical picture at presentation Labs & stool markers Genetics Serology Microbiome?

Clinical predictors: IBD surgery

Gupta N, et al. Gastroenterology 2006;130:1069-1077

↓ RiskYounger

ageFeverAzathioprin

eInfliximab5-ASAs

↑ RiskFemale

genderPoor growthAbscessFistulaStricture

Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113

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

Labs & stool markers

Not useful to predict behavior Predictive of disease relapse

CRP (Crohn’s) Calprotectin

Genetics

Disease course NOD 2 & IL23 R: limited predictive value

Steroid response Infliximab response

De Iudicibus SJ Clin Gastroenterol. 2011 Jan;45(1):e1-7Dubinsky et al. Inflamm Bowel Dis. 2010 Aug;16(8):1357-66.

Predictors of Phenotype & Complications

SB FS IP SB surgery

UC-like

pANCA ASCA

Anti OMP-C Anti CBir1

Anti I2

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

Dubinsky et al. Clin Gastr Hep 2008;6:1105-1111

Antibody response sum & phenotype

Serology & time to surgery

Can mucosal healing predict phenotype change & complications?

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;16:2626e32Froslie et al. Gastroenterology 2007:133(2):412-422van Assche G, et al . Curr Drug Targets 2010;11:227e33Thakkar K et al. Am J Gastroenterol 2009;104:722e7Louis E et al Gastroenterology 2012;142:63e70.e65

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

The end