Transcript Risk stratification of pediatric IBD: What disease

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
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
Years
30 40
50
60
70
80
Percent of Cases
25
20
15
10
5
0
Loftus, Gastroenterology 2003; 124:abstract 278
Puberty
Social
Growth
Sexual
development
Development,
Bone
Independence
Density
Emotional
Growth,
Relationships
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?
Natural History of Pediatric IBD
Phenotypes, behavior & complications
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?
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
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
Crohn’s Disease: Behavior & Surgery
34%
5 years
25
44%
Perianal 9-27%
first intestinal resection
EPIMAD
1998-2002
0-17 years
N = 404
Median f/u 84 months (52-124)
Vernier-Massouille et al. Gastroenterol 2008;135:1106–1113
Crohn’s disease Steroid therapy
3 months
1 year
84% complete or partial response
31% steroid dependent
8% surgery
N= 109
Markowitz J et a.l. Clin Gastroenterol Hepatol. 2006 Sep;4(9):1124-9.
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
IL10 & IL10 Receptor Mutations
Pre transplant
Day 108 post
Ulcerative colitis: Initial Location
Pancolitis
Left sided colitis
Extensive colitis
Proctitis
78%
18%
9%
5%
Atypical features
2004-2009
0-18 years
N=670
Rectal Sparing
5%
Backwash ileitis
10%
UGI lesions
4%
Levine A et al. Inflamm Bowel Dis 2012;000:000–000)
Ulcerative Colitis: Behavior
• 28% hospitalized within 3 years
• 36% with acute severe colitis steroid refractory
• 61% needed colectomy within 1 year pre biologics
Colectomy
1 year
5 years
8%
26%
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)
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
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
Can we predict pediatric IBD
course?
Phenotype & behavior evolution
Risk of complications
Current risk assessment tools
 Clinical picture at presentation
 Labs & stool markers
 Genetics
 Serology
 Microbiome?
Clinical predictors: IBD surgery
↑ Risk
Female gender
Poor growth
Abscess
Fistula
Stricture
↓ Risk
Younger age
Fever
Azathioprine
Infliximab
5-ASAs
Gupta N, et al. Gastroenterology 2006;130:1069-1077
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):e1-7
Dubinsky et al. Inflamm Bowel Dis. 2010 Aug;16(8):1357-66.
Predictors of Phenotype & Complications
SB
pANCA
ASCA
Anti OMP-C
Anti CBir1
Anti I2
FS
IP
SB
surgery
UC-like
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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
Antibody response sum & phenotype
Dubinsky et al. Clin Gastr Hep 2008;6:1105-1111
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;16:2626e32
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
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