Diagnosis and misdiagnosis of IBD in · PDF fileDiagnosis and misdiagnosis of IBD in children ... Sorbonne Paris Cité F. Ruemmele, ... B2) Penetrang)B3)

Diagnosis and misdiagnosis of IBD in children

Frank Rümmele IBD Clinics and Mucosal Immunology Program

Pediatric Gastroenterology Hôpital Necker-Enfants Malades, Paris

INSERM U989 Université Paris Descartes, Sorbonne Paris Cité

F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité

Benchimol E Gut 2009

Prevalence of IBD in children <18y in Ontario


Benchimol E Gut 2009


AGE Change in Incidence Rate

95% CI P-value*

0-4 +5.0% / year 0.5% - 10.5% 0.032

5-9 +7.6% / year 4.4% - 10.8% <0.0001

10-14 +0.63% / year -0.9% – 2% 0.41

15-17 -0.21% / year -1.3% – 0.9% 0.72

Changes in IBD incidence rates by age group

Pediatric CD has unique characteristics in comparison to adult onset CD

•  Pediatric –  Colon involved

•  80% at 8 yr of age •  decreases with age

–  Isolated Ileal involvment •  Rare at <8 yrs of age

–  Posi<ve FH in 30% –  Stricturing in 46% –  Surgery in 71%

•  Adult –  Colon only involved in <20%

–  Ileum involved in 80%

–  Posi<ve FH in 14% –  Stricturing in 29% –  Surgery in 55%


5p13

10q21

ATG16L

PTPN2

NKX2-‐3

IRGM

3p21

7p12 ICOSLG

6q27 21q21

6q21 17q21

CDKAL1 17q21

IL12B 13q14

1q32 12q12

1q24 c11orf30

1q23 10p11

1q13 9p24

8q24

IL23R TNFSF15 IBD5

NOD2

2007 2008 2006 2005 2000

Prior to GWAS WTCCC GWAS Early GWAS GWAS meta-‐analysis

Summary of Confirmed CD Loci

~20% gene8c risk ~ 10% overall risk

Pediatric Specific Genes ? Kugathasan et al. Nature Genetics 2008 2 loci (DcR3?) Imielinski et al. Nature Genetics 2009 5 loci (IL27?)


Pigneur et al IBD 2009

N= 206 N= 412

Differing natural history


Evolu8on of Disease Behaviour

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10

Years aUer diagnosis

percen

tage of cases

Inflammatory B1 Stricturing B2

Penetra<ng B3

p< 0.0001

Vernier-‐Massouille et al. Gastroenterology 2008; 135: 1106-‐13

n=404 with follow-‐up ≥2 years


Evolu8on of Disease Behaviour

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10

Years aUer diagnosis

percen

tage of cases

Inflammatory B1 Stricturing B2

Penetra<ng B3

p< 0.0001

Vernier-‐Massouille et al. Gastroenterology 2008; 135: 1106-‐13

n=404 with follow-‐up ≥2 years


Pediatric IBD Pediatric Crohn’s disease


It looks like Crohn’s Disease

– lessions to be learned from Crohn-like diseases ?





Neutrophil disorders:

Defect of the oxidative burst

•  defective elimination of micro-organisms •  dysfunction of macrophages and neutrophils

n  Defective superoxide production n  NBT test: nitroblue tetrazolium n  (chemotaxis defects)

1) Chronic Granulmatose Disease (CGD)


Neutrophil disorders:

Metabolic Disorder Hypoglycemia

Infections (skin) Oral/perianal Aphtosis Colonic/SB inflammation

2) Glykogen Storage Disease 1b


0-‐2 years: 31% UC 33% IC 34% CD

2-‐17 years 25% UC

9% IC 66% CD

44% posi<ve family history

19% posi<ve family history

Up to 70% treatment failures

Heyman et al Pediatrics 2005

Early-‐onset pediatric IBD


Early-‐onset pediatric IBD

IL10 signaling defects: Severe treatment resistent colitis perianal inflammation XIAP Severe treatment resistent colitis (20% of pat) Hemophagocytic lymphohistiocytosis EBV-related

Genetically determined Diseases ?


A.F., 11.5 years, 20.5 kg, 131 cm fa<gue, asthenic, disturbed ea<ng behaviour with refusal of alimenta<on « anorexia » weight loss over several months

psychotherapy for anorexia nervosa

PiMalls clinical case


PiMalls clinical case


Ø  Pediatric onset of IBD: the earlier the more severe ? Ø  IBD-‐like disease: CGD, Glykogen Storage Disease 1b Ø  Very early onset IBD = gene<c defects (« disease

models ») Ø  Proof of concept with IL10 signaling deficience Ø  other candidates: IL22, XIAP, TGF, Smad ???

Ø  IL10 signaling defects: Ø  Severe treatment resistent coli<s Ø  perianal inflamma<on

Ø  T reg deficiency (FOXP3)

Ø  Small bowel >> colon Ø  Associated autoimmunity Treatment op8ons

BMT

Summary

[email protected]

Thank you !

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Diagnosis and misdiagnosis of IBD in · PDF fileDiagnosis and misdiagnosis of IBD in children ... Sorbonne Paris Cité F. Ruemmele, ... B2) Penetrang)B3)