Transcript The Very Young Patient - Advances in Inflammatory Bowel Diseases

Immunodeficiencies Complicated by IBD:
The Very Young Patient
Ted Denson, MD
Schubert-Martin Pediatric Inflammatory Bowel Disease
Center
The speaker has no financial arrangement(s) with a company whose product figures
prominently in the presentation or with a company making a competing product.
Objectives
• Review the epidemiology of very-early onset
IBD
• Understand current concepts of
pathogenesis in very-early onset IBD
• Discuss diagnostic approach to suspected
immunodeficiency with very-early onset IBD
Case (I)
• 9 month old white female
• Chief compliant: bloody diarrhea
• Poor growth and microcytic anemia
• Endoscopy: moderately active colitis, normal upper GI tract and terminal ileum,
normal UGI/SBFT
Questions(I):
• How common is IBD in very young
children? What age defines “very young”?
• Is this “CD” or “UC” or IBD-U (IC) or
primary immune deficiency/dysregulation?
• What is the natural history?
The Frequency of UC or IC Diagnoses
Increases in VEO IBD
0
10
20Paris30
A1a
Years
40 50Paris60
70
A1b
80 years
Percent of Cases
Location & serology
Infantile
VEO
211/1370 < age 6 (15%)
Heyman et al J Ped 2005
Ileal Involvement Increases after Age 8
10
20
30
60
70
80 years
Percent of Cases
0
Years
40 50
Hugot et al IBD 2005
A Higher Frequency of VEO CD Patients are
Initially Classified as UC/IC
10
20
30
60
70
80 years
Percent of Cases
0
Years
40 50
Gupta et al Am J Gastro 2008
IBD Location and Development of
Mucosal Immunity
Early
Onset
100
VeryEarly
Onset
Frequency
75
Ileum ± Colon
50
25 Infantile
Isolated Colitis
0
0
Th2 Bias
5
Age
10
15
Balanced Th1:Th2
Humoral Immunity
Cellular Immunity
Denson,, The Life Cycle and IBD 2009
Hugot et al IBD 2005
Levine et al, IBD 2011
Natural History of Very Young Patients
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More severe extensive disease
Higher rates of colectomy
Change in classification from UC/IBDU to CD
Higher rates of colorectal cancer?
IBD Incidence is Increasing in VEO Age Group
• Administrative database: Ontario 1994-2009
• Incidence increased 7.4%/year in age <6
• Incidence increased 7.4%/year in age 6-9
• Incidence increases 2.2%/year in age ≥10
• CD diagnosed under age 6 used fewer health
services and had lower rates of surgery
• UC diagnosed under age 6 not different
Benchimol et al Gastro 2014
Outcomes in Infantile Autoimmune
Enteropathy
Ruemelle et al Gastro 2010
Questions(II):
• What causes VEO IBD?
• How is this the same or different than EO
or adult-onset IBD?
• What work-up should I do if a primary
immune deficiency is suspected?
Current Hypothesis for Pathogenesis of IBD
Genetic
Predisposition
n=163+
IBD
Enteric Flora
Environmental
Triggers
Genetic Pathogenesis of Crohn’s Disease
Intestinal
barrier:
Loss of
bacterial
sensing
and
killing
Adaptive
Immune
System:
Gain of
function
Schreiber et al Semin Immunology 2009
Genetic Pathogenesis of Ulcerative Colitis
Intestinal
barrier:
Epithelialintrinsic
dysfunction
Adaptive
Immune
System:
Gain of
function
Schreiber et al Semin Immunology 2009
The allelic architecture of common susceptibility
variants for pediatric IBD is similar to adult onset
• Tested 160/163 adult-onset risk genotypes which explain
~ 20% of the genetic susceptibility
• 1047 pediatric-onset IBD cases and 1663 healthy
controls from RISK study
• Replicated 88% CD and 90% UC variants
• Sequencing approaches needed for more
comprehensive dissection of known risk loci and
discovery of rare damaging mutations
Kugathasan et al, under review 2014
PRO-KIIDS RISK Cohort
Pathogenesis of IBDs
1: Maladaptive response to
intestinal injury & the
enteric flora
CD: defective innate
antimicrobial response
UC: defective epithelial
response
TCR
MHC
Class II
CD4
CD28
CTLA4
B7
2: T-cell
activation
including
enteric flora
antigens
FUT2
3:Cytokines &
chemokines
Selectins
Activated
Mo
PMN
IL-8
Integrins ICAM-1
Monocyte
4: Leukocyte adhesion &
recruitment
MAdCAM-1
Resting
Mo
Naive
T cell
GM-CSF auto-antibodies
Anti-flagellin antibodies
B cell
IL27
CD4+
T cell
TNF
Treg
IL-12
IL-4
IL-23
IFNg
Th1
Th2
Lymphocyte
IL-17
Th17
IL-5
IL-13
IL-10
TGFb
IBD Genes Shaped by Response to Infection and Overlap with
Immune Deficiencies
Cho et al Nature 2012
Age of onset of IBD-like Symptoms in Patients with Monogenic Diseases.
Immunoregulation: BMT
Epithelial Barrier
T & B Cell Defects: BMT
Immunoregulation: BMT
Phagocyte Defect: BMT
CVID: BMT
Autoinflammatory: BMT
Uhlig et al Gastro 2014
Variants in nicotinamide adenine dinucleotide phosphate oxidase complex
components determine susceptibility to very early onset IBD
Muise et al Gastroenterology 2014
NEOPICS
Gastroenterology 2014 147, 680-689
Copyright © 2014 AGA Institute
VEO Enterocolitis
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Severe “CD” or “UC” phenotype
May be initially diagnosed as milk-protein allergy
Refractory to medications
CVID: lymphopenia with hypogammaglobulinemia
Primary phagocyte defect: CGD or GSD1b
Combined microbial response and regulatory T cell
defects: XIAP mutations
Effector & regulatory lymphocyte defects: WiskottAldrich syndrome
Regulatory defects: IL10R or FOXP3 mutations
Stem cell defects: telomere shortening, DKC1 mutations
May benefit from BMT
Cannioto et al Eur J Ped 2009
Functional Screening
Disorder
Presumed IBD Pathogenesis
Screening Test
Common Variable
Defective cellular and/or humoral
Lymphocyte subsets, IgA, IgM,
Immune Deficiency immunity
IgG, IgE, vaccine titers
CGD
Defective phagocyte microbial killing Neutrophil oxidative burst
Dyskeratosis
Premature telomere shortening
Congenita
leading to stem cell dysfunction
IPEX Syndrome
Defective regulatory T cell function
Telomere length in PBMC
FOXP3 expression by flow
cytometry
IL10R Mutations
Defective IL-10 anti-inflammatory
IL-10 signaling in PBMC
action
(research assay)
Wiskott-Aldrich
Effector & regulatory lymphocyte
WASP expression by flow
Syndrome
defects
cytometry
XIAP deficiency
Combined microbial response and
XIAP expression by flow
regulatory T cell defects
cytometry
Case (II)
• Hypogammaglublinemia: IVIG replacement
• Steroid dependent and then refractory
• Maximum 6TG level of 180 with leucopenia on AZA 3.5 mg/kg
• Severe infusion reaction with second dose of infliximab
• Colectomy and J-pouch at 23 months of age with path diagnosis of “UC”
• Recurrent antibiotic responsive pouchitis
• 4 years of age: CTE with distal jejunal and ileal inflammation
• Scope with pre-pouch ileal ulcers
• Adalimumab & periodic antibiotics: remission with mucosal healing
Top Research Questions:
• What is the definition of VEO IBD?
• What is the natural history of VEO IBD?
• What is the pathogenesis of VEO IBD?
• Which patients with severe VEO IBD have a
primary immune disorder which will benefit from
BMT?
• What are the optimal medical and surgical
approaches in VEO IBD?
• NEOPICs study: Muise & Snapper