1. Immunodeficiencies Complicated by IBD: The Very Young Patient Ted Denson, MD Schubert-Martin Pediatric Inflammatory Bowel Disease Center

2. 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.

3. 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

4. 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

5. 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?

6. The Frequency of UC or IC Diagnoses Increases in VEO IBD 010 20304050 6070 80 years Percent of Cases Heyman et al J Ped 2005 Years 211/1370 < age 6 (15%) Paris A1aParis A1b Location & serology Infantile VEO

7. Ileal Involvement Increases after Age 8 010 20304050 6070 80 years Percent of Cases Hugot et al IBD 2005 Years

8. A Higher Frequency of VEO CD Patients are Initially Classified as UC/IC 010 20304050 6070 80 years Percent of Cases Gupta et al Am J Gastro 2008 Years

9. IBD Location and Development of Mucosal Immunity Frequency Age Ileum ± Colon Isolated Colitis Humoral Immunity Cellular Immunity Th2 Bias Balanced Th1:Th2 Denson,, The Life Cycle and IBD 2009 Hugot et al IBD 2005 Levine et al, IBD 2011 Infantile Very- Early Onset Early Onset

10. Natural History of Very Young Patients More severe extensive disease Higher rates of colectomy Change in classification from UC/IBDU to CD Higher rates of colorectal cancer?

11. 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

12. Outcomes in Infantile Autoimmune Enteropathy Ruemelle et al Gastro 2010

13. 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?

14. Current Hypothesis for Pathogenesis of IBD Enteric Flora Environmental Triggers Genetic Predisposition n=163+ IBD

15. Genetic Pathogenesis of Crohn’s Disease Schreiber et al Semin Immunology 2009 Intestinal barrier: Loss of bacterial sensing and killing Adaptive Immune System: Gain of function

16. Genetic Pathogenesis of Ulcerative Colitis Schreiber et al Semin Immunology 2009 Intestinal barrier: Epithelial- intrinsic dysfunction Adaptive Immune System: Gain of function

17. The allelic architecture of common susceptibility variants for pediatric IBD is similar to adult onset Kugathasan et al, under review 2014 PRO-KIIDS RISK Cohort 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

18. 1: Maladaptive response to intestinal injury & the enteric flora CD: defective innate antimicrobial response UC: defective epithelial response 2: T-cell activation including enteric flora antigens 3:Cytokines & chemokines Resting Mo Activated Mo Selectins PMN Integrins Monocyte MAdCAM-1 Lymphocyte ICAM-1 4: Leukocyte adhesion & recruitment IL-8 IL-23 IL-12 IFN  TNF Th1 Th2 IL-5 IL-4 CD4 + T cell Naive T cell B cell MHC Class II B7 TCR CD4 CD28 CTLA4 IL-17 Th17 IL-13 GM-CSF auto-antibodies Anti-flagellin antibodies Treg IL-10 TGF  FUT2 IL27 Pathogenesis of IBDs

19. IBD Genes Shaped by Response to Infection and Overlap with Immune Deficiencies Cho et al Nature 2012

20. Age of onset of IBD-like Symptoms in Patients with Monogenic Diseases. Uhlig et al Gastro 2014 Immunoregulation: BMT Epithelial Barrier T & B Cell Defects: BMT Immunoregulation: BMT Phagocyte Defect: BMT CVID: BMT Autoinflammatory: BMT

21. 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

22. Cannioto et al Eur J Ped 2009 VEO Enterocolitis 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: Wiskott- Aldrich syndrome Regulatory defects: IL10R or FOXP3 mutations Stem cell defects: telomere shortening, DKC1 mutations May benefit from BMT

23. Functional Screening

24. 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

25. 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