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Transcript
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 • • • • 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 • • • • • • • • • • 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