+ = Lecture Objectives. Necessary and Sufficient 9/30/2011. Celiac Disease: Definition

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1 The Spectrum of Gluten Related Disorders Please Welcome Gluten Sensitivity, The New Kid on the Block. Disclosure Alessio Fasano, M.D. Stock/Shareholder Alba Therapeutics Alessio Fasano, M.D. Mucosal Biology Research Center and Center for Celiac Research University of Maryland School of Medicine Environmental Factors Lecture Objectives Gluten + Genes = Celiac Disease Not So Fast! Microbiome Celiac Disease: Definition Celiac disease is an autoimmune condition Occurs in genetically susceptible individuals DQ2 and/or DQ8 positive HLA haplotype is necessary but not sufficient A unique autoimmune disorder because: both the environmental trigger (gluten) and the autoantigen (tissue Transglutaminase) are known elimination of the environmental trigger leads to a complete resolution of the disease Clinic Outcome Celiac Disease Autoimmune Pathogenesis The Clinical Manifestations of Celiac Disease are More Heterogeneous Than Previously Appreciated + = Necessary and Sufficient A. Fasano, N Engl J Med 2003;348:

2 CD prevalence (%) 9/30/2011 Trend of Celiac Disease Diagnosis in USA Since the CFCR 2003 Epidemiology Study 2003 CFCR Epidemiology Study ~180,000 CD diagnosed Since the CFCR epidemiology study published in 2003 the diagnosis of CD doubled approximately every 3 years. Currently ~180,000 of the projected 3,000,000 subjects affected by CD have been diagnosed. Increased Prevalence Over Time in U.S.A. (in Line with Other Autoimmune Diseases) % Celiac Disease Autoimmune Pathogenesis % 0.45% + = year During the past 35 years the true prevalence of CD in USA doubled every 15 years. C. Catassi et al, Annal Med 2010 Necessary but NOT Sufficient The Epidemics Of Celiac Disease: Which Additional Factors are Driving this Epidemic? Gluten Causes Gut Leakiness in Everybody Quality of gluten; Quantity of gluten; Breast Feeding; Maturity of gut functions influencing Ag trafficking and handling: - GALT - PRRs - Mucous production - Barrier function (i.e.; leaky gut) Changes in microbiome composition Timing of gluten introduction Clemente MG et al Gut 2003; Drago et al Scand J Gastroenterol 2006; Sapone A. et al. JADD

3 The Epidemics Of Celiac Disease: Which Additional Factors are Driving this Epidemic? The Hygiene Hypothesis Quality of gluten; Quantity of gluten; Breast Feeding; Maturity of gut functions influencing Ag trafficking and handling: - GALT - PRRs - Mucous production - Barrier function (i.e.; leaky gut) Changes in microbiome composition Timing of gluten introduction Environmental Triggers: Gut Microorganisms Environmental Triggers: Are we sure they are just environment? The Complexity of the Human Body Over the years we came to appreciate the complexity of the human body The Real Story of Our Genetic Complexity: We Inherit two Parallel Genomes Human Genome: Inherited from both parents, stable, never change in its composition Microbiome: Inherited from the mother, extremely dynamic, changes from individual to individual and in the same individual over time Only 30,000 genes, 99.5% identical to chimpanzee, cannot explain such complexity and difference with other primates. However, it would be inappropriate to describe the human body without considering the 300,000,000,000 bacteria (collectively defined as microbiome) gladly living inside us and that express ~100 fold more genes that the human genome. 3

4 Microbiome (140-fold Human Genome) Dynamic Human Genome (~30,000 genes) Stable Metabonome Phylum Level Comparison of DQ2/DQ8 Positive Babies at Risk for CD and Reference (Palmer) Babies Jazz Palmer s babies Pop Our babies Clinical Outcome Classic Gluten Free Market The Gluten Free Diet: Not Only Celiac Disease! low fat diet low carb diet gluten free diet GFD Consumers ~60 Millions Medical Necessity Millions No Medical Necessity Millions For the American general population adopting a gluten-free diet is becoming an increasingly popular solution. The market for gluten-free food and beverage products grew at a compound annual growth rate of 28 percent from 2004 to 2008, to finish with almost $1.6 billion in retail sales last year. By 2015 the market is expected to reach about $5.2 billion in sales. The fact that approximately 3 million Americans suffer from celiac disease and only a fraction of these patients have been diagnosed implies that patients suffering of other forms of proven gluten reaction, including gluten sensitivity and wheat allergy, contribute to this market growth. The rest of the market is filled by people affected by maladies claimed to be affected by gluten exposure, including autism, ADHD, multiple sclerosis, and IBS. Wheat Allergy (IgE-mediated) ~3/500,000 Celiac Disease (Autoimmune-based) ~2.7-3 Millions Gluten Sensitivity (Immune-based?) ~17-20 Millions Proposed New Classification of Gluten Related Disorders YES Celiac Disease Biomarkers Autoimmune Gluten Ataxia Symptomitic Silent Potential Dermatitis herpetiformis Gluten Related Disorders Pathogenesis Allergic YES Respiratory Allergy NO Food Allegy Not Autoimmune Not allergic (Innate immunity?) Wheat allergy WDEIA Gluten sensitivity Contact Urticaria Gluten Sensitivity: Definition Cases of gluten reaction in which both allergic and autoimmune mechanisms have been ruled out (diagnosis by exclusion criteria) Negative immuno-allergy tests to wheat; Negative CD serology (EMA and/or ttg) and in which IgA deficiency has been ruled out; Negative duodenal histopathology; Presence of biomarkers of gluten immune-reaction (AGA+); Presence of clinical symptoms that can overlap with CD or wheat allergy symptomatology; Resolution of the symptoms following implementation of a GFD 4

5 Gluten Sensitivity: What is the Magnitude of the Problem? The CFCR Experience ( ) The Epidemics Of Autism and Schizophrenia As Part of The Trend of Gluten Sensitivity? Nr. of the patients seen at the CFCR clinic: 5,896 Nr. of patients fulfilling criteria for GS: 347 Prevalence in our cohort: 1:17 (6%) Symptoms: Abdominal pain (IBS): 68% Eczema and/or rash: 40% Headache: 35% Foggy mind : 34% Fatigue: 33% Diarrhea: 33% Depression: 22% Anemia: 20% Numbness legs/arms/fingers: 20% Joint pain: 11% How Gluten Sensitivity Relates to Autism and Schizophrenia? All disease begins in the gut - Hippocrates 460 BC A. Epithelial Events Timeline: Hours (Everybody) Conclusions B. Innate Immunity Events Timeline: Days (GS) C. Adaptive Immunity Events Timeline: Weeks-Years (CD) The gut is not like Las Vegas: what happens in the gut does not stay in the gut A.F AC Gliadorphins Casomorphins Activated inflammatory cells The intestinal mucosa is the battlefield on which friends and foes need to be recognized and properly managed to find the ideal balance between tolerance and immune response. <20 ppm >20 ppm Clemente MG et al Gut 2003; Drago et al Scand J Gastroenterol 2006; Sapone A. et al. JADD