Celiac Disease Myths. Objectives. We Now Know. Classical Celiac Disease. A Clinical Update in Celiac Disease

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1 4:15 5:00pm Presenter Disclosure Information A Clinical Update in Celiac Disease SPEAKER Benjamin Lebwohl, MD, MS The following relationships exist related to this presentation: Benjamin Lebwohl, MD, MS has no financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Objectives Review and discuss the prevalence and risk factors for celiac disease Identify recent advances and developments in celiac disease and discuss their application to clinical practice Discuss the newest treatments for celiac disease Celiac Disease Myths Celiac Disease: Rare Affects children only Affects the gastrointestinal tract only You can grow out of it We Now Know Common Affects children and adults Can develop celiac disease at any age Can affect multiple organ systems outside of the gastrointestinal tract Can have celiac disease and not have diarrhea Can have celiac disease and be overweight Children generally don t grow out of it. Abdominal distension Abdominal pain Chronic diarrhea Anorexia Weight loss Muscle wasting Classical Celiac Disease Reference: A summary of NASPGHAN, AGA and WHO Guidelines

2 Non Classical Celiac Disease Iron or folate deficiency Short stature Silent Celiac Disease Chronic constipation Irritable Bowel Syndrome Dental enamel defects Neurological (ataxia, neuropathy, epilepsy) Elevated liver enzymes Infertility Osteoporosis Delayed puberty Fatigue Screening First degree relatives DM1 In retrospect More Diagnoses We Are Recognizing More Cases Murray, et al. Clin Gastro Hep 2003;1:19-27 Ludvigsson, et al. Am J Gastroenterol. 2013;108: Most U.S. Patients With Celiac Disease Are Undiagnosed Seroprevalence: 0.7% 1.0% Path to Diagnosis Percentage undiagnosed: Olmsted County (2001): 95% Wyoming (2003): 90% Washington County, Maryland (1989): 89% NHANES ( ): 83% Clinical Suspicion Serology Biopsy Start glutenfree diet Rubio-Tapia, et al. Am J Gastroenterol 2012;107: Undiagnosed celiac disease (false negatives) Not celiac disease (false positives) Fasano, et al. Arch Intern Med. 2003;163: Katz, et al. Am J Gastroenterol 2010; 106: Murray, et al. Clin Gastro Hep 2003;1:19-27 Catassi et al. Ann Med 2010; 42: 530-8

3 Serologies Underperformance of Small Intestinal Biopsy During Endoscopy Tissue Transglutaminase (TTG) IgA Sensitivity ~90% Specificity ~98% May miss patients with low total IgA IgG serologies Deamidated gliadin peptide IgG TTG IgG Gastrointest Endosc 2012;76: Men are Biopsied Less Often Duodenal Villous Atrophy and Ethnicity in the United States Ethnic Group Prevalence of Villous Atrophy (%) Other Americans 1.8 North Indian 2.0 Punjabi 3.1 Other North Indian 1.5 South Indian 0 East Asian 0.15 Hispanic 1.1 Middle Eastern 1.5 Jewish 1.8 Ashkenazi 1.8 Sephardic 1.4 Gastrointest Endosc. 2012;76: Krigel, et al. Clin Gastroenterol Hepatol 2016;14: Quantity of Gluten? Celiac Disease in India Region North Northeast South Positive serology 1.23% 0.87% 0.1% Celiac disease 0.85% 0.47% 0.01% DQ2/DQ8 38% 31% 36% Wheat intake < > Rice intake < > Role of Genetic Testing: HLA DQ2/DQ8 DQ2/DQ8 Celiac disease 100% General population 40% Used to exclude celiac disease ROLE 1. Assessing relatives 2. Questionable diagnosis 3. Already on gluten free diet Ramakrishna BS, et al. Am J Gastroenterol. 2016;111:

4 Increasing Seroprevalence Antibiotics Celiac Disease Controls Odds Ratio (95% CI) Setting Rise Air Force Base (US) 0.2% in % in 2006 Finland 1.05% in % in 2000 Any Antibiotics 27.0% 21.1% 1.40 ( ) 1 2 Courses 23.0% 18.3% 1.36 ( ) 3 Courses 6.7% 4.2% 1.58 ( ) Maryland (US) 0.21% in % in 1989 Rubio-Tapia, et al. Gastroenterology : Lohi, et al. Aliment Pharmacol Ther : Catassi, et al. Ann Med : Marild K et al. BMC Gastroenterol. 2013;13:109. The Hygiene Hypothesis H. pylori Colonization: Protective? 1 / / 496 H. pylori prevalence in non CD patients: 8.8% H. pylori prevalence in CD patients: 4.4% Kondrashova, et al. Ann Med 2008;40: Lebwohl, B et al. Am J Epidemiol. 2013;178: Established and Proposed Risk Factors for Celiac Disease Gluten HLA DQ2/D8 Family history of celiac disease Infant feeding practices? Rotavirus infection Campylobacter infection Elective Caesarian section Summer season of birth Antibiotic use Acid suppression medication Maternal iron supplementation Lack of H. pylori colonization Gluten Free Diet High cost, poor availability and palatability Inaccurate information Risks when dining out Social pressures (peer, cultural) Inadequate food and drug labeling Contaminated supplements

5 Non Responsive Celiac Disease Common: Not celiac disease Inadvertent gluten exposure Bacterial overgrowth of the small intestine Irritable Bowel Syndrome Lactose intolerance Pancreatic exocrine insufficiency Microscopic colitis Uncommon: Refractory Celiac Disease type 1 Rare: Refractory Celiac Disease type 2 Refractory Celiac Disease Persistent symptoms and villous atrophy despite adherence to the gluten free diet. Serologies negative RCD Type 1 Polyclonal T cell population Steroids, 5 ASA, immunomodulators RCD Type 2 Monoclonal T cell population Progression to Enteropathy Associated T Cell Lymphoma Poor prognosis Developing Celiac Disease Therapy REDUCE GLUTEN EXPOSURE REDUCE INTESTINAL PERMEABILITY Immunotherapies - ALV003/Latiglutenase * -BL Tight junction regulation (larazotide)* -TTG inhibition -HLA DQ2/DQ8 blockade -Anti IL-15* (Hu-Mik-Beta, AMG-714) -Vaccine (Nexvax2) * In Phase II Studies Wungjiranirun M et al. Am J Gastroenterol. 2016;111: Sollid and Khosla. J Int Med. 2011;269: Medical Follow Up Intervention Frequency Comment Dietician At least once Gluten avoidance Calories Vitamins Fiber Check symptoms 3 4 times during first year Annually TTG, confirm adherence 3 4 times during first year Annually Should normalize in 6 12 months Nutritional status At diagnosis Annually CBC, iron studies, B12 folate, (25) D Bone density At diagnosis (Adults) Pneumococcal vaccination Slightly increased risk of PNA Follow up biopsy 2 years Controversial Mucosal Recovery Gluten Gluten Free Diet Green and Cellier. N Engl J Med 2007;357:

6 Should We Confirm Mucosal Healing? The need for repeated assessment of duodenal histopathology has been controversial and practice in this way varies across practitioners. Pre serologic era: to confirm diagnosis Current era: to confirm adherence to the gluten free diet Prognostic implications? Consequences of Persistent Villous Atrophy Outcome Mortality (Aliment Pharmacol Ther 2013;37:332 9.) Ischemic Heart Disease (PLOS One 2015; 30;10:e ) Low Birth Weight (Clin Gastroenterol Hepatol 2015;13: ) Lymphoproliferative Malignancy (Ann Intern Med 2013;159: ) Hazard Ratio (95% CI) Interpretation 1.01 ( ) No increased risk 0.97 ( ) No increased risk 0.98 ( ) No increased risk 2.26 ( ) Increased risk Haines, et al. Aliment Pharmacol Ther 2008;28: Rostom, et al. Gastroenterology 2006;131: Hip Fracture (J Clin Endocrinol Metab 2014;99: ) 1.67 ( ) Increased risk What to Tell Patients? The risk of lymphoma, while increased, remains low. Among 1000 patients with celiac disease followed for 10 years 7 out of 1000 will develop lymphoma Persistent villous atrophy: 10 out of 1000 Healing: 4 out of 1000 Is Gluten Bad for All of Us? Case A 53 year old woman started a gluten free diet 8 months ago on the advice of her neighbor as a treatment of her longstanding irritable bowel syndrome. She reported an ~80% improvement initially, but symptoms have recurred as of late. She is not sure if this is due to not being strict enough in terms of avoiding gluten, or whether the gluten free diet is irrelevant and she can resume a regular diet. Popularity of the Gluten Free Diet NHANES Prevalence of celiac disease 0.79% Male = Female 83% undiagnosed On a gluten free diet without a diagnosis of celiac disease: : 0.5% : 1.03% Ditah, et al. Gastroenterology 2014;146:S471.

7 The Gluten Paradox 2006 Patients with Celiac Disease Individuals On a Gluten Free Diet Rubio-Tapia, et al. Am J Gastroenterol 2012;107: Google Trends. Julia Belluz. vox.com Google Trends. Julia Belluz. vox.com Google Trends. Julia Belluz. vox.com 2015 Why People Go Gluten Free Diagnosed by physician celiac disease Symptoms (intestinal/extraintestinal) that improved after trying the diet Weight loss strategy Heart health Brain health General health Google Trends. Julia Belluz. vox.com

8 Test First, Test Right What Difference Does it Make? Once the gluten free diet is started, celiac markers normalize Serologies: 6 12 months Duodenal biopsy: months to years Gluten free diet is a life long prescription (for now) Need for medical follow up Implications for family screening Delay of other diagnoses Cost and consequences of the gluten free diet Difficulty if/when symptoms recur Accumulation of food intolerances Unpack the Terminology N=84 79% female, mean age 43 Additional food intolerances common Alternative diagnosis: 30% SIBO Fructose/lactose intolerance Microscopic colitis Gastroparesis Tavakkoli, et al. Dig Dis Sci. 2014;59: Gluten sensitivity What do you mean by that? Tested for celiac disease? Why avoiding gluten? Nonceliac? Or not tested? Ruling out Celiac Disease HLA testing for DQ2/DQ8 Serology (TTG) if on a gluten containing diet Consider a gluten challenge Patient care Education Research Advocacy

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