GLUTEN RELATED DISORDERS

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1 Celiac disease Overcoming clinical challenges Disclosures Scientific Advisory Board Cellimune, Immunsant, Innovate Pharmaceuticals Peter HR Green MD Phyllis and Ivan Seidenberg Professor of Medicine Director, Celiac Disease Center Columbia University New York, NY GLUTEN RELATED DISORDERS Analysis of NHANES data CD overall 0.71% (95% CI %) Among whites 1.01% (95% CI %) Those on GFD without CD 0.63% (95% CI %) Only 17% were aware they had CD QUESTIONS? Within the USA 1. what ethnic group has the greatest prevalence? 2. What regions have the greatest prevalence? Celiac disease prevalence 1.74% Americans 1.83% Highest in Punjabis 3.08% Lower in S Indian 0%, E Asian 0.15% and Hispanic 1.06% Jewish 1.8% 1

2 Lower Prevalence of Celiac Disease and Gluten-Related Disorders in Persons Living in Southern vs Northern Latitudes of the United States. Gastroenterology Feb % 1.11% >40 OR % OR % Most U.S. Patients With Celiac Disease Are Undiagnosed Seroprevalence: 0.7%-1.0% Female = male Percentage undiagnosed: Olmsted County (2001): 95% Wyoming (2003): 90% Washington County, Maryland (1989): 89% NHANES ( ): 83% NHANES ( ) <50% Rubio-Tapia, et al. Am J Gastroenterol 2012;107: DIAGNOSIS OF CELIAC why the underdiagnosis? Patient Endoscopist Case Finder Pathologist 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: BIOPSY 4 to 6 in descending duodenum 2 from bulb (increases diagnosis by 13%) Gonzales, GIE 2010 ULTRA SHORT CELIAC CELIAC CONFINED TO THE BULB Celiac patients with villous atrophy in the bulb only are younger (p=0.03), less frequently present with diarrhoea (p<0.0001), have lower ttg titres (p<0.0001), and higher folate levels (p=0.02) than in conventional celiac disease. Celiac patients with villous atrophy in the bulb appear to have milder clinical phenotype (Mooney, Gastroenterology, 2016) 2

3 BIOPSY 4 to 6 in descending duodenum 2 from bulb (increases diagnosis by 13%) Gonzales, GIE bite per pass of the forceps Latorre, GIE, 2015 What is the role of a follow-up Biopsy? Controversial Not necessary: if symptoms resolve and TTG normalizes Helpful: more sensitive than TTG in detecting gluten exposure Helpful: normal TTG does not reflect status of the mucosa Asymptomatic patients Prognostic implications? Consequences of Persistent Villous Atrophy Outcome Mortality (Aliment Pharmacol Ther 2013;37:332-9.) Ischemic Heart Disease (DDW 2014: Su1437) Hazard Ratio (95% CI) 1.01 ( ) 0.97 ( ) Interpretation No increased risk No increased risk Follow-up Biopsy? Helpful Prognostic Patients want to know Therefore advised Lymphoproliferative Malignancy (Ann Intern Med 2013;159: ) 2.26 ( ) Increased risk Hip Fracture (J Clin Endocrinol Metab 2014;99: ) 1.67 ( ) Increased risk 3

4 NON-RESPONSIVE PATIENT Does the patient have celiac disease? AT DIAGNOSIS 1. Biopsy? no = no definite diagnosis 2. Serology? ttg IgA false +, temporary gluten autoimmunity, Lack of standardization, ttg IgG or DGP only + test low yield 1. Other Tests? Saliva, stool antibody tests 2. HLA DQ2/8? ROLE OF HLA TESTING HLA DQ2 DQ8 NECESSARY DQ2 90% celiacs, DQ8 8% (not NYC) Remainder ½ DQ2 (which is DQ2 -) Haplotype vs alleles (what does your lab report?) ROLE exclude celiac disease screen family members seronegative VA patients already on GF diet NON-RESPONSIVE CELIAC Biopsy YES villous atrophy 1. Negative serology tests Total 72 Female 51.4% Mean age 59 (29-85 years) Presented w/ diarrhea 76.4% Mean time of follow up 26.4 (months) All attended the celiac center as poorly responsive celiac disease over a 10 year period MEDICATION RELATED VILLOUS ATROPHY MRVA MEDICATIONS = OLMESARTAN, MECOPHENOLATE, MTX CAUSES OF SERONEGATIVE VILLOUS ATROPHY Drug history (olmesartan, methotrexate, azathioprine, colchicine, mycophenolate mofetil) Travel / residence history Anti-enterocyte Abs Quantitative immunoglobulins Stool giardia Ag Breath test SIBO HIV REVIEW BIOPSY 4

5 CAUSES OF SERONEGATIVE VILLOUS ATROPHY Drug history (olmesartan, methotrexate, azathioprine, colchicine, mycophenolate mofetil) Travel / residence history Anti-enterocyte Abs Quantitative immunoglobulins Stool giardia Ag Breath test SIBO HIV REVIEW BIOPSY Those with well established diagnosis of celiac disease USA, Leffler et al. Clin Gastro Hepatol 2007 N = 113 NON- OR POORLY RESOPNSIVE CELIAC Positive TTG IgA or villous atrophy on biopsy DIETITIAN EXCLUDE SIBO lactose intolerance fructose intolerance microscopic colitis or IBD IBS DEFINITION Persistent symptoms + villous atrophy despite 6 12 months of a GF diet we would require ve serology 5

6 CLASSIFICATION Based on characterization of the IELs TYPE I normal IEL phenotype CD3+, CD8+ TYPE II aberrant IEL phenotype Intracytoplasmic expression of CD3, without expression of surface T-cell markers (CD3, CD8) associated with clonal TCRγ gene rearrangement cryptivc T cell lymphoma Cellier, Lancet 2000 TYPE IA H&E TYPE II H&E CD3 CD8 CD3 CD8 CLASSIFICATION Based on characterization of the IELs TYPE I normal IEL phenotype CD3+, CD8+ TYPE II aberrant IEL phenotype Intracytoplasmic expression of CD3, without expression of surface T-cell markers (CD3, CD8) associated with clonal TCRγ gene rearrangement (requires IHC, FLOW, PCR) cryptivc T cell lymphoma Cellier, Lancet 2000 TYPE I good prognosis TYPE II poor prognosis progression to overt lymphoma 5 year survival 40-57% VALUE OF CORRECTLY CLASSIFYING PATIENTS ENABLES APPROPRIATE THERAPY AND DEVELOPMENT OF STUDIES OR PROTOCOLS Dietitian/Nutritional support/ hydration STEROIDS Budesonide (Brar, AJG, 2007) Immunosuppression cyclosporine, AZA, infliximab, alemtuzumab, interleukin 10, cladribine, Stem cell transplantation Anti IL15 (current study at CUMC) type II TYPE I good prognosis TYPE II poor prognosis progression to overt lymphoma 5 year survival 40-57% VALUE OF CORRECTLY CLASSIFYING PATIENTS ENABLES APPROPRIATE THERAPY AND DEVELOPMENT OF STUDIES OR PROTOCOLS 6

7 Dietition/Nutritional support/ hydration STEROIDS Budesonide (Brar, AJG, 2007) Immunosuppression cyclosporine, AZA, infliximab, alemtuzumab, interleukin 10, cladribine, Stem cell transplantation Anti IL15 (current study at CUMC) type II NON-RESPONSIVE CELIAC Common Need systematic evaluation Gluten ingestion common cause Sero-negative villous atrophy interesting! NORTH AMERICAN SOCIETY FOR THE STUDY OF CELIAC 7