The prospective study and the new ESPGHAN protocol L. Greco, D. Mičetić-Turk Mediterranean Network for Celiac Disease Istanbul, June 30th 2012 1 1 1 1

New recommendations The histology might be omitted in symptomatic cases, who have: - high IgA anti-tTG titres (above 10x upper normal limit), - verified by EMA positivity, - HLA DQ2 and/or DQ8 heterodimer positive.

Who should be tested for CD? Children and adolescents with the otherwise unexplained symptoms and signs Asymptomatic children and adolescents with increased risk for CD 6 6

Children and adolescents with otherwise unexplained symptoms and signs of: chronic or intermittent diarrhoea failure to thrive weight loss stunted growth delayed puberty amenorrhoea iron-deficiency anaemia nausea or vomiting chronic abdominal pain cramping or distension chronic constipation chronic fatigue recurrent aphthous stomatitis (mouth ulcers) dermatitis herpetiformis-like rash fracture with inadequate traumas / osteopenia / osteoporosis abnormal liver biochemistry 7 7

Asymptomatic children and adolescents with increased risk for CD: type 1 diabetes mellitus autoimmune thyroid disease autoimmune liver disease Down’s syndrome Turner syndrome Williams’ syndrome selective IgA deficiency 1st degree relatives with CD dermatitis herpetiformis 8 8

Dermatitis herpetiformis Down syndrome Dermatitis herpetiformis Dental enamel defects Turner syndrome 9

What is the optimal approach for MEDICEL prospective study? 10 10 10

Diagnosis of CD history physical examination diagnostic tools: CD specific antibody tests: Anti-TG2, anti-DGP, EMA HLA testing for DQ2 and DQ8 histological analysis of duodenal biopsies 11 11 11 11 11

If you suspect it - you will detect it Diagnosis of CD If you suspect it - you will detect it 12 12 12 12

New diagnostic tests serological tests tissue transglutaminase Ab (t-TG)‏ reliable, relatively inexpensive test rapid finger-prick t-TG test 13 13

New diagnostic tests new microsystems simultaneus multiple Ab test IgA determination HLA-DQ2/DQ8 status Prince HE. Evaluation of the INOVA diagnostics enzyme-linked immunosorbent assay kits for measuring serum immunoglobulin G (IgG) and IgA to deamidated gliadin peptides. Clin Vaccine Imunol 2006. Aleanzi M, et al. Celiac disease: antibody recognition against native and selectively deamidated gliadin peptides. Clin Chem. 2001 14 14

MEDICEL – prospective study Background CD is a prevalent and curable condition affecting 1% of the population The occurence of coeliac disease is increasing over time CD is more prevalent than clinically detected Prevalence among family members ~ 10% 15 15 15 15

Aims To investigate the incidence of CD To evaluate characteristics and severity of symptoms To estimate CD risk by HLA-SNPs determination in first degree relatives To evaluate whether in cases with positive serological and genetic markers and with clinical symptoms the omission of biopsies is possible in Mediterranean countries? Other?? 16 16 16 16

Study design Prospective multicenter observation study in persons, who will be diagnosed based on: - Standarized symptom assessment - Physical examination - Serology – rapid test or more extensive serology -HLA testing - Histology Conditions for participation: - To recruit at least 50-100 patients - Ethical approval by the local ethical committee 17 17 17 17

Standarized questionnaire on: Methods Standarized questionnaire on: family history clinical symptoms and CD related diseases malignances? 18 18 18 18

Methods Blood sampling for serology - central lab / local lab 2-5ml blood for TG2, DGP, EMA Rapid tTG test DNA sampling 2-3ml EDTA blood frozen as total blood (HLA DQ2/DQ8 , non-HLA genes)‏ Saliva sampling 19 19 19 19

Methods Histology – at least 5 biopsies from duodenum (4 from 2nd and 3rd part and 1 from the bulb) - Marsh criteria Statistical analysis Financial calculation Participating clinical centres Sampling and delivery Central / local lab 20 20 20 20

Data safety Every particiapting centre should treat the patient’s data confidentially. Data analysis -data will be sent encoded to coordinator – Prof Luigi Greco 21 21 21 21

“Working with the web-database and Biobanking” MEDICEL meeting 2011 Bologna. April 5 2011 Jose Ramon Bilbao

The MediCel database… a newborn project http//medicel.sedyne.org type your name

This will be important for follow-up… The MediCel database… a newborn project http//medicel.sedyne.org This is an anonymous database Samples are coded: country_XX You should have your code safe with you country_XX = patient ID This will be important for follow-up…

The MediCel database… a newborn project http//medicel.sedyne.org

All fields are (*) compulsory! The MediCel database… a newborn project http//medicel.sedyne.org SNP-based DQ2.5 DQ2.2 DQ8 Provide affordable HLA testing All fields are (*) compulsory! …but are they necessary? is age at Dx enough? …will check Provide HLA testing other genetic studies? SNP-based DQ2.5 DQ2.2 DQ8

The MediCel database… a newborn project http//medicel.sedyne.org symptoms/signs are we happy?

The MediCel database… a newborn project http//medicel.sedyne.org symptoms/signs are we happy?

Benefits of the study For individuals – diagnosis For MEDICEL partners New knowledge on local level For MEDICEL project New knowledge – epidemiology of CD in mediterannean countries New knowledge – clinical picture New knowledge – genetics (non-HLA genes)‏ Evaluation of new ESPGHAN protocol 29 29 29 29