Potential Celiac Disease (CD) in children with CD Family Risk: Clinical Correlates and Outcome

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1 Potential Celiac Disease (CD) in children with CD Family Risk: Clinical Correlates and Outcome Carlo Catassi, 1,2 Elena Lionetti, 3 Stefania Castellaneta, 4 Alfredo Pulvirenti, 5 Elio Tonutti, 6 Ruggiero Francavilla, 7 Alessio Fasano, 1 and the Italian Working Group of Weaning and CD risk. 1 Center for Celiac Research, University of Maryland, Baltimore MD (USA), 2 Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy, 3 Department of Pediatrics, University of Catania, Italy, 4 Department of Pediatrics, San Paolo Hospital, Bari, Italy, 5 Department of Clinical and Molecular Biomedicine, University of Catania, Italy, 6 Department of Immunopathology and Allergology, Udine Hospital, Udine, Italy, 7 Department of Developmental Biomedicine, University of Bari, Italy,

2 Background 1. Potential celiac disease (CD) is characterized by a serum celiac-type antibody response associated with a normal or minimally abnormal intestinal mucosa at the biopsy The destiny of potential CD is variable but may evolve into overt CD over time; 2 15m 24m 36m Tot 3. However, in young children CD-related autoantibodies may disappear over time without dietary treatment, suggesting the possibility of a fluctuating CD-type response influenced by regulatory immune events Identifying children that can reverse the autoimmune process may help clarifying factors involved in either CD development or restoration of gluten tolerance. 1 Fasano A and Catassi C, Gastroenterology Tosco A, et al, Clin Gastr Hepatol Simell S, et al, Am J Gastr Simell S, et al. Scand J Gastroenterol Liu E, et al. Clin Gastroenterol Hepatol 2003

3 Aims of the study In a large cohort of children at family risk for CD participating in the Italian Baby Study on Weaning and CD risk we aimed to evaluate: 1)the frequency of potential CD; 15m 24m 36m Tot 2)the natural history of CD-related antibodies in children with potential CD left on a normal diet; 3)any possible discriminating factors between children with potential or overt CD.

4 The Italian Baby-Study on Weaning and CD Risk Infants at family risk for CD Enrolment from 2003 to 2009 in 20 Italian centers 4th 6th month Group A GFD from 0 to 4 6 months Group B Gluten introduction at 4-6 months Gluten introduction at 12 months 12th month 12 months: diet with gluten Positive for serology: a) TTG > 20 U.I. and EMA pos; b) AGA IgG in IgA deficit; c) AGA IgA and IgG in <2 yrs HLA-DQ2/DQ8 + IgA tot AGA, EMA and TTG at 15 months AGA, EMA, and TTG at 24 and 36 months and 5 years

5 Patients and Methods 1. The study-group included Italian children participating in the Italian Baby Study on Weaning and CD risk, and fulfilling the criteria for the small intestinal biopsy. 2. Diagnosis of CD was made in children with a CD-compatible HLA genotype, a Marsh- Oberhuber 0-1 (potential CD) or 2-3 (overt CD) lesion at the biopsy, and one of the following: 1) IgA ttg and EMA positivity; 2) AGA IgG positivity associated with IgA deficiency; 3) AGA IgA positivity in children aged less than two years with clinical suspicion of CD. 3. Potential CD children were followed-up and CD-related antibodies were determined every 6 months for 2 years. In patients with persistent antibody-positivity and/or symptoms after 2 years biopsies were repeated. 4. The following attributes were evaluated: age, sex, relative/s with CD, antitransglutaminase titre, HLA alleles, age at gluten introduction, and duration of breastfeeding. 5. To investigated the presence of attributes with predictive power for potential CD vs overt CD we trained a decision tree based on the C4.5 algorithm.

6 Results 1. Frequency of potential CD 101 positives (5 refused biopsy) 25% Potential CD-children (n=24) F 13 (50%); median age 2.1 years (range 1-5) 14 Marsh 0, 10 Marsh 1 23 TTG and EMA pos (1 AGA IgG pos) All asymptomatic Normal nutritional parameters No other autoimmune diseases 75% Overt CD (72) Potential CD (24)

7 Risultati 2. Natural history of 24 children with potential CD 24 potential CD TTG + EMA+ n=23 TTG-, EMA AGA IgG + (IgA deficiency) n=1 gluten-free diet n=3 gluten-containing diet n=20 gluten-containing diet n=1 15m 24m 36m Tot After 1 year TTG EMA negative n=16 TTG EMA positive n=2 TTG EMA fluctuating n=2 AGA IgG negative n=1 After 2 years TTG EMA negative n=17 TTG EMA positive n=1 TTG EMA fluctuating n=2 AGA IgG negative n=1 Overall: 86% negative Villous atrophy 5% CD 9% fluctuating

8 Results 3. Anti-tTG values of the 21 potential CD-children continuing gluten-consumption at each time of follow-up

9 Results: decision-tree 4. Factors associated with potential CD versus overt CD 15m 24m 36m Tot Precision 88.5% Sensitivity 0.93 Specificity 0.76

10 Conclusions 1. The frequency of potential CD is high in at-risk infants, however the percentage of spontaneous disappearance of CD-related antibodies is about 86% (at 2 years from the first positivity). 2. Our study shows that in asymptomatic antibody-positive children with TTG levels < 11 folds the decision of performing the biopsy should be preceded by a period of repeated serological testing. 3. Breastfeeding may have a preventive role on future development of CD. 4. A prolonged follow-up of this cohort will clarify whether these children will develop CD later in life.

11 Thanks to Study-coordinator group Carlo Catassi (Ancona) Elena Lionetti (Catania) Stefania Castellaneta (Bari) Ruggiero Francavilla (Bari) Associazione Italiana Celiachia Adriano Pucci Elisabetta Tosi Serologycal testing Menarini diagnostics (Firenze) Massimo Donnini (Firenze) Elio Tonutti (Udine) HLA typing Bionat (Palermo) Sandro Drago Giovanni Maggiore Alessandro Raffa Statistical analysis Alfredo Pulvirenti (Catania) The Italian working group on weaning and CD risk (SIGENP) Sergio Amarri (Reggio Emilia) Maria Barbato, Giulia Maiella, Ilaria Celletti (Roma) Cristiana Barbera, Maria Kuvidi (Torino) Graziano Barera, Giulia Tronconi (Milano) Antonella Bellantoni (Reggio Calabria) Emanuela Castellano (Genova) Giuseppe Castellucci (Foligno) Carlo Catassi, Francesca Aniballi, Simona Gatti (Ancona) Maurizio Corvo (Milano) Ruggiero Francavilla, Stefania Castellaneta (Bari) Graziella Guariso (Padova) Giuseppe Iacono (Palermo) Elena Lionetti (Catania) Giuseppe Lombardi (Pescara) Giuseppe Magazzù, Donatella Sindoni (Messina) Carlo Polloni (Rovereto) Marinella Scotta (Varese) Riccardo Troncone, Giovanna Limongelli (Napoli) Giovanna Zuin (Milano) Claudio Ughi (Pisa)