Antibodies in the Diagnosis of Coeliac Disease: A Biopsy-Controlled, International, Multicentre Study of 376 Children with Coeliac Disease and 695 Controls

PLOS ONE, Dec 2019

Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgG-antibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive (≥10 ULN, recommend gluten-free diet), negative (<1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB >90% and PPV/NPV >95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9–57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was <11%. The procedures were either equivalent or even better in children <2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgA-aTTG positivity (≥10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed.

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Antibodies in the Diagnosis of Coeliac Disease: A Biopsy-Controlled, International, Multicentre Study of 376 Children with Coeliac Disease and 695 Controls

Multicentre Study of 376 Children with Coeliac Disease and 695 Controls. PLoS ONE 9(5): e97853. doi:10.1371/journal.pone.0097853 Antibodies in the Diagnosis of Coeliac Disease: A Biopsy- Controlled, International, Multicentre Study of 376 Children with Coeliac Disease and 695 Controls Johannes Wolf 0 Dirk Hasenclever 0 David Petroff 0 Thomas Richter 0 Holm H. Uhlig 0 Martin W. Laab 0 Almuthe Hauer 0 Martin Stern 0 Xavier Bossuyt 0 Jan de Laffolie 0 Gunter Flemming 0 Danilo Villalta 0 Wolfgang Schlumberger 0 Thomas Mothes 0 Karol Sestak, Tulane University, United States of America 0 1 Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University and University Hospital , Leipzig, Germany , 2 Institute for Medical Informatics, Statistics & Epidemiology of the University , Leipzig, Leipzig, Germany , 3 Coordination Centre for Clinical Trials of the University , Leipzig, Germany , 4 Children's Hospital of the Clinical Centre ''Sankt Georg'' , Leipzig, Germany , 5 Translational Gastroenterology Unit, Experimental Medicine, University of Oxford, John Radcliffe Hospital , Oxford, England , 6 University Children's Hospital , Dresden, Germany , 7 University Children's Hospital , Graz , Austria , 8 University Children's Hospital , Tu bingen, Germany, 9 Laboratory Medicine, Immunology , University Hospitals Leuven, Catholic University , Leuven , Belgium , 10 University Children's Hospital , Gieben, Germany , 11 University Children's Hospital , Leipzig, Germany , 12 Allergy and Clinical Immunology Unit, Azienda Ospedaliera ''San Maria degli Angeli'' , Pordenone, Italy, 13 EUROIMMUN AG Labormedizinische Diagnostika AG, Lu beck , Germany Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgGantibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive ($10 ULN, recommend gluten-free diet), negative (,1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB .90% and PPV/NPV .95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9-57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was ,11%. The procedures were either equivalent or even better in children ,2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgAaTTG positivity ($10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed. - Funding: This work was partially funded by the State of Mecklenburg-Vorpommern and European Union (European Fund for Regional Development [EFRE]). H. Uhlig received support from the DZG (Deutsche Zo liakiegesellschaft). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have read the journals policy and have the following conflicts. Thomas Mothes and Holm Uhlig share in a patent of dGli antibody assays. Wolfgang Schlumberger is a board member and shareholder of EUROIMMUN AG. All other authors have declared that no competing interests exist. . These authors contributed equally to this work. Coeliac disease (CD) is an autoimmune mediated enteropathy with tissue transglutaminase (TTG) as autoantigen and is triggered by an abnormal immune response to wheat gluten and related cereal peptides in genetically predisposed persons. The clinical presentation ranges from typical malabsorption signs to rather atypical symptoms and conditions that can affect any organ system. Until recently, the diagnosis of CD was based on the assessment of the highly variable clinical status, assays of different specific antibodies, the histological eva (...truncated)


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Johannes Wolf, Dirk Hasenclever, David Petroff, Thomas Richter, Holm H. Uhlig, Martin W. Laaβ, Almuthe Hauer, Martin Stern, Xavier Bossuyt, Jan de Laffolie, Gunter Flemming, Danilo Villalta, Wolfgang Schlumberger, Thomas Mothes. Antibodies in the Diagnosis of Coeliac Disease: A Biopsy-Controlled, International, Multicentre Study of 376 Children with Coeliac Disease and 695 Controls, PLOS ONE, 2014, Volume 9, Issue 5, DOI: 10.1371/journal.pone.0097853