Spanish National Registry of Paediatric Coeliac Disease: Changes in the Clinical Presentation in the 21st Century.

OBJECTIVES: Over the last several decades, there has been a tendency towards a predominance of less symptomatic forms of coeliac disease (CD) and an increase in the patient age at diagnosis. This study aimed to assess the clinical presentation and diagnostic process of paediatric CD in Spain. METHODS: A nationwide prospective, observational, multicentre registry of new paediatric CD cases was conducted from January 2011 to June 2017. The data regarding demographic variables, type of birth, breast-feeding history, family history of CD, symptoms, height and weight, associated conditions, serological markers, human leukocyte antigen (HLA) phenotype, and histopathological findings were collected. RESULTS: In total, 4838 cases (61% girls) from 73 centres were registered. The median age at diagnosis was 4 years. Gastrointestinal symptoms were detected in 71.4% of the patients, and diarrhoea was the most frequent symptom (45.9%). The most common clinical presentation was the classical form (65.1%) whereas 9.8% ofthe patients were asymptomatic. There was a trend towards an increase in the age at diagnosis, proportion of asymptomatic CD cases, and usage of anti-deamidated gliadin peptide antibodies and HLA typing for CD diagnosis. There was, however, a decreasing trend in the proportion of patients undergoing biopsies. Some of these significant trend changes may reflect the effects of the 2012 ESPGHAN diagnosis guidelines. CONCLUSIONS: Paediatric CD in Spain is evolving in the same direction as in the rest of Europe, although classical CD remains the most common presentation form, and the age at diagnosis remains relatively low.

Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study.

Vedolizumab is a humanised monoclonal antibody that binds to integrin α4ß7 expressed in T-cells, inhibiting its binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is specifically expressed in the small intestine and colon, playing a fundamental role in T-cell migration to the gastrointestinal tract. Vedolizumab has been shown to be effective in treating adults with inflammatory bowel disease; however, efficacy data for paediatric use are scarce. The objective of the present study was to assess the effectiveness and safety of vedolizumab for inducing and maintaining clinical remission in children with inflammatory bowel disease. We conducted a retrospective multicentre study of patients younger than 18 years with inflammatory bowel disease refractory to anti-tumour necrosis factor alpha (anti-TNF-α) drugs, who underwent treatment with vedolizumab. Clinical remission was defined as a score < 10 points in the activity indices. We included 42 patients, 22 of whom were male (52.3%), with a median age of 13.1 years (IQR 10.2-14.2) at the start of treatment. Of the 42 patients, 14 (33.3%) had Crohn's disease (CD) and 28 (66.7%) had ulcerative colitis (UC). At the start of treatment with vedolizumab, the Paediatric Crohn's Disease Activity Index was 36 (IQR 24-40) and the Paediatric Ulcerative Colitis Activity Index was 47 (IQR 25-65). All of them had received prior treatment with anti-TNF and 3 patients ustekinumab. At week 14, 69% of the patients responded to the treatment (57.1% of those with CD and 75% of those with UC; p=0.238), and 52.4% achieved remission (35.7% with CD and 60.7% with UC; p=0.126). At 30 weeks, the response rate was 66.7% (46.2% and 78.3% for CD and UC, respectively; p=0.049), and 52.8% achieved remission (30.8% and 65.2% for CD and UC, respectively; p=0.047). Among the patients with remission at week 14, 80% of the patients with CD and 84.5% of those with UC maintained the remission at 52 weeks. Adverse effects were uncommon and mild. Three patients (7.1%) presented headaches, 1 presented alopecia, 1 presented anaemia and 1 presented dermatitis.Conclusion: The results show that treatment with vedolizumab is a safe and effective option for achieving clinical remission in paediatric patients with inflammatory bowel disease with primary failure or loss of response to other treatments, especially in UC. What is Known: • Vedolizumab is effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. • Most studies and clinical trials have been performed on adult populations, and there is currently no indication for paediatric populations. What is New: • Children with inflammatory bowel disease refractory to anti-TNF presented higher clinical remission rates than those published for adults. • There are few publications of this magnitude on paediatric populations treated with vedolizumab and with long-term follow-up (52 weeks).

[Rational application of the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 criteria for the diagnosis of coeliac disease]. / Aplicación racional de los nuevos criterios de la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 para el diagnóstico de la enfermedad celíaca.

Coeliac disease is a systemic immune-mediated disorder triggered by the ingestion of gluten, which is given in genetically predisposed subjects. It manifests with a wide variety of clinical symptoms, specific serological markers, HLA-DQ2/DQ8 haplotype and enteropathy. The criteria followed for this have usually been those established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since 1969. These criteria have advanced from the need of several intestinal biopsies to, thanks to the development of serological tests of high sensitivity and specificity, considering the enteropathy as one more element in this diagnosis and makes it possible to perform a diagnosis without the need of an intestinal biopsy in certain circumstances. The updated review of the 2012 criteria in 2019 provides new evidence on some aspects, such as the role of HLA, the diagnosis of asymptomatic patients, and the effectiveness of the serological markers. These aspects are reviewed in detail, with the aim of facilitating the rational application of the new 2020 criteria at all care levels. In this sense, Paediatric Primary Care is fundamental in the search for active cases and to perform a first serological study, being recommended that the diagnosis is always established by a Paediatric Gastroenterologist.

Spanish Pediatric Inflammatory Bowel Disease Diagnostic Delay Registry: SPIDER Study From Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica.

Background and Aims: Diagnostic delay (DD) is especially relevant in children with inflammatory bowel disease, leading to potential complications. We examined the intervals and factors for DD in the pediatric population of Spain. Methods: We conducted a multicentric prospective study, including 149 pediatric inflammatory bowel disease patients, obtaining clinical, anthropometric, and biochemical data. Time to diagnosis (TD) was divided into several intervals to identify those where the DD was longer and find the variables that prolonged those intervals. Missed opportunities for diagnosis (MODs) were also identified. Results: Overall TD was 4.4 months (interquartile range [IQR] 2.6-10.4), being significantly higher in Crohn's disease (CD) than in ulcerative colitis (UC) (6.3 [IQR 3.3-12.3] vs. 3 [IQR 1.6-5.6] months, p = 0.0001). Time from the visit to the first physician until referral to a pediatric gastroenterologist was the main contributor to TD (2.4 months [IQR 1.03-7.17] in CD vs. 0.83 months [IQR 0.30-2.50] in UC, p = 0.0001). One hundred and ten patients (78.3%) visited more than one physician (29.9% to 4 or more), and 16.3% visited the same physician more than six times before being assessed by the pediatric gastroenterologist. The number of MODs was significantly higher in CD than that in UC patients: 4 MODs (IQR 2-7) vs. 2 MODs ([IQR 1-5], p = 0.003). Referral by pediatricians from hospital care allowed earlier IBD diagnosis (odds ratio 3.2 [95% confidence interval 1.1-8.9], p = 0.025). Conclusions: TD and DD were significantly higher in CD than those in UC. IBD patients (especially those with CD) undergo a large number of medical visits until the final diagnosis.

Predictors of Response to Exclusive Enteral Nutrition in Newly Diagnosed Crohn´s Disease in Children: PRESENCE Study from SEGHNP.

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014-2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6-8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn's Disease activity index [wPCDAI] < 12.5). Faecal calprotectin (FC) levels (µg/g) decreased significantly after EEN (830 [IQR 500-1800] to 256 [IQR 120-585] p < 0.0001). Patients with wPCDAI ≤ 57.5, FC < 500 µg/g, CRP >15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6-8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn's disease regardless of the location of disease and disease activity.

[Anti-tissue transglutaminase antibodies not related to gluten intake]. / Anticuerpos antitransglutaminasa no relacionados con la ingesta de gluten.

INTRODUCTION: Anti-tissue transglutaminase antibodies (tTG) have high specificity for coeliac disease (CD). However, positive anti-tTG antibodies have been described in non-coeliac patients. Aim To assess positive anti-tTG antibodies not related to gluten intake. PATIENTS AND METHODS: Retrospective review and follow up conducted on patients with suspected CD (increase anti-tTG levels and gastrointestinal symptoms) but with atypical serology results, positive anti-tTG with gluten free diet and a decrease in anti-tTG levels despite gluten intake. RESULTS: A total of 9 cases were reviewed in which 5 cases had Marsh 3 involvement in the initial biopsy, and were diagnosed with CD (Group A). They began a gluten free diet and also a cow's milk protein (CMP) free diet because of their nutritional status. When CMP was re-introduced, anti-tTG increased, and returned to normal after the CMP was withdrawn again. The other 4 patients had a normal initial biopsy (Group B). Gluten was not removed from their diet, but they started a CMP free diet because a non IgE mediated CMP allergy was suspected. Symptoms disappeared, and anti-tTG was normal after CMP free diet with gluten intake. All the patients had susceptibility haplotype HLA DQ2/DQ8. CONCLUSIONS: CMP ingestion after an exclusion diet can induce an increase in anti-tTG in some coeliac subjects. CMP can produce this immune response if there were no gluten transgressions. This response has also been observed in non-IgE mediated CMP allergy patients with the susceptibility haplotype HLA DQ2/DQ8.

Aplicación racional de los nuevos criterios de la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 para el diagnóstico de la enfermedad celíaca / Rational application of the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2020 criteria for the diagnosis of coeliac disease

La enfermedad celíaca es un proceso sistémico de carácter inmunológico, desencadenado por el consumo de gluten, que se da en sujetos genéticamente predispuestos. Se expresa con una gran variedad de síntomas clínicos, marcadores serológicos específicos, haplotipo HLA-DQ2/DQ8 y enteropatía. El tratamiento consiste en eliminar de por vida el gluten de la dieta, por lo que es fundamental un diagnóstico adecuado. Los criterios seguidos para ello han sido habitualmente los establecidos por la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) desde 1969. Estos criterios han ido evolucionando desde la necesidad de varias biopsias intestinales para el diagnóstico a, gracias al desarrollo de pruebas serológicas de alta sensibilidad y especificidad, considerar la enteropatía como un elemento más en este diagnóstico y posibilitar en determinadas circunstancias realizarlo sin necesidad de biopsia intestinal. La revisión actualizada en 2019 de los criterios 2012 aporta nueva evidencia sobre algunos aspectos, como el papel del HLA, el diagnóstico de los pacientes asintomáticos y la eficacia de los marcadores serológicos. Estos aspectos se revisan en detalle, con el objetivo de facilitar la aplicación de los nuevos criterios 2020 de una forma racional en todos los niveles asistenciales. En este sentido el pediatra de Atención Primaria es fundamental para la búsqueda activa de casos y realizar un primer estudio serológico, recomendándose que el diagnóstico sea siempre establecido por un pediatra gastroenterólogo

Coeliac disease is a systemic immune-mediated disorder triggered by the ingestion of gluten, which is given in genetically predisposed subjects. It manifests with a wide variety of clinical symptoms, specific serological markers, HLA-DQ2/DQ8 haplotype and enteropathy. The criteria followed for this have usually been those established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since 1969. These criteria have advanced from the need of several intestinal biopsies to, thanks to the development of serological tests of high sensitivity and specificity, considering the enteropathy as one more element in this diagnosis and makes it possible to perform a diagnosis without the need of an intestinal biopsy in certain circumstances. The updated review of the 2012 criteria in 2019 provides new evidence on some aspects, such as the role of HLA, the diagnosis of asymptomatic patients, and the effectiveness of the serological markers. These aspects are reviewed in detail, with the aim of facilitating the rational application of the new 2020 criteria at all care levels. In this sense, Paediatric Primary Care is fundamental in the search for active cases and to perform a first serological study, being recommended that the diagnosis is always established by a Paediatric Gastroenterologist

DEVELOPMENT AND VALIDATION OF TWO FOOD FREQUENCY QUESTIONNAIRES TO ASSESS GLUTEN INTAKE IN CHILDREN UP TO 36 MONTHS OF AGE.

BACKGROUND AND OBJECTIVE: precise information on gluten consumption is crucial for specifically studying the impact of gluten introduction and gluten intake in celiac disease development. Our aim was to develop and validate tools (food frequency questionnaires, FFQs) for the assessment of gluten consumption in Spanish children aged 7-36 months. METHODS: a total of 342 children, who attended primary healthcare centers for routine health surveys or La Fe Hospital for minor health problems as well as healthy children (recruited in nurseries and primary schools) participated in this survey. We have developed two different FFQs (one for 7-12 months and other for 13-36 months). For validation, results from two FFQs were compared with results of 2-day food records and also with the gold standard 7-day records. The mean gluten intake obtained by the 2DR vs. FFQ and the 7DR vs. FFQ, were compared using the Bland Altman plot method and also Lin's concordance correlation coefficient. RESULTS: we found a good agreement between our FFQs and the 2DR and 7DR according to the results of both the Bland-Altman plots and Lin's concordance correlation coefficient. CONCLUSIONS: our two new FFQs are therefore the only validated questionnaires available to determine gluten consumption in Spanish children. They are user-friendly and offer excellent instruments to assess gluten intake in children up to 36 months of age.

Antecedentes y objetivos: una información precisa sobre el consumo de gluten es muy importante para estudiar el verdadero impacto de la introducción y la ingesta de gluten en el desarrollo de la enfermedad celiaca. El objetivo del estudio fue desarrollar y validar herramientas (cuestionarios de frecuencia de consumo, CFC) para evaluar el consumo de gluten en niños con edades comprendidas entre los 7 y 36 meses. Métodos: se incluyeron un total de 342 niños reclutados en el Hospital Universitario y Politécnico de La Fe, así como en guarderías y escuelas de primaria con problemas menores de salud. Se desarrollaron dos CFC diferentes (uno para niños de 7 a 12 meses y otro para niños de 13 a 36 meses). Para su validación, los resultados obtenidos con los CFC se compararon con un registro alimentario de dos días (2RA) y también con un registro alimentario de soete días (7RA), considerado el "estándar de oro". La ingesta media de gluten obtenida de la comparación del 2RA vs. CFC y de 7RA vs. CFC fueron comparadas usando el método de Bland Altman plot y también el coeficiente de correlación de concordancia de Lin's. Resultados: de acuerdo a los resultados de los dos métodos estadísticos usados para la validación, se encontró una buena correlación entre los CFC y los registros alimentarios de dos y siete días, lo que indica que los CFC son fiables para la evaluación de la ingesta de gluten. Conclusiones: estos dos nuevos CFC son los únicos validados y disponibles en España para la evaluación de la ingesta de gluten. Además, son herramientas útiles y fáciles de usar para el cálculo del consumo de gluten en niños de hasta tres años de edad.

Anticuerpos antitransglutaminasa no relacionados con la ingesta de gluten / Anti-tissue transglutaminase antibodies not related to gluten intake

INTRODUCCIÓN: Los anticuerpos antitransglutaminasa (ATG) poseen alta especificidad para el diagnóstico de enfermedad celíaca (EC). Sin embargo, se han descrito anticuerpos ATG positivos en pacientes no celíacos. OBJETIVO: Valorar la presencia de anticuerpos ATG positivos no relacionados con la ingesta de gluten. PACIENTES Y MÉTODOS: Revisión retrospectiva de historias clínicas y seguimiento de pacientes con sospecha de EC y con un comportamiento serológico atípico, es decir, anticuerpos ATG positivos a pesar de una dieta sin gluten y disminución de anticuerpos ATG tomando gluten. RESULTADOS: Se incluyeron 9 casos. De ellos, 5 casos tenían afectación histológica Marsh 3 en la biopsia inicial y diagnóstico de EC (grupo A). Se retiró el gluten de la dieta y se retiraron las proteínas de leche de vaca (PLV) por la afectación nutricional. Al reintroducir las PLV aumentaron los ATG y al retirarlas se volvieron a normalizar. Los otros 4 pacientes presentaban una biopsia inicial normal (grupo B): en estos no se retiró el gluten, pero sí las PLV por sospecha de alergia no IgE mediada. Los síntomas desaparecieron y se normalizaron los ATG al retirar las PLV manteniendo dieta con gluten. Todos presentan el haplotipo de susceptibilidad para EC. CONCLUSIONES: En algunos celíacos, la reintroducción de PLV en la dieta tras un período de exclusión induce un aumento de los anticuerpos ATG IgA. Si se han descartado transgresiones con gluten, las PLV pueden causar esta respuesta inmune. Hemos observado también esta respuestaen pacientes con alergia no IgE, mediada por las PLV, portadores del haplotipo de susceptibilidad HLA DQ2/DQ8

INTRODUCTION: Anti-tissue transglutaminase antibodies (tTG) have high specificity for coeliac disease (CD). However, positive anti-tTG antibodies have been described in non-coeliac patients. Aim To assess positive anti-tTG antibodies not related to gluten intake. PATIENTS AND METHODS: Retrospective review and follow up conducted on patients with suspected CD (increase anti-tTG levels and gastrointestinal symptoms) but with atypical serology results, positive anti-tTG with gluten free diet and a decrease in anti-tTG levels despite gluten intake. RESULTS: A total of 9 cases were reviewed in which 5 cases had Marsh 3 involvement in the initial biopsy, and were diagnosed with CD (Group A). They began a gluten free diet and also a cow's milk protein (CMP) free diet because of their nutritional status. When CMP was re-introduced, anti-tTG increased, and returned to normal after the CMP was withdrawn again. The other 4 patients had a normal initial biopsy (Group B). Gluten was not removed from their diet, but they started a CMP free diet because a non IgE mediated CMP allergy was suspected. Symptoms disappeared, and anti-tTG was normal after CMP free diet with gluten intake. All the patients had susceptibility haplotype HLA DQ2/DQ8. CONCLUSIONS: CMP ingestion after an exclusion diet can induce an increase in anti-tTG in some coeliac subjects. CMP can produce this immune response if there were no gluten transgressions. This response has also been observed in non-IgE mediated CMP allergy patients with the susceptibility haplotype HLA DQ2/DQ8

Development and validation of two food frequency questionnaires to assess gluten intake in children up to 36 months of age / Desarrollo y validación de dos cuestionarios de frecuencia de consumo para evaluar la ingesta de gluten en niños hasta los 3 años

Background and objective: precise information on gluten consumption is crucial for specifically studying the impact of gluten introduction and gluten intake in celiac disease development. Our aim was to develop and validate tools (food frequency questionnaires, FFQs) for the assessment of gluten consumption in Spanish children aged 7-36 months. Methods: a total of 342 children, who attended primary healthcare centers for routine health surveys or La Fe Hospital for minor health problems as well as healthy children (recruited in nurseries and primary schools) participated in this survey. We have developed two different FFQs (one for 7-12 months and other for 13-36 months). For validation, results from two FFQs were compared with results of 2-day food records and also with the gold standard 7-day records. The mean gluten intake obtained by the 2DR vs. FFQ and the 7DR vs. FFQ, were compared using the Bland Altman plot method and also Lin’s concordance correlation coefficient. Results: we found a good agreement between our FFQs and the 2DR and 7DR according to the results of both the Bland-Altman plots and Lin’s concordance correlation coefficient. Conclusions: our two new FFQs are therefore the only validated questionnaires available to determine gluten consumption in Spanish children. They are user-friendly and offer excellent instruments to assess gluten intake in children up to 36 months of age (AU)

Antecedentes y objetivos: una información precisa sobre el consumo de gluten es muy importante para estudiar el verdadero impacto de la introducción y la ingesta de gluten en el desarrollo de la enfermedad celiaca. El objetivo del estudio fue desarrollar y validar herramientas (cuestionarios de frecuencia de consumo, CFC) para evaluar el consumo de gluten en niños con edades comprendidas entre los 7 y 36 meses. Métodos: se incluyeron un total de 342 niños reclutados en el Hospital Universitario y Politécnico de La Fe, así como en guarderías y escuelas de primaria con problemas menores de salud. Se desarrollaron dos CFC diferentes (uno para niños de 7 a 12 meses y otro para niños de 13 a 36 meses). Para su validación, los resultados obtenidos con los CFC se compararon con un registro alimentario de dos días (2RA) y también con un registro alimentario de siete días (7RA), considerado el “estándar de oro”. La ingesta media de gluten obtenida de la comparación del 2RA vs. CFC y de 7RA vs. CFC fueron comparadas usando el método de Bland Altman plot y también el coeficiente de correlación de concordancia de Lin’s. Resultados: de acuerdo a los resultados de los dos métodos estadísticos usados para la validación, se encontró una buena correlación entre los CFC y los registros alimentarios de dos y siete días, lo que indica que los CFC son fiables para la evaluación de la ingesta de gluten. Conclusiones: estos dos nuevos CFC son los únicos validados y disponibles en España para la evaluación de la ingesta de gluten. Además, son herramientas útiles y fáciles de usar para el cálculo del consumo de gluten en niños de hasta tres años de edad (AU)