Non-alcoholic fatty liver disease (NAFLD) is rapidly increasing alongside overweight and obesity, not only in adults but also in children and adolescents. It is unknown what impact the development of ...NAFLD in childhood may have in later life. The importance of early detection and treatment lies in its potential for progression to cirrhosis, liver cancer and liver-related death, as well as its associated extrahepatic comorbidities. Vibration-Controlled Transient Elastography (VCTE) with Controlled Attenuation Parameter (CAP) is an effective, non-invasive and safe diagnostic method to estimate the degree of fibrosis and steatosis in the liver, but little is known about its applicability in the paediatric population. 1) To assess the prevalence of significant liver fibrosis (Liver Stiffness Measurement (LSM) greater than or equal to6.5 kPa) using VCTE, and that of non-alcoholic fatty liver disease (greater than or equal to225 dB/m) using CAP in children and adolescents. 2) To determine the optimal cut-off points of the CAP to achieve maximum concordance with the Magnetic Resonance Imaging (MRI) findings in the diagnosis of mild, moderate and severe NAFLD in children and adolescents. Cross-sectional population-based study which will include 2,866 subjects aged between 9 and 16 years. Participants will undergo: anamnesis, physical examination, blood extraction, VCTE, MRI and questionnaires on socio-demographic data, personal and family medical history and lifestyle assessment.
Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of ...considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.
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Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to ...identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment.
We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs.
Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10–7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3).
We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.
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•Baseline gene expression in blood associates with the response to anti-TNF drugs.•RNA-seq identified 102 genes associated with the response to anti-TNF drugs.•PRTN3, LTF, LCN, and CEACAM8 are overexpressed in responder children.•Cancer-related genes impact the response to anti-TNF drugs.•Overexpressed genes in responder children directly link to TNF processes.
Vedolizumab is a humanised monoclonal antibody that binds to integrin α4β7 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).
La esofagitis eosinofílica es una enfermedad emergente, crónica, mediada por el sistema inmune y caracterizada por síntomas de disfunción esofágica e inflamación con infiltración eosinofílica aislada ...en el esófago. Es más frecuente en varones y en sujetos atópicos y los síntomas varían con la edad: en niños pequeños se manifiesta con vómitos, dolor abdominal y problemas con la alimentación y en niños mayores y adolescentes con disfagia e impactación alimentaria. El diagnóstico se basa en la presencia de síntomas e inflamación esofágica con ≥ 15 eosinófilos/campo de gran aumento, tras descartar otras causas de eosinofilia esofágica. Sin tratamiento, la enfermedad suele persistir y puede evolucionar a formas fibroestenóticas más frecuentes en el adulto. Las opciones terapéuticas incluyen inhibidores de la bomba de protones, dieta de eliminación empírica y corticoides deglutidos. Tras el tratamiento de inducción es aconsejable la terapia de mantenimiento. La dieta es el único tratamiento que se dirige a la causa de la enfermedad, al identificar los alimentos desencadenantes. La respuesta a los tratamientos requiere la evaluación histológica, por la escasa concordancia entre los síntomas y la inflamación esofágica.
El manejo práctico de la esofagitis eosinofílica presenta desafíos debido, entre otras causas, a la falta de disponibilidad actual de fármacos específicos y a su abordaje con tratamientos dietéticos, en ocasiones, complejos. El presente documento, elaborado por el Grupo de Trabajo de Trastornos Gastrointestinales Eosinofílicos de la Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátricas, tiene como objetivo facilitar el abordaje diagnóstico y terapéutico de la esofagitis eosinofílica pediátrica, con base en las recientes guías de consenso basadas en la evidencia.
Eosinophilic oesophagitis is an emerging and chronic disorder mediated by the immune system, and is characterised by symptoms of oesophageal dysfunction and inflammation with isolated eosinophil infiltration in the oesophagus. It is more common in males and in atopic subjects, and the symptoms vary with age. In younger children, there is vomiting, abdominal pain and dietary problems, with dysphagia and food impaction in older children and adolescents. The diagnosis is based on the presence of symptoms and oesophageal inflammation with ≥ 15 eosinophils / high power field, and after ruling out other causes of oesophageal eosinophilia. Without treatment, the disease usually persists and can progress to fibrostenotic forms more common in adults. The treatment options included proton pump inhibitors, empirical elimination diets, and swallowed topical corticosteroids. Maintenance therapy is advisable after the induction treatment. Diet is the only treatment that is directed at the cause of the disease, on identifying the triggering food or foods. The response to the treatments requires a histological assessment due to the poor agreement between the symptoms and the oesophageal inflammation.
The practical management of Eosinophilic oesophagitis presents with challenges, due to, among other causes, the current lack of availability of specific drugs, and to its approach with, occasionally complex, diet treatments. The present document, prepared by the Working Group on Eosinophilic Gastrointestinal Disorders of the Spanish Society of Paediatric Gastroenterology, Hepatology and Nutrition, has as its objective to help in the diagnostic and therapeutic approach to paediatric eosinophilic oesophagitis, based on the recent evidence-based consensus guidelines.
To assess the short- and long-term efficacy of proton pump inhibitor (PPI) therapy for pediatric eosinophilic esophagitis (EoE) in real-world practice with a step-down strategy, and to evaluate ...factors predictive of PPI responsiveness.
We collected data regarding the efficacy of PPIs during this cross-sectional analysis of the prospective nationwide RENESE registry. Children with EoE treated with PPI monotherapy were included. Histological remission was defined as a peak eosinophilic count of <15 eosinophils (eos)/high-power field (hpf). Factors associated with PPI responsiveness were identified using multivariate logistic regression analysis.
After induction therapy, histological and clinico-histological remission were observed in 51.4% (n = 346) and 46.5% of children, respectively. Normal endoscopic appearance of the esophagus was associated with a higher possibility odds ratio (OR), 9.20; 95% confidence interval (CI), 2.10-40.16, and fibrostenotic phenotype was associated with a lower possibility (OR, 0.36; 95% CI, 0.18-0.74) of histological remission. Long-term therapy with a step-down strategy effectively maintained histological remission in 68.5% and 85.3% of children at 7 months (n = 108) and 16 months (n = 34), respectively. Complete initial histological remission (≤5 eos/hpf) was associated with a higher possibility of sustained histological remission (OR, 5.08; 95% CI, 1.75-14.68). Adverse events were infrequent and mild.
We confirmed the efficacy of PPIs for a large cohort of children with EoE with sustained histological remission using a step-down strategy. Children with fibrostenotic phenotypes are less likely to respond to induction therapy. Furthermore, patients with complete initial histological remission are more likely to experience long-term histological remission.
Biologics are recommended to treat paediatric ulcerative colitis (UC) that is chronically active or steroid-dependent despite aminosalicylic acids (5-ASA) and thiopurine treatments. Anti-tumour ...necrosis factor inhibitors (Anti-TNF inhibitors) are the agents of choice and vedolizumab could be considered as second-line biologic therapy.In the current case, we aim to describe a successful long-term treatment with vedolizumab in a 9-year-old boy with severe UC and primary non-response to infliximab. Concomitant azathioprine was used, and steroid refractoriness was also detected. Drug and anti-drug antibody levels were negative after infliximab induction so a switch to a 6-week-induction vedolizumab regimen followed by a maintenance regimen as a monotherapy was decided. The clinical response and tolerability to vedolizumab allowed long-term disease remission. Vedolizumab is currently non-authorised to treat paediatric patients and there is limited data on long-term treatments to date. This case contributes to the literature by adding evidence on the long-term efficacy and safety of vedolizumab in paediatric UC.
Celiac disease (CD) is an autoimmune disorder, which damages the small intestine and is caused by ingestion of gluten in genetically susceptible individuals. The only known effective treatment is a ...lifelong gluten-free diet. Genetic risk factors have been identified and nearly all patients are HLA-DQ2 and/or HLA-DQ8 positive. Specific autoantibodies, IgA antitissue transglutaminase-2, antiendomysium, and antideaminated forms of gliadin peptide antibodies, are widely used as diagnostic aids in celiac patients. However, the discovery of new biomarkers may help in the diagnosis and follow-up of the disease. Recently, the molecule REG Iα, involved in tissue regeneration, has been proposed as a new biomarker of CD. REG Iα expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after gluten-free diet. In this article we review the main biomarkers for diagnosis and monitoring of CD, focusing on the immune response-related mechanisms.
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