The CTLA4 variants may interact with the IL23R- and NOD2-conferred risk in development of Crohn's disease

<p>Abstract</p> <p>Background</p> <p>The <it>CTLA4 </it>(cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of <it>CTLA4 </it>with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases.</p> <p>Methods</p> <p>Six polymorphisms within the <it>CTLA4 </it>region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the <it>CTLA4 </it>variants and other genetic factors known to confer the disease susceptibility.</p> <p>Results</p> <p>No crude associations with Crohn's disease were found for the tested <it>CTLA4 </it>variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the <it>NOD2 </it>(the p.Leu1007fsX1008, rs5743293) or the <it>IL23R </it>(p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of <it>CTLA4 </it>CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with <it>CTLA4 </it>was apparent only in the strata defined by presence minor alleles at the <it>NOD2 </it>rs5743293 (here the <it>CTLA4 </it>CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or <it>IL23R </it>rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked <it>CTLA4 </it>markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014).</p> <p>Conclusions</p> <p>A protective effect of a <it>CTLA4 </it>haplotype was unmasked after stratification for the risk variants in the <it>NOD2 </it>and <it>IL23R </it>genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.</p

DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis

Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn’s disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P &lt; 0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD

Infant formulas for the treatment of functional gastrointestinal disorders:A position paper of the ESPGHAN Nutrition Committee

Functional gastrointestinal disorders (FGID), such as infant regurgitation, infant colic, and functional constipation, are common and typically physiological phenomena during the early months of an infant's life and account for frequent consultations with pediatricians. Various infant formulas are marketed for their management and are frequently given by parents to infants before a medical consultation. However, the evidence supporting their effectiveness is limited and some have altered nutritional compositions when compared to standard formulas. Thus, these products should only be used under medical supervision and upon medical advice. Marketing and over-the-counter sales do not ensure proper medical guidance and supervision. The aim of this position paper is to review the current evidence regarding the safety and efficacy of formulas specifically formulated for addressing regurgitation, colic, and constipation, recognized as FGID. The objective is to provide guidance for clinical management based on the highest quality of available evidence. A wide search using Pubmed, MEDLINE, EMBASE and Cochrane Database of Systematic Reviews was performed including the MESH terms infant formula, colic, constipation, regurgitation, reflux, palmitate, lactase, lactose, magnesium, hydrolyzed protein, prebiotics or probiotics. 752 papers were identified and screened. Finally, 72 papers were included in the paper. In the absence of evidence, recommendations reflect the authors' combined expert opinion. Final consensus was obtained by multiple e-mail exchange and meetings of the Nutrition Committee. (1) For breastfed infants experiencing FGID such as regurgitation, colic, or constipation, transitioning from breastfeeding to commercial formulas is not recommended. (2) In general, whether an infant is breastfed or formula-fed, it's crucial to reassure parents that FGIDs are normal and typically do not necessitate treatment or change to a special formula. (3) Thickened formulas, often termed anti-reflux formulas, may be considered in specific cases of regurgitation. (4) The usage of specialized formulas for infants with colic is not advised due to a lack of clinical evidence. (5) In the case of constipation in infants, the use of formulas enriched with high β-palmitate and increased magnesium content may be considered to soften the stool. Generally, there is limited evidence supporting the use of specialized formulas for FGID. Breastfeeding should never be discontinued in favor of formula feeding.</p

Nutrition in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto Inflammatory Bowel Disease Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition

Background and Aims:A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients.Methods:A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature.Results:A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment;macronutrients needs;trace elements, minerals, and vitamins;nutrition as a primary therapy of pediatric IBD;probiotics and prebiotics;specific dietary restrictions;and dietary compounds and the risk of IBD.Conclusions:This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD

Infliximab in young paediatric IBD patients : it is all about the dosing

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients = 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 mu g/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3);p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01);p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP;p = 0.56). Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN

We acknowledge all the authors of the ESPGHAN/ESPR/ESPEN/CSPEN pediatric parenteral nutrition guidelines for their contributions and vote (Christian Braegger, University Children’s Hospital, Zurich, Switzerland; Jiri Bronsky, University Hospital Motol, Prague, Czech Republic; Cristina Campoy, Department of Paediatrics, School of Medicine, University of Granada, Granada, Spain; Magnus Domellof, Department of Clinical Sciences, Pediatrics, Umeå University, Sweden; Nicholas Embleton, Newcastle University, Newcastle upon Tyne, UK; Mary Fewtrell, UCL Great Ormond Street Institute of Child Health, London, UK; Natasa Fidler, University Medical Centre Ljubljana, Ljubljana, Slovenia; Axel Franz, University Children’s Hospital, Tuebingen, Germany; Oliver Goulet, University Sordonne-Paris-Cite; Paris-Descartes Medical School, Paris, France; Corina Hartmann, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel and Carmel Medical Center, Israel; Susan Hill, Great Ormond Street Hospital for Children, NHS Foundation Trust and UCL Institute of Child Health, London, UK; Iva Hojsak, Children’s Hospital Zagreb, University of Zagreb School of Medicine, University of J. J. Strossmayer School of Medicine Osijek, Croatia; Sylvia Iacobelli, CHU La Reunion, Saint Pierre, France; Frank Jochum, Ev. Waldkrankenhaus Spandau, Berlin, Germany; Koen Joosten, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands; Sanja Kolacek, Children’s Hospital, University of Zagreb School of Medicine, Zagreb, Croatia; Alexandre Lapillone, Paris-Descartes University, Paris, France; Szimonetta Lohner, Department of Pediatrics, University of Pecs, Pecs, Hungary; Dieter Mesotten, KU Leuven, Leuven, Belgium; Walter Mihatsch, Ulm University, Ulm, and Helios Hospital, Pforzheim, Germany; Francis Mimouni, Department of Pediatrics, Division of Neonatology, The Wilf Children’s Hospital, the Shaare Zedek Medical Center, Jerusalem, and the Tel Aviv University, Tel Aviv, Israel; Christian Molgaard, Department of Nutrition, Exercise and Sports, University of Copenhagen, and Paediatric Nutrition Unit, Rigshospitalet, Copenhagen, Denmark; Sissel Moltu, Oslo University Hospital, Oslo, Norway; Antonia Nomayo, Ev. Waldkrankenhaus Spandau, Berlin, Germany; John Puntis, The General Infirmary at Leeds, Leeds, UK; Arieh Riskin, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel; Miguel Saenz de Pipaon, Department of Neonatology, La Paz University Hospital, Red de Salud Materno Infantil y Desarrollo e SAMID, Universidad Autonoma de Madrid, Madrid, Spain; Raanan Shamir, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; Tel Aviv University, Tel Aviv, Israel; Peter Szitanyi, General University Hospital, First Faculty of Medicine, Charles University in Prague, Czech Republic; Merit Tabbers, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Chris van den Akker, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Hans van Goudoever, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Sacha Verbruggen, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; Cai Wei, Shanghai Jiao Tong University, Shanghai, China; Weihui Yan, Department of Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China) and the members of the ESPR Section on Nutrition, Gastroenterology and Metabolism (Fredrik Ahlsson, Uppsala University Children’s Hospital and Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden; Sertac Arslanoglu, Division of Neonatology, Department of Pediatrics, Istanbul Medeniyet University, Istanbul, Turkey; Wolfgang Bernhard, Department of Neonatology, Children’s Hospital, Faculty of Medicine, Eberhard-Karls- University, Tübingen, Germany; Janet Berrington, Newcastle Neonatal Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Signe Bruun, Hans Christian Andersen Hospital for Children and Adolescents, Odense University Hospital, Odense, Denmark; Christoph Fusch, Department of Pediatrics, Paracelsus Medical School, General Hospital of Nuremberg, Nuremberg, Germany; Shalabh Garg, South Tees Hospitals, Middlesborough, UK; Maria Gianni, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Ann Hellstrom, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Claus Klingenberg, Department of Pediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway; Helen Mactier, Neonatal Unit, Princess Royal Maternity Hospital, Glasgow, UK; Neena Modi, Section of Neonatal Medicine, Department of Medicine, Chelsea and Westminster Campus, Imperial College London, London, UK; Niels Rochow, Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Paola Rogerro, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Umberto Simeoni, Division of Pediatrics, CHUV & University of Lausanne, Lausanne, Switzerland; Atul Singhal, Paediatric Nutrition, UCL Great Ormond Street Institute of Child Health, London, UK.; Ulrich Thome, Department of Neonatology, Universitatsklinikum Leipzig, Leipzig, Germany; Anne Twomey, Department of Neonatology, The National Maternity Hospital, Dublin, Ireland; Mireille Vanpee, Karolinska University Hospital, Stockholm, Sweden; Gitte Zachariassen, Hans Christian Andersen Hospital for Children and Adolescents, Odense University Hospital, Odense, Denmark) for their vote.Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre-and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options

Predicting Outcomes in Pediatric Crohn’s Disease for Management Optimization: Systematic Review and Consensus Statements from PIBD-Ahead Program

A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk

The Medical Management of Paediatric Crohn's Disease : an ECCO-ESPGHAN Guideline Update

Objective: We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]. Methods: We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached >= 80% agreement and were retained. Results: We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone. Conclusions: We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.Peer reviewe

ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition

Background: Previous guidelines on Paediatric Parenteral Nutrition (PN) were published in 2010, by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR) were published. The aim of the present paper was to provide up-to-date evidence for health professionals working with infants, children and adolescents receiving PN. Methods: The current document is a revision of the 2005 guidelines produced by the same 3 organizations (ESPEN, ESPGHAN, ESPR) together with the Chinese Society of Parenteral and Enteral Nutrition (CSPEN). Experts participating in the guideline updating process were all professionals with extensive experience in managing PN from a wide range of European countries, Israel and China. The guideline development process was coordinated by a guideline steering committee. Each chapter of the guideline was prepared by a separate author group. These author groups were responsible for screening titles and abstracts identified by a systematic literature search for inclusion, for conducting additional expert searches (including secondary sources such as other published valid guidelines), for evaluating the quality of studies included in the given chapter and assigning evidence levels to the literature. Based on the evidence level of included studies experts formulated and graded recommendations. A consensus conference was held in February 2015. All chapter manuscripts were revised following the recommendations of the consensus conference and then reviewed and edited by the project steering committee. Final consensus on each individual guideline and its individual recommendations was achieved and assessed by online voting. This process lasted until January 2018. Funding for the consensus conference (including travel expenses for participants) was provided by all participating societies. No other funding was received for the guideline updating process and participants received no payment. Support was provided by the Hungarian Cochrane organization. Results/conclusions: The present document provides guideline for the use of PN across the wide range of pediatric patients, ranging from extremely premature infants up to teenagers weighing up to and over 100 kg [1]. It covers their individual macro- and micronutrient needs [2], [3], [4], [5], [6], [7], [8], fluid requirements [9], venous access [10], organizational aspects [11], home parenteral nutrition [12], standardized vs. individualized PN [13], and last but not least a wide range of safety considerations for prevention and management of complications such central line associated bloodstream infections (CLABSI) [14]