Search

Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery. Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression. Fifty‐six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25–75: 1.2–29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN‐IBD (n= 31), corticosteroids (n= 35), antibiotics (n= 10), anti‐TNF (n= 27), immunosuppressants (n= 28). Thirty‐six patients (64%) required surgery, within 4.8 months (IQR: 25–75: 1.8–17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35–72.73], p= 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15–8.03], p= 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17–11.20], p= 0.03). In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection. Prevalence of strictures in pediatric Crohn's disease range from 20% at diagnosis to 40% after 10 years of disease.Currently no treatment can reverse the fibrosing process.Early surgery might be beneficial in some patients: thus, it is important to identify patients with a high probability of failure of medical treatment, leading to discuss early surgery. Prevalence of strictures in pediatric Crohn's disease range from 20% at diagnosis to 40% after 10 years of disease. Currently no treatment can reverse the fibrosing process. Early surgery might be beneficial in some patients: thus, it is important to identify patients with a high probability of failure of medical treatment, leading to discuss early surgery. In this study, small bowel dilation proximal to the stricture of >28 mm on magnetic resonance enterography was associated with risk of surgical resection.Previous exposure to antibiotics increased the odds of surgery for small bowel stricture. In this study, small bowel dilation proximal to the stricture of >28 mm on magnetic resonance enterography was associated with risk of surgical resection. Previous exposure to antibiotics increased the odds of surgery for small bowel stricture.

Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. We conducted a retrospective and multicenter study in France among the “GETAID pédiatrique” centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation. Effectiveness of the switch from SC Adalimumab to IV Infliximab in pediatric Crohn's disease patients. Adalimumab (ADA) and Infliximab (IFX) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD).Currently ADA is often used as first line therapy. Adalimumab (ADA) and Infliximab (IFX) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). Currently ADA is often used as first line therapy. We demonstrated the efficacy of IFX as second line therapy after loss of response (LOR) or intolerance to ADA in pediatric CD patients at 1 year.IFX could be an interesting therapeutic choice in patients experiencing LOR to ADA before switching for another class of biotherapy. We demonstrated the efficacy of IFX as second line therapy after loss of response (LOR) or intolerance to ADA in pediatric CD patients at 1 year. IFX could be an interesting therapeutic choice in patients experiencing LOR to ADA before switching for another class of biotherapy.

Ustekinumab is known to be efficient in adult patients suffering from moderate to severe Crohn disease (CD) and ulcerative colitis (UC) resistant to anti-tumor necrosis factor-alpha (TNF-a). Here, we described the clinical course of treatment with ustekinumab in French pediatric inflammatory bowel disease (IBD) patients treated with ustekinumab. This study includes all pediatric patients treated by ustekinumab injection for IBD (CD and UC), between January 2016 and December 2019. Fifty-three patients were enrolled, 15 males and 38 females. Forty-eight patients (90%) had a diagnosis of CD and 5 (9.4%) had UC. Sixty-five percent of CD patients presented an ileocolitis. Perineal disease was observed in 20 out of 48 CD patients (41.7%), among them 9 were treated surgically. All patients included were resistant to anti-TNF-a treatment. Fifty-one percent had presented side effects linked to anti-TNF-a, including psoriasis and anaphylactic reaction. The average Pediatric Crohn Disease Activity Index (PCDAI) at induction was 28.7 (5–85), 18.7 (0–75) at 3 months of treatment and 10 (0–35) at the last follow-up. The average Pediatric Ulcerative Colitis Activity Index at induction was 47 (25–65), 25 (15–40) at 3 months of treatment and 18.3 (0–35) at the last follow-up. No severe side effects were observed. In this retrospective, multicentral study, ustekinumab proved to be efficient in pediatric patients resistant to anti-TNF-a. PCDAI has been significantly improved in patients with severe disease, treated with ustekinumab.

•DOCK11 deficiency is a new X-linked immune-related actinopathy.•DOCK11 deficiency leads to impaired CDC42 activity, abnormal actin cytoskeleton remodeling, and immune dysregulation.

European Crohn’s Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-tumor necrosis factor (TNF) biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome. The objective of the present study was to compare early “Top-Down” use of adalimumab (ADA) immunomodulator/biologics-naive patients to conventional “Step-Up” management. One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with ADA between 2008 and 2019 were included and allocated to the ADA-Top Down (n = 59) or ADA-Step Up group (n = 61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a weighted Pediatric Crohn’s Disease Activity Index (wPCDAI) < 12.5. Clinical and biological data were collected at 12 and 24 months. At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI = 31?±?16 vs 31.3?±?15.2, respectively, P= 0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% vs 51%, P< 0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months [hazard ratio (HR) = 0.36, 95% CI (0.15–0.87), P= 0.02]. Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 vs 28/55 respectively, P< 0.001). Serum levels of ADA were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8?±?4.3 vs 10.4?±?3.9 µg/mL, respectively, P< 0.01). There were no serious adverse events. Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients.

XBP1 activation in neonatal and adult doxycycline-inducible murine models of ADPKD due to a hypomorphic polycystin-1 missense mutation orthologous to human PC1R2220W delays cyst formation. Activating XBP1s, a pro-chaperone inducer of the endoplasmic reticulum stress response, can improve steady-state expression, ciliary trafficking, and cleavage of the mutant protein, providing initial in vivoproof of concept that modulating levels of poorly functioning hypomorphic PC1 alleles can slow progression of kidney cyst formation in ADPKD.

ObjectiveGATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy.DesignWe analysed PDAC transcriptomic data, stratifying cases according to GATA4and GATA6expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.ResultsGATA4messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4and GATA6. Reduced expression of GATA4had a minor transcriptional impact but low expression of GATA4enhanced the effects of GATA6low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4and GATA6expression significantly decreased in metastases and negatively correlated with basal markers.ConclusionsGATA4and GATA6cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

The first ECCO-ESPGHAN guidelines for the medical management of pediatric Crohn disease (CD) were published in 2014. Whether their implementation, and the consequent increased use of an upfront anti-tumor necrosis factor therapy, have changed the course of the disease has not been investigated yet. We aimed at comparing the evolution of pediatric CD patients diagnosed and treated before and after 2014. Single-center retrospective study including all children diagnosed with CD from January 2010 to December 2018. Patients diagnosed between 2010 and 2014 (group 1) were compared to those diagnosed after 2014 (group 2). For each patient, at baseline and every 6-month, number of relapses, the occurrence of complication, therapy received and biological parameters were noted, as well as any endoscopic or radiologic evaluation. One hundred and fifty-four patients were included in the analysis, 78 (51%) diagnosed after 2014. The cumulative probability of a relapse-free and surgery-free course was significantly higher for patients treated according to the guidelines (log rank hazard ratio [HR] = 1,818, P= 0.003 and HR = 3,15, 95% confidence interval, P= 0.04, respectively). Mucosal healing rate was significantly higher among patients of group 2 at 1 and 2 years (P= 0.04 and P= 0.05, respectively), while no significant difference was observed for transmural healing rates, as well as for the risk of complications. The implementation of the 2014 CD guidelines appears to have a significant impact on disease outcomes, with a significantly lower risk for relapse and surgery, while no effect could be observed on the risk of developing complications.

Supplemental Digital Content is available in the text

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.

FOXP3deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Tregcells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Tregcells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Tregcells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Tregcell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.

It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7–5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in “emotional functioning” subdomain (mean: 42.8?±?11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those “with active disease”, 95% confidence interval [CI] 2.77--8.70, P?

Neurological adverse effects (NAEs) induced by biotherapies have been reported in the literature mainly in adult patients with inflammatory bowel disease (IBD), rheumatic diseases, or psoriasis. There are scant data in children. Aims of this study are to report and describe noninfective NAE associated with anti-TNFa antibodies in pediatric IBD, and to evaluate their incidence. We retrospectively collected all reports of NAE in pediatric IBD treated with anti-TNFa antibodies recorded in the French Pharmacovigilance Database. To estimate the national incidence of NAEs, we extrapolated data from the French regional inception population-based cohort EPIMAD. Between 2000 and 2018, 231 adverse events in pediatric IBD exposed to anti-TNFa antibodies were reported to this Database. Seventeen NAEs (7.36%) were collected: 8 severe NAE (1 demyelinating neuropathy, 1 optic neuritis, 1 acute transverse myelitis, 1 polyradiculoneuritis, 1 sensorineural hearing loss, 1 seizure, 1 stroke, and 1 glioma), 7 moderate NAE (headaches), and 2 neuropsychic events. The median delay between anti-TNFa start and NAE occurrence was 6 months (range: 13 days to 26 months). In 10 of 17 patients, anti-TNFa antibodies were stopped. Nine of 17 patients had a complete resolution (including 2 severe NAE) and 8 of 17 a partial resolution (including 6 severe NAE). We estimate the incidence of severe NAE in pediatric IBD treated with anti-TNFa antibodies at 1 case for 10,000 patients-year in France. NAE associated with anti-TNFa antibodies in pediatric IBD are rare. In severe NAE, we recommend to discontinue anti-TNFa therapy and to consider alternative treatment.

With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19. An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members. Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%. Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other. An infographic accompanying this article can be found at http://links.lww.com/MPG/B842.

IntroductionThe optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children.MethodsA writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text.ResultsThe commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text.ConclusionThe viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn’s disease, CD: n=62; ulcerative colitis, UC: n=20; age-matched controls n=43), and after 10-12 weeks’ induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall.

Despite existence of international guidelines for diagnosis and management of inflammatory bowel diseases (IBD) in children, there might be differences in the clinical approach. A survey on clinical practice in paediatric IBD was performed among members of the ESPGHAN Porto IBD working group and interest group, PIBD-NET, and IBD networks in Canada and German-speaking countries (CIDsCANN, GPGE), using a web-based questionnaire. Responses to 63 questions from 106 paediatric IBD centres were collected. Eighty-four percentage of centres reported to fulfil the revised Porto criteria in the majority of patients. In luminal Crohn disease (CD), exclusive enteral nutrition is used as a first-line induction therapy and immunomodulators (IMM) are used since diagnosis in the majority of patients. Infliximab (IFX) is mostly considered as first-line biological. Sixty percentage of centres have experience with vedolizumab and/or ustekinumab and 40% use biosimilars. In the majority of ulcerative colitis (UC) patients 5-aminosalicylates are continued as concomitant therapy to IMM (usually azathioprine [AZA]/6-MP). After ileocaecal resection (ICR) in CD patients without postoperative residual disease, AZA monotherapy is the preferred treatment. A majority of centres follows both the Porto diagnostic criteria as well as paediatric (ESPGHAN/ECCO) guidelines on medical and surgical IBD management. This reflects the value of international societal guidelines. However, potentially desirable answers might have been given instead of what is true daily practice, and the most highly motivated people might have answered, leading to some bias.

The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ~20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults. These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

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. 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. 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. This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Supplemental Digital Content is available in the text

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.

Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)–like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents. Whole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-?B) activation at diagnosis and after treatment by hematopoietic stem cell transplantation. We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-?B–dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-?B activation and correction of regulatory T cells frequency. Along with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4)mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.

Supplemental Digital Content is available in the text

Supplemental Digital Content is available in the text

Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees’ members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an “add-on” to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.