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BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Background and AimAcute severe colitis [ASC] is associated with significant morbidity in paediatric patients with ulcerative colitis [UC]. Most outcome studies in ASC since tumour necrosis factor alpha [TNFα] antagonists became available have focused on the first year after admission. The aim of this study was to characterise the longer-term outcomes of paediatric patients admitted with ASC.MethodsThis retrospective study was conducted in 25 centres across Europe and North America. Data on patients with UC aged ResultsOf the 141 patients admitted with ASC, 137 [97.1%] were treated with intravenous corticosteroids. Thirty-one [22.6%] patients were escalated to second-line therapy, mainly to infliximab. Sixteen patients [11.3%] underwent colectomy before discharge. Long-term follow-up showed colectomy-free rates were 71.3%, 66.4% and 63.6% at 1, 3 and 5 years after initial ASC admission, respectively, and were similar across different age groups. Sub-analysis of colectomy rates in patients with new-onset disease [42.5% of the cohort] yielded similar results. In a multivariate analysis, use of oral steroids in the 3 months before admission, erythrocyte sedimentation rate >70 mm/h, and albumin ConclusionsHigh colectomy rates were demonstrated in paediatric UC patients admitted with ASC. Additional studies are required to determine whether intensification of anti-TNFα treatment, close therapeutic drug monitoring, and use of new drugs alter this outcome.

Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific “humanized” mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.