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Background and Aims We aimed to identify serum metabolites associated with mucosal and transmural inflammation in paediatric Crohn disease [pCD]. Methods In all, 56 pCD patients were included through a pre-planned sub-study of the multicentre, prospective, ImageKids cohort, designed to develop the Paediatric Inflammatory Crohn magnetic resonance enterography [MRE] Index [PICMI]. Children were included throughout their disease course when undergoing ileocolonoscopy and MRE and were followed for 18 months, when MRE was repeated. Serum metabolites were identified using liquid chromatography/mass spectroscopy. Outcomes included: PICMI, the simple endoscopic score [SES], faecal calprotectin [FCP], and C-reactive protein [CRP], to assess transmural, mucosal, and systemic inflammation, respectively. Random forest models were built by outcome. Maximum relevance minimum redundancy [mRMR] feature selection with a j-fold cross-validation scheme identified the best subset of features and hyperparameter settings. Results Tryptophan and glutarylcarnitine were the top common mRMR metabolites linked to pCD inflammation. Random forest models established that amino acids and amines were among the most influential metabolites for predicting transmural and mucosal inflammation. Predictive models performed well, each with an area under the curve [AUC] > 70%. In addition, serum metabolites linked with pCD inflammation mainly related to perturbations in the citrate cycle [TCA cycle], aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. Conclusions We extend on recent studies, observing differences in serum metabolites between healthy controls and Crohn disease patients, and suggest various associations of serum metabolites with transmural and mucosal inflammation. These metabolites could improve the understanding of pCD pathogenesis and assessment of disease severity. [ABSTRACT FROM AUTHOR]

Background and Aims Treatment guidelines for paediatric Crohn's disease [CD] suggest early use of anti-tumour necrosis factor alpha [anti-TNFα] in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. Methods Children with newly diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF [<90 days after diagnosis] and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission [SSFR] without treatment intensification [specified as SSFR*] and sustained steroid-free mild/inactive disease without treatment intensification [specified as SSFMI*]. Penalised logistic regression model-based standardisation was applied to estimate the relative risks [RR] of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients, based on presence of predictors of poor outcome [POPOs] and disease activity at diagnosis. Results In total, 331 children (median age 13.9 years [IQR 12.2–15.3]) were enrolled, with 135 [41%] receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* [30% vs 14%, p  <0.001] and SSFMI* [69% vs 33%, p  <0.001], with RRs of 2.95 [95% CI 1.63-5.36] and 4.67 [95% CI 2.46-8.87], respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared with mild/inactive disease at diagnosis (5.50 [95% CI 2.51-12.05] vs 2.91 [95% CI 0.92-9.11]), and those with any POPO compared with no POPO (5.05 [95% CI 2.45-10.43] vs 3.41 [95% CI 0.54-21.7]). Conclusion In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients. [ABSTRACT FROM AUTHOR]

Background Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. Methods Pre- [ n  = 86], and 10–14-week post-treatment [ n  = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [ n  = 48; five 5-mg/kg infusions over 22 weeks] or CONV [ n  = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. Results FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. Conclusion FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. Trial registration number NCT02517684. [ABSTRACT FROM AUTHOR]

Background and Aims Despite recent approvals for new drugs to treat adults with Crohn's disease or ulcerative colitis, there are only two approved advanced treatment options [infliximab and adalimumab] for children with inflammatory bowel disease [IBD]. There are many potential new therapies being developed for adult and paediatric IBD. Moreover, regulatory agencies in both the European Union and USA have processes in place to support the early planning and initiation of paediatric studies. Nevertheless, unacceptable delays in approvals for use of drugs in children persist, with an average 7-year gap, or longer, between authorization of new IBD drugs for adults and children. Methods A 2-day virtual meeting was held during April 14–15, 2021 for multi-stakeholders [clinical academics, patient community, pharmaceutical companies and regulators] to discuss their perspectives on paediatric drug development for IBD. Results The multi-stakeholder group presented, discussed and proposed actions to achieve expediting the approval of new drugs in development for paediatric IBD. Conclusions Collaborative action points for all stakeholders are required to make progress and facilitate new drug development for children with IBD. [ABSTRACT FROM AUTHOR]

Background and Aims Thromboprophylaxis use in paediatric inflammatory bowel disease [IBD] is inconsistent. Current guidelines only support treating children with acute severe colitis with risk factors. We convened an international RAND panel to explore thromboprophylaxis in paediatric IBD inpatients in the context of new evidence. Methods We convened a geographically diverse 14-person panel of paediatric gastroenterologists alongside supporting experts. An online survey was sent before an online meeting. Panellists were asked to rate the appropriateness of thromboprophylaxis in hospitalised paediatric IBD patients via 27 scenarios of varying ages, gender, and phenotype, with and without thrombotic risk factors. Anonymised results were presented at the meeting. A second modified survey was distributed to all panellists present at the meeting. Results from the second survey constitute the RAND panel results. The validated RAND disagreement index defined disagreement when ≥ 1. Results The combined outcome of thromboprophylaxis being considered appropriate until discharge and inappropriate to withhold was seen in 20 of 27 scenarios, including: all patients with new-onset acute severe colitis; all flares of known ulcerative colitis, irrespective of risk factors except in pre-pubescent patients with limited disease and no risk factors; and all Crohn's patients with risk factors. Disagreement was seen in five scenarios regarding Crohn's without risk factors, where outcomes were already uncertain. Conclusions RAND panels are an established method to assess expert opinion in areas of limited evidence. This work therefore constitutes neither a guideline nor a consensus; however, the findings suggest a need to re-evaluate the role of thromboprophylaxis in future guidelines. [ABSTRACT FROM AUTHOR]

Background and Aims Guidelines regarding thromboprophylaxis for venous thromboembolisms [VTEs] in children with inflammatory bowel disease [IBD] are based on limited paediatric evidence. We aimed to prospectively assess the incidence of VTEs in paediatric-onset IBD [PIBD], characterize PIBD patients with a VTE and identify potential IBD-related risk factors. Methods From October 2016 to September 2020, paediatric gastroenterologists prospectively replied to the international Safety Registry, monthly indicating whether they had observed a VTE case in a patient <19 years with IBD. IBD details [type, Paris classification, clinical and biochemical disease activity, treatment] and VTE details [type, location, treatment, outcome] were collected. To estimate VTE incidence, participants annually reported the number of PIBD patients, data source and catchment area of their centre. A systematic literature review and meta-analysis was performed to calculate the VTE incidence in the general paediatric population. Results Participation of 129 PIBD centres resulted in coverage of 24 802 PIBD patients. Twenty cases of VTE were identified [30% Crohn's disease]. The incidence of VTEs was 3.72 (95% confidence interval [CI] 2.27–5.74) per 10 000 person-years, 14-fold higher than in the general paediatric population (0.27 [95% CI 0.18–0.38], p < 0.001). Cerebral sinus venous thrombosis was most frequently reported [50%]. All but one patient had active IBD, 45% were using steroids and 45% were hospitalized. No patient received thromboprophylaxis, whereas according to current PIBD guidelines, this was recommended in 4/20 patients. Conclusion There is an increased risk of VTEs in the PIBD population compared to the general paediatric population. Awareness of VTE occurrence and prevention should be extended to all PIBD patients with active disease, especially those hospitalized. [ABSTRACT FROM AUTHOR]

Introduction Many diseases can imitate inflammatory bowel disease [IBD] clinically and pathologically. This review outlines the differential diagnosis of IBD and discusses morphological pointers and ancillary techniques that assist with the distinction between IBD and its mimics. Methods European Crohn's and Colitis Organisation [ECCO] Topical Reviews are the result of an expert consensus. For this review, ECCO announced an open call to its members and formed three working groups [WGs] to study clinical aspects, pathological considerations, and the value of ancillary techniques. All WGs performed a systematic literature search. Results Each WG produced a draft text and drew up provisional Current Practice Position [CPP] statements that highlighted the most important conclusions. Discussions and a preliminary voting round took place, with subsequent revision of CPP statements and text and a further meeting to agree on final statements. Conclusions Clinicians and pathologists encounter a wide variety of mimics of IBD, including infection, drug-induced disease, vascular disorders, diverticular disease, diversion proctocolitis, radiation damage, and immune disorders. Reliable distinction requires a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The management of inflammatory bowel disease [IBD] is complex, and requires tight control of disease activity, close monitoring to avoid treatment side effects, health care professionals with expertise in IBD, and an interdisciplinary, holistic approach. Despite various efforts to standardise structures, processes, and outcomes, 1–8 and due to the high variability at the local, national, and international levels, there are still no clear definitions or outcome measures available to establish quality of care standards for IBD patients which are applicable in all contexts and all countries. For this reason, the European Crohn's and Colitis Organisation [ECCO] supported the construction of a list of criteria summarising current standards of care in IBD. The list comprises 111 quality standard points grouped into three main domains [structure n = 31, process n = 42, outcomes n = 38] and is based on scientific evidence, interdisciplinary expert consensus, and patient-oriented perspectives. The list of proposed criteria is intended to represent the position of ECCO regarding the optimum quality of care that should be available to patients. Since health care systems and regulations vary considerably between countries, this list may require adaptation at local and national levels. It is recognised that not all these criteria that have been identified as optimal will be available in every unit. However, ECCO will continue its efforts to develop and coordinate projects and initiatives that will help to guarantee optimal quality of care for all IBD patients. [ABSTRACT FROM AUTHOR]

Background Transition programmes are designed to prepare adolescent inflammatory bowel disease [IBD] patients for transfer to adult care. It is still unclear which outcome parameters define 'successful transition'. Therefore, this study aimed to identify outcomes important for success of transition in IBD. Methods A multinational Delphi study in patients, IBD nurses, and paediatric and adult gastroenterologists was conducted. In stage 1, panellists commented on an outcome list. In stage 2, the refined list was graded from 1 to 9 [least to very important], by an expert and a patient panel. In stage 3, the expert panel ranked important outcomes from 1 to 10 [least to most important]. Descriptive statistics and Mann–Whitney U-tests were performed. Results The final item list developed in stage 1 was tested by the expert [ n = 74 participants, 52.7% paediatric] and patient panel [ n = 61, aged 16–25 years, 49.2% male]. Respectively, ten and 11 items were found to be important by the expert and patient panel. Both panels agreed on eight of these items, of which six reflected self-management skills. In stage 3, the expert panel formed a top-ten list. The three most important items were: decision-making regarding IBD [mean score 6.7], independent communication [mean score 6.3] and patient satisfaction [mean score 5.8]. Conclusion This is the first study identifying outcomes that IBD healthcare providers and patients deem important factors for successful transition. Self-management skills were considered more important than IBD-specific items. This is a first step to further define success of transition in IBD and subsequently evaluate the efficacy of different transition models. [ABSTRACT FROM AUTHOR]