STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.  Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia.

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.

Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Quantitative assessment of terminal ileum motility on MR enterography in Crohn disease: a feasibility study in children.

OBJECTIVES: Investigate the relationship between quantified terminal ileal (TI) motility and histopathological activity grading, Crohn Disease MRI Index (CDMI) and faecal calprotectin. METHODS: Retrospective review of children with Crohn disease or unclassified inflammatory bowel disease, who underwent MR enterography. Dynamic imaging for 25 patients (median age 12, range 5 to 16) was analysed with a validated motility algorithm. The TI motility score was derived. The primary reference standard was TI Endoscopic biopsy Assessment of Inflammatory Activity (eAIS) within 40 days of the MR enterography. Secondary reference standards: (1) the Crohn Disease MRI Index (CDMI) and (2) faecal calprotectin levels. RESULTS: MR enterography median motility score was 0.17 a.u. (IQR 0.12 to 0.25; range 0.05 to 0.55), and median CDMI was 3 (IQR 0 to 5.5). Forty-three percent of patients had active disease (eAIS > 0) with a median eAIS score of 0 (IQR 0 to 2; range 0 to 5). The correlation between eAIS and motility was r = - 0.58 (p = 0.004, N = 23). Between CDMI and motility, r = - 0.42 (p = 0.037, N = 25). Motility score was lower in active disease (median 0.12 vs 0.21, p = 0.020) while CDMI was higher (median 5 vs 1, p = 0.04). In a subset of 12 patients with faecal calprotectin within 3 months of MR enterography, correlation with motility was r = - 0.27 (p = 0.4). CONCLUSIONS: Quantified terminal ileum motility decreases with increasing histopathological abnormality in children with Crohn disease, reproducing findings in adults. TI motility showed a negative correlation with an MRI activity score but not with faecal calprotectin levels. KEY POINTS: • It is feasible to perform MRI quantified bowel motility assessment in children using free-breathing techniques. • Bowel motility in children with Crohn disease decreases as the extent of intestinal inflammation increases. • Quantified intestinal motility may be a candidate biomarker for treatment efficacy in children with Crohn disease.

Transition Services for Paediatric Inflammatory Bowel Disease: A Multicentre Study of Practice in the United Kingdom.

OBJECTIVES: Patients with paediatric inflammatory bowel disease (IBD) constitute one of the largest cohorts requiring transition from paediatric to adult services. Standardised transition care improves short and long-term patient outcomes. This study aimed to detail the current state of transition services for IBD in the United Kingdom (UK). METHODS: We performed a nationwide study to ascertain current practice, facilities and resources for children and young people with IBD. Specialist paediatric IBD centres were invited to contribute data on: timing of transition/transfer of care; transition resources available including clinics, staff and patient information; planning for future improvement. RESULTS: Twenty of 21 (95%) of invited centres responded. Over 90% of centres began the transition process below 16 years of age and all had completed transfer to adult care at 18 years of age. The proportion of patients in the transition process at individual centres varied from 10% to 50%.Joint clinics were held in every centre, with a mean of 12.9 clinics per year. Adult and paediatric gastroenterologists attended at all sites. Availability of additional team members was patchy across the UK, with dietetic, psychological and surgical attendance available in <50% centres. A structured transition tool was used in 75% of centres. Sexual health, contraception and pregnancy were discussed by <60% of teams. CONCLUSIONS: This study provides real-world clinical data on UK-wide transition services. These data can be used to develop a national strategy to complement current transition guidelines, focused on standardising services whilst allowing for local implementation.

Detecting inflammation in inflammatory bowel disease - how does ultrasound compare to magnetic resonance enterography using standardised scoring systems?

BACKGROUND: Magnetic resonance enterography (MRE) is the current gold standard for imaging in inflammatory bowel disease, but ultrasound (US) is a potential alternative. OBJECTIVE: To determine whether US is as good as MRE for the detecting inflamed bowel, using a combined consensus score as the reference standard. MATERIALS AND METHODS: We conducted a retrospective cohort study in children and adolescents <18 years with inflammatory bowel disease (IBD) at a tertiary and quaternary centre. We included children who underwent MRE and US within 4 weeks. We scored MRE using the London score and US using a score adapted from the METRIC (MR Enterography or Ultrasound in Crohn's Disease) trial. Four gastroenterologists assessed an independent clinical consensus score. A combined consensus score using the imaging and clinical scores was agreed upon and used as the reference standard to compare MRE with US. RESULTS: We included 53 children. At a whole-patient level, MRE scores were 2% higher than US scores. We used Lin coefficient to assess inter-observer variability. The repeatability of MRE scores was poor (Lin 0.6). Agreement for US scoring was substantial (Lin 0.95). There was a significant positive correlation between MRE and clinical consensus scores (Spearman's rho = 0.598, P=0.0053) and US and clinical consensus scores (Spearman's rho = 0.657, P=0.0016). CONCLUSION: US detects as much clinically significant bowel disease as MRE. It is possible that MRE overestimates the presence of disease when using a scoring system. This study demonstrates the feasibility of using a clinical consensus reference standard in paediatric IBD imaging studies.

Detecting inflammation in the unprepared pediatric colon - how reliable is magnetic resonance enterography?

BACKGROUND: Pediatric inflammatory bowel disease frequently affects the colon. MR enterography is used to assess the small bowel but it also depicts the colon. OBJECTIVE: To compare the accuracy of MR enterography and direct visualization at endoscopy in assessing the colon in pediatric inflammatory bowel disease. MATERIALS AND METHODS: We included children with inflammatory bowel disease who had undergone both MR enterography and endoscopy, and we restrospectively assessed the imaging and endoscopic findings. We scored the colonic appearance at MR using a total colon score. We then compared scores for the whole colon and for its individual segments with endoscopy and histology. RESULTS: We included 15 children. An elevated MR colonic segmental score predicted the presence of active inflammation on biopsy with a specificity of 90% (95% confidence interval [CI] 79.5-96.2%) and sensitivity of 60% (CI 40.6-77.3%); this compares reasonably with the predictive values for findings at colonoscopy - specificity 85% (CI 73.4-92.9%) and sensitivity 53.3% (CI 34.3%-71.6%). Accuracy did not change significantly with increasing bowel distension. CONCLUSION: MR-derived scores had comparable accuracy to those derived during visualization at colonoscopy for detecting biopsy-proven inflammation in our patient group. MR enterography might prove useful in guiding biopsy or monitoring treatment response. Collapse of a colonic segment did not impair assessment of inflammation.

Safety and Efficacy of Split-Dose Thiopurine vs Low-Dose Thiopurine-Allopurinol Cotherapy in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Split-dose thiopurine and allopurinol-thiopurine cotherapy strategies have been suggested as rescue therapeutic options for children with inflammatory bowel disease (IBD) and impaired thiopurine metabolism. We compared the efficacy and safety of these regimens in patients who previously failed conventional thiopurine treatment. METHODS: Children with IBD treated with split-dose thiopurine or low-dose thiopurine-allopurinol cotherapy were retrospectively identified. Medical records were reviewed for demographics, treatment regimen, reason for thiopurine failure, side effects, and discontinuation of treatment. Laboratory findings were evaluated at different time points. RESULTS: After prior therapeutic failure, 42 patients were on split-dose regimen (group A) and 20 patients were on thiopurine-allopurinol cotherapy (group B). Twelve patients crossed from group A to group B because of treatment failure, 1 patient was lost at follow-up, and 1 patient discontinued the treatment. The final cotherapy group comprised 29 children (group C), while the split-dose group (group D) included 31 children. Intention-to-treat analysis showed significant differences between split-dose regimen and thiopurine-allopurinol cotherapy for 6-thioguanine nucleotide (6-TGN)/6-methyl mercaptopurine (6-MeMP) ratio ( P < 0.001), 6-TGN ( P < 0.05), and 6-MeMP ( P < 0.001) at 1-3 months. As per protocol analysis, there was a significant difference between group C and group D at 6 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.05) and at 12 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.001). Side effects were more frequent in allopurinol-thiopurine cotherapy ( P < 0.05). DISCUSSION: In children with IBD and impaired thiopurine metabolism, split-dose thiopurine and low-dose thiopurine-allopurinol cotherapy are both effective therapeutic strategies. The latter shows higher efficacy but a higher side effect rate, suggesting the use of split-dose regimen as the first-line approach.

Young persons and healthcare professionals experience of virtual gastroenterology consultations: a multicentre survey conducted during the COVID-19 pandemic.

Objective: To explore Young Persons (YP) and healthcare professionals (HCP) experiences of virtual consultations (VC) and establish whether developmentally appropriate healthcare can be delivered virtually. Method: YP and HCP questionnaire surveys were designed and piloted. Electronic questionnaire links were sent by post, email or text message January-April 2021 to YP aged 13-25 years old, with predefined chronic gastrointestinal conditions, attending a gastroenterology/hepatology VC. HCP undertaking VC were invited to complete staff questionnaire. Results were anonymous and collated using Excel version 2302. Results: Five UK hospital trusts participated, with 35 HCP responses. Of the 100 YP completing the survey 66% were female and 34% male aged between 13 years and 25 years (median: 18 years). 13% were new appointments and 87% follow ups, 29% were by video, 69% by phone and 2% gave no response. 80% of HCP spoke to YP directly but not privately (69%). 87% of YP and 88% HCP found VC useful. 83% of YP want VC again, although 20% preferred face to face. 43% of HCP required improved phone/internet connection. 77% of YP required hospital appointments for tests following VC. Conclusions: Overall respondents were satisfied with VC, finding them useful, convenient and time saving. Successful VC rely on appropriate patient selection and availability of reliable technology. Patient preference is key which may alter with time.

SARS-CoV-2 and the Gastrointestinal Tract in Children.

Coronavirus disease 2019 (COVID-19), caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is predominantly a respiratory disease. However, its significant impact on the gastrointestinal (GI) system is now well-known. SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 (ACE-2) receptor, which is abundantly expressed on lung cells, but also on enterocytes. Several etiopathogenetic mechanisms have been postulated to explain the GI involvement in COVID-19, including loss in intestinal absorption, microscopic mucosal inflammation and impaired ACE-2 function, which plays a significant role in maintaining gut homeostasis. In children the GI manifestations include anorexia, nausea, vomiting, diarrhea and abdominal pain, which may represent the earliest presenting symptoms of the disease. However, although rare, a significant GI mucosal inflammation, such as terminal ileitis mimicking an atypical appendicitis, and other GI manifestations have been reported. COVID-19 pandemic has posed a significant challenge in healthcare provision in term of ability in providing safe diagnostic procedures, face-to-face consultations, and offering comprehensive care. For instance, changes in health services have raised the risk of empirical or sub-optimal management of chronic GI disorders such as inflammatory bowel disease (IBD) due to delayed endoscopic and clinical assessment. This review will discuss the acute GI involvement in COVID-19 in children and reflect on challenges and major changes observed in clinical practice during COVID-19 pandemic by sharing both the published literature and personal experience. We also suggest potential strategies for providing optimal gastroenterology care during this unprecedented era.

Ferric carboxymaltose treatment for iron deficiency anemia in children with inflammatory bowel disease: Efficacy and risk of hypophosphatemia.

BACKGROUND: Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS: We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS: All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS: 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS: FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.

Impact of COVID-19 on diagnosis and management of paediatric inflammatory bowel disease during lockdown: a UK nationwide study.

BACKGROUND: COVID-19 has impacted on healthcare provision. Anecdotally, investigations for children with inflammatory bowel disease (IBD) have been restricted, resulting in diagnosis with no histological confirmation and potential secondary morbidity. In this study, we detail practice across the UK to assess impact on services and document the impact of the pandemic. METHODS: For the month of April 2020, 20 tertiary paediatric IBD centres were invited to contribute data detailing: (1) diagnosis/management of suspected new patients with IBD; (2) facilities available; (3) ongoing management of IBD; and (4) direct impact of COVID-19 on patients with IBD. RESULTS: All centres contributed. Two centres retained routine endoscopy, with three unable to perform even urgent IBD endoscopy. 122 patients were diagnosed with IBD, and 53.3% (n=65) were presumed diagnoses and had not undergone endoscopy with histological confirmation. The most common induction was exclusive enteral nutrition (44.6%). No patients with a presumed rather than confirmed diagnosis were started on anti-tumour necrosis factor (TNF) therapy.Most IBD follow-up appointments were able to occur using phone/webcam or face to face. No biologics/immunomodulators were stopped. All centres were able to continue IBD surgery if required, with 14 procedures occurring across seven centres. CONCLUSIONS: Diagnostic IBD practice has been hugely impacted by COVID-19, with >50% of new diagnoses not having endoscopy. To date, therapy and review of known paediatric patients with IBD has continued. Planning and resourcing for recovery is crucial to minimise continued secondary morbidity.

Lymphocytic leiomyositis and myenteric ganglionitis are intrinsic features of cystic fibrosis: studies in distal intestinal obstruction syndrome and meconium ileus.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS). METHODS AND PATIENTS: Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied. RESULTS: Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF. CONCLUSIONS: Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry.

OBJECTIVE: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. DATA SOURCE: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. STUDY DESIGN: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. PRINCIPAL FINDINGS: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. CONCLUSIONS: A quality improvement based approach to data quality monitoring and improvement is feasible and effective.

Treatment of intractable ulcerating enterocolitis of infancy by allogeneic bone marrow transplantation.

BACKGROUND & AIMS: Intractable ulcerating enterocolitis of infancy (IE) is an uncommon, autosomal-recessive, and devastating inflammatory bowel disorder that arises as a consequence of a poorly defined underlying immunologic disorder. Infants with IE suffer from recurrent severe oro-anal disease and an enterocolitis that is unresponsive to conventional immunosuppressive therapy and requires early pancolectomy to control the severity of the disease. Despite such aggressive treatment these individuals remain at high risk of Epstein-Barr virus-driven lymphomatous proliferations, including non-Hodgkin's lymphoma. The underlying genetic basis for this disease remains undefined. This report aims to describe the use of bone marrow transplantation as a treatment for this condition. METHODS: This was a case series report. RESULTS: We describe the successful treatment of IE by allogeneic bone marrow transplantation in 2 brothers, now aged 7 and 11 years, one of whom had developed an Epstein-Barr virus-related monomorphous B-lymphocyte lymphoproliferative disorder. This treatment has resulted in prolonged clinical remission in both boys and abrogated the need for aggressive immunosuppression. CONCLUSIONS: Bone marrow transplantation can be used for the treatment of intractable ulcerating enterocolitis of infancy, which may support a role in other intractable inflammatory bowel conditions in the pediatric population.

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

OBJECTIVES: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. METHODS: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. RESULTS: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. CONCLUSIONS: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.

The role of exclusive enteral nutrition in the management of orofacial granulomatosis in children.

BACKGROUND: Orofacial granulomatosis (OFG) is a term used to describe a persistent, painless swelling of lips and orofacial region. It can be associated with ulceration, gingival hypertrophy and cobble stone appearance of the buccal mucosa. OFG is commonly associated with Crohn's disease and can precede the intestinal manifestation of the disease. Exclusive enteral nutrition (EEN) is a recognized treatment for induction of remission for Crohn's disease. The aim of this study was to review the use of EEN in the management of OFG in children. METHODS: Retrospective review of medical records of all children diagnosed with OFG between 2007 and 2012 was conducted. Presence of comorbidities, progression to inflammatory bowel disease (IBD) and response to EEN was evaluated. RESULTS: Twenty-nine children were included, mean age at diagnosis was 9 years (standard deviation 3.9) years. Ten children had isolated OFG and 19 had OFG and IBD, of which 12 presented with OFG and IBD and 7 developed IBD later. Median time to progression to IBD was 33 months (inter quartile range: 9.8-85.5). Twenty-two children completed 6 weeks of EEN, and 19 showed clinical improvement in the OFG appearance. CONCLUSION: EEN appears to be an effective treatment option for children with isolated OFG or OFG and IBD.

Adalimumab as a second-line biological therapy in children with refractory ulcerative colitis.

AIM: The role of adalimumab in medically refractory ulcerative colitis (UC) in children remains to be defined. The aim of this study was to describe 11 cases of paediatric patients who received adalimumab as a second-line anti-TNF-α treatment for paediatric UC. METHODS: A retrospective review of all patients with UC who received adalimumab between April 2008 and October 2013 at our hospital was conducted. Clinical efficacy and safety were assessed. RESULTS: Eleven patients (three boys, eight girls) with a median age of 13.8 years (5.7-16.6 years) were included. All patients had been previously treated with infliximab. Six patients achieved and maintained clinical remission, with a median duration of treatment of 25 months. One patient was successfully weaned off adalimumab after 26 months of therapy. Treatment was unsuccessful in four out of 11 patients (36%) who underwent colectomy 4-13 months (median 7 months) from the first adalimumab dose. The remaining patient developed extensive rash and was switched to alternative therapy. CONCLUSION: In this case series, our experience shows that there is a role for adalimumab as a combination therapy in a subgroup of children with refractory UC.