Use of Infliximab Biosimilar Versus Originator in a Pediatric United Kingdom Inflammatory Bowel Disease Induction Cohort.

OBJECTIVES: The aim of the study was to summarize short-term effectiveness, safety, and cost of using infliximab biosimilar (IFX-B) drugs, (Inflectra [Hospira] and Remsima [NAAP]) compared to originator infliximab (IFX-O) (Remicade [MSD]) in biologic naive pediatric inflammatory bowel disease in the United Kingdom. METHODS: Prospective audit of patients starting anti-tumour necrosis factor (TNF) therapy. Disease severity, response to treatment, and remission rate was measured by Pediatric Crohn's Disease Activity Index (PCDAI) and/or Physician Global Assessment. RESULTS: Between March 2015 and February 2016, 278 patients (175 IFX-O, 82 IFX-B, and 21 Adalimumab) were started on anti-TNF therapy. This was compared with collected data on 398 patients started on IFX-O from 2011 to 2015. At initiation, median PCDAI was 36 (20,48) (n = 42) in the IFX-O group and 28 (20,40) (n = 29) in the IFX-B group, (P = 0.08). Immunosuppression rates were similar: 150/175 (86%) for IFX-O and 65/82 (79%) for IFX-B (P > 0.05). Post induction, median PCDAI score was 5 (0,11) (n = 19) and 0 (0,8) (n = 15) in the IFX-O and IFX-B groups, respectively (P = 0.35). There was no difference in response to treatment using Physician Global Assessment 85% (n = 28) in IFX-O group and 86% (n = 19) in IFX-B group (P > 0.05). Adverse events at initiation and post induction were not different between both groups (P > 0.05). Using conservative calculations, £875,000 would have been saved for a 1-year period with universal adoption of biosimilars in patients who were instead treated with IFX-O. CONCLUSIONS: IFX-B is likely as effective as IFX-O in treating IBD in comparable pediatric populations. Sites should adopt infliximab biosimilar for new starts due to cost reduction with no difference in other parameters.

Real-life Anti-tumor Necrosis Factor Experience in More Than 500 Patients: High Co-immunosuppression Rates But Low Rates of Quantifying Treatment Response.

OBJECTIVE: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. RESULTS: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only "fair agreement"; P < 0.001.Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient' follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. CONCLUSIONS: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.

Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with microvillus inclusion disease.

Microvillus inclusion disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo-tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed "secretory granules." However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography, we studied biopsies from MVID patients (3× Myosin 5b mutations and 1× Syntaxin3 mutation) and compared them to controls and genome-edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from 2 patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra-/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo-tubular organelles as Rab11-Rab8-positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters sodium-hydrogen exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator. Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea.

Gastric leiomyoma in a child with Gorlin-Goltz syndrome: First pediatric case.

Gorlin-Goltz syndrome (GGS), also known as nevoid basal cell carcinoma syndrome (MIM 109 400), is a rare genetic condition with a prevalence between 1/56 000 and 1/256 000. Clinical presentation is usually characterized by multiple basal cell carcinomas, odontogenic jaw keratocysts, palmar or plantar pitting and skeletal anomalies. It is furthermore associated with the development of various tumors beside basal cell carcinoma, among which medulloblastoma is the most frequent. Increased incidence of other mesenchymal neoplasms, however, is also well known: recently the first adult case of gastric leiomyoma in GGS was reported, and the inclusion of "fibromas and leiomyomas of other organs" in the minor criteria for the diagnosis was suggested. We report the first case of a pediatric patient with GGS who also developed a gastric leiomyoma: the present case illustrates the need for this change to the diagnostic criteria to encompass the highly variable presentations and phenotype in GGS.

Contemporary outcomes for ulcerative colitis inpatients admitted to pediatric hospitals in the United Kingdom.

BACKGROUND: Pediatric ulcerative colitis (UC) care is variable with a lack of appropriate guidelines to guide practice until recently. METHODS: UC inpatients <17 years old admitted to 23 U.K. pediatric hospitals had clinical details collected between September 2010 and 2011. Comparative data for 248 patients were available from a previous audit in 2008. RESULTS: One hundred and seventy-six patients (98 males) of median age 13 years (interquartile range, 10-13) were analyzed; 23 were elective surgical admissions, 47 new diagnoses, and 106 needed acute medical care for established UC. Median length of stay was 6 days (interquartile range, 3-10) with no deaths. Eighty-eight of 126 patients (70%) with active disease had standard stool cultures performed (3 [2%] were positive), and 57 (45%) had Clostridium difficile toxin tested (none positive). Twenty-five of 66 (38%) emergency admissions had an abdominal x-ray on admission, and 13 of 66 patients (20%) had a Pediatric Ulcerative Colitis Activity Index score. There were 3 cases of toxic megacolon and 2 thromboses. Eighty-one of 116 patients (71%) responded to steroids. Nineteen patients who did not respond adequately to steroids received rescue therapy (7 infliximab, 11 ciclosporin, and 1 both) with overall response rate of 90%; 7 patients needed surgery acutely, 5 without previous rescue therapy. Compared with the 2008 data, stool culture rates improved significantly (86 of 121 [71%] versus 76 of 147 [52%], P = 0.001) as did heparinization rates (15 of 150 [10%] versus 5 of 215 [2%], P = 0.002) and rescue therapy usage (17 of 33 [52%] versus 10 of 38 [26%], P = 0.03). CONCLUSIONS: There were signs of improving UC care with significantly increased rates of stool culture and rescue therapy. The majority of sites, however, did not use Pediatric Ulcerative Colitis Activity Index scores.

The organisation and structure of inflammatory bowel disease services for children and young people in the UK in 2010: significant progress but still room for improvement.

BACKGROUND: Inflammatory bowel disease (IBD) is becoming more common in children. While treatment options remain limited the appropriate organisation and delivery of services are an integral part of good care. METHODS: All eligible UK paediatric sites were invited to submit data for organisation of paediatric IBD services as of 1 September 2010. Comparison, when relevant, was made with the previous paediatric audit (2008) and the concurrently running adult audit. RESULTS: 24/25 (96%) of sites submitted data. The median number of patients managed and the median number of new IBD (ulcerative colitis and Crohn's disease only) cases per annum was 178 (IQR 136-281) and 32 (IQR 23-50), respectively. There was an increase in the IBD workforce including whole-time equivalent (WTE) IBD nurses (1.0 vs 1.5 WTE nurses, p=0.02). 1023 patients 16 years and younger were looked after in the 202 adult sites who submitted data; only 78/202 sites indicated they cared for 16-year-old and younger children; approximately half of these 78 sites had age-appropriate support facilities. Most paediatric sites have access to urgent endoscopy (83%), telephone advice (100%) and urgent clinic appointments (91%). Most sites did not have: shared care pathways with primary care (74%), annual reviews (71%), real time patient management systems (83%) and research network trial participation (78%). CONCLUSIONS: Many aspects of paediatric IBD care in the UK are good and have shown significant improvement over recent years. There are areas in need of further change and specific regional and national action plans should address identified deficiencies before any future audit of paediatric and adult IBD services.

Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations.

Familial non-Hodgkin lymphoma (NHL) is rare and in most cases, no underlying cause is identifiable. We report homozygous truncating mutations in the mismatch repair gene MSH2 (226C-->T; Q76X) in three siblings who each developed T-cell NHL in early childhood. All three children had hyperpigmented and hypopigmented skin lesions. Constitutional biallelic MSH2 mutations have previously been reported in five individuals, all of whom developed malignancy in childhood. Familial lymphoma has not been reported in this context or in association with biallelic mutations in the other mismatch repair genes MLH1, MSH6 or PMS2. In addition, hypopigmented skin lesions have not previously been reported in biallelic MSH2 carriers. Our findings therefore expand the spectrum of phenotypes associated with biallelic MSH2 mutations and identify a new cause of familial lymphoma. Moreover, the diagnosis has important management implications as it allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the proband, and the provision of cascade genetic testing and tumour screening for relatives.

Surgery results in significant improvement in growth in children with Crohn's disease refractory to medical therapy.

Inflammatory bowel disease (IBD) in children can cause significant impairment in linear growth, and delay in pubertal onset. The aim of this study was to assess the impact of surgery on linear growth in children with Crohn's disease (CD) who were resistant to medical therapy, and had documented evidence of growth impairment. We performed a retrospective study on eight consecutive patients with refractory disease who had attended the paediatric IBD clinic. All patients underwent surgery as part of their treatment. Height and weight were recorded at least 6 months prior to surgery, at the time of surgery, and 6 months post surgery. Growth velocities and height Z-scores were calculated. All patients had evidence of sustained growth suppression prior to surgery. Three patients had evidence of growth failure. There was a significant increase in height velocity from 0.15 cm/month before surgery to 0.54 cm/month after surgery (P = 0.006). There was also a significant decrease in the modified Harvey-Bradshaw index (HBI) of disease activity from 2.00 before surgery, to 0.84 after surgery (P = 0.003). Improvements in height Z-score and weight velocity after surgery were not significant on statistical analysis. Our study demonstrates that before surgery, children with CD refractory to therapy have sustained growth suppression, and in some cases may even have growth failure. Surgical intervention before puberty appears to result in a significant improvement in height velocity and disease activity. These findings need to be further investigated with carefully designed prospective studies.