Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Prevalence of Inflammatory Bowel Disease in Pediatric and Adult Populations: Recent Estimates From Large National Databases in the United States, 2007-2016.

BACKGROUND: The latest estimate of the prevalence of inflammatory bowel disease (IBD) in the United States was based on 2009 data, which indicates a need for an up-to-date re-estimation. The objectives of this study were to investigate the prevalence of all forms of IBD including ulcerative colitis (UC), Crohn's disease (CD), and IBD unspecified (IBDU). METHODS: Pediatric (age 2-17) and adult (age ≥18) IBD patients were identified from 2 large claims databases. For each year between 2007 and 2016, prevalence was calculated per 100,000 population and standardized based on the 2016 national Census. A fixed-effects meta-analytical model was used for overall prevalence. RESULTS: The pediatric prevalence of IBD overall increased by 133%, from 33.0/100,000 in 2007 to 77.0/100,000 in 2016. Among children, CD was twice as prevalent as UC (45.9 vs 21.6). Prevalence was higher in boys than girls for all forms of IBD, in contrast to the adult population where the prevalence was higher in women than men. We also found that the 10-17 age subgroup was the major contributor to the rising pediatric IBD prevalence. For adults, the prevalence of IBD overall increased by 123%, from 214.9 in 2007 to 478.4 in 2016. The prevalence rates of UC and CD were similar (181.1 vs 197.7) in 2016. CONCLUSIONS: Inflammatory bowel disease continues to affect a substantial proportion of the US population. In 2016, 1 in 209 adults and 1 in 1299 children aged 2-17 were affected by IBD. Prevalence of IBD has been increasing compared with previously published 2009 data.

Ileal immune dysregulation in necrotizing enterocolitis: role of CD40/CD40L in the pathogenesis of disease.

OBJECTIVES: CD40, a co-stimulatory molecule, plays a critical role in coordinating enteric inflammatory immune responses. In necrotizing enterocolitis (NEC), upregulation of IL-10, a CD40-modulated cytokine, has been described, but the role of the IL-10 receptor (IL-10Rß), CD40, and its ligand CD40L in disease pathogenesis is unknown. The study herein investigates ileal expression of CD40, CD40L, and IL-10R in a rat model of NEC. SUBJECTS AND METHODS: NEC was induced in newborn rats using established methods of formula feeding, asphyxia, and cold stress. Expression of CD40, CD40L, IL-10Rß, and other proinflammatory molecules, including Toll-like receptor-4 (TLR-4) and IL-18, was assessed by immunoblotting. Tissue infiltration by macrophages, monocytes, and T cells was examined by confocal immunohistochemistry. RESULTS: Ileum from rat pups with NEC showed increased expression of TLR-4, IL-18, and IL-10Rß. Sections from both NEC and control pups demonstrated preservation of ileal cells expressing CD40/CD40L. The distal ileum of controls expressed both CD40 and CD40L; conversely, neither molecule was detected in ileal tissue from NEC pups. Additional studies showed that treatment with epidermal growth factor (EGF), previously shown to ameliorate the severity of NEC in an animal model, did not restore CD40 expression. CONCLUSIONS: Ileal cytokine dysregulation, manifested by decreased CD40/CD40L and increased IL-10Rß expression, may be involved in the pathogenesis of NEC. Dampened CD40 signaling may be related to enhanced IL-10 expression and a suppressed T-cell response to injury. We speculate that augmenting CD40-CD40L interactions may achieve a protective effect in this NEC model.

Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells.

BACKGROUND: Barrett esophagus (BE) is a premalignant condition that develops due to prolonged gastroesophageal reflux disease (GERD). In some but not all cases, BE progresses to Barrett-associated adenocarcinoma. p27 is a tumor-suppressor protein that regulates the cell's division cycle and appears to be frequently inactivated in Barrett-associated adenocarcinoma due to increased degradation or cytoplasmic mislocalization. Reduced or mislocalized p27 would remove it from its nuclear targets and result in increased proliferation. Although bile acid and hydrochloric acid (HCl) are linked to the pathogenesis of BE, not every patient with BE has a history of GERD. Eosinophilic esophagitis mimics GERD, but eosinophil granule proteins, known to mediate inflammation, have not been linked to BE. It was unknown whether mediators of esophagitis affect p27 expression and/or localization in normal esophageal cells. We assessed the effects of bile acid, HCl, and eosinophil granule proteins on p27 protein expression, localization, and its ability to regulate cell proliferation. MATERIALS AND METHODS: Human esophageal epithelial (HET-1A) cells were incubated with chenodeoxycholic acid (CDC), HCl, and eosinophil granule proteins (major basic protein, MBP; and eosinophil peroxidase, EPO). Cell viability analysis, immunoblot, immunofluorescence microscopy, and flow cytometric analysis were performed. RESULTS: Exposure of HET-1A cells to CDC, HCl, MBP, and EPO did not affect total p27 levels. CDC, HCl, MBP, and EPO caused mislocalization of p27 from the nucleus to the cytoplasm. Flow cytometry showed that CDC exposure also increased HET-1A cell proliferation. CONCLUSIONS: Mislocalization of p27 caused by mediators of GERD or eosinophilic esophagitis may serve as an early marker of increased cell proliferation, which may contribute to the risk for esophageal dysplasia.

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

BACKGROUND AND OBJECTIVES: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. METHODS: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. RESULTS: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. CONCLUSIONS: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy.

OBJECTIVE: Transfusions prevent secondary stroke in children with sickle cell anemia (SCA) but also cause iron overload. Alternatives for stroke prophylaxis with effective therapy to reduce iron burden are needed. STUDY DESIGN: For 35 children with SCA and stroke, transfusions were prospectively discontinued. Hydroxyurea was prescribed for stroke prophylaxis, and phlebotomy removed excess iron. Initial patients discontinued transfusions before hydroxyurea therapy, but later patients overlapped transfusions with hydroxyurea until tolerating full-dose therapy. RESULTS: Children received hydroxyurea for 42 +/- 30 months (range, 3-104 months). Hydroxyurea (26.7 +/- 4.8 mg/kg per day) led to mild neutropenia (3.9 +/- 2.3 x 10(9)/L) with significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin. Stroke recurrence rate was 5.7 events per 100 patient-years, but children receiving overlapping hydroxyurea therapy had only 3.6 events per 100 patient-years. For 26 children with >6 months of phlebotomy, 14,311 +/- 12,459 mL blood (315 +/- 214 mL/kg) was removed, with serum ferritin decreasing from a median of 2722 to 298 ng/mL. Among patients completing phlebotomy, liver biopsy documented normal histology and no excess iron deposition. CONCLUSIONS: For children with SCA and stroke, hydroxyurea effectively prevents secondary stroke and serial phlebotomy leads to complete resolution of transfusional iron overload.

Emerging concepts in celiac disease.

PURPOSE OF REVIEW: There has been an explosion in knowledge about celiac disease (CD) in the last decade based on the availability of serologic screening tests and the elucidation of some of the important disease susceptibility genes. What has been discovered is that CD is among the most common inherited diseases with a worldwide prevalence of almost 1% of the population. Also, there has been a tremendous expansion of the possible clinical presentations in patients with CD, many of them predominantly or even exclusively extraintestinal. Over the last year, both the North American Society of Pediatric Gastroenterology and Nutrition, and the NIH, through the mechanism of a consensus development conference held in May 2004, have published guidelines outlining the current state of knowledge and the areas where more research is needed. RECENT FINDINGS: This review will stress the most recent findings in CD in the areas of genetics, pathogenesis, epidemiology, screening and diagnosis, and natural history. It will stress the importance of HLA DQ2 and DQ8 as disease susceptibility genes, and the interaction of the environmental triggers (gliadins and glutenins) with these gene products to trigger the immunologic response in the gut that is responsible for the pattern of injury. Recent reports that stress the importance of screening high-risk groups (i.e. siblings of index cases and first degree relatives, patients with Type I diabetes, patients with Downs syndrome, patients with IgA deficiency) will be highlighted. The identification of the most sensitive and specific screening tests will be summarized with an explanation of special situations that affect the interpretation of these tests. Finally, the long-term morbidities associated with CD will be characterized supporting the case for early diagnosis and treatment. SUMMARY: The implications of these recent findings are of tremendous importance for both pediatricians and internists. Screening of high-risk groups, and of patients with the common symptoms of irritable bowel syndrome, iron deficiency anemia, unexplained arthritis, and even chronic elevations of aminotransferases is becoming the accepted standard of practice. Much research remains to be done to further refine our understanding of CD, and to devise more effective strategies for treatment, compliance, and prevention of long-term complications.