Lissy de Ridder

Genetic susceptibility has a more important role in pediatric‐onset Crohn's disease than in adult‐onset Crohn's disease

Background: Genetic susceptibility may play a more important role in the etiology of early‐onset inflammatory bowel disease (IBD) than in late‐onset IBD, and therefore pediatric‐onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric‐onset IBD, to compare them with those of patients with adult‐onset IBD and with controls, and to identify genotype–phenotype associations. Methods: Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; ‐207G→C, 1672C→T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G→A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric‐onset and 696 adult‐onset IBD patients. Phenotypic classification was based on disease localization and behavior. Results: Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric‐onset Crohns disease (CD) than in patients with adult‐onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2–42.0). Homozygosity for single‐nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric‐onset CD than in patients with adult‐onset CD (6.1% versus 1.1%, P = 0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0–53.8) and a positive family history (6.1% versus 20%, CI 1.2–9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4–4). Conclusions: Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric‐onset CD than in patients with adult‐onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric‐onset CD cohort.

Magnetic Resonance Enterography for Suspected Inflammatory Bowel Disease in a Pediatric Population

Objectives: The aim of the study was to determine the accuracy of magnetic resonance enterography (MRE) in diagnosing and differentiating pediatric inflammatory bowel disease (IBD). The secondary aims were to determine the accuracy of MRE in grading disease activity and determine the interobserver agreement for individual MRE parameters. Patients and Methods: Pediatric patients scheduled to undergo esophagogastroduodenoscopy, ileocolonoscopy with biopsies, and barium enteroclysis for suspected IBD were included and underwent MRE. MRE images were evaluated by 3 observers. The accuracy of MRE was calculated using the clinical diagnosis based on endoscopic, histopathological, and barium enteroclysis examinations as reference standard. Results: Thirty-three patients were available for analysis. IBD was correctly diagnosed in, respectively, 61%, 61%, and 91% of the patients by the 3 observers, with a specificity of 80%, 90%, and 60%. Differentiation between Crohn disease (CD) and ulcerative colitis (UC) was accurately done in, respectively, 67%, 53%, and 80% of patients with CD and 0%, 14%, and 43% of patients with UC. Disease activity was understaged on MRE in the majority of patients. Intraclass correlation coefficients for measurements of bowel thickness were 0.52 (observer 1–2; observer 1–3) and 0.34 (observer 2–3). Interobserver agreement on bowel wall enhancement and stenosis was moderate to good (κ 0.59, 0.56, and 0.56 and κ 0.62, 0.32, 0.30, respectively). Conclusions: Sensitivity and specificity values of MRE for diagnosing pediatric IBD were moderate to good. CD, but not UC, was accurately diagnosed by MRE in a large proportion of patients. Activity was understaged in a large proportion of patients. Interobserver agreement for individual MRE parameters was fair to good.

Infliximab use in children and adolescents with inflammatory bowel disease.

Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-α, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non–placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non–life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.

Rectal bleeding in children : endoscopic evaluation revisited

Objectives Rectal bleeding is an alarming event both for the child and parents. It is hypothesized that colonoscopy instead of sigmoidoscopy and adding esophago-gastro-duodenoscopy in case of accompanying complaints, improves the diagnostic accuracy in children with prolonged rectal bleeding. Study design All pediatric patients undergoing colonoscopy because of prolonged rectal bleeding over an 8-year period at the Emma Childrens Hospital/Academic Medical Centre were reviewed. Patient demographics, clinical features, number and extent of endoscopic examinations and the endoscopic and histopathological findings were assessed. Results A total of 147 colonoscopies were performed in 137 pediatric patients (63 boys) because of prolonged rectal bleeding. Inflammatory bowel disease and polyp(s) were the most prevalent diagnoses. In 72% of patients diagnosed as Crohns disease, focal, chronically active gastritis was seen on histology, giving support to the diagnosis Crohns disease. In 22% of the cases polyps would have been missed in the case where only sigmoidoscopy was performed. No complications after endoscopic intervention were seen. Conclusions Colonoscopy is the investigation of choice in children with prolonged rectal bleeding. In patients presenting with accompanying complaints such as abdominal pain or diarrhea, it is advisable to perform ileocolonoscopy combined with esophago-gastro-duodenoscopy. This combines a high diagnostic yield with a safe procedure.

Development and Function of Immune Cells in an Adolescent Patient with a Deficiency in the Interleukin-10 Receptor

Objective: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in “classical” IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. Methods: Biomaterial was collected from the IL10RA-deficient patient, pediatric patients with IBD, and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. Results: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of tumor necrosis factor &agr; compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T-cell cytokines interferon &ggr; and IL-17 agreeing with high numbers of T-bet+ and IL-17+ cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patients decreased peripheral blood mononuclear cell-derived tumor necrosis factor production. Conclusions: With time and during immunosuppressive treatment the IL10RA-deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing interferon &ggr; and IL-17-mediated T-cell responses.OBJECTIVEnMonogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in classical IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants.nnnMETHODSnBiomaterial was collected from the IL10RA-deficient patient, pediatric IBD patients and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays.nnnRESULTSnThe IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of TNFα compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T cell cytokines IFNγ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient decreased peripheral blood mononuclear cell-derived TNFα production.nnnCONCLUSIONSnWith time and during immunosuppressive treatment the IL10RA- deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing IFNγ and IL-17-mediated T-cell responses.

CMV Infection in Pediatric Severe Ulcerative Colitis - A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN

Background: Data on the clinical course and outcomes of pediatric patients with cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very limited. The aim of our study was to compare outcomes of children with ASC who were CMV positive or CMV negative. Methods: This was a multicenter retrospective case-controlled study, from centers affiliated with the Pediatric Inflammatory Bowel Disease Porto Group of European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. We included CMV-positive children hospitalized for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter, matched with CMV-negative controls. Results: A total of 56 children were included; 15 CMV positive and 41 CMV negative. More CMV-positive patients were resistant to intravenous corticosteroids as compared with CMV negative (93% and 56% respectively, P = 0.009). Fourteen of the CMV-positive children (93%) were treated with ganciclovir [5/14 (36%) with 5u2009mg/kg and 9/14 (64%) with 10u2009mg/kg]. During hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy (P = 0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and CMV-negative patients required colectomy, respectively (P = 0.049); the significance was not retained on multivariate analysis. Conclusions: A higher prevalence of CMVpositivity was found in pediatric ulcerative colitis patients who required colectomy within 12 months of hospitalization for ASC. Further studies are needed to clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients.BACKGROUNDnData on the clinical course and outcomes of pediatric patients with cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very limited. The aim of our study was to compare outcomes of children with ASC who were CMV-positive or CMV-negative.nnnMETHODSnThis was a multicenter retrospective case-controlled study, from centers affiliated with the Pediatric IBD Porto Group of ESPGHAN. We included CMV -positive children hospitalized for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter, matched with CMV-negative controls.nnnRESULTSnA total of 56 children were included; 15 CMV-positive and 41 CMV-negative. More CMV-positive patients were resistant to intravenous corticosteroids as compare to CMV negative (93% and 56% respectively, p=0.009). Fourteen of the CMV-positive children (93%) were treated with ganciclovir (5/14 (36%) with 5mg/kg and 9/14 (64%) with 10mg/kg). During hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy (p=0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and negative patients required colectomy, respectively (p=0.049); the significance was not retained on multivariate analysis.nnnCONCLUSIONSnA higher prevalence of CMV-positivity was found in pediatric UC patients who required colectomy within 12 months of hospitalization for ASC. Further studies are needed to clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients.