J. C. Escher

Infliximab therapy in 30 patients with refractory pediatric Crohn disease with and without fistulas in the Netherlands

Objective: The purpose of this study was to describe the clinical experience with the anti–tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands. Design: Descriptive. Methods: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003. Results: Thirty patients (aged 7–18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index ≤10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis. Conclusions: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.

Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease.

Celiac disease (CD) is caused by inflammatory CD4+ T-cell responses to dietary gluten. It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores. High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1–2 lesions, whereas increased numbers of IL-17 secreting cells were not observed. Intraepithelial lymphocytes, CD4+ T cells and also neutrophils secreted IL-21. Flow cytometry of lamina propria cells revealed a large population of IL-21- and interferon-γ (IFN-γ)-secreting CD3+ T cells that did not secrete IL-17A. Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions. As duodenal tissue damage increases contact with microbe-associated molecular patterns, we hypothesized that microbial sensing by Toll-like receptors (TLRs) modulates T cell–derived cytokine secretion. Costimulation with TLR3 ligands during polyclonal T-cell activation significantly increased IL-21 secretion, whereas TLR2 ligands selectively enhanced IL-17A. These results demonstrate that an IL-17A-independent increase in IL-21 production by CD4+ T cells is characteristic of pediatric CD. We hypothesize that incidental IL-17 secretion is caused by tissue damage rather than gluten-specific responses.

Pediatric Achalasia in the Netherlands: Incidence, Clinical Course, and Quality of Life.

OBJECTIVE To assess incidence and clinical course of Dutch patients with achalasia diagnosed before 18 years of age as well as their current symptoms and quality of life (QoL). STUDY DESIGN Retrospective medical chart review and a cross-sectional study assessing current clinical status using the Eckardt score and reflux disease questionnaire. General QoL was measured using Kidscreen-52 for patients <18 years of age or to 36-Item Short Form Health Survey for patients ≥18 years of age. RESULTS Between 1990 and 2013, 87 children (mean age 11.4 ± 3.4 years, 60% male) diagnosed with achalasia in the Netherlands were included. Mean incidence was 0.1/100,000/y (range 0.03-0.21). Initial treatment was pneumodilation (PD) in 68 (79%) patients and Heller myotomy (HM) in 18 (21%) patients. Retreatment was required more often after initial PD compared with initial HM (88% vs 22%; P < .0001). More complications of initial treatment occurred after HM compared with PD (55.6% vs 1.5%; P < .0001). Three esophageal perforations were seen after HM (16.7%), 1 after PD (1.5%). Sixty-three of 87 (72%) patients were prospectively contacted. Median Eckardt score was 3 (IQR 2-5), with 32 patients (44.5%) having positive scores suggesting active disease. Reflux disease questionnaire scores were higher after initial HM vs PD (1.71 [0.96-2.90] vs 0.58 [0-1.56]; P = .005). The 36-Item Short Form Health Survey (n = 52) was lower compared with healthy population norms for 7/8 domains. Kidscreen-52 (n = 20) was similar to population norms. CONCLUSIONS Pediatric achalasia is rare and relapse rates are high after initial treatment, especially after pneumodilation, but with more complications after HM. Symptoms often persist into adulthood, without any clinical follow-up. QoL in adulthood was decreased.

1 Functional consequences of a novel IL-10 receptor alpha mutation on innate and adaptive immunity in early-onset inflammatory bowel disease

M.A. van Leeuwen1, S. Veenbergen1, R. Kersseboom2, L.F. de Ruiter1, H. Raatgeep1, D.J. Lindenbergh-Kortleve1, Y. SimonsOosterhuis1, L. de Ridder1, G.J.A. Driessen3, J.C. Escher1, J.N. Samsom1 *. 1Erasmus Medical Centre Sophia Children’s Hospital, Dept. of Paediatric Gastroenterology, Rotterdam, 2Erasmus Medical Centre, Dept. of Clinical Genetics, Rotterdam, 3Erasmus Medical Centre, Dept. of Paediatric Infectious Disease and Immunology, Rotterdam, Netherlands