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Objective The increasing incidence of pediatric Crohn's disease (CD) is well known in Western countries in the last two decades. This study was conducted to delineate the trends of incidence during this period and clinical patterns of pediatric CD in Taiwan. Methods All children admitted to National Taiwan University Hospital between 1990 and 2009 who met the Porto Criteria for CD were included. Annual enrollment and clinical characteristics were retrospectively reviewed. The incidence was calculated by dividing the number of index cases by total hospitalized pediatric cases to minimize the bias caused by the growing number of hospitalized patients there. We quoted data and statistics from the Department of Health, Executive Yuan, Taiwan, and Accounting and Statistics, Executive Yuan, Taiwan, to present the social-economic changes in Taiwan in the recent decades. Results The cumulative hospital-based incidence of CD rose from 13.2 per 100,000 to 25.4 per 100,000 children admitted to this hospital in the past two decades. The median age of diagnosis in the first decade of this study was less than that of the second decade. The other study parameters, including gender, disease activity at diagnosis, duration from disease onset to diagnosis, anatomic location and disease behavior, and symptoms at diagnosis, were not different. Conclusions This study showed that the hospital-based incidence of pediatric CD has been increasing in Taiwan in recent decades. Factors contributing to such an increase could be physicians' awareness of the disease, easier access to health care, and environmental factors.

Background: Osteoprotegerin (OPG) may have proinflammatory roles in addition to its contribution to the maintenance of bone mass. Exclusive enteral nutrition (EEN) is an established therapy for the induction of remission in Crohn's disease (CD). The aims of this study were to ascertain serum, fecal, and mucosal expression of OPG in children with CD and to investigate the effects of EEN on OPG expression. Methods: OPG was measured by enzyme-linked immunosorbent assay in serum, mucosal, and fecal samples collected from children with CD and controls. Fecal and Serum OPG was measured prior to and following 6–8 weeks of EEN therapy. Results: Children with CD (n = 82) and controls (n = 45) were included. Mucosal and fecal OPG levels were elevated in CD compared to controls (P = 0.018 and P < 0.0001, respectively). Serum OPG was elevated in children with severe CD (P = 0.005). Serum and fecal OPG levels dropped significantly following EEN therapy (P = 0.0001 and P = 0.002, respectively). Conclusions: Increased serum and fecal OPG are seen in active CD and likely originate from the inflamed gut. Fecal and serum OPG decrease following EEN therapy. Further investigation of OPG and related proteins in the setting of IBD is now required. (Inflamm Bowel Dis 2011;)

Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD.

The Pediatric Crohn's Disease Activity Index (PCDAI) is the outcome measure of choice in clinical trials of pediatric Crohn's disease. The aim of this study was to provide knowledge on its performance and accuracy of different cutoff scores.Longitudinal data prospectively generated from four sources were used, including the REACH and budesonide trials, a North-American inflammatory bowel diseases (IBD) registry, and a cohort aimed at evaluating growth. Cutoff values of disease activity were determined by physician global assessment from the pooled cohort using serial receiver operator characteristic curves and area under the curve (AUC) as well as comparing the overall accuracy. Test-retest reliability and responsiveness were ascertained by comparing the baseline and follow-up scores, using an external anchor.A total of 437 children were included (268 (61%) males, mean age 12.9+/-2.6 years). To define remission, a composite definition of10 points or7.5 points without the height item had the highest accuracy; this addressed the limitation that height is not a responsive item. The best cutoff of 10-27.5 was determined for mild disease, 30-37.5 for moderate disease, 40-100 for severe disease, and a change of12.5 points for response (AUC 0.8-0.9; P0.001). Ninety children whose disease remained unchanged showed fair test-retest reliability (intraclass correlation coefficient=0.74-0.8; P0.001). The PCDAI showed good responsiveness, as reflected from the correlational (r=0.7; P0.001), distributional (Guyatt's responsiveness statistics=0.9), and diagnostic utility analysis (AUC 0.85 (95% confidence interval 0.81-0.88).The clinimetric properties of the PCDAI are sufficient to support its use in clinical research. Cutoff values suggested by this study differ slightly from those previously published on much smaller cohorts.

Crohn's disease is characterized by chronic inflammation involving any portion of the gastrointestinal tract. Treating Crohn's disease is a major challenge for clinicians, as no curative therapy currently exists. Pediatric Crohn's disease is characterized by frequent relapses, a wide extent of disease, a high prevalence of extraintestinal manifestations, and a severe clinical course. The classic therapeutic approach is known as the 'step-up' strategy, and follows a progressive course of treatment intensification as disease severity increases. Although this approach is usually effective for symptom control, many patients become either resistant to or dependent on corticosteroids. The efficacy of infliximab suggests that, rather than a progressive course of treatment, early intense induction may reduce complications associated with conventional treatment and improve quality of life. Intensive early therapy with infliximab is known as the 'top-down' strategy. Such therapy offers the potential for altering the natural history of Crohn's disease, and is changing treatment paradigms. However, the relatively new concept of an early aggressive or 'top-down' treatment approach is not yet widely accepted, especially in pediatric patients. The results of our current study demonstrate that early and intensive treatment of pediatric Crohn's disease patients with infliximab, at initial diagnosis, was more effective for maintaining remission and reducing flares.

Crohn’s disease is a chronic inflammatory disorder of the GI tract that often presents during childhood and adolescence. Children with Crohn’s disease are often subjected to repeated radiologic examinations throughout the course of their illness, thereby raising great concern over the potential harm of cumulative radiation exposure. Magnetic resonance enterography is a new modality that provides detailed images of the GI tract without exposure to ionizing radiation. This article reviews past methods of bowel imaging, the scope of the problem with regard to radiation exposure, as well as the technical aspects, indications, and current evidence for magnetic resonance enterography in children with Crohn’s disease. Various examples of inflammatory, stricturing and penetrating disease activity are provided.

Background: Improving granulocyte function may represent an effective therapy for Crohn's disease (CD). We performed a Phase I-2 trial of sargramostim (SRG) in children with CD. Methods: This was multicenter, open-label study in 6–16-year-old patients with moderate to severely active CD. Patients received either 4 or 6 μg/kg SRG subcutaneously daily for 8 weeks, with and without concomitant corticosteroids (CS). The primary endpoint was identification of a safe and tolerable dose in children. The secondary endpoint was establishment of the pharmacokinetics (PK). Efficacy, a tertiary endpoint, was measured by the Pediatric CD Activity Index (PCDAI). Response was defined as a decrease from baseline of ≥12.5 points and remission as absolute PCDAI of ≤10. Results: In all, 22 patients were enrolled: 12 and 10 received 4 and 6 mg/kg, respectively; 19 completed the course. Both doses were found to be safe and well tolerated. Mild injection-site reactions occurred in 90% of patients. Three patients required dose reductions due to elevated absolute neutrophil counts. Following 4 μg/kg the mean area under the curve (AUC) was 2.64 and 2.80 ngh/mL for the 6–11- and 12–16-year-old groups, respectively. The mean half-life (t1/2) was 1.22 and 1.59 hours, respectively. Following 6 μg/kg, the mean AUC was 5.01 ngh/mL for the 12–16-year-old group, a 1.8-fold increase. A total of 16/18 patients (88%) achieved remission or response. Conclusions: Sargramostim at both 4 and 6 mg/kg was well tolerated. PK analysis suggested dose proportionality unaffected by CS exposure. Remission and response data are encouraging, but further trials are needed to assess efficacy. (Inflamm Bowel Dis 2010)

Kalyan Ray Parashette1, Raghavendra Charan Makam2, Carmen Cuffari31Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; 2Department of Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA; 3Division of Pediatric Gastroenterology, The Johns Hopkins Children’s Center, Baltimore, MD, USAAbstract: Anti-tumor necrosis factor alpha (TNF-α) therapy has re-defined our treatment paradigms in managing patients with Crohn’s disease (CD) and ulcerative colitis. Although the ACCENT studies showed proven efficacy in the induction and maintenance of disease remission in adult patients with moderate to severe CD, the pediatric experience was instrumental in bringing forth the notion of “top-down” therapy to improve overall clinical response while reducing the risk of complications resulting from long-standing active disease. Infliximab has proven efficacy in the induction and maintenance of disease remission in children and adolescents with CD. In an open-labeled study of 112 pediatric patients with moderate to severe CD, 58% achieved clinical remission on induction of infliximab (5 mg/kg) therapy. Among those patients who achieved disease remission, 56% maintained disease remission on maintenance (5 mg/kg every 8 weeks) therapy. Longitudinal follow-up studies have also shown that responsiveness to infliximab therapy also correlates well with reduced rates of hospitalization, and surgery for complication of long-standing active disease, including stricture and fistulae formation. Moreover, these children have also been shown to improve overall growth while maintaining an effective disease remission. The pediatric experience has been instructive in suggesting that the early introduction of anti-TNF-α therapy may perhaps alter the natural history of CD in children, an observation that has stimulated a great deal of interest among gastroenterologists who care for adult patients with CD.Keywords: Crohn’s disease, infliximab, pediatric

Infliximab, a murine monoclonal antibody directed against TNF-α, has been approved for the induction and maintenance of remission in moderate-to-severe pediatric Crohn’s disease that is unresponsive to conventional therapy. Infliximab is administered intravenously and can be infused over 2–3 h. The recommended induction dosing schedule consists of a series of three 5 mg/kg doses of infliximab delivered at weeks 0, 2 and 6. Regularly scheduled maintenance therapy is recommended to be given every 8 weeks. While initially it was believed that the administration of concomitant immunomodulators would significantly enhance the clinical efficacy of infliximab, recent data and safety concerns have called the benefit of such a strategy into question. Currently, clinical research on the use of infliximab in pediatric Crohn’s disease has focused on the unmet need of being able to identify which patients could benefit most from infliximab therapy.

Improvements in insulin resistance after anti-TNF-alpha therapy have been reported in inflammatory conditions, although no changes were noted in adult patients with Crohn's disease. There is no information concerning insulin resistance and substrate metabolism in children with Crohn's disease after anti-TNF-alpha therapy. Our aim was to describe changes in carbohydrate and lipid metabolism in children with active Crohn's disease after their initial dose of infliximab. Children with active Crohn's disease underwent measurement of plasma insulin and glucose just before and 2 wk after their initial infusion of infliximab, an anti-TNF-alpha antibody. In addition, resting energy expenditure, with determination of both carbohydrate and lipid oxidation rates, was determined. Measurements were conducted in both fasting and parenterally fed states. Despite no changes in resting energy expenditure, a significant reduction (p0.05) in RQ (5%) and carbohydrate oxidation rate (24%), with a corresponding increase in lipid oxidation rate (42%) was found during parenteral nutrition infusion. No differences in plasma insulin, glucose, and insulin resistance were noted when comparing pre- and postinfliximab measurements.

The relationship between the age at diagnosis and disease course is poorly defined in children with Crohn's disease (CD). We examined the presentation and course of disease in patients 0-5 compared to 6-17 yr of age at diagnosis.We analyzed uniform data from 989 consecutive CD patients collected between January 2000 and November 2003, and stored in the Pediatric IBD Consortium Registry. The statistical tests account for the length of follow-up of each patient.In total, 98 patients (9.9%) were of 0-5 yr of age at diagnosis. The mean follow-up time was 5.6 +/- 5.0 yr in the younger group and 3.3 +/- 2.8 yr in the older group (P0.001). Race/ethnicity differed by the age group (P= 0.015); a larger proportion of the younger group was Asian/Pacific Islander or Hispanic, and a larger proportion of the older group was African American. The initial classification as ulcerative colitis or indeterminate colitis was more common among the 0-5 yr of age group (P0.001). The 6-17 yr of age patients presented with more abdominal pain (P0.001), weight loss (P= 0.001), or fever (P= 0.07), while the 0-5 yr of age patients presented with more rectal bleeding (P= 0.008). The 6-17 yr of age patients were more likely to be treated with antibiotics (P0.001), 6-mercaptopurine/azathioprine (P0.001), infliximab (P= 0.001), or corticosteroids (P= 0.0006). The 6-17 yr of age patients had a higher cumulative incidence of treatment with 5-aminosalicylates (P= 0.009) or methotrexate (P= 0.04). The risk for developing an abscess (P= 0.001), a fistula (P= 0.02), a stricture (P= 0.05), or a perianal fissure (P= 0.06) was greater in the 6-17 yr of age patients.The 6-17 yr of age patients with CD appear to have a more complicated disease course compared to 0-5 yr of age children. The 0-5 yr of age group may represent a unique disease phenotype and benefit from different approaches to management. Long-term prospective studies are required to validate these findings.

Crohn’s disease affects more than 500000 individuals in the United States, and about 25% of cases are diagnosed during the pediatric period. Imaging of the bowel has undergone dramatic changes in the past two decades. The endoscopy with biopsy is generally considered the diagnostic reference standard, this combination can evaluates only the mucosa, not inflammation or fibrosis in the mucosa. Actually, the only modalities that can visualize submucosal tissues throughout the small bowel are the computed tomography (CT) enterography (CTE) with the magnetic resonance enterography (MRE). CT generally is highly utilized, but there is growing concern over ionizing radiation and cancer risk; it is a very important aspect to keep in consideration in pediatric patients. In contrast to CTE, MRE does not subject patients to ionizing radiation and can be used to detect detailed morphologic information and functional data of bowel disease, to monitor the effects of medical therapy more accurately, to detect residual active disease even in patients showing apparent clinical resolution and to guide treatment more accurately.

BACKGROUND Pediatric Crohn's disease (CD) is a lifelong, debilitating, and costly disease. In previous studies, CD incidence increased with higher geographic latitude in the Northern Hemisphere. This may indicate a role for lower vitamin D status as a risk factor for CD. Analysis of worldwide incidence of pediatric CD has not been previously reported. METHODS We undertook a systematic review of population-based studies reporting incidence of pediatric CD and published between 2003 and 2013. Included studies had well-defined diagnostic criteria for CD, evidence of high case ascertainment, reported incidence according to age group, and provided a specific location. Average daily ambient ultraviolet radiation (UVR) for each location was derived from satellite data. Negative binomial regression was used to assess the association between pediatric CD incidence and latitude and ambient UVR, adjusting for the study year. RESULTS Twenty-eight articles provided 39 incidence data points. Incidence of pediatric CD increased with higher latitude, and in association with a greater number of months where the average daily UVR was lower than a previously published threshold of 1.488 kJ/m. Incidence of pediatric CD increased over calendar time. CONCLUSIONS After applying rigorous quality assessment criteria, and including only population-based studies, there was a modest increase in incidence of pediatric CD with higher latitude and greater number of months with low ambient UVR. Reporting using nonconsistent diagnostic criteria and age groups, with poorly defined geographic locations, makes it difficult to compare data across different studies.

Delayed growth is common in pediatric Crohn's disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being the presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia, and weight loss are all manifestations of circulating TNF-alpha, which is elevated in CD. The ability to secrete TNF-alpha may be affected by polymorphisms in the TNF-alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset CD are affected by TNF promoter genotype.Genotyping for TNF-alpha and NOD2/CARD15 single nucleotide polymorphisms was performed in 87 patients with detailed growth records. Parameters including disease location and disease severity were recorded, and the effect of these polymorphisms on Z-scores for height and weight at disease onset and during follow-up were analyzed.Lower age of onset was linked to more height retardation, while the presence of colonic disease and the absence of ileal disease were more likely to predict the absence of growth retardation. The presence of two polymorphisms thought to decrease circulating TNF-alpha was associated with higher mean Z-scores for height and a trend toward less growth retardation. Two other polymorphisms were modestly associated with disease severity.Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.

Objective: The Pediatric Crohn's Disease Activity Index (PCDAI) is a validated measure of disease activity comprised of historical, laboratory and physical examination parameters. It has been suggested that an abbreviated PCDAI may be of similar utility without requiring laboratory evaluations or calculated height velocity. The aim of this study was to compare an abbreviated PCDAI and the original PCDAI and also compare the abbreviated PCDAI and a quality-of-life measurement. Methods: The authors prospectively analyzed quality of life and disease activity, using the IMPACT-35 Questionnaire, the PCDAI and an abbreviated PCDAI consisting of three historical items (abdominal pain, stools and patient functioning) and three physical examination items (weight, abdomen and perirectal disease). Results: Forty subjects aged 5-24 years (22 males) were included in analysis. Correlations were performed between the original PCDAI, an abbreviated PCDAI and the IMPACT-35, There was a significant, strong correlation between the PCDAI and the abbreviated PCDAI (n = 40, r = 0.849, p

The incidence and prevalence of Crohn’s disease (CD) among children in developed countries is extremely high. Although, dietary factors have long been implicated, to date no single causative element has been identified. Risks or benefits for CD from dietary elements would depend on their appropriate metabolism within the gut by xenobiotic metabolising enzymes (XME). The metabolising capacity among individuals differs and is determined by the level and/or activity of the specific XME. As the latter is the function of the DNA variants that code them, we propose that certain individuals exposed to dietary elements are likely to be more or less susceptible for CD. We highlight this hypothesis by describing gene–environment interaction (G×E) mechanisms that could determine susceptibility for CD. We suggest that investigating these mechanisms will be paramount for the appropriate identification of susceptible populations, such that preventive and/or therapeutic interventions could be adequately targeted.

Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-alpha antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-alpha antibody recently approved for pediatric Crohn's disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-alpha therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn's disease and to discuss open issues regarding safety as well as future perspectives.

BackgroundNeutrophil expression of the Fcγ receptor I (CD64) is upregulated in adult patients with clinically active inflammatory bowel disease (IBD). We tested the relationship of CD64 with mucosal inflammation and clinical relapse in pediatric Crohn's disease (CD).MethodsIn a cohort of 208 newly diagnosed CD and 43 non-IBD controls, ileal expression of FcγRI/S100A9 was determined by RNA sequencing from biopsies obtained at ileocolonoscopy. In a second cohort, we tested for the peripheral blood polymorphonuclear neutrophil (PMN) CD64 index from 26 newly diagnosed CD, 30 non-IBD controls, and 83 children with established CD.ResultsIleal FcγRIA mRNA expression was significantly elevated in CD at diagnosis compared with non-IBD controls (P < 0.001), and correlated with ileal S100A9 (calprotectin) expression (r = 0.83, P < 0.001). The median (range) PMN CD64 index for newly diagnosed CD was 2.3 (0.74-9.3) compared with 0.76 (0.39-1.2) for non-IBD controls (P < 0.001) with 96% sensitivity and 90% specificity at the cut point of 1.0. The PMN CD64 index significantly correlated with mucosal injury as measured by the simple endoscopic score for CD (r = 0.62, P < 0.001). Patients with CD in clinical remission receiving maintenance therapy with a PMN CD64 index 1.0 (P < 0.01).ConclusionsAn elevated PMN CD64 index is associated with both mucosal inflammation and an increased risk for clinical relapse in pediatric CD. The PMN CD64 index is a reliable marker for sustained remission in patients with CD receiving maintenance therapy.

Tumor necrosis factor-alpha plays a central role in chronic intestinal inflammation of Crohn's disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn's disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn's disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn's disease.Fifteen consecutive children (mean age 12.8 +/- 3.2 yr) with medically refractory Crohn's disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response.In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients.Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn's disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn's disease.

Background & Aims: The Pediatric Crohn's Disease Activity Index (PCDAI) is a multi-item measure that, in contrast to the adult-derived CDAI, includes linear growth and places less emphasis on subjectively reported symptoms but more on laboratory parameters of intestinal inflammation. This study compared the feasibility, validity, and responsiveness of PCDAI vs. CDAI in the assessment of Crohn's disease activity among pediatric patients. Methods: Eighty-one children and adolescents with Crohn's disease were studied. A gastroenterologist provided a categorical global assessment of disease activity as quiescent, mild, moderate, or severe after interview and physical examination. CDAI and PCDAI scores were calculated by an independent appraiser. Results: Mean values within each category for CDAI and PCDAI differed significantly between strata. PCDAI values were quiescent, 6.8 ± 6.6; mild, 18.7 ± 7.3; moderate, 38.5 ± 12.9; and severe, 54.2 ± 14.0. CDAI values were quiescent, 23.5 ± 53.6; mild, 96.0 ± 60.7; moderate, 184.5 ± 97.0; and severe, 284.4 ± 85.8. Individual scores showed less overlap between strata for PCDAI than for CDAI. PCDAI showed better correlation with serum orosomucoid and platelet count, laboratory parameters of inflammation not included in either index. Conclusions: Both PCDAI and CDAI reflect disease activity in pediatric Crohn's disease. PCDAI is better at discriminating between levels of disease activity. GASTROENTEROLOGY 1999;116:527-531

Introduction: Nutritional therapy has been reported to have an almost equivalent efficacy to that of corticosteroids in achieving clinical remission in active Crohn’s disease (CD). However, the effects of both treatments on intestinal mucosal inflammation rarely are reported. In a randomized controlled trial in children with active CD, the authors compared the efficacy of nutritional therapy alone with that of corticosteroids on clinical variables and intestinal mucosal healing.