[Show abstract][Hide abstract] ABSTRACT: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.
PLoS ONE 06/2015; 10(6):e0128074. DOI:10.1371/journal.pone.0128074 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD.
Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively.
Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001).
MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel disease associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and an overlap syndrome. Prospective unbiased multi-center data regarding the frequency of IBD-LD in pediatric IBD patients is lacking. We examined early alanine amino transferase (ALT) and gamma glutamyl transpeptidase (GGT) elevations in children diagnosed with IBD and assessed the likelihood of IBD-lD.
Data came from the prospective observational Pediatric IBD Collaborative Research Group Registry (PIBDCR) enrolling children <16 years within 30 days of diagnosis. AIH, PSC and overlap syndrome were diagnosed by local institutional criteria.
1569 subjects had liver enzymes available. 757 had both ALT and GGT, 800 had ALT only (no GGT) and 12 had GGT only (no ALT). Overall, 29/1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1/661 (0.15%) of patients with both ALT and GGT≤50 IU/L compared to 21/42 (50%) of patients with both ALT and GGT>50 (odds ratio 660, P < 0.0001) Of the 29 patients with IBD-LD, 21 had PSC, 2 AIH and 6 overlap syndrome. IBD-LD was more common in patients with ulcerative colitis (UC) and IBD-unclassified (IBD-U) than in those with Crohn's Disease (CD) (4% vs. 0.8% respectively. P < 0.001).
Elevation of both ALT and GGT within 90 days after diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all pediatric patients newly diagnosed with IBD.
Journal of pediatric gastroenterology and nutrition 05/2014; 59(3). DOI:10.1097/MPG.0000000000000409 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: & Aims: Standard therapy for children newly diagnosed with Crohn's disease CD includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early ≤3 months after diagnosis treatment with an anti-tumor necrosis factor TNFα with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients.
We analyzed data from the RISK Study, an observational research program that enrolled patients <17 y old diagnosed with inflammatory non-penetrating, non-stricturing CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children median age 11.8 y, 61% male, 63% with pediatric CD activity index scores>30, and median level of C-reactive protein 5.6-fold the upper limit of normal, we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early IM, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission pediatric CD activity index scores ≤10, and growth at 1 y for 204 children. Treatment following 3 months was a covariate.
Early treatment with anti-TNFα was superior to early treatment with an immunomodulator 85.3% vs 60.3% in remission; relative risk [RR]=1.41; 95% confidence interval [CI], 1.14-1.75; P=.0017, whereas early immunomodulator therapy was no different than no early immunotherapy 60.3% vs 54.4% in remission; RR=1.11; 95% CI, 0.83-1.48; P=.49 in achieving remission at 1 y. Accounting for therapy >3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator RR=1.51; 95% CI, 1.20-1.89; P=.0004, whereas early immunomodulator therapy was no different than no early immunotherapy RR=1.00; 95% CI, 0.75-1.34; P=.99. The mean height z-score increased compared to baseline only the early anti-TNFα group.
In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFαproduced better overall clinical and growth outcomes at 1 y than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA.
Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy).
Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used.
Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.
Journal of pediatric gastroenterology and nutrition 07/2012; 56(1). DOI:10.1097/MPG.0b013e31826ac41a · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid-related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD.
Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined.
BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD ≤ 30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD ≤ 30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD ≤ 30 days of diagnosis. Two-thirds (77/119) of patients received BUD for ≤ 6 months.
BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD.
Journal of pediatric gastroenterology and nutrition 01/2012; 55(2):200-4. DOI:10.1097/MPG.0b013e31824a09c2 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Pediatric Crohn's Disease Activity Index (PCDAI) has become the standard outcome measure in pediatric Crohn's disease (CD) clinical research. Other versions have been proposed but without systematic evaluation. The aim was to assess validity and responsiveness of the abbreviated PCDAI (abbrPCDAI), short PCDAI (shPCDAI), and modified PCDAI (modPCDAI) as measures of disease activity and to compare these with a mathematically weighted version developed here (wPCDAI).
The raw data from four prospectively collected datasets were used, totaling 437 children with CD (including two clinical trials). Discriminant validity utilized physician global assessment of disease activity (PGA), and construct validity the correlation with PGA and laboratory results. Feasibility and face validity were ascertained by a survey of 33 experts in pediatric CD.
The wPCDAI had better performance than the PCDAI in construct validity and responsiveness and it discriminated better between the disease activity categories (area under the receiver operator characteristic [ROC] 0.97; 95% confidence interval [CI]: 0.95-0.99). In comparison to the original PCDAI, the noninvasive versions (abbrPCDAI and shPCDAI) had lower face, construct, and discriminant validity but were judged to be significantly more feasible. The modPCDAI performed well in the construct validation but was consistently inferior in all other parameters. Cutoffs that correspond to remission, response, and gradations of disease activity were determined for each index.
The newly weighted wPCDAI performed better than the original PCDAI and is more feasible. The noninvasive versions (shPCDAI and abbrPCDAI) are inferior to the full PCDAI, but when needed in retrospective studies either may be equally used.
[Show abstract][Hide abstract] ABSTRACT: The primary purpose of this study was to test whether recombinant human growth hormone (rhGH) supplementation would enhance protein synthesis and accretion of lean body mass. Eight adolescents (six males and two females; 17.2 +/- 2.6 years; age range, 13.7-21.2 years) participated in a randomized double-blind placebo-controlled cross-over trial of rhGH. We employed stable isotopes to measure proteolysis and protein synthesis during fasting and fed conditions during two 6-month treatment conditions. We also measured bone mineral density (BMD), markers of bone turnover, and body composition. Whole-body proteolysis, phenylalanine catabolism, and protein synthesis did not differ during treatment with rhGH vs. placebo. Enteral nutrition suppressed proteolysis and increased protein synthesis similarly during placebo and rhGH treatments. We conclude that rhGH is unlikely to provide sufficient metabolic benefit to warrant its use as an adjunct treatment in clinically stable adolescents with Crohn disease. A high prevalence of vitamin D deficiency and suboptimal BMD existed, which deserves further investigation and clinical attention.
[Show abstract][Hide abstract] ABSTRACT: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE.
Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed.
Sixty subjects with EE (46 [75%] boys, mean age 7.5 ± 4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ± 4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement.
Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.
Journal of pediatric gastroenterology and nutrition 06/2011; 53(6):651-8. DOI:10.1097/MPG.0b013e318228cee6 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to report the global experience with placement, complication rate, and recording of esophageal pH using the BRAVO capsule at our institution.
We recorded the rate of any technical problems and complications during placement in all of the patients (ages 4-22 years) who received this device during a 2-year period. All of the patients undergoing esophagogastroduodenoscopy with the placement of BRAVO pH capsule were included in this analysis. We also examined the pH data recorded on days 1 and 2 for significant day-to-day variability during 2 days of pH monitoring.
Two hundred eighty-nine BRAVO pH probes were placed from January 1, 2006 to December 31, 2008. At least 1 day of data was obtained in 278 patients (96.2%). Two days of data were obtained in 274 patients (94.8%). Of all of the reported complications, 1% occurred before deployment of the capsule, 4% occurred during deployment of the capsule, and 9% occurred after successful deployment of the capsule. One patient experienced a superficial esophageal tear that was associated with failure of the capsule to release from the delivery system. No patient requested removal of the capsule and all of the capsules detached within 14 days. In 9.12% of our patients, reflux index was normal on day 1 and abnormal on day 2. There was no statistically significant difference between reflux index recorded on day 1 versus day 2 (P = 0.686).
The BRAVO pH capsule is easy to place, safe, and well tolerated by children. Performing a 48-hour study detected abnormal reflux in an additional 9% of our patients.
Journal of pediatric gastroenterology and nutrition 04/2011; 53(4):404-8. DOI:10.1097/MPG.0b013e3182203caa · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal Crohn disease (ECD) is more common than it was originally thought to be. Only limited information, however, is available regarding its significance and effect on clinical course in the pediatric population. The aim of the study was to determine the prevalence of ECD in our patient population and compare clinical features and severity of disease among patients with ECD and nonesophageal Crohn disease (NECD).
Medical records of all patients with ECD diagnosed during a 12-year period based on specific endoscopic and histological criteria were reviewed and compared with a random group of patients with NECD.
During the study period, 81 (20%) patients with ECD were identified. Mean age at diagnosis was 12 (range 4-19 years) with a male predominance of 63%. Only 29 (36%) patients had symptoms suggestive of upper gastrointestinal involvement. Endoscopic ulcers were present in 45 (56%) of patients with ECD, whereas noncaseating granulomas were found in 10 (12%) of those patients. The majority (89%) of these patients had concomitant gastric and/or duodenal involvement. When compared with 160 random patients with NECD, patients with ECD had higher mean Pediatric Crohn Disease Activity Index scores (40.2 vs 23.9; P < 0.001), more penetrating-type disease (12% vs 2%; P = 0.001), and a greater frequency of perianal involvement (51% vs 33%; P = 0.005) at diagnosis. No differences, however, were noted between the 2 groups in terms of need for surgical resection throughout duration of follow-up.
Patients with ECD may represent a phenotype of Crohn disease with a more severe presentation. Patients with perianal disease at the time of initial physical examination should be considered for an upper endoscopy in addition to the colonoscopy to exclude esophageal involvement despite the absence of specific upper gastrointestinal symptoms. These observations should foster additional investigation into ECD phenotype to determine appropriate treatment and prognosis.
Journal of pediatric gastroenterology and nutrition 03/2011; 52(3):291-4. DOI:10.1097/MPG.0b013e3181ec21b5 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC.
Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy).
Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year.
Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.
The American Journal of Gastroenterology 01/2011; 106(5):981-7. DOI:10.1038/ajg.2010.493 · 10.76 Impact Factor