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1.  Association of variants of the interleukin-23 receptor (IL23R) gene with susceptibility to pediatric Crohn’s disease 
Background & Aims
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs11209026, within the interleukin-23 receptor (IL23R) locus and Crohn’s disease (CD) as a consequence of a genome wide association study of this disease in adults. We examined the effects of this and other previously reported SNPs at this locus with respect to CD in children.
Methods
Utilizing data from our ongoing genome-wide association study in our cohort of 142 pediatric CD cases and 281 matched controls, we investigated the association of the previously reported SNPs at the IL23R locus with the childhood form of this disease.
Results
Using a Fisher’s exact test, the minor allele frequency (MAF) of rs1120902 in the cases was 1.75% while it was 6.61% in controls, yielding a protective odds ratio (OR) of 0.25 (95% CI 0.10 – 0.65; one-sided P = 9.2×10−4). Furthermore, of all the SNPs previously reported, rs11209026 was the most strongly associated. A subsequent family-based association test (which is more resistant to population stratification) with 65 sets of trios derived from our initial patient cohort yielded significant association with rs11209026 in a transmission disequilibrium test (one-sided P=0.0017). In contrast, no association was detected to the CARD15 gene for the IBD phenotype.
Conclusions
The OR of the IL23R variant in our pediatric study is highly comparable with that reported previously in a non-Jewish adult IBD case-control cohort (OR=0.26). As such, variants in IL23R gene confer a similar magnitude of risk of CD to children as for their adult counterparts.
doi:10.1016/j.cgh.2007.04.024
PMCID: PMC4287202  PMID: 17618837
IL23R; gene; association; Crohn’s Disease
2.  Routine use of thiopurines in maintaining remission in pediatric Crohn’s disease 
AIM: To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.
METHODS: The multi-center Pediatric Inflammatory Bowel Disease Network (PIBDNet) cohort study prospectively collected data on thiopurine naïve patients initiating mercaptopurine (6MP) or azathioprine. Patients with a diagnosis of Crohn’s disease (CD) were included in our study upon entering remission as determined by physician global assessment (PGA) within 365 d of initiation of thiopurines. The primary outcome of the study was maintenance of steroid-free remission (SFR) at each follow up visit. Patients were considered treatment failures if there had been a change in PGA from remission to mild, moderate or severe disease; disease relapse between visits; need for rescue therapy (biologic therapy, methotrexate, steroids); thiopurine discontinuation, hospitalization or surgical intervention. A secondary outcome defined treatment failure as a change from remission to moderate or severe (not mild) in addition to the previously defined criteria.
RESULTS: Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Forty-five of 65 (69%) of included patients achieved remission within 180 d of thiopurine initiation. For the primary outcome, 47% and 23% of patients remained in SFR at 6 and 12 mo. The mean thiopurine dose at initiation for the 65 included patients was 0.89 ± 0.31 mg/kg per day. Metabolite levels were obtained in 48% (31/65) of the included patients with a mean 6TG level of 258 pmole/8 × 108 RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo.
CONCLUSION: Thiopurines were less effective in maintaining remission for pediatric CD in this “real world” cohort than has been previously described. Variation in thiopurine dosing and metabolite measurement was found among practitioners.
doi:10.3748/wjg.v20.i27.9185
PMCID: PMC4112859  PMID: 25083093
Crohn’s disease; Pediatric; Remission; Thiopurines; Mercaptopurine
3.  Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature 
The Journal of Clinical Investigation  2014;124(8):3617-3633.
Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
doi:10.1172/JCI75436
PMCID: PMC4109533  PMID: 25003194
4.  Impact of exome sequencing in inflammatory bowel disease 
Approaches to understanding the genetic contribution to inflammatory bowel disease (IBD) have continuously evolved from family- and population-based epidemiology, to linkage analysis, and most recently, to genome-wide association studies (GWAS). The next stage in this evolution seems to be the sequencing of the exome, that is, the regions of the human genome which encode proteins. The GWAS approach has been very fruitful in identifying at least 163 loci as being associated with IBD, and now, exome sequencing promises to take our genetic understanding to the next level. In this review we will discuss the possible contributions that can be made by an exome sequencing approach both at the individual patient level to aid with disease diagnosis and future therapies, as well as in advancing knowledge of the pathogenesis of IBD.
doi:10.3748/wjg.v19.i40.6721
PMCID: PMC3812471  PMID: 24187447
Sequencing; Exome; Genetics; Inflammatory bowel disease
5.  Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci 
PLoS ONE  2014;9(5):e96153.
Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P = 1.49×10–19). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process.
doi:10.1371/journal.pone.0096153
PMCID: PMC4006814  PMID: 24788701
6.  Enthesitis is an Extraintestinal Manifestation of Pediatric Inflammatory Bowel Disease 
Annals of paediatric rheumatology  2012;1(4):10.5455/apr.102920121510.
Background
Enthesitis is an extra-intestinal manifestation of inflammatory bowel disease (IBD) in adults. However, little has been published about the prevalence or characteristics of enthesitis in pediatric IBD.
Methods
We conducted a cross-sectional study of children and young adults ages 4–21 years with IBD. Subjects were recruited among those receiving routine care in a gastroenterology clinic. All subjects underwent a clinical examination of the entheses and joints, and completed a study questionnaire.
Results
We enrolled 43 subjects, who had a median age of 16 years and a median time from IBD diagnosis of 2.7 years. 32 subjects (74%) had Crohn disease, 10 subjects (23%) had indeterminate colitis, and 1 subject (2%) had ulcerative colitis. At least one tender enthesis was present in 21% of subjects and 12% had more than 2 tender entheses. The most commonly affected entheses were located at the inferior patella, the femoral greater trochanter, and the proximal humerus. The presence of enthesitis was associated with a higher intensity of recent musculoskeletal pain (p=0.03).
Conclusions
Enthesitis is a prevalent extra-intestinal manifestation of pediatric IBD and is associated with increased musculoskeletal pain. Future studies should evaluate the functional and long-term impact of enthesitis on children with IBD.
doi:10.5455/apr.102920121510
PMCID: PMC3860180  PMID: 24349861
Enthesitis; inflammatory bowel disease; extra-intestinal manifestations; enthesitis-related arthritis
7.  Family functioning and health-related quality of life in adolescents with pediatric inflammatory bowel disease 
Objectives
To examine the relationship between family functioning and health-related quality of life (HRQOL) in a sample of adolescents with inflammatory bowel disease (IBD), and to specify the domains of family functioning with which these families experience difficulties.
Methods
Sixty-two adolescents, aged 13–17 years, with a confirmed diagnosis of IBD completed assessments of HRQOL. Each adolescent’s primary caregiver completed a measure of family functioning. Pediatric gastroenterologists provided data for disease severity assessments.
Results
A series of multivariate analyses of variance showed that adolescents from families with clinically elevated difficulties in problem solving, communication, and general family functioning endorsed lower HRQOL (i.e., social functioning, general well-being) after statistically controlling the effects of disease severity and diagnosis. As many as 25% of families reported clinically elevated difficulties across domains of family functioning.
Conclusions
Findings suggest that family functioning may be an important predictor of HRQOL among the adolescents with IBD, and that many families experience difficulties in their daily interactions. Close monitoring of family functioning may be a salient feature for prevention and intervention efforts and beneficial in promoting optimal psychosocial outcomes among the adolescents with IBD.
doi:10.1097/MEG.0b013e3283417abb
PMCID: PMC3677963  PMID: 21079514
adolescents; family functioning; inflammatory bowel disease; quality of life
8.  Treatment Adherence in Adolescents With Inflammatory Bowel Disease: The Collective Impact of Barriers to Adherence and Anxiety/Depressive Symptoms 
Journal of Pediatric Psychology  2011;37(3):282-291.
Objective Knowledge of factors impacting adolescents’ ability to adhere to their inflammatory bowel disease (IBD) regimen is limited. The current study examines the collective impact of barriers to adherence and anxiety/depressive symptoms on adolescent adherence to the IBD regimen. Methods Adolescents (n = 79) completed measures of barriers to adherence, adherence, and anxiety/depressive symptoms at one of two specialty pediatric IBD clinics. Results Most adolescents reported barriers to adherence and 1 in 8 reported borderline or clinically elevated levels of anxiety/depressive symptoms. Anxiety/depressive symptoms moderated the relationship between barriers to adherence and adherence. Post hoc probing revealed a significant, additive effect of higher anxiety/depressive symptoms in the barriers–adherence relationship, with adherence significantly lower among adolescents with higher barriers and higher anxiety/depressive symptoms. Conclusions In order to optimize adherence in adolescents, interventions should target not only barriers to adherence but also any anxiety/depressive symptoms that may negatively impact efforts to adhere to recommended treatment.
doi:10.1093/jpepsy/jsr092
PMCID: PMC3306169  PMID: 22080456
adherence; adolescent; anxiety; barriers; depression
10.  Paediatric Parenting Stress in Inflammatory Bowel Disease: Application of the Pediatric Inventory for Parents 
Child  2011;38(2):273-279.
Background
The psychosocial functioning of caregivers of adolescents managing inflammatory bowel disease (IBD) has been understudied; yet, poor caregiver functioning can place youth at risk for compromised disease management. The current study addressed this limitation by examining a sample of caregivers of adolescents with IBD. Study aims included: 1) document rates of paediatric parenting stress, 2) identify associated sociodemographic predictors of parenting stress, and 3) compare previously published rates of parenting stress to those within other paediatric chronic conditions, including cancer, type 1 diabetes, obesity, sickle cell disease, bladder exstrophy.
Methods
Caregivers of adolescents with an IBD diagnosis (Mage = 15.4±1.4, 44.4% female, 88.7% Caucasian) and receiving tertiary care within a gastroenterology clinic (N = 62) completed the Pediatric Inventory for Parents (PIP) as a measure of paediatric parenting stress with Frequency and Difficulty as PIP subscales. Paediatric gastroenterologists provided disease severity assessments.
Results
Adolescents with IBD were experiencing relatively mild disease activity. Bivariate correlations revealed that PIP-Difficulty was positively associated with Crohn’s disease severity (r = 0.38, p < 0.01). Caregiver age was negatively associated with the frequency of parenting stress total (r = −.25, p = .05) and communication scores (r = −.25, p <.05). The frequency and difficulty of parenting stressors within the IBD sample were similar to rates within type 1 diabetes, but were significantly lower to rates identified in other paediatric chronic conditions.
Conclusions
Caregivers of adolescents with IBD seem to experience low rates of parenting stress when their adolescents are receiving outpatient care and during phases of IBD relative inactivity. The sociodemographic characteristics of IBD families (i.e., primarily Caucasian, well-educated, and higher socioeconomic status) likely encourage greater access to financial and psychosocial resources, which may aid in promoting more optimal stress management.
doi:10.1111/j.1365-2214.2010.01200.x
PMCID: PMC3123674  PMID: 21299591
Inflammatory bowel disease; parenting distress; adolescence; Pediatric Inventory for Parents; sociodemographics
11.  Human gut microbiome viewed across age and geography 
Nature  2012;486(7402):222-227.
Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ between human populations when viewed from the perspective of component microbial lineages, encoded metabolic functions, stage of postnatal development, and environmental exposures, we characterized bacterial species present in fecal samples obtained from 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas, as well as the gene content of 110 of their microbiomes. This cohort encompassed infants, children, teenagers and adults, parents and offspring, and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the representation of genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial species assemblages and functional gene repertoires were noted between individuals residing in the USA compared to the other two countries. These distinctive features are evident in early infancy as well as adulthood. In addition, the similarity of fecal microbiomes among family members extends across cultures. These findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations, and the impact of Westernization.
doi:10.1038/nature11053
PMCID: PMC3376388  PMID: 22699611
12.  Disease Activity, Behavioral Dysfunction, and Health-related Quality of Life in Adolescents with Inflammatory Bowel Disease 
Inflammatory Bowel Diseases  2010;17(7):1581-1586.
Background
Approximately 20-25% of all IBD cases have an onset in childhood or adolescence. Beyond disease severity, little is known regarding determinants of health-related quality of life (HRQOL) in this population. This study aimed to identify behavioral correlates of HRQOL and examine behavioral/emotional dysfunction (e.g., internalizing/externalizing symptoms) as the mechanism through which disease severity impacts HRQOL.
Methods
62 adolescents (M = 15.47 years, SD = 1.42) with IBD (79% Crohn’s disease) and their parents were recruited from one of two pediatric IBD specialty clinics located in the Midwest or Northeast region of the United States. Participants completed a demographic questionnaire, the Youth Self-Report version of the Child Behavior Checklist, and the IMPACT-III. Disease severity was calculated for Crohn’s disease and ulcerative colitis using standardized measures.
Results
Greater disease severity, externalizing symptoms, and internalizing symptoms were all independently associated with lower HRQOL. Furthermore, internalizing symptoms partially mediated the relationship between disease activity and HRQOL, reducing the effect of disease severity on HRQOL from 22% to 9% in the mediation model. A Sobel test examining the significance of the indirect effect of disease severity on HRQOL via behavioral dysfunction was marginally non-significant (p = .053).
Conclusions
Non-disease specific variables (e.g., behavioral dysfunction) play an important role in impacting HRQOL. Behavioral dysfunction serves as the mechanism through which disease severity partially impacts HRQOL. Continued research to identify other predictors of HRQOL in pediatric IBD will greatly enhance our future ability to design interventions to improve HRQOL and maximize health outcomes.
doi:10.1002/ibd.21520
PMCID: PMC3117046  PMID: 21674715
Inflammatory Bowel Disease; Adolescents; Quality of Life; Behavioral Dysfunction
13.  Meta-Analysis Increases to 71 the Tally of Confirmed Crohn’s Disease Susceptibility Loci 
Franke, Andre | McGovern, Dermot P.B. | Barrett, Jeffrey C. | Wang, Kai | Radford-Smith, Graham L. | Ahmad, Tariq | Lees, Charlie W. | Balschun, Tobias | Lee, James | Roberts, Rebecca | Anderson, Carl A. | Bis, Joshua C. | Bumpstead, Suzanne | Ellinghaus, David | Festen, Eleonora M. | Georges, Michel | Haritunians, Talin | Jostins, Luke | Latiano, Anna | Mathew, Christopher G. | Montgomery, Grant W. | Prescott, Natalie J. | Rotter, Jerome I. | Schumm, Philip | Sharma, Yashoda | Simms, Lisa A. | Taylor, Kent D. | Whiteman, David | Wijmenga, Cisca | Baldassano, Robert N. | Barclay, Murray | Bayless, Theodore M. | Brand, Stephan | Buning, Carsten | Cohen, Albert | Colombel, Jean-Frederick | Cottone, Mario | Stronati, Laura | Denson, Ted | De Vos, Martine | D’Inca, Renata | Dubinsky, Marla | Edwards, Cathryn | Florin, Tim | Franchimont, Denis | Gearry, Richard | Glas, Jürgen | Van Gossum, Andre | Guthery, Stephen L. | Halfvarson, Jonas | Hommes, Daan | Hugot, Jean-Pierre | Laukens, Debby | Lawrance, Ian | Lemann, Marc | Levine, Arie | Libioulle, Cecile | Louis, Edouard | Mowat, Craig | Newman, William | Panés, Julián | Phillips, Anne | Proctor, Deborah D. | Regueiro, Miguel | Rutgeerts, Paul | Sanderson, Jeremy | Sans, Miquel | Seibold, Frank | Steinhart, A. Hillary | Stokkers, Pieter C.F. | Torkvist, Leif | Ublick, Gerd Kullak | Raychaudhuri, Soumya | Green, Todd | Walters, Thomas | Targan, Stephan R. | Brant, Steven R. | Rioux, John D. | D’Amato, Mauro | Weersma, Rinse | Kugathasan, Subra | Griffiths, Anne M. | Mansfield, John C. | Vermeire, Severine | Duerr, Richard H. | Silverberg, Mark S. | Satsangi, Jack | Schreiber, Stefan | Cho, Judy H. | Annese, Vito | Hakonarson, Hakon | Daly, Mark J. | Parkes, Miles
Nature genetics  2010;42(12):1118-1125.
doi:10.1038/ng.717
PMCID: PMC3299551  PMID: 21102463
14.  The Contributions of Child Behavioral Functioning and Parent Distress to Family Functioning in Pediatric Inflammatory Bowel Disease 
The objective of this study was to examine the relative contributions of both parental and adolescent functioning to family functioning in adolescent patients with inflammatory bowel disease (IBD) and their families. Participants were 45 adolescents (27 male, 18 female) 13–17 years old (M = 15.41 years, SD = 1.32) with IBD and their parents. Families completed measures of patient behavioral functioning and depression, parent distress and family functioning. Disease severity assessments were completed via data provided by patients’ gastroenterologists. Results indicated that parent-reported patient behavioral problems accounted for a significant 26% of variance in family functioning. Post-hoc analysis revealed that externalizing behavior problems accounted for the majority of this variance compared to internalizing behavior problems. These results suggest that externalizing problems may have a more significant impact on these families than previous research indicates. Moreover, externalizing behaviors may significantly impact family adaptation and should be taken into consideration during routine clinical care. Further research is needed to replicate and expand upon these findings.
doi:10.1007/s10880-011-9228-5
PMCID: PMC3062159  PMID: 21359503
Inflammatory bowel disease; Family functioning; Behavior; Distress; Internalizing; Externalizing
15.  Oral Medication Adherence and Disease Severity in Pediatric Inflammatory Bowel Disease 
Objective
The purpose of this study was to examine the relationship of oral medication adherence and perceived adherence barriers with disease severity in a sample of adolescents with IBD.
Methods
Participants included 62 adolescents, aged 13–17 years, diagnosed with IBD and their parents. Measures of parent- and patient-rated oral medication adherence and related barriers, behavioral and emotional functioning per parent- and self-report, and disease severity per physician reported medical chart data were obtained.
Results
Fifteen percent of the sample reported clinically elevated depressive symptoms and 24% reported clinically elevated internalizing behavioral problems. Number of reported adherence barriers was 2.6 ± 1.5, and no participants reported zero barriers. Parental ratings of medication adherence (t = −2.11, p < .05) and perceived barriers to adherence (t = 2.05, p < .05) significantly predicted disease severity after statistically controlling for the contributions of behavioral and disease parameters to disease severity.
Conclusions
Results suggest that oral medication adherence and perceived adherence barriers are significantly related to disease severity in adolescents with IBD. These patients also may be at risk for increased behavioral and emotional problems which may impact health outcomes as well. Clinicians should make particular efforts to attend to medication adherence issues with their patients. Working with patients and families to develop solutions for eliminating adherence barriers might result in better disease outcomes.
doi:10.1097/MEG.0b013e328344019c
PMCID: PMC3073772  PMID: 21304318
Adherence; disease severity; inflammatory bowel disease; behavior; Barriers; Crohn’s disease; Ulcerative colitis
16.  Patient and Parent Psychosocial Factors Associated with Health-Related Quality of Life in Pediatric Inflammatory Bowel Disease 
Objectives
To examine the mediating role of youth depressive symptoms in the relationship between parent distress and youth health-related quality of life (HRQOL) in a sample of adolescents with inflammatory bowel disease (IBD).
Methods
Sixty-two adolescents, aged 13-17 years, with a confirmed diagnosis of IBD completed assessments of depressive symptoms and HRQOL. Each adolescent’s primary caregiver completed a measure of parent stress related to their child’s illness. Pediatric gastroenterologists provided data for disease severity assessments.
Results
Multiple regression analyses revealed that adolescent depressive symptoms fully mediated the relationship between parent distress and several dimensions of HRQOL (i.e., General Well-Being, Emotional Functioning, Social Functioning, and Total HRQOL). Moreover, mediation was observed after statistically controlling for the impact of disease severity, IBD diagnosis, and significant demographic parameters on HRQOL.
Conclusions
Findings suggests that adolescent depressive symptoms may serve as the mechanism through which parent distress is linked to poorer HRQOL in adolescents with IBD. Close monitoring of parent illness-related distress and adolescent depressive symptoms as well as clinical interventions targeting these factors, are needed to promote optimal outcomes in adolescents with IBD.
doi:10.1097/MPG.0b013e3181f5714e
PMCID: PMC3058639  PMID: 21297508
Inflammatory Bowel Disease; Adolescents; Quality of Life; Parent Distress; Depression
17.  Inflammatory Bowel Disease in African-American Children Compared to Other Racial/Ethnic Groups in a Multi-Center Registry 
Background and Aims
Few epidemiological investigations characterize inflammatory bowel disease (IBD) in non-Caucasian children. Our study compared IBD characteristics between African-Americans and non-African-Americans enrolled in a multi-center pediatric IBD registry with endoscopic- and pathology-based diagnosis.
Methods
The study retrieved data entered from January 2000–October 2003 on children 1 to 17 years old, inclusive, followed by a consortium of academic and community U.S. pediatric gastroenterology practices. Analyses examined racial/ethnic differences by comparing the proportions of African-Americans and non-African-Americans in: each diagnostic disease classification (any IBD, Crohn's disease, ulcerative colitis, indeterminate colitis); age group (<6y, 6–12y or >12y) at diagnosis or symptom onset; presence of extraintestinal manifestations, Z-scores for height and weight, immunomodulatory therapy, anatomic disease location and abnormal hemoglobin, albumin or sedimentation rate at diagnosis.
Results
1,406 patients had complete data, 138 (10%) of whom were African-American. African-Americans more often: were >12y of age at diagnosis (52% vs. 37%, OR 1.82, 95% CI 1.28–2.59) and symptom onset (46% vs. 30%, OR 1.99, 95% CI 1.40–2.84); had Crohn's disease (78% vs. 59%, OR 2.36, 95% CI 1.56–3.58); had low hemoglobin at diagnosis (39% vs. 17%, OR 3.15, 95% CI 1.92–5.17).
Conclusions
IBD in African-American children and adolescents presents more commonly with CD and at older ages compared to non-African-Americans. Racial/ethnic differences in the epidemiology of IBD, particularly CD, among American youths require further investigation.
doi:10.1016/j.cgh.2008.07.032
PMCID: PMC3273485  PMID: 18848910
18.  Common variants at five new loci associated with early-onset inflammatory bowel disease 
Nature Genetics  2009;41(12):1335-1340.
The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD1. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn’s disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.
doi:10.1038/ng.489
PMCID: PMC3267927  PMID: 19915574
19.  Incidence of Stricturing and Penetrating Complications of Crohn’s Disease Diagnosed in Pediatric Patients 
Inflammatory Bowel Diseases  2010;16(4):638-644.
Background
The development of disease complications is poorly characterized in pediatric patients with Crohn’s disease (CD).
Methods
We retrospectively determined the cumulative incidence of stricturing and penetrating complications of CD prior to first surgery utilizing data from 989 consecutively enrolled CD patients (age 0–17 years at diagnosis) collected between January 2000 and November 2003 and stored in the Pediatric IBD Consortium Registry.
Results
Mean age at diagnosis was 11.5 ± 3.8 (standard deviation) years. Median follow-up time was 2.8 years. Prior to first surgery, the cumulative incidence of stricturing or penetrating complications was 27% at 5 years and 38% at 10 years from the diagnosis of inflammatory bowel disease. The cumulative incidence of complicated disease was lowest in isolated colonic disease (P = 0.009). Penetrating complications that followed stricturing complications prior to first surgery occurred within 2 years of stricturing complications (cumulative incidence was 13% at 2 years from diagnosis of stricturing disease). Stricturing complications that followed penetrating complications prior to first surgery occurred within 8 years of penetrating complications (cumulative incidence was 26% at 8 years from diagnosis of penetrating complications).
Conclusions
Strictures, abscesses, and fistulas are common in pediatric CD. Earlier aggressive management may be indicated. Prospective study is required to identify genetic and serologic markers that predict a patient’s risk for the development of complicated disease and to determine optimal treatment regimens.
doi:10.1002/ibd.21099
PMCID: PMC3258512  PMID: 19760783
abscess; fistula; non-inflammatory disease; complicated disease; children; adolescence; outcomes; database; registry; inflammatory bowel disease
20.  Presentation and Disease Course in Early- Compared to Later-Onset Pediatric Crohn’s Disease 
BACKGROUND
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.
METHODS
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.
RESULTS
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 (P < 0.001). 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 (P < 0.001). The 6–17 yr of age patients presented with more abdominal pain (P < 0.001), 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 (P < 0.001), 6-mercaptopurine/azathioprine (P < 0.001), 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.
CONCLUSIONS
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.
doi:10.1111/j.1572-0241.2008.02000.x
PMCID: PMC3258513  PMID: 18796101
21.  Reduced Intracellular T-Helper 1 Interferon-Gamma in Blood of Newly Diagnosed Children With Crohn’s Disease and Age-Related Changes in Th1/Th2 Cytokine Profiles 
Pediatric research  2008;63(3):257-262.
Abnormal cytokine production by T-helper 1 (Th1)/T-helper 2 (Th2) lymphocytes has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined Th1/Th2 cytokine status in pediatric IBD patients, and results have been inconsistent. We used flow cytometric detection of intra-cellular IFN-γ/IL-4 cytokine production to investigate CD4+, Th1, and Th2 cells in the peripheral blood of children with untreated, newly diagnosed Crohn’s disease (CD) (n = 23) and matched healthy controls (n = 49). Th1 cytokine levels were lower in CD patients compared with controls (p = 0.006) and strongly correlated with levels of albumin and hematocrit (r = 0.51, p = 0.007 and r = 0.35, p = 0.052, respectively). An age-dependent increase in Th1 cells was observed (p < 0.0005); however, no correlation was found between age, clinical end points, %CD4+, or Th2 cell numbers. In conclusion, the Th1 cytokine levels in blood are lower in early onset CD patients than in healthy children and are directly associated with disease-related clinical parameters. In future studies of pediatric IBD patients, it will be critical to consider the effect of age and disease progression on cytokine status in intestinal mucosa and peripheral blood.
doi:10.1203/PDR.0b013e318163a897
PMCID: PMC3252046  PMID: 18287963
22.  Treatment Adherence in Paediatric Inflammatory Bowel Disease: Perceptions from Adolescent Patients and Their Families 
The objective of this study was to examine patient- and parent-perceived factors that impact adherence to inflammatory bowel disease treatment using a qualitative descriptive individual interview approach. Sixteen adolescents and their parents were recruited from May through August 2007 and interviewed about medication adherence using an open-ended semi-structured interview format. Interviews were audio recorded, transcribed, and coded into themes. Parent-child dyads identified forgetting, interfering activities, parent-child conflict and oppositional behaviour, and inadequate planning for treatment as challenges to adherence. Participants reported that family support and good parent-child relationships, routines, monitoring and reminding, and organizational tools such as pill boxes facilitated treatment adherence. Other issues that emerged included immediacy of treatment effects and parent-adolescent responsibility for treatment. Patients and parents experience a number of challenges related to adherence within behavioural, educational, organizational, and health belief domains. Behavioural interventions should focus on these issues, reduction of perceived barriers, and effective transition of responsibility for treatment adherence. Future research considerations are discussed.
doi:10.1111/j.1365-2524.2010.00951.x
PMCID: PMC3052867  PMID: 21143544
Adolescent Health; Bowel Disease; Compliance; Chronic Disease Management
23.  Brief Report: Barriers to Treatment Adherence in Pediatric Inflammatory Bowel Disease 
Journal of Pediatric Psychology  2009;35(9):1005-1010.
Objective To examine perceived barriers to medication adherence in inflammatory bowel disease (IBD) treatment and their relationship with adherence using a combined forced choice and semi-structured interview assessment approach. Methods Sixteen adolescents with IBD and their parents participated in an open-ended interview regarding adherence barriers and completed quantitative measures of adherence, barriers to treatment, and disease severity. Results The most commonly identified barriers to adherence were forgetting, interference with other activities, difficulty swallowing pills, and not being at home. Number of reported barriers was positively correlated with objective nonadherence for 6-MP/azathioprine. Nonadherence frequency was 42% for 6-MP/azathoprine and 50% for 5-ASA medications. Conclusions Using a combined assessment approach, patients and parents reported several barriers to treatment adherence that are appropriate for clinical intervention. This is critical given the significant medication nonadherence observed in this sample and the relationship between total number of barriers and disease management problems.
doi:10.1093/jpepsy/jsp126
PMCID: PMC2948828  PMID: 20026567
adherence; barriers; compliance; inflammatory bowel disease; medication
24.  Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 
Anderson, Carl A. | Boucher, Gabrielle | Lees, Charlie W. | Franke, Andre | D’Amato, Mauro | Taylor, Kent D. | Lee, James C. | Goyette, Philippe | Imielinski, Marcin | Latiano, Anna | Lagacé, Caroline | Scott, Regan | Amininejad, Leila | Bumpstead, Suzannah | Baidoo, Leonard | Baldassano, Robert N. | Barclay, Murray | Bayless, Theodore M. | Brand, Stephan | Büning, Carsten | Colombel, Jean-Frédéric | Denson, Lee A. | De Vos, Martine | Dubinsky, Marla | Edwards, Cathryn | Ellinghaus, David | Fehrmann, Rudolf S.N. | Floyd, James A.B. | Florin, Tim | Franchimont, Denis | Franke, Lude | Georges, Michel | Glas, Jürgen | Glazer, Nicole L. | Guthery, Stephen L. | Haritunians, Talin | Hayward, Nicholas K. | Hugot, Jean-Pierre | Jobin, Gilles | Laukens, Debby | Lawrance, Ian | Lémann, Marc | Levine, Arie | Libioulle, Cecile | Louis, Edouard | McGovern, Dermot P. | Milla, Monica | Montgomery, Grant W. | Morley, Katherine I. | Mowat, Craig | Ng, Aylwin | Newman, William | Ophoff, Roel A | Papi, Laura | Palmieri, Orazio | Peyrin-Biroulet, Laurent | Panés, Julián | Phillips, Anne | Prescott, Natalie J. | Proctor, Deborah D. | Roberts, Rebecca | Russell, Richard | Rutgeerts, Paul | Sanderson, Jeremy | Sans, Miquel | Schumm, Philip | Seibold, Frank | Sharma, Yashoda | Simms, Lisa | Seielstad, Mark | Steinhart, A. Hillary | Targan, Stephan R. | van den Berg, Leonard H. | Vatn, Morten | Verspaget, Hein | Walters, Thomas | Wijmenga, Cisca | Wilson, David C. | Westra, Harm-Jan | Xavier, Ramnik J. | Zhao, Zhen Z. | Ponsioen, Cyriel Y. | Andersen, Vibeke | Torkvist, Leif | Gazouli, Maria | Anagnou, Nicholas P. | Karlsen, Tom H. | Kupcinskas, Limas | Sventoraityte, Jurgita | Mansfield, John C. | Kugathasan, Subra | Silverberg, Mark S. | Halfvarson, Jonas | Rotter, Jerome I. | Mathew, Christopher G. | Griffiths, Anne M. | Gearry, Richard | Ahmad, Tariq | Brant, Steven R. | Chamaillard, Mathias | Satsangi, Jack | Cho, Judy H. | Schreiber, Stefan | Daly, Mark J. | Barrett, Jeffrey C. | Parkes, Miles | Annese, Vito | Hakonarson, Hakon | Radford-Smith, Graham | Duerr, Richard H. | Vermeire, Séverine | Weersma, Rinse K. | Rioux, John D.
Nature genetics  2011;43(3):246-252.
Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10-8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC.
doi:10.1038/ng.764
PMCID: PMC3084597  PMID: 21297633
25.  Determinants of Changes in Linear Growth and Body Composition in Incident Pediatric Crohn’s Disease 
Gastroenterology  2010;139(2):430-438.
Background and Aims
Pediatric Crohn’s disease (CD) is associated with deficits in growth, lean mass (LM), and fat mass (FM). This study assessed changes in height and body composition in children and adolescents with CD following diagnosis, and identified determinants of these changes.
Methods
Whole body LM and FM were assessed using DXA in 78 CD subjects at diagnosis and 6, 12, and a median of 43 (range 24–63) months later. Race- and sex-specific Z-scores for lean mass (LM-ht-Z) and fat mass (FM-ht-Z) relative to height were derived using reference data in >900 controls. Serum cytokines and growth factors were measured and quasi-least squares regression was used to identify determinants of changes in height and body composition Z-scores.
Results
LM-ht-Z and FM-ht-Z (both p<0.005) improved significantly following diagnosis; however, females had persistent LM deficits vs. controls (−0.50 ± 1.02, p<0.05) at the final visit. Serum interleukin-6, TNF-α, and lipopolyscaccharide binding protein (LBP) decreased significantly (all p<0.001). Greater increases in LM-ht-Z were associated with infliximab therapy (p<0.05), increases in albumin (p<0.001), and decreases in ESR (p<0.05), interleukin-6 (p<0.005), and LBP (p<0.05). Greater increases in FM-ht-Z were associated with glucocorticoid, methotrexate, and infliximab therapy, and increases in albumin (p<0.05) and growth hormone binding protein (p<0.05). Overall, height-Z did not improve; however, greater increases in IGF-1 (p<0.05) and decreases in TNF-α (p<0.05), interleukin-6 (p<0.05) and LBP (p<0.05) levels were associated with increases in height-Z.
Conclusions
Immune-mediated mechanisms contribute to growth and body composition deficits in CD. Therapies should target these deficits.
doi:10.1053/j.gastro.2010.04.044
PMCID: PMC2910790  PMID: 20417635
Crohn’s disease; body composition; growth; nutrition; children

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