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Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine., Competing Interests: Dr Otley reports Advisory Board for AbbVie; research funding from AbbVie, Janssen, Takeda, Lilly, and Pfizer. The remaining authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcomes in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS). CS tapering and escalation to additional therapy or colectomy were by protocol. Patients with baseline or week 4 or week 12 FC levels were included in the analysis. Our primary outcome was CS-free remission on mesalamine at week 52. We compared the prognostic value of a baseline FC as well as a change in FC by week 4 or week 12 in predicting clinical outcomes., Results: The study included 352 children (113 initial mesalamine, 239 initial CS, mean age 12.6 years) with UC. At Week 52, 135 (38.3%), 84 (23.8%), and 19 (5.4%) children achieved CS-free remission, needed anti-tumor necrosis factor therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.901.00) and week 12 FC levels (OR 0.91, 95% CI 0.87-0.96) were associated with outcomes, with the latter having a stronger association with CS-free remission. Patients with a >75% decrease by 12 weeks, had a 3-fold increased likelihood of CS-free remission at 1 year., Discussion: Longitudinal changes in FC may predict 1 year outcomes better than values at diagnosis in children with a new diagnosis of UC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis., Methods: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis)., Results: Mean age was 12.7 years; 49.6% (n = 212) were girls, and 83% (n = 351) were Caucasian. Severe total Mayo score was present in 28% (n = 120), mean PUCAI score was 49.8 ± 20.1, and 33% (n = 142) had severe mucosal disease with extensive involvement in 82% (n = 353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%., Conclusions: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.

Objectives: Children with Crohn's disease may present with malnutrition and linear growth impairment, which can be secondary to insufficient caloric intake, chronic inflammation, malabsorption, and suppression of growth-promoting hormones. We evaluated clinical, serologic, and genetic data to determine risk factors for impaired anthropometrics in Crohn's disease at diagnosis., Methods: Our study evaluated 772 children newly diagnosed with Crohn's disease, inflammatory phenotype, enrolled in the RISK Stratification Project to determine the factors associated with anthropometric impairment. Data were collected on demographics, growth parameters, disease location, serologic and immunologic markers, and disease severity. We performed a genome-wide association study of genetic polymorphisms associated with inflammatory bowel disease. Regression analysis determined associations between anthropometrics and clinical, serologic, and genetic variables., Results: There were 59 (7%) children with height z score <-2, 126 (14%) with a weight z score <-2, and 156 (17%) with a body mass index z score <-2. Linear growth impairment was associated with hypoalbuminemia (P = 0.0052), elevated granulocyte-macrophage colony stimulating factor autoantibodies (P = 0.0110), and elevated CBir antibodies against flagellin (P = 0.0117). Poor weight gain was associated with female sex (P = 0.0401), hypoalbuminemia (P = 0.0162), and thrombocytosis (P = 0.0081). Malnutrition was associated with hypoalbuminemia (P = 0.0061) and thrombocytosis (P = 0.0011). Children with moderate or severe disease had lower weight (P = 0.02 and P = 1.16×10, respectively) and body mass index z scores (P = 2.7 × 10 and P = 1.01 × 10, respectively) than children with quiescent and mild disease. There was no association between age of diagnosis, Tanner stage, or disease location and having impaired anthropometrics. There was no genome-wide association between the genetic polymorphisms and the serologic variables and anthropometric measurements., Conclusions: This is the largest study evaluating growth in treatment-naïve children with Crohn's disease, inflammatory phenotype. It is the first study to use genome-wide sequencing to assess for genetic determinants of growth impairment. Granulocyte-macrophage colony stimulating factor autoantibodies and CBir antibodies are more likely to be elevated in children with growth impairment. Future investigations should evaluate the relationship between genetic polymorphisms, pathologic immune responses, and the biological pathways regulating growth.

Background: Treatment of pediatric inflammatory bowel disease (IBD) with monoclonal anti- tumor necrosis factor-alpha (TNFα) can result in immunogenicity and formation of anti-drug antibodies (ADAs). ADAs are associated with loss of clinical response and worsening disease progression. Data examining treatment interventions to overcome ADA in pediatric patients with IBD are lacking., Results: Medical records were reviewed from 234 children and adolescents with IBD treated with infliximab or adalimumab who underwent therapeutic drug monitoring (626 tests). All patients who had detectable antibodies were further analyzed. A total 58 patients (24.8%) developed ADA while being treated with infliximab or adalimumab. The incidence of antibody development was 12.9 per 100 person-years of anti-TNF treatment. Twenty-eight patients underwent dose optimization and 54% had undetectable ADA on follow-up monitoring. The mean duration of antibody suppression was 16.8 ± 10.9 months in those who were successfully suppressed with optimization. Patients who switched to a second anti-TNF medication were not more likely to develop antibodies to the second agent., Conclusions: With limited therapies for IBD and the chronicity of the disease, we advocate salvage of the current anti-TNF through dose optimization in pediatric patients with antibody level <10 U/mL.

Purpose of Review: Prospective and inception inflammatory bowel disease (IBD) cohorts offer excellent opportunities to develop risk stratification strategies, use relevant tissue to explore the biology of IBD progression, and study the natural history of IBD in the era of biological therapy. Adult IBD care can learn important lessons from recent pediatric IBD studies., Recent Findings: A recent multicenter inception cohort of pediatric IBD patients examining genetic, serologic, and microbiome data at diagnosis has been able to create a model for prediction of disease complications, describe compositional changes in gut microbiota associated with disease severity, identify markers of intestinal fibrosis, and confirm how important early life environmental exposures affect disease severity and phenotype. Analysis of gene and protein expression in mucosal samples has been shown to offer both diagnostic information about differentiation of ulcerative colitis (UC) vs. crohn's disease as well as implications for treatment efficacy. Important developments in treatment of growth failure with antitumor necrosis factor therapy, the effect of oral medication noncompliance, and dietary IBD therapy are outlined., Summary: Pediatric IBD research has been focusing on better phenotyping at diagnosis, and development of molecular signatures of future disease behavior by using relevant intestinal tissue rather than blood. This has moved IBD from being a heterogeneous group of diseases with an unknown disease course to a better-defined condition in which patients are accurately risk stratified and treated based on individualized distinct biological and clinical information.

Objectives: Elevated granulocyte-macrophage colony-stimulating factor auto-antibodies (GM-CSF Ab) are associated with increased intestinal permeability and stricturing behavior in Crohn disease (CD). We tested for familial association of serum GM-CSF Ab level in CD and ulcerative colitis (UC) families., Methods: Serum GM-CSF Ab concentration was determined in 230 pediatric CD probands and 404 of their unaffected parents and siblings, and 45 UC probands and 71 of their unaffected parents and siblings. A linear mixed effects model was used to test for familial association. The intra-class correlation coefficient (ICC) was used to determine the degree of association of the serum GM-CSF Ab level within families in comparison with the degree of association among families., Results: The median (IQR) serum GM-CSF Ab concentration was higher in CD probands than in UC probands (1.5 [0.5,5.4] μg/mL vs 0.7 [0.3, 1.6] μg/mL, P = 0.0002). The frequency of elevated serum GM-CSF Ab concentration ≥1.6 μg/mL was increased in unaffected siblings of CD probands with elevated GM-CSF Ab, compared with unaffected siblings of CD probands without elevated GM-CSF Ab (33% vs 13%, respectively, P = 0.04). A similar result was observed within UC families. In families of CD patients, the mean (95th CI) ICC was equal to 0.153 (0.036, 0.275), P = 0.001, whereas in families of UC patients, the mean (95th CI) ICC was equal to 0.27 (0.24, 0.31), P = 0.047., Conclusions: These data confirmed familial association of serum GM-CSF Ab levels. This could be accounted for by either genetic or environmental factors shared within the family.

Background: Iron deficiency and anemia affect up to 50% to 75% of patients with inflammatory bowel disease (IBD). Iron deficiency in IBD may be difficult to diagnose because of the effect of inflammation on iron status biomarkers. Thus, there is a need for better methods to accurately determine iron status in IBD., Objective: The aim of the study was to investigate the association of inflammation with hemoglobin content of reticulocytes (CHr) and the utility of CHr in comparison to standard iron biomarkers., Methods: We conducted a cross-sectional study of children with IBD. Iron biomarkers (CHr, ferritin, soluble transferrin receptor [sTfR], hepcidin, hemoglobin) were measured along with systemic biomarkers of inflammation (C-reactive protein, α1-acid glycoprotein]. Spearman correlations were used to evaluate the relation of inflammation and iron biomarkers. The criterion standard for iron deficiency was defined as inflammation-corrected ferritin <15 μg/L or sTfR >8.3 mg/L. Receiver operating characteristic curves were used to estimate the prognostic values of all iron biomarkers to identify patients with iron deficiency., Results: We analyzed data in 62 children ages 5 to 18 years. Sixty-nine percent of our subjects had Crohn disease and 31% had ulcerative colitis, of which 42% were girls and 53% African American. The prevalence of anemia was 32%, of iron deficiency was 52% using ferritin <15 μg/L or sTfR >8.3 mg/L, 39% using red blood cell distribution width of >14.5%, 26% using body iron stores of <0 mg/kg body weight, 25% using CHr of <28 pg, and 11% using mean corpuscular volume of <75 fL/cell. The prevalence of elevated CRP or AGP was 48%. After correcting ferritin and sTfR levels for inflammation, the prevalence of iron deficiency was 68%. CHr was correlated with C-reactive protein (rs -0.44, P < 0.001) and α1-acid glycoprotein (rs -0.37, P < 0.05). The optimal prognostic value for inflammation-adjusted CHr to predict iron deficiency was 34 pg (area under the receiver operating characteristic of 0.70), with 88% sensitivity and 30% specificity., Conclusions: Iron deficiency and anemia are common in this pediatric IBD cohort. All explored iron biomarkers, including CHr, were affected by inflammation and should be adjusted. A single iron biomarker is unlikely to best predict iron deficiency in pediatric IBD. Iron intervention studies are needed to examine the response of iron biomarkers to iron supplementation in the setting of inflammation.

Background: Infliximab (IFX) is an effective treatment for the management of moderate to severe inflammatory bowel disease (IBD). Low-serum IFX levels are associated with the development of antibodies to IFX (ATI), which subsequently associated with clinical relapse and increased morbidity. The primary purpose of this study is to examine the relation between dose and interval to IFX level. Secondary goal is to evaluate the relation between IFX level and ATI in a pediatric IBD population., Methods: We performed a retrospective chart review of all children diagnosed with IBD and treated with IFX at a tertiary care pediatric IBD center. We performed our analysis based on prescribed dosing intervals and rounded dose up to 5 or 10 mg/kg as indicated in clinical practice., Results: Our study included 278 samples from 129 children on IFX. ATI were detected in 37 samples (13.3%). Low IFX levels (<3 μg/mL) were detected in 37.2% of children receiving IFX. Samples with ATI present had significantly lower levels of IFX than samples in which ATI were not present. For the dose 5 mg/kg, Q6 dosing had significantly higher IFX levels than Q8 dosing (P = 0.009). Higher IFX levels were seen with interval shortening rather than dose escalation., Conclusions: We demonstrate that low IFX levels are associated with development of immunogenicity to IFX as measured by ATI. We demonstrate that interval shortening rather than dose escalation results in higher IFX levels. We suggest that given the high number of IFX levels below 3 μg/mL in patients, early IFX level evaluation or primary initiation of Q6 week dosing be considered.

Background: Mucosal healing predicts clinical remission and improved outcomes in patients with Crohn disease (CD). Magnetic resonance enterography (MRE) is a noninvasive imaging modality that can assess small and large bowel wall inflammation. Evidence suggests that MRE may be an acceptable alternative to evaluate mucosal healing over endoscopy. Our objective is to determine whether MRE remission predicts clinical remission at follow-up in children with CD., Methods: We performed an institutional review board-approved retrospecitve chart review using our prospectively maintained MRE CD database. Inclusion criteria were all children who underwent an MRE more than 6 months after diagnosis with CD who had follow-up of at least 1 year from imaging., Results: A total of 101 children with CD underwent MRE, a median of 1.3 years from diagnosis with a median follow-up of 2.8 years after MRE. Active inflammation was detected in 65 MRE studies, whereas 36 MRE studies demonstrated MRE remission. A total of 88.9% of children demonstrating MRE remission were in clinical remission at follow-up, whereas only 44.6% of those demonstrating MRE active inflammation achieved clinical remission. Children demonstrating MRE-active inflammation were more likely to have a change in medication (44.6% vs 8.3%) and more likely to undergo surgery (18.5% vs 2.8%)., Conclusions: MRE remission is associated with clinical remission at follow-up at least 1 year after MRE. MRE remission was associated with fewer medication changes and fewer surgeries suggesting that, similar to endoscopic remission, MRE remission demonstrates improved outcome. Additional research is needed to confirm that MRE can be used as a surrogate for mucosal healing.

Objectives: Vitamin D is critical for skeletal health; hypovitaminosis D is common in pediatric inflammatory bowel disease (IBD), yet optimal repletion therapy is not well studied. We aimed to conduct a pilot trial comparing the efficacy of 2 vitamin D regimens of weekly dosing for the repletion of hypovitaminosis D in pediatric IBD., Methods: Subjects identified from our IBD clinic with 25-hydroxyvitamin D (25[OH]D) concentrations <30 ng/mL were randomized to 10,000 (n = 18) or 5000 (n = 14) IU of oral vitamin D3/10 kg body weight per week for 6 weeks. Serum 25(OH)D, Ca, and parathyroid hormone concentrations were measured at baseline, week 8, and week 12., Results: In the higher dosing group, serum 25(OH)D increased from 23.7 ± 8.5 ng/mL at baseline to 49.2 ± 13.6 ng/mL at 8 weeks; P < 0.001. In the lower dosing group, serum 25(OH)D increased from 24.0 ± 7.0 ng/mL at baseline to 41.5 ± 9.6 ng/mL at 8 weeks; P < 0.001. At 12 weeks, serum 25(OH)D concentrations were 35.1 ± 8.4 and 30.8 ± 4.2 ng/mL for the higher and lower dose regimens, respectively. Mean serum Ca and parathyroid hormone concentrations did not significantly change during the study. No patient exhibited hypercalcemia, and no serious adverse events occurred., Conclusions: Both treatment arms were safe and effective at normalizing vitamin D nutriture in pediatric IBD. Although significant repletion of 25(OH)D concentration was achieved in both dosing groups at 8 weeks, this effect was lost by the 12-week follow-up. Maintenance vitamin D therapy following initial repletion is likely required to maintain long-term normalized vitamin D status.

Objectives: Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD., Methods: WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay., Results: We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD., Conclusions: Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.

Background: Vitamin D deficiency and low bone mineral density (BMD) are complications of inflammatory bowel disease. Vitamin D deficiency is more prevalent among African Americans compared with whites. There are little data comparing differences in serum 25-hydroxyvitamin D (25OHD) concentrations and BMD between African American and white children with Crohn disease (CD)., Methods: We compared serum 25OHD concentrations of African American children with CD (n = 52) to white children with CD (n = 64) and healthy African American controls (n = 40). We also analyzed BMD using dual-energy x-ray absorptiometry results from our pediatric CD population., Results: African American children with CD had lower serum 25OHD concentrations (16.1 [95% confidence interval, CI 14.5-17.9] ng/mL) than whites with CD (22.3 [95% CI 20.2-24.6] ng/mL; P < 0.001). African Americans with CD and controls exhibited similar serum 25OHD concentration (16.1 [95% CI 14.5-17.9] vs 16.3 [95% CI 14.4-18.4] ng/mL; NS). African Americans with CD exhibited no difference in serum 25OHD concentration when controlling for seasonality, disease severity, and surgical history, although serum 25OHD concentration was significantly decreased in overweight children (body mass index ≥85%, P = 0.003). Multiple regression analysis demonstrated that obese African American girls with CD had the lowest serum 25OHD concentrations (9.6 [95% CI 6.8-13.5] ng/mL). BMD was comparable between African American and white children with CD (z score -0.4 ± 0.9 vs -0.7 ± 1.2; NS)., Conclusions: African American children with CD are more likely to have vitamin D deficiency compared with white children with CD, but have similar BMD. CD disease severity and history of surgery do not affect serum 25OHD concentrations among African American children with CD. African American children have low serum 25OHD concentrations, independent of CD, compared with white children. Future research should focus on how race affects vitamin D status and BMD in children with CD.

Background and Objective: Colonic dysbiosis contributes to the development of colonic inflammation in ulcerative colitis (UC). Fecal microbial transplantation (FMT) is being proposed as a novel treatment for UC because it can eliminate dysbiosis; however, no prospective data exist. We initiated a pilot study to evaluate feasibility and safety of FMT in children with UC., Methods: Ten children, 7 to 21 years of age, with mild-to-moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission., Results: No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self-limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline., Conclusions: Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self-limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC.

Background and Objective: Children with Crohn disease (CD) often undergo cross-sectional imaging during clinical evaluation. Magnetic resonance enterography (MRE) is becoming the preferred radiologic assessment due to the lack of radiation exposure; however, there are few data in children with CD comparing MRE with objective disease measures. The aim of the present study was to compare MRE with endoscopy, histopathology, and laboratory evaluation in children with CD., Methods: We performed an institutional review board-approved query of our prospective CD MRE database, which includes data in children with CD undergoing MRE since 2008., Results: A total of 147 MRE studies were performed in 119 different children with symptomatic CD. Of those, 53 (39.6%) MRE studies were performed at diagnosis to evaluate small bowel disease burden. A total of 117 (79.6%) MRE studies displayed active and/or chronic disease, whereas 30 (20.4%) MRE studies were normal. When compared with normal MRE studies, active inflammation on MRE was associated with a higher mean C-reactive protein (3.6 vs 1.1, P < 0.001), higher erythrocyte sedimentation rate (36 vs 22, P = 0.0.31), higher platelet value (439 vs 352, P = 0.033), and lower albumin (3.4 vs 3.7, P = 0.049). Comparison between MRE and endoscopy demonstrated excellent agreement when ulcers were present, and moderate agreement with histopathology., Conclusions: Active inflammation on MRE is associated with higher C-reactive protein, erythrocyte sedimentation rate, platelets, and lower albumin in children with CD. MRE displays excellent agreement with endoscopic disease described by ulcers but poor agreement with mild mucosal disease described by erythema and friability. The present study adds to a growing body of evidence that MRE provides excellent assessment of inflammation and measures disease activity in CD.

Objectives: Although it is known that extraintestinal manifestations (EIMs) commonly occur in pediatric inflammatory bowel disease (IBD), little research has examined rates of EIMs and their relation to other disease-related factors in this population. The purpose of this study was to determine the rates of EIMs in pediatric IBD and examine correlations with age, sex, diagnosis, disease severity, and distribution., Patients and Methods: Data were prospectively collected as part of the Pediatric IBD Collaborative Research Group Registry, an observational database enrolling newly diagnosed IBD patients <16 years old since 2002. Rates of EIM (occurring anytime during the period of enrollment) and the aforementioned variables (at baseline) were examined. Patients with indeterminate colitis were excluded from the analysis given the relatively small number of patients., Results: One thousand nine patients were enrolled (mean age 11.6 +/- 3.1 years, 57.5% boys, mean follow-up 26.2 +/- 18.2 months). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs. Eighty-seven percent of EIM occurred within the first year. Increased disease severity at baseline (mild vs moderate/severe) was associated with the occurrence of any EIM (P < 0.001), arthralgia (P = 0.024), aphthous stomatitis (P = 0.001), and erythema nodosum (P = 0.009) for both Crohn disease (CD) and ulcerative colitis (UC) during the period of follow-up. Statistically significant differences in the rates of EIMs between CD and UC were seen for aphthous stomatitis, erythema nodosum, and sclerosing cholangitis., Conclusions: EIMs as defined in this study occur in approximately one quarter of pediatric patients with IBD. Disease type and disease severity were commonly associated with the occurrence of EIMs.

Objective: Post hoc analyses evaluated the effect of infliximab upon concurrent perianal Crohn disease (CD) in a subpopulation of 31 patients from REACH, a randomized trial of 112 children with moderately to severely active luminal CD., Materials and Methods: The Pediatric Crohn Disease Activity Index perirectal subscore was used to assess perianal symptom activity and therapeutic response. Patients with no symptoms or asymptomatic tags received a score of 0; those with "1-2 indolent fistula, scant drainage, no tenderness" received a score of 5; and those with "active fistula, drainage, tenderness or abscess" received a score of 10. Initial perirectal subscores of 10 or 5 decreasing to 0 were considered complete response. Subscores of 10 decreasing to 5 were considered partial response. All patients were followed for efficacy and safety through week 54., Results: Twenty-two patients with baseline perianal disease were randomized at week 10 following a 3-dose infliximab induction regimen. At week 2, 40.9% (9/22) of patients with signs and symptoms of perianal disease at baseline attained response (4 partial and 5 complete). At week 54, 72.7% (16/22) of patients with signs and symptoms of perianal disease attained response (1 partial and 15 complete). Nine patients developed perianal signs and symptoms during treatment; 7 had complete response and 2 had no response at week 54. The incidence of adverse events for patients with perianal symptoms at baseline and for those in the overall REACH population was similar (95.7% vs 94.6%)., Conclusions: Infliximab rapidly reduced concurrent perianal disease signs and symptoms in this REACH cohort.

Objectives: We analyzed growth outcomes in children newly diagnosed with Crohn disease and determined whether growth abnormalities persist despite current therapies., Patients and Methods: Clinical and growth data were prospectively obtained on an inception cohort younger than 16 years old at diagnosis and Tanner I to III during the study., Results: In all, 176 children (mean age 10.1 years; 65% male) with mild (33%) or moderate/severe (67%) disease at diagnosis were studied. Disease activity at 1 year was inactive/mild (89%) or moderate/severe (11%). First-year treatments included immunomodulators (60%), corticosteroids (77%), 5-aminosalicylates (61%), infliximab (15%), and enteral nutrition (10%). By 2 years, 86% had received immunomodulators and 36% infliximab. Mean height z scores at diagnosis, 1 year, and 2 years were -0.49 +/- 1.2 standard deviations (SDs), -0.50 +/- 1.2, and -0.46 +/- 1.1, respectively. Of the subjects, 10%, 8%, and 6.5% had height z scores less than -2 SD at diagnosis, 1 year, and 2 years. A height velocity z score less than -1SD was seen in 45% of subjects at 1 year and 38% at 2 years. The mean height velocity z score, however, increased between 1 and 2 years from -0.71 to 0.26 (P < 0.03). Corticosteroid use greater than 6 months in the first year was associated with abnormal height velocity at 1 year (adjusted odds ratio = 4.5; 95% confidence interval [CI] = 2.2-9.6). No statistically significant effect on height velocity z scores was noted when comparing those receiving or not receiving infliximab., Conclusions: Growth delay persists in many children with CD following diagnosis, despite improved disease activity and the frequent use of immunomodulators and biologics. Additional strategies to improve growth outcomes require development.

Background: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC., Methods: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohn's and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and "backwash ileitis" in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC., Results: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities., Conclusions: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms "ulcerative colitis," "Crohn disease," and "indeterminate colitis." The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Objectives: This study evaluated the safety, tolerability, and efficacy of natalizumab, a humanized monoclonal immunoglobulin-G4 antibody to [alpha]4 integrin, in adolescent patients with moderately to severely active Crohn disease (CD)., Patients and Methods: In a single-arm study, 38 adolescent patients (ages 12-17 y) with active CD (Pediatric Crohn Disease Activity Index [PCDAI] >30) received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks. The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs. Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed. Efficacy outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of C-reactive protein and serum albumin., Results: Thirty-one patients (82%) received 3 natalizumab infusions. The most common adverse events were headache (26%), pyrexia (21%) and CD exacerbation (24%). Clinical response (> or =15-point decrease from baseline PCDAI) and remission (PCDAI < or =10) rates were greatest at week 10 (55% and 29%, respectively). Three patients (8%) tested positive for anti-natalizumab antibodies. The peak level (61.0 and 66.3 microg/mL) and half-life (92.3 and 96.3 h) of natalizumab were comparable after the first and third infusions. Mean [alpha]4 integrin receptor saturation was 93% at 2 hours and <40% at 4 weeks after the first and third infusions. Increase from baseline in circulating lymphocytes ranged from 106% to 122% at 2 weeks and 45% to 65% at 4 weeks after each infusion., Conclusion: Natalizumab (3 mg/kg) was well tolerated in these adolescent patients with active CD, with a safety and efficacy profile similar to that of adult natalizumab-treated CD patients. Future studies should evaluate long-term safety and efficacy.

Background and Objectives: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions., Methods: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol., Results: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease., Conclusions: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Objectives: To determine the incidence, etiology and outcome of pancreatitis at a regional children's hospital., Methods: Chart review of all patients with pancreatitis seen during a 6 year period at the Children's Hospital of Wisconsin. The diagnosis of pancreatitis required either a serum amylase or lipase >3 times normal or radiographic evidence of pancreatitis., Results: Two hundred fourteen episodes of pancreatitis in 180 patients were documented. The most common etiologies were systemic disease (14%), trauma (14%), drug induced (12%), biliary tract disease (12%), infectious (8%), and idiopathic (8%), which made up 68% of the total cases. Eleven patients died, all from underlying systemic illnesses. The serum amylase and lipase were elevated in 82% and 83% of patients respectively., Conclusions: Pancreatitis is more common in children than previously thought. Upon careful assessment fewer cases were found to be idiopathic than in previous series. The outcome of pancreatitis depends on co-morbid conditions.

Dermatologic extraintestinal manifestations of Crohn disease may be refractory to treatment with corticosteroids and immunomodulators. The authors describe four children with Crohn disease with dermatologic manifestations: pyoderma gangrenosum, orofacial involvement, erythema nodosum, and idiopathic lymphedema. These dermatologic conditions were unresponsive to conventional therapy but had rapid and sustained response to the anti-TNF-alpha antibody infliximab. No adverse reactions occurred. Infliximab should be considered for treating the extraintestinal dermatologic manifestations of Crohn disease in children.