Publications by authors named "Anne M Griffiths"

185 Publications

Assessing disease activity using the pediatric Crohn's disease activity index: Can we use subjective or objective parameters alone?

World J Gastroenterol 2021 Aug;27(30):5100-5111

Division of Pediatrics, IWK Health, Halifax, NS B3K6R8, Canada.

Background: The pediatric Crohn's disease activity index (PCDAI) is used as a standard tool to assess disease activity in clinical trials for pediatric Crohn's disease.

Aim: To examine which items on the PCDAI drive assessment of disease activity, and how subgroups of subjective and objective items reflect change in disease state over time.

Methods: Selective raw data from three prospectively collected datasets were combined, including 703 children with full PCDAI data at baseline, at 3-mo (Q1, = 670), and 1-year (Q4, = 474). Change in individual PCDAI scores from baseline to Q1 and to Q4 were examined using the non-weighted PCDAI.

Results: Abdominal pain, well-being, weight, and stooling had the highest change scores over time. Objective indicators including albumin, abdominal exam, and height velocity followed. Change scores for well-being and abdominal exam did not explain significant variance at Q1 but were significant predictors at Q4 ( < 0.001 and < 0.05). Subjective and objective subgroups of items predicted less variance (18% and 22%) on total PCDAI scores at Q1 and Q4 compared to the full PCDAI, or a composite scale (both 32%) containing significant predictors.

Conclusion: Although subjective items on the PCDAI change the most over time, the full PCDAI or a smaller composite of items including a combination of subjective and objective components classifies disease activity better than a subgroup of either subjective or objective items alone. Reliance on subjective or objective items as stand-alone proxies for disease activity measurement could result in misclassification of disease state.
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http://dx.doi.org/10.3748/wjg.v27.i30.5100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384732PMC
August 2021

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

Am J Hum Genet 2021 09 26;108(9):1765-1779. Epub 2021 Aug 26.

Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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http://dx.doi.org/10.1016/j.ajhg.2021.07.013DOI Listing
September 2021

Early Change in Fecal Calprotectin Predicts One-Year Outcome in Children Newly Diagnosed with Ulcerative Colitis.

J Pediatr Gastroenterol Nutr 2021 Aug 24. Epub 2021 Aug 24.

Division of Pediatric Gastroenterology, Dept of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA Division of Gastroenterology, Brendan Gastroenterology & Hepatology & Nutrition, Nationwide Children's Hospital, Columbus, OH, USA Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada Division of Pediatric Gastroenterology, Nutrition & Liver Diseases, Hasbro Children's Hospital, and the Alpert School of Medicine at Brown University. Providence, RI, USA Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of East Ontario, Ottawa, ON, Canada Division of Pediatric Gastroenterology, Cohen Children's Medical Center of New York, New Hyde Park, NY, USA Pediatric Gastroenterology and Nutrition, Goryeb Children's Hospital-Atlantic Health, Morristown, NJ, USA Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.

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 outcome 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-TNF therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (OR 0.95, 95% CI 0.90 - 1.00) 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 three-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 new diagnosis of UC.
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http://dx.doi.org/10.1097/MPG.0000000000003291DOI Listing
August 2021

Prospective Evaluation of Endoscopic and Histologic Indices in Pediatric Ulcerative Colitis Using Centralized Review.

Am J Gastroenterol 2021 Aug 13. Epub 2021 Aug 13.

SickKids Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.

Introduction: We aimed to evaluate the reliability and validity of the Ulcerative Colitis (UC) Endoscopic Index of Severity (UCEIS) and Mayo Endoscopy Score (MES) and to validate the Robarts Histopathology Index (RHI) and Nancy Index (NI) in pediatric UC. We examined rectosigmoid and pancolonic versions of each instrument.

Methods: Single-center cross-sectional study of 60 prospectively enrolled participants. Through central endoscopy review, 4 pediatric gastroenterologists assigned rectosigmoid and pancolonic (mean of 5 colonic segments) UCEIS and MES scores. Two blinded pathologists assigned rectosigmoid and pancolonic RHI and NI scores. We assessed reliability with intraclass correlation coefficients and weighted kappa statistics and explored construct validity with correlations, boxplots, and receiver operator characteristic curves.

Results: The UCEIS and MES displayed almost perfect intra-rater and inter-rater reliability (intraclass correlation coefficient and weighted kappa ≥0.85), moderate-to-strong correlation with histologic/clinical activity and fecal calprotectin (FC), and very strong correlation with global endoscopic severity (r > 0.9). Rectosigmoid UCEIS and MES scores of 0 were highly specific (≥95%) for endoscopic and histologic remission throughout the colon. Pancolonic endoscopy scores correlated more strongly with histologic activity, clinical activity, and systemic inflammatory markers and better discriminated between degrees of active disease. RHI and NI showed moderate-to-strong correlation (r = 0.5-0.83) with endoscopic/clinical activity and FC.

Discussion: Our findings support the reliability and construct validity of the UCEIS and MES and the construct validity of the RHI and NI in pediatric UC. Normal rectosigmoid findings predicted pancolonic healing, but, given active disease, pancolonic endoscopic assessment more accurately captured global disease burden.
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http://dx.doi.org/10.14309/ajg.0000000000001400DOI Listing
August 2021

Impact of Drug Approval Pathways for Paediatric Inflammatory Bowel Disease.

J Crohns Colitis 2021 Aug 11. Epub 2021 Aug 11.

Alimentiv Inc. (formerly Robarts Clinical Trials, Inc.), London, ON, Canada.

Background And Aims: Timely access to approved medications is a priority in paediatric inflammatory bowel disease (IBD). To date, the timing of drug studies in paediatric IBD has been suboptimal with most studies conducted long after approval has been granted for adult IBD. This delay in approval leads to extensive off-label prescribing of medications in children, often without clear guidance on optimal dosing. The European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have implemented drug development frameworks in an attempt to address these challenges. However, access to information on these regulatory pathways in paediatric IBD is limited. We summarised the time from adult to paediatric approval of IBD therapies, outlining the regulatory approval pathway between the EMA and FDA, with the goal of identifying areas for improvement.

Methods: We reviewed publicly accessible data from the EMA and the FDA to identify therapeutic agents approved between 2005-2021 for paediatric IBD.

Results And Conclusion: Five drugs are currently approved for use in the paediatric IBD population, with long interval delays after adult approval. The impact of these drug development processes in paediatric IBD is awaited. Further consideration needs to be given to the age of enrollment along with novel, more efficient trial designs in an effort to improve access for paediatric IBD patients to newer therapies.
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http://dx.doi.org/10.1093/ecco-jcc/jjab140DOI Listing
August 2021

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

Gastroenterology 2021 Jul 20. Epub 2021 Jul 20.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

Inflammatory bowel disease increases the risk of venous thromboembolism in children: a population-based matched cohort study.

J Crohns Colitis 2021 Jun 27. Epub 2021 Jun 27.

SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background And Aims: Although venous thromboembolism (VTE) is a well-known complication of inflammatory bowel disease (IBD) in adults, limited data exist on the risk in children. We report the incidence of VTE among children with and without IBD.

Methods: We conducted a matched cohort study within a distributed network of population-based Canadian provincial health administrative databases. Children diagnosed with IBD <16 years were identified using validated algorithms from administrative data in Alberta, Manitoba, Nova Scotia, Ontario, and Québec and compared to age- and sex-matched children without IBD. Hospitalizations for VTE within five years of IBD diagnosis were identified. Generalized linear mixed-effects models were used to pool province-specific incidence rates and incidence rate ratios (IRR) with 95% confidence intervals (CI). Hazard ratios (HR) from Cox proportional hazards models were pooled with fixed-effects meta-analysis.

Results: The five-year incidence of VTE among 3593 children with IBD was 31.2 (95%CI 23.7-41.0) per 10,000 person-years (PY) compared to 0.8 (95%CI 0.4-1.7) per 10,000 PY among 16,289 children without IBD (unadjusted IRR 38.84, 95%CI 16.59-90.83; adjusted HR 22.91, 95%CI 11.50-45.63). VTE was less common in Crohn's disease than ulcerative colitis (unadjusted IRR 0.47, 95%CI 0.27-0.83; adjusted HR 0.52, 95%CI 0.29-0.94). Findings were similar for deep vein thrombosis (DVT) and pulmonary embolism (PE) when comparing children with and without IBD.

Conclusions: The risk of VTE is much higher in children with IBD than controls without IBD. While the absolute risk is low, we found a higher incidence rate than previously described in the pediatric literature.
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http://dx.doi.org/10.1093/ecco-jcc/jjab113DOI Listing
June 2021

Imputing missing patient-level data and propensity score matching in cost-effectiveness analysis in Crohn's disease.

Expert Rev Pharmacoecon Outcomes Res 2021 Jun 17:1-10. Epub 2021 Jun 17.

Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada.

: The effect of imputing missing data followed by propensity score analysis on the incremental cost-effectiveness ratio (ICER) in a cost-effectiveness analysis is unknown. The objective was to compare alternative approaches in grouping data following imputation and prior to calculating propensity scores for use in economic evaluation.: Patient-level data from an observational study of 573 children with Crohn's disease were used in a microsimulation model to determine the incremental cost of early anti-tumor necrosis factor-α treatment compared to standard care per remission week gained. Multiple imputation of a missing covariate followed by propensity score matching to create comparator groups was approached in two ways. The Within approach calculated propensity scores on each imputed dataset separately, while the Across method averaged propensity scores to create one matched population resulting in multiple sets of health state transition probabilities.: The incremental cost per remission week gained ranged from CAD$2,236 to CAD$12,464 (mean CAD$4,266) with Within datasets and was CAD$4,679 per remission week gained with the Across dataset.: Imputation of missing patient-level data and propensity score analysis increases methodological uncertainty in cost-effectiveness analysis. The present study indicated that the Across approach may be less cumbersome, and slightly reduce bias and variance.
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http://dx.doi.org/10.1080/14737167.2021.1936501DOI Listing
June 2021

Intestinal Ultrasound in Pediatric Inflammatory Bowel Disease: Promising, but Work in Progress.

Inflamm Bowel Dis 2021 May 20. Epub 2021 May 20.

Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, The Netherlands.

Intestinal ultrasound (IUS) is increasingly used and promulgated as a noninvasive monitoring tool for children with inflammatory bowel disease because other diagnostic modalities such as colonoscopy and magnetic resonance imaging cause significant stress in the pediatric population. The most important parameters of inflammation that can be assessed using IUS are bowel wall thickness and hyperemia of the bowel wall. Research has shown that IUS has the potential to be a valuable additional point-of-care tool to guide treatment choice and to monitor and predict treatment response, although evidence of its accuracy and value in clinical practice is still limited. This review gives an update and overview of the current evidence on the use and accuracy of IUS in children with inflammatory bowel disease.
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http://dx.doi.org/10.1093/ibd/izab125DOI Listing
May 2021

An Assessment of the Validity and Reliability of the Pediatric Child Health Utility 9D in Children with Inflammatory Bowel Disease.

Children (Basel) 2021 Apr 27;8(5). Epub 2021 Apr 27.

Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.

Health utilities relevant to children are lacking, compromising health funding and policy decisions for children. The Child Health Utility 9D (CHU9D) is a recently developed preference-based health utility instrument designed for use in children. The objective was to examine the validity of the CHU9D in a cohort of 285 Canadian children aged 6.5 to 18 years of age with Crohn's disease (CD) and ulcerative colitis (UC), (collectively inflammatory bowel disease (IBD)). The correlation and agreement between paired CHU9D and Health Utility Index (HUI) assessments were determined with Spearman coefficients and Bland-Altman levels of agreement. Total and domain utilities were calculated for the CHU9D using Australian adult and youth tariffs. Algorithms for HUI2 and HUI3 were used. Domain correlations were determined between domains with expected overlap between instruments. In CD and in UC, correlations between CHU9D, HUI2, and HUI3 utilities ranged between 0.62 to 0.67 and 0.67 to 0.69, respectively ( < 0.05). CHU9D utilities were lower using youth tariffs compared to adult tariffs. A large range in health utilities suggested a heterogeneous quality of life. The CHU9D is a good option for preference-based utility measurement in pediatric IBD. Additional research is required to derive pediatric tariffs to conduct economic evaluation in children.
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http://dx.doi.org/10.3390/children8050343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146594PMC
April 2021

One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study.

Aliment Pharmacol Ther 2021 06 28;53(12):1300-1308. Epub 2021 Apr 28.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics and IBD Centre, SickKids Hospital, University of Toronto, Toronto, ON, Canada.

Background: The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking.

Aim: To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics.

Methods: Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 μg/g if not re-colonoscoped.

Results: At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (μg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy.

Conclusion: Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.
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http://dx.doi.org/10.1111/apt.16388DOI Listing
June 2021

A Systematic Review of Monogenic Inflammatory Bowel Disease.

Clin Gastroenterol Hepatol 2021 Mar 18. Epub 2021 Mar 18.

SickKids Inflammatory Bowel Disease Centre, Hospital for Sick Children, Toronto, Canada; Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada; Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, Canada. Electronic address:

Background & Aims: Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). Here, we systematically review the literature to determine the clinical features, genetic profile, and previously used treatment strategies in monogenic IBD.

Methods: A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. A total of 750 individual monogenic IBD cases were identified from 303 eligible articles.

Results: The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA, and TTC7A. In total, 63.4% of patients developed IBD before 6 years of age, 17.4% developed IBD between ages 10 and 17.9 years, and 10.9% developed IBD after age 18. There was a substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extraintestinal comorbidity (EIC) before IBD onset, but 76.0% developed at least 1 EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation were performed in 27.1%, 32.9%, and 23.1% of patients, respectively.

Conclusions: Monogenic IBD cases, although rare, have varied extraintestinal comorbidities and limited treatment options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.
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http://dx.doi.org/10.1016/j.cgh.2021.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448782PMC
March 2021

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease.

Sci Rep 2021 Mar 15;11(1):5945. Epub 2021 Mar 15.

SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.
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http://dx.doi.org/10.1038/s41598-021-85399-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960730PMC
March 2021

Agreement on Symptoms Between Children With Ulcerative Colitis and Their Caregivers: Towards Developing the TUMMY-UC.

J Pediatr Gastroenterol Nutr 2021 Aug;73(2):e35-e38

Shaare Zedek Medical Center, Jerusalem, Israel.

Abstract: As part of the development of the TUMMY-UC, a patient-reported outcome (PRO) measure for pediatric ulcerative colitis (UC), we aimed to explore agreement on UC symptoms between children and their caregivers. We conducted 44 interviews with children ages 8-12 years, who completed the PRO version of the TUMMY-UC, and their caregivers, who completed the observer-reported outcome (obsRO) version. There was excellent agreement between the total TUMMY-UC PRO and obsRO scores (intra-class correlation coefficient = 0.92 [95% confidence interval 0.74-0.98]). The obsRO scores were always within the same disease-activity category as the corresponding PRO score (ie, remission, mild and moderate-severe disease). There was a strong correlation of the TUMMY-UC PRO and obsRO scores with physician global assessment of disease activity (r = 0.94 and r = 0.90, respectively, P < 0.001) and the pediatric UC activity index (r = 0.95 and r = 0.96; P < 0.001). These data support conceptual equivalence between the PRO and obsRO TUMMY-UC versions, and provide support for their incorporation into one score.
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http://dx.doi.org/10.1097/MPG.0000000000003120DOI Listing
August 2021

Utilization of Whole Exome Sequencing Data to Identify Clinically Relevant Pharmacogenomic Variants in Pediatric Inflammatory Bowel Disease.

Clin Transl Gastroenterol 2020 12;11(12):e00263

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.

Introduction: We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing data set derived from a cohort of more than 1,000 patients with inflammatory bowel disease (IBD).

Methods: Pediatric patients diagnosed with IBD underwent whole exome sequencing. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care.

Results: We identified actionable pharmacogenomic variants in 63% of patients. Importantly, 5% of patients with IBD were at risk for serious adverse effects from anesthesia and 3% were at increased risk for thrombosis.

Discussion: We identified exonic variants in most of our patients with IBD that directly impact clinical care.
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http://dx.doi.org/10.14309/ctg.0000000000000263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710220PMC
December 2020

STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.

Gastroenterology 2021 04 19;160(5):1570-1583. Epub 2021 Feb 19.

Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt/Main, Germany. Electronic address:

Background: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.

Methods: Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.

Results: In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.

Conclusions: STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
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http://dx.doi.org/10.1053/j.gastro.2020.12.031DOI Listing
April 2021

Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

J Pediatr Gastroenterol Nutr 2021 03;72(3):456-473

Child Life and Health, University of Edinburgh, Department of Paediatric Gastroenterology, The Royal Hospital for Sick Children, Edinburgh.

Background: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups.

Methods: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists).

Results: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries.

Conclusions: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
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http://dx.doi.org/10.1097/MPG.0000000000003017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221730PMC
March 2021

Accurate Classification of Pediatric Colonic Inflammatory Bowel Disease Subtype Using a Random Forest Machine Learning Classifier.

J Pediatr Gastroenterol Nutr 2021 02;72(2):262-269

Division of Gastroenterology, Hepatology and Nutrition, SickKids Hospital, Department of Paediatrics, University of Toronto.

Background: The pediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling of colonic IBD, but labels are exclusively based on features atypical for ulcerative colitis (UC).

Aim: The aim of the study was to develop an algorithm and identify features that discriminate between pediatric UC and colonic Crohn disease (CD).

Methods: Baseline clinical, endoscopic, radiologic, and histologic data, including the PIBD class features in 74 colonic IBD (56: UC, 18: colonic CD) patients were collected. The PIBD class features and additional features common to UC were used to perform initial clustering, using similarity network fusion (SNF). We trained a Random Forest (RF) classifier on the full dataset and used a leave-one-out approach to evaluate model accuracy. The top-features were used to build a new classifier, which we tested on 15 previously unused patients. We then performed clustering with SNF on the top RF features and assessed ability to discriminate between UC and colonic-CD independent of a supervised model.

Results: The initial SNF clustering with 58 patients demonstrated 2 groups: group 1 (n = 39, 90% UC) and group 2 (n = 19, 68% colonic-CD). Our RF classifier correctly labelled 97% of the 58 patients based on leave-one-out cross validation and identified the 7 most important features (3 histological and 4 endoscopic) to clinically distinguish these groups. We trained a new RF classifier with the top 7 features and found 100% accuracy in a set of 15 held-out patients. Finally, post hoc clustering with these 7 features revealed 2 groups of patients: group 1 (n = 55, 98% UC) and group 2 (n = 18, 94% colonic-CD).

Conclusions: A combination of supervised and unsupervised analyses identified a short list of features, which consistently distinguish UC from colonic CD. Future directions include validation in other populations.
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http://dx.doi.org/10.1097/MPG.0000000000002956DOI Listing
February 2021

Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

Gastroenterology 2021 01 23;160(1):403-436.e26. Epub 2020 Sep 23.

IBD Centre, SickKids Hospital, University of Toronto, Toronto, Canada. Electronic address:

Background & Aims: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management.

Methods: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence.

Results: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density.

Conclusions: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.
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http://dx.doi.org/10.1053/j.gastro.2020.07.065DOI Listing
January 2021

Association of Early Postinduction Adalimumab Exposure With Subsequent Clinical and Biomarker Remission in Children with Crohn's Disease.

Inflamm Bowel Dis 2021 06;27(7):1079-1087

Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Background: Data on the association between early postinduction serum adalimumab (ADA) trough levels (TLs) and objective outcomes are scarce. The aim of this study was to investigate whether early ADA TLs at weeks 4 and 8 are associated with clinical and biomarker remission at week 24 in pediatric Crohn's disease (CD).

Methods: Adalimumab TLs at weeks 4 and 8 were prospectively measured in anti-TNF-naïve children initiating treatment with ADA monotherapy for luminal inflammatory CD. The primary outcome was combined clinical and biomarker remission at week 24, defined as achieving steroid-free clinical remission (Pediatric CD activity index <10) and biomarker remission (fecal calprotectin <250 µg/g and CRP <5 µg/mL).

Results: Among 65 patients, 39 (60%) achieved combined clinical/biomarker remission at week 24 without dose escalation. Adalimumab TLs at both weeks 4 and 8 were significantly higher in remitters vs nonremitters at week 24 (P < 0.001 and P = 0.002, respectively). Adalimumab levels at weeks 4 and 8 were good predictors of combined clinical/biomarker remission at week 24 (area under the curve, 0.887, 95% CI, 0.798-0.942; and area under the curve, 0.761, 95% CI, 0.632-0.899, respectively). The best ADA TL cutoffs at weeks 4 and 8 for predicting clinical/biomarker remission at week 24 were 22.5 µg/mL (80% sensitivity, 90% specificity, positive likelihood ratio [LR+] 8.0, negative LR [LR-] 0.2) and 12.5 µg/mL (94% sensitivity, 60% specificity, LR+ 2.4, LR- 0.1), respectively. Higher induction doses per m2 correlated positively with TLs at weeks 4 and 8.

Conclusion: Greater early ADA exposure is associated with superior clinical/biomarker outcomes at week 24.
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http://dx.doi.org/10.1093/ibd/izaa247DOI Listing
June 2021

Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease.

J Crohns Colitis 2021 Mar;15(3):419-431

SickKids Hospital, University of Toronto, Toronto, ON, Canada.

Background: Paediatric data on the association between diagnostic delay and inflammatory bowel disease [IBD] complications are lacking. We aimed to determine the effect of diagnostic delay on stricturing/fistulising complications, surgery, and growth impairment in a large paediatric cohort, and to identify predictors of diagnostic delay.

Methods: We conducted a national, prospective, multicentre IBD inception cohort study including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis >75th percentile. Multivariable proportional hazards [PH] regression was used to examine the association between diagnostic delay and stricturing/fistulising complications and surgery, and multivariable linear regression to examine the association between diagnostic delay and growth. Predictors of diagnostic delay were identified using Cox PH regression.

Results: Overall (64% Crohn's disease [CD]; 36% ulcerative colitis/IBD unclassified [UC/IBD-U]; 57% male]), median time to diagnosis was 4.2 (interquartile range [IQR] 2.0-9.2) months. For the overall cohort, diagnostic delay was >9.2 months; in CD, >10.8 months and in UC/IBD-U, >6.6 months. In CD, diagnostic delay was associated with a 2.5-fold higher rate of strictures/internal fistulae (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.41-4.56). Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.013 standard deviations [95% CI 0.005-0.021]. Associations persisted after adjusting for disease location and therapy. No independent association was observed between diagnostic delay and surgery in CD or UC/IBD-U. Diagnostic delay was more common in CD, particularly small bowel CD. Abdominal pain, including isolated abdominal pain in CD, was associated with diagnostic delay.

Conclusions: Diagnostic delay represents a risk factor for stricturing/internal fistulising complications and growth impairment in paediatric CD.

Podcast: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944510PMC
March 2021

Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.

Gastroenterology 2020 12 10;159(6):2092-2100.e5. Epub 2020 Aug 10.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD.

Methods: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR.

Results: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029).

Conclusions: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.
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http://dx.doi.org/10.1053/j.gastro.2020.08.005DOI Listing
December 2020

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

J Crohns Colitis 2020 Aug 8. Epub 2020 Aug 8.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background And Aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures.

Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied.

Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)).

Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904088PMC
August 2020

Gut microbiome in primary sclerosing cholangitis: A review.

World J Gastroenterol 2020 Jun;26(21):2768-2780

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease (IBD) and the "gut-liver" axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including , and , among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including bile acids (BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.
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http://dx.doi.org/10.3748/wjg.v26.i21.2768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284173PMC
June 2020

Thiopurine Monotherapy in Paediatric Inflammatory Bowel Disease: 20 Years After Markowitz.

J Pediatr Gastroenterol Nutr 2020 06;70(6):758-759

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

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http://dx.doi.org/10.1097/MPG.0000000000002697DOI Listing
June 2020

Body Composition Using Air Displacement Plethysmography in Children With Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2020 07;71(1):52-58

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Medical Centre, Cincinnati, OH.

Objective: The aim of the study was to assess the body composition of children with inflammatory bowel disease (IBD) and to study the accuracy of clinically available tools in predicting excess body fatness. We aimed at also exploring the influence of adiposity on pharmacokinetics during early Infliximab exposure.

Methods: Prospective cohort study in 5- to 17-year-old children with IBD initiating Infliximab therapy. Patient demographic, phenotypic, and laboratory data at the time of Infliximab initiation were recorded. Body composition was assessed using air displacement plethysmography (ADP). fat mass index (FMI = fat mass [kg]/(height [m])) was calculated to determine excess adiposity (defined as FMI ≥75th centile). Anthropometrics (weight, height, mid upper arm circumference [MUAC] and triceps skin fold thickness [TSF]) were obtained and MUAC and TSF measurements were used to calculate arm fat area (AFA) and arm muscle area z-scores. Statistical analysis was applied as appropriate.

Results: Fifty-three (68% male; 55% Crohn disease [CD], 45% ulcerative colitis [UC], median [IQR] age 15 [13-16] years) children with IBD were included. Twenty-four percentage of children with IBD (21% CD, 29% UC) had excess adiposity. Four children (31%) with FMI ≥75th centile were not identified by body mass index (BMI) alone (kappa of 0.60), and 2 children (15%) were not identified by AFA z-score alone. The intra- and interobserver reliability of MUAC and TSFT measurements was excellent. There was no difference in Infliximab trough levels at the end of induction between those with FMI less than or ≥75th centile.

Conclusions: Excess adiposity affects approximately 1 in 4 young patients with IBD and can be missed by routine obesity screening. Our exploratory study did not raise concerns of underexposure to infliximab in those children with excess adiposity during early drug exposure.
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http://dx.doi.org/10.1097/MPG.0000000000002683DOI Listing
July 2020

Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center.

Gastroenterology 2020 06 19;158(8):2208-2220. Epub 2020 Feb 19.

SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

Methods: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0-18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses.

Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6-18 years. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation.

Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.
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http://dx.doi.org/10.1053/j.gastro.2020.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283012PMC
June 2020

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

Nat Commun 2020 02 21;11(1):995. Epub 2020 Feb 21.

NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-14275-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035382PMC
February 2020

Differentiation of Colonic Inflammatory Bowel Disease: Re-examination of Paediatric Inflammatory Bowel Disease Classes Algorithm With Resected Colon As the Criterion Standard.

J Pediatr Gastroenterol Nutr 2020 02;70(2):218-224

Division of Gastroenterology, Hepatology and Nutrition.

Objectives: Differentiation of Crohn disease (CD) from ulcerative colitis (UC) is challenging when inflammation is predominantly colonic. The paediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling, but used physician-assigned diagnosis as the criterion standard. We aimed to reassess the PIBD classes using pathology of subsequently resected colon as the criterion standard.

Method: Single-centre study of patients diagnosed with colonic IBD between 2002 and 2017 and subsequently treated with colectomy. Baseline pretreatment data were reviewed and the PIBD classes algorithm was independently applied by 2 reviewers to assign a label of UC/IBD-unclassified (IBD-U)/colonic-CD. Concordance between the algorithm-based, precolectomy clinical, and pathologic examination of resected colon diagnosis were assessed. Changes in diagnosis during postcolectomy follow-up were recorded.

Results: Sixty-two children underwent colectomy for medically refractory colonic IBD. Diagnosis based on pathologic review of resected colon CD:4;UC:56;IBDU:2. The clinical, PIBD classes algorithm, and colectomy diagnoses were concordant in 51 of 62 patients (81%, Fleiss kappa 0.48). Precolectomy clinical diagnosis was concordant with colectomy diagnosis in 58 of 62 patients (94%, weighted-kappa 0.65). The PIBD classes label was concordant with colectomy diagnosis in 51 of 62 patients (82%, weighted-kappa 0.38); resected colon pathology was typical of UC in 6 patients with PIBD classes label of IBD-U based on single class 2 feature and in 3 with PIBD classes label of CD based on single class 1 feature.

Conclusions: Concordance of PIBD classes algorithm diagnosis applied before colectomy with a diagnostic label based on pathologic examination of a subsequently resected colon is only fair. Caution is needed in stringent application of colonic CD and IBD-U labels based on presence of single feature.
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http://dx.doi.org/10.1097/MPG.0000000000002544DOI Listing
February 2020

Fecal Markers of Inflammation and Disease Activity in Pediatric Crohn Disease: Results from the ImageKids Study.

J Pediatr Gastroenterol Nutr 2020 05;70(5):580-585

Department of Gastroenterology, Sydney Children's Hospital Randwick, Sydney, Australia.

Background: Noninvasive and accurate methods to monitor inflammatory bowel disease are required. As a planned ancillary study of the prospective ImageKids cohort, we aimed to assess the performance of fecal calprotectin (FC) with comparison to 3 fecal inflammatory markers; S100A12 (FA12), tumor pyruvate kinase isoenzyme type M2 (FM2PK) and fecal osteoprotegerin (FOPG) as indicators of a number of disease characteristics.

Methods: The ImageKids study was a multicenter study designed to develop 2 magnetic resonance enterography-based measures for children with Crohn disease (6-18 years old). All patients underwent magnetic resonance enterography, a complete ileocolonoscopic evaluation and provided a fecal sample. Fecal samples were assay for FC, FA12, FM2PK, and FOPG by ELISA.

Results: One-hundred fifty-six children provided 190 fecal samples. Median (interquartile range) for fecal makers were FC, 602 (181-1185) μg/g; FA12, 21 (3-109) μg/g; FM2PK, 16 (2-20) U/mL; and FOPG, 125 (125-312) μg/g. All markers correlated with simple endoscopic severity index for Crohn disease and with other constructs of disease activity, but FC had the highest overall correlations. FA12, however, predicted mucosal healing with significantly higher specificity (87% vs 70%, P = 0.004) and equivalent sensitivity (91% vs 90%) compared to FC.

Conclusion: This study has confirmed that FC is useful, and overall best, marker to monitor mucosal inflammation in inflammatory bowel disease. FA12, however, appears to be a more suitable maker for prediction of mucosal healing in children.
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http://dx.doi.org/10.1097/MPG.0000000000002615DOI Listing
May 2020
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