Pre-Diagnosis Diet Predicts Response to Exclusive Enteral Nutrition and Correlates with Microbiome in Pediatric Crohn Disease.

Exclusive enteral nutrition (EEN) is effective in inducing remission in pediatric Crohn disease (CD). EEN alters the intestinal microbiome, but precise mechanisms are unknown. We hypothesized that pre-diagnosis diet establishes a baseline gut microbiome, which then mediates response to EEN. We analyzed prospectively recorded food frequency questionnaires (FFQs) for pre-diagnosis dietary patterns. Fecal microbiota were sequenced (16SrRNA) at baseline and through an 18-month follow-up period. Dietary patterns, Mediterranean diet adherence, and stool microbiota were associated with EEN treatment outcomes, disease flare, need for anti-tumor necrosis factor (TNF)-α therapy, and long-term clinical outcomes. Ninety-eight patients were included. Baseline disease severity and microbiota were associated with diet. Four dietary patterns were identified by FFQs; a "mature diet" high in fruits, vegetables, and fish was linked to increased baseline microbial diversity, which was associated with fewer disease flares (p < 0.05) and a trend towards a delayed need for anti-TNF therapy (p = 0.086). Baseline stool microbial taxa were increased (Blautia and Faecalibacterium) or decreased (Ruminococcus gnavus group) with the mature diet compared to other diets. Surprisingly, a "pre-packaged" dietary pattern (rich in processed foods) was associated with delayed flares in males (p < 0.05). Long-term pre-diagnosis diet was associated with outcomes of EEN therapy in pediatric CD; diet-microbiota and microbiota-outcome associations may mediate this relationship.

Outcomes Following Acute Severe Colitis at Initial Presentation: A Multi-centre, Prospective, Paediatric Cohort Study.

AIM: To assess contemporary outcomes in children with acute severe ulcerative colitis [ASUC] at initial presentation. METHODS: Between April 2014 and January 2019, children aged <17 years, with new onset ASUC (Paediatric Ulcerative Colitis Activity Index [PUCAI ≥65) were prospectively followed in a Canadian inception cohort study. 16S rRNA amplicon sequencing captured microbial composition of baseline faecal samples. Primary endpoint was corticosteroid-free clinical remission with intact colon at 1 year [PUCAI <10, no steroids ≥4 weeks]. RESULTS: Of 379 children with new onset UC/IBD-unclassified, 105 [28%] presented with ASUC (42% male; median [interquartile range; [IQR]) age 14 [11-16] years; extensive colitis in all). Compared with mild UC, gut microbiome of ASUC patients had lower α-diversity, decreased beneficial anaerobes, and increased aerobes; 54 [51%] children were steroid-refractory and given infliximab [87% intensified regimen]. Corticosteroid-free remission at 1 year was achieved by 62 [61%] ASUC cohort (by 34 [63%] steroid-refractory patients, all on biologics; by 28 [55%] steroid responders,13 [25%] on 5- aminosalicylic acid [5-ASA], 5 [10%] on thiopurines, 10 [20%] on biologics). By 1 year, 78 [74%] escalated to infliximab including 24 [47%] steroid-responders failed by 5-ASA and/or thiopurines. In multivariable analysis, clinical predictors for commencing infliximab included hypoalbuminaemia, greater PUCAI, higher age, and male sex. Over 18 months, repeat corticosteroid course[s] and repeat hospitalisation were less likely among steroid-refractory versus -responsive but -dependent patients (adjusted odds ratio [aOR] 0.71 [95% CI 0.57-0.89] and 0.54 [95% CI 0.45-0.66], respectively). CONCLUSION: The majority of children presenting with ASUC escalate therapy to biologics. Predictors of need for advanced therapy may guide selection of optimal maintenance therapy.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

ADALIMUMAB VERSUS INFLIXIMAB IN LUMINAL PEDIATRIC CROHN'S DISEASE: COMPARABLE OUTCOMES IN A PROSPECTIVE MULTICENTER COHORT STUDY.

BACKGROUND: This study compared real-world effectiveness between adalimumab (ADA) and infliximab (IFX) in children with Crohn's disease (CD). METHODS: Children enrolled into the prospective Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) National Inception Cohort between 2014 and 2020 who commenced ADA or IFX as first anti-tumor necrosis factor (antiTNF) agent for luminal CD were included. Multivariate logistic regression modelled the propensity of commencing ADA; propensity score matching was used to match IFX-treated children to ADA-treated children. The primary outcome at one year was steroid-free clinical remission (SFCR). Secondary outcomes at one year were I) combined SFCR and c-reactive protein (CRP) remission; II) treatment intensification; and III) antiTNF durability. Odds ratios (aOR) and hazard ratio (aHR) adjusted for concomitant immunomodulator use with 95% confidence interval (CI) are reported. RESULTS: In the propensity score matched cohort of 147 ADA-treated and 147 IFX-treated children, 92 (63%) ADA- and 87 (59%) IFX-treated children achieved SFCR at one year (aOR: 1.4, 95% CI 0.9-2.4); 75 of 140 (54%) ADA- and 85 of 144 (59%) IFX-treated children achieved combined SFCR and CRP remission (aOR: 1.0, 95% CI 0.6-1.6). ADA-treated children less frequently underwent treatment intensification (21 [14%]) compared to IFX-treated children (69 [47%]) (P<0.0001). Discontinuation of antiTNF occurred in 18 (12%) ADA-treated and 15 (10%) IFX-treated children (aHR: 1.2, 95% CI 0.6-2.2). CONCLUSION: Children with Crohn's disease achieved favourable outcomes at one year with either ADA or IFX as first antiTNF agents. Those receiving IFX did not have significantly superior outcomes compared to clinically similar children receiving ADA.

Prospective Validation of the Lémann Index in Children: A Report From the Multicentre Image Kids Study.

BACKGROUND: The Lémann Index [LI] and the recently updated LI are tools for measuring structural bowel damage in adults with Crohn's disease [CD] but have not been evaluated in children. We aimed to validate the updated LI in the prospective multicentre ImageKids study of paediatric CD. METHODS: We included children with CD undergoing magnetic resonance enterography [MRE], pelvic magnetic resonance imaging [MRI] and ileocolonoscopy. Half were followed for 18 months, when MRE was repeated. Serum was collected for fibrosis-related proteomic markers. The LI was calculated by central readers from the MRE, ileocolonoscopy, physical examination and surgical data. Reliability and construct validity were assessed at baseline, while responsiveness and test-retest reliability were explored longitudinally. RESULTS: In total, 240 children were included (mean age, 14.2 ± 2.5 years; median disease duration, 2.2 years [interquartile range, IQR 0.25-4.42]; median baseline LI, 4.23 [IQR 2.0-8.8]). The updated LI had excellent inter-observer reliability (interclass correlation coefficient [ICC] = 0.94, 95% confidence interval [CI] 0.92-0.95) but poor, although statistically significant, correlation with radiologist and gastroenterologist global assessments of damage and with serum proteomic levels of fibrotic markers [rho = 0.15-0.30, most p < 0.05]. The updated LI had low discriminative validity for detecting damage (area under the receiver operating characteristic curve [AUC-ROC] 0.69, 95% CI 0.62-0.75). In 116 repeated MREs, responsiveness was suboptimal for differentiating improved from unchanged disease [AUC-ROC 0.58, 95% CI 0.45-0.71]. Test-retest reliability was high among stable patients [ICC = 0.84, 95% CI 0.72-0.91]. CONCLUSION: Overall, the updated LI had insufficient psychometric performance for recommending its use in children. An age-specific index may be needed for children with shorter disease duration than typical adult cohorts.

Development and Validation of the TUMMY-UC: A Patient-Reported Outcome for Pediatric Ulcerative Colitis.

BACKGROUND & AIMS: The TUMMY-UC is a patient-reported outcome measure for pediatric ulcerative colitis (UC) with an observer-reported outcome version for children aged <8 years. It includes eight items selected by concept elicitation interviews. We aimed to finalize the TUMMY-UC by cognitive interviews (stage 2) and to evaluate the index for its psychometric properties (stage 3). METHODS: The TUMMY-UC items were first finalized during 129 cognitive debriefing interviews. Then, in a prospective, multicenter validation study, 84 children who underwent colonoscopy or provided stool for calprotectin completed the TUMMY-UC and various measures of disease activity. Assessments were repeated after 7 and 21 days for evaluating reliability and responsiveness. RESULTS: During stage 2, the items were formatted with identical structure to ensure conceptual equivalence and weighted based on ranking of importance. In stage 3, the TUMMY-UC total score had excellent reliability in repeated assessments (intraclass correlation coefficient, 0.90; 95% confidence interval, 0.84-0.94). It also had moderate to strong correlations with all constructs of disease activity: r = 0.70 with UC endoscopic index of severity, r = 0.63 with the IMPACT-III questionnaire, r = 0.43 with calprotectin, r = 0.80 with the Pediatric Ulcerative Colitis Activity Index, r = 0.75 with global assessment of disease activity, and r = 0.46 with C-reactive protein (all P < .015). The index had excellent discrimination of disease activity, with a score of <9 defining remission (area under the receiver operating characteristic curve, 0.95; 95% confidence interval, 0.93-0.99). The ΔTUMMY-UC showed high responsiveness and differentiated well between children who experienced changed from those with no change. CONCLUSIONS: The TUMMY-UC, constructed from patient-reported outcome and observer-reported outcome versions, is a reliable, valid and responsive index that can be now used in practice and clinical trials.

Development, Validation, and Evaluation of the Pediatric Inflammatory Crohn's Magnetic Resonance Enterography Index From the ImageKids Study.

BACKGROUND & AIMS: Cross-sectional imaging is important in the assessment of transmural inflammation in Crohn's disease (CD). Small bowel involvement is often more extensive in pediatric CD, requiring a panentering measuring tool. We undertook to develop a magnetic resonance enterography (MRE)-based index that would measure inflammation in all segments of the intestine, without rectal contrast. METHODS: Children with CD underwent ileocolonoscopy and MRE and half were prospectively followed for 18 months when MRE was repeated. Item generation and reduction were performed by a Delphi panel of pediatric radiologists, a systematic literature review, a cross-sectional study of 48 MREs, and a steering committee. Formatting and weighting were performed using multivariate modeling adjusted by a steering committee. MREs were read locally and centrally. Reliability, validity, and responsiveness were determined using several clinimetric and psychometric approaches. RESULTS: Thirty items were initially generated and reduced to 5 using regression analysis on 159 MREs: wall thickness, wall diffusion weighted imaging, ulcerations, mesenteric edema, and comb sign. In the validation cohort of 81 MREs, the weighted global PICMI correlated well with the radiologist global assessment (r = 0.85; P < .001) and with the simple endoscopic score in a subsample with ileocolonic disease (r = 0.63; P < .001). Interobserver and test-retest reliability were high (interclass correlation coefficients, 0.84; 95% confidence interval [CI], 0.79-0.87; and 0.81, 95% CI, 0.65-0.90, respectively; both P < .001). Excellent responsiveness was found at repeated visits (n = 116 MREs; area under the receiver operating characteristic curve 0.96; 95% CI, 0.93-0.99). Transmural healing was defined as PICMI ≤10 and response as a change of >20 points with excellent discriminative validity (area under the receiver operating characteristic curve = 0.96; 95% CI, 0.93-0.99). CONCLUSIONS: The PICMI is a valid, reliable, and responsive index for assessing transmural inflammation in pediatric CD. It scores the entire bowel length and does not require intravenous contrast or rectal enema and, therefore, is suitable for use in children. (ClinicalTrials.gov, Number: NCT01881490.).

Anti TNF treatment of complex perianal fistulas in children without luminal Crohn's disease: Is it an option?

OBJECTIVES: Complex perianal fistulas (CPFs) in children even in the absence of luminal symptoms prompt evaluation for Crohn's disease (CD). Reports of isolated CPF in children, however, are sparse. In perianal CD, antitumor necrosis factor α (anti TNF) therapy is recommended. We aimed to describe our experience with anti TNF therapy in children with isolated CPF without evidence of luminal CD. METHODS: We retrospectively reviewed charts of patients with isolated CPF who were treated with anti TNF agents between 2011 and 2019 in a tertiary center. MRI pelvis findings at baseline versus end of follow up were scored using MAGNIFI-CD. Outcomes included clinical remission, radiological response and radiological remission based on MAGNIFI-CD score at end of follow up. RESULTS: Overall, 17 patients were identified, [10 males (59%), mean age at anti TNF initiation 13.4 ± 2.9 years]. Median time from perianal disease onset to anti TNF was 16.5 months (IQR 9.4-36.4). None of the patients had luminal inflammation. Prior to anti TNF, all patients had been treated with antibiotics without sufficient improvement, and 9/17 with abscess drainage and or Seton insertion. Nine patients (53%) were treated with infliximab while 8 (47%) received adalimumab. Median duration of follow up was 30.7 months (IQR = 12.7-44.8). At the end of follow up 9 patients (53%) achieved clinical remission. When comparing MRI prior to and after anti TNF, 36% (5/14) had radiologic response, of whom 2 (14%) achieved radiologic resolution. CONCLUSION: Anti TNF agents may be an effective treatment option for children with isolated CPF. Whether these patients should be considered part of the CD phenotypic spectrum or a distinct entity is unclear. LEVELS OF EVIDENCE: Therapeutic.

Long-Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease: Associations With Adalimumab Exposure.

BACKGROUND/AIMS: Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long-term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes. METHODS: Single-center retrospective study. Pediatric CD activity index, C-reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time-dependent covariates. RESULTS: Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5-15.7) 65% males) initiated ADA. One hundred and seventy-four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6-38.4) months follow-up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti-tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti-TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono- and immunomodulator combination therapy. Among pre-/early pubertal children mean height (-0.82) normalized to -0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements. CONCLUSION: ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure.

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

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.

Online Acceptance and Commitment Therapy and Nutrition Workshop for Parents of Children with Inflammatory Bowel Disease: Feasibility, Acceptability, and Initial Effectiveness.

Parents of children with inflammatory bowel disease (IBD) are important members of their healthcare team and influence their child's adaptation to disease. The primary aim of this research was to test the feasibility and acceptability of a three-session online parent workshop based on acceptance and commitment therapy (ACT) and address concerns about eating well and nutrition in IBD. The secondary aim was to explore the initial effectiveness of this workshop in parent reported psychological flexibility, mindfulness, experiential avoidance, cognitive fusion, valued living, and symptoms of depression, anxiety, and stress. We used a single arm pragmatic prospective study design with parents of children attending the IBD program at a tertiary pediatric healthcare centre in Canada. Mixed methods patient reported outcomes were measured at baseline, immediate post participation, and 3 months post participation in the workshop. Thirty-seven parents enrolled in the study and feasibility and acceptability goals were largely met. Parents qualitatively described changes to their parenting, what aspects of the workshop were most helpful, and targeted feedback on how to improve workshop. Findings suggest that providing parents of children with IBD a brief online ACT workshop including nutrition guidance is feasible and leads to changes in parenting behaviours.

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

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.

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

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.

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

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.

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

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.

Biopsychosocial Correlates of Presence and Intensity of Pain in Adolescents With Inflammatory Bowel Disease.

Background: There is growing consensus that pain in pediatric inflammatory bowel disease (IBD) is not fully explained by disease-related processes. However, previous studies have largely measured individual biological, psychological, or social risk factors for pain in isolation. Further, not all youth with IBD presenting to clinic will report presence of pain, and those who do vary in their reports of pain intensity. This study therefore extends prior research by determining biopsychosocial correlates of both presence and intensity of pain in adolescents with IBD, in order to inform targeted pain management intervention approaches. Methods: Adolescents with IBD followed at SickKids, Toronto, and their parents were consecutively enrolled from outpatient clinic. IBD characteristics (diagnosis, time since diagnosis, patient-reported disease activity) were collected. Adolescents reported on current pain (NRS-10), internalizing symptoms (Strengths and Difficulties Questionnaire), and pain catastrophizing (Pain Catastrophizing Scale-Child). Parents reported on protective responses to child pain (Adult Responses to Child Pain) and pain catastrophizing (Pain Catastrophizing Scale-Child). Hurdle models were conducted to examine predictors of presence and intensity of pain in the same model. Biological (patient-reported disease activity, IBD diagnosis subtype, illness duration), psychological (internalizing symptoms, pain catastrophizing), and social (parent pain catastrophizing, parent protective responses) factors were entered as predictors, adjusting for age and sex. Results: Participants included 100 adolescents (12-18; Mean = 15 years) with IBD (60% Crohn's Disease, 40% Ulcerative Colitis or IBD-unclassified) and 76 parents. The majority of the sample was in clinical remission or reported minimal symptoms. Half of participants reported no current pain; for those reporting pain, intensity ranged 1-7 (M = 3.43, SD = 1.98). Disease activity (OR = 53.91, p < 0.001) and adolescent internalizing symptoms (OR = 7.62, p = 0.03) were significant predictors of presence of pain. Disease activity (RR = 1.37, p = 0.03) and parent protective responses (RR = 1.45, p = 0.02) were significant predictors of intensity of pain. Conclusions: Results suggest that the experience of pain in pediatric IBD is biopsychosocially determined. Patient-reported disease activity and internalizing symptoms predicted presence of pain, while disease activity and parent protective responses predicted intensity of pain. While medical intervention in pediatric IBD is focused on disease management, results suggest that depression/anxiety symptoms as well as parent protective responses may be important targets of pain management interventions in pediatric IBD.

Magnetic Resonance Cholangiopancreatography Severity Predicts Disease Outcomes in Pediatric Primary Sclerosing Cholangitis: A Reliability and Validity Study.

Magnetic resonance cholangiopancreatography (MRCP) has not been assessed as a surrogate biomarker in pediatrics. We aimed to determine the inter-rater reliability, prognostic utility, and construct validity of the modified Majoie endoscopic retrograde cholangiopancreatography classification applied to MRCP in a pediatric primary sclerosing cholangitis (PSC) cohort. This single-center, retrospective, cohort study included children with PSC undergoing diagnostic MRCP between 2008 and 2016. Six variations of the Majoie classification were examined: 1) intrahepatic duct (IHD) score, 2) extrahepatic duct (EHD) score (representing the worst intrahepatic and extrahepatic regions, respectively), 3) sum IHD-EHD score, 4) average IHD score, 5) average EHD score, and 6) sum average IHD-EHD score. Inter-rater reliability was assessed using weighted kappas and intraclass correlation coefficients (ICCs). Ability to predict time to PSC-related complications (ascites, esophageal varices, variceal bleed, liver transplant [LT], or cholangiocarcinoma) (primary outcome) and LT (secondary outcome) was assessed with Harrell's concordance statistic (c-statistic) and univariate/multivariable survival analysis. Construct validity was further assessed with Spearman correlations. Forty-five children were included (67% boys; median, 13.6 years). The inter-rater reliability of MRCP scores was substantial to excellent (kappas/ICCs, 0.78-0.82). The sum IHD-EHD score had the best predictive ability for time to PSC complication and LT (c-statistic, 0.80 and SE, 0.06; and c-statistic, 0.97 and SE, 0.01, respectively). Higher MRCP scores were independently associated with a higher rate of PSC-related complications, even after adjusting for the PSC Mayo risk score (hazard ratio, 1.74; 95% confidence interval, 1.14-2.). MRCP sum scores correlated significantly with METAVIR fibrosis stage, total bilirubin, and platelets (r = 0.42, r = 0.33, r = -0.31, respectively; P < 0.05). Conclusion: An MRCP score incorporating the worst affected intrahepatic and extrahepatic regions is reliable and predicts meaningful outcomes in pediatric PSC. Next steps include prospective validation and responsiveness assessment.

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

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.

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

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.

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

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.