Serum Metabolites Relate to Mucosal and Transmural Inflammation in Pediatric Crohn Disease.

BACKGROUND AND AIMS: We aimed to identify serum metabolites associated with mucosal and transmural inflammation in pediatric Crohn disease (pCD). METHODS: Fifty-six pCD patients were included through a pre-planned sub-study of the multicenter, prospective, ImageKids cohort, designed to develop the Pediatric Inflammatory Crohn's MRE Index (PICMI). Children were included throughout their disease course when undergoing ileocolonoscopy and magnetic resonance enterography (MRE) and followed for 18 months when MRE was repeated. Serum metabolites were identified using liquid chromatography/mass spectroscopy. Outcomes included: PICMI, the simple endoscopic score (SES), faecal calprotectin (FCP), and C-reactive protein (CRP), to assess transmural, mucosal, and systemic inflammation, respectively. Random forest models were built by outcome. Maximum relevance minimum redundancy (mRMR) feature selection with a j-fold cross validation scheme identified the best subset of features and hyperparameter settings. RESULTS: Tryptophan and glutarylcarnitine were the top common mRMR metabolites linked to pCD inflammation. Random forest models established that amino acids and amines were among the most influential metabolites for predicting transmural and mucosal inflammation. Predictive models performed well, each with an area under the curve (AUC) > 70%. In addition, serum metabolites linked with pCD inflammation mainly related to perturbations in citrate cycle (TCA cycle), aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. CONCLUSIONS: We extend on recent studies, observing differences in serum metabolite between healthy controls and Crohn disease patients, and suggest various associations of serum metabolites with transmural and mucosal inflammation. These metabolites could improve the understanding of pCD pathogenesis and assess disease severity.

Enteral nutrition compared with corticosteroids in children with Crohn's disease: A long-term nationwide study from the epi-IIRN.

BACKGROUND: Both corticosteroids and exclusive enteral nutrition (EEN) have been used as induction therapy in children with Crohn's disease (CD). AIM: To compare in a nationwide study the long-term outcomes of children with CD receiving either EEN or corticosteroids as induction therapy. METHODS: We retrieved data of all children diagnosed with CD (2005-2020) from the epi-IIRN cohort covering 98% of the Israeli population. The primary outcome was time to complicated disease course (i.e., surgery, steroid-dependency, or at least 2 biologic class). Patients were matched individually utilising propensity score adjustments. RESULTS: We included 410 children treated with EEN and 375 with corticosteroids without other treatments (median follow-up, 4.73 [IQR: 2.2-7.2] years [1433 patient-years]). For 274 matched children, the probability of a complicated course was higher with corticosteroids than EEN at 0.5, 3 and 5 years (14% vs. 4%, 42% vs. 27% and 54% vs. 41%, respectively, p = 0.0066), despite similar use of biologics. Steroid-dependency (10% vs. 2%, 15% vs. 3%, and 20% vs. 5%, respectively, p = 0.00018), and hospitalisations (20% vs. 11%, 37% vs. 26%, and 55% vs. 38%, respectively, p = 0.002) were higher with corticosteroids. During follow-up, children receiving corticosteroids as induction treatment were more often further exposed to corticosteroids, and those on EEN were more often further exposed to nutritional treatment (p < 0.001). Induction with EEN had no advantage over corticosteroids regarding survival probability of surgeries, biologic use and growth. CONCLUSIONS: EEN in paediatric CD is associated with lower long-term risks of corticosteroid dependency and hospitalisation than corticosteroids. These results may lend support to favouring nutritional therapy in paediatric CD.

Durability of the First Biologic in Children and Adults With Ulcerative Colitis: A Nationwide Study from the epi-IIRN.

BACKGROUND: In this nationwide study, our objective was to compare the durability of first-line biologics in ulcerative colitis (UC), categorized into monotherapy and combotherapy with immunomodulators. METHODS: We utilized data from the nationwide epi-IIRN cohort from 2005 to 2020. Durability was defined as consistent treatment without surgery. Comparisons were based on stringent propensity score-matching. RESULTS: We included 15 111 patients with UC, of whom 2322 (15%) received biologics, with a median follow-up of 7.0 years (interquartile range, 3.8-11.0). The durability rate was similar between pediatric-onset and adults after 1 and 5 years from initiation of treatment (72% and 43% vs 71% and 43%, respectively; P = .8). Durability of adalimumab vs infliximab after 1 or 5 years was similar, whether prescribed as monotherapy (65%/46% vs 63%/33%, respectively; n = 182 matched pairs, P = .3) or combotherapy (78%/56% vs 91%/58%, respectively; n = 46 matched pairs, P = .4). Durability of infliximab was higher as combotherapy (85%/50%) vs monotherapy (69%/42%; n = 174 matched pairs, P = .007), while it was similar for adalimumab (80%/52% vs 74%/52%; n = 53 matched pairs, P = .4). The durability rate was similar for vedolizumab monotherapy (77%/56%) compared with adalimumab monotherapy (69%/52%; n = 125 matched patients, P = .1), and infliximab monotherapy (73%/55% vs 62%/44%; n = 78 matched patients, P = .1). However, combotherapy of antitumor necrosis factors (TNFs) had longer durability than vedolizumab (85%/50% vs 75%/43%, respectively; n = 131 matched pairs, P = .02). CONCLUSION: After 5 years of treatment, 43% of the patients with UC sustained their first biologic, with similar durability in pediatric and adult-onset onset disease. Anti-TNFs had similar durability to vedolizumab and superior durability when prescribed as combotherapy.

Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort.

BACKGROUND & AIMS: In this nationwide study, we explored whether early initiation of biologics is associated with improved outcomes in children and adults with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All patients diagnosed with CD or UC in Israel (2005-2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort, encompassing 98% of the population. We compared disease duration at biologics initiation (ie, 0-3 months, >3-12 months, >1-2 years, and >2-3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias. RESULTS: Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2-3 years (31%) and 0-3 months (18%; P = .02; number needed to treat, 7.7), whereas there was no difference between the 0-3-month and >3-12-month periods. The 10-year probability of steroid dependency for the 0-3-month period (19%) differed both from the >2-3-year (31%; P < .001) and 1-2-year periods (37%; P < .001). In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods. Similar trends were noted in the pediatric population. CONCLUSIONS: Very early initiation of biologics was not associated with some outcomes except for a modest risk reduction of surgery and steroid dependency for CD, which requires confirmation in future studies. In UC, early introduction of biologics was not associated with reduced risk of colectomy or steroid dependency.

Fatigue in pediatric inflammatory bowel diseases: A systematic review and a single center experience.

OBJECTIVES: We aimed to review the literature on fatigue in pediatric inflammatory bowel diseases (PIBD), to explore how it is measured, and approximate its rate in an inception pediatric cohort. METHODS: Studies on fatigue were systematically reviewed and selected by two authors. Next, we retrieved the two fatigue-related questions of the IMPACT-III questionnaire at 4 and 12 months after diagnosis from a prospectively maintained cohort of PIBD patients, each scoring 0-100 (lower scores imply more fatigue), and 44 healthy controls. RESULTS: The systematic review identified 14 studies reporting fatigue in children, of which nine had fatigue as the primary outcome and only two provided rates of fatigue. No standalone index was identified for measuring fatigue specifically for PIBD. Of 80 children included in the inception cohort, 62 (78%) scored an average of ≤75 on the two IMPACT-III questions (approximating at least mild fatigue), 26 (33%) scored ≤50 (at least moderate fatigue) and nine (11%) scored ≤25 (severe fatigue). In comparison, only four (9%) healthy children scored at least moderate fatigue (p = 0.007). Fatigue rates at 12 months were only slightly and nonsignificantly lower. Fatigue of any severity was reported in 92% children with active disease versus 63% of those in clinical remission (p = 0.01). CONCLUSION: Literature reporting on fatigue in PIBD is scarce, and no PIBD-specific tool is available to measure fatigue. In our cohort, fatigue-related questions were frequently scored low in children with IBD, mainly among children with active disease but also during clinical remission.

Durability of Adalimumab and Infliximab in Children With Crohn's Disease: A Nationwide Comparison From the epi-IIRN Cohort.

BACKGROUND: In a nationwide cohort, we aimed to compare the durability of infliximab and adalimumab as first biologic treatment in children with Crohn's disease (CD), stratified as combotherapy or monotherapy. METHODS: We used data from the epi-IIRN cohort that includes all patients with inflammatory bowel diseases in Israel. Durability was defined as consistent treatment without surgery or treatment escalation. All comparisons followed stringent propensity-score matching in Cox proportional hazard models. RESULTS: Of the 3487 children diagnosed with CD since 2005, 2157 (62%) received biologics (1127 [52%] infliximab, 964 [45%] adalimumab and 52 [2%] vedolizumab as first biologic), representing a higher proportion than that among adults diagnosed during the same time period (5295 of 15 776 [34%]; P < .001). Time from diagnosis to initiation of biologic was shorter in pediatric-onset compared with adult-onset disease (median time during the last 3 years was 2.7 months [interquartile range 1.2-5.4] vs 5.2 months [2.6-8.9]; P < .001). The durability of adalimumab monotherapy after 1 and 5 years from initiation of treatment was better than infliximab monotherapy (79%/54% vs 67%/37%, respectively; n = 452 matched children; hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.3-2.3; P < .001), while in those treated with combotherapy, durability was similar (94%/66% with infliximab vs 90%/54% with adalimumab; n = 100; HR, 1.7; 95% CI, 0.9-3.3; P = .1). Durability was higher in children treated with infliximab combotherapy vs infliximab monotherapy (87%/45% vs 75%/39%; n = 440; HR, 1.4; 95% CI, 1.1-1.8; P = .01). The durability of adalimumab monotherapy was similar to infliximab combotherapy (83%/53% vs 89%/56%, respectively; n = 238; HR, 0.9; 95% CI, 0.7-1.2; P = .4). CONCLUSION: Our results support using adalimumab monotherapy as a first-line biologic in children with CD. When infliximab is used, combotherapy may be advantageous over monotherapy.

Durability of the First Biologic in Patients with Crohn's Disease: A Nationwide Study from the epi-IIRN.

BACKGROUND: In this nationwide study we aimed to compare the durability of the first initiated biologic in Crohn's disease [CD], stratified by monotherapy and combotherapy. METHODS: We used data from the epi-IIRN cohort, which includes 98% of the Israeli inflammatory bowel disease population [2005-2020]. Durability was defined as consistent treatment without surgery or added medications [except for combination therapy with thiopurines or methotrexate]. All comparisons were based on stringent propensity-score matching and paired time-to-event analyses. RESULTS: A total of 19 264 patients with CD were included, of whom 7452 [39%] received biologics with a median follow-up of 6.8 years (interquartile range [IQR] 3.6-10.7). Time to biologics decreased gradually from 6.7 years [IQR 2.7-10.4] in 2005 to 0.2 years [0.07-0.23] in 2020. The durability of the first biologic after 1 and 3 years was higher with adalimumab monotherapy [88%/61%] than vedolizumab monotherapy [81%/59%; n = 394 matched patients, p = 0.04] and similar between infliximab monotherapy and vedolizumab monotherapy [65%/43%; n = 182 matched patients, p = 0.1]. Durability was higher in adalimumab monotherapy vs infliximab monotherapy [83%/62% vs 71%/48% at 1/3 years; p <0.001] and it was similar in adalimumab monotherapy vs infliximab combotherapy [87%/63% vs 80%/58%, respectively; p = 0.1]. Durability was higher in combotherapy compared with monotherapy for both infliximab [85%/64% vs 67%/43%, respectively; n = 496 matched pairs, p <0.001], and adalimumab [93%/76% vs 82%/62%, respectively; n = 540 matched pairs, p <0.001]. CONCLUSION: Durability of the first biologic in CD was highest for adalimumab monotherapy. Combotherapy further increased the durability of adalimumab and infliximab. Unless otherwise indicated, our data may support using anti-tumour necrosis factors [TNFs] as first-line biologics in CD, particularly adalimumab if monotherapy is advised.

Residence in Peripheral Regions and Low Socioeconomic Status Are Associated With Worse Outcomes of Inflammatory Bowel Diseases: A Nationwide Study From the epi-IIRN.

BACKGROUND: Timely access to quality medical care impacts patient outcomes in inflammatory bowel disease (IBD). In a nationwide study from the epidemiology group of the Israeli IBD research nucleus we aimed to assess the impact of residence and socioeconomic status (SES) on disease outcomes. METHODS: We utilized data from the 4 health maintenance organizations in Israel, representing 98% of the population. Regions were defined as central, northern and southern; SES was graded from lowest to highest (from 1 to 4) as per Israel Central Bureau of Statistics. The primary outcome was steroid dependency, with secondary outcomes of surgeries and biologic therapy use. RESULTS: A total of 28 216 IBD patients were included: 15 818 (56%) Crohn's disease (CD) and 12 398 (44%) ulcerative colitis; 74%, 12% and 14% resided in central, southern, and northern Israel, respectively (SES 1: 21%, SES 4: 12%). Lower SES was associated with steroid dependency (20% in SES 1 vs 12% in SES 4 in CD; P < .001; and 18% vs 12% in ulcerative colitis; P < .001), and higher surgery rates (12% vs 7%; P < .001, and 1.4% vs 0.7%; P = .115, respectively). There were higher steroid dependency and CD surgery rates in peripheral vs central regions. In multivariable models, both SES and peripheral region were independently associated with poorer outcomes. CONCLUSIONS: We found that lower SES and peripheral residence were associated with deleterious outcomes in IBD. This should be considered by policymakers and should encourage strategies for improving outcomes in populations at risk.

In a novel nationwide population study, we found that patients with inflammatory bowel disease living in peripheral regions and those with lower socioeconomic status had significantly worse inflammatory bowel disease outcomes, notably higher corticosteroid dependency, higher surgery rate, and higher repeat surgery rate.

Validation of predictive models for disease outcomes in paediatric ulcerative colitis: A multicentre prospective inception cohort.

BACKGROUND: Several studies have proposed models to predict disease outcomes in paediatric ulcerative colitis (UC), notably PROTECT, Schechter and PIBD-ahead, but none has been validated by external cohorts AIM: To explore these models in a prospective multicentre inception cohort METHODS: Children newly diagnosed with UC in 17 centres were followed at disease onset and 3 and 12 months thereafter, as well as at last visit. Outcomes included steroid-free remission (SFR) and acute severe colitis (ASC). RESULTS: Of the 223 included children, 74 (34%), 97 (43%) and 52 (23%) presented with mild, moderate and severe disease, respectively. SFR rate was 35% at 3 months and 47% at 12 months (62% of those with mild disease at diagnosis vs. 41% in moderate-severe disease; p = 0.01). Thirty-six (16%) children developed ASC during the first month after diagnosis, and 53 (24%) during the first year. The AUC of the PROTECT model for predicting SFR at 3 and 12 months was 0.78 [95% CI 0.65-0.92] and 0.57 [95% CI 0.47-0.66], respectively. The sensitivity/specificity/PPV/NPV of Schechter's criteria to predict sustained SFR at 12 months was 50%/60%/35%/74%. ASC was predicted only by the PUCAI score at diagnosis and at 3 months. CONCLUSIONS: The PROTECT model had a good predictive utility for SFR at 3 months, but not at 12 months. The other predictive models did not achieve sufficient accuracy, which was far from that reported in the original studies. This highlights the necessity for external validation of any prediction model prior to its implementation into clinical practice.

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.

Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study.

BACKGROUND: Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. METHODS: VEDOKIDS was a paediatric, multicentre, prospective cohort study done in 17 centres in six countries. We report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Children (aged 0-18 years) with IBD who had commenced vedolizumab were followed up at baseline and at 2, 6, and 14 weeks. Children were managed according to local prescribing practices without standardisation of dosing or criteria for escalation, but the study protocol suggested dosing of 177 mg/m2 body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. FINDINGS: Between May 19, 2016, and April 1, 2022, 142 children (76 [54%] girls and 66 [46%] boys; mean age 13·6 years [SD 3·6]) were enrolled. 65 (46%) children had Crohn's disease, 68 (48%) had ulcerative colitis, and nine (6%) had unclassified IBD (those with unclassified IBD were analysed with the ulcerative colitis group). 32 (42% [95% CI 30-54]) of 77 children with ulcerative colitis and 21 (32% [23-45]) of 65 children with Crohn's disease were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with ulcerative colitis than in those with Crohn's disease (11·5 µg/mL [IQR 5·5-18·1] vs 5·9 µg/mL [3·0-12·7]; p=0·006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 µg/mL at week 14 (area under the curve 0·69 [95% CI 0·41-0·98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. INTERPRETATION: Vedolizumab showed good safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with ulcerative colitis. Vedolizumab should be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). FUNDING: The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

The Modified Mucosal Inflammation Noninvasive Index and Endoscopic Remission in Adults With Crohn's Disease.

The Mucosal Inflammation Noninvasive Index is a validated noninvasive tool to assess endoscopic remission in pediatric Crohn's disease. In this study, we evaluated a modified version of the Mucosal Inflammation Noninvasive Index on adult cohorts to explore its validly in adult Crohn's disease.

Inflammatory bowel disease among first generation immigrants in Israel: A nationwide epi-Israeli Inflammatory Bowel Disease Research Nucleus study.

BACKGROUND: Israel has a high rate of Jewish immigration and a high prevalence of inflammatory bowel disease (IBD). AIM: To compare IBD prevalence in first-generation immigrants vs Israel-born Jews. METHODS: Patients with a diagnosis of IBD as of June 2020 were included from the validated epi-IIRN (Israeli IBD Research Nucleus) cohort that includes 98% of the Israeli population. We stratified the immigration cohort by IBD risk according to country of origin, time period of immigration, and age group as of June 2020. RESULTS: A total of 33544 patients were ascertained, of whom 18524 (55%) had Crohn's disease (CD) and 15020 (45%) had ulcerative colitis (UC); 28394 (85%) were Israel-born and 5150 (15%) were immigrants. UC was more prevalent in immigrants (2717; 53%) than in non-immigrants (12303, 43%, P < 0.001), especially in the < 1990 immigration period. After adjusting for age, longer duration in Israel was associated with a higher point prevalence rate in June 2020 (high-risk origin: Immigration < 1990: 645.9/100000, ≥ 1990: 613.2/100000, P = 0.043; intermediate/low-risk origin: < 1990: 540.5/100000, ≥ 1990: 192.0/100000, P < 0.001). The prevalence was higher in patients immigrating from countries with high risk for IBD (561.4/100000) than those originating from intermediate-/low-risk countries (514.3/100000; P < 0.001); non-immigrant prevalence was 528.9/100000. CONCLUSION: Lending support to the environmental effect on IBD etiology, we found that among immigrants to Israel, the prevalence of IBD increased with longer time since immigration, and was related to the risk of IBD in the country of origin. The UC rate was higher than that of CD only in those immigrating in earlier time periods.

Development of a multimodal machine-learning fusion model to non-invasively assess ileal Crohn's disease endoscopic activity.

BACKGROUND AND OBJECTIVE: Recurrent attentive non-invasive observation of intestinal inflammation is essential for the proper management of Crohn's disease (CD). The goal of this study was to develop and evaluate a multi-modal machine-learning (ML) model to assess ileal CD endoscopic activity by integrating information from Magnetic Resonance Enterography (MRE) and biochemical biomarkers. METHODS: We obtained MRE, biochemical and ileocolonoscopy data from the multi-center ImageKids study database. We developed an optimized multimodal fusion ML model to non-invasively assess terminal ileum (TI) endoscopic disease activity in CD from MRE data. We determined the most informative features for model development using a permutation feature importance technique. We assessed model performance in comparison to the clinically recommended linear-regression MRE model in an experimental setup that consisted of stratified 2-fold validation, repeated 50 times, with the ileocolonoscopy-based Simple Endoscopic Score for CD at the TI (TI SES-CD) as a reference. We used the predictions' mean-squared-error (MSE) and the receiver operation characteristics (ROC) area under curve (AUC) for active disease classification (TI SEC-CD≥3) as performance metrics. RESULTS: 121 subjects out of the 240 subjects in the ImageKids study cohort had all required information (Non-active CD: 62 [51%], active CD: 59 [49%]). Length of disease segment and normalized biochemical biomarkers were the most informative features. The optimized fusion model performed better than the clinically recommended model determined by both a better median test MSE distribution (7.73 vs. 8.8, Wilcoxon test, p<1e-5) and a better aggregated AUC over the folds (0.84 vs. 0.8, DeLong's test, p<1e-9). CONCLUSIONS: Optimized ML models for ileal CD endoscopic activity assessment have the potential to enable accurate and non-invasive attentive observation of intestinal inflammation in CD patients. The presented model is available at https://tcml-bme.github.io/ML_SESCD.html.

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.).

Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix.

BACKGROUND: Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. AIM: To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. METHODS: We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery. RESULTS: We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. CONCLUSION: Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.

Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN).

BACKGROUND AND OBJECTIVES: Both perianal and pediatric-onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult-onset perianal CD and their disease course. METHODS: We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD-9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease. RESULTS: A total of 12,905 patients were included (2186 [17%] pediatric-onset, 10,719 [83%] adults), with a median follow-up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P  < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6-4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1-3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid-dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age. CONCLUSION: PCD is more common in pediatric-onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.

Existing Prediction Models of Disease Course in Paediatric Crohn's Disease Are Poorly Replicated in a Prospective Inception Cohort.

BACKGROUND: Several groups have proposed models to predict disease outcomes in paediatric Crohn's disease [CD], notably the RISK, GROWTH, and the Porto group, but none were externally validated. We aimed to explore these predictive models and individual predictors summarised by the PIBD-ahead project in a prospective inception cohort of paediatric CD. METHODS: We included children who were diagnosed with CD at two medical centres and followed them at 3 and 12 months thereafter as well as at the last follow-up. Outcomes included steroid-free remission [SFR], surgery, and stricturing/fistulising disease. RESULTS: In all 155 children were included (median follow-up of 31 [16-48] months, 107 [71%] had moderate-to-severe disease). Stricturing and penetrating disease at diagnosis were noted in 34 [22%] and two [1.3%] children, respectively, and these were excluded from the relevant analyses. At 1 year, 10 [8.3%] developed new stricturing disease, two [1.7%] developed penetrating disease, seven [5%] required intestinal surgery, and 15 [10%] required perianal surgery. The sensitivity/specificity/positive predictive value [PPV]/negative predictive value [NPV] of the GROWTH criteria for predicting SFR at 12 months [occurring in 70% of children] were 20%/85%/76%/31% and for surgery at 2 years were 96%/20%/16%/96%, respectively. Strictures were predicted by the RISK model with sensitivity/specificity/PPV/NPV of 33%/73%/18%/86%, respectively. The sensitivity/specificity/PPV/NPV of the Porto criteria to predict surgery were 86%/10%/4%/94%, respectively. None of the Pediatric Inflammatory Bowel Disease-ahead [PIBD-ahead] predictors were associated with surgery or stricturing disease. CONCLUSIONS: None of the three main predictive models in paediatric CD achieved sufficient accuracy, far from that reported in the original cohorts. This highlights the necessity of external validation in any prediction model prior to its implementation in clinical practice.