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.

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.

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.

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.).

Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN.

OBJECTIVE: Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD). DESIGN: We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days. RESULTS: Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with ß-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA. CONCLUSION: ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.

COVID-19 Vaccine Is Effective in Inflammatory Bowel Disease Patients and Is Not Associated With Disease Exacerbation.

BACKGROUND & AIMS: Studies have shown decreased response to coronavirus disease 2019 (COVID-19) vaccinations in some populations. In addition, it is possible that vaccine-triggered immune activation could trigger immune dysregulation and thus exacerbate inflammatory bowel diseases (IBD). In this population-based study we used the epi-Israeli IBD Research Nucleus validated cohort to explore the effectiveness of COVID-19 vaccination in IBD and to assess its effect on disease outcomes. METHODS: We included all IBD patients insured in 2 of the 4 Israeli health maintenance organizations, covering 35% of the population. Patients receiving 2 Pfizer-BioNTech BNT162b2 vaccine doses between December 2020 and June 2021 were individually matched to non-IBD controls. To assess IBD outcomes, we matched vaccinated to unvaccinated IBD patients, and response was analyzed per medical treatment. RESULTS: In total, 12,109 IBD patients received 2 vaccine doses, of whom 4946 were matched to non-IBD controls (mean age, 51 ± 16 years; median follow-up, 22 weeks; interquartile range, 4-24). Fifteen patients in each group (0.3%) developed COVID-19 after vaccination (odds ratio, 1; 95% confidence interval, 0.49-2.05; P = 1.0). Patients on tumor necrosis factor (TNF) inhibitors and/or corticosteroids did not have a higher incidence of infection. To explore IBD outcomes, 707 vaccinated IBD patients were compared with unvaccinated IBD patients by stringent matching (median follow-up, 14 weeks; interquartile range, 2.3-20.4). The risk of exacerbation was 29% in the vaccinated patients compared with 26% in unvaccinated patients (P = .3). CONCLUSIONS: COVID-19 vaccine effectiveness in IBD patients is comparable with that in non-IBD controls and is not influenced by treatment with TNF inhibitors or corticosteroids. The IBD exacerbation rate did not differ between vaccinated and unvaccinated patients.

Perianal Crohn's Disease Is Associated With Poor Disease Outcome: A Nationwide Study From the epiIIRN Cohort.

BACKGROUND & AIMS: Limited population-based data have explored perianal involvement in Crohn's disease (CD) and compared the disease course between severe and non-severe perianal CD (PCD). We aimed to explore the disease course of these phenotypes in a population-based study of CD. METHODS: Cases were identified from the epi-IIRN cohort and included 2 Israeli health maintenance organizations covering 78% of the population. We validated specific algorithms to identify fistulizing PCD and to differentiate severe from non-severe disease by medication utilization, International Classification of Disease, 9th Revision codes, and perianal procedures. RESULTS: A total of 12,904 CD patients were included in an inception cohort from 2005 (2186 pediatric-onset, 17%) providing 86,119 person-years of follow-up. Fistulizing PCD was diagnosed in 1530 patients (12%) (574 with severe PCD, 4%). The prevalence of PCD was 7.9%, 9.4%, 10.3%, and 11.6% at 1, 3, 5, and 10 years from CD diagnosis, respectively. At 5 years, PCD patients were more likely to be hospitalized (36% in non-PCD vs 64% in PCD; P < .001), undergo inflammatory bowel disease-related surgeries (9% vs 38%, respectively; P < .001), and develop anorectal cancer (1.2/10,000 person-years for non-PCD vs 4.2/10,000 for PCD; P = .01). Severe PCD was associated with poorer outcomes compared with non-severe PCD, as shown for hospitalizations (61% in non-severe PCD vs 73% in severe; P = .004) and surgeries (35% vs 43%; P = .001). CONCLUSIONS: Despite higher utilization of immunomodulators and biologics, PCD is associated with poor disease outcomes, especially in severe PCD.

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.

Benign Evolution of SARS-Cov2 Infections in Children With Inflammatory Bowel Disease: Results From Two International Databases.

The coronavirus disease 2019 (COVID-19) pandemic caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents most often with mild clinical symptoms, but the severe forms are of major concern.1 SARS-CoV-2 enters human cells via the angiotensin-converting enzyme 2 receptor, expressed on epithelial and endothelial cells.2 Because the highest angiotensin-converting enzyme 2 expression is in the terminal ileum and colon, and up-regulated further during inflammation, and many COVID-19 patients experience gastrointestinal symptoms, longitudinal data are necessary to determine whether inflammatory bowel disease (IBD) patients are at risk for severe or complicated COVID-19. A recent analysis in IBD patients from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry showed older age, steroid medication, and comorbidities as risk factors for severe evolution, and the same study showed that the 29 IBD patients younger than age 20 had only mild disease courses.3 This report describes the disease course of COVID-19 in an expanded sample of pediatric IBD patients from 2 international databases.

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

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.

Corona Virus Disease 2019 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology, and Nutrition.

INTRODUCTION: With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19. METHODS: An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members. RESULTS: Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%. CONCLUSIONS: Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other.

Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn's Disease.

BACKGROUND & AIMS: Bowel healing is an important goal of therapy for patients with Crohn's disease (CD). Although there have been many studies of mucosal healing, transmural healing (ie, in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal, transmural healing and levels of calprotectin and C-reactive protein in children with CD. METHODS: We collected data from a multi-center study designed to develop 2 magnetic resonance enterography (MRE)-based measures for children with CD (6-18 years old). In our analysis of 151 children (mean age, 14.2 ± 2.4 years), all patients underwent MRE and a complete ileocolonoscopic evaluation; fecal levels of calprotectin and blood levels of C-reactive protein were measured. Mucosal healing was defined as simple endoscopic severity index in CD score below 3, transmural healing as an MRE visual analogue score below 20 mm, and deep healing as a combination of transmural and mucosal healing. RESULTS: We identified mucosal healing with transmural inflammation in 9 children (6%), transmural healing with mucosal inflammation in 38 children (25%), deep healing in 21 children (14%), and mucosal and transmural inflammation in 83 children (55%). The median level of calprotectin was lowest in children with deep healing (mean level, 10 µg/g; interquartile range, 10-190 µg/g), followed by children with either transmural or mucosal inflammation, and highest in children with mucosal and transmural inflammation (810 µg/g; interquartile range, 539-1737 µg/g) (P < .001). Fecal level of calprotectin identified children with deep healing with an area under the receiver operating characteristic curve value of 0.93 (95% CI, 0.89-0.98); level of C-reactive protein identified children with deep healing with an area under the receiver operating characteristic curve value of 0.81 (95% CI, 0.71-0.9). A calprotectin cutoff value of 100 µg/g identified children with deep healing with 71% sensitivity and 92% specificity; a cutoff value of 300 µg/g identified children with mucosal healing with 80% sensitivity and 81% specificity. CONCLUSIONS: In a prospective study of children with CD, we found that one-third have healing in only the mucosa or the bowel wall (not both). Levels of fecal calprotectin below 300 µg/identify children with mucosal healing, but a lower cutoff value (below 100 µg/g) is needed to identify children with deep healing. Clinicaltrials.gov no: NCT01881490.

[ESTABLISHING A REGISTRY FOR INFLAMMATORY BOWEL DISEASE PATIENTS IN MACCABI HEALTHCARE SERVICES - JOINT PROJECT BETWEEN HOSPITALS, EPI-IIRN GROUP AND COMMUNITY MEDICINE].

INTRODUCTION: Inflammatory bowel diseases (IBD) are becoming a significant cause for chronic long term complex morbidity, particularly among adolescents and young adults. IBD patients require multidisciplinary management and considerable health resources. Recent advances and developments in the diagnostics and therapeutic options require identification and tight monitoring of these patients at both hospital and community level for better management and care. AIMS: To establish at Maccabi Healthcare Services (MHS) a dedicated registry for inflammatory bowel disease patients for long term monitoring in order to optimize care, better use of health resources and to promote high quality research. METHODS: A national project, initiated and headed by a team from Shaare Zedek Medical Center aimed to resolve the complexity in identifying IBD patients at the community setting. The project included data from all Israeli HMOs and major hospitals, that was incorporated into various algorithms to determine prevalence and incidence and to distinguish between Crohn's disease and ulcerative colitis diagnoses. Eventually, an algorithm that includes the number of diagnoses, number of purchases and duration of IBD-related medications showed the best results for separating those that suffer from IBD and those that do not. This algorithm was further validated by chart review. RESULTS: According to the established registry criteria there were 14488 IBD patients in MHS, 13000 active. Additionally we have established an ongoing platform for ongoing monitoring of clinical, therapeutic, laboratory and imaging information. DISCUSSION: Establishing an IBD registry in MHS was enabled by a national project that combined deep professional knowledge of the disease by leading academic centers together with advanced informatics and community large data. We now move on to operate the registry in real life, together with live monitoring of various parameters in order to promote excellent care, communication with patients, management and control and to enable prospective high quality research.

Which PCDAI Version Best Reflects Intestinal Inflammation in Pediatric Crohn Disease?

INTRODUCTION: There is increasing interest in measuring mucosal inflammation in Crohn disease (CD), but there are minimal data correlating the Pediatric Crohn's Disease Activity Index (PCDAI) versions (PCDAI, weighted Pediatric Crohn's Disease Activity Index [wPCDAI], abbreviated Pediatric Crohn's Disease Activity Index [abbrPCDAI], and the short Pediatric Crohn's Disease Activity Index [shPCDAI]) with mucosal inflammation. METHODS: We aimed to compare the 4 PCDAI versions head to head with endoscopic degree of inflammation as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD), fecal calprotectin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and to explore cut-off values that are associated with mucosal healing. We used the prospectively collected data from the ImageKids study on 100 children with CD undergoing colonoscopy and from the Growth Relapse and Outcomes with Therapy study (n = 222), in which 145 children had calprotectin data at week 12 after diagnosis. RESULTS: All 4 PCDAI versions had fair correlation with the SES-CD (r = 0.42-0.45, all P < 0.001) and CRP (r = 0.32-0.45, all P < 0.01); the wPCDAI and PCDAI were superior to the shorter versions when comparing the blood tests. All versions had poor correlation with calprotectin, and only the wPCDAI reached significance (r = 0.26, P = 0.002 vs r = 0.15, P = 0.07 for PCDAI; r = 0.08, P = 0.37 for shPCDAI; r = 0.06, P = 0.5 for abbrPCDAI). The best cut-off to identify endoscopic mucosal healing was <12.5 points for the wPCDAI (sensitivity 58% and specificity 84%) and <10 for PCDAI (sensitivity 63% and specificity 77%). CONCLUSIONS: The more feasible wPCDAI and the PCDAI had comparable correlation with measures of endoscopic inflammation. These were slightly superior to the other 2 shorter versions, but still none of the PCDAI versions can give a valid assessment of mucosal healing.

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.

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.

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.

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.

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

BACKGROUND AND AIMS: We aimed to identify serum metabolites associated with mucosal and transmural inflammation in paediatric Crohn disease [pCD]. METHODS: In all, 56 pCD patients were included through a pre-planned sub-study of the multicentre, prospective, ImageKids cohort, designed to develop the Paediatric Inflammatory Crohn magnetic resonance enterography [MRE] Index [PICMI]. Children were included throughout their disease course when undergoing ileocolonoscopy and MRE and were 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 the citrate cycle [TCA cycle], aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. CONCLUSIONS: We extend on recent studies, observing differences in serum metabolites 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 assessment of disease severity.

Gut Microbial Signatures in Pediatric Crohn's Disease Vary According to Disease Activity Measures and Are Influenced by Proxies of Gastrointestinal Transit Time: An ImageKids Study.

INTRODUCTION: We investigated relationships between disease activity measures and the gut microbiome in children with Crohn's disease (CD) and how these were confounded by gastrointestinal transit time. METHODS: Microbiome was profiled (16S rRNA sequencing) in feces from 196 children with CD. Sixty participants also provided samples after 18 months. Mural inflammation (Pediatric Inflammatory Crohn's Magnetic Resonance Enterography Index, PICMI), the simple endoscopic score for CD, and the weighted pediatric Crohn's disease activity index (wPCDAI) were assessed. Fecal calprotectin, plasma C-reactive protein (CRP), and fecal water content (FWC), a proxy of gastrointestinal transit time, were measured too. RESULTS: Microbiome α diversity, clustering, and differential taxa were related to disease status, but varied remarkably by disease activity measure used. The strongest relationships between microbiome and disease activity status were observed using wPCDAI; fewer or no relationships were seen using more objective measures like PICMI. Taxa predictive of disease activity status were dependent on the disease activity measure used with negligible overlap. Active disease was associated with more pathobionts (eg, Viellonella, Enterobacterales) and fewer fiber-fermenting organisms. The effect FWC had on microbiome superseded the effect of active disease for all disease activity measures, particularly with wPCDAI. Accounting for FWC, the differences in microbial signatures explained by disease activity status were attenuated or lost. CONCLUSIONS: In CD, microbiome signatures fluctuate depending on the measure used to assess disease severity; several of these signals might be secondary disease effects linked with changes in gut motility in active disease. PICMI appears to be less influenced when studying relationships between microbiome and mural inflammation in CD.

Microbiome signatures are related to Crohn's disease status but vary remarkably by disease activity measure used. The effect gut transit time has on microbiome supersedes and confounds the effect of active disease, particularly with the use of less objective disease activity measures.