Objectives and Study

Recent studies such as the GEM project have identified microbial, serological and metabolomic markers that may help predict inflammatory bowel disease (IBD) well in advance of diagnosis, with the ultimate goal of pre-disease prevention. In this population-based study, we used the epi-Israeli IBD Research Nucleus (IIRN) validated cohort to explore the utility of routine blood tests as markers for pre-diagnostic IBD prediction in the pediatric population.

Methods

We included all blood tests from all IBD patients diagnosed from 2005-2020 in three of the four Israeli health maintenance organizations (HMOs), and individually matched each to two non-IBD controls. Means were compared using Welch's t-test with false discovery rate correction to account for multiple comparisons. Trends over time were analyzed to detect tests that showed divergence between cases and controls ≥1 year before diagnosis.

Results

Pre-diagnosis results from 228 different blood tests were collected for 7,041 Crohn’s disease (CD) patients and 5,590 ulcerative colitis (UC) patients, including 1,352 children with CD and 666 children with UC (mean age 13.4±3.2 years for CD and 12.9 ± 3.8 years for UC). Median pre-diagnosis data collection duration was 42 (IQR 12-71) months for CD and 41 (IQR 11-70) months for UC. Eleven tests (4.8%) showed significant differences between CD and controls ≥1 year before diagnosis (Figure); hemoglobin and MCH already diverged at 29 and 26 months, respectively, before diagnosis. In UC patients, no tests showed statistically significant differences ≥1 year pre-diagnosis.

Conclusions

We were able to detect changes in routine blood tests long before diagnosis of pediatric CD, opening the possibility of detecting early signals of future CD diagnosis in children undergoing routine blood tests. These may be used for developing prediction models for prevention strategies.

Objectives and Study

Exclusive enteral nutrition (EEN) treatment is as effective to corticosteroids (CS) for induction of remission in pediatric Crohn's disease (CD) with fewer side effects but long-term data are scarse. In this nationwide study we aimed to compare the risk of complicated disease course (CDC) after 2 years of follow-up in children with CD receiving EEN or CS at disease onset.

Methods

Data of children diagnosed with CD in the epi-IIRN (2005-2020) were retrieved from the four Israeli Health-Maintenance-Organizations covering 98% of the population. CDC was defined as CD-related surgery, steroid-dependency, or >1 biologic classes. Secondary outcomes included hospitalizations, use of any biologics, anthropometrics and labs reflecting nutritional-status. To account for confounding by indication bias, we utilized propensity-score individual matching.

Results

: A total of 785 children with CD were induced after diagnosis with either EEN (n=410) or CS (n=375); mean age 13.3±3.5 years, 59% males. Propensity-score successfully matched 116 pairs of whom 85 (36%) had CDC. The survival-probability of CDC at 6, 12, 18 and 24 months was higher in the CS group compared to EEN at all time-points (5% vs. 4%, 12% vs. 10%, 22% vs. 13%, and 27% vs. 16%, respectively, p=0.045; figure 1). The survival-probability of hospitalization was higher in the CS group (16% vs 9%, 20% vs. 2%, 25% vs. 14% and 27% vs. 15%, respectively, p=0.024; figure 2). Hemoglobin and albumin improved more in the EEN group (p=0.046, p=0.035; table 1). During the two years from diagnosis the median height-z-score decreased in the CS group, while it improved in the EEN group (p<0.005, Figure 3).

Conclusions

EEN as induction therapy in pediatric CD is associated with a lower long-term risk of CDC and superior improvement in haemoglobin, albumin and growth compared with CS. This even when adjusting to baseline disease severity and patients' characteristics.

Objectives and Study

Early-life hygiene exposures are believed to modify the risk of inflammatory bowel disease (IBD), but prospectively collected data are scarce. In a prospective bi-national cohort, we aimed to examine whether early-life hygiene-related factors influenced the risk of IBD and test its consistency across cohorts.

Methods

We followed 117,493 participants from the Swedish ABIS and Norwegian MoBa cohorts, from birth (1997-2009) throughout 2021, for IBD diagnoses defined by national registers. Data on hygiene-related exposures, including having pets, rural vs urban living, daycare attendance, siblings, household crowding (<25sqm/person), drinking water (private vs public water source), and bedsharing were retrieved from repeated questionnaires during the first three years of life. Cox model yielded adjusted hazard ratios (aHRs) for IBD accounting for the child’s sex, parental IBD, parental education level, parental origin, and maternal comorbidities. Cohort-specific estimates were pooled using a random-effects model.

Results

During 2,026,362 person-years (PYR) of follow-up, 451 participants developed IBD (ABIS, n=113; 31/100,0000 PYR; MoBa, n=338; 20/100,000 PYR). In pooled estimates, children attending daycare by 36 months of life, vs not, seemed less likely to later develop IBD (aHR=0.73; 95%CI=0.52-1.01), particularly Crohn’s disease (aHR=0.60; 95%CI=0.37- 0.98); in contrast, children having one or more older siblings seemed at higher risk of IBD (aHR=1.17; 95%CI=0.96-1.42; aHR for each additional older sibling, aHR=1.12; 95%CI=1.01-1.24). Rural vs urban living, having pets, and early-life drinking water were not significantly linked to later IBD (Figure 1). In MoBa, but not in ABIS, bedsharing was associated with an increased risk of IBD, particularly ulcerative colitis (aHR=1.67; 95%CI=1.01-2.78).

Figure 1. Hygiene-related exposures of early-life and pooled hazard ratios (HR) for inflammatory bowel disease.

Conclusions

In this Scandinavian birth cohort study, some, but not all, hygiene-related exposures of early life were associated with IBD risk; their lack of consistency in direction and magnitude of associations on IBD risk should warrant further research.

Objectives and Study

We prospectively evaluated the interpretability, diagnostic yield and tolerance of high-resolution (impedance-)manometry (HR(I)M), 24hr-pH-impedance (pH-MII) and pH-MII with manometry (pH-MII+mano, 2 catheters).

Methods

Patients who were scheduled for the aforementioned tests between May 2020 and June 2021 were asked to participate. Included patients were divided in age groups(0-4yrs;4-12yrs;> 12yrs) and completed the DISCO-RC questionnaire, which addresses nervousness, annoyance, pain, fright, boredom and tiredness on a 5-point Likert-scale. Questions are scored from 0(not at all) to 4(extreme), total score 0-24. Three months later we evaluated if these tests resulted in clinical management, that would likely not have occurred without testing. Differences between tests were assessed (Mann Whitney U or Kruskal Wallis test).

Results

Forty-nine HR(I)M, 36 pH-MII and 9 pH-MII+mano were performed in 62 participants (age: 13[0-18]yrs) referred for evaluation of esophageal motility, gastroesophageal reflux and rumination respectively. Nine(25%) pH-MII catheters were placed under sedation. Seven (7.4%) tests (5 HRM & 2 pH-MII) were uninterpretable. Respectively 32/35(91.4%) and 18/21(85.7%) of the abnormal HRM and pH-MII explained symptoms. All normal tests were considered clinically helpful by the attending physician. Sixty-seven (71.3%) tests led to clinical management that would likely not have occurred without testing.
Median DISCO-RC scores were 7.0[1-17], 6.0[0-19] and 14.0[9-17] in HR(I)M, pH-MII and pH-MII+mano, respectively. DISCO-RC scores and subscores were comparable between HR(I)M and pH-MII, but pH-MII+mano were significantly higher than HR(I)M and pH-MII (p=0.033 & p=0.005), due to higher DISCO-RC-subscores on the pain and fatigue domain. No differences in DISCO-RC-scores were found between age groups.

Conclusions

HRM, pH-MII and pH-MII+mano are well interpretable and clinically useful. HR(I)M and pH-MII are reasonably tolerated and had DISCO-RC-scores comparable to e.g. gastro-intestinal colonoscopy under general sedation (van Wassenaer, 2022). pH-MII+mano is less well tolerated and should be reserved for patients in whom the diagnosis of rumination cannot be made without.

Objectives and Study

One of the numerous challenges to disease management in inflammatory bowel disease (IBD) is the need for repeated invasive assessment by endoscopy and imaging particularly in the pediatric population. Existing noninvasive assessment using calprotectin has low specificity and wide heterogeneity. Cell free DNA (cfDNA) are nucleosome-size fragments of DNA released from dying cells into body fluids. In this pilot study, we hypothesized that circulating human cell free DNA (cfDNA) levels would be elevated in the stool of patients with active IBD.

Methods

We developed a novel platform for minimally invasive assessment of the source of specific cell types in humans, based on DNA methylation patterns of cfDNA in body fluids. Children (0-18 years) were prospectively enrolled various stages of disease. Stool samples were assessed for total human DNA content and cfDNA with intestinal (duodenum and colon) and immunological markers. Demographic, clinical, laboratory, endoscopic, and histological data were prospectively collected at diagnosis and various stages of disease using the prospective inception registry of Shaare Zedek Medical Center. These measures were correlated with cfDNA markers. Disease activity was measured by wPCDAI in CD and PUCAI in UC.

Results

196 stool-derived DNA samples were collected from 122 children with Crohn's disease (CD), 74 with ulcerative colitis (UC) and 40 controls. Total human DNA (Figure 1A) and cfDNA with intestine and leukocyte markers differentiated between controls and IBD (CD and UC). cfDNA levels correlated with clinical disease activity in UC (Figure 1B) but not in CD. Children in remission had similar cfDNA levels as in controls.

Conclusions

In this pilot study we show that stool human DNA and cfDNA can differentiate between controls and children with IBD. In UC, cfDNA correlated with disease activity. Further studies are required to validate and apply this novel tool in clinical practice.

Objectives and Study

Ulcerative proctitis (UP) is an uncommon presentation in pediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of UP in children, and to identify predictors of poor outcomes.

Methods

The retrospective cohort study involved 37 sites affiliated with the IBD Interest group of ESPGHAN. Data were collected from patients aged<18 years diagnosed with UP between 01/01/2016-31/12/2020.

Results

We identified 250 patients with UP (median age at diagnosis 14.5 [IQR 12.3-15.9] years), with a median follow-up of 2.7 (IQR 1.7-3.9) years. The most common presenting symptoms were bloody stools (94%), abdominal pain (60%) and diarrhea (53%). At diagnosis, the median pediatric ulcerative colitis activity index (PUCAI) score was 25 (IQR 20-35) and most children had normal inflammatory markers. Nevertheless, endoscopic Mayo scores of 2 and 3 were identified in 55% and 19%, respectively. The median fecal calprotectin level was 720 mcg/g (IQR 310-1800); Notably ,19 patients (11.7%) had a calprotectin level <100mcg/g. By the end of induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 52%, 50% 73%, respectively. The rates of treatment escalation to biologics at 1, 3 and 5 years were 11%, 23% and 45% (Figure 1). In multivariate cox-regression analysis, the PUCAI score at diagnosis was highly associated with initiation of biologics and subsequent events with acute severe colitis and IBD-associated admissions. By the end of follow-up, 3.4% of patients underwent colectomy. Cecal patch (P=0.009), higher PUCAI score (P=0.009) and lack of steroid-free clinical remission (P=0.005) by the end of induction were associated with proximal disease extension, identified in 48%.

Conclusions

We present data on the clinical presentation and natural history of the largest cohort, to date, of pediatric patients with UP. These patients exhibit high rates of proximal disease extension and treatment escalation.

Objectives and Study

We aimed to describe disease activity (DA) patterns in a Danish nationwide cohort including all paediatric inflammatory bowel disease (pIBD) patients diagnosed < 18 years of age between 1996 and 2018.

Methods

Paediatric patients diagnosed with Crohn’s disease (pCD) or ulcerative colitis (pUC) were identified from national registers. DA was assessed in both incident and prevalent pIBD patients and categorised as mild-moderate in case of a course of topical corticosteroids, oral budesonide, or topical 5-ASA. Episodes were categorised as severe if they involved hospitalization, surgery, oral corticosteroids or biological therapy. The DA patterns for 5- and 10-year periods were assessed.

Results

1,965 pCD and 1,838 pUC incident patients were included. At diagnosis severe DA was found in 87% in pCD and 80% in pUC, in addition to 6.1% of pUC patients who had a colectomy the first year. After 5 years of disease the annual proportion of pCD and pUC with no DA 70% and 61%. This remained constant after 10 years (pCD:72% and pUC: 64%). In pUC, 12% and 16% required colectomy 5 and 10 years after diagnosis.

In prevalent pCD (N=2,515) and pUC (N=2,428) the proportion with no DA each calendar year was stable (pCD: 59%-73% and pUC: 50%-60%, prior to 2010). The majority of pCD and pUC patients experienced one or two years with at least one episode of DA within the first five years (pCD: 51%, pUC: 53%). During the first 10 years from diagnosis, the decreasing DA pattern was the most common in both pCD and pUC (43% and 47%, respectively) (Figure).

Conclusions

DA patterns in pIBD are characterised by a high proportion of severe activity initially with a decreasing pattern after 5 and 10 years follow-up. No change in the proportion of patients with no DA was seen despite the introduction of biologic therapy in the period.

Objectives and Study

The objectives of this study were to evaluate the efficacy and safety of adalimumab biosimilar (ADL-BioS) in pediatric inflammatory bowel disease (IBD).

Methods

This is a multicenter, observational study that enrolled all consecutive pediatric IBD patients treated with ADL-BioS from an Inflammatory Bowel Disease Network which encompasses all IBD centers in the area licensed to prescribe biologics for IBD. Study outcomes were clinical remission at weeks 14 and 52, treatment persistence, and adverse events. Factors related to clinical remission and treatment persistence were examined.

Results

Forty-one IBD children (Crohn's disease: 95.1%; ulcerative colitis: 2.44%; IBD unclassified: 2.44%) were included: nine (22.0%) patients were switched from the originator to ADL-BioS. Two (4.88%) patients underwent multiple switches (from ABP501 to GP2017). At weeks 14 and 52, 70.73% and 72.0% of patients achieved clinical remission, respectively. Dose escalation was required in 2.43% and 17.1% of patients during induction and maintenance, respectively. Patients with a shorter disease duration had a higher rate of remission at weeks 14(OR 0.72, 95%CI 0.53-0.95, p=0.029) and 52(OR 0.65, 95%CI 0.42-0, 92, p=0.027). In addition, remission at week 52 was associated with having not switched from the originator(OR 0.08, 95%CI 0.01-0.55, p=0.016) and lower CRP levels at baseline(OR 0, 23, 95%CI 0.05-0.73, p=0.03). Four adverse events occurred (incidence rate: 10.1/100 person-year). After 1 and 2 years, treatment persistence was 85.4%(Figure). Patients with longer disease duration had a greater risk of treatment discontinuation(HR 1.38, 95%CI 1.02-1.87, p=0.036).

Figure. Treatment persistence with adalimumab biosimilar estimated according to the Kaplan-Meier method and table with the number of subjects at risk

Conclusions

To the best of our knowledge, this is the first real-world study specifically addressing the use of ADL-BioS in pediatric IBD. ADL-BioS appears to be effective in children with IBD, with high treatment persistence rates and a low incidence of non-serious adverse events.