Pediatric Crohn's Disease Activity Index Research Articles

Role of MR Enterography in Evaluation of Disease Activity in Pediatric Crohn’s Disease: Correlation between MR Enterography and Pediatric Crohn’s Disease Activity Index Scores

AbstractObjectives The aim of the study was to assess the role of MR Enterography (MRE) in the diagnosis and follow-up of children with Crohn’s disease (CD) and to correlate disease activity indices with known MRE features of active disease.Methods This was a retrospective study including 24 patients (median age 11 years, 17 males) with clinically and histologically proven CD who underwent MRE. Two previously validated MRE scores—Magnetic Resonance Enterography Global Score (MEGS) and CD MRI index (CDMI)—were calculated. A correlative analysis was made between the Pediatric Crohn’s Disease Activity Index (PCDAI) score and MRE scores as well as individually with each MR variable. Comparison of both the MR scores was made between patients with different disease activity.Results MEGS and PCDAI scores showed strong positive correlation (r = 0.724, p = < 0.001); CDMI and PCDAI scores showed moderate positive correlation (r = 0.661, p = 0.0004). There was statistically significant difference in the MR scores between patients grouped by clinical activity. Among individual MR variables, mural thickness and enhancement best predicted the disease activity.Conclusions MRE-based scores and findings correlate with clinical activity in pediatric CD. Thereby, MRE can be considered a valuable tool in the management of CD, predicting disease activity and offering a potential alternative to endoscopy in monitoring patients during follow-up.

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial.

Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial. Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed. Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ± 2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P < 0.001 and body mass index from -0.4 (-1.0-0.5) to 0.0 (-0.8-0.9), P = 0.005. Pediatric CD activity index and erythrocyte sedimentation rate at week 4 correlated negatively with height z score changes (P = 0.043 and P = 0.048, respectively), whereas sustained clinical and biologic remission (week 4-72) were positively associated with changes in height z scores. Significant improvement in linear growth was predicted by lower pediatric CD activity index and erythrocyte sedimentation rate at the end of induction and sustained clinical remission (P = 0.05) and sustained normal C-reactive protein (P = 0.001) at all visits. In children with moderate-to-severe CD, ADL treatment had a significant effect on linear growth, with normalization of weight and body mass index (clinicaltrials.gov no: NCT02256462).

Pulmonary Manifestations in Adolescents With Inflammatory Bowel Disease.

Objectives. The available literature on pulmonary disease in pediatric inflammatory bowel disease is limited. We evaluated the prevalence of pulmonary manifestations in pediatric inflammatory bowel disease and their association with disease severity. Methods. Patients completed the St. George's Respiratory Questionnaire (SGRQ), a self-reported measure of quality of life in patients with pulmonary disease. Chart review provided demographic information and Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index scores. Regression models were utilized to evaluate associations between SGRQ score and clinical risk factors. Results. The prevalence of pulmonary manifestations was 9.62% (95% confidence interval = 5.48% to -15.36%). PCDAI scores in Crohn's disease patients with pulmonary symptoms were significantly higher (SGRQ mean = 10.71 ± 10.94) than in patients without such symptoms. SGRQ score was also higher in patients with indeterminate colitis (8.64, 95% confidence interval = 0.72-16.57, P = .03), when compared with Crohn's disease. Conclusions. Additional investigations including pulmonary function tests and imaging could provide further insight into this issue.

Trait Perfectionism and Psychosocial Outcomes in Adolescents With Inflammatory Bowel Disease.

The aim of this prospective cross-sectional study was to examine perfectionism, disease self-management, and psychosocial outcomes in a sample of adolescents with inflammatory bowel disease (IBD). Adolescent patients with IBD and caregivers were enrolled in the study. Patients completed the Child and Adolescent Perfectionism Scale, the Strengths and Difficulties Questionnaire (SDQ), and the TRANSITION-Q. Parents completed the Multidimensional Perfectionism Scale and the parent form of the SDQ. Health care providers reported on disease activity using the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn Disease Activity Index (PCDAI). Ninety adolescents (mean age 15.17 ± 1.49, range = 12-18) with diagnosed IBD (51 CD, 37 UC, and 2 IBD-U) and 76 primary caregivers participated in the study. Results indicated high rates of self-oriented perfectionism in adolescents with IBD (59% of sample reported elevated rates; 33% of sample in the clinical range). After accounting for age, sex, and disease activity, self-oriented perfectionistic striving was associated with better disease self-management; nonetheless, adolescent and parent perfectionistic strivings were also related to higher adolescent internalizing symptoms (standardized beta = 0.22 and 0.29, respectively). Additionally, perfectionistic concerns (self-critical and socially prescribed perfectionism) were associated with higher rates of adolescent-reported externalizing symptoms (standardized beta 0.30 and 0.24). Further, multilevel mixed modelling found no differences within-dyad in relation to perfectionism, but documented that adolescents report higher levels of externalizing symptoms compared with parents. The present study explores the prevalence and presentation of perfectionism in a sample of adolescents with IBD. Results suggest dimensions of perfectionism are differentially associated with psychosocial and disease management outcomes, suggesting further evidence of the relationship between perfectionism, maladaptive coping, and subsequent influences on health outcomes in the context of pediatric chronic illness.

Role of Thiopurines in Pediatric Inflammatory Bowel Diseases: A Real-Life Prospective Cohort Study.

Use of thiopurines for inflammatory bowel diseases (IBDs) is declining in some parts of the world. We aimed to explore outcomes of thiopurines and predictors of response in a real-world prospective cohort of children with dose optimization. Children with IBD treated with thiopurines without biologics were enrolled. Dosing was guided by thiopurine S-methyltransferase-activity at baseline and by clinical response and toxicity at 4 months; 1 year into the study, therapeutic drug monitoring at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 months (SFR), using the intention-to-treat approach. A total of 129 children were included (74% Crohn disease [CD] and 26% ulcerative colitis [UC]). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal erythrocyte sedimentation rate/C-reactive protein in 20 (21%) and 9 (27%), respectively. At 4 months, mean corpuscular volume/white blood cell ratio and Δ absolute neutrophil count weakly correlated with 6-thioguanine (r = 0.33, P = 0.02 and r = 0.32, P = 0.02, respectively). In CD, SFR was associated with 4-month median weighted Pediatric Crohn Disease Activity Index (2.5 [IQR 0-7.5] in responders vs 5 in nonresponders [0-12.5], P = 0.048) and Δabsolute neutrophil count (1.7 [IQR 0.7-4.1] vs 0.05 [-2.3-0.9]; P = 0.03). Mild drug-related adverse events were recorded in 30 children (22%), 3 required stopping the drug. In this real-life prospective cohort using dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of C-reactive protein and erythrocyte sedimentation rate. Thiopurines remain a viable option in the treatment algorithm of mild-moderate pediatric IBD, especially in girls whose risk for lymphoma is lower.

A256 TRENDS IN THE PREVALENCE AND SEVERITY OF ANEMIA IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN THE LAST DECADE

Abstract Background Anemia is one of the most common extraintestinal manifestations in patients with inflammatory bowel disease (IBD) at diagnosis. Studies have shown that anemia was associated with low levels of quality of life, which improves with the correction of anemia in adults. Recent data have shown an increase in the incidence and severity of pediatric IBD. Aims To investigate the prevalence of anemia in children at diagnosis of IBD and the trends in the past decade. The secondary aim was to investigate the associations between hemoglobin (Hb) levels and disease characteristics. Methods Eligible patients (age ≤18 years, diagnosed with IBD from 2009 to 2018) were retrospectively identified through our IBD database. Disease localization and phenotype were defined according to the Paris Classification of IBD. Anemia was defined by Hb levels according to WHO targets. The annual prevalence of anemia was calculated according to subtype (inflammatory vs iron deficiency). The Pediatric Crohn’s Disease Activity Index (PCDAI) and the Pediatric Ulcerative Colitis Activity Index (PUCAI) were used to assess the disease severity at diagnosis. Results We included 887 patients (439 females), mean (SD) age of 13.1 (3.4) years. Of these, 519 (58.5%) were identified with anemia within 30 days of diagnosis. The median (IQR) Hb level was 108 (98 -114) g/dL. Severe anemia (&amp;lt; 70 g/dL) was present in 1.8 % of patients. The prevalence of anemia at diagnosis remained relatively stable ranging from 60.2% in 2009 to 60.4% in 2018. The annual proportion of inflammatory vs iron-deficiency anemia is displayed in figure 1. Anemia was more prevalent in Crohn’s disease (CD) (62.2%) than Ulcerative colitis (UC) (57.9%) or IBD-unclassified (39.6%). The disease severity scores were higher in those with anemia. The median (IQR) PCDAI and PUCAI were respectively 37.5 (27.5–47.5) and 55.0 (40.0–65.0) in the anemic group as compared to 27.5 (20.0–37.50) and 35.0 (25.0–55.0) in the non-anemic group; P&amp;lt;0.0001. Patients with anemia had a lower BMI z-score [median (IQR) -0.84 (-1.84 - 0.08)] than the non-anemic patients [median (IQR) -0.38 (-1.21 - 0.43)]; P&amp;lt;0.001. The prevalence of anemia correlated significantly with disease location: upper intestinal involvement [L4a(67.7%) L4b(63.6%) L4aL4b(60.7%) none (52.8%)] P = 0.024 for CD; for UC [E1(21.1%) E2(44.4%) E3(75.0%) E4 (71.1%)] P&amp;lt;0.0001. A moderate correlation was found between Hb levels and C-reactive protein (r= -0.312, 95% CI: -0.378 to -0.243, P&amp;lt;0.0001). Conclusions Anemia remains a prevalent symptom in pediatric patients with IBD, and it is correlated with the extent of intestinal involvement and disease severity. The impact of anemia at Diagnosis and during follow-up on the levels of quality of life and physical activity is currently under investigation. Funding Agencies None

A236 REAL LIFE HEALTH CARE UTILIZATION IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN THE ERA OF BIOLOGICS

Abstract Background The burden associated with the management of pediatric patients with inflammatory bowel disease (IBD) has been rising over the past years as the incidence of IBD is increasing in children. In addition, the widespread use of biologics and a treat-to-target approach also contributes to the increase of healthcare utilization. Aims The purpose of this study was to assess the health care services utilization and the associated factors in a prospective cohort of children diagnosed with IBD in Quebec. Methods Patients diagnosed from 2013 to 2015 and followed up until the transfer to adult care were identified in our IBD database. Data on IBD related services and treatments: imaging procedures, hospitalizations and outpatient visits, medications from diagnosis to transition was extracted. We analyzed the healthcare utilization according to the baseline disease severity (pediatric Crohn’s disease activity index (PCDAI) or pediatric ulcerative colitis activity index (PUCAI)) at diagnosis, and according to exposition to intravenous biologics. Results A total of 144 patients were included in the study [(77 males), Crohn’s disease (98), Ulcerative Colitis (31) and IBD-unclassified (15); median (interquartile(IQR)) age at diagnosis 15.2(14.3–16.3)]. The median(IQR) duration of follow up at the IBD clinic was 2.9 (1.8–3.9) years. The median (min-max) number of imaging procedures varied largely: esophagogastroduodenoscopy 1(0–2), Colonoscopy 1(1–6), abdominal ultrasound 1(0–13), abdominal MRI 1(0–4), tomodensitometry 0(0–2), Bone densitometry 1(0–5). Patients had various follow-up encounters (median (min-max)): outpatient visits 9 (1–28), IBD nurses phone follow-up 4(0–33). A total of 64.6% of patients had at least one hospitalization [median(min-max) number 1(0–10); median duration 4(0–150 days)] and 35.41% had at least one emergency room visit. Baseline disease severity did not predict the disease burden: the mean number of encounters was 3.0 /year in the moderate/severe group as compared to 2.5/year in the mild group; P= 0.61. Among the, 63.5% of patients exposed to an intravenous biologic (Infliximab or Vedolizumab), those exposed earlier (&amp;lt;3 months after diagnosis) used more health care services (mean = 3.3/year) than those exposed later (mean =2.23/year); P &amp;lt;0.0001. In addition, the median (interquartile (IQR)) cumulative days of healthcare utilization (missing school days) for patients treated with intravenous biologics was 48.5 (32.4–67.9) days during pediatric care. Conclusions Adolescents with IBD have several encounters between the diagnosis and transition to adult care. Disease severity at diagnosis was not related to a higher level of health services utilization during follow-up. However, treatment with intravenous biologics was associated with a high health service utilization and school missing during follow-up. Funding Agencies None

Quantitative evaluation of Crohn's disease using dynamic contrast-enhanced MRI in children and young adults.

To evaluate the clinical usefulness of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in children and young adults with Crohn's disease. From August 2017 to October 2018, 30 patients with Crohn's disease (21 males and 9 females; mean age 15.1 ± 2.5years) underwent DCE-MRI with MRI enterography. We assessed the endoscopic finding, pediatric Crohn's disease activity index (PCDAI), C-reactive protein (CRP) level (mg/dL), Crohn's disease MR index (CDMI) score, and the perfusion parameters of DCE-MRI (Ktrans, Kep, and Ve) at the ileocecal region between the inactive and active groups based on the histopathologic status. The active Crohn's disease group showed higher PCDAI, CRP, and CDMI scores than the inactive group (22.2 ± 18.8 vs. 6.3 ± 6.4, p = 0.027; 1.32 ± 1.79 vs. 0.10 ± 0.13, p = 0.005; 7.4 ± 3.9 vs. 4.5 ± 3.0, p = 0.047, respectively). The active Crohn's disease group showed a higher Ktrans value than the inactive group (0.31 ± 0.12 vs. 0.16 ± 0.46min-1, p = 0.002). Endoscopic finding; PCDAI, CRP, and CDMI scores; and Ktrans value were significant parameters in the identification of the active Crohn's disease (p = 0.002, p < 0.001, p = 0.029, p = 0.006, and p < 0.001, respectively). Ktrans value was the most significant value for identifying active Crohn's disease in the multivariate logistic regression analysis (p = 0.013). Ktrans value could discriminate between inactive and active Crohn's diseases. Ktrans value may have the potential to monitor the pediatric Crohn's disease activity. • With dynamic contrast-enhanced MRI, we can quantitatively monitor the Crohn's disease status in pediatric patients and provide proper management plans to clinicians. • The Ktransvalue of dynamic contrast-enhanced MRI perfusion parameter, as well as the clinical pediatric Crohn's disease activity index, C-reactive protein level, the endoscopic score, and the Crohn's disease MR index, was higher in the active Crohn's disease than in the inactive group based on the histopathologic status. • The Ktransvalue among the dynamic contrast-enhanced MRI perfusion parameters was the most significant differentiating parameter for the active Crohn's disease from inactive status among those parameters (p=0.013).

P655 Pharmacokinetics of ustekinumab in children and adolescents with moderately to severely active Crohn’s disease: Results from UniStar, a phase 1 study

Abstract Background Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD) or ulcerative colitis. In the UniStar study, the pharmacokinetics (PK) of UST and its relationship with efficacy was evaluated in children who failed prior therapy. UniStar consisted of a PK portion (week 0–16) and extension (week 16–216); we report data through week 16. Methods UniStar is a multicentre, double-blind study (NCT02968108) designed to assess the PK, safety, and efficacy of UST in children (2–&amp;lt;18 years) with moderately to severely active CD, Paediatric CD Activity Index (PCDAI) score &amp;gt;30, and evidence of inflammation as measured by C-reactive protein &amp;gt;3.0 mg/l or faecal calprotectin &amp;gt;250 µg/g or ulcerations on ileocolonoscopy despite adequate treatment with corticosteroids and/or immunomodulators and/or anti-TNF therapies. Patients were randomised (1:1) and stratified by body weight (BW) and prior anti-TNF use for induction to one of 2 weight range-based IV doses: 130mg vs. 390 mg if BW ≥40 kg and 3mg/kg vs. 9 mg/kg if BW &amp;lt;40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW &amp;lt;40 kg. UST PK outcomes were assessed and compared with adult Phase 3 CD trials. Results 44 patients (59% ≥40 kg; &amp;gt;90% anti-TNF exposed) were randomised and treated with UST (n = 23 lower dose; n = 21 higher dose). Baseline demographics were generally similar between treatment groups. Most patients (67%) had a severe CD (PCDAI &amp;gt;40). At weeks 0 (1 h after infusion), 3, 6, and 8, mean serum UST concentrations (SUC) in the lower- (51.3, 7.7, 3.0, 1.6 μg/ml) and higher-dose groups (149.0, 23.7, 9.1, 4.8 μg/ml) were generally dose proportional (Figure 1a). Following SC UST at week 8, the impact of the difference in induction doses had diminished by week 16 when mean SUC was 1.5 µg/ml in the lower-dose group vs. 1.8 µg/ml in the higher-dose group. In the overall paediatric population (combined doses), serum UST concentrations were comparable to those in the reference adult CD studies (Figure 1b and c). In the higher dose group, we observed a pattern toward lower mean serum UST concentrations in patients weighing &amp;lt;40 kg vs. those weighing ≥40 kg; thus, UST should be dosed higher in patients &amp;lt;40 kg. Overall at week 8 and week 16, more patients achieved clinical response (PCDAI reduction ≥15) and biomarker improvement with higher UST concentrations, although this pattern was not observed for clinical remission (PCDAI ≤10; Figure 2). Conclusion Overall, UST PK was generally comparable between paediatric and adult patients with CD. A trend towards better efficacy outcomes with higher UST concentrations was observed in children similar to adults with CD.

DOP71 Efficacy, safety, and tolerability of ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: Results from, UniStar, a phase 1 study

Abstract Background Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD). The objective of this study was to evaluate the pharmacokinetics (PK), safety, and efficacy of UST in paediatric patients with moderately to severely active CD who had failed treatment with corticosteroids (CS) and/or immunomodulators (IM) and/or anti-tumour necrosis factor (TNF) therapies. Here, we report the safety and efficacy results through Week 16; PK results are reported separately. Methods This was a Phase 1, multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108) in patients aged 2 to &amp;lt;18 years (body weight [BW] ≥10 kg) with a Paediatric CD Activity Index (PCDAI) score &amp;gt;30 and at least an abnormal C-reactive protein &amp;gt;3.0 mg/l or faecal calprotectin &amp;gt;250 µg/g), or ulcerations in the ileum or colon upon ileocolonoscopy despite adequate treatment with CS ± IM ± anti-TNF therapy. Patients were randomised (1:1) and stratified by weight and prior anti-TNF use for induction to one of 2 weight range-based intravenous (IV) doses: 130mg vs. 390 mg if BW ≥40 kg and 3 mg/kg vs. 9 mg/kg if BW &amp;lt;40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW &amp;lt;40 kg. Results Forty-four patients (59% ≥40kg BW; &amp;gt;90% anti-TNF exposed) were randomised (n = 23 lower dose; n = 21 higher dose) and treated with UST. Baseline characteristics are summarised in Table 1. At week 16, in the lower dose and higher dose groups, 52%/52% achieved clinical response (reduction in PCDAI ≥15) and 22%/29% had clinical remission (PCDAI ≤10), respectively (Table 2). In addition, 32% and 28% of patients showed endoscopic response (reduction in Simple Endoscopic Score for CD of ≥50%), respectively. Through week 16, 73% of patients reported ≥1 adverse event (AE; 82.6% lower dose vs. 62% higher dose); 2 discontinued due to AEs (1 in each group). Serious AEs occurred in 16% of patients (26% lower dose and 5% higher dose, with CD exacerbation being the most frequent (13%/5%, respectively). Infections occurred in 41% of patients (1 was serious, which was intestinal abscess that spontaneously resolved with sequelae). No injection site reactions, opportunistic infections, malignancies, or deaths were reported. No antibodies to UST were observed. Conclusion As early as 3 weeks and through 16 weeks, both the lower and higher doses of UST (IV week 0 and SC at week 8) improved clinical and endoscopic disease activity in this previously treatment-refractory group of children with CD. The safety profile was consistent with that for UST in adults with CD.

P262 Trends in the prevalence and severity of anaemia in paediatric patients with inflammatory bowel disease in the last decade

Abstract Background Anaemia is one of the most common extraintestinal manifestations in patients with inflammatory bowel disease(IBD) at diagnosis. Studies have shown that anaemia was associated with low levels of quality of life, which improves with the correction of anaemia in adults. Recent data have shown an increase in the incidence and severity of paediatric IBD. We aim to investigate the trends in the prevalence of anaemia in children at diagnosis of IBD in the last decade. The secondary aim was to investigate the associations between haemoglobin (Hb) levels and disease characteristics. Methods Eligible patients (age ≤18 years, diagnosed with IBD from 2009 to 2018) were retrospectively identified through a prospective IBD database maintained at CHU Sainte-Justine, Montreal, Canada. Disease localisation and phenotype were defined according to the Paris Classification of IBD. Anaemia was defined by Hb levels according to WHO targets. The annual prevalence of anaemia was calculated according to subtype (inflammatory vs. iron deficiency). The Pediatric Crohn’s Disease Activity Index(PCDAI) and the Pediatric ulcerative colitis Activity(PUCAI) Index were used to assess the disease severity at diagnosis. Results We included 887 patients (439 females), mean(SD) age of 13.1 (3.4) years. Of these, 519 (58.5%) were identified with anaemia within 30 days of diagnosis. The median (IQR) Hb level at diagnosis was 108 (98 −114) g/dl. Severe anaemia(&amp;lt; 70 g/dl) was present in 1.8 % of patients. The prevalence of anaemia at diagnosis remained relatively stable ranging from 60.2% in 2009 to 60.4% in 2018. The annual proportion of inflammatory vs. iron-deficiency anaemia is displayed in Figure 1. Anaemia was more prevalent in CD (62.2%) than UC (57.9%) or IBD-U(39.6%). The median(IQR) PCDAI and PUCAI were respectively 37.5 (27.5–47.5) and 55.0 (40.0–65.0) in the anaemic group as compared with 27.5 (20.0–37.50) and 35.0 (25.0–55.0) in the non-anaemic group; p &amp;lt; 0.0001. Patients with anaemia had a lower BMI z-score [median(IQR) −0.84(−1.84–0.08)] than the non-anaemic patients[median(IQR) −0.38(−1.21–0.43)]; p &amp;lt; 0.001. The prevalence of anaemia correlated significantly with disease location: upper intestinal involvement [L4a(67.7%) L4b(63.6%) L4aL4b(60.7%) none (52.8%)] p = 0.024 for CD; for UC[E1(21.1%) E2(44.4%) E3(75.0%) E4 (71.1%)] p &amp;lt; 0.0001. A moderate correlation was found between Hb levels and C-reactive protein (r = −0.312, 95% CI: −0.378 to −0.243, p &amp;lt; 0.0001). Conclusion Anaemia remains a prevalent symptom in paediatric patients with IBD, and it is correlated with the extent of intestinal involvement and disease severity. The impact of anaemia at diagnosis and during follow-up on the levels of quality of life and physical activity is currently under investigation.

P517 A randomised, placebo-controlled pilot trial of faecal microbiota transplantation for paediatric Crohn’s disease

Abstract Background The role of faecal microbiota transplant (FMT) in Crohn’s disease (CD) remains unclear. Small, open-label case series have shown high rates of clinical remission but protocols have varied across studies, and no randomised controlled trials (RCT) have been performed. We present a protocol for the first pilot RCT of FMT in paediatric CD patients, using a novel colonoscopic + oral capsular intervention that uses fresh-frozen and prepared, lyophilised donor stool. We will measure improvements in clinical disease activity, inflammatory biomarkers, endoscopic markers of mucosal inflammation, as well as, assess key aspects of trial feasibility. Methods Patients 3–17 years with active CD, on stable medication doses for 4 weeks are eligible. Patients will have an initial colonoscopy during which they will receive an infusion into the terminal ileum of normal saline (placebo) or prepared healthy donor stool (RBX2660; Rebiotix, USA) (active). This will be followed by 6-weeks of bi-weekly oral capsular therapy, containing methylcellulose (placebo) or lyophilised healthy adult donor stool (RBX7455; Rebiotix, USA). Randomisation is 2:1 to active and placebo arms (n = 45). Patients will be followed over 24 weeks. (Figure 1) Results Study feasibility will be assessed by: rate of recruitment, completion of sample collections, and frequency and type of adverse events. Clinical outcomes will be measured serially using: Paediatric Crohn’s Disease Activity Index (PCDAI), faecal calprotectin, blood inflammatory markers, and Simple Endoscopic Score for Crohn’s Disease (SES-CD) at baseline and end-of-study. Stool 16s rRNA, metagenomics, and urine metabolomics profiles will be performed on collected stool and urine samples. Patients who complete the placebo arm will be eligible to enter an open-label extension study. Results will be measured through ITT and PP analyses. Proportions and percentages will be reported on feasibility outcomes; odds ratios, mean differences and 95% confidence intervals will be reported on clinical outcomes as preliminary estimates of efficacy. Conclusion This is the first pilot RCT of FMT in the treatment of CD. Recruitment commenced April 2019 and 13 patients have met screening criteria, with 5 enrolled thus far. This study is novel for its focus on paediatric CD patients, and its use of a combined oral + colonoscopic FMT delivery method. The results of this trial will offer preliminary estimates of efficacy for FMT-based therapies in CD, and may support expansion to a future larger multicenter paediatric RCT using our validated study protocol.

OP38 Top-down infliximab superior to step-up in children with Moderate-to-Severe Crohn’s disease: A multicentre randomised controlled trial

Abstract Background In newly diagnosed paediatric Crohn’s disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but mostly used once patients are refractory, the so-called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective if initiated earlier in the disease course. We investigated whether initiation of IFX directly after diagnosis of moderate-to-severe CD, i.e. top-down (TD) treatment, results in a higher long-term remission rate compared with SU treatment. Methods For this international randomised controlled trial (RCT) patients aged 3–17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) &amp;gt;40 were included. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone combined with AZA as a maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. The primary endpoint of this study was sustained clinical remission (wPCDAI &amp;lt;12.5) at week 52 without the need for additional therapy or surgery. Secondary endpoints included patient rate using IFX at week 52, mucosal healing (SES-CD &amp;lt;3) and low faecal calprotectin levels (&amp;lt;250 μg/g) at week 10. Results 100 patients were included in 12 centres. Three out of 100 patients did not start with the study after randomisation (n = 97; 49 TD vs. 48 SU). At 52 weeks, 21/48 (44%) of TD patients were in clinical remission without a need for treatment intensification or surgery, while in the SU group this number was significantly lower (8/48, p = 0.004). After induction therapy, IFX was (re)started in 19/49 (39%) TD patients compared with 30/48 (62%) SU patients within 52 weeks (p = 0.019). At week 10, significantly more TD (27/44, 61%) than SU treated patients (17/44, 39%) were in clinical remission (p = 0.033). Fifty-seven of 97 consented to endoscopy at week 10. Endoscopic remission rates were higher in TD (16/27 [59%], median SES-CD 1 [IQR 0–5]) than SU treated patients (5/30 [17%], median SES-CD 6 [IQR 3–16], p = 0.001). Similarly, low faecal calprotectin levels were more frequent in the TD group (n = 75; TD 21/40 [53%] vs. SU 9/35 [26%], p = 0.027). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. TD treatment was superior to SU in achieving sustained clinical remission. Therefore, we advise to start IFX directly after diagnosis in moderate-to-severe paediatric Crohn’s disease patients.

Partial enteral nutrition induces clinical and endoscopic remission in active pediatric Crohn's disease: results of a prospective cohort study.

The aim of this study was to evaluate rates of clinical remission, endoscopic remission, and mucosal healing after a 6-week treatment period with partial enteral nutrition (PEN) and to compare them to those obtained by standard exclusive enteral nutrition (EEN) treatment in children with active Crohn's disease (CD). Twenty-five patients with active CD (median age 13.6 years, range 3.6-18.0) were recruited to either PEN (n = 12) or EEN (n = 13) treatment groups. The PEN group received 75% of their dietary needs from a polymeric formula plus one meal per day from an anti-inflammatory diet (AID). Patients were assessed at weeks 0, 1, 3, and 6 using clinical and laboratory parameters. Endoscopic assessment was performed at induction and week 6. On intention to treat analysis, clinical remission (Pediatric CD Activity Index < 10) was achieved in 69.2% and 75.0% of EEN and PEN patients, respectively (p = 0.999). The endoscopic remission (Simple Endoscopic Score for CD (SES-CD) ≤ 2) rates were 45.5% in both groups, while mucosal healing rates (SES-CD = 0) were 45.5% with EEN and 27.3% with PEN (p = 0.659).Conclusion: The results of our prospective pilot study suggest that PEN, allowing one meal from AID, could be as effective as EEN in inducing clinical and endoscopic remission in children with active CD. However, larger randomized controlled studies are warranted to confirm our findings.Trial registration: This clinical trial was registered under the number ClinicalTrials.govidentifier: NCT03176875.What is Known:• Exclusive enteral nutrition is a first-line treatment in active pediatric Crohn's disease; however, patients often find it difficult to adhere to.• Exclusive enteral nutrition is more effective than corticosteroids in achieving mucosal healing.What is New:• This is the first prospective study on partial enteral nutrition in active pediatric Crohn's disease, evaluating not only clinical, but also endoscopic remission.• A novel approach of partial enteral nutrition that allows one meal per day from an anti-inflammatory diet was as effective as exclusive enteral nutrition in inducing clinical and endoscopic remission in active Crohn's disease.

Correlation of Dickkopf-1 with Inflammation in Crohn Disease

To explore the potential roles of Dickkopf-1 (DKK-1) and b-catenin in Crohn disease, and to evaluate the effects of a tumor necrosis factor (TNF)-a inhibitor on Wnt signaling in patients with the disease. We enrolled 21 patients who received infliximab treatment for one year and achieved clinical remission during the treatment period. Disease activity was graded according to the Pediatric Crohn's Disease Activity Index (PCDAI). Peripheral blood and colonic mucosal specimens were collected from all patients with Crohn disease and from 14 healthy controls. DKK-1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). Total RNA for DKK-1 and b-catenin from the frozen colonic tissue were obtained via real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), and albumin were also measured in patients with Crohn disease before and after infliximab therapy. The serum levels of DKK-1 were significantly higher in patients with Crohn disease than in healthy controls (P=0.003) and were decreased in those treated with infliximab (P=0.026). Serum DKK-1 level was correlated with levels of ESR (r=0.527, P=0.025), CRP (r=0.502, P=0.034), albumin (r=0.363, P=0.021) and PCDAI (r =0.462, P=0.054) in Crohn disease. DKK-1 mRNA expression in the colonic mucosa was higher in patients than in controls and decreased after infliximab treatment. b-catenin expression in the colonic mucosa was lower in patients than in controls and increased after infliximab treatment. However, the differences were not significant (P<0.05). DKK-1 might be an important mediator of the pathogenesis of Crohn disease, and changes in DKK-1 levels may serve as biomarkers of inflammation in these patients.

Inflammatory bowel disease is associated with increased gut-to-blood penetration of short-chain fatty acids: A new, non-invasive marker of a functional intestinal lesion.

What is the central question of this study? 'Leaky gut' has been found in intestinal and extra-intestinal diseases. However, functional evaluation of intestinal permeability is not widely used as a diagnostic marker, possibly owing to significant limitations of currently used permeability assays. There is an unmet need for development of a new, non-invasive test to assess intestinal function. What is the main finding and its importance? We show that an increased blood-to-stool ratio of the concentration of gut bacteria-produced short-chain fatty acids may be used as a marker of gut permeability. Our findings lay the groundwork for establishing a new, non-invasive, risk-free diagnostic tool in diseases associated with intestinal barrier malfunction, such as inflammatory bowel disease. Intestinal diseases, such as inflammatory bowel disease (IBD), are characterized by an impaired gut-blood barrier commonly referred to as 'leaky gut'. Therefore, functional evaluation of the gut-blood barrier is a promising diagnostic marker. We hypothesized that short-chain fatty acids (SCFAs) produced by gut bacteria might serve as a marker in IBD. Animal experiments were performed on male Sprague-Dawley rats with acetic acid-induced colitis and in sham control animals. The gut-blood barrier permeability was determined by assessing the ratios of the following: (i) portal blood concentration of SCFAs (Cp ) to faecal concentration of SCFAs (Cf ); (ii) systemic blood concentration of SCFAs (Cs ) to faecal concentration of SCFAs (Cf ); and (iii) Cp and Cs of fluorescein isothiocyanate (FITC)-dextran administered into the colon. As a clinical study, we evaluated Cs , Cf and the Cs /Cf ratio of SCFAs in six paediatric patients with IBD, assessed as mild/moderate/severe by the Paediatric Ulcerative Colitis Activity Index (PUCAI) and the Paediatric Crohn's Disease Activity Index (PCDAI) at the time of sample collection, and nine age-matched healthy control subjects. Rats with histologically confirmed IBD had significantly increased ratios of Cp /Cf and Cs /Cf for SCFAs. This was positively correlated with the plasma FITC-dextran concentration. Likewise, IBD patients showed a significantly higher Cs /Cf ratio for SCFAs, including acetic, valeric, isocaproic, caproic and propionic acids, in comparison to control subjects. In conclusion, in the rats and in paediatric patients with IBD we found an increased blood-to-stool ratio of SCFAs, suggesting an increased gut-to-blood penetration of SCFAs. These findings pave the way for a new, non-invasive diagnostic tool in IBD and other diseases accompanied by intestinal barrier malfunction.

A Symptom Self-report Tool for Children With Inflammatory Bowel Disease (IBDnow).

Clinical symptom evaluation for children with inflammatory bowel disease (IBD) is typically done using composite tools: the Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI). Both rely on clinician interpretation of child or parent symptom recall. No universal self-report tool has yet been developed for children with IBD to assess and report their symptoms. The research objective was to develop a self-report tool that produced information congruent with that obtained by clinicians using the PUCAI or PCDAI. A children's symptom self-report tool (IBDnow) was developed with picture and text Likert symptom scales. The clinician and child completed their reports during the same outpatient consultation. Agreement levels were calculated at the individual level (identical child and clinician answers), category level (symptom severity), and aggregate level (cohort scores). Internal consistency was measured with Cronbach alpha. One hundred children from Christchurch (New Zealand) (n = 65), and Sydney (Australia) (n = 35) completed the study (Crohn's Disease (CD):88, ulcerative colitis (UC):12), mean age 13.9 years (±3.6). Mean individual agreement was 0.76 (±0.19). Category severity had very good or good inter-rater reliability for 5 of the 7 symptom scales and overall severity agreement of 76%. Aggregate mean scores were significantly different between clinicians (14.9, ±18.8), and participants (21.6, ±19.4), (P <0.005, confidence interval -9.0, -4.4), but 60 pairs had scores within a 10% margin. Cronbach alpha was 0.74. This self-report tool had good proportionate agreement between raters, and good crude agreement for symptom categories. Assigning PUCAI or PCDAI scores caused inter-rater discrepancies to be misleadingly magnified. Pediatric gastroenterologists may consider utilizing IBDnow to elicit symptom self-reports from children with IBD to enable them to communicate meaningful information on their ongoing symptom burden. This would be a positive step in helping children feel included in clinical encounters and promoting self-management, at the same time producing valid, subjective symptom recall.

Development of Infliximab Target Concentrations During Induction in Pediatric Crohn Disease Patients.

Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders. Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes. We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5-40) and 14 μg/mL (8.3-24) compared to 18.8 μg/mL (9.1-23, P < 0.001) and 7.8 μg/mL (4-13.2, P < 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration >5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29 μg/mL. We found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial

Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n= 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n= 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week12. Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P= .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68-115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P= .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P= .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34-10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

Predictors of Long-term Clinical and Endoscopic Remission in Children With Crohn Disease Treated With Infliximab.

We aimed to identify early noninvasive predictors of clinical and endoscopic remission in children with Crohn disease (CD) under infliximab (IFX). Prospective observational study conducted in children with moderate-to-severe CD starting IFX. All patients underwent weighted pediatric CD activity index (wPCDAI) assessment, C-reactive protein and fecal calprotectin (FC) at week 0, 14, and 48. Endoscopy was performed at 0 and 48 weeks. The primary outcome was to determine the ability of 14-week wPCDAI, C-reactive protein, and FC to predict 1-year steroid-free clinical remission and mucosal healing. As a secondary outcome we evaluated their concordance with Simple Endoscopic Score for CD (SES-CD) at week 48. Forty-one children were enrolled. At 1 year, 21 (51%) and 16 (39%) were in clinical and endoscopic remission. Only combined postinduction FC and wPCDAI were able to predict 1-year clinical and endoscopic remission (hazard ratio 4.81 [95% confidence interval 1.76-20.45], P = 0.05 and hazard ratio 5.51 [95% confidence interval 1.83-26.9], P = 0.03). One-year SES-CD moderately correlated with FC (r = 0.52; P = 0.001). The FC cut-off value for mucosal healing was 120.5 μg/g (area under the curve 0.863, 83% sensitivity, 75.5% specificity; P = 0.005). The concordance between wPCDAI and SES-CD was excellent and good for severe disease and remission (k 0.87 and 0.76). Post induction FC combined with wPCDAI can predict 1-year clinical and endoscopic response to IFX in pediatric CD. FC shows a moderate correlation with SES-CD, whereas wPCDAI has a good concordance with endoscopic remission or severe disease, but not with mild and moderate disease.