ANTIBIOTICS, URBAN ENVIRONMENT AND WESTERN DIET PATTERN INCREASE RISK OF PAEDIATRIC INFLAMMATORY BOWEL DISEASE: A META-ANALYSIS

Background: Our team (Xiong et al. 2021) recently developed an infliximab population pharmacokinetic (popPK) model in children and young adults with Crohn’s disease (CD). We found that prediction accuracy improved when all five covariates of drug clearance were included. Given the dynamic changes in the four covariates (weight, albumin, sedimentation rate, neutrophil CD64 expression) that occur during induction, we hypothesized that model-informed precision dosing to predict early trough concentrations (cTrough) from baseline covariates alone would be imprecise. Therefore, our aims were to: 1. Test the precision of the model predicted (a priori) cTrough compared to the observed cTrough at dose3 and dose4 and 2. Test whether disease progression modeling would provide more precise predictions.
Methods: REFINE is a prospective cohort of 78 children and young adults receiving infliximab at four medical centers from 2014-2019. The DSH retrospective cohort includes 161 children and young adults with CD who started infliximab at a single center from 2019-2021. REFINE cTroughs were obtained at every infusion while the DSH cohort had cTroughs obtained either at dose3, dose4 or both. Model imprecision was calculated by the root mean square error (RMSE%) and percent bias by the mean prediction error (MPE%). The Pearson r and R² were used to calculate the correlation between the observed and the model predicted cTrough.
Results: The median (IQR) age at the start of infliximab was 14.3 (11-16) years with 32% female, and 85% white race. The median starting dose was 7.1 (5.5-10) mg/kg. Using the combined cohorts, we first calculated the observed percent improvement of all four covariates from dose1-dose3 and from dose1-dose4 (Table1). We then assessed the a priori predicted cTrough at dose3 and dose4 for both cohorts using the Xiong et al. popPK model and Bayesian estimation under three conditions. Condition1: cTrough were predicted using only the four baseline (pre-treatment) covariates of clearance. Condition2: cTrough were calculated using a combination of the baseline covariates and the calculated improvement (from baseline as shown in Table1) in all four covariates at either dose3 or dose4. Condition3: combination of Condition2 and one observed cTrough (week2 for dose3 and week6 for dose4 predictions). As shown, the MPE% improved when the simulated dose3 covariates were included in the prediction (Table2, A2). Furthermore, the correlations between the predicted and observed dose3 cTrough also improved for ConditionA3. For dose4, incorporating the week6 level improved the RMSE% and Pearson correlation (ConditionB3).
Conclusions: Disease progression modeling improves the precision of predicting the targeted dose3 (week6) cTrough. Disease progression modeling will be incorporated in our PK dashboard to perform more accurate model-informed precision dosing.

Introduction: Both the Crohn’s Disease Exclusion Diet combined with Partial enteral nutrition (CDED+PEN) and exclusive enteral nutrition (EEN) induce remission in mild-to-moderate pediatric Crohn’s Disease (CD) and are associated with a marked decrease in fecal kynurenine (Kyn) levels. This suggests a link between the clinical outcome of dietary therapy and changes in tryptophan (TRP) metabolism. TRP is necessary for the formation of serotonin and melatonin. Alterations in serotonin-melatonin pathway were observed in colitis. Dietary TRP is also metabolized through the KYN pathway. KYN pathway metabolites such as KYN and quinolinic acid (QUIN) have been suggested to play a vital role in modulating the intestinal immune response. Here, we characterize the changes in fecal TRP metabolites induced by CDED+PEN or EEN and their association with remission.

Methods: We investigated the changes in 21 TRP metabolites (belonging to serotonin, KYN or indole pathways) in fecal samples from previously performed a 12-week prospective trial (Ghiboub et al, 2022) comparing two different nutritional therapies (CDED+PEN vs EEN) for remission induction in mild to moderate pediatric CD. After 6 weeks, the EEN group could return to a free diet with 25% of calories from PEN. The primary outcome was the tolerability to the dietary therapy. Secondary endpoints were intention-to-treat (ITT) remission at week (W)6 (defined by Pediatric CD Activity Index (PCDAI) ≤ 10) and corticosteroid-free ITT sustained remission at W12. TRP metabolites at week (W)0, W6 and W12 of 73 samples were measured by liquid chromatography coupled with high-resolution mass spectrometry. The data were analyzed according to clinical outcome groups of baselines (W0), induced remission (W06_rem), no-remission (W06_nr), sustained remission (W12_sr) and non-sustained remission (W12_nsr).

Results: In CDED+PEN, the drops in some components of KYN pathway such as KYN (P= 9.67E-4) and QUIN (P= 0.04) were associated with W06_rem, which were maintained in W12_sr (P= 0.003 and 0.02, respectively). In EEN, a significant decrease in QUIN was also associated with W06_rem (P= 0.02) and W12_sr (P= 0.03). Remarkably, serotonin pathway metabolites such as melatonin, N-acetyl-serotonin and 5-OH-tryptophan, were increased in samples from patients maintaining remission at W12 with both CDED+PEN and EEN. Importantly, in samples from patients failing to sustain remission, no significant changes were observed. The ratios of KYN/melatonin and QUIN/melatonin performed well as markers for remission.

Conclusion: The reduction in KYN pathway compounds and the increase in serotonin pathway compounds are associated with diet-induced and sustained remission. Further studies are warranted to assess causality and the association of these metabolites with specific diet and lifestyle factors, affecting sustained clinical remission.

Upadacitinib (UPA), a selective Janus kinase (JAK)-1 inhibitor approved for adults with ulcerative colitis (UC), has limited pediatric data. However, it may be a viable therapeutic option in children with previously refractory inflammatory bowel disease (IBD). We aimed to evaluate response and safety of UPA induction in patients with refractory pediatric IBD.

Methods: This is a single-center retrospective cohort study of patients with pediatric IBD refractory to ≥1 biologic and/or small molecule therapies treated with UPA. Data collected from the electronic medical record included demographics, disease characteristics, labs, and adverse events. Clinical response was defined as a decrease in Pediatric Crohn Disease Activity Index (PCDAI) ≥15 or Pediatric Ulcerative Colitis Activity Index (PUCAI) ≥20. Secondary endpoints included change in physician global assessment (PGA) and labs. Continuous and ordinal variables were analyzed using the Wilcoxon signed-rank test.

Results: Of 23 patients prescribed UPA, 11 met criteria (4 Crohn's, 5 UC and 2 IBD-Unclassified). Reasons for exclusion included insurance denial (8 patients), transfer of care (3), <14 days of therapy (1). The median age at initiation was 15 years (IQR 13,17), 36% were female, and 82% were non-Hispanic white. The median disease duration was 2.4 years (1.6, 7.5). Of the 7 patients with UC/IBDU, 5 had pancolitis, and all had history of severe disease (prior PUCAI >65). All patients with Crohn disease had predominantly colonic disease and 3 had perianal disease. Indications for UPA were failure of biologic therapy, steroid dependence, and refractory perianal disease. Nine patients were refractory to ≥2 biologics/JAK inhibitors. One patient was on prednisone at initiation. At baseline, 63% had severe disease based on PGA and 82% had moderate to severe disease based on PUCAI/PCDAI. UPA induction dosing was 45mg daily for patients ≥39 kg and 30mg for patients <39 kg.

Follow up was at a minimum 4 weeks post-UPA initiation with median of 70 days (IQR 51,108). Table 1 compares baseline and follow up labs and disease activity. Clinical response was achieved in 73%, and 80% achieved remission (p=0.006) as measured by PCDAI/PUCAI. 63% had quiescent disease measured by PGA (p=0.006). Prednisone was successfully stopped in 1 patient by 8 weeks, and 1 patient underwent diverting ileostomy in the first 2 weeks. There were no allergic reactions to UPA. Three adverse events included nausea, acne, and worsening tics in known tic disorder.

Conclusion: This is a single center experience using UPA to treat a refractory pediatric population with IBD. Clinical response was achieved in most patients during induction with few reported adverse events. Further prospective data collection of an expanded cohort is ongoing. Selective JAK inhibition may be an effective and targeted approach in pediatric patients with IBD.

Background and Aims
Genetic and environmental factors influence pathogenesis of inflammatory bowel disease (IBD). Rising IBD incidence in developing countries and among immigrant populations in developed countries suggests diet and other environmental factors may impact disease expression post migration. Up to one-third of Crohn’s disease cases are diagnosed before age 21 years, yet the role of diet and environmental factors in paediatric IBD (PIBD) pathogenesis is not well understood. The aim therefore was to run a meta-analysis to understand the contribution of diet and other environmental factors in PIBD.
Methods: A systematic search was conducted in Medline, Embase and CINAHL databases to identify studies reporting associations between diet and other environmental exposures prior to paediatric IBD diagnosis. Environmental factors reported in two or more studies that had comparable outcome measures underwent meta-analyses providing pooled estimates (odds ratios (OR) and/or hazard ratios) and 95% confidence intervals (CI).
Results: Of 4763 studies screened, 35 observational studies (24 case control, 10 cohort and 1 cross sectional) that included 461,4902 participants were analysed. The pooled OR for PIBD among those exposed to antibiotics during early childhood and who had 1-4 course/s or >4 antibiotic courses had markedly higher odds of PIBD diagnosis (OR 4.54 (1.47 -14.02, p=0.009); 2.55 (1.79 -3.65; p=0.000) and 3.46 (2.14 – 5.60; p=0.000) respectively). Higher education/high SES/full-time parent employment and urban living had higher odds of PIBD (OR 2.55 (1.40 – 4.63; p=0.002) and 1.70 (0.96 – 3.00; p=0.067) respectively). For dietary patterns, regular/higher vegetable intake was associated with lower risk of PIBD (OR 0.47(0.2 – 1.06; p=0.067)), while regular intake of sugary beverages and/or candies conferred higher risk (OR 2.02 (1.06 – 3.85; p=0.033)). Breastfeeding results were mixed (OR 1.05 (0.90 – 1.22, p=0.5)). Older maternal age (>29 years) was a risk factor (OR 2.55 (0.81 – 8.06; p=0.111)) for PIBD.
Conclusion: Higher frequency and age of first antibiotic use in early childhood conferred substantially greater risk of PIBD. Older maternal age was identified as a novel PIBD risk factor. Other early life exposure factors that conferred higher odds of PIBD, included urban / busier lifestyle/ less poverty and western diet pattern consisting of regular sugary beverages/foods and low vegetable intake. These are all factors that impact gut microbiota, indicating an urgent need for research in this field of PIBD research.
Figure 1. Forest plot showing summary adjusted hazard ratios and odds ratios for antibiotic exposure and paediatric inflammatory bowel disease risk at various ages of childhood
Figure 2. Forest plot showing summary odds ratios for western dietary pattern during childhood years and paediatric inflammatory bowel disease risk