Objectives and Study

Studies have reported conflicting findings regarding the association of timing of biologics initiation with disease course in IBD. In this nationwide study we aimed to explore whether early initiation of biologics is associated with better outcomes in pediatric Crohn’s disease(CD) and ulcerative colitis(UC).

Methods

Data of children(0-18 years) diagnosed with IBD in the epi-IIRN cohort from 2005-2020 were retrieved covering 98% of the population. To control for confounding by indication, we compared treatment strategies using the cloning, censoring and weighting method to emulate a target trial. Inverse probability of treatment weights were fitted per patient to adjust for time-varying confounders and selection bias. Survival probabilities were compared at 10 years post diagnosis through weighted Kaplan-Meier estimators. The 95%CIs were calculated using bootstrap with 500 replicates.

Results

Of the 34,375 patients diagnosed with IBD, 2,157(29%) children with CD and 561(25%) with UC received biologics and included in the analysis. In total, 478CD and 73UC patients received biologics during the first three months after diagnosis, 575 and 134 during 3-12 months, 315 and 109 during 1-2 years, and 170 and 66 during 2-3 years post diagnosis. In CD, there was a modest although insignificant decrease in IBD-related surgeries at 10 years post diagnosis when initiating biologics prior to 3 months compared to the other periods (probability without surgery 0.75[95%CI 0.67- 0.83] of 0-3 months vs 0.68[0.61-0.75] of 2-3 years;p=0.2). A similar observation was apparent for steroid-dependency (0.78[CI 0.72-0.84] vs 0.74[CI 0.69-0.79];p=0.31)(Figure). In UC, there was a significant decrease in steroid-dependency among early initiators (0.7[0.69-0.7] vs 0.41[0.40-0.41];p<0.001) but not in colectomy rates(Figure).

Conclusions

In CD numerical but not statistical superiority was apparent for early initiators whereas in UC, this was apparent only for steroid dependency and not for surgery. Taken together it seems that the added benefit of early initiation of biologic is modest on average.

Objectives and Study

Peutz-Jeghers Syndrome (PJS) is characterized by the development of small intestinal hamartomatous polyps from the first decade of life. Management in children centers on the prevention of polyp-related intussusception. A strategy of surveillance including small bowel capsule (SBC) followed by polypectomy is increasingly being implemented. There is limited understanding of the polyp burden observed on SBC in these individuals. Herein we describe our detailed observations on polyp burden in pediatric patients with PJS.

Methods

We performed a retrospective longitudinal observational study including all patients with PJS followed through our institution who underwent SBC between 1/2010 and 12/2020. The SBCs were read in tandem(JWS/NRF, TMA). Findings were categorized by number of polyps per tertile, total number, largest visualized polyp and % luminal occlusion by largest polyp. Statistical inferences were made utilizing RStudio 2022.07.2.

Results

The cohort included 19 patients (M;12, mean age 14.0 SE 0.46 years) who underwent 65 (Median;3) studies, 54 complete, 41 categorized as good / excellent quality. There was no gender difference in polyp number (Figure 1A) but polyps (Figure 1B) were significantly larger in males (p=0.01). Estimated polyp size and luminal occlusion were directly related (p <0.002). The number of polyps was related to study duration (p = 0.0049). There was no significant relationship between symptoms and either largest polyp size or total polyp number. In contrast with earlier studies, studies following the introduction of a DBE strategy showed largest observed polyp size to be significantly decreased with age, (p = 0.026) when adjusted for gender.

Conclusions

Most polyps observed with SBC in pediatric PJS are smaller than 10 mm, they favor involvement of the middle tertile and are larger in males. Polyp burden does not relate to symptoms. In our cohort, the introduction of an SBC surveillance – DBE strategy was associated with significant overall reduction in polyp burden.

Objectives and Study

Children born <29 weeks’ gestation have full-scale intelligence quotients (FSIQ) 12 points lower than term-born populations and are more likely to have cognitive impairments. This study aimed to determine whether supplementing infants born <29 weeks’ gestation with the estimated in utero dose of DHA improves IQ.

Methods

1273 infants born <29 weeks’ gestation were randomised to receive an enteral DHA supplement (providing 60 mg/kg/day of DHA) or a control emulsion (without DHA) from within 3 days of their first feed to 36 weeks’ post menstrual age. 656 children were eligible and invited to undergo the Wechsler Preschool and Primary Scale of Intelligence (FSIQ, 4th edition) at five years’ corrected age and parents of 952 children were invited to complete questionaries about behaviour, quality of life, symptoms of asthma and allergies, and diagnosed health complications. Analyses were intention to treat, and missing data were addressed using multiple imputation.

Results

FSIQ was available for 480 (73%; 241 in the DHA group, 239 control group) and 731 parents completed the questionnaires (77% 361 in the DHA group, 370 control group). Following imputation, children in the DHA group (n=323) had a significantly higher FSIQ (mean 95.4, SD 17.3) compared with children in the control group (n= 333; mean 91.9, SD 19.1; adjusted mean difference 3.5, 95% confidence interval 0.4 to 6.5, P=0.03). Parent-rated questionnaire results were comparable for the two groups for behaviour, quality of life, allergies, and health complications, suggesting no long term adverse effects.

Conclusions

Meeting estimated in utero DHA levels during the neonatal period is one of the few strategies to improve FSIQ for infants born <29 weeks’ gestation.

Objectives and Study

Alagille syndrome (ALGS) is a rare, multisystem disorder caused by mutations in JAG1 or NOTCH2 with hepatic manifestations that include elevated bile acids (BAs) and pruritus associated with impaired sleep and quality of life. Results from the phase 3 ASSERT study (NCT04674761) that evaluated efficacy and safety of odevixibat, an ileal bile acid transporter inhibitor, in patients with ALGS are presented.

Methods

Patients with a confirmed diagnosis of ALGS, history of significant pruritus, and elevated BAs were randomized 2:1 to odevixibat 120 μg/kg/day or placebo, respectively. The primary endpoint was change from baseline to month 6 in observer-reported scratching score. Secondary endpoints included change from baseline to the average of weeks 20 and 24 in serum BAs and change from baseline to month 6 in sleep parameters. Safety monitoring included assessment of treatment-emergent adverse events (TEAEs). Two-sided P values are reported.

Results

Overall, 52 patients (mean age, 6.3 years) received odevixibat (n=35) or placebo (n=17); all 52 patients completed the study. Odevixibat treatment for 24 weeks resulted in highly statistically significant and clinically meaningful improvements in pruritus at month 6 vs placebo (P=0.0024; Figure); changes occurred rapidly with odevixibat and were sustained. Additionally, BAs were significantly reduced at the average of weeks 20 and 24 with odevixibat vs placebo (P=0.0012; Figure). Odevixibat-treated patients experienced improvements in multiple sleep parameters at month 6 vs placebo (Figure). Incidence of drug-related TEAEs was similar across groups (23% vs 18% for odevixibat vs placebo). Incidence of treatment-emergent and drug-related diarrhoea was 29% and 11%, respectively, with odevixibat, and 6% each with placebo.

Conclusions

The ASSERT study met its primary and key secondary endpoints. Odevixibat treatment in patients with ALGS led to rapid, sustained, and highly significant improvements in pruritus, reductions in BAs, and improvements in sleep. Odevixibat was generally well tolerated.

Objectives and Study

Irritable bowel syndrome (IBS) is a common chronic medical condition, in both children and adults. Despite available (non-) pharmacological treatments, symptoms persist in approximately 25% of young IBS-patients. Fecal microbiota transplantation (FMT) might be an effective alternative treatment through manipulation of the intestinal microbiota for refractory adolescents with IBS.
Objective To assess the efficacy of FMT in adolescents with refractory IBS.

Methods

Thirty-two patients (16-21 years) with refractory IBS were randomized (1:1) to receive two allogeneic (healthy donor) or autologous (own) fecal infusions at baseline and after 6 weeks. Abdominal symptoms were assessed using the IBS Severity-Scoring-System. To evaluate clinical efficacy the proportion of responders (patients with ≥50 points reduction in the IBS-SSS total score) were evaluated at 12 weeks after the first FMT and at 6 months follow-up. Secondary outcome included health-related quality of life (QoL).

Results

At baseline, median (IQR) IBS-SSS total score did not significantly differ between groups (allogeneic 325 (250-360) vs. autologous 335 (251 – 362)). Response rates were 40% and 38% 12 weeks after the first allogeneic and autologous FMT, respectively. At 6 months follow-up, significantly more patients responded after allogeneic fecal infusions (60% vs. 25% autologous FMT, p = .048). Total QoL score at baseline did not differ between groups (allogeneic: 73 (61-86) vs. autologous: 70 (50-78)). At 12 weeks and 6 months follow-up total QoL score was significantly better after allogeneic than autologous FMT (82 (76-90) vs. 73 (58-81), p = .028 and 84 (74-92) vs. 68 (52-78), p = .007, respectively).

Conclusions

Allogeneic (healthy donor) fecal infusions were more effective than autologous fecal infusions after six months follow-up in reducing symptoms of IBS and improving health-related quality of life. The results of this trial provide preliminary evidence for the use of FMT in adolescents with refractory IBS.

Objectives and Study

Children with Familial Adenomatous Polyposis (FAP) develop adenomatous polyps by the second decade of life, however, there is considerable intra- and inter-patient variability in disease expression including polyp distribution and growth characteristics. Polyp size is a principal determinant of the risk of harboring cancer so that understanding the downstream pathways influencing adenoma growth may identify potential checkpoints amenable to pharmacologic intervention. We have completed a pilot study comparing the protein expression profile from polyp and non-polyp mucosa derived from a single region in the large intestine in patients with pediatric FAP.

Methods

We harvested 6 polyps (mean 14mm diameter) and 4 normal, non-polyp mucosal specimens from the left side of the colon in two patients with FAP undergoing elective colectomy for the standard clinical indications. We carried out a quantitative proteomic and phosphoproteomic analysis on both polyp and non-polyp mucosa. We analyzed the differential protein expression levels of 5253 proteins and 4232 phosphopeptides between the two groups of tissue.

Results

From >500 proteins and phosphopeptides significantly altered in expression between polyps and mucosa, we defined >200 significant differences in protein expression, with several enzymes regulating key pathways found to be differentially expressed in mucosal tissue (Fig. 1A) or polyp tissue (Fig. 1B)

Conclusions

We observed significant differential expression of several key enzymatic regulators of mRNA metabolism as well as protooncogenes involved in the regulation of apoptosis triggered by DNA damage. Our observations suggest that several pharmacologic agents currently undergoing clinical trial may be effective chemopreventive agents in pediatric FAP. In addition, we may have identified a potential interface between microbiome expression and adenomatous polyp growth.

Objectives and Study

We tested in a randomised double-blind trial, conducted in Germany and Spain, whether lower milk protein intake in the second year of life leads to lower BMI at 2 years of age.

Methods

1624 healthy, 12 months-old children were assigned to receive cows’ milk–based iso-caloric toddler formula with either lower (experimental) or higher (standard) protein content (LP: 1.5g protein/100 kcal vs. HP: 6.1g protein/100 kcal). Weight, length, and BMI (expressed as z-scores based on the 2006 WHO growth standards) were determined at ages 12, 18 and 24 months. The primary endpoint was BMI at 24 months adjusted for baseline BMI, sex and site. Dietary intake was assessed by 24-h recalls.

Results

1476 children in the LP (n = 744) and HP (n = 736) milk group were followed until 24 months. Total protein intake was ≈20% lower in the LP compared to the HP group and provided 14% (±3) vs. 18% (±3) from total energy respectively. Growth was generally adequate. BMI zscore was lower in the LP compared to the HP group at 18 (estimated difference: -0.07 [95%CI -0.12; -0.02]; p=0.039) but not different at 24 months (-0.04 [-0.10; 0.03]; p=0.258). Weight and length were significantly lower at 24 months in the LP compared to the HP group (both p<0.001). Between 12 and 24 months we observed age-appropriate length growth and weight gain in the LP but significantly increased weight and length in the HP group: difference in weight (0.09 [0.05; 0.12]; p<0.001) and in length (0.12 [0.08; 0.16]; p<0.001).

Conclusions

Protein content of toddler milk in the second year of life affects concurrent growth and weight gain. Lower protein supply decreased BMI at 18 but not at 24 months of age. Follow-up until 6 years of age is ongoing to assess later obesity risk.

This trial was registered at clinicaltrials.gov as NCT02907502.

Objectives and Study

Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders resulting in disrupted bile composition, cholestasis, and pruritus. We evaluated maralixibat, an ileal bile acid transporter inhibitor, in a Phase 3 placebo-controlled study open to participants with all PFIC types at higher doses than previously studied.

Methods

Participants aged 1-18 years had moderate to severe pruritus and elevated serum bile acid (sBA) levels. Participants were randomized 1:1 to maralixibat 570 µg/kg twice daily or placebo for 26 weeks. Primary and key secondary endpoints were mean change from Baseline in pruritus and sBA, respectively, in participants with non-truncating BSEP deficiency (BSEP cohort). Mean change in pruritus and sBA were also analyzed in All-PFIC cohort (BSEP cohort plus other PFIC types).

Results

93 participants were enrolled (maralixibat=47, placebo=46): 31 in the BSEP cohort, 64 in All-PFIC cohort (31 BSEP, 13 FIC1, 9 MDR3, 7 TJP2, 4 MYO5B) and 29 in exploratory cohort (heterozygosis, variants not found, post-surgical, intermittent sBA). Mean baseline age, sBA, pruritus, and liver biochemistries were balanced between groups. Mean reduction in pruritus (0-4 ItchRO scale) for maralixibat vs placebo was -1.7 vs -0.6 (p=0.0098) in BSEP cohort and -1.8 vs -0.6 (p<0.0001) in All-PFIC cohort. 64% (maralixibat) vs 26% (placebo) of participants achieved clinically meaningful 1-point pruritus reduction (p=0.0023). Mean reduction in sBA for maralixibat vs placebo was -176 vs. 11 µmol/L (p=0.0013) in BSEP cohort and -157.5 vs. 2.9 (p<0.0001) in All-PFIC cohort. In All-PFIC cohort, total and direct bilirubin and weight significantly improved under maralixibat vs placebo. The most common adverse event was diarrhea (57.4% maralixibat vs 19.6% placebo; mostly mild and transient, median duration 5.5 days).

Conclusions

In the largest clinical study in children with PFIC, maralixibat significantly reduced pruritus and sBA and improved bilirubin and growth, with a well-tolerated safety profile.