HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

Objectives: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data.

Methods: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab).

De Novo Crohn's Disease Diagnosed in the Setting of Acute SARS-Cov-2 Infection Requiring Escalation of Infliximab Therapy Guided by Personalized Pharmacokinetics.

Here, we describe a 7-year-old girl who was diagnosed with an early-onset Crohn's disease in the setting of COVID-19 illness. Her disease process responded poorly to standard infliximab dosing, necessitating repeat hospitalizations and red blood cell transfusions. Remission was subsequently induced using a personalized infliximab pharmacokinetic profile based on therapeutic drug monitoring.

Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics.

Background: The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD).

Acute pancreatitis is associated with gut dysbiosis in children.

Background: Pediatric acute pancreatitis (AP) is associated with significant morbidity. Therefore, improved understanding of children who will develop severe AP is critical. Adult studies have reported AP associated gut dysbiosis, but pediatric studies are lacking.

The Role of Therapeutic Drug Monitoring in Children.

The use of biologic therapies has changed the treatment landscape for children with inflammatory bowel disease. While the novel biologics have improved clinical outcomes, there remains a significant gap in achieving endoscopic remission, prolonged steroid-free remission, and drug durability. Contributing to this gap is the paucity of real-world pharmacokinetic studies in children and a failure to dose optimize therapy during induction.

Racial Disparities in Pediatric Inflammatory Bowel Disease Care: Differences in Outcomes and Health Service Utilization Between Black and White Children.

Objective: To describe racial inequities in pediatric inflammatory bowel disease care and explore potential drivers.

Methods: We undertook a single-center, comparative cohort study of newly diagnosed Black and non-Hispanic White patients with inflammatory bowel disease, aged <21 years, from January 2013 through 2020. Primary outcome was corticosteroid-free remission (CSFR) at 1 year.

Transcriptome analysis in acute gastrointestinal graft- host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease.

We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion.

Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance.

Background: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance.

Aims: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients.

Pilot trial of iBDecide: Evaluating an online tool to facilitate shared decision making for adolescents and young adults with ulcerative colitis.

Introduction: This pilot, randomized controlled trial aimed to evaluate the usability, among adolescents and young adults (AYAs) with ulcerative colitis (UC), of a web-based tool ('iBDecide') designed to facilitate shared decision making (SDM).

Methods: AYAs with UC (n = 35) were randomized to intervention (iBDecide, n = 14) and control (n = 12) arms before a scheduled clinic visit. We measured the usability of iBDecide, SDM, preferred decision-making style, decision conflict and intervention use.

Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis.

Background & Aims: We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response.

Methods: We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model.

Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis.

Background And Aims: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes.

Methods: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression.

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease.

Background: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance.

Aims: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up.

iBDecide: A web-based tool to promote engagement in shared decision-making among adolescents with ulcerative colitis.

Background: Adolescents and young adults (AYAs) seek increased autonomy and self-efficacy. AYAs must learn to manage their medical care in preparation for transition to adult healthcare. Our team's research found that AYAs need more information about their disease and treatment OBJECTIVE: To develop and test the usability of a decision tool "iBDecide" to promote shared decision-making among AYAs with ulcerative colitis (UC) who are beginning to manage their treatment and medications METHODS: Using design thinking, 14 AYAs, 6 healthcare providers, 4 designers, a social worker, and a human factors researcher developed a shared decision-making tool.

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

Unlabelled: Achieving and maintaining target serum trough infliximab levels improves outcomes in children and young adults with inflammatory bowel disease. Our goal was to improve adherence to an infliximab therapy guideline. The primary aim was to increase the percentage of patients with infliximab levels ≥5 μg/mL and results checked in the last 12 months from 73% to ≥80% from July 2017 to January 2018.

Real-World Infliximab Pharmacokinetic Study Informs an Electronic Health Record-Embedded Dashboard to Guide Precision Dosing in Children with Crohn's Disease.

Standard-of-care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn's disease (CD) are common. The primary aim was to conduct a real-world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic.

Achieving Target Infliximab Drug Concentrations Improves Blood and Fecal Neutrophil Biomarkers in Crohn's Disease.

Background: The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations.