Ruben J. Colman

Background: Immune-mediated extraintestinal manifestations (IM-EIMs) are common in paediatric inflammatory bowel disease (pIBD). This systematic review and meta-analysis aimed to summarise the incidence and prevalence of IM-EIMs in pIBD. Methods: MEDLINE, EMBASE, CENTRAL and clinicaltrials.gov were searched up to May 6, 2024, for studies that included pIBD (2-17 years) patients diagnosed with IM-EIMs. Primary outcomes included the incidence and prevalence of IM-EIMs among pIBD. Meta-analysis included pooled proportions of prevalence with DerSimonian-Laird random-effects analysis. Results: The pooled proportion of IM-EIMs among pIBD overall was 10% (95% CI, 8-12%; I2=97.2%) among 65 studies (35,343 patients). The pooled proportion of IM-EIMs was 10% (95% CI, 7-13%; I2=94.8%) among 37 Crohn’s disease (CD) studies (7657 patients), compared to 11% (95% CI, 7-15%; I2=93.3%) among 39 ulcerative colitis (UC) studies (4698 patients). Enthesitis was the highest reported individual IM-EIM (23%, 95% CI, 4-50%; I2=94.7%) in pIBD. Arthritis was the second highest reported individual IM-EIM (8%, 95% CI, 6-10%; I2=96%) in pIBD, followed by primary sclerosing cholangitis (PSC) in UC (5%, 95% CI, 4-7%; I2=81%). Uveitis, pyoderma gangrenosum, autoimmune hepatitis and PSC in CD were the lowest reported IM-EIMs at 1% or less. The largest difference in proportions between IBD phenotypes was PSC, which was 4% higher in UC than CD. Conclusions: While musculoskeletal manifestations are common, fewer than 5% of pIBD patients experience ophthalmological, dermatological, and liver IM-EIMs. The small number of studies resulted in significant methodological and statistical heterogeneity. Multicentre collaborative efforts are needed to systematically describe the epidemiology of IM-EIMs in pIBD.

Background: Point-of-care intestinal ultrasound (IUS) is a non-invasive tool to evaluate inflammation in patients with inflammatory bowel disease (IBD). Limited studies have evaluated the role of IUS during routine clinical care. This study investigated the addition of IUS as part of routine clinic visits compared to standardized indices collected in real-world care to evaluate the role of IUS as a treat-to-target measure. Methods: This cross-sectional study included pediatric patients ( 250 ranged between 2.3-2.5 mm, based on disease phenotype. Discussion: Integrating IUS with clinical symptoms during routine clinic visits was superior to shPCDAI alone in predicting CD activity, and may potentially be superior to PUCAI for UC. Incorporating IUS into routine visits may accelerate treatment decisions, thereby advancing an improved point-of-care treat-to-target approach.

Proactive therapeutic drug monitoring (TDM) for tumor necrosis factor alpha antagonist (anti-TNF) therapy in adult inflammatory bowel disease (IBD) remains controversial, with inconsistent findings from clinical trials and meta-analyses. Pediatric societal guidelines endorse the implementation of proactive TDM. However, the integration of TDM into clinical practice by pediatric gastroenterologists has not been characterized. This study was undertaken to delineate the practice patterns, attitudes, and barriers associated with anti-TNF TDM among pediatric gastroenterologists across the United States. A 28-item questionnaire was developed based on prior adult surveys and current pediatric literature, undergoing 3 rounds of iteration. The survey was comprised of physician demographics, center demographics, TDM practice behavior questions and case-scenarios. The survey was deployed through the ImproveCareNow Learning Health System Network between February and June 2023. Among 380 invitees, 256 (77%) completed the questionnaire. Among respondents, 67% (171) were academic-affiliates, and 55% (140) were female. There was notable variability in the number of patients with IBD seen per practice. All respondents reported using TDM for infliximab, and the majority for adalimumab, and the vast majority utilizing a proactive TDM approach. The principal barriers to TDM implementation were insurance denials, cost, and logistical challenges. More respondents indicated they would initiate TDM during infliximab induction for severe ulcerative colitis than for Crohn's disease. In contrast to the adult literature, most pediatric gastroenterologists report undertaking proactive TDM for anti-TNF agents in IBD management. Precision dosing tools reflective of an individual's pharmacokinetics are desired and need to be further studied.

Background/Objectives: In adolescent patients with ulcerative colitis refractory to anti-tumor necrosis factor (TNF) therapy, episodes of acute severe ulcerative colitis (ASUC) require hospitalization or surgery. Upadacitinib can be a potential colectomy-sparing agent in adult ASUC patients receiving intensified dosing. Methods: This case series evaluates clinical outcomes of intensified rescue upadacitinib dosing in adolescent patients with ASUC. We included adolescents admitted with anti-TNF refractory ASUC treated with 30 mg twice daily upadacitinib. The primary outcome was the proportion of patients who remained colectomy-free at the most recent follow-up. Results: Five patients (aged 14–18) exhibited varying responses to upadacitinib; 2 responded rapidly, while 3 had partial response. All the patients remained on upadacitinib and were colectomy-free during follow-up (55–203 days). Three (60%) ultimately received dual advanced therapy with ustekinumab and upadacitinib. At most recent follow-up, 60% were in clinical/biochemical remission without corticosteroids. Conclusions: In select cases, intensified upadacitinib may be a potential colectomy-sparing option for adolescent ASUC patients refractory to anti-TNF therapy.

Background: Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties. Methods: MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn’s disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized. Results: Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn’s Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn’s Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn’s Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation. Conclusions: The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

Introduction The only biologic therapy currently approved to treat moderate to severe Crohn’s disease in children (Methods and analysis Conduct a clinical trial to assess rates of deep remission between Crohn’s disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6–22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5–10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn’s disease activity indexEthics and dissemination ). The study protocol has been approved by the Cincinnati Children’s Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT05660746.

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). Methods: This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. Results: This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. Conclusions: This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

Summary: 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.Methods: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non‐linear mixed effects modelling. For the evaluation of the exposure–response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole‐genome metagenomic sequencing was conducted at baseline and week 2.Results: A two‐compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid‐free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate‐producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml.Conclusions: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.