Operating Properties of Disease Activity Indices in Pediatric Inflammatory Bowel Disease: A Systematic Review.

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.

The operating properties of pediatric inflammatory bowel disease clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices in this population.

Home-based fecal calprotectin utilization in a general pediatric gastroenterology clinic.

OBJECTIVE: Remote investigation and monitoring have gained importance in ambulatory practice. A home-based fecal calprotectin (FC) test has been developed where the sample is processed and analyzed at home through a smartphone application. We aimed to assess the use of standard ELISA (sFC) versus home-based (hFC) FC testing in a general pediatric gastroenterology clinic. METHODS: Ambulatory pediatric patients with hFC or sFC performed between August 2019 and November 2020 were included. Data regarding demographics, clinical characteristics, medication use, investigations, and final diagnosis, categorized as inflammatory bowel disease (IBD), functional gastrointestinal (GI) disorders, organic non-IBD (ONI) GI disorders, non-GI disorders, and undetermined after 6 months of investigation, were recorded. RESULTS: A total of 453 FC tests from 453 unique patients were included. Of those, 249 (55%) were hFC. FC levels (median) were higher in children with IBD compared to non-IBD diagnosis (sFC 795 vs. 57 µg/g, hFC 595 vs. 47 µg/g, p < 0.001), and in ONI compared to functional GI disorders (sFC 85 vs. 54 µg/g, p = 0.003, hFC 57 vs. 40 µg/g, p < 0.001). No significant difference was observed between different ONI GI disorders or subtypes of functional disorders. Age did not significantly influence levels. CONCLUSIONS: Overall, hFC and sFC provide similar results in the general pediatric GI ambulatory setting. FC is a sensitive but not disease-specific marker to identify patients with IBD. Values appear to be higher in ONI GI disorders over functional disorders, although cut-off values have yet to be determined.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

ADALIMUMAB VERSUS INFLIXIMAB IN LUMINAL PEDIATRIC CROHN'S DISEASE: COMPARABLE OUTCOMES IN A PROSPECTIVE MULTICENTER COHORT STUDY.

BACKGROUND: This study compared real-world effectiveness between adalimumab (ADA) and infliximab (IFX) in children with Crohn's disease (CD). METHODS: Children enrolled into the prospective Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) National Inception Cohort between 2014 and 2020 who commenced ADA or IFX as first anti-tumor necrosis factor (antiTNF) agent for luminal CD were included. Multivariate logistic regression modelled the propensity of commencing ADA; propensity score matching was used to match IFX-treated children to ADA-treated children. The primary outcome at one year was steroid-free clinical remission (SFCR). Secondary outcomes at one year were I) combined SFCR and c-reactive protein (CRP) remission; II) treatment intensification; and III) antiTNF durability. Odds ratios (aOR) and hazard ratio (aHR) adjusted for concomitant immunomodulator use with 95% confidence interval (CI) are reported. RESULTS: In the propensity score matched cohort of 147 ADA-treated and 147 IFX-treated children, 92 (63%) ADA- and 87 (59%) IFX-treated children achieved SFCR at one year (aOR: 1.4, 95% CI 0.9-2.4); 75 of 140 (54%) ADA- and 85 of 144 (59%) IFX-treated children achieved combined SFCR and CRP remission (aOR: 1.0, 95% CI 0.6-1.6). ADA-treated children less frequently underwent treatment intensification (21 [14%]) compared to IFX-treated children (69 [47%]) (P<0.0001). Discontinuation of antiTNF occurred in 18 (12%) ADA-treated and 15 (10%) IFX-treated children (aHR: 1.2, 95% CI 0.6-2.2). CONCLUSION: Children with Crohn's disease achieved favourable outcomes at one year with either ADA or IFX as first antiTNF agents. Those receiving IFX did not have significantly superior outcomes compared to clinically similar children receiving ADA.

Epidemiologic Burden and Projections for Eosinophilic Esophagitis-Associated Emergency Department Visits in the United States: 2009-2030.

BACKGROUND & AIMS: Patients with poorly controlled eosinophilic esophagitis (EoE) may require unplanned emergency department (ED) visits for the management of dysphagia or food impactions. We evaluated the epidemiologic burden of EoE on ED utilization in the United States. METHODS: Data from the US Nationwide Emergency Department Sample were used to estimate weighted annual EoE-associated ED visits from 2009 to 2019. Temporal trends in population-adjusted rates of EoE visits were assessed using joinpoint regression. Autoregressive integrated moving average models were used to project EoE-associated ED visits to 2030. We also evaluated endoscopic utilization, requirement for hospitalization, and ED-related charges in patients with EoE presenting to the ED. RESULTS: A total of 11,125 unweighted (49,507 weighted) ED visits for EoE were included (69.0% male; mean age, 32.4 y). The annual volume of EoE-associated ED visits increased from 2934 (95% CI, 2437-3431) in 2009 to 8765 (95% CI, 7514-10,015) in 2019, and is projected to reach 15,445 (95% prediction interval, 14,672-16,218) by 2030. From 2009 to 2019, the number of EoE-associated ED visits increased by an average of 11.5% per year (95% CI, 10.3%-12.7%). The proportion of patients admitted to the hospital from the ED decreased from 25.6% in 2009 to 2011 to 14.0% in 2017 to 2019. Half of EoE patients presenting to the ED required an endoscopy, and nearly 40% required an esophageal foreign body removal. Total mean inflation-adjusted charges for an EoE-associated ED visit were $9025 US dollars in 2019. CONCLUSIONS: The volume of EoE-associated ED visits tripled between 2009 and 2019 and is projected to further double by 2030. This represents a substantial burden of unanticipated health care resource utilization and highlights a potential opportunity to optimize outpatient EoE care.

Patients With Crohn's Disease and Permanent Ileostomy Are Universally Excluded From Clinical Trials: A Systematic Review.

INTRODUCTION: We performed a systematic review to investigate whether patients with Crohn's disease (CD) and permanent ileostomy (PI) have been included in clinical trials evaluating biologics and small molecules. METHODS: MEDLINE, Embase and Cochrane library (CENTRAL) data bases were searched from inception to May 16, 2022 for placebo controlled induction and/or maintenance randomized controlled trials assessing biologics and oral small molecules in adult patients with active CD. RESULTS: Of the 81 induction and maintenance trials assessing biologics and oral small molecules in CD, none permitted the enrollment of patients with PI. Patients with CD and PI have been universally excluded from pharmaceutical trials of biologics and small molecules to date. DISCUSSION: There is an urgent need to identify barriers to enrollment and develop eligibility and outcome measures enabling the inclusion of patients with CD and PI into clinical trials.

Proactive Therapeutic Drug Monitoring Versus Conventional Management for Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Proactive therapeutic drug monitoring (TDM) has been proposed to improve outcomes in patients with inflammatory bowel disease (IBD) treated with tumor necrosis factor (TNF)α antagonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing proactive TDM with conventional management in patients with IBD. METHODS: We identified RCTs in patients with IBD treated with TNFα antagonists comparing proactive TDM (routine assessments of trough concentration with dose adjustments to maintain predetermined trough concentration, regardless of disease activity) with conventional management (clinically driven dose adjustments). The primary outcome was failure to maintain clinical remission. Certainty of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: On meta-analysis of 9 RCTs (8 RCTs in adults, and focusing on maintenance phase), there was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM (267/709; 38%) vs conventional management (292/696; 42%) (relative risk [RR], 0.96; 95% confidence interval [CI], 0.81-1.13) with moderate heterogeneity (inconsistency index = 36%) (Grading of Recommendations, Assessment, Development and Evaluations; low certainty evidence), with no differences in patients with Crohn's disease (RR, 0.87 ; 95% CI, 0.66-1.15) and ulcerative colitis (RR, 0.88; 95% CI, 0.72-1.07). Disease duration, concomitant immunomodulators, disease activity at baseline, and optimization of therapy before randomization did not modify this association. No differences were observed in risk of developing antidrug antibodies or serious adverse events. Patients in the proactive TDM arm were more likely to undergo dose escalation (RR, 1.56; 95% CI, 1.25-1.94). CONCLUSIONS: Routine proactive TDM to target biologic concentration to specific thresholds, regardless of disease activity, did not offer clinical benefit in patients with IBD treated with TNFα antagonists in RCTs conducted to date. We cannot exclude the possibility of benefit in disease subtypes and phases of therapy (induction) not represented in these RCT populations.

Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.

BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.

Epidemiology of Musculoskeletal Manifestations in Pediatric Inflammatory Bowel Disease: A Systematic Review.

OBJECTIVE: Pediatric inflammatory bowel disease (p-IBD) is a chronic relapsing gastrointestinal disorder of childhood with long-term morbidity. Several extraintestinal manifestations are described, the most common being joint pain and/or inflammation. However, patient and disease characteristics, treatments, and outcomes of p-IBD-associated musculoskeletal disease are not well established. Our study aims to summarize the recent literature on the epidemiology of musculoskeletal manifestations in p-IBD in the era of biologics. METHODS: A systematic search of PubMed, Embase, Cochrane Library, Web of Science Core Collection, and Cumulative Index to Nursing and Allied Health Literature databases was performed with relevant keywords. Studies in English published from January 1, 2000, to December 21, 2020, were included. In total, 3893 articles were identified and screened. Study and population characteristics and outcomes of interest were recorded. Risk of bias assessment was performed using the Joanna Briggs Institute Critical Appraisal Tools. RESULTS: Thirteen studies were included for full review, which were primarily single-center observational studies with retrospective or cross-sectional designs. The diagnostic criteria and definitions used for musculoskeletal manifestations varied. Musculoskeletal manifestation prevalence ranged from 2% to 35%. Only one study assessed the response of musculoskeletal manifestations to biologics. Risk of bias demonstrated heterogeneity in study quality. CONCLUSION: This is the first systematic review of musculoskeletal manifestations in p-IBD. Analysis was limited because of variability in study design and data-reporting methods. Definitions varied among included studies, with a clear lack in standardization. Our study demonstrates the need for standardized assessment of musculoskeletal manifestations of p-IBD and further research to explore optimal management to advance care for this group of children.

Association of teledermatology workflows with standardising co-management of rashes by primary care physicians and dermatologists.

INTRODUCTION: For patients with a rash, the effect of teledermatology workflow on utilization has not been defined. We compared utilization across four teledermatology workflows in patients with a rash. METHODS: The observational longitudinal cohort study included 28,857 Kaiser Permanente Northern California members with a new rash diagnosis seen in primary care and with dermatology advice obtained using teledermatology. The workflows differed in camera and image quality; who took the picture; how the image was forwarded; and synchronicity and convenience. RESULTS: On average, 23% of patients had a follow-up office visit in dermatology within 90 days of their primary care visit. In multivariable analysis, the four technologies differed substantially in the likelihood of a follow-up dermatology office visit. In contrast, the likelihood was only negligibly related to medical centre or primary care provider. DISCUSSION: Technologies and workflows that offer the mobility of a smartphone with a high level of synchronicity in communication were associated with standardised co-management of rashes.

Systematic Review and Meta-Analysis: Clinical, Endoscopic, Histological and Safety Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

BACKGROUND AND AIMS: Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. METHODS: MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. RESULTS: In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. CONCLUSIONS: Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Impact of Drug Approval Pathways for Paediatric Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Timely access to approved medications is a priority in paediatric inflammatory bowel disease [IBD]. To date, the timing of drug studies in paediatric IBD has been suboptimal, with most studies conducted long after approval has been granted for adult IBD. This delay in approval leads to extensive off-label prescribing of medications in children, often without clear guidance on optimal dosing. The European Medicines Agency [EMA] and U.S. Food and Drug Administration [FDA] have implemented drug development frameworks in an attempt to address these challenges. However, access to information on these regulatory pathways in paediatric IBD is limited. We summarised the time from adult to paediatric approval of IBD therapies, outlining the regulatory approval pathway between the EMA and FDA, with the goal of identifying areas for improvement. METHODS: We reviewed publicly accessible data from the EMA and the FDA to identify therapeutic agents approved over 2005-2021 for paediatric IBD. RESULTS AND CONCLUSIONS: Five drugs are currently approved for use in the paediatric IBD population, with long interval delays after adult approval. The impact of these drug development processes in paediatric IBD is awaited. Further consideration needs to be given to the age of enrolment along with novel, more efficient trial designs in an effort to improve access for paediatric IBD patients to newer therapies.

Clinical, Endoscopic, and Safety Placebo Rates in Induction and Maintenance Trials of Crohn's Disease: Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Precision in estimating placebo rates is important for clinical trial design. AIM: To quantify placebo rates across relevant endpoints in Crohn's disease [CD] trials and identify the factors influencing these rates in a contemporary meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from inception to March 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for CD. Placebo response and remission rates for induction and maintenance trials were extracted and pooled by random-effects to quantify placebo rates across studies. Mixed-effects meta-regression was used to evaluate the effects of study-level characteristics on placebo rates. RESULTS: In 125 studies [91 induction, 46 maintenance], placebo clinical remission and response rates for induction studies were 18% (95% confidence interval [CI] 16, 21%], and 32% [95% CI 29, 35%], respectively, and for maintenance studies were 28% [95% CI 23, 34%] and 30% [95% CI 24, 37%], respectively. Endoscopic remission and response rates in induction studies were 8% [95% CI 4, 18%] and 16% [95% CI 11, 23%], respectively. Trials enrolling patients with prior biologic exposure, longer disease duration, and higher CD activity index scores were associated with lower placebo clinical remission rates. Increased duration of follow-up, more follow-up visits, and a greater proportion of patients with colonic disease distribution were associated with higher clinical placebo rates. CONCLUSIONS: Placebo remission and response rates in CD trials vary according to the phase of the trial, endpoint assessed, and induction or maintenance design. These contemporary estimates will help to inform future CD trial design.

Advances in Therapeutic Drug Monitoring in Biologic Therapies for Pediatric Inflammatory Bowel Disease.

In the current era of treat-to-target strategies, therapeutic drug monitoring (TDM) has emerged as a potential tool in optimizing the efficacy of biologics for children diagnosed with inflammatory bowel disease (IBD). The incorporation of TDM into treatment algorithms, however, has proven to be complex. "Proactive" TDM is emerging as a therapeutic strategy due to a recently published pediatric RCT showing a clear benefit of "proactive" TDM in anti-TNF therapy. However, target therapeutic values for different biologics for different disease states [ulcerative colitis (UC) vs. Crohn's disease (CD)] and different periods of disease activity (induction vs. remission) require further definition. This is especially true in pediatrics where the therapeutic armamentarium is limited, and fixed weight-based dosing may predispose to increased clearance leading to decreased drug exposure and subsequent loss of response (pharmacokinetic and/or immunogenic). Model-based dosing for biologics offers an exciting insight into dose individualization thereby minimizing the chances of losing response. Similarly, point-of-care testing promises real-time assessment of drug levels and individualized decision-making. In the current clinical realm, TDM is being used to prolong drug durability and efficacy and prevent loss of response. Ongoing innovations may transform it into a personalized tool to achieve optimal therapeutic endpoints.

One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study.

BACKGROUND: The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking. AIM: To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics. METHODS: Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 µg/g if not re-colonoscoped. RESULTS: At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (µg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy. CONCLUSION: Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn's Disease.

Inflammatory bowel disease (IBD), clinically defined as Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn's Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn's Disease.

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.