Gut metabolome and microbiota signatures predict response to treatment with exclusive enteral nutrition in a prospective study in children with active Crohn's disease.

BACKGROUND: Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization. OBJECTIVES: This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD. METHODS: In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR). RESULTS: Of 37 patients recruited, 15 responded (FCal < 250 µg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (µmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN. CONCLUSIONS: We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.

Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study.

BACKGROUND: We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. METHODS: Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. FINDINGS: Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1-46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7-43·7), 34·4% (29·9-39·0), and 34·7% (29·8-39·5), and for adalimumab 35·9% (95% CI 31·2-40·5), 32·9% (26·8-39·2), and 28·9% (21·9-36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1-10·0 mg/L for infliximab and 10·1-12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4-38·2), 54·5% (49·4-59·0), and 60·0% (54·1-65·2), and for adalimumab 32·1% (26·7-37·1), 47·2% (40·2-53·4), and 68·4% (50·9-79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30-0·67], adalimumab: 0·39 [0·22-0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11-1·95]), obesity (vs not obese 1·62 [1·08-2·42]), baseline white cell count (1·06 [1·02-1·11) per 1 × 109 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17-3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1-49·4) among patients treated with infliximab and 20·3% (13·8-26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31-0·52], adalimumab 0·42 [95% CI 0·24-0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13-1·88]) but not for adalimumab (HR 1·60 [0·92-2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20-3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11-2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. INTERPRETATION: Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs. FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare.

Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals.

Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.

Impact of mental health comorbidity in children and young adults with inflammatory bowel disease: a UK population-based cohort study.

OBJECTIVE: To evaluate the impact of mental health comorbidity in children and young adults with inflammatory bowel disease (IBD). DESIGN: Retrospective observational study. SETTING: Representative population, routinely collected primary care data from the UK Optimum Patient Care Research Database (2015-2019). PARTICIPANTS: Patients with IBD aged 5-25 years with mental health conditions were compared with patients with IBD of the same age without mental health conditions. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes comprised quality-of-life indicators (low mood, self-harm, parasuicide, bowel symptoms, absence from school or work, unemployment, substance use and sleep disturbance), IBD interventions (medication, abdominal surgery, stoma formation and nutritional supplements) and healthcare utilisation (primary care interactions and hospital admissions). RESULTS: Of 1943 individuals aged 5-25 years with IBD, 295 (15%) had a mental health comorbidity. Mental health comorbidity was associated with increased bowel symptoms (adjusted incident rate ratio (aIRR) 1.82; 95% CI 1.33 to 2.52), sleep disturbance (adjusted HR (aHR) 1.63; 95% CI 1.02 to 2.62), substance use (aHR 3.63; 95% CI 1.69 to 7.78), primary care interactions (aIRR 1.33; 95% CI 1.12 to 1.58) and hospital admissions (aIRR 1.87; 95%CI 1.29 to 2.75). In individuals ≥18 years old, mental health comorbidity was associated with increased time off work (aHR 1.55; 95% CI 1.21 to 1.99). CONCLUSIONS: Mental health comorbidity in children and young adults with IBD is associated with poorer quality of life, higher healthcare utilisation and more time off work. It is imperative that affected young patients with IBD are monitored and receive early mental health support as part of their multidisciplinary care. TRIAL REGISTRATION NUMBER: The study protocol was specified and registered a priori (ClinicalTrials.gov study identifier: NCT05206734).

YouTube as a Source of Information for Food, Diet-Related Items, and Advisory Comments for the Management of Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) often use the Internet to seek information beyond that received from healthcare professionals. This study assessed the perceptions of YouTube presenters on the role of diet in the management of IBD. METHODS: Videos discussing dietary aspects (food, diet-related items, and advisory comments [FODRIACs]) in the management of IBD were included. The perceptions of presenters toward each FODRIAC were labeled as positive, negative, or neutral/intermediate, and FODRIACs were classified according to their underlying role in the management of IBD (eg, symptom management, gut inflammation). Subgroup analysis was performed by type of video presenter (patients vs healthcare professionals), type of IBD (Crohn's disease vs ulcerative colitis), and reporting of scientific evidence supporting presenters' perceptions. RESULTS: We identified 122 FODRIACs within 160 videos. Patient videos received a higher number of likes (median 85 [interquartile range, 35-156]) than healthcare professional videos (median 44 [interquartile range, 16-1440]) (P = .01). Scientific evidence was cited in 2 (3%) of 76 patient videos compared with 25 (35%) of 71 healthcare professional videos (P < .001). Positive perceptions were expressed about avocadoes, salmon, bananas, white bread, and rice, whereas negative perceptions were reported for processed, high-fat and high-sugar foods and carbonated drinks. Fewer negative perceptions were expressed in videos supported by scientific evidence than in videos that lacked evidence (scientific: 4 positive, 0 negative vs nonscientific: 7 positive, 20 negative; P = .01). CONCLUSIONS: We have identified FODRIACs proposed as beneficial or detrimental in the management of IBD. The effect this information has on dietary practice as patients with IBD self-manage their condition needs further exploration.

Take-Home Messages from 20 Years of Progress in Dietary Therapy of Inflammatory Bowel Disease.

BACKGROUND: A significant body of literature has interrogated the critical role of diet in the development and management of inflammatory bowel disease (IBD). SUMMARY: This review provides a summary and critical appraisal of the literature in this area, focussing on four distinct themes: nutritional epidemiology, animal and in vitro experiments, enteral nutrition, and food-based dietary therapies. KEY MESSAGES: Nutritional epidemiology and data from experiments in animals indicate that a western-type diet pattern is associated with increased risk of IBD onset. However, these findings have not been consistently replicated in the dietary management of IBD. Exclusive enteral nutrition (EEN) is the only dietary therapy with reproducible evidence of efficacy in the management of active Crohn's disease (CD). Use of EEN may also be useful for improving perioperative outcomes in CD, and as an adjuvant therapy to biologic therapy. Several dietary therapies for CD and ulcerative colitis have been proposed in the literature, but replication in well-controlled studies is needed before their routine use enters the clinical setting. Precision nutritional therapy might be an attractive therapeutic paradigm in a heterogenous disease like IBD. However, no recommendations for personalised dietary therapy can currently be made, and it is imperative we unravel the complex interplay between diet and gut inflammation before we are able to do so. Undoubtedly, diet is of critical importance in the development and management of IBD. However, the exact mechanism by which diet causes gut inflammation is still elusive, and dietary guidance is difficult to formulate.

Nationwide Real-World Exclusive Enteral Nutrition Practice Over Time: Persistence of Use as Induction for Pediatric Crohn's Disease and Emerging Combination Strategy With Biologics.

BACKGROUND: Exclusive enteral nutrition (EEN) is the recommended first-line induction treatment in pediatric patients with active luminal Crohn's disease (CD). We aimed to provide a nationwide overview of evolving EEN practices during an era of increasing biologic use. METHODS: We analyzed a prospectively identified nationwide cohort of newly diagnosed pediatric patients with CD in Scotland between January 1, 2015, and June 30, 2022. Patients who received EEN for any indication were divided into 6-monthly epochs and examined over time. Differences during the COVID-19 pandemic (March 16, 2020, to July 19, 2021) were examined. Data were retrospectively collected from electronic medical records: demographics, anthropometrics, concomitant treatments, aspects of EEN administration, and remission/response rates. Descriptive statistics and linear regression were used for analyses. RESULTS: A total of 649 patients with CD were identified (63% male; median age 12.6 [interquartile range, 10.8-14.8] years); 497 (77%) of 649 received EEN as postdiagnosis induction therapy with a median course length of 7.7 (interquartile range, 5.9-8.0) weeks. Including repeat courses, 547 EEN courses were examined. An increasing incidence of CD was observed over time with no significant changes in EEN usage, remission or response rates, nasogastric tube usage, or course completion (all P > .05). Increasing use of EEN combined with biologics (combination induction) as first-line induction was observed over time (P < .001). Considering COVID-19, lower rates of EEN usage were observed (P = .008) with no differences in remission, oral administration, and course completion rates (all P > .05). CONCLUSIONS: Over the past 7.5 years, except during the COVID-19 pandemic, EEN usage rates have not changed despite an increase in biologic use, although combination induction is an emerging trend.

Children and Young Adults With Inflammatory Bowel Disease Have an Increased Incidence and Risk of Developing Mental Health Conditions: A UK Population-Based Cohort Study.

BACKGROUND: The burden of mental health conditions in children and young adults with inflammatory bowel disease remains unclear. We assessed this using a primary care database in the United Kingdom. METHODS: A retrospective, observational study compared children and young adults with incident inflammatory bowel disease 5 to 25 years of age (2010-2020) against population control subjects. Outcomes comprised incident depression, anxiety disorder, eating disorders, body image disorders, attention-deficit disorders, behavioral disorders, adjustment disorders, acute stress disorder, schizophrenia, bipolar disorder, posttraumatic stress disorder, self-harm, parasuicide (including suicide), and sleep disturbance. The any mental health condition category comprised any of these conditions. RESULTS: A total of 3898 young patients with incident inflammatory bowel disease were matched to 15 571 control subjects. Inflammatory bowel disease patients were significantly more likely to develop new posttraumatic stress disorder (adjusted hazard ratio [aHR], 2.47; 95% confidence interval [CI], 1.23-4.94), eating disorders (aHR, 1.85; 95% CI, 1.05-3.26), self-harm (aHR, 1.49; 95% CI, 1.00-2.21), sleep disturbance (aHR, 1.40; 95% CI, 1.15-1.71), depression (aHR, 1.34; 95% CI, 1.16- 1.56), anxiety (aHR, 1.25; 95% CI, 1.06-1.48), and any mental health condition (aHR, 1.28; 95% CI, 1.12-1.46). Male inflammatory bowel disease patients aged 12 to 17 years, and patients with Crohn's disease appear to have the highest risk for developing new mental health conditions. CONCLUSIONS: Young inflammatory bowel disease patients have a significantly higher incidence and risk of new mental health conditions. Mental health remains a critically overlooked aspect of inflammatory bowel disease patient management. Further research into identifying optimal monitoring tools and support for these patients is required to improve patient care. The study protocol was specified and registered a priori.ClinicalTrials.gov study identifier: NCT05206734.

The State of Clinical Trials in Pediatric Inflammatory Bowel Disease.

The gap between available biologic and small molecule therapy for inflammatory bowel disease for children and adults remains large. At present only 2 anti-TNF agents are licensed for pediatric use compared with multiple other agents with different mechanisms of action being used in adults. The reasons are many but largely revolve around the inadequate acceptance of adult efficacy data to children, and the reluctance of industry to commit to early pediatric drug development for fear of inadequate return on investment. We suggest common sense steps that need to be taken to improve this situation.

Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy.

No real-world data are available on subcutaneous infliximab (SC-IFX) in pediatric inflammatory bowel disease (PIBD). We report a single-center cohort experience of an elective switching program from biosimilar intravenous infliximab to SC-IFX, 120 mg fortnightly, as maintenance. Clinical and laboratory data were collected for 7 patients with infliximab trough levels collected prior and at 6 and 40 weeks after the switch. High treatment persistence was registered with a single patient discontinuing the treatment due to high IFX antibodies, already present before switching. All patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). No newly-developed IFX antibodies were detected and no adverse reactions or rescue therapies were recorded. Our real-world data support the feasibility of an elective switch to SC-IFX in PIBD as maintenance with potential advantages concerning medical resources and patient satisfaction.

Development and Validation of the Glasgow Exclusive Enteral Nutrition Index of Compliance.

BACKGROUND AND AIMS: Treatment adherence is key to the efficacy of exclusive enteral nutrition [100% EN] in active Crohn's disease [CD], but there are no biomarkers to objectively estimate this. We explored faecal parameters as biomarkers of compliance with 100% EN, and subsequently developed and validated the Glasgow Exclusive Enteral Nutrition Index of Compliance [GENIE]. METHODS: Healthy adults replaced all [100% EN] or part [85% EN, 50% EN, 20% EN] of their diet with a formula for 7 days. Faecal pH, water content, short chain fatty acids, and branched chain fatty acids [BCFAs] were measured before [D0] and after [D7] each intervention. Optimal biomarkers and threshold values were derived using receiver operating characteristic curve analyses and machine learning to develop the GENIE. The GENIE was then validated in 30 CD children, during and after 100% EN. RESULTS: In all, 61 adults were recruited. D7 faecal pH and the ratios of BCFAs to either acetate or butyrate performed the best to differentiate between patients on 100% EN from <100% EN. Two models were generated; one included faecal metabolites (Laboratory GENIE, L-GENIE; sensitivity, specificity, and positive predictive value [PPV] of 88%, 94%, and 92%) and a second one [Clinical Genie, C-GENIE] which considers only faecal pH [sensitivity, specificity, and PPV of 84%, 86%, and 81%]. Validation of GENIE in CD children found that C-GENIE outperformed L-GENIE, producing a sensitivity, specificity, and PPV of 85%, 88%, and 88%, respectively. CONCLUSIONS: GENIE can help predict adherence to 100% EN and may complement current conventional dietary assessment.

Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition.

Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.

Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study.

BACKGROUND: Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. METHODS: VEDOKIDS was a paediatric, multicentre, prospective cohort study done in 17 centres in six countries. We report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Children (aged 0-18 years) with IBD who had commenced vedolizumab were followed up at baseline and at 2, 6, and 14 weeks. Children were managed according to local prescribing practices without standardisation of dosing or criteria for escalation, but the study protocol suggested dosing of 177 mg/m2 body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. FINDINGS: Between May 19, 2016, and April 1, 2022, 142 children (76 [54%] girls and 66 [46%] boys; mean age 13·6 years [SD 3·6]) were enrolled. 65 (46%) children had Crohn's disease, 68 (48%) had ulcerative colitis, and nine (6%) had unclassified IBD (those with unclassified IBD were analysed with the ulcerative colitis group). 32 (42% [95% CI 30-54]) of 77 children with ulcerative colitis and 21 (32% [23-45]) of 65 children with Crohn's disease were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with ulcerative colitis than in those with Crohn's disease (11·5 µg/mL [IQR 5·5-18·1] vs 5·9 µg/mL [3·0-12·7]; p=0·006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 µg/mL at week 14 (area under the curve 0·69 [95% CI 0·41-0·98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. INTERPRETATION: Vedolizumab showed good safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with ulcerative colitis. Vedolizumab should be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). FUNDING: The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

An Optimised Monophasic Faecal Extraction Method for LC-MS Analysis and Its Application in Gastrointestinal Disease.

Liquid chromatography coupled with mass spectrometry (LC-MS) metabolomic approaches are widely used to investigate underlying pathogenesis of gastrointestinal disease and mechanism of action of treatments. However, there is an unmet requirement to assess faecal metabolite extraction methods for large-scale metabolomics studies. Current methods often rely on biphasic extractions using harmful halogenated solvents, making automation and large-scale studies challenging. The present study reports an optimised monophasic faecal extraction protocol that is suitable for untargeted and targeted LC-MS analyses. The impact of several experimental parameters, including sample weight, extraction solvent, cellular disruption method, and sample-to-solvent ratio, were investigated. It is suggested that a 50 mg freeze-dried faecal sample should be used in a methanol extraction (1:20) using bead beating as the means of cell disruption. This is revealed by a significant increase in number of metabolites detected, improved signal intensity, and wide metabolic coverage given by each of the above extraction parameters. Finally, we addressed the applicability of the method on faecal samples from patients with Crohn's disease (CD) and coeliac disease (CoD), two distinct chronic gastrointestinal diseases involving metabolic perturbations. Untargeted and targeted metabolomic analysis demonstrated the ability of the developed method to detect and stratify metabolites extracted from patient groups and healthy controls (HC), highlighting characteristic changes in the faecal metabolome according to disease. The method developed is, therefore, suitable for the analysis of patients with gastrointestinal disease and can be used to detect and distinguish differences in the metabolomes of CD, CoD, and HC.

The inexorable increase of biologic exposure in paediatric inflammatory bowel disease: a Scottish, population-based, longitudinal study.

BACKGROUND: The use of biologics in paediatric-onset inflammatory bowel disease (PIBD) is rapidly changing. AIMS: To identify the incidence and prevalence of biologic use within Scottish PIBD services, and to describe patient demographics and outcomes for those patients who required escalation of therapy beyond anti-tumour necrosis factor alpha (anti-TNFα) agents METHODS: We captured a nationwide cohort of prospectively identified patients less than 18 years of age with PIBD (A1 phenotype; diagnosed <17 years of age) within paediatric services over a 4.5-year period (1 January 2015-30 June 2019). All patients who received infliximab, adalimumab, vedolizumab or ustekinumab during the study period and/or received their first dose of these biologics were audited retrospectively. RESULTS: Scotland-wide PIBD-prevalence cases increased from 554 to 644 over the study period. A total of 495 incident new-start biological therapies were commenced on 403 PIBD patients: 295 infliximab (60%), 161 adalimumab (32%), 24 vedolizumab (5%) and 15 ustekunumab (3%). The proportion of new-start biologics changed with infliximab initiation rates decreasing (87%-54%) while adalimumab (13%-31%), vedolizumab (0%-9%) and ustekinumab (0%-6%) all increased. The incidence rate (first dose of new biologic not including biosimilar switch) increased from 6.9% to 8.1% over the study period and point prevalence rates (any biologic use) increased from 20.2% to 43.5% - an average annual percentage increase of 20%. Biosimilar penetration of new-start anti-TNFα agents increased from 3% to 91%. Demographics and outcomes of those patients receiving vedolizumab and ustekinumab were similar. CONCLUSIONS: Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing, inexorably increasing PIBD biologics landscape.

Optimized Infliximab Induction Predicts Better Long-Term Clinical and Biomarker Outcomes Compared to Standard Induction Dosing.

OBJECTIVES: To evaluate the efficacy of standard and optimized infliximab induction dosing in attaining corticosteroid (CS) free clinical remission at week 52 and the effect that post-induction trough levels have on long-term outcome. METHODS: Inflammatory bowel disease (IBD) patients ≤18 years commenced on infliximab between August 1, 2016, and August 1, 2018, from Vancouver, Canada, and Glasgow, Scotland, were included. The Glasgow cohort followed standard induction while the Vancouver cohort undertook induction optimization based on clinical, biomarker, and proactive infliximab trough levels. Baseline characteristics and laboratory values were documented. RESULTS: In total, 140 children were included [median age 14.1 years (interquartile range (IQR) 12.0-16.0)]; 54% male. CS-free clinical remission at week 52 was higher in the optimized group compared to the standard cohort [65/78 (83%) vs. 32/62 (52%), P < 0.001]. Combined CS-free clinical and biomarker remission (CRP < 5 mg/L) was also higher in the optimized compared to the standard cohort [65/78 (83%) vs 25/62 (40%), P < 0.001]. The median post-induction trough level was higher in children who were in CS-free clinical remission at week 52 [3.6 mg/L (1.5-7.1)] vs. those who were not [2.0 mg/L (0.8-4.1), P = 0.04]. The odds of attaining a therapeutic post-induction trough level were almost 4-fold higher in the optimized group than the standard cohort (OR 3.97, 95% CI: 1.89-8.68, P < 0.001). CONCLUSIONS: Standard infliximab induction resulted in less favorable long-term outcomes for pediatric IBD patients. Optimizing induction using clinical, biomarker, and proactive trough levels resulted in higher post-induction trough levels and a greater odds of attaining long-term clinical remission.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Development, Validation, and Evaluation of the Pediatric Inflammatory Crohn's Magnetic Resonance Enterography Index From the ImageKids Study.

BACKGROUND & AIMS: Cross-sectional imaging is important in the assessment of transmural inflammation in Crohn's disease (CD). Small bowel involvement is often more extensive in pediatric CD, requiring a panentering measuring tool. We undertook to develop a magnetic resonance enterography (MRE)-based index that would measure inflammation in all segments of the intestine, without rectal contrast. METHODS: Children with CD underwent ileocolonoscopy and MRE and half were prospectively followed for 18 months when MRE was repeated. Item generation and reduction were performed by a Delphi panel of pediatric radiologists, a systematic literature review, a cross-sectional study of 48 MREs, and a steering committee. Formatting and weighting were performed using multivariate modeling adjusted by a steering committee. MREs were read locally and centrally. Reliability, validity, and responsiveness were determined using several clinimetric and psychometric approaches. RESULTS: Thirty items were initially generated and reduced to 5 using regression analysis on 159 MREs: wall thickness, wall diffusion weighted imaging, ulcerations, mesenteric edema, and comb sign. In the validation cohort of 81 MREs, the weighted global PICMI correlated well with the radiologist global assessment (r = 0.85; P < .001) and with the simple endoscopic score in a subsample with ileocolonic disease (r = 0.63; P < .001). Interobserver and test-retest reliability were high (interclass correlation coefficients, 0.84; 95% confidence interval [CI], 0.79-0.87; and 0.81, 95% CI, 0.65-0.90, respectively; both P < .001). Excellent responsiveness was found at repeated visits (n = 116 MREs; area under the receiver operating characteristic curve 0.96; 95% CI, 0.93-0.99). Transmural healing was defined as PICMI ≤10 and response as a change of >20 points with excellent discriminative validity (area under the receiver operating characteristic curve = 0.96; 95% CI, 0.93-0.99). CONCLUSIONS: The PICMI is a valid, reliable, and responsive index for assessing transmural inflammation in pediatric CD. It scores the entire bowel length and does not require intravenous contrast or rectal enema and, therefore, is suitable for use in children. (ClinicalTrials.gov, Number: NCT01881490.).

Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix.

BACKGROUND: Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. AIM: To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. METHODS: We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery. RESULTS: We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. CONCLUSION: Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.