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.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS: Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.

Predicting Outcomes in Pediatric Ulcerative Colitis for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms. METHODS: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements. RESULTS: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis. CONCLUSIONS: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.

Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

Prospective Evaluation of Endoscopic and Histologic Indices in Pediatric Ulcerative Colitis Using Centralized Review.

INTRODUCTION: We aimed to evaluate the reliability and validity of the Ulcerative Colitis (UC) Endoscopic Index of Severity (UCEIS) and Mayo Endoscopy Score (MES) and to validate the Robarts Histopathology Index (RHI) and Nancy Index (NI) in pediatric UC. We examined rectosigmoid and pancolonic versions of each instrument. METHODS: Single-center cross-sectional study of 60 prospectively enrolled participants. Through central endoscopy review, 4 pediatric gastroenterologists assigned rectosigmoid and pancolonic (mean of 5 colonic segments) UCEIS and MES scores. Two blinded pathologists assigned rectosigmoid and pancolonic RHI and NI scores. We assessed reliability with intraclass correlation coefficients and weighted kappa statistics and explored construct validity with correlations, boxplots, and receiver operator characteristic curves. RESULTS: The UCEIS and MES displayed almost perfect intra-rater and inter-rater reliability (intraclass correlation coefficient and weighted kappa ≥0.85), moderate-to-strong correlation with histologic/clinical activity and fecal calprotectin (FC), and very strong correlation with global endoscopic severity (r > 0.9). Rectosigmoid UCEIS and MES scores of 0 were highly specific (≥95%) for endoscopic and histologic remission throughout the colon. Pancolonic endoscopy scores correlated more strongly with histologic activity, clinical activity, and systemic inflammatory markers and better discriminated between degrees of active disease. RHI and NI showed moderate-to-strong correlation (r = 0.5-0.83) with endoscopic/clinical activity and FC. DISCUSSION: Our findings support the reliability and construct validity of the UCEIS and MES and the construct validity of the RHI and NI in pediatric UC. Normal rectosigmoid findings predicted pancolonic healing, but, given active disease, pancolonic endoscopic assessment more accurately captured global disease burden.

Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment.

BACKGROUND & AIMS: Although inflammatory bowel diseases (IBD) associated with primary sclerosing cholangitis (PSC) have been well characterized in adults, there have been few pediatric studies, and these were small and produced conflicting results. We investigated features of PSC-IBD in children, compared with children with IBD without PSC. METHODS: We performed a retrospective study of 74 children with PSC-IBD, diagnosed from 2000 through 2018, who were each matched with 2 children with ulcerative colitis or IBD-unclassified (controls) based on sex, date of birth, and type of IBD. We compared IBD distribution and clinical activity (remission, medication use, hospitalization, or colectomy) and patient growth between groups. Data were extracted from each hospital contact and analyzed using mixed effects analyses or Cox proportional hazards regression, adjusting for time-dependent medication exposure. RESULTS: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Patients with PSC-IBD were more likely to be treated with only 5-ASA, compared with controls (odds ratio [OR], 3.04; 95% CI, 1.44-6.41) and to have IBD in clinical remission (OR, 2.94; 95% CI, 1.78-4.87). Risk of colectomy or treatment with a biologic agent was lower in patients with PSC-IBD than controls (hazard ratio, 0.24; 95% CI, 0.12-0.52). However, determination of IBD severity based on symptoms underestimated severity based on endoscopic activity in patients with PSC-IBD. Among patients with IBD in clinical remission, those with PSC were less likely to have endoscopic remission (OR, 0.44; 95% CI, 0.20-0.96). Patients with PSC-IBD were shorter and had lower weight over time, compared with controls. CONCLUSIONS: In a retrospective study, we found that features of IBD differed between children with vs without PSC, similar to adults. Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.

Clinical Characteristics and Long-term Outcomes of Children With Fibrosing Pancreatitis.

OBJECTIVES: Fibrosing pancreatitis (FP) shares clinical features with autoimmune pancreatitis (AIP), although both entities have not been definitely linked. This study aimed to assess the presence of AIP criteria in an historic FP patient cohort and investigate the clinical features, management, and long-term outcomes of pediatric FP (P-FP). METHODS: Clinical data of 14 P-FP patients from Toronto and 42 P-FP cases from a literature review were collected and compared to pediatric AIP (P-AIP). Toronto P-FP patients were recontacted to assess their current health status using a brief questionnaire. RESULTS: Jaundice and abdominal pain were the symptoms at presentation in 44 of 56 (79%) and 50 of 56 (89%) P-FP patients, respectively. Common findings on cross sectional imaging were an enlarged pancreas head with narrowing of the distal common bile duct (51/54, 94%). Histopathology mainly showed gland fibrosis (39/39, 100%). Three of twelve (25%) P-FP patients had elevated IgG4 in serum. None of the patients were treated with corticosteroids, but some underwent surgical or endoscopic intervention. Toronto patients were followed for a median of 13.6 years (interquartile range: 2.9-22.8). Complications during follow-up included exocrine pancreatic insufficiency (3/14, 21%) and pancreatic gland atrophy (5/13, 38%); but none of the patients had disease relapse or developed diabetes type 3c. Five (5/14, 36%) patients developed other immune-mediated diseases over time. CONCLUSIONS: Clinical features of patients with P-FP resembled those recently described in a subgroup of P-AIP presenting with jaundice. Long-term outcome of these patients is generally good, with or without invasive interventions. As some patients may develop exocrine pancreatic insufficiency and/or other immune-mediated diseases, ongoing clinical monitoring is recommended.

Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium.

OBJECTIVES: Most patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). The liver and colon express MAdCAM-1, a target of lymphocyte homing integrins. Vedolizumab (VDZ) is an α4ß7 integrin antibody used to treat IBD. We investigated liver outcomes in children with PSC-IBD treated with VDZ. METHODS: Patients were identified within the Pediatric PSC Consortium, a multicenter research registry. Retrospective demographic, phenotypic, biochemical, radiological, histopathologic and IBD data for up to 1 year of VDZ therapy were collected. Liver biochemical and IBD responses were defined as: a 75% or greater reduction in initial γ-glutamyltransferase (GGT), or a GGT that fell to <50 IU/L and improved Mayo endoscopy grade or IBD activity scores after 9 to 12 months. RESULTS: Thirty-seven patients were identified from 19 centers. VDZ was initiated at median age of 16 years [IQR 15-18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response after 9 to 12 months. For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response. Final GGT after 9 to 12 months was 51 [IQR 28-71] in IBD patients in remission versus 127 [IQR 63-226] in those with active IBD, (P = 0.066). CONCLUSIONS: Liver biochemistry worsened over time in IBD unresponsive to VDZ but remained unchanged in IBD patients in remission. VDZ did not improve liver biochemistry in pediatric PSC-IBD. Progressive liver disease may be more common in patients with medically refractory IBD.

Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn's disease.

BACKGROUND AND AIMS: Treatment goals in Crohn's disease (CD) have evolved to target mucosal healing. There is now a drive to determine if noninvasive measures can adequately identify the attainment and persistence of this goal. Currently, data describing the relationship between clinical indices and endoscopic appearance in pediatric CD are sparse. Our aim was to compare endoscopic severity with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) in children with newly diagnosed CD. METHODS: All children aged ≤17 years newly diagnosed with CD enrolled in an inception cohort at sites of the Canadian Children Inflammatory Bowel Disease Network were eligible. Clinical disease activity at presentation was evaluated by the wPCDAI and conventional biochemical parameters. Severity of disease at ileocolonoscopy was assessed by the simple endoscopic score for CD (SES-CD), with segmental subscores noted. We evaluated the association of SES-CD and disease activity markers using the Pearson test of correlation, the Spearman rank coefficient, and linear regression models. RESULTS: Two hundred eighty patients from 11 centers were included in the analysis. The median wPCDAI score was 60 (interquartile range, 40-80; 53% severe). Median SES-CD was 16 (interquartile range 10-22; 51% severe). The wPCDAI correlated weakly with SES-CD (r = .39, P < .001). Examination of the individual components that contribute to the wPCDAI demonstrated weak correlation with the SES-CD for all items apart from stooling (moderate correlation, r = .50, P < .001). Routine blood tests did not correlate well with the SES-CD. In regression models, variation in clinical symptoms accounted for most of the variation in both the wPCDAI and SES-CD, with no additional benefit from routine blood tests. CONCLUSIONS: In children with newly diagnosed CD, wPCDAI correlates poorly with endoscopic disease activity. As treatment paradigms evolve to target mucosal healing, clinical markers should not be used in isolation to determine disease activity.

Anticipatory care of children and adolescents with inflammatory bowel disease: a primer for primary care providers.

PURPOSE OF REVIEW: About 10-20% of patients with newly diagnosed inflammatory bowel disease (IBD) are under 18 years of age, with incidence increasing in young children. Children with IBD have unique healthcare needs, which require coordination between primary care providers and pediatric gastroenterologists to provide appropriate care. This review highlights some key elements of anticipatory care in pediatric IBD, including vaccination, risk of serious infection and malignancy, psychosocial and educational needs, and cannabis use. RECENT FINDINGS: Therapies for IBD that include anti-tumor necrosis factor medications, especially when combined with corticosteroids are associated with higher risks of serious infections. Vaccination remains the best way to prevent infections. Live vaccinations should be avoided during immunosuppression, but the schedule should be otherwise completed, including vaccination for influenza, pneumococcus and meningococcus, and human papillomavirus. Malignancy risk is increased in IBD patients, both because of disease factors and resulting from immunomodulatory medications. Children with IBD are at risk for mental health disorders and negative educational outcomes, so identification of at-risk children and early intervention are important. SUMMARY: High-quality care in pediatric IBD requires coordination between pediatric gastroenterologists and primary care providers, with careful attention paid to the specific needs of children with IBD.

Symptoms Do Not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC-IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC-IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. METHODS: We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC-IBD and 50 children with only IBD (controls; UC or IBD-unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC-IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. RESULTS: Patients with PSC-IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6-21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC-IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC-IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC-IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut-point, 93 µg/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC-IBD than controls. CONCLUSIONS: Children with PSC-IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC-IBD; levels below 93 µg/g are associated with mucosal healing.

New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children.

OBJECTIVES: To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use. STUDY DESIGN: We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) ≥×2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method. RESULTS: The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified. CONCLUSIONS: Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped.

Can MR enterography screen for perianal disease in pediatric inflammatory bowel disease?

BACKGROUND: Pediatric Crohn's disease is associated with perianal disease (PAD). Magnetic resonance enterography (MRE) assesses small bowel involvement in pediatric inflammatory bowel disease (PIBD). Pelvic MRI (P-MRI) is the gold standard for assessing PAD. PURPOSE: To determine if MRE can accurately detect PAD in PIBD, distinguishing perianal fistulae (PAF) from perianal abscesses (PAA), referenced against P-MRI. STUDY TYPE: Retrospective. POPULATION: Seventy-seven PIBD patients, 27 females (mean age 14.1 years), with P-MRI and MRE within 6 months. FIELD STRENGTH/SEQUENCE: 1.5T and 3T; P-MRI: sagittal fat suppressed (FS) T2 fast spin-echo (FSE), coronal short tau inversion recovery, axial T1 FSE, coronal and axial postcontrast FS T1 FSE; MRE: coronal balanced steady-state free-precession (SSFP), coronal cine SSFP, coronal and axial single-shot T2 FS, axial SSFP, coronal ultrafast 3D T1 -weighted gradient echo FS (3D T1 GE), axial diffusion-weighted imaging, coronal and axial postcontrast 3D T1 GE FS. ASSESSMENT: Two radiologists independently, then by consensus, assessed randomized MRI exams, recording PAF number, location, and length; and PAA number, location, length, and volume. Sensitivity analysis used clinical disease as the gold standard, calculated separately for P-MRI and MRE. STATISTICAL TESTS: Comparing MRE and P-MRI consensus data, sensitivity, specificity, positive, and negative predictive values (P/NPV) were calculated. Inter- and intrareader reliability were assessed using kappa statistics. RESULTS: P-MRI and MRE were paired, detecting PAD in 73 patients, PAF in 63, and PAA in 31 P-MRI. MRE sensitivities, specificities, PPV, and NPV were: PAD 82%, 100%, 100%, 23%; PAF 74%, 71%, 92%, 38%; PAA 51%, 85%, 69%, 72%; clinical 82%, 22%, 37%, 69%; clinical P-MRI 96%, 8%, 37%, 80%. MRE interreader agreement for PAD was moderate (kappa = 0.51 [0.29-0.73]), fair for PAF and PAA. DATA CONCLUSION: Using a standard technique, MRE can detect PAD with high specificity and moderate sensitivity in PIBD, missing some PAF and small PAA. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1638-1645.

Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS: Drug clearance is affected by a number of patient and disease factors. For thiopurines, adjusting dosing by monitoring 6-thioguanine (6TGN) and 6-methylmercaptopurine ((6MMP) levels is demonstrated to maximize response and minimize toxicity, while monitoring metabolite levels when treating with anti-tumor necrosis factor (anti-TNF) remain controversial. While in adults the use of TDM in the setting of loss of response to anti-TNF therapy is established, in children, only a small number of studies exist, but these too have encouraging results. There are however, conflicting data regarding the optimal timing of TDM, comparing "reactive" monitoring and "proactive" monitoring. No such data exist in pediatrics. TDM is cost-effective, and dose reduction may represent a safety benefit. There are limited adult data for use of TDM for the newer biologics, vedolizumab and ustekinumab, but early results suggest similarly promising utility. The use of TDM in pediatric IBD is increasing in clinical practice, with similar efficacy to adults demonstrated in children with loss of response to anti-TNF therapy. More prospective studies are needed in children to examine proactive monitoring and utility of TDM with newer biologics.

Pulse wave velocity measurement as a marker of arterial stiffness in pediatric inflammatory bowel disease: a pilot study.

In adults with inflammatory bowel disease (IBD), the incidence of cardiovascular events is increased, leading to long-term morbidity. Arterial stiffness (AS) measured by pulse wave velocity (PWV) is a validated early precursor of cardiovascular disease (CVD), and measurement of PWV was shown to be a feasible test in children. The aim of this study was to assess AS in children with IBD. In this prospective study, we determined PWV between the carotid and femoral artery (PWVcf) in 25 children and adolescents with IBD (11 females, median age 14.1 years, median disease duration 2.8 years). The majority (68%) of the subjects were in clinical remission, and 48% received anti-tumor necrosis factor alpha (TNFα) treatment. AS was not increased in this cohort of children and adolescents with IBD, who did not have signs of cardiovascular disease, such as arterial hypertension. CONCLUSION: PWV seems to be normal in children with IBD in remission or with mild disease activity. Larger studies should assess its potential role as a valid and non-invasive follow-up marker in children with IBD, to avoid cardiovascular complications. What is Known : • Inflammatory bowel disease (IBD) is a risk factor of cardiovascular disease (CVD). • Pulse wave velocity (PWV) measurement is the current gold standard to assess arterial stiffness (AS), which is an early predictor of CVD. What is New: • This is the first study using PWV measurements to determine AS in children with IBD. • In children with IBD in remission or only mild disease activity AS is not increased.

Pediatric Esophageal Foreign Bodies: The Role of Socioeconomic Status in Ingestion Patterns.

OBJECTIVE: Pediatric esophageal foreign bodies (EFBs) are common and can result in serious complications. Little is known about the influence of socioeconomic status (SES) on EFB ingestion in children. The goal was to study SES as a risk factor for dangerous foreign body ingestion and in-hospital complications in children. METHODS: This was a retrospective cohort study of children presenting to a tertiary care pediatric hospital with an esophageal foreign body from 2010 to 2021. SES was assessed for each patient by linking their postal code to the Ontario Marginalization Index to determine a quintile score across four dimensions of deprivation: residential instability, material deprivation, dependency, and ethnic concentration. Dangerous EFBs were defined as magnets, batteries, sharp objects, or bones. In-hospital complications included: intensive care unit admission, prolonged length of stay, and postoperative sequelae. RESULTS: A total of 680 patients were included. Dangerous EFB ingestion was higher for children with increased residential instability (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6) and increased material deprivation (OR, 2.2; CI, 1.9-2.8), which was similarly true for odds of complications. Odds of dangerous EFB ingestion were higher in older children (OR, 1.1; CI, 1.0-1.1) and odds of complications were higher in children with comorbidities (OR, 1.1; CI, 1.0-1.3). CONCLUSION: Higher levels of housing instability and material deprivation are associated with dangerous EFB ingestion and complications related to EFB ingestion. These findings emphasize the role that SES plays on child health outcomes and the need for initiatives to mitigate these disparities. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2945-2953, 2024.

High Healthcare Costs in Childhood Inflammatory Bowel Disease: Development of a Prediction Model Using Linked Clinical and Health Administrative Data.

BACKGROUND: The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile). METHODS: Using data from the Canadian Children IBD Network inception cohort (≤16 years of age, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting. RESULTS: The mean cost among 487 children with IBD was CA$15 168 ± 15 305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71. CONCLUSIONS: The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

Cost of caring for children with IBD is high­CA$15 168 between 31 and 365 days from diagnosis in 487 Canadian children. Predictors of high costs included anti-tumor necrosis factor therapy and mental health care, with lower costs in those with a primary-care provider.

Outcomes Following Acute Severe Colitis at Initial Presentation: A Multi-centre, Prospective, Paediatric Cohort Study.

AIM: To assess contemporary outcomes in children with acute severe ulcerative colitis [ASUC] at initial presentation. METHODS: Between April 2014 and January 2019, children aged <17 years, with new onset ASUC (Paediatric Ulcerative Colitis Activity Index [PUCAI ≥65) were prospectively followed in a Canadian inception cohort study. 16S rRNA amplicon sequencing captured microbial composition of baseline faecal samples. Primary endpoint was corticosteroid-free clinical remission with intact colon at 1 year [PUCAI <10, no steroids ≥4 weeks]. RESULTS: Of 379 children with new onset UC/IBD-unclassified, 105 [28%] presented with ASUC (42% male; median [interquartile range; [IQR]) age 14 [11-16] years; extensive colitis in all). Compared with mild UC, gut microbiome of ASUC patients had lower α-diversity, decreased beneficial anaerobes, and increased aerobes; 54 [51%] children were steroid-refractory and given infliximab [87% intensified regimen]. Corticosteroid-free remission at 1 year was achieved by 62 [61%] ASUC cohort (by 34 [63%] steroid-refractory patients, all on biologics; by 28 [55%] steroid responders,13 [25%] on 5- aminosalicylic acid [5-ASA], 5 [10%] on thiopurines, 10 [20%] on biologics). By 1 year, 78 [74%] escalated to infliximab including 24 [47%] steroid-responders failed by 5-ASA and/or thiopurines. In multivariable analysis, clinical predictors for commencing infliximab included hypoalbuminaemia, greater PUCAI, higher age, and male sex. Over 18 months, repeat corticosteroid course[s] and repeat hospitalisation were less likely among steroid-refractory versus -responsive but -dependent patients (adjusted odds ratio [aOR] 0.71 [95% CI 0.57-0.89] and 0.54 [95% CI 0.45-0.66], respectively). CONCLUSION: The majority of children presenting with ASUC escalate therapy to biologics. Predictors of need for advanced therapy may guide selection of optimal maintenance therapy.

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).