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.

Transition Readiness in Youth with Inflammatory Bowel Disease.

OBJECTIVES: To examine readiness of adolescents and young adults (AYAs) with inflammatory bowel disease (IBD) to transition to adult care. STUDY DESIGN: A cross-sectional multicenter study evaluating transition readiness in individuals with IBD 16-19 years old prospectively recruited from 8 Canadian IBD centers using the validated ON Taking Responsibility for Adolescent to Adult Care (ON TRAC) questionnaire. Secondary aims included (1) screening for depression and anxiety using the 8-item Personal Health Questionnaire Depression Scale and The Screen for Child Anxiety Related Emotional Disorders questionnaires, respectively; (2) evaluating the association between depression and anxiety with readiness and disease activity; and (3) subjectively evaluating AYA readiness based on physician and parent assessments. RESULTS: In total, 186 participants (139 adolescent, 47 young adult) were enrolled, mean age 17.4 years (SD, 0.87). ON TRAC scores determined that 26.6% of AYAs at pediatric and 40.4% at adult centers reached the threshold of readiness. On multivariable linear regression analysis age was positively (P = .001) and disease remission negatively (P = .03) associated with ON TRAC scores. No statistically significant differences were determined across centers. A significant percentage of AYAs reported moderate-to-severe depression (21.7%) and generalized anxiety (36%); however, neither were significantly associated with ON TRAC scores. Notably, physician and parental assessment of AYA readiness correlated poorly with ON TRAC scores (⍴ = 0.11, ⍴ = 0.24, respectively). CONCLUSIONS: Assessment of transition readiness in AYAs with IBD highlighted that a large proportion do not have adequate knowledge or behavior skills needed for transition to adult care. This study infers that readiness assessment tools are essential during transition to identify deficits in knowledge and behavior skills that could be specifically targeted by the youth, caregivers, and multidisciplinary team.

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.

Discontinuation of Immunosuppressive Medications in Children With Inflammatory Bowel Disease on Combination Therapy.

We determined the frequency and factors associated with the first clinical relapse after immunomodulator (IM) withdrawal in a cohort of children with inflammatory bowel disease on combination therapy. A total of 105 patients (89 with Crohn disease [CD]) in clinical remission were included (91 [86.7%] were on infliximab, 53 [50.5%] with methotrexate, and 52 on azathioprine). The median duration of combination therapy was 2.1 years (interquartile range [IQR] 1.3-2.8). Only 11 (10.5%) patients experienced a clinical relapse over a median duration of follow-up of 12.0 months (IQR 5.0-19.0) after IM discontinuation. The median baseline pediatric CD activity index in those with CD who relapsed after IM discontinuation was 47.5 (IQR: 35.0-55.0) versus those who did not relapse (median 35.0, IQR: 20.0-52.5; P = 0.04). In the patients who did not relapse, the median IFX trough level at IM discontinuation was 6.2 and 3.8 µg/mL in those who relapsed.

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.

Long-term Outcomes of Infliximab Use for Pediatric Crohn Disease: A Canadian Multicenter Clinical Practice Experience.

BACKGROUND: Data on long-term real-world outcomes of infliximab in pediatric Crohn disease are limited. AIM: The aim of the study was to evaluate infliximab optimization and durability in children with Crohn disease. METHODS: We performed a retrospective review of children with Crohn disease who started infliximab from January 2008 to December 2012 in 4 Canadian tertiary care centers. A priori factors associated with optimization and discontinuation from loss of response were evaluated using logistic regression and Cox proportional hazards model, respectively. RESULTS: One hundred eighty children (54.4% boys) started infliximab; all completed induction. Median age at infliximab start was 14.3 years (Q1, Q3: 12.8, 15.9 years) and median time from diagnosis to infliximab start was 1.5 years (Q1, Q3: 0.6, 3.5 years). At last follow-up, 87.1% were maintained on infliximab (median duration follow-up 85.9 weeks [Q1, Q3: 43.8, 138.8 weeks]). Infliximab optimization occurred in 57.3% (dose escalation 15.2%, interval shortening 3.9%, both 38.2%), primarily due to loss of response. Younger age at diagnosis (<10 years old) and nonstricturing, nonpenetrating behavior were associated with optimization (odds ratio 6.5, 95% confidence interval [CI] 2.0-21.1 and odds ratio 2.1, 95% CI 1.0-4.2, respectively). The 1- and 2-year durability of infliximab (percentage in follow-up who were continuing on infliximab) were 95.5% (95% CI 90.4-98.3) and 91.0% (95% CI 82.4-96.3), respectively. Annual discontinuation due to loss of response occurred at 3.2% per year (95% CI 1.1-5.2). CONCLUSIONS: Children with Crohn disease maintain a durable response to infliximab. Optimization occurs frequently and allows for continued use. Younger age at diagnosis and nonstricturing, nonpenetrating behavior are associated with increased need for infliximab optimization.

Conservative Management of Downhill Esophageal Varices Secondary to Central Line-related Thrombosis After Hematopoietic Stem Cell Transplant.

Occlusive central line-related complications are not infrequent in children undergoing cancer therapy, but are generally not associated with life-threatening complications. Thrombosis of the superior vena cava (SVC) is rarely described in such patients, and downhill esophageal varices have been described in children and adults as a complication of altered SVC blood flow. The management of patients with SVC thrombosis and associated varices is complicated by the need to treat the thrombus weighed against bleeding risk. We present a 14-year-old adolescent with a history of acute leukemia and central line-related complications, including SVC thrombosis with subsequent formation of downhill esophageal varices. Conservative management consisting of anticoagulation alone resulted in resolution of the varices with no bleeding complications.

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.

Pre-Diagnosis Diet Predicts Response to Exclusive Enteral Nutrition and Correlates with Microbiome in Pediatric Crohn Disease.

Exclusive enteral nutrition (EEN) is effective in inducing remission in pediatric Crohn disease (CD). EEN alters the intestinal microbiome, but precise mechanisms are unknown. We hypothesized that pre-diagnosis diet establishes a baseline gut microbiome, which then mediates response to EEN. We analyzed prospectively recorded food frequency questionnaires (FFQs) for pre-diagnosis dietary patterns. Fecal microbiota were sequenced (16SrRNA) at baseline and through an 18-month follow-up period. Dietary patterns, Mediterranean diet adherence, and stool microbiota were associated with EEN treatment outcomes, disease flare, need for anti-tumor necrosis factor (TNF)-α therapy, and long-term clinical outcomes. Ninety-eight patients were included. Baseline disease severity and microbiota were associated with diet. Four dietary patterns were identified by FFQs; a "mature diet" high in fruits, vegetables, and fish was linked to increased baseline microbial diversity, which was associated with fewer disease flares (p < 0.05) and a trend towards a delayed need for anti-TNF therapy (p = 0.086). Baseline stool microbial taxa were increased (Blautia and Faecalibacterium) or decreased (Ruminococcus gnavus group) with the mature diet compared to other diets. Surprisingly, a "pre-packaged" dietary pattern (rich in processed foods) was associated with delayed flares in males (p < 0.05). Long-term pre-diagnosis diet was associated with outcomes of EEN therapy in pediatric CD; diet-microbiota and microbiota-outcome associations may mediate this relationship.

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).

Incidence and prevalence of eosinophilic esophagitis in children.

OBJECTIVES: The aim of the present study was to conduct a systematic review with meta-analysis on the epidemiology of eosinophilic esophagitis (EoE) in children. METHODS: Studies investigating incidence and prevalence of EoE in children (≤ 18 years) were identified in a systematic review of MEDLINE (1950-2011) and Embase (1980-2011). Meta-analyses were performed for incidence and subgroups with ≥ 5 studies: esophagogastroduodenoscopy (EGD) for any indication, histologic esophageal disease, and celiac disease, and EGD for abdominal pain. We used a random effects model, Q statistic to assess heterogeneity, and joinpoint analysis to assess time trends. RESULTS: We included 25 studies. The incidence of EoE varied from 0.7 to 10/100,000 per person-year and the prevalence ranged from 0.2 to 43/100,000. The incidence and prevalence increased over time. Prevalence was highest in children with food impaction or dysphagia (63%-88%). The pooled prevalence was 3.7% (95% confidence interval [CI] 2.4-5.1) in EGD for any indication, 24% (95% CI 19-28) in histologic esophageal disease, 2.3% (95% CI 1.0-3.6) in celiac disease, and 2.6% (95% CI 1.2-4.1) in EGD for abdominal pain. CONCLUSIONS: During the last 2 decades, the incidence and prevalence of EoE in children have increased significantly; however, the population-based incidence and prevalence of EoE vary widely across geographic variations, potentially because of variations in case of ascertainment between centers. Because EoE is common among children with food impaction and dysphagia, children with this presenting complaint should be rapidly identified at triage for timely endoscopic assessment.

Immunization history of children with inflammatory bowel disease.

BACKGROUND: Protection against vaccine-preventable diseases is important in children with inflammatory bowel disease (IBD) due to frequent immunosuppressive therapy use. The chronic relapsing nature and treatment regimen of IBD may necessitate modified timing of immunizations. OBJECTIVE: To evaluate the completeness of immunizations in children with IBD. METHODS: Immunization records of all children with IBD followed at the Alberta Children's Hospital (Calgary, Alberta) were reviewed. For children with incomplete immunization according to the province of Alberta schedule, the reasons for such were clarified. Demographic data and age at diagnosis were also collected. RESULTS: Immunization records were obtained from 145 (79%) children with IBD. Fifteen children had incomplete routine childhood immunizations, including two with no previous immunizations. The most common incomplete immunizations included hepatitis B (n=9), diphtheria, tetanus, acellular pertussis at 14 to 16 years of age (n=7), and diphtheria, tetanus, acellular pertussis, inactivated polio at four to six years of age (n=6). The reasons for incomplete immunization included use of immunosuppressive therapy at time of scheduled immunization; IBD-related symptoms at time of scheduled immunization; parental refusal; recent move from elsewhere with different immunization schedule; unawareness of routine immunization; and needle phobia. CONCLUSIONS: Although the majority of children with IBD had complete childhood immunizations, suboptimal immunizations were present in 10%. With increasing use of immunosuppressive therapy in IBD, physicians caring for children with IBD must periodically evaluate immunization status and ensure the completeness of childhood immunizations.

Inflammatory Bowel Disease Among Canadian Children: Comparison Between Children of Non-European Descent and Children of European Descent.

BACKGROUND: Inflammatory bowel disease (IBD) phenotypes may differ between countries and ancestral groups. The study aim was to examine ancestry and subtype variations of children newly diagnosed with IBD. METHODS: Children newly diagnosed with IBD enrolled into the Canadian Children Inflammatory Bowel Disease Network inception cohort study were categorized into 8 ancestral groups. Prospectively collected data at diagnosis and follow-up were compared between ancestral groups. RESULTS: Among 1447 children (63.2% Crohn's disease, 30.7% ulcerative colitis), 67.8% were European, 9.4% were South Asian, 3.8% were West Central Asian and Middle Eastern, 2.3% were African, 2.2% were East/South East Asian, 2.0% were Caribbean/Latin/Central/South American, 9.9% were mixed, and 2.6% were other. Children of African descent with ulcerative colitis had an older age of diagnosis compared with children of European descent (median 15.6 years vs 13.3 years; P = .02). Children of European descent had a higher proportion of positive family history with IBD (19.3% vs 12.1%; P = .001) compared with children of non-European descent. Children of European descent also had a lower proportion of immigrants and children of immigrants compared with children of non-European descent (9.8% vs 35.9%; P < .0001; and 3.6% vs 27.2%; P < .0001, respectively) . CONCLUSIONS: Important differences exist between different ancestral groups in pediatric patients with IBD with regard to age of diagnosis, family history, and immigrant status. Our study adds to the knowledge of the impact of ancestry on IBD pathogenesis.

This study explores the ancestral and phenotypic variation of Canadian children newly diagnosed with inflammatory bowel disease. It identifies differences between children of European and non-European descent in phenotypes of inflammatory bowel disease, disease location and behavior, family history, and immigrant status.

Postoperative complications following colectomy for ulcerative colitis in children.

BACKGROUND AND AIMS: Colectomy rates for ulcerative colitis (UC) and data on postcolectomy complications in children are limited. Thus, we assessed colectomy rates, early postcolectomy complications, and clinical predictors in children with UC undergoing a colectomy. METHODS: Children (18 years old or older) with UC who underwent colectomy from 1983 to 2009 were identified (n=30). All of the medical charts were reviewed. The diagnostic accuracy of International Classification of Diseases codes for UC and colectomy were validated. The primary outcome was postoperative complications defined as Clavien-Dindo classification grade II or higher. The yearly incidence of colectomies for pediatric UC was calculated and temporal trends were evaluated. RESULTS: The sensitivity and positive predictive value of UC and colectomy International Classification of Diseases codes were 96% and 100%, respectively. The median ages at UC diagnosis and colectomy were 10.9 and 12.1 years, respectively. All of the children had pancolitis and 63% underwent emergent colectomy. Postoperatively, 33% experienced at least 1 complication. Patients with emergent colectomy were more likely to have a postoperative complication compared with patients with elective colectomy (90% vs 50%; P=0.03). For emergent colectomy, postoperative complications were associated with a disease flare of ≥2 weeks before admission (60% vs 0%; P=0.03) and >2 weeks from admission to colectomy (78% vs 22%; P=0.04). The average annual rate of pediatric colectomy was 0.059/100,000 person-years and stable from 1983 to 2009 (P>0.05). CONCLUSIONS: Colectomy UC was uncommon and rates have remained stable. Postcolectomy complications were common, especially in patients undergoing emergent colectomy. Optimizing timing of colectomy may reduce postoperative complications.

Declining Corticosteroid Use for Inflammatory Bowel Disease Across Alberta: A Population-Based Cohort Study.

Background and Aims: Corticosteroid-free remission is a primary treatment goal in IBD which may be achieved with greater use of anti-TNF therapy. We defined temporal trends of corticosteroid use, anti-TNF use, hospitalization and surgery in a prevalent IBD cohort within the province of Alberta, Canada. Methods: Health administrative data were used to identify medication dispensing, hospitalizations and surgery in individuals with IBD from 2010 to 2015. Temporal trends were calculated using log-binomial regression for medications and log-linear models for hospitalizations and surgery rates. Analyses were stratified based on geographic location. Results: Of 28890 individuals with IBD, 50.3% had Crohn's disease. One in six individuals (15.45%) were dispensed a corticosteroid. Corticosteroid use decreased in both metropolitan areas (AAPC -20.08%, 95% CI: -21.78 to -18.04) and non-metropolitan areas (AAPC -18.14%, 95% CI: -20.78 to -18.04) with a similar pattern for corticosteroid dependence. Corticosteroid dependence was more prevalent in UC vs. CD (P < 0.05), and in the pediatric IBD cohort (13.45) compared to the adult (8.89) and elderly (7.54) cohorts (per 100 prevalent population, P < 0.001). The proportion of individuals dispensed an anti-TNF increased over the study period (AAPC 12.58%, 95% CI: 11.56 to 13.61). Significantly more non-metropolitan versus metropolitan residing individuals were hospitalized for any reason, for an IBD-related, or IBD-specific indication (all P < 0.001) though the proportion requiring IBD surgery was similar between groups. Conclusions: An increase in anti-TNF use corresponded to a decline in corticosteroid use and dependence in those with IBD. Inequities in IBD care still exist based on location and age.

Early Serum Infliximab Levels in Pediatric Ulcerative Colitis.

Background: Data on serum infliximab concentrations during induction in pediatric ulcerative colitis are limited. The study aim is to evaluate the relationship between serum infliximab concentrations during induction and short-term clinical remission in children with ulcerative colitis. Methods: We carried out a prospective, multi-center cohort study in pediatric patients with ulcerative colitis. Serum infliximab concentrations were collected at peak dose #1, week 1, trough pre-dose #2, and trough pre-dose #3. Infliximab dosing was left to investigator discretion. Clinical remission was defined by pediatric ulcerative colitis activity index <10 at week 8. Results: Twenty-four of thirty-four subjects (71%) achieved clinical remission at week 8. The median infliximab concentrations were 33.0 µg/mL (interquartile range: 26.5-52.1 µg/mL) pre-dose #2 and 22.5 µg/mL (interquartile range:15.9-32.3 µg/mL) pre-dose #3. Trough pre-dose #2 infliximab concentration yielded area under receiver operator characteristic curve 0.7, 95% CI: 0.5-0.9 in predicting week 8 clinical remission; a cut-off of 33.0 µg/mL yielded 62.5% sensitivity, 66.7% specificity. Trough pre-dose #3 infliximab concentrations were lower for subjects <10 years compared to ≥ 10 years [median 15.9 µg/mL, interquartile range (IQR) 8.5-21.8 µg/mL vs. 27.7 µg/mL, IQR 17.2-46.7 µg/mL, p = 0.01] and correlated with baseline weight (Spearman's rank correlation coefficient 0.45, p = 0.01). The median half-life following first IFX dose was 6.04 days (IQR 5.3-7.9 days). Conclusions: Infliximab concentrations ≥33 µg/mL prior to the second dose were associated with week 8 clinical remission. As young age and low body weight impact infliximab concentration, prospective studies with proactive adjustment in pediatric patients with ulcerative colitis should be carried out. Clinicians caring for children with UC should diligently adjust and monitor infliximab to optimize response.

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 patients with inflammatory bowel disease. 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.

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.

Transient Elastography in the Evaluation of Cystic Fibrosis-Associated Liver Disease: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Complications of cystic fibrosis-associated liver disease (CFLD) are a leading nonpulmonary cause of death. Transient elastography (TE) has recently been investigated to detect CFLD. This study reviews the current literature for TE in the detection CFLD. A meta-analysis was performed to determine the ideal liver stiffness measurement (LSM) cutoff. METHODS: PubMed, Medline, EMBASE and Web of Science were searched from inception until April 2016 for publications involving the detection of CFLD with TE. Data were extracted using a fixed protocol (a priori design) including study design, population characteristics, probe size and AST Platelet Ratio Index (APRI). RESULTS: Diagnostic properties were summarized from six studies of 605 patients. Cutoff for LSM was determined using pooled data submitted by authors. The cutoff for LSM and APRI were ≥5.95 kPa and ≥0.329 respectively, yielding a sensitivity, specificity and area under receiver operator characteristic of 55%, 87%, 0.76, 52%, 93% and 0.84 for LSM and APRI, respectively. When LSM ≥5.95 kPa and APRI ≥0.329, the sensitivity, specificity, positive predictive value and negative predictive value were 43%, 99%, 92% and 87% with a diagnostic odds ratio of 74.9. A bivariate metaregression model showed that pediatric specific cutoffs for liver stiffness and APRI may not be necessary. CONCLUSION: Individually, LSM and APRI have poor sensitivity but good specificity for detecting CFLD. They are most useful when combined. We propose that patients with LSM ≥5.95 kPa and APRI ≥0.329 be investigated thoroughly for the presence of cystic fibrosis-associated liver disease.