Kappelman, Michael D.

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

INTRODUCTION: Although an additional coronavirus disease 2019 vaccine dose for immunocompromised persons has been recommended in some countries, further data to guide vaccination strategies for patients with inflammatory bowel disease (IBD) are urgently needed. We sought to identify factors affecting initial humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among patients with IBD. METHODS: In this prospective cohort of SARS-CoV-2 immunized patients with IBD, we evaluated associations between participant age, sex, vaccine type, medication use, and the presence of a detectable antireceptor binding domain antibody and quantitative antibody level. RESULTS: In total, 1,909 participants were included (1,123, 692, and 94 received BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively) of whom 96% achieved a positive antibody response. On multivariable analysis, factors associated with lack of antibody response were older age ( P = 0.043), BNT162b2 vs mRNA-1273 (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0–3.9), and combination therapy with anti-TNF and 6MP, azathioprine, or methotrexate (OR 4.2, 95% CI 2.4–7.3). The use of 5-aminosalicylate or sulfasalazine (OR 0.3, 95% CI 0.1–0.8) and ustekinumab (OR 0.2, 95% CI 0.05–0.8) was associated with decreased odds of lacking antibody response. DISCUSSION: Most patients with IBD mount an initial response to SARS-CoV-2 vaccination; however, older patients and those treated with anti-TNF and immunomodulator have blunted responses and may benefit the most from an additional vaccine dose. Patients treated with other classes of immunosuppressive medications have more robust initial immune responses to vaccination. These data should inform key decisions about patient selection for additional coronavirus disease 2019 vaccine doses in patients with IBD.

Abstract Background Severe acute respiratory syndrome coronavirus 2 vaccination is recommended for all individuals with inflammatory bowel disease (IBD), including those on immunosuppressive therapies; however, little is known about vaccine safety and efficacy in these patients or the impact of vaccination on IBD disease course. Methods We evaluated coronavirus disease 2019 (COVID-19) vaccine–related adverse events (AEs) and the effect of vaccination on IBD disease course among participants in the PREVENT-COVID (Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID) study, a prospective, observational cohort study. Localized and systemic reactions were assessed via questionnaire. Disease flare was defined by worsening IBD symptoms and change in IBD medications. Outcomes were stratified by vaccine type and IBD medication classes. Results A total of 3316 individuals with IBD received at least 1 COVID-19 vaccine. Injection site tenderness (68%) and fatigue (46% dose 1, 68% dose 2) were the most commonly reported localized and systemic AEs after vaccination. Severe localized and systemic vaccine-related AEs were rare. The mRNA-1273 vaccine was associated with significantly greater severe AEs at dose 2 (localized 4% vs 2%, systemic 15% vs 10%; P &lt; .001 for both). Prior COVID-19 infection, female sex, and vaccine type were associated with severe systemic reactions to dose 1, while age &lt;50 years, female sex, vaccine type, and antitumor necrosis factor and vedolizumab use were associated with severe systemic reactions to dose 2. Overall rates (2%) of IBD flare were low following vaccination. Conclusions Our findings provide reassurance that the severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with IBD, which may help to combat vaccine hesitancy and increase vaccine confidence.

Abstract Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9–5.2). Most (94%) Crohn’s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%–15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

SummaryBackgroundReal‐world comparative benefits and risks of infliximab (IFX) and adalimumab (ADA) in patients with ulcerative colitis (UC) are unclear.AimTo evaluate the comparative effectiveness and safety of IFX and ADA in patients with UC who were new users of anti‐TNF agents.MethodsUsing an administrative claims database (Optum Labs Data Warehouse), we identified patients who received first anti‐TNF (IFX, ADA) prescription after a 12‐month period without any anti‐TNF treatment (baseline), and with a minimum 6‐month follow‐up after anti‐TNF initiation. Primary outcome measures were: all‐cause and UC‐related hospitalisation, abdominal surgery, corticosteroid use >60 days after starting anti‐TNF, and serious infections. We performed 2:1 propensity‐score matched Cox proportional hazard analysis, and inverse probability‐of‐treatment weight (IPTW) analysis, accounting for healthcare utilisation, comorbidities and use of UC‐related medication.ResultsWe included 1400 new users of anti‐TNF agents (age, 43 ± 15 years; 52% males), from 2006 to 2014. On propensity‐score matched analysis, there was no significant difference in the risk of UC‐related hospitalisation [IFX vs. ADA; adjusted hazard ratio (aHR), 1.04; 95% confidence interval (CI) 0.71–1.51], corticosteroid use (aHR, 0.85; 95% CI, 0.68–1.06) and serious infections (aHR, 0.62; 95% CI, 0.29–1.34) between IFX‐ and ADA‐treated patients; the number of surgical events was very small. On IPTW analysis, risk of corticosteroid use was significantly lower in IFX – as compared to ADA – treated patients (aHR, 0.82; 95% CI, 0.68–0.99). Results were stable on multiple sensitivity analyses.ConclusionsIn a large retrospective cohort of patients with UC who were new users of anti‐TNF agents, IFX‐treated patients may have lower corticosteroid use than ADA‐treated patients, but risk of hospitalisation and serious infections were comparable.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20–1.96) for clinical remission and 1.74 (95% CI, 1.33–2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4–11.1) for clinical remission and 5.0 (95% CI, 3.4–10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.

ABSTRACTBackground:Inflammatory bowel disease–associated liver diseases (IBD‐LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD‐LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and γ‐glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD‐LD.Methods:Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age <16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria.Results:A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD‐LD. IBD‐LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT ≤ 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT > 50 (odds ratio 660, P < 0.0001). Of the 29 patients with IBD‐LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD‐LD was more common in patients with ulcerative colitis and IBD‐unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P < 0.001).Conclusions:Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD‐LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD.

ABSTRACTObjectives:Despite a paucity of published supporting data, 5‐aminosalicylate (5‐ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5‐ASA.Methods:Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5‐ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy).Results:Study subjects included 213 patients newly diagnosed as having UC who received oral 5‐ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5‐ASA used.Conclusions:Forty percent of children taking 5‐ASA as primary maintenance therapy at diagnosis are in CS‐free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.