Citations

Abstract Background Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin αvβ6 IgG autoantibodies (anti-αvβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-αvβ6 autoantibodies predate UC development and to study associations between anti-αvβ6 and disease outcomes in newly diagnosed UC patients. Methods In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-αvβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-αvβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-αvβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model. Results Anti-αvβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Additionally, the predictive performance of anti-αvβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-αvβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-αvβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D). Conclusion Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Abstract Aim There are limited data on the impact of 2 vs 3 doses of COVID-19 vaccine in patients with inflammatory bowel disease (IBD). The primary aim of the study was to assess the efficacy of COVID-19 vaccine based on number of administered doses in patients with IBD. Methods We conducted a retrospective cohort study using TriNetX, a multi-institutional database to compare patients with IBD who received 1, 2, or 3 doses of BNT162b2 or mRNA-1273 to unvaccinated IBD patients (1.1.2020-7.26.2022) to assess the risk of COVID-19 after 1:1 propensity score matching. We also evaluated the impact of vaccine on a composite of severe COVID-19 outcomes including hospitalization, intubation, intensive care unit care, acute kidney injury, or mortality. Results After propensity score matching, vaccinated patients with 2 (adjusted OR [aOR], 0.8; 95% confidence interval [CI], 0.6-0.9) and 3 doses (aOR, 0.7; 95% CI, 0.5-0.9) were found to have a lower risk of COVID-19 compared with unvaccinated patients. Vaccinated patients with IBD had a lower risk of severe COVID-19 outcomes (aOR, 0.7; 95% CI, 0.6-0.9) compared with unvaccinated patients. There was no difference in the risk of COVID-19 in IBD patients with 2 compared with 3 doses (aOR, 0.97; 95% CI, 0.7-1.3). However, IBD patients with 2 doses were at an increased risk for hospitalization due to COVID-19 (aOR, 1.78; 95% CI, 1.02-3.11) compared with those that received 3 doses. Conclusion Vaccinated patients with IBD had a lower risk of severe COVID-19 outcomes compared with unvaccinated patients. A third dose of COVID-19 vaccine compared with 2 doses decreases the risk of hospitalization but not breakthrough infection in patients with IBD.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49–0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48–0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5–17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 μg/mL (SD 67) and a median of 22 μg/mL (interquartile range 12–38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Lay SummaryWe demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. Methods Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. Results Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. Conclusions Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

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 < .001 for both). Prior COVID-19 infection, female sex, and vaccine type were associated with severe systemic reactions to dose 1, while age <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.