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BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the European Union. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histologic evaluation was performed at baseline, Week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease in the pouch, and Pouchitis Disease Activity Index histologic component were evaluated. Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (standard deviation) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 versus placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% confidence interval]: W14: -8.4 [-14.3 to -2.6]; W34: -7.0 [-12.0 to -2.0]). More patients receiving vedolizumab versus placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference, 32.4 percentage points [p.p] [9.7, 51.4]; W34: 52.1% vs 12.9%; difference, 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), Simple Endoscopic Score for Crohn's Disease remission (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), and MH (W14: 16.7% vs 2.5%; difference, 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 than those without. CONCLUSIONS: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. (ClinicalTrials.gov number, NCT02790138.).
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BACKGROUND & AIMS: Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease. METHODS: Patients with Crohn's disease undergoing ileocolic resection were prospectively recruited in 6 academic centers. Biopsy samples from the neoterminal ileum, colon, and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence. RESULTS: A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 patients with Crohn's disease were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared with patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the 3 biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features. CONCLUSIONS: Ileal and colonic mucosa-associated microbiome deviations precede development of new-onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.
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OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , Femenino , Masculino , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/epidemiología , Persona de Mediana Edad , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , Adulto , Anciano , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Vacunación , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/sangreRESUMEN
BACKGROUND AND AIMS: The modified Rutgeerts score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn's disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, 2 new scores have been proposed. This study assessed the interobserver agreement of the current score (mRS) and the new endoscopic score for ePOR in CD. METHODS: Sixteen Dutch academic and nonacademic inflammatory bowel disease specialists assessed endoscopic videos (n = 71) of postoperative CD patients (n = 66) retrieved from 9 Dutch centers. Each video was assessed for degree of inflammation by 4 gastroenterologists using the mRS and the new proposed endoscopic score: the REMIND score (separate score of anastomosis and neoterminal ileum) and the updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body, and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, and colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed by using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was .67 (95% confidence interval [CI], .59-.74). The weighted kappa for the REMIND score was .73 (95% CI, .65-.80) for lesions in the neoterminal ileum and .46 (95% CI, .35-.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts score was .69 (95% CI, .62-.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, and colonic and ileal blind loop was .61 (95% CI, .49-.73), .63 (95% CI, .54-.72), .61 (95% CI, .49-.74), .83 (95% CI, .62-1.00) and .68 (95% CI, .46-.89), respectively. CONCLUSIONS: The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, although only moderate for anastomotic lesions. Because therapeutic decisions in clinical practice are based on these assessments, and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.
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Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection. Biomarkers have the potential to predict CD outcomes and guide clinical decision-making. This review aims to summarize the current literature on promising biomarkers associated with CD outcomes and their potential clinical implications. The identification of reliable biomarkers for CD outcomes is of paramount importance in tailoring treatment strategies, monitoring disease activity, and predicting the risk of complications. Clinical prognostic factors traditionally used to assess disease severity, and the likelihood of complications have limitations in accuracy and predictive value. Thus, there is a need for more precise biomarkers, particularly in newly diagnosed and treatment-naive patients. Pharmacogenomic markers, such as TPMT and NUDT15 polymorphisms, have been utilized to identify patients at risk of adverse events with thiopurine therapy. Several biomarkers, including HLA haplotypes, oncostatin M expression, and transcriptomic profiles, have shown associations with response to anti-TNF therapy. Confocal laser endomicroscopy and single-cell analyses hold promise in predicting treatment response to specific therapies. The identification of biomarkers associated with post-operative recurrence in CD is crucial, as it could lead to changes in management algorithms. Several promising microbiome signatures and proteomic profiles have been identified. In conclusion, biomarkers have the potential to revolutionize the management of CD by providing valuable prognostic information and guiding treatment decisions. However, further research and validation are necessary to establish their clinical utility and integration into routine practice.
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BACKGROUND: Risk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence. AIMS: To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. METHODS: Multiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score ≥i2 or modified Rutgeerts' score ≥i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies. RESULTS: In total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors. CONCLUSION: Risk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required.
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Enfermedad de Crohn , Recurrencia , Humanos , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/patología , Factores de RiesgoRESUMEN
BACKGROUND: Primary sclerosing cholangitis associated with inflammatory bowel disease (IBD-PSC) carries significant morbidity compared to IBD without PSC. Alterations in microbial composition and bile acid (BA) profiles have been shown to modulate chronic inflammation in IBD, but data in IBD-PSC is scarce. We aimed to assess the differences in gut microbiome composition as well as in the BA profile and BA-related microbial functions between IBD-PSC and IBD-only. METHODS: 54 IBD-PSC and 62 IBD-only subjects were enrolled from 2012 to 2021. Baseline samples were collected for fecal DNA shotgun metagenomic sequencing, fecal and serum BA quantitation using mass spectrometry and fecal calprotectin. Liver fibrosis measured by transient elastography (TE) was assessed in the IBD-PSC group. Data was analyzed using general linear regression models and Spearman rank correlation tests. RESULTS: Patients with IBD-PSC had reduced microbial gene richness (p=0.004) and significant compositional shifts (PERMANOVA: R2=0.01, p=0.03) compared to IBD-only. IBD-PSC was associated with altered microbial composition and function, including decreased abundance of Blautia obeum, increased abundance of Veillonella atypica, Veillonella dispar and Clostridium scindens (q<0.05 for all), and increased abundance of microbial genes involved in secondary BA metabolism. Decreased serum sulfated and increased serum conjugated secondary BA were associated with IBD-PSC and increased liver fibrosis. CONCLUSION: We identified differences in microbial species, functional capacity and serum BA profiles in IBD-PSC compared with IBD-only. Our findings provide insight into the pathophysiology of IBD associated with PSC and suggest possible targets for modulating the risk and course of IBD in subjects with PSC.
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INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.