关键词： Ustekinumab   Inflammatory bowel disease   Drug response prediction  

摘要： Background Biologics against tumor necrosis factor-alpha (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. Methods We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. Results There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. Conclusions The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.

关键词： Diseases   Immunology   Biomedicine   general   Cancer Research   Metabolic Diseases   Infectious Diseases   Molecular Medicine   Neurosciences  

摘要： A translational study reveals a role for interleukin-1-fibroblast-neutrophil signaling in drug-resistant inflammatory bowel disease, opening a potential path to targeted treatment.

关键词： Inflammatory bowel disease   Colitis   Cytomegalovirus  

摘要： Background: The prevalence and significance of cytomegalovirus (CMV) colitis in pediatric acute severe colitis is unknown. The aim of this study was to determine the prevalence of CMV in colonic mucosa of children with acute severe refractory colitis and compare the clinical characteristics and outcomes of CMV positive and negative patients. Methods: In a case-control study, colonic biopsy specimens from children with severe refractory colitis were tested for CMV, and matched with non-refractory IBD controls. We characterized CMV positive patients by assessing laboratory values, concurrent medications, and need for surgery as compared with CMV negative refractory colitis patients. Results: Colonic biopsies from 96 patients were evaluated for CMV;48 with severe refractory colitis, and 48 non-refractory controls. There was an increased prevalence of CMV in severe refractory colitis [7/48 (14.6%), P < 0.0001];all were previously CMV negative. Viral DNA burden on immunohistochemistry was not predictive of response to antiviral therapy or need for surgery at 12 months. Lymphopenia was seen in all CMV positive patients, but this did not demonstrate statistical significance (P = 0.09). We did not see an association between azathioprine or infliximab use and the need for surgery at 12 months. Conclusions: There is an increased prevalence of CMV in colonic biopsies of pediatric patients with severe refractory colitis. Viral burden does not predict clinical outcomes or subsequent need for colectomy. (c) 2021 Elsevier Masson SAS. All rights reserved.

关键词： Molecular Medicine   Antibodies   Cancer Research   Pharmacotherapy  

摘要： Background and aims Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment. Methods MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated. Results Data from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52;95% CI 0.44-0.62), adalimumab (RR 0.31;95% CI 0.14-0.69), golimumab (RR 0.29;95% CI 0.10-0.83), certolizumab pegol (RR 0.30;95% CI 0.14-0.67) and natalizumab (RR 0.20;95% CI 0.11-0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75;95% CI 0.61-0.91) and higher rates of infusion reactions (RR 2.36;95% CI 1.85-3.01). Conclusions Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologi

关键词： Chemokines   Cytokines   Inflammatory bowel disease   Mucosal immunology   Neutrophils   Biomedicine   general   Cancer Research   Metabolic Diseases   Infectious Diseases   Molecular Medicine   Neurosciences  

摘要： Transcriptomic and histological profiling of gut biopsies from multiple independent cohorts of patients with inflammatory bowel disease identifies distinct histopathological, molecular and cellular features associated with treatment response, providing insights for patient stratification and precision therapy. Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.

关键词： Crohn's disease   gastrointestinal bleed   IL-17   IL-17 inhibitor   inflammatory bowel disease   interleukin-17   psoriasis   secukinumab   ulcerative colitis  

摘要： Psoriasis is a chronic autoimmune skin disorder that can vary in severity and extent of disease. While localized disease can be managed with topical medications, widespread disease often requires systemic therapy including biologics. This medication class targets different components of the immune system and thus modulates disease activity. The biologic secukinumab is a human monoclonal antibody against interleukin-17A used for the treatment of psoriasis and psoriatic arthritis;cases of inflammatory bowel disease (IBD) have been observed in clinical trials to be associated with this medication. This review aims to provide evidence for the relationships between secukinumab treatment and the development of IBD. We have examined review articles and original research papers, published between 2010 and 2020, using the following keywords: psoriasis, psoriatic arthritis, secukinumab, IBD, Crohn's disease, ulcerative colitis, interleukin-17, IL-17, IL-17 inhibitor. Case reports have noted an association between secukinumab use and IBD and have called for IBD pre-screening in patients who will be prescribed this medication. Clinical trials concluded that secukinumab was associated with IBD, while retrospective studies have had mixed results, with most studies showing no statistical significance between secukinumab and IBD but having seen patients with history of IBD or family histories experience new-onset IBD or flare-ups. Given the utilization of secukinumab as a therapy for psoriasis and psoriatic arthritis, appropriate screening and risk stratification could help limit morbidity and mortality that can be associated with secukinumab-induced IBD.

关键词： COVID-19   Crohn's disease   Latin America   Ulcerative colitis  

摘要： Background and Aim One of the most impacted regions by the pandemic globally, Latin America is facing socioeconomic and health-care challenges that can potentially affect disease outcomes. Recent data suggest that inflammatory bowel disease (IBD) patients do not have an increased risk of the development of COVID-19 complications. However, the impact of COVID-19 on IBD patients living in least developed areas remains to be fully elucidated. This study aims to describe the outcomes of IBD patients diagnosed with COVID-19 in countries from Latin America based on data from the SECURE-IBD registry. Methods Patients from Latin America enrolled in the SECURE-IBD registry were included. Descriptive analyses were used to summarize clinical and sociodemographic characteristics. The studied outcomes were (i) a composite of need for intensive care unit admission, ventilator use, and/or death (primary outcome) and (ii) a composite of any hospitalization and/or death (secondary outcome). Multivariable regression was used to identify risk factors of severe COVID-19. Results During the study period, 230 cases (Crohn's disease: n = 115, ulcerative colitis: n = 114, IBD-unclassified [IBD-U]: n = 1) were reported to the SECURE-IBD database from 13 different countries. Primary outcome was observed in 17 (7.4%) patients, and the case fatality rate was 1.7%. In the adjusted multivariable model, the use of systemic corticosteroids (odds ratio [OR] 10.97;95% confidence interval [CI]: 3.44-34.99) was significantly associated with the primary outcome. Older age (OR 1.03;95% CI: 1.00-1.05), systemic corticosteroids (OR 9.33;95% CI: 3.84-22.63), and the concomitant presence of one (OR 2.14;95% CI: 0.89-5.15) or two (OR 10.67;95% CI: 1.74-65.72) comorbidities were associated with the outcome of hospitalization or death. Conclusion Inflammatory bowel disease patients with COVID-19 in Latin America appear to have similar outcomes to the overall global data. Risk factors of severe COVID-19 are sim

关键词： Tumour necrosis factor alpha   Inflammatory bowel disease   Biological drugs   CD27 ligand  

摘要： Objective: Circulating lymphocyte subtypes are not fully explored parameters for monitoring chronic T cell activation during inflammatory bowel disease (IBD). Tumor necrosis factor alpha (TNF alpha), one of the main mediators of IBD related inflammation induces expression of CD70 on T cells. CD70 limits T cell expansion and controls CD27 receptor on activated B lymphocytes. Aim of this study was to assess the number and the frequency of CD70+ T cells and CD27+ B cells in IBD patients during inactive phase of the disease under or without anti-TNF alpha treatment. Design: We studied 91 patients with inactive IBD, 31 untreated, 29 treated with infliximab (IFX), and 31 treated with adalimumab (ADA). Lymphocyte phenotypes were assessed by flow cytometry using anti-CD45, CD19, CD27, CD3, and CD70 monoclonal antibodies. IFX and ADA actual capacity of TNF alpha neutralization in serum was estimated by the recoveryELISA technique. Results: Whereas CD3+ T cells were increased in treated compared to untreated patients, the percentage of the CD70+ T cells was significantly lower in treated patients indicating a 'cooling' effect of the biological therapy. This effect differs between samples according to the therapeutic range of the circulating drug. Although the CD19+ B-cell percentage tended to be lower in treated patients, CD19+27+ memory B cells did not show significant differences between groups. Conclusions: Frequency of peripheral blood CD70+ T cells was significantly reduced by treatment with anti-TNF alpha antibodies. Monitoring of this parameter of T cells can give better insight to the disease progression and therapy application in IBD patients.