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1.
Gastroenterology ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831380
2.
Artigo em Inglês | MEDLINE | ID: mdl-33746097

RESUMO

BACKGROUND AND AIMS: Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). However, there has not been a detailed evaluation of the characteristics of the published cases of monogenic IBD. Here we systematically review the literature to determine the clinical features, genetic profile, and previously used treatments strategies in monogenic IBD. METHODS: A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. Seven hundred and fifty individual monogenic IBD cases were identified from 303 eligible articles. RESULTS: The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA and TTC7A. In total, 63.4% of patients developed IBD before six years of age, 17.4% between ages 10 and 17.9 years, and 10.9% after 18 years of age. There was substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extra-intestinal comorbidity (EIC) before IBD onset but, 76.0% developed at least one EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation (HSCT) were performed in 27.1%, 32.9%, and 23.1% of patients, respectively. CONCLUSION: Monogenic IBD cases while rare have varied extra-intestinal comorbidities and limited treatments options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.

3.
Gut ; 70(5): 865-875, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33753421

RESUMO

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

4.
Science ; 371(6534): 1154-1159, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707263

RESUMO

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , /fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quimiocina CCL5/metabolismo , Colo/microbiologia , Colo/patologia , Doença de Crohn/imunologia , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Inflamação , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
BMJ Open ; 11(2): e043584, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579769

RESUMO

OBJECTIVE: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers. DESIGN: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires. SETTINGS: A multisite healthcare delivery system located in Los Angeles County. PARTICIPANTS: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions. MAIN OUTCOMES: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection. RESULTS: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors. CONCLUSION AND RELEVANCE: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.


Assuntos
Anticorpos Antivirais/sangue , Pessoal de Saúde , Estudos Soroepidemiológicos , Adulto , Teorema de Bayes , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Los Angeles/epidemiologia , Masculino , Pessoa de Meia-Idade , /imunologia
6.
Hum Mol Genet ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555323

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

7.
Inflamm Bowel Dis ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33501934

RESUMO

BACKGROUND: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. METHODS: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. RESULTS: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). CONCLUSIONS: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

8.
Gastroenterology ; 160(5): 1709-1724, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33421512

RESUMO

BACKGROUND & AIMS: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. METHODS: Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on ß-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase. RESULTS: Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances ß-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression. CONCLUSION: Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.

10.
Gastroenterology ; 160(5): 1546-1557, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33359885

RESUMO

BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.

11.
J Crohns Colitis ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300546

RESUMO

BACKGROUND AND AIMS: It is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal-pouch anal anastomosis (IPAA). We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis to those with pouchitis alone. METHODS: Patients undergoing IPAA surgery for inflammatory bowel disease who subsequently developed pouchitis with concomitant pre-pouch ileitis (pre-pouch ileitis group) were matched by year of IPAA surgery and pre-operative diagnosis (ulcerative colitis or inflammatory bowel disease-unclassified) with patients who developed pouchitis alone (pouchitis group). Primary outcomes were development of Crohn's disease (CD)-like complications (non-anastomotic strictures or perianal disease >6 months after ileostomy closure) and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank test was used to compare outcome-free survival and Cox regression was performed to identify predictors of outcomes. RESULTS: There were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival (log-rank p=0.0002) and pouch failure-free survival (log-rank p=0.046) were significantly lower in the pre-pouch ileitis group. Pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions (log-rank p=0.0005) and immunosuppressive therapy (log-rank p<0.0001). Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (HR 3.8; p=0.0007), need for surgical/endoscopic interventions (HR 4.1; p=0.002) and immunosuppressive therapy (HR 5.0; p=0.0002). CONCLUSIONS: Pre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD.

12.
Gastroenterology ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33160965

RESUMO

BACKGROUND AND AIMS: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC) and non-inflammatory bowel disease (non-IBD) controls. METHODS: Using bulk RNA-seq or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; CD=495; UC=387; non-IBD=94), we analyzed the relationship of ACE2 with demographics, disease activity and prognosis. We examined the outcome of anti-TNF and anti-IL12/IL-23 treatment on SB and colonic ACE2 expression in three clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC, when compared to non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated BMI) associated with poor COVID-19 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-TNF rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB, but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease but normalized following anti-cytokine therapy suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy may be important in the context of SARS-CoV-2 infection and potentially explain reports of reduced morbidity from COVID-19 in IBD patients treated with anti-cytokines.

13.
Gastroenterology ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33098885

RESUMO

BACKGROUND AND AIMS: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thromboembolic disease (TED). Recent reports have demonstrated that both monogenic and polygenic factors contribute to TED and 10% of healthy subjects are genetically at high risk for TED. Our aim was to utilize whole-exome sequencing and genome-wide genotyping to determine the proportion of IBD patients genetically at risk for TED and investigate the effect of genetic risk of TED in IBD. METHODS: The TED polygenic risk score was calculated from genome-wide genotyping. Thrombophilia pathogenic variants were extracted from whole-exome sequencing. In total, 792 IBD patients had both whole-exome sequencing and genotyping data. We defined patients at genetically high risk for TED if they had a high TED polygenic risk score or carried at least 1 thrombophilia pathogenic variant. RESULTS: We identified 122 of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 of 792 subjects whose documented TED status were available, 63 of the 715 patients (8.8%) had TED events. Genetic TED risk was significantly associated with increased TED event (odds ratio, 2.5; P = .0036). In addition, we confirmed an additive effect of monogenic and polygenic risk on TED (P = .0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P = .048). CONCLUSIONS: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify approximately 1 in 7 patients with IBD who will experience 2.5-fold or greater risk for TED.

15.
Cell ; 183(3): 666-683.e17, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991841

RESUMO

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.

16.
JCI Insight ; 5(20)2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32897876

RESUMO

ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn's disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn's disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.

17.
Nat Rev Rheumatol ; 16(9): 536, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32733005

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18.
Front Physiol ; 11: 503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670075

RESUMO

Background: Cardiac Bridging Integrator 1 (cBIN1) is a membrane deformation protein that generates calcium microdomains at cardiomyocyte t-tubules, whose transcription is reduced in heart failure, and is released into blood. cBIN1 score (CS), an inverse index of plasma cBIN1, measures cellular myocardial remodeling. In patients with heart failure with preserved ejection fraction (HFpEF), CS diagnoses ambulatory heart failure and prognosticates hospitalization. The performance of CS has not been tested in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: CS was determined from plasma of patients recruited in a prospective study. Two comparative cohorts consisted of 158 ambulatory HFrEF patients (left ventricular ejection fraction (LVEF) ≤ 40%, 57 ± 10 years, 80% men) and 115 age and sex matched volunteers with no known history of HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were also analyzed for comparison. CS follows a normal distribution with a median of 0 in the controls, which increases to a median of 1.9 (p < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class (p = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, p = 0.01, hazard ratio 1.9). Compared to a model with demographics, clinical risk factors, and NT-proBNP, adding CS to the model improved the overall continuous net reclassification improvement (NRI 0.64; 95% CI 0.18-1.10; p = 0.006). Although performance for diagnosis and prognosis was similar to CS, NT-proBNP did not prognosticate between patients whose NT-proBNP values were > 400 pg/ml. Conclusion: CS, which is mechanistically distinct from NT-proBNP, successfully differentiates myocardial health between patients with HFrEF and matched controls. A high CS reflects advanced NYHA stage, pathologic cardiac muscle remodeling, and predicts 1-year risk of cardiovascular events in ambulatory HFrEF patients. CS is a marker of myocardial remodeling in HFrEF patients, independent of volume status.

19.
Nat Rev Rheumatol ; 16(8): 415-433, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661321

RESUMO

Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4ß7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/complicações , Espondilartrite/etiologia , Animais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Espondilartrite/sangue , Espondilartrite/epidemiologia , Espondilartrite/terapia
20.
medRxiv ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32511625

RESUMO

Angiotensin-Converting Enzyme 2 ( ACE2 ) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from uninvolved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD.

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