Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 42 (10) ◽  
pp. 1740-1745 ◽  
Author(s):  
Alf Kastbom ◽  
Lisbeth Ärlestig ◽  
Solbritt Rantapää-Dahlqvist
Keyword(s):  
Rheumatoid Arthritis ◽  
Angina Pectoris ◽  
Nlrp3 Inflammasome ◽  
Genetic Variants ◽  
Protein Complexes ◽  
Increased Risk ◽  
Variant Alleles ◽  
Traditional Risk Factors ◽  
Cv Disease ◽  
Ischemic Attack

Objective.Inflammasomes are intracellular protein complexes important for the production of pro-inflammatory cytokines. Studies have suggested that the NLRP3 inflammasome influences both the severity of rheumatoid arthritis (RA) and development of atherosclerosis. Therefore, we investigated whether functional genetic variants related to the NLRP3 inflammasome influence the risk of cardiovascular (CV) disease (CVD) in patients with RA.Methods.The incidence of CVD was assessed in 522 patients with established RA by a retrospective survey of medical records in combination with a 6-year prospective followup. NLRP3-Q705K and CARD8-C10X genotypes were analyzed in relation to CVD by logistic regression, adjusting for traditional risk factors, antirheumatic treatment, and age at the onset of RA.Results.Carriage of the NLRP3-Q705K minor allele was associated with an increased risk of stroke/transient ischemic attack (TIA; OR 2.01, 95% CI 1.0–4.1, p = 0.05), while CARD8-C10X was not associated with any type of CV event. Patients with ≥ 1 variant allele in both polymorphisms had an increased risk of CVD when compared with patients without variant alleles present in both polymorphisms (adjusted OR 3.05, 95% CI 1.42–6.54, p = 0.004). Stratification showed that this risk was confined to stroke/TIA (adjusted OR 5.09, 95% CI 2.27–11.44, p < 0.0001) and not to myocardial infarction (MI)/angina pectoris (adjusted OR 1.58, 95% CI 0.67–3.73). Risk estimates were consistently higher among female patients.Conclusion.Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in Swedish patients with established RA.

Cardiovascular Risk in Rheumatoid Arthritis and Mechanistic Links: From Pathophysiology to Treatment

2020 ◽  
Vol 18 (5) ◽  
pp. 431-446 ◽  
Author(s):  
George E. Fragoulis ◽  
Ismini Panayotidis ◽  
Elena Nikiphorou
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Current Evidence ◽  
Pharmacological Intervention ◽  
Cvd Risk ◽  
The Past ◽  
Increased Risk ◽  
Cv Disease ◽  
Obesity Hypertension ◽  
Inflammatory Burden

Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis. Inflammation, however, can spread beyond the joints to involve other organs. During the past few years, it has been well recognized that RA associates with increased risk for cardiovascular (CV) disease (CVD) compared with the general population. This seems to be due not only to the increased occurrence in RA of classical CVD risk factors and comorbidities like smoking, obesity, hypertension, diabetes, metabolic syndrome, and others but also to the inflammatory burden that RA itself carries. This is not unexpected given the strong links between inflammation and atherosclerosis and CVD. It has been shown that inflammatory cytokines which are present in abundance in RA play a significant role in every step of plaque formation and rupture. Most of the therapeutic regimes used in RA treatment seem to offer significant benefits to that end. However, more studies are needed to clarify the effect of these drugs on various parameters, including the lipid profile. Of note, although pharmacological intervention significantly helps reduce the inflammatory burden and therefore the CVD risk, control of the so-called classical risk factors is equally important. Herein, we review the current evidence for the underlying pathogenic mechanisms linking inflammation with CVD in the context of RA and reflect on the possible impact of treatments used in RA.

scholarly journals Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Luis Rodríguez-Rodríguez ◽  
Raquel López-Mejías ◽  
Mercedes García-Bermúdez ◽  
Carlos González-Juanatey ◽  
Miguel A. González-Gay ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Basis ◽  
Strong Association ◽  
Premature Mortality ◽  
Base Pairs ◽  
Increased Risk ◽  
Atherosclerotic Process ◽  
Cv Disease ◽  
Polygenic Diseases

Cardiovascular (CV) disease is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). It is the result of an accelerated atherosclerotic process. Both RA and atherosclerosis are complex polygenic diseases. Besides traditional CV risk factors and chronic inflammation, a number of studies have confirmed the role of genetic factors in the development of the atherogenesis observed in RA. In this regard, besides a strong association between theHLA-DRB1*04shared epitope alleles and both endothelial dysfunction, an early step in the atherosclerotic process, and clinically evident CV disease, other polymorphisms belonging to genes implicated in inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G>A, rs1800629) of theTNFAlocus, the rs1801131 polymorphism (A>C; position + 1298) of theMTHFRlocus, or a deletion of 32 base pairs on theCCR5gene, seem to be associated with the risk of CV disease in patients with RA. Despite considerable effort to decipher the genetic basis of CV disease in RA, further studies are required to better establish the genetic influence in the increased risk of CV events observed in patients with RA.

scholarly journals Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity

2010 ◽  
Vol 69 (11) ◽  
pp. 1920-1925 ◽  
Author(s):  
Daniel H Solomon ◽  
Joel Kremer ◽  
Jeffrey R Curtis ◽  
Marc C Hochberg ◽  
George Reed ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Incidence Rate ◽  
Characteristic Curve ◽  
C Statistic ◽  
The Usa ◽  
Traditional Risk Factors ◽  
And Gender ◽  
Cv Disease ◽  
Prospective Longitudinal

BackgroundCardiovascular (CV) disease has a major impact on patients with rheumatoid arthritis (RA), however, the relative contributions of traditional CV risk factors and markers of RA severity are unclear. The authors examined the relative importance of traditional CV risk factors and RA markers in predicting CV events.MethodsA prospective longitudinal cohort study was conducted in the setting of the CORRONA registry in the USA. Baseline data from subjects with RA enrolled in the CORRONA registry were examined to determine predictors of CV outcomes, including myocardial infarction, stroke or transient ischemic attack. Possible predictors were of two types: traditional CV risk factors and markers of RA severity. The discriminatory value of these variables was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) in logistic regression. The authors then assessed the incidence rate for CV events among subjects with an increasing number of traditional CV risk factors and/or RA severity markers.ResultsThe cohort consisted of 10 156 patients with RA followed for a median of 22 months. The authors observed 76 primary CV events during follow-up for a composite event rate of 3.98 (95% CI 3.08 to 4.88) per 1000 patient-years. The c-statistic improved from 0.57 for models with only CV risk factors to 0.67 for models with CV risk factors plus age and gender. The c-statistic improved further to 0.71 when markers of RA severity were also added. The incidence rate for CV events was 0 (95% CI 0 to 5.98) for persons without any CV risk factors or markers of RA severity, while in the group with two or more CV risk factors and three or more markers of RA severity the incidence was 7.47 (95% CI 4.21 to 10.73) per 1000 person-years.ConclusionsTraditional CV risk factors and markers of RA severity both contribute to models predicting CV events. Increasing numbers of both types of factors are associated with greater risk.

Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRÉ Study

2011 ◽  
Vol 71 (3) ◽  
pp. 341-344 ◽  
Author(s):  
A M van Sijl ◽  
I A M van den Oever ◽  
M J L Peters ◽  
M Boers ◽  
B A C Dijkmans ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Renal Dysfunction ◽  
Cardiovascular Events ◽  
Filtration Rate ◽  
Estimated Gfr ◽  
Lower Baseline ◽  
Traditional Risk Factors ◽  
Cv Disease

BackgroundPatients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) disease, largely independently of traditional CV risk factors. Renal dysfunction is associated with CV morbidity and mortality in the general population, but data on this association in RA are lacking.ObjectiveTo investigate the association between renal function and CV events in RA.MethodsThe CARRÉ Study is an ongoing prospective cohort study of Dutch patients with RA, which records CV events. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease formula. Logistic regression determined the association between estimated GFR and the occurrence of CV events.Results353 patients were followed for 3 years, and 23 (7%) had a CV event. Patients who had an event had a significantly lower baseline GFR than those who did not (59 vs 79 ml/min, p=0.001). This association remained significant after adjustment for traditional risk factors: in this analysis, a decrease in GFR of 5 ml/min was associated with a 30% (95% CI 7% to 59%) increase in the occurrence of CV events. During follow-up, an unfavourable change in GFR was noted in patients who later had a CV event compared with those who did not.ConclusionThese data confirm that, in RA, renal dysfunction is associated with a higher risk of CV disease independently of traditional CV risk factors.

scholarly journals Lack of Association betweenABO,PPAP2B,ADAMST7,PIK3CG, andEDNRAand Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Raquel López-Mejías ◽  
Fernanda Genre ◽  
Mercedes García-Bermúdez ◽  
Begoña Ubilla ◽  
Santos Castañeda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Variants ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Carotid Ultrasonography ◽  
Carotid Plaques ◽  
Media Thickness ◽  
Artery Disease ◽  
Cv Disease

Introduction. Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified theABOrs579459,PPAP2Brs17114036, andADAMTS7rs3825807 polymorphisms as genetic variants associated with coronary artery disease and thePIK3CGrs17398575 andEDNRArs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA.Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology.Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders.Conclusion. Our results do not confirm association betweenABOrs579459,PPAP2Brs17114036,ADAMTS7rs3825807,PIK3CGrs17398575, andEDNRArs1878406 and subclinical atherosclerosis and CV disease in RA.

Increased Incidence of Stroke and Transient Ischemic Attack in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis in Germany

2021 ◽  
pp. 1-8
Author(s):  
Kathleen Trömmer ◽  
Karel Kostev ◽  
Louis Jacob ◽  
Christian Tanislav
Keyword(s):  
Rheumatoid Arthritis ◽  
Ankylosing Spondylitis ◽  
Transient Ischemic Attack ◽  
Propensity Scores ◽  
Cox Regression ◽  
Inflammatory Diseases ◽  
Young Patients ◽  
Vascular Events ◽  
Increased Risk ◽  
Ischemic Attack

<b><i>Background:</i></b> As chronic inflammatory diseases may be associated with an increased risk of vascular events, the aim of the present study was to assess the incidence of stroke and transient ischemic attack (TIA) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). <b><i>Methods:</i></b> Patients diagnosed with RA and AS in 1,262 general practices in Germany between 2000 and 2015 were selected. RA and AS patients were matched to patients without RA or AS using propensity scores based on age, sex, physician, co-diagnoses, and co-therapies. The Kaplan-Meier curves and Cox regression models were used to study the incidence of stroke and TIA as a function of RA and AS. <b><i>Results:</i></b> In the study population (<i>N</i> = 29,106; mean age 54.8 years; 65% women), 24,580 patients had RA and 4,526 had AS. RA was significantly associated with the stroke (hazard ratio [HR] = 1.42, confidence interval [CI]: 1.25–1.60) and TIA (HR = 1.69, CI: 1.46–1.95). The association between RA and stroke was strongest in the age group 18–40 years (HR = 3.45, CI: 1.30–9.18). The HR for stroke in AS was 1.41 (CI: 0.99–2.00) and for TIA 1.62 (1.08–2.44). <b><i>Conclusion:</i></b> RA was significantly associated with stroke and TIA, with young patients being at a particularly increased risk. AS was tendentially associated with stroke and TIA.

scholarly journals Myocardial Perfusion in Rheumatoid Arthritis Patients: Associations with Traditional Risk Factors and Novel Biomarkers

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Miguel Bernardes ◽  
Tiago S. Vieira ◽  
Maria João Martins ◽  
Raquel Lucas ◽  
Lúcia Costa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Assessment ◽  
Myocardial Perfusion ◽  
Silent Myocardial Ischemia ◽  
Tertiary Referral Hospital ◽  
Reactive Protein ◽  
Perfusion Defects ◽  
Novel Biomarkers ◽  
Traditional Risk Factors ◽  
Cv Disease

Introduction. Cardiovascular (CV) diseases are a major cause of death in rheumatoid arthritis (RA) patients. Novel biomarkers [B-type natriuretic peptide (BNP); osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) ratio; and dickkopf-1 (DKK-1)] have been used in CV risk assessment. We analysed, in established RA patients, the presence of silent myocardial ischemia and its association with clinical variables, BNP, and bone and atheroma biomarkers. Methods. From a single-center tertiary referral hospital, RA patients asymptomatic for CV disease were submitted to myocardial perfusion scintigraphy (MPS) under adenosine stress and biomarkers measurements. Logistic regression was used to estimate crude odds ratios (OR) and 95% confidence intervals (CI). Results. In 189 patients, perfusion defects were frequent (25%) and associated with BNP ≥ 100 pg/mL (OR = 5.68; 95% CI: 2.038–15.830), fourth log OPG/RANKL ratio quartile (OR = 2.88; 95% CI: 1.091–7.622), and DKK-1 ≥ 133 pmol/L (OR = 2.69; 95% CI: 1.058–6.840). Similar associations were confirmed in those with C-reactive protein > or ≤ 3 mg/L. No relationship was found with the majority of traditional CV factors nor with disease variables. Conclusions. Our results corroborated the hypothesis that MPS could reveal subclinical CV dysfunction, supported the utility of BNP measurements as a screening tool, and put in perspective the potential usefulness of complementary approaches in CV risk assessment in RA patients.

Sign in / Sign up

Export Citation Format

Share Document