Cardiovascular Risk In Rheumatoid Arthritis Research Articles

A review on cardiovascular risk in rheumatoid arthritis

A systemic inflammatory disease known as rheumatoid arthritis (RA) is distinguished by excessive cardiovascular disease (CVD) morbidity and death. Traditional CV risk factors may partially contribute to CV disease in RA. Shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, changes in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction are some of the mechanisms that link RA and CVD. The detailed pathogenetic pathway by which this association between RA and CVD might be explained is still not entirely known. It is crucial for controlling cardiovascular risk in people with RA. Optimizing care of traditional risk factors in addition to those inherent to RA is necessary to lessen the burden caused by CVD. The potential effect of planned Cardiac risk management in these individuals is highlighted by findings for under diagnosis and inadequate treatment of conventional CVD risk factors in RA. Present cardiovascular standards suggest RA patients to be examined for and treated for CVD risk factors without appropriate treatment goals. Utilizing potent anti-rheumatic medications that can reduce disease activity and treating the conventional CV risk factors should both be part of the therapy of CV risk in RA. There is currently insufficient scientific data to develop therapy targets for RA-related CVD risk factors. Thus, more study is required on the traditional CVD risk factor screening and management in RA patients.

Influence of Abdominal Obesity on the Relationship of Low-Density Lipoprotein Cholesterol with Atherosclerosis and Cardiovascular Risk in Rheumatoid Arthritis

Methods. Coronary artery calcium, number of coronary plaques, and extensive ( 5 plaques) or obstructive (>50% stenosis) disease was evaluated with computed tomography angiography in 150 patients at baseline and 101 patients 6.9±0.4 years later. Cardiovascular events were recorded. Oxidized LDL was measured with monoclonal antibody E06. Serum cholesterol loading capacity on macrophages was measured as intracellular cholesterol content with a fluorometric assay. Results. Abdominal obesity was not associated with per-patient number of coronary plaques or coronary artery calcium score at baseline. Low LDLc positively associated with number of plaques (b 2.13 [95% confidence interval 1.03 to 3.22]), likelihood of extensive or obstructive plaque (odds ratio 6.58, 95% confidence interval [1.63 to 26.46]), and log-transformed CAC (b 1.90 [0.89 to 2.91]) exclusively in nonobese patients (p-for-interaction <0.001, 0.061, and 0.001 respectively). Low LDLc associated with increased likelihood of >median oxidized LDL and higher ratio of cholesterol loading capacity to LDLc in nonobese patients (p-for-interaction 0.041 and 0.001 respectively). Abdominal obesity negatively associated with likelihood of plaque stenosis progression (odds ratio 0.19 [0.07 to 0.54]). Low LDLc associated with greater likelihood of per-segment plaque formation (OR 4.68 [2.26 to 9.66]) and increased stenotic severity (odds ratio 5.35 [1.62 to 17.67]) only in nonobese patients (p-for-interaction 0.002 and 0.040 respectively). Abdominal obesity was not linked to cardiovascular risk (Hazard Ratio 1.57, 95% confidence interval [0.66-3.73]). Low LDLc associated with higher cardiovascular risk in nonobese (Hazard Ratio 7.94 [1.52 to 41.36]) but not obese patients (p-for-interaction=0.017). Conclusion. Abdominal obesity was not linked to plaque progression or cardiovascular risk in RA. Only in nonobese patients, low LDLc associated with higher atherosclerosis burden, plaque progression and cardiovascular risk. This may reflect higher oxidation and macrophage cholesterol loading capacity of LDL when LDLc is <70mg/dl.

Comparison of the cardiovascular risk profile of rheumatoid arthritis versus hand osteoarthritis patients.

It is clear that there is an increased cardiovascular (CV) risk in rheumatoid arthritis (RA) as a result of systemic inflammation. Hand osteoarthritis (HOA) patients, also have an increased CV risk, but the causes are still debated. Our objective was to compare CV risk factors and risk scores between HOA and RA patients. Thirty-five HOA patients were matched by age (< 3years) and sex to 35 RA patients in a case-control study. We compared their CV risk profiles and their risk of occurrence of CV events at 10years using the risk equations SCORE1, SCORE2, and QRISK3. There was a significant increase in SCORE1, SCORE2, but not in QRISK3 in the RA group compared to the HOA group, provided that the multiplication coefficient for RA was applied. This increase was found to no longer be significant for SCORE1 when RA patients have low disease activity (DAS28 ≤ 3.2; n = 8). There was no difference between groups in the frequency of metabolic syndrome, blood pressure, abdominal circumference, body mass index, uricemia, triglyceridemia, HDL cholesterolemia, or pain intensity. Conversely, HOA patients had higher LDL cholesterol and fasting blood glucose levels, in the main analysis and in the subgroup of moderate/high RA activity patients (DAS28 > 3.2; n = 26). We found a higher CV risk in RA compared to HOA patients with moderate/high disease activity. The increased CV risk reported in OA remains to be confirmed in HOA, but these patients appear to have a pro-atherogenic lipid and glycemic profile.

A Systematic Review and Meta-Analysis of the Association between Uric Acid and Allantoin and Rheumatoid Arthritis.

Alterations in the circulating concentrations of uric acid and its degradation product, allantoin, might account for the systemic pro-oxidant state and the increased cardiovascular risk in rheumatoid arthritis (RA). We sought to address this issue by conducting a systematic review and meta-analysis of the association between the plasma/serum concentrations of uric acid and allantoin and RA. We searched PubMed, Scopus, and Web of Science from inception to 20 June 2023 for studies comparing plasma/serum concentrations of uric acid and allantoin between RA patients and healthy controls. We assessed the risk of bias with the JBI Critical Appraisal Checklist for analytical studies and the certainty of evidence with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group system. In the 19 studies selected for analysis, there were non-significant differences in uric acid concentrations between RA patients and controls (standard mean difference, SMD = 0.11, 95% CI -0.07 to 0.30, p = 0.22; I2 = 87.9%, p < 0.001; low certainty of evidence). By contrast, the concentrations of allantoin were significantly higher in RA patients (SMD = 1.10, 95% CI 0.66 to 1.55, p < 0.001; I2 = 55.6%, p = 0.08; extremely low certainty of evidence). In meta-regression, a significant association was observed between the SMD of uric acid concentrations and body mass index, a risk factor for atherosclerosis and cardiovascular disease (t = 3.35, p = 0.007). Our study has shown a significant increase in the concentrations of the oxidative stress biomarker allantoin in patients with RA. Further research is warranted to investigate the interplay between uric acid, allantoin, redox balance, and cardiovascular disease in this group. (PROSPERO registration number: CRD42023441127).

Effect of thrombocytosis on cardiovascular risk in rheumatoid arthritis

BACKGROUND: Patients with rheumatoid arthritis have a high level of comorbidity, and their most common and socially significant conditions are cardiovascular diseases, which represent a major cause of mortality. Currently, there are no data on the differences in cardiovascular risk scales in patients with rheumatoid arthritis depending on the presence or absence of thrombocytosis.&#x0D; AIM: To assess and compare cardiovascular risk according to conventional scales in patients with thrombocytosis and normal thrombocytes.&#x0D; MATERIALS AND METHODS: The study involved 85 patients diagnosed with rheumatoid arthritis: 40 with thrombocytosis [including 25 (62,5%) women] and 45 with normal thrombocytes [including 29 (64,4%) women]. The following scales were used to assess risk of cardiovascular complications: Systematic COronary Risk Evaluation with adjustment factor 1.5 (mSCORE), Reynolds Risk Score (RRS), QRESEARCH Cardiovascular Risk Algorithm (QRISK3), Assessing Cardiovascular Risk to Scottish Intercollegiate Guidelines Network / SIGN to Assign Preventative Treatment (ASSIGN).&#x0D; RESULTS: The obtained findings have demontrated that according to the mSCORE and RRS scales the patients of both groups had almost identical parameters; however, according to the ASSIGN and QRISK3 high risk of cardiovascular complications has been detected nearly twice as frequently in the patients with rheumatoid arthritis and thrombocytosis in comparison with those with normal level of thrombocytes. It is also worth noting that more frequent determination of high risk of cardiovascular complications by the QRISK3 was statistically significant.&#x0D; CONCLUSIONS: The QRISK3 calculation has shown significantly higher prevalence of high-risk cardiovascular complications among the patients with platelet counts 450 ∙ 109/l compared with those with platelet levels within the reference values. Thus, the QRISK3 scale can be considered as more informative for estimating risk of cardiovascular complications in rheumatoid arthritis.

ATP-binding cassette G1 membrane transporter-mediated cholesterol efflux capacity influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis

ObjectivesCholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. MethodsCoronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. ResultsABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28–0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53–0.94]) and low-attenuation plaques (RR 0.63 [0.43–0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with <median but not higher CRP and in prednisone users but not nonusers (p-for-interaction = 0.021, 0.033 and 0.008 respectively). ConclusionABCG1-CEC inversely associated with plaque burden and vulnerability, and plaque progression conditionally on cumulative inflammation and corticosteroid dose. ABCG1-CEC inversely associated with events specifically in patients with noncalcified plaques, lower inflammation and in prednisone users.

Abstract 11968: Association Between Reduction in Inflammation and Change in Cardiovascular Risk: Results From the Liira Study

Background: Coronary microvascular disease (CMD) is associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD, as measured by coronary flow reserve (CFR). However, it is not known whether reducing inflammation results in improvement in CMD or other CV correlates. The objective of this study was to determine the association between reducing inflammation with changes in CV risk. Methods: The Lipids, Inflammation and CV risk in RA (LiiRA) study recruited RA patients age ≥18 yrs with active RA about to initiate a TNFi as part of clinical care. All subjects underwent a stress myocardial perfusion PET scan to quantify CFR at baseline and after 24 weeks. A lower CFR in the absence of obstructive CAD is indicative of CMD, CFR&lt; 2.5 defined CMD. Inflammatory markers and hs-cTnT were performed at baseline and 24 weeks. Primary and secondary outcomes was change in CFR and hs-cTnT, respectively, and tested by Spearman correlations. Results: A total of 66 subjects completed the study, 80% female, mean RA duration 7.7 yrs. Baseline estimated ASCVD risk was 5.6%, yet 47% had evidence of CMD. We observed a significant reduction in all inflammatory markers between baseline and follow-up, along with improvements in RA disease activity; however, no change in the mean CFR or hs-cTnT was observed. A reduction in hsCRP and IL-1beta was associated with a reduction in hs-cTnT. A non-significant trend for correlation of reduced IL-1beta with higher CFR was observed among subjects with CMD at baseline (Figure). Conclusion: There was a high prevalence of CMD at baseline, but CFR did not significantly improve. Reducing inflammation was correlated with improvements in measures of CV risk, mainly in the subset of patients with detectable hs-cTnT, particularly via the IL-1beta pathway. These data suggest that hs-cTnT may be a useful marker when considering targeting inflammation to reduce CV risk in RA.

Autoimmune diseases and atherothrombotic risk

Clinical investigators have long observed that patients with rheumatoid arthritis, inflammatory bowel disease, lupus, and psoriasis have increased rates of incident cardiovascular disease, often a decade earlier than among healthy individuals in the general population. 1 Solomon DH Karlson EW Rimm EB et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003; 107: 1303-1307 Crossref PubMed Scopus (1033) Google Scholar , 2 England BR Thiele GM Anderson DR Mikuls TR Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ. 2018; 361k1036 PubMed Google Scholar For example, psoriasis, a common T-helper cell type 1/17 immunological disorder, confers an increased risk of myocardial infarction over the life span with the greatest relative increase in risk among those with severe disease in their 30s and 40s. 3 Gelfand JM Neimann AL Shin DB Wang X Margolis DJ Troxel AB Risk of myocardial infarction in patients with psoriasis. JAMA. 2006; 296: 1735-1741 Crossref PubMed Scopus (1466) Google Scholar Yet, to date, most studies of chronic inflammatory disorders and cardiovascular risk have focused on one disease entity at a time and used sampling techniques of moderate sample size. Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UKThese findings warrant targeted cardiovascular prevention measures, in particular in younger patients with autoimmune diseases, and further research into pathophysiological mechanisms underlying these complications. Full-Text PDF

C-reactive protein and 10-year cardiovascular risk in rheumatoid arthritis

ObjectivesTo evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events. MethodsERS-RA was calculated in 1,251 “Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)” database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L]. ResultsThe mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000–0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity. ConclusionIn a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively targeting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients.

IMPAIRED SKIN MICROCIRCULATION DYNAMICS IN PATIENTS WITH RHEUMATOID ARTHRITIS: ASSOCIATION WITH ARTERIAL STIFFNESS AND CORONARY MICROVASCULAR PERFUSION

Objective: Rheumatoid arthritis (RA) is characterized by excess cardiovascular risk. Laser Speckle Contrast Imaging (LSCI) is a novel and highly reproducible technique for the real-time evaluation of skin microcirculation. However, relevant data using non-invasive laser techniques remain far too limited in RA, especially in patients free from cardiovascular risk factors with relatively suppressed inflammatory load. Design and method: We assessed skin microvascular function in a well-characterized sample of RA patients free from hypertension and cardiovascular diseases with low levels of systemic inflammation, compared to non-RA individuals. Microvascular function was dynamically evaluated using LSCI coupled with a post-occlusive reactive hyperaemia protocol. Applanation tonometry with the Sphygmocor device was applied to assess a) subendocardial viability ratio (SEVR) or Buckberg index as a functional marker of microvascular myocardial perfusion, b) carotid-femoral pulse wave velocity (PWV) as a marker of macrovascular dysfunction. Results: We studied 35 patients with RA at remission or low disease activity, and 35 controls matched for cardiovascular risk factors. Skin microvascular responses were impaired in RA patients compared to controls, specifically baseline flux [46.8(18.9) vs 36.4(13.9) LSPUs, p &lt; 0.001], occlusion flux [12.4(13.5) vs 7.0(3.6) LSPUs, p = 0.001], time-to-peak [7.0(0.4) vs 11.0(8) sec, p &lt; 0.001], peak magnitude [113.1(25.4) vs 99.1(32.5) LSPUs, p = 0.017], peak-to-baseline magnitude [136.5(75.2) vs 172.1(65.9) %, p = 0.014], baseline cutaneous vascular conductance (CVC) (0.54 ± 0.15 vs 0.44 ± 0.14 LSPUs/mmHg, p = 0.006), and percentage increase in CVC [139.5(75.3) vs 172.1(67.3) %, p = 0.011]. Moreover, SEVR was lower in RA patients compared to controls (140.6 ± 21.8 vs 157.2 ± 25.2%, p = 0.046), whereas PWV did not significantly differ. SEVR strongly and significantly correlated with nearly all LSCI indices (baseline and occlusion flux, peak magnitude, peak-to-baseline magnitude, baseline CVC, and percentage CVC increase). PWV significantly correlated only with baseline flux, occlusion flux, and time-to-peak. Conclusions: Microcirculation dynamics appear impaired even in RA patients with relatively low inflammatory load, regardless of cardiovascular risk factors. Importantly, we showed for the first time an association between impaired skin microvascular dynamics assessed with LSCI and microvascular myocardial perfusion using SEVR. Further studies need to evaluate the prognostic potential of LSCI in terms of cardiovascular risk in RA.

Cardiovascular Risks and Risk Stratification in Inflammatory Joint Diseases: A Cross-Sectional Study.

BackgroundIt is well established that patients with inflammatory joint diseases (IJD) have an increased cardiovascular (CV) mortality and morbidity. According to the 2016 EULAR recommendations on CV risk management, rheumatologists should ensure appropriate management of CV risk in rheumatoid arthritis (RA) and other IJDs. The aim was to assess the CV risk and CV disease in Middle-European patients with IJD.MethodsA retrospective chart review was performed for CV risk factors and CV disease in outpatients of a rheumatology outpatient clinic. CV risk was assessed according to the 2016 European Guidelines on CV disease prevention and also using 2 other approaches to compare the results with data from Norwegian and Spanish cohorts.ResultsOut of 432 patients, the prevalence of CV disease reached from 8.7% in spondyloarthritis (SpA) and 12.8% in psoriatic arthritis (PsA) to 18.7% in patients with RA. The number of CV risk factors did not differ between patients with RA, SpA, PsA, and non-inflammatory rheumatic disease (NIRD) (with 1.68 ± 0.13, 1.70 ± 0.13, 2.04 ± 0.16, and 1.78 ± 0.34, respectively). CV risk assessment could be performed in 82 patients after exclusion because of missing data and age. Stratification according to ESC guidelines showed low in 50%, moderate in 12.2%, high in 20.7%, and very high CV risk in 17.1% of patients aged between 40 and 65 years. CV risk in the Middle-European patients with IJD was higher than in the German general population (p = 0.004), and similar to the Norwegian patients with IJD, although patients with Middle-European PsA were at higher risk than the Norwegian patients (p = 0.045). Compared to the Spanish patients, Middle-European patients with IJD were more likely assigned to the high- to a very high-risk group (34.2 vs. 16.2%, p < 0.001), especially in RA disease (49.1 vs. 21%, respectively, p < 0.001).DiscussionHigh prevalence of established CV disease together with high CV risk in patients with IJD urges for increased vigilance for CV risk factors followed by appropriate interaction by the treating physicians. The prospective use of an international CV risk assessment tool will allow not only estimation of the individual CV risk but also provide data for direct comparisons with the general population and other international cohorts.

Influence of anti-TNF therapy and homocysteine level on carotid intima-media thickness in rheumatoid arthritis patients.

It is a well-known fact that disruptions in the immune system and systemic inflammation are associated with accelerated atherosclerosis in rheumatoid arthritis (RA) patients. Elevated levels of tumor necrosis factor α (TNF-α), a major pro-inflammatory cytokine, are involved in endothelial cell activation of medium and large arteries, leading to increased endothelial permeability, generation of superoxide anion radical and hydrogen peroxide, and decreased availability of nitric oxide (NO). The present study aims to determine the influence of anti-TNF therapy and homocysteine (Hcy) levels on the carotid intima-media thickness (IMT) in patients with RA. Assessments were performed on 115 patients diagnosed with RA on biological treatment to determine the evolution of IMT and Hcy levels. Carotid ultrasonography was used to assess the IMT, as a fast and easy tool for the prediction of cardiovascular events in patients with RA. The first measurement of IMT was noted as IMT1, followed by a second measurement after 1 year, noted as IMT2. The group of patients was divided into approximately three equal groups, each being treated with a different biological product, respectively, etanercept, adalimumab, and infliximab. In the 3 groups, after 1 year of anti-TNF-α therapy, IMT2 progression was significantly reduced compared to baseline. No significant differences were found among the three groups of treatment. A strong association was observed between IMT1-IMT2 in the etanercept group (P<0.001, r=0.758), in the adalimumab group (P<0.001, r=0.761) and in the infliximab group (P<0.001, r=0.829). The low level of Hcy2 after 12 months of anti-TNF-α therapy was significantly correlated with a decrease in IMT2 (P<0.001) in patients who had a high level of Hcy and IMT >0.9 mm at baseline. The results from the present study showed that biological treatment and the low level of homocysteinemia reduced the cardiovascular risk in RA, regardless of the treatment chosen (infliximab, adalimumab, or etanercept).

Epicardial Adipose Tissue Volume As a Marker of Subclinical Coronary Atherosclerosis in Rheumatoid Arthritis.

To assess epicardial adipose tissue volume (EATV) and its link to coronary atherosclerosis and plaque morphology in patients with rheumatoid arthritis (RA) and in age- and sex-matched controls. Computed tomography angiography was used to evaluate EATV and coronary plaque in 139 RA patients and 139 non-RA controls. All models assessing the effect of EATV on plaque were adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking status, family history of coronary artery disease, and obesity (body mass index of ≥30 kg/m2 ). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Mean ± SD log-transformed EATV was similar in patients with RA (4.69 ± 0.36) and controls (4.70 ± 0.42). EATV was higher in RA patients with atherosclerosis compared to those without atherosclerosis (P = 0.046). In stratified analyses, EATV was associated with the number of segments with plaque in RA patients (rate ratio 1.20 [95% CI 1.01-1.41] per 1-SD increment of log-unit increase in EATV) but not in controls (P for interaction = 0.089). Likewise, EATV (per 1-SD log-unit increase) was related to the presence of multivessel or obstructive disease (OR 1.63 [95% CI 1.04-2.61]), noncalcified plaque (OR 1.78 [95% CI 1.17-2.70]), and vulnerable plaque (OR 1.77 [95% CI 1.03-3.04]) in RA patients but not in controls (P for interaction ≤ 0.048 for each). Among RA patients, EATV was associated with the number of segments with plaque in those with RA for <10 years who did not develop any cardiovascular risk factors and who were not obese (P for interaction ≤ 0.017). Despite similar EATVs in RA patients and controls, EATVs were associated with greater plaque burden and presence of plaques with a noncalcified component and vulnerability features only in RA patients. EAT may be more pathogenic in RA and play a role in early-stage atherosclerosis. Its value as a biomarker of subclinical atherosclerosis and cardiovascular risk in RA warrants further studies.

Evaluation of Pre-miRNA-146a rs2910164 Variations and sCD40 Ligand in Egyptian Patients with Rheumatoid Arthritis

Abstract Background: Patients with Rheumatoid Arthritis (RA) are at greater risk of developing Cardiovascular (CV) events with higher rate of subsequent mortality. MicroRNAs (miR-NAs) such as MiR-146a are thought to have an important role in the pathogenesis of RA. CD40-CD40L interaction is poten-tially involved in atherogenesis and plaque rupture in RA, it can be a risk factor in development of accelerated vascular complications in RA patients. Aim of Work: Our aim is to evaluate the level of sCD40L, investigate the genetic variations (polymorphisms) in pre-miRNA-146a rs2910164 in a cohort of Egyptian RA patients and detect their possible relation to CV risk in RA. Methods: 108 RA patients were enrolled in our study and were divided into 2 groups according to presence and absence of CV risk along with 49 controls. Genotyping of pre-microRNA-146a rs2910164 polymorphism was done by Taq-Man real-time PCR and serum sCD40L levels were measured using human soluble CD40L ELISA assay. Results: sCD40L concentration was significantly lower in RA patients without CV risk and RA patients with CV risk when compared to control group (p < 0.001), but there was no statistically significant difference when comparing both patients' groups (p=0.5). The genotype and allele frequencies of pre-microRNA-146a rs2910164 did not show a statistically significant difference between the studied groups. When comparing RA group without CV risk, RA group with CV risk and control group, GG genotype was 41.8%, 39.6% and 32.7%, GC was 40%, 49.1% and 51% and CC was 18.2%, 11.3% and 16.3%, respectively. G allele frequency in RA without CV risk group, RA with CV risk group and control group was 35.2%, 35.2% and 29.5% and C allele frequency was 34.7%, 31.4% and 33.9%, respectively. Conclusion: Pre-miRNA-146a rs2910164 gene variations were not associated with RA and does not increase the sus-ceptibility to cardiovascular disease. Low serum levels of sCD40L were detected in RA patients irrespective of the presence of cardiovascular risk. Evaluating sCD40L in patients not receiving any treatment and comparing them with post-treatment levels is recommended.

POS0205 AMELIORATION OF ENDOTHELIAL DYSFUNCTION WITH JAK INHIBITION IN RHEUMATOID ARTHRITIS: JAK CV-RISK REDUCTION STUDY

Background:Cardiovascular (CV) disease is the leading cause of premature mortality and sudden death in Rheumatoid Arthritis (RA). Conventional CV risk factors and disease specific risk factors are responsible for endothelial dysfunction (ED) in RA. ED is the barometer of CV health and key initial event in atherosclerosis. Tofacitinib, a JAK inhibitor, is in clinical use since 2012 and has had the most extensive development program in RA, but its impact on ED has not yet been explored in humans.Objectives:To investigate the impact of tofacitinib on endothelial dysfunction in RAMethods:40 RA patients fulfilling the 2010 Rheumatoid Arthritis classification criteria with active disease (DAS28&gt;3.2) were randomized to receive 24 weeks of treatment with Tofacitinib (5mg bd, n=20) and placebo (n=20) as an adjunct to existing stable antirheumatic drugs. Primary endpoints included endothelial dysfunction assessed by FMD using Angiodefender and lipids were estimated at baseline and after 12 weeks of treatment. The secondary end points included: DAS28, ESR, CRP, HAQ-DI and cardiovascular risk using SCORE chart assessed at week 0 and 12.Results:At baseline, endothelial function was impaired and levels of inflammatory measures were elevated in both groups. CV risk SCORE was high and HAQ-DI was impaired at baseline. After treatment, FMD improved significantly in the tofacitinib group from (8.16±1.38% to 10.98±2.33%, p≤0.05) as compared to placebo (7.12±0.25% to 8.04±0.30%, p=0.35) (Fig. 1A). DAS28 (Fig. 1B), ESR and CRP (Fig. 1C) levels improved significantly in tofacitinib group as compared to placebo (p≤0.05). Tofacitinib significantly decreased HAQ-DI and SCORE (Fig. 1D) values as compared to placebo. There was significant increase in HDL (p≤0.05) after treatment with tofacitinib as compared to placebo. After 12 weeks of treatment, FMD and HDL increased by 34.55% and 13.58% respectively where as DAS28, ESR and CRP decreased by 37.40%, 36.10% and 76.59% respectively in the tofacitinib group. Significant negative correlation was observed between FMD and DAS28 (r= -0.50, p≤0.05) and CRP (r= -52, p≤0.05) after treatment with tofacitinib where as no such correlation was found in placebo group.Figure 1.Impact of Tofacitinib on FMD, DAS 28, CRP &amp; SCOREConclusion:First study to show that tofacitinib, apart from its anti inflammatory activity, improves endothelial dysfunction and cardiovascular risk in RA. Thus, JAK inhibition with tofacitinib has vasculoprotective and cardioprotective effect mediated through anti-inflammatory and probably other mechanisms. This study would stimulate further research in exploring the vasculoprotective and cardioprotective potential of tofacitinib in RA.

LncRNA MIAT downregulates IL-1β, TNF-ɑ to suppress macrophage inflammation but is suppressed by ATP-induced NLRP3 inflammasome activation

ABSTRACT Cardiovascular disease (CVD) has been identified as the leading cause of premature deaths in rheumatoid arthritis (RA), accounting for about 40 to 50% of all deaths. Macrophage inflammation is regarded as a key point to link to the two diseases. Recently, long non-coding RNAs (lncRNAs) have acknowledged as a regulator of inflammation significantly. Here, we firstly found that lncRNA myocardial infarction associated transcript (lncRNA MIAT), a crucial lncRNA to regulate CVD, expressed increasingly in synovium and myocardial tissues of collagen-induced arthritis (CIA) mice. Besides, we also verified that the increased infiltration of macrophage occurred in those tissues of the CIA. In vitro, we found that macrophage inflammation induced by LPS could up-regulate lncRNA MIAT expression. LncRNA MIAT seemed to inhibit the expression of IL-1β, TNF-ɑ and be suppressed by ATP-induced NLRP3 inflammasome activation pathway. Therefore, these data indicated an anti-inflammatory effect of lncRNA MIAT in macrophage and an original research direction for high cardiovascular risk in RA.

Erectile Dysfunction and Cardiovascular Risk in Men With Rheumatoid Arthritis: A Population-based Cohort Study.

Both erectile dysfunction (ED) and rheumatoid arthritis (RA) are associated with increased cardiovascular (CV) risk. It is unknown if these diagnoses are associated or if their combination confers additional CV risk. We aimed to define the incidence of ED in RA, and to determine if ED correlates with increased CV risk in RA. Medical information concerning RA, ED, and CV diagnoses for men with RA (n = 260) diagnosed in Olmsted County, Minnesota, and age-matched male comparators was extracted from a comprehensive medical record system. ED incidence was similar between the RA cohort and comparators (HR 0.80, 95% CI 0.55-1.16). In men with RA, ED diagnosis was associated with a trend toward an increase in peripheral arterial disease (HR 2.22, 95% CI 0.98-5.03) and a significantly decreased rate of myocardial infarction (HR 0.26, 95% CI 0.07-0.90), heart failure (HR 0.49, 95% CI 0.25-0.94), and death (HR 0.56; 95% CI 0.36-0.87). In men with RA and ED, phosphodiesterase-5 inhibitor use was associated with a decreased risk of death (HR 0.35, 95% CI 0.16-0.79), with a trending decreased risk of some CV diagnoses. Incidence of ED was not statistically increased in RA. Although patients with both RA and ED had a similar overall CV risk to those with RA alone, men with both RA and ED had decreased risk of heart failure, myocardial infarction, and death, as well as an increased risk of peripheral arterial disease. Further studies are needed to clarify these associations and their implications for pathogenesis and therapeutics.

The Impact of Biologic Drugs on High-Density Lipoprotein Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients.

One of the most intriguing conundrums in patients with rheumatoid arthritis (RA) is the lack of correlation between cholesterol levels and cardiovascular (CV) events, diminishing the reliability of plasmatic lipid levels in estimating the CV risk. High-density lipoprotein cholesterol efflux capacity (HDLc-EC) directly indicates the functional ability of HDL to scavenge cholesterol from vascular wall and may provide better information on the atherogenic risk. The aim of this study was to examine the effects of different disease-modifying antirheumatic drugs on HDLc-EC in RA. Consecutive RA patients treated with different biologic disease-modifying antirheumatic drugs or methotrexate monotherapy were longitudinally observed. Demographic and clinical features as well as lipid profile were recorded at baseline, 24-week, and 52-week follow-up. At the same time points, HDLc-EC was evaluated using J771 macrophages and a fluorometric assay. We analyzed 100 RA patients on methotrexate, infliximab, tocilizumab, abatacept, or rituximab. No significant changes in the lipoprotein levels were detected, whereas the mean HDLc-EC statistically increased from baseline (22.5% ± 4.8%) to 24 weeks (24.5% ± 5.7%; p < 0.001) and 52 weeks (25.1% ± 5.9%; p < 0.001). Patients on tocilizumab showed the highest increase in HDLc-EC, already at 24 weeks. Patients on treatment with infliximab or rituximab showed a significant increase in HDLc-EC at 52 weeks. No significant changes were detected in abatacept and methotrexate groups. Some treatments may impact cholesterol reverse transport in RA. The improved HDLc-EC, independently from lipid levels, may be one of the missing links between inflammation, lipids, and CV risk in RA.

Increased sympathetic and haemodynamic responses to exercise and muscle metaboreflex activation in post-menopausal women with rheumatoid arthritis.

Rheumatoid arthritis (RA) patients present exacerbated blood pressure responses to exercise, but little is known regarding the underlying mechanisms involved. This study assessed autonomic and haemodynamic responses to exercise and to the isolated activation of muscle metaboreflex in post-menopausal women with RA. Participants with RA showed augmented pressor and sympathetic responses to exercise and to the activation of muscle metaboreflex. These responses were associated with multiple pro- and anti-inflammatory cytokines and with pain. The results of the present study support the suggestion that an abnormal reflex control of circulation is an important mechanism underlying the exacerbated cardiovascular response to exercise and increased cardiovascular risk in RA. Studies have reported abnormal cardiovascular responses to exercise in rheumatoid arthritis (RA) patients, but little is known regarding the underlying mechanisms involved. This study assessed haemodynamic and sympathetic responses to exercise and to the isolated activation of muscle metaboreflex in women diagnosed with RA. Thirty-three post-menopausal women diagnosed with RA and 10 matched controls (CON) participated in this study. Mean arterial pressure (MAP), heart rate (HR) and muscle sympathetic nerve activity (MSNA frequency and incidence) were measured during a protocol of isometric knee extension exercise (3min, 30% of maximal voluntary contraction), followed by post-exercise ischaemia (PEI). Participants with RA showed greater increases in MAP and MSNA during exercise and PEI than CON (ΔMAPexercise =16±11 vs. 9±6mmHg, P=0.03; ΔMAPPEI =15±10 vs. 5±5mmHg, P=0.001; ΔMSNAexercise =17±14 vs. 7±9burstsmin-1 , P=0.04; ΔMSNAPEI =14±10 vs. 6±4burstsmin-1 , P=0.04). Autonomic responses to exercise showed significant (P<0.05) association with pro- (i.e. IFN-γ, IL-8, MCP-1 and TNFα) and anti-inflammatory (i.e. IL-1ra and IL-10) cytokines and with pain. In conclusion, post-menopausal women with RA showed augmented pressor and sympathetic responses to exercise and to the activation of muscle metaboreflex. These findings provide mechanistic insights that may explain the abnormal cardiovascular responses to exercise in RA.

Largely Accelerated Arterial Aging in Rheumatoid Arthritis Is Associated With Inflammatory Activity and Smoking in the Early Stage of the Disease.

Background: Rheumatoid arthritis (RA) patients have a shorter life expectancy than the general population primarily due to cardiovascular comorbidities. Objectives: To characterize arterial aging in RA. Patients and Methods: Coronary calcium score (CCS) were available from 112 RA patients; out of these patients, follow-up CCS were measured for 54 randomly selected individuals. Control CCS were obtained from the MESA database (includes 6,000 < participants); arterial age was calculated from CCS. Results: RA patients were significantly older (10.45 ± 18.45 years, p < 0.001) in terms of the arterial age than the age-, gender-, and race-matched controls. The proportion of RA patients who had zero CCS was significantly less (p < 0.01) than that of those in the MESA reference group. Each disease year contributed an extra 0.395 years (p < 0.01) on the top of the normal aging process. However, the rate of the accelerated aging is not uniform, in the first years of the disease it is apparently faster. Smoking (p < 0.05), previous cardiovascular events (p < 0.05), and high blood pressure (p < 0.05) had additional significant effect on the aging process. In the follow-up study, inflammatory disease activity (CRP > 5 mg/L, p < 0.05) especially in smokers and shorter than 10 years of disease duration (p = 0.05) had the largest impact. Conclusion: Arterial aging is faster in RA patients than in control subjects, particularly in the first 10 years of the disease. Inflammation, previous cardiovascular events, and smoking are additional contributing factors to the intensified coronary atherosclerosis progression. These data support that optimal control of inflammation is essential to attenuate the cardiovascular risk in RA.