Cardiovascular Disease In Rheumatoid Arthritis Research Articles

A study of carotid intima media thickness in patients with rheumatoid arthritis and its correlation with acute phase reactants and disease activity

Introduction: There is increased risk of cardiovascular morbidity and mortality in patients of rheumatoid arthritis (RA) due to accelerated atherosclerosis. In this study we measured Carotid artery intima media thickness (CIMT) as a surrogate marker for subclinical atherosclerosis in RA patients without pre-existing cardiovascular disease. This study also analyzed the correlation between CIMT, disease duration, Simplified Disease Activity Index (SDAI) and acute phase reactants. Methods: A cross-sectional study was conducted on 90 patients divided into two groups of 45 patients of RA and another 45 control subjects. Subjects with RA and age and sex matched healthy controls were included in the study without pre-existing CV risk factors. Complete clinical evaluation, hematological and biochemical profile done. ESR, CRP and platelet count were used as markers of acute phase reactants. All the RA patients included in the study were evaluated for their disease activity using Simplified Disease Activity Index (SDAI). All the subjects including the controls evaluated for carotid intima media thickness by using carotid ultrasonography. CIMT measured in common carotid artery bilaterally by examining throughout common carotid artery up to 2 cm proximal to bifurcation. CIMT measurement taken at the site of greatest thickness. All measurements taken in diastole, measured in phase when lumen diameter is at its smallest and IMT at its largest. Mean value of 6 readings (3 from each side) taken as final CIMT for evaluation. B mode (linear probe) USG was used to determine carotid IMT. Results: 45 cases and similar control subjects included in the study with mean age (SD) as 45.07 (14.81) years. We found female preponderance with 37 females out of 45 cases. Mean (SD) disease duration in male subjects was 5.38(2.40) years while in females was 5.09 (2.78) years. CRP was found to be significantly increased in cases group with mean (SD) of 5.75(8.85) mg/dl. ESR significantly raised to 35.22(13.55) mm/hour in cases group compared to control group where it was 16.16(5.71) mm/hr. Mean (SD) platelets (x10³/mm³) were 229.24(69.80) in cases while controls had 290.33(83.85), so platelets correlation with disease could not be established. CIMT was significantly raised in cases group. Mean (SD) CIMT in cases was 0.95(1.06) mm whereas in control group it was 0.60(0.16) mm with p value of 0.002. Moderate positive correlation was found between CIMT (mm) and SDAI and this correlation was statistically significant with p=0.001. For every 1 unit increase in CIMT, the SDAI increases by 2.92 units. A strong positive correlation between CIMT (mm) and Disease Duration (Years), and this correlation was statistically significant (rho = 0.9, p = <0.001). For every 1 unit increase in CIMT (mm), the Disease Duration (Years) increases by 1.26 units. Conversely, for every 1 unit increase in Disease Duration (Years), the CIMT (mm) increases by 0.19 units. Conclusion: A strong correlation was observed between CIMT and disease duration in rheumatoid arthritis. Hence, CIMT can be a useful surrogate marker for detecting atherosclerosis in patients with RA. In view of the relation to duration of disease, established RA patients should regularly be screened to identify the evidence of atherosclerosis and manage it earlier. Prevention of cardiovascular disease in RA requires an integrated approach encompassing cardiovascular risk factors screening and management, effective and sustained control of RA disease activity, high index of suspicion and prompt investigation of suspected cardiac disease.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022

BackgroundRemnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. MethodsA total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). ResultsRA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58–3.35) per 1 mmol/L increase, and 2.40 (1.36–4.25) and 2.81 (1.60–4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. ConclusionsCirculating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Prevention of Atherosclerotic Cardiovascular Disease in Rheumatoid Arthritis: Persistent Low-grade In-flammation May be an Impediment Needing Attention

Objective: To determine the status of ‘residual inflammatory risk’ (RIR) and ‘residual cholesterol risk’ (RCR) in patients with Rheumatoid Arthritis (RA) in remission with the aim of estimating their atheroscle-rotic cardiovascular disease (ASCVD) risk. Methods: The study included patients with RA in remission during their last two clinic visits on treatment with disease- mod-ifying anti-rheumatic drugs (DMARDs). Using the QRISK-3 calculator, participants were stratified into four risk categories for ASCVD: ‘Very high’, ‘High’, ‘Moderate’, and ‘Low’. Patients were prescribed lipid-lowering drugs targeting low-density lipoprotein cholesterol (LDL-C) levels to &lt;50 mg/dl, &lt;70 mg/dl, &lt;100 mg/dl or &lt;130 mg/dl, respectively. Those with a history of ASCVD before or during the follow-up period was excluded from the study. Multimorbidity were also recorded in all the patients. Results: The study included 130 patients with RA in remission. The results showed that despite being in remission and taking treatment for lipid control, 81 (62%) and 91 (70%) patients still had ‘RIR’ and ‘RCR’, respectively. Hypertension, hypothyroidism, type-2 diabetes mellitus and obesity were the common multimorbidity. Conclusions: Persistent RIR in 62% of patients despite being in remission, could possibly be due to the current ‘liberal’ definition of RA permitting hs-CRP level up to &lt;10 mg/l, which is five-fold higher than the recommended &lt;2 mg/l for ASCVD prevention. Hence it may be necessary to revise the definition of ‘remission’ in RA factoring in the suggested lower level of hs-CRP. Additionally, rheumatologists might need to be more vigilant in lipid management with appropriate patient education regarding RCR.

The Relationship of Inflammatory Chemokine, CXCL12, with NT-proBNP: A Marker of Congestive Heart Failure in Rheumatoid Arthritis Patients

Background: Cardiovascular disease (CVD) is the most considerable long-term outcome of rheumatoid arthritis (RA) and the leading cause of premature death in RA patients. The pathogenesis of CVD in RA is largely determined by persistent systemic inflammation and its underlying factors, including chemokines. In this regard, C-X-C motif chemokine ligand 12 (CXCL12) has a crucial role in the CVD and RA pathogenesis. For the first time, plasma CXCL12 was related to conventional CV risk and well-established cardiac biomarkers in RA patients. Methods: This study was conducted on 30 RA patients who have been newly diagnosed, 30 under-treatment RA patients, and 30 healthy subjects. The plasma levels of CXCL12 and N-terminal pro-B-type natriuretic peptide (NT-ProBNP) were measured using the enzyme-linked immunosorbent assay (ELISA) technique. The high sensitivity C-reactive protein (HS-CRP) concentration was evaluated in plasma samples using the ADVIA 1800 Clinical Chemistry System based on the latex-enhanced immunoturbidimetric assay. The CVD risk was measured by calculating the Framingham risk score (FRS) and systematic coronary risk evaluation (SCORE). Results: The mean FRS and plasma concentration of high-density lipid (HDL), NT-proBNP, and HS-CRP were significantly different between the three groups (P = 0.029, P &lt; 0.001, P = 0.016, P &lt; 0.001, respectively). A significant positive correlation was found between CXCL12 with disease activity score-28 (DAS-28) (P = 0.024, r = 0.293) and NT-proBNP (P &lt; 0.0001, r = 0.570) in the patients’ group. Conclusions: Based on the results, there was a significant relationship between the inflammatory mediator CXCL12 and a well-known cardiac biomarker, NT-proBNP.

Cardiovascular disease risk in early rheumatoid arthritis: the impact of cartilage oligomeric matrix protein (COMP) and disease activity

BackgroundTo investigate whether baseline serum cartilage oligomeric matrix protein (COMP), patient characteristics, traditional cardiovascular disease (CVD) risk factors and disease activity over time predict CVD, in early rheumatoid arthritis (RA).MethodsThis study included patients with early RA (< 12 months disease duration) (n = 233) recruited 1995–2005. Potential predictors of CVD and coronary artery disease (CAD) were assessed using Cox regression.ResultsA first ever diagnosis of CVD occurred in 70 patients, and CAD in 52. Age, sex, hypertension and diabetes predicted CVD and CAD. COMP was associated with increased risk of CVD and CAD [crude hazard ratios (HRs) per SD 1.45; 95% CI 1.17–1.80 and 1.51; 95% CI 1.18–1.92, respectively]. When adjusted for age, sex, hypertension, diabetes and ESR, results where similar but did not reach significance [HRs 1.32, 95% CI 0.99–1.74 and 1.35, 95% CI 0.99–1.86]. Baseline disease activity did not independently predict CVD. High DAS28 (> 5.1) at two years was associated with increased risk of subsequent CVD [adjusted HR 2.58; 95% CI 1.10–6.04] and CAD. ESR and CRP at two years as well as cumulative disease activity over 2 years independently predicted CVD and CAD.ConclusionCOMP may be a novel predictor of CVD and CAD in RA. Active disease two years after RA diagnosis, as well as cumulative disease activity, was associated with increased risk of CVD and CAD, independent of traditional CVD risk factors. Awareness of the particularly increased CVD risk among difficult to treat patients is important in order to further reduce CVD in RA.

Dyslipidemia in rheumatoid arthritis: the possible mechanisms

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called “lipid paradox”. The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

CXCL9 and its Receptor CXCR3, an Important Link Between Inflammation and Cardiovascular Risks in RA Patients.

Cardiovascular disease (CVD) is the most common cause of mortality in rheumatoid arthritis (RA), and Inflammation has a decisive role in its pathogenesis. CXCL9 contributes to multi aspects of inflammatory reactions associated with the pathogenesis of CVD. In the current study, we evaluated the association of plasma CXCL9 and CXCR3 gene expression with Cardiovascular risk factors in RA patients for the first time. Thirty newly diagnosed, 30 on-treatment RA patients, and 30 healthy subjects were recruited in this study. The plasma concentration of CXCL9 and CXCR3 gene expression were measured using ELISA and Real-Time PCR, respectively. The CVD risk was evaluated using Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE). The plasma levels of CXCL9 were significantly higher in the newly diagnosed and on-treatment RA patients compared to the control group (P < 0.0001 and P < 0.001, respectively). Also, The CXCR3 gene expression was strongly elevated in newly diagnosed and on-treatment patients (P < 0.001 and P < 0.01, respectively). The CXCL9 and CXCR3 were significantly associated with RA disease activity (P = 0.0005, r = 0.436; P = 0.0002, r = 0.463, respectively). The FRS was remarkably higher in newly diagnosed and on-treatment patients (P = 0.014 and P = 0.035, respectively). The CXCR3 gene expression significantly correlated with age, systolic blood pressure, FRS, and SCORE (P = 0.020, r = 0.298; P = 0.006, r = 0.346; P = 0.006, r = 0.349; P = 0.007, r = 0.341, respectively). The CXCL9 plasma concentration had a significant negative correlation with plasma HDL and LDL levels (P = 0.033, r = -0.275; P = 0.021, r = -0.296, respectively). CXCL9 and CXCR3 correlates with different variables of CVD in RA.

Antirheumatic drugs and cardiovascular disease in rheumatoid arthritis

Antirheumatic drugs and cardiovascular disease in rheumatoid arthritis

Association between periodontitis and cardiovascular health in rheumatoid arthritis patients: Prospective effect of periodontal treatment on cardiovascular risk

Rheumatoid arthritis (RA) patients are more likely to develop cardiovascular disease (CVD), which increases the risk of morbidity and mortality. Periodontitis is known to be associated with CVD, yet its relationship with CVD in RA is limited. To examine the relationship between periodontitis with subclinical atherosclerosis and with long term CVD risk. Examining if periodontitis treatment can be associated with CVD improvement was well thought out. This prospective interventional study included 49 adults with RA. Demographic, clinical and therapeutic data and laboratory markers were assessed. Dental examination for periodontitis was performed. The carotid intima media thickness (CIMT) and Framingham risk score (FRS) were evaluated. Medical treatment was provided to RA patients with periodontitis, and assessments were repeated after 6 months. The mean age of the patients was 46.4 ± 12.4 years, disease duration 10.9 ± 5.4 years and 79.6% were females. 25 (51%) patients had subclinical atherosclerosis, 30 (61.2%) had periodontitis and 25 (51%) had both. RA patients with subclinical atherosclerosis had higher clinical attachment loss (CAL) (3.12 ± 1.45) and higher probing depth (PD) (4.96 ± 1.37) compared to those without (p < 0.001). CAL (β = 0.01, 95 %CI: 0–0.01, p < 0.001), and PD (β = 0.01, 95% CI: 0–0.01; p < 0.001) were independently associated with CIMT. The 30 patients after treatment of periodontitis showed an average improvement in the mean CIMT (0.14 mm, p < 0.001). Periodontitis is associated with subclinical atherosclerosis in RA. Treatment of periodontitis could improve the cardiovascular health in RA patients and prompts physicians to early diagnose and treat periodontitis.

OA05 Harnessing high throughput multiplex immunoassays and protein association networks to identify diagnostic protein biomarkers of rheumatoid arthritis-cardiovascular disease (RA-CVD) multimorbid axis

Abstract Background/Aims People with rheumatoid arthritis (RA) have higher mortality rates compared to the general population, primarily due to excess cardiovascular (CV) disease (CVD). The earliest stages of RA are associated with CV abnormalities but biomarkers to identify CVD in early RA are lacking. We aimed to identify focused protein biomarkers that associate with cardiac magnetic resonance imaging (CMR) abnormalities in a treatment-naïve, new-onset RA trial cohort and the predominant inflammatory and metabolic pathways involved in RA-CVD. Methods CADERA (Coronary Artery Disease in Early RA) was a bolt-on study to a parent RCT in an early RA inception cohort. 81 treatment-naïve early RA patients underwent CMR at baseline as part of CADERA. Proximity extension immunoassay (OIink) was used to measure normalised protein expression across inflammation, cardiovascular II/III and cardiometabolic panels in CADERA patients. Bayesian mixed effects linear regression was used to identify significant proteins associated with CMR parameters of myocardial oedema/fibrosis and vascular stiffness at baseline. Then, an expanded protein-protein interaction (PPI) network using above proteins was created using an induced network approach (String-DB) and k-means clustering applied to identify protein clusters that were subsequently subjected to Gene ontology (GO) and KEGG enrichment analysis. Results Of 340 proteins analysed using Olink, 108 proteins were associated with CMR markers of myocardial fibrosis/oedema (64 proteins) and vascular stiffness (44 proteins) Table 1 highlights the top 5 proteins for each CMR parameter. K-means clustering of the expanded PPI network identified 4 clusters with roles in vascular endothelial growth factor receptor binding and JAK-STAT signalling pathway (cluster 1); IL27 receptor binding and NF-kappa B signalling pathway (cluster 2); Macrophage CSF receptor binding and ErbB signalling pathway (cluster 3); and IL10 receptor activity and complement and coagulation cascades (cluster 4). Conclusion This is the first study to identify protein biomarkers of RA-CVD, an area of unmet clinical need, using a combination of targeted high throughput immunoassays, Bayesian and network analyses. Targeted techniques such as Olink may help identify potential diagnostic biomarkers of RA-CVD. Pathway analysis provides insight into the inter-relationship between inflammation and metabolic mediators of RA-CVD axis. Disclosure R. Shukla: None. N. Black: None. D. Plant: None. C. Miller: None. S. Plein: None. M.H. Buch: None.

Remotely Supervised Weight Loss and Exercise Training to Improve Rheumatoid Arthritis Cardiovascular Risk: Rationale and Design of the Supervised Weight Loss Plus Exercise Training-Rheumatoid Arthritis Trial.

Patients with rheumatoid arthritis (RA) remain at an increased risk for cardiovascular disease (CVD) and mortality. RA CVD results from a combination of traditional risk factors and RA-related systemic inflammation. One hypothetical means of improving overall RA CVD risk is through reduction of excess body weight and increased physical activity. Together, weight loss and physical activity can improve traditional cardiometabolic health through fat mass loss, while also improving skeletal muscle health. Additionally, disease-related CVD risk may improve as both fat mass loss and exercise reduce systemic inflammation. To explore this hypothesis, 26 older persons with RA and overweight/obesity will be randomized to 16 weeks of a usual care control arm or to a remotely Supervised Weight Loss Plus Exercise Training (SWET) program. A caloric restriction diet (targeting 7% weight loss) will occur via a dietitian-led intervention, with weekly weigh-ins and group support sessions. Exercise training will consist of both aerobic training (150 minutes/week moderate-to-vigorous exercise) and resistance training (twice weekly). The SWET remote program will be delivered via a combination of video conference, the study YouTube channel, and study mobile applications. The primary cardiometabolic outcome is the metabolic syndrome Z score, calculated from blood pressure, waist circumference, high-density lipoprotein cholesterol, triglycerides, and glucose. RA-specific CVD risk will be assessed with measures of systemic inflammation, disease activity, patient-reported outcomes, and immune cell function. The SWET-RA trial will be the first to assess whether a remotely supervised, combined lifestyle intervention improves cardiometabolic health in an at-risk population of older individuals with RA and overweight/obesity.

Endothelial dysfunction detected by brachial reactivity as a marker of cardiovascular disease in rheumatoid arthritis: Literature review

Endothelial dysfunction detected by brachial reactivity as a marker of cardiovascular disease in rheumatoid arthritis: Literature review

Increased Risk of Cardiovascular Diseases in Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is an autoimmune condition in which the body's jointsare attacked by the immune system, leaving the patient disabled in severe cases, with irreversible joint damageand a lower quality of life. RA patients are more likely to develop cardiovascular (CV) disease, which increases their risk of morbidity and mortality. This study systematically reviews various CV diseases that might occur with RA including heart failure (HF), coronary artery disease, acute coronary syndrome, ischemic heart disease, stroke, cardiac death, venous thromboembolism, and valvular diseases. The relation between these complications and RA is specifically assessed. Systematic search was carried out on literature reporting the risk of each of the CV diseases in RA patients from databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases searched were MEDLINE(through PubMed) and Google Scholar usinga combination of keywords and medical subject headings (MeSH). Our keywords were mainly "cardiovascular diseases" and "arthritis and rheumatoid". We found a total of 33articles reporting each CV comorbidity. Interestingly, a wide spectrum of CV diseases is reported in patients with RA. Many tools were implemented in the diagnosis of each disease such as carotid intima-media thickness for atherosclerosis and echocardiography for HF. We confirmed that RA is associated with an increased risk of different CV events, and prophylactic measures should be implemented.

Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis

BackgroundSerum uric acid (SUA) acts as an antioxidant and abnormally low SUA may raise the risk of developing atherosclerotic disorders. There is a U-shaped association between SUA with cardiovascular diseases (CVDs) in general population. However, the prevalence of hypouricemia and its influence on CVDs in rheumatoid arthritis (RA) remains unclear.MethodsThis cross-sectional study collected clinical data from a Chinese RA cohort. Hypouricemia was defined as SUA ≤ 3.0 mg/dL, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL. CVDs were defined as a history of angina pectoris, myocardial infarction, heart failure, stroke and peripheral arterial disease. Restricted cubic spline regression and logistic regression analysis were conducted to evaluate the associations between SUA levels and CVDs.ResultsAmong 1130 RA patients recruited, the mean age was 53.2 years and 79.0% were female. The prevalence of hypouricemia and hyperuricemia were 10.6% and 12.0%, respectively. RA patients with hyperuricemia had a higher rate of CVDs than normouricemic patients (27.9% vs. 7.1%, P < 0.05). Surprisingly, RA patients with hypouricemia also had a higher rate of CVDs (20.7% vs. 7.1%, P < 0.05) even without higher traditional cardiovascular risk factors. A U-shaped association between SUA levels and total CVDs was found (Pnon-linear < 0.001). Multivariate logistic regression analysis revealed that compared with normouricemia, both hypouricemia [adjusted OR (AOR) = 4.707, 95% CI 2.570–8.620] and hyperuricemia (AOR = 3.707, 95% CI 2.174–6.321) were associated with higher risk of CVDs.ConclusionsHypouricemia may be a potential risk factor of CVDs in RA patients

Associations between Cardiovascular Outcomes and Rheumatoid Arthritis: A Nationwide Population-Based Cohort Study.

Despite a growing burden posed by cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients, large-scale studies on the association between the characteristics of RA patients and CVD risks and studies adjusted for various confounding factors are lacking. In this large-scale nationwide cohort study, we aimed to investigate the association between CVD risk and RA and factors that may increase CVD risk using a dataset provided by the Korean National Health Insurance Service (NHIS). We enrolled 136,469 patients with RA who participated in national health examinations within two years of RA diagnosis between 2010 and 2017 and non-RA controls matched by age and sex (n = 682,345). The outcome was the occurrence of myocardial infarction (MI) or stroke. MI was defined as one hospitalization or two outpatient visits with ICD-10-CM codes I21 or I22. Stroke was defined as one hospitalization with ICD-10-CM codes I63 or I64 and a claim for brain imaging (CT or MRI). The Cox proportional hazard model and Kaplan-Meier curve were used for analysis. The mean follow-up duration was 4.7 years, and the incidence rate of CVD was higher in the RA group than the control group (MI: 3.20 vs. 2.08; stroke: 2.84 vs. 2.33 per 1000 person-years). The risk of MI and stroke was about 50% and 20% higher, respectively, in RA patients. The association between RA and CVD was prominent in females after adjusting for confounding variables. The association between RA and risk of MI was significant in individuals without DM. Therefore, appropriate screening for CVD is important in all RA patients including females and younger patients.

Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis.

To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA). Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted. Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P=0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P=0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P=0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P=0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients. Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

Interrelationship of Metabolic Syndrome and Rheumatoid Arthritis in North Indian Population

Objective: The metabolic syndrome (MetS) may be responsible for occurrence of high frequency of cardiovascular disease in rheumatoid arthritis (RA) patients. An association between inflammatory activity of RA and MetS has also been speculated. This study was designed to see whether presence of MetS along with RA increases the severity of disease and to find the risk association of the disease severity markers of RA namely TNF-α, anti-CCP, RF, CRP and ESR with MetS. Methodology: 185 patients of RA (EULAR 2010) were recruited and assessed for MetS according to NCEP/ATP III criteria. Serum level of disease specific biomarkers of RA namely TNF-α, anti-CCP, RF, CRP and ESR were quantified in all patients and compared between RA with MetS and only RA patients. Cytokine TNF-α, anti-CCP, RF, and CRP were assayed through ELISA. Results: The prevalence of MetS among RA patients was 41.2%. The mean age of RA cases with MetS is significantly older (55.65yrs) with increased disease duration. The levels of TNF-α, anti-CCP, CRP and ESR along with EULAR &amp; DAS score were significantly (p&lt;0.05) high in RA with MetS. TNF-α showed maximum risk (OR=6.3; p=0.03) in development of MetS. Longer disease duration with high anti-CCP, CRP and DAS-28 were also contributing significantly in MetS development. Conclusion: A positive vicious cycle is working between the pathogenesis of RA and MetS through inflammatory cytokines and biomarkers. MetS in RA is associated with increased disease severity. Keywords: Rheumatoid arthritis, Metabolic syndrome, Biomarkers, Cytokine TNF-α, Disease severity

HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory polyarthritis independent of CRP and anti-CCP status

BackgroundHaplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA) are associated with radiological outcome, anti-TNF response and all cause-mortality in RA. RA is associated with cardiovascular (CV) morbidity and mortality, but the increased prevalence of risk factors of CV disease in RA only partially explains this association. The aim of this study was to investigate whether amino acids at positions 11, 71 and 74 of HLA-DRB1 are associated with cardiovascular (CV) mortality in inflammatory polyarthritis (IP).MethodsThe Norfolk Arthritis Register (NOAR) is an incidence register of IP: recruitment 1990–2007, final follow-up 2011. Two thousand five hundred fourteen patients had available genetic and mortality data. Amino acids at positions 11, 71 and 74 of HLA-DRB1 were determined. Univariate Cox proportional hazard models were applied to assess the association of genetic markers and both all-cause mortality and cardiovascular mortality.ResultsAmong 2514 participants, 643 (25.6%) died during the study, and 343 (53.3%) of these deaths were attributed to CV causes. One thousand six hundred fifty (65.6%) participants were female, 709 (32.3%) were anti-CCP-positive and the median age of participants was 54.HLA-DRB1 haplotypes associated with susceptibility to rheumatoid arthritis (RA) consistently show the same magnitude and direction of association for overall and CV mortality in IP. For example, the SEA-haplotype, associated with the lowest susceptibility to RA, and the best radiographic outcome, was found to be associated with decreased CV mortality (HR 0.67, 95% CI 0.47, 0.91, p=0.023). Mediation analysis revealed associations were independent of anti-CCP status.ConclusionsHLA-DRB1 haplotypes associated with susceptibility to RA also predispose to increased risk of CV mortality in IP, independent of known CV risk factors. Associations were independent of anti-CCP status, which suggests in the future, genetic factors will add to the prediction of risk of cardiovascular mortality beyond serological markers.

P213 HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory arthritis

Abstract Background/Aims Haplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA), are associated with radiological outcome, anti-TNF response and all cause-mortality. RA is associated with cardiovascular (CV) morbidity and mortality, but increased prevalence of risk factors of CV disease in RA only partially explains this association. The aim was to investigate whether haplotypes associated with RA disease susceptibility and disease severity are associated with CV mortality. Methods The Norfolk Arthritis register (NOAR) is a primary care-based inception cohort of patients with inflammatory polyarthritis (IP). NOAR patients with at least 2 years of follow-up and available mortality and genetic data were included. Mortality data was provided by the Office for National Statistics. Univariate Cox proportional hazard models were applied using STATA/IC 14.0. Models for CV mortality were adjusted for CV risk factors selected using stepwise regression: namely obesity, gender and hypertension. Hazard models were applied to the entire cohort of patients with inflammatory polyarthritis (IP). When calculating differences between highest and lowest risk genetic factors, bivariate analysis was used. Results HLA-DRB1 amino acids, haplotypes or haplotype groups associated with RA susceptibility are also associated with CV mortality as shown in the table. HLA-DRB1 polymorphisms encoding amino-acid haplotypes associated with an increased or decreased susceptibility to RA consistently show the same magnitude and direction of association for overall and CV mortality in IP. For example, the SEA-haplotype, associated with the lowest susceptibility to RA, and the best radiographic outcome, was found to be associated with decreased CV mortality (HR 0.67, 95% CI 0.47, 0.91, p = 0.023). The relative difference in CV mortality between carriers of the high susceptibility VKA haplotype and carriers of the SEA haplotype was significant (HR 1.67, 95% CI 1.13, 2.48, p = 0.01). Associations were independent of anti-CCP status. Conclusion HLA-DRB1 haplotypes associated with susceptibility to RA also predispose to increased risk of CV mortality in IP, independent of known CV risk factors and anti-CCP status, which suggests that, in the future, genetic factors will add to prediction of risk of cardiovascular mortality beyond serological markers. Disclosure S.D. Sharma: None. D. Plant: None. J. Bowes: Grants/research support; British Heart Foundation. A. Macgregor: None. A. Barton: Grants/research support; BMS. Other; Speaker Fees from Roche Chugai. S. Viatte: None.

Antirheumatic therapy is associated with reduced complement activation in rheumatoid arthritis.

BackgroundThe complement system plays an important role in pathophysiology of cardiovascular disease (CVD), and might be involved in accelerated atherogenesis in rheumatoid arthritis (RA). The role of complement activation in response to treatment, and in development of premature CVD in RA, is limited. Therefore, we examined the effects of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) on complement activation using soluble terminal complement complex (TCC) levels in RA; and assessed associations between TCC and inflammatory and cardiovascular biomarkers.MethodsWe assessed 64 RA patients starting with MTX monotherapy (n = 34) or TNFi with or without MTX co-medication (TNFi±MTX, n = 30). ELISA was used to measure TCC in EDTA plasma. The patients were examined at baseline, after 6 weeks and 6 months of treatment.ResultsMedian TCC was 1.10 CAU/mL, and 57 (89%) patients had TCC above the estimated upper reference limit (<0.70). Compared to baseline, TCC levels were significantly lower at 6-week visit (0.85 CAU/mL, p<0.0001), without significant differences between the two treatment regimens. Notably, sustained reduction in TCC was only achieved after 6 months on TNFi±MTX (0.80 CAU/mL, p = 0.006). Reductions in TCC after treatment were related to decreased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and interleukin 6, and increased levels of total, high and low-density lipoprotein cholesterol. Similarly, baseline TCC was significantly related to baseline CRP, ESR and interleukin 6. Patients with endothelial dysfunction had higher baseline TCC than those without (median 1.4 versus 1.0 CAU/mL, p = 0.023).ConclusionsPatients with active RA had elevated TCC, indicating increased complement activation. TCC decreased with antirheumatic treatment already after 6 weeks. However, only treatment with TNFi±MTX led to sustained reduction in TCC during the 6-month follow-up period. RA patients with endothelial dysfunction had higher baseline TCC compared to those without, possibly reflecting involvement of complement in the atherosclerotic process in RA.