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The chapter describes the phenomenon of cancer villages in China, which have come to widespread public attention only within the past decade. So-called because they constitute cancer clusters that are mainly found in the rural countryside, their stories show that even China, with its socialist past and rhetoric of egalitarianism, has not been immune from environmental inequity and injustice. The chapter focuses on one of the best-known sets of cancer villages as a case study, the Wengyuan County Cancer Villages in Guangdong Province. In providing context to the challenges that these communities face as well as the causes of their plight, the chapter seeks to put this issue into the context of the broader environmental justice movement and global work toward sustainable development.

Background In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics. Methods RA patients aged 30–70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up. Results A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15–32% of patients. C-statistics ranged 0.68–0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results. Conclusions The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.

Objectives Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. Methods Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. Results Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5–6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P Conclusion Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.

Smoking cessation in patients with RA is associated with reduced CVD event rates and improved lipid profiles and predicts lower RA disease activity

Background Aberrant hemostasis is implicated in the increased CVD risk experienced by patients with rheumatoid arthritis (RA) (1). Large circulating concentrations of plasminogen activator inhibitor-1 (PAI-1) predict cardiovascular event rates (2). PAI-1 levels are markedly smaller in American and African black populations than in those of European descent (3,4). Whether this protection persists in black persons who have RA is unknown. Objectives This study compared hemostasis factors among African black and white RA patients Methods PAI-1, tissue factor pathway inhibitor (TFPI) and tissue plasminogen activator (t-PA) levels were measured by ELISA in 236 (114 black; 122 white) African RA patients. Data were analysed in mixed regression models. Results In age and sex adjusted analysis, PAI-1 concentrations were larger in black compared to white patients with RA (median (interquartile range (IQR))=12.4 (3.1-28.7) versus 5.4 (1.5-25.0) ng/ml, p=0.006). In all patients, body mass index (BMI) (β (SE)=0.022 (0.007), p=0003), waist circumference (β (SE)=0.007 (0.003), p=0.04) and tetracycline use (β (SE)=0.291 (0.133), p=0.03) were associated with logarithmically transformed PAI-1 levels. Population grouping did not influence these relationships (interaction p>/=0.8) but impacted rheumatoid factor (RF) positivity- and azathioprine use-PAI-1 level associations (interaction p=0.03 and 0.004, respectively). In stratified analysis, RF positivity was associated with PAI-1 levels in white (β (SE)=0.344 (0.139), p=0.01) but not black patients (β (SE)=-0.102 (0.143), p=0.5), and azathioprine use was associated with PAI-1 levels in black (β=0.400 (0.155), p=0.01) but not white patients (β (SE)=0.305 (0.184), p=0.1). In age, sex, BMI, RF positivity and azathioprine and tetracycline use adjusted analysis, black population origin remained associated with PAI-1 levels (β (SE)=0.175 (0.091), p=0.05). In age and sex adjusted analysis, TFPI and t-PA levels did not differ in black compared to white RA patients (median (IQR)=221.0 (149.8-410.5) versus 225.0 (130.4-357.2) pg/ml, p=0.6, and 6.7 (4.9-9.1) versus 7.4 (4.4-10.0) pg/ml, p=0.3). Conclusion PAI-1 concentrations are substantially larger in African black compared to white patients with RA. References [1] Van den Hoever IAM, Sattar N, Nurmohamed MT. Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis 2014;73:954-7. [2] Jung RG, Motazedian P, Ramirez FD, et al. Association between plasminogen activator-1 and cardiovascular events: a systematic review and meta-analysis. Thrombosis J (2018) 16:12. [3] Festa A, D’Agostino R, Rich SS, et al. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics and non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Circulation 2003;107:2422-7. [4] De Lange Z, Rijken DC, Hoekstra T, et al. In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time. PLoS One 2013;8 (12): e83151. Disclosure of Interests None declared

Rheumatoid arthritis (RA) impacts arterial and diastolic function. This study examined whether arterial properties can determine diastolic function in RA. In 173 RA patients, arterial function measures including carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification, and the magnitude and timing of the forward and reflected waves were measured using applanation tonometry. Diastolic function parameters including the ratio of early-to-late transmitral velocity (E/A) and ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening (e') were measured using echocardiography. The timing of the reflected wave was associated with E/A; PWV was related to E/e'. The timing of the reflected wave, forward wave magnitude, and pulse pressure amplification were associated with impaired relaxation; PWV was related to increased left ventricular (LV) filling pressure. Early wave reflection and PWV are associated with LV-impaired relaxation and increased filling pressure, respectively, in RA.

Objective.We determined the performance of the Framingham score and the Systematic COronary Risk Evaluation (SCORE) in assessing high-risk atherosclerosis in patients with rheumatoid arthritis (RA).Methods.We assembled 330 cases without established cardiovascular disease (CVD), diabetes, and moderate or severe chronic kidney disease among 451 consecutive Spanish patients who underwent CVD risk screening and carotid ultrasound-determined plaque assessment. The findings were validated in 90 black and 97 white African patients.Results.When sensitivity for the Framingham score was set at 80% in receiver-operator curve analysis [area under the curve (AUC) = 0.799], the corresponding cutoff value and specificity were 7.3% and 63%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 10.8% and 65%, respectively. When sensitivity for SCORE (AUC = 0.747) was set at 80%, the cutoff value and specificity were 0.5% and 58%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 1.5% and 50%, respectively. Upon applying a cutoff value of 7.3% for the Framingham and 0.5% for SCORE in African white patients with RA, the corresponding sensitivities and specificities were 67% and 72%, and 67% and 55%, respectively. CVD risk equations did not discriminate between black African patients with and without plaque (AUC = 0.544 and 0.549 for Framingham score and SCORE, respectively).Conclusion.The Framingham score and SCORE at markedly low cutoff values of 7.3% to 10.8% and 0.5% to 1.5%, respectively, can usefully estimate plaque presence in RA. Effective population-specific CVD risk assessment strategies are needed in black African patients with RA.

Background Patients with rheumatoid arthritis (RA) experience an increased frequency of heart failure with a preserved ejection fraction (HFpEF) (1). The treatment of HFpEF is currently suboptimal. Elucidation of the underlying pathophysiological mechanisms of HFpEF may provide potential targets for its management. Diastolic dysfunction often precedes the progression to HFpEF (2). Abnormalities in aortic function contribute to diastolic dysfunction in non-RA populations (3,4). Objectives The aim of this study was to determine whether impaired aortic function is associated with left ventricular diastolic dysfunction in RA. Methods Arterial function was determined by applanation tonometry using SphygmoCor software and left ventricular diastolic function was assessed by echocardiography in 176 patients with RA. Markers of arterial function included carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification and the magnitude and timing of the forward and reflected waves. Markers of diastolic function included the ratio of early-to-late transmitral blood flow velocity (E/A), the ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (e’)(E/e’) and the septal and lateral e’. Relationships of comprehensively evaluated arterial function with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results The timing of the forward (Ft) and reflected (Rt) waves were each associated with E/A (Ft: partial r=0.20, p=0.02; Rt: partial r=0.30, p=0.001) and Rt was further associated with lateral e’ (partial r=0.36, p 12: OR (95% CI)=1.58 (1.04-2.38), p=0.03). Conclusions Aortic stiffness and time to wave reflection are associated with increased filling pressure and impaired relaxation of the left ventricle, respectively. The development of diastolic dysfunction in RA may be partly mediated by changes in large artery function. References: [1] Davis JM, Roger VL, Crowson CS, et al. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheumatol 2008;58:2603-11. [2] Aurigemma GP, Gottdiener JS, Shemanski L, et al. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042-8. [3] Peterson VR, Woodiwiss AJ, Libhaber CD, et al. Cardiac diastolic dysfunction is associated with aortic wave reflection, but not stiffness in a predominantly young-to-middle-aged community sample. Am J Hypertens 2016;29:1148-57. [4] Cauwenberghs N, Knez J, Tikhonoff V, et al. Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population. J Hypertens 2016;34:762-71. Disclosure of Interest: None declared

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p ≥ 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p ≤ 0.05). In stratified analysis, apelin was associated with CSP (partial r = − 0.33, p = 0.01), CPP (partial r = − 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = − 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = − 0.24, p = 0.05) in those with a DAS28 joint

ObjectivesPatients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA.MethodsIn 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions.Results5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all pConclusionsIn a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Nesfatin is an anti-inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro-inflammatory properties and is pro-atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (β = 0.650, p

Objective.Arterial properties influence cardiovascular disease (CVD) risk. We identified potential determinants of arterial function in patients with rheumatoid arthritis (RA).Methods.Relationships of traditional cardiovascular risk factors and RA characteristics with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pulse pressure amplification, and forward wave pressure) were identified in multivariable backward regression models among 177 patients without established CVD (118 white, 32 Asian, 22 black, 5 mixed ancestry).Results.Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial function. These factors were particularly associated with wave reflection and pressure pulsatility: RA duration (p = 0.04), rheumatoid factor status (p = 0.01 to 0.03), leukocyte counts (p = 0.02 to 0.05), and total cholesterol (p < 0.01 to 0.03). Body mass index (p < 0.01 to 0.02) and insulin resistance (p < 0.01 to 0.01) were related to reduced wave reflection and peripheral pulse pressure. Exercise (p = 0.02) and alcohol consumption (p < 0.01) were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumor necrosis factor-α inhibition (p < 0.01) was related to reduced pulse wave velocity, and tetracycline use (p = 0.02) to decreased peripheral pulse pressure.Conclusion.Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The relative effect of arterial stiffness, wave reflection, and pressure pulsatility on CVD risk in RA needs further study.

Atherosclerotic cardiovascular disease risk is increased in rheumatoid arthritis (RA). Wave reflection occurs at arterial branching points, which are particularly prone to atherosclerosis. We explored the relationship of wave reflection with atherosclerosis in RA.One hundred and sixty three RA patients (110 white, 31 Asian, 17 black and 5 of mixed ancestry) without cardiovascular disease participated. Arterial stiffness, wave reflection, pressure pulsatility, plaque in the extracranial carotid artery tree and the mean of the left and right common carotid arteries intima-thickness were determined. Associations were identified in multivariable regression models.One SD increase in reflected wave pressure (OR (95% CI) = 2.54 (1.41-4.44), p=0.001), reflection magnitude (OR (95% CI) = 1.84 (1.17-2.89), p=0.008), central pulse pressure (OR (95% CI) = 1.89 (1.12-3.22), p=0.02) and peripheral pulse pressure (OR (95% CI) = 2.09 (1.23-3.57), p=0.007) were associated with plaque. The association of wave reflection with plaque was independent of arterial stiffness and pressure pulsatility, and was present in both hypertensive and normotensive RA patients. In receiver operator characteristic curve analysis, the optimal cutoff value for reflected wave pressure in predicting plaque presence was 25 mmHg with a sensitivity, specificity, positive predictive value and negative predictive value of 45.2%, 89.3%, 78.6% and 66.2%, respectively; a reflected wave pressure of25 mmHg was associated with plaque in univariate and adjusted analysis (p0.0001 for both). Arterial function was not independently related to carotid intima-media thickness.Consideration and therapeutic targeting of wave reflection may improve cardiovascular disease prevention in RA.

Background In the non-rheumatoid arthritis (RA) population, arterial stiffness contributes to cardiovascular disease risk beyond brachial blood pressure and other established cardiovascular risk factors. The increased cardiovascular disease risk in RA is now well documented. In this regard, how RA impacts on arterial stiffness remains uncertain. Objectives The aim of the present study was to identify potential determinants of comprehensively assessed arterial stiffness in a relatively large group of ethnically diverse patients with RA. Methods Relationships of traditional cardiovascular risk factors and RA characteristics with 9 arterial stiffness markers including central systolic and pulse pressure, pulse wave velocity, augmentation index, forward and reflected wave pressure, reflection magnitude, brachial-to-aortic pulse pressure amplification (a marker of reduced wave reflection) and peripheral pulse pressure were identified in multivariable backward regression models among 177 (118 white, 32 Asian, 22 black, 5 mixed ancestry) patients without established cardiovascular disease. Results Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial stiffness. RA duration (partial r=0.17, p=0.04), rheumatoid factor status (partial r=-0.19 to 0.20, p=0.01 to 0.03), leukocyte counts (partial r=0.16 to 0.19, p=0.02 to 0.05) and total cholesterol (-0.18 to 0.26, p=0.00 to 0.03) were associated with enhanced central systolic blood pressure or/and wave reflection markers. C-reactive protein (partial r=-0.24, -0.17 and -0.20, respectively, p≤0.05) was paradoxically related to reduced central pulse pressure, pulse wave velocity and forward wave pressure, and body mass index (partial r=-0.39 to 0.42, p=0.00 to 0.02) and insulin resistance (partial r=-0.21 to -0.20, p=0.00 to 0.01) to reduced wave reflection and peripheral pulse pressure. Exercise (partial r=0.19, p=0.02) and alcohol (partial r=-0.27, p=0.00) consumption were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumour necrosis factor-α inhibition (partial r=-0.25, p=0.00) was related to reduced pulse wave velocity and tetracycline use (partial r=-0.20, p=0.02) to reduced peripheral pulse pressure. Conclusions Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The role of arterial stiffness in cardiovascular disease risk in RA needs further study. Disclosure of Interest None declared

Background Nesfatin-1 comprises a peptide that is involved in appetite suppression, energy homeostasis and fluid regulation, and was recently documented to participate in a range of cardiometabolic pathways (1,2). There is currently a need for the identification of novel biomarkers in the elucidation of CVD risk and its stratification in persons with rheumatoid arthritis (RA). The role of nesfatin-1 in cardiovascular disease risk among RA patients is uncertain. Objectives We investigated the potential impact of nesfatin-1 on subclinical cardiovascular disease manifestations in patients with RA by determining the associations of nesfatin-1 concentrations with atherosclerosis and circulating levels of matrix metalloproteinase (MMP)-2 that mediates plaque stability and those of MMP-3 and MMP-9 that cause plaque vulnerability. Methods Nesfatin-1 concentrations were measured in 236 (114 black; 122 white) RA patients. Relationships of nesfatin-1 concentrations with ultrasound determined carotid intima-media thickness (cIMT) and plaque and MMP levels were identified in confounder adjusted multivariate regression models. Results Nesfatin-1 concentrations were inversely associated with c-IMT (β (SE) = -0.022 (0.008), p=0.00) and directly with MMP-2 levels (β (SE) =0.117 (0.031), p=0.00). After adjustment for conventional risk factors and RA characteristics, these associations persisted (c-IMT: β (SE) = -0.017 (0.008), p=0.04; MMP-2: β (SE) =0.116 (0.033), p=0.00). Patient characteristics did not influence the nesfatin-1-to-cIMT relation (interaction p≥0.7). By contrast, the Disease Activity Score in 28 joints (DAS28) and Clinical Disease Activity Index impacted the nesfatin-1-to-cIMT association (interaction p=0.04 and 0.02, respectively). Nevertheless, in stratified analysis, nesfatin-1 concentrations were related to those of MMP-2 in patients with no or mild (β (SE) =0.148 (0.054), p=0.00) and moderate or high disease activity (β (SE) =0.086 (0.041), p=0.04) as determined by DAS28 (cut-off value 3.6) as well as by CDAI (cut-off value =10) (β (SE) =0.130 (0.048), p=0.00 and 0.107 (0.046), p=0.02), respectively). Conclusions Nesfatin-1 concentrations are consistently associated with a reduced atherosclerosis burden and increased MMP-2 levels in patients with RA. References Oh-I S, Shimizu H. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443:709–712. Dore R, Levata L, Lehnert H, Schulz C. Nesfatin-1: functions and physiology of a novel regulatory peptide. Journal of Endocrinology. 2016; e-pub ahead of print: doi: 10.1530/JOE-16–0361. Disclosure of Interest None declared

Background Heart failure contributes to the excess mortality experienced by patients with rheumatoid arthritis (RA) (1). Impaired diastolic function represents a pre-clinical cardiac alteration which is highly predictive of cardiac events and often progresses to heart failure. Diastolic dysfunction is the most common cause of heart failure in patients with a preserved ejection fraction. Whereas RA is associated with an increased prevalence of impaired diastolic function (2,3), the pathophysiological mechanisms that mediate this comorbidity await further elucidation. Objectives This study aimed to identify potential determinants of ventricular (LV) diastolic function in patients with RA. Methods LV diastolic function was determined in 176 patients with RA; 9 patients had established cardiovascular disease. LV diastolic function was determined by echocardiography from the ratio of early-to-late transmitral blood flow velocity (E/A), the ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (e9) (E/e9), and the lateral e9. Relationships of comprehensively evaluated traditional cardiovascular risk factors and RA characteristics with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results Disease duration (partial r=-0.23, p=0.00), rheumatoid factor status (partial r=-0.16, p=0.04) and erythrocyte sedimentation rate (partial r=-0.16, p=0.04) were associated with lower logarithmically transformed (log) E/A. Upon further adjustment for left ventricular mass index or relative wall thickness, these relationships remained significant (p≤0.05). Diastolic blood pressure was related to log E/e9 (partial r=-0.16, p=0.04); this association was no longer significant after additional adjustment for left ventricular mass index (p=0.06) or relative wall thickness (p=0.06). Disease duration (partial r=-0.32, p=0.00), waist-to-hip ratio (partial r=-0.29, p=0.00) and triglycerides (partial r=-0.17, p=0.03) were related to log lateral e9. These relationships remained significant upon further adjustment for left ventricular mass index (for all p=0.00) or relative wall thickness (for all p=0.00). In sensitivity analysis among RA patients without established cardiovascular disease (n=167), the results were not materially altered. Conclusions Modifiable traditional cardiovascular disease risk factor and disease characteristics are consistently associated left ventricular diastolic function in RA. References Nicola PJ, Crowson CS, Maradit-Kremers H et al. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum 2006;54:60–7. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A et al. Echocardiographic findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum 2004;33:231–8. Liang KP, Myasoedova E, Crowson CS et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis 2010;69:1665–70. Disclosure of Interest None declared

This study compared the estimated prevalence and potential determinants of left ventricular (LV) diastolic dysfunction upon applying different classification criteria in rheumatoid arthritis (RA). LV diastolic function was assessed echocardiographically by pulsed Doppler (E/A), tissue Doppler (E/e′, lateral and septal e′), and left atrial volume index in 176 RA patients. Relationships of traditional cardiovascular risk factors and RA characteristics with LV diastolic function and dysfunction according to previous and current criteria were determined in multivariate regression models. Waist-hip ratio was associated with E/A (standardised β (SE) = -0.28±0.09, p=0.0002) and lateral e′ (standardised β (SE) = 0.26±0.09, p=0.01); low diastolic blood pressure was related to E/e′ (standardised β (SE) = -0.16±0.08, p=0.04). Diastolic dysfunction prevalence differed upon applying previous (59%) compared to current (22%) criteria (p<0.0001). One SD increase in waist-hip ratio was associated with diastolic dysfunction when applying current criteria (OR = 2.61 (95% CI = 1.51–4.52), p=0.0006), whereas one SD increase in diastolic blood pressure was inversely related to diastolic dysfunction upon using previous criteria (OR = 0.57 (95% CI = 0.40–0.81), p=0.002). In conclusion, application of current and previous diastolic dysfunction criteria markedly alters the prevalence and risk factors associated with diastolic dysfunction in RA.

Background and aims Apelin-APJ signaling reduces cardiovascular disease (CVD) risk. In rheumatoid arthritis (RA), the atherosclerosis burden and plaque vulnerability to rupture are increased. We explored relationships between apelin concentrations and subclinical CVD in RA. Methods Apelin levels were measured in 235 (114 black, 121 white) RA patients. Associations between apelin concentrations and ultrasound determined carotid artery intima-media thickness (cIMT) and plaque, and levels of matrix metalloproteinase (MMP)-2 and -9 that mediate plaque stability and vulnerability respectively, were identified in confounder adjusted multivariate regression analysis. Results In all patients, apelin concentrations were directly associated with those of MMP-2 (β (SE) = 0.324 (0.112), p = 0.004) and inversely with those of MMP-9 (β (SE) = -0.239 (0.060), p = 0.000). Apelin concentration-subclinical CVD relations were influenced by population origin, RA disease activity, erythrocyte sedimentation rate (ESR) and interleukin (IL)-6 concentrations (interaction p = 0.001 to 0.04). Accordingly, the apelin-MMP-2 concentration relationship was reproduced in white (β (SE) = 0.367 (0.146), p = 0.01) but not black RA patients (β (SE) = 0.197 (0.220), p = 0.4), and only in those without (but not with) large erythrocyte sedimentation rates (β (SE) = 0.428 (0.143), p = 0.003) or interleukin-6 levels (β (SE) = 0.485 (0.288), p = 0.04). By contrast, the apelin-MMP-9 concentration relation was reproduced more consistently. Apelin levels were inversely related to cIMT in patients with RA remission or mild (β (SE) = -0.068 (0.033), p = 0.04) but not moderate or high disease activity (β (SE) = 0.015 (0.112), p = 0.7). Conclusions Apelin concentrations are associated with altered plaque stability mediator levels and atherosclerosis in patients with RA. These relations are partially dependent on population origin and systemic inflammatory status.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [β = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [β (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [β (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [β (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [β (SE) = -0.286 (0.202), p = 0.2], and in those with a small [β (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [β (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.

Our objective was to examine associations of traditional and non-traditional cardiovascular risk factors with relative leukocyte telomere length and confounder adjusted relationships of relative telomere length with endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis (RA).Relative telomere length of leukocyte DNA in whole blood was determined using quantitative RT-PCR in 205 (101 black) African patients with RA.In demographic characteristic adjusted analysis, relative telomere length tended to be larger in black compared to white patients (median (IQR)=0.54 (0.42-0.54) and 0.48 (0.37-0.60) (p=0.07), respectively). In black patients, waist circumference, systolic, diastolic and mean blood pressure were associated with relative telomere length (β (SE)=-0.00270 (0.00114) (p=0.02), -0.00185 (0.00060) (p=0.003), -0.00243 (0.00112) (p=0.03) and -0.00225 (0.00075) (p=0.003), respectively); in white patients, age, anti-cyclic citrullinated antibody positivity, biologic agent use, a cholesterol-HDL cholesterol ratio of4 and the number of major traditional risk factors were related to relative telomere length (β (SE) =-0.00242 (0.00113) (p=0.03), 0.06629 (0.03374) (p=0.05), -0.09321 (0.04310) (p=0.03), 0.08225 (0.03420) (p=0.02) and 0.04046 (0.01719) (p=0.02), respectively). One SD increase in relative telomere length was associated with carotid plaque (OR (95% CI)=1.65 (0.99-2.75) (p=0.05)) and vascular cell adhesion molecule-1 concentrations (β (SE)=-0.05031 (0.02480) (p=0.04)) in black and white patients, respectively.This study disclosed paradoxically direct relationships between relative telomere length and cardiovascular risk factors in white and atherosclerosis in black African RA patients. The role of relative telomere length in cardiovascular risk and its stratification in RA requires longitudinal investigation.

To the Editor: We thank Dr. Makrilakis and colleagues for their interest1 in our study of 236 patients with rheumatoid arthritis (RA) that documented a potential role of the adipokine chemerin in atherogenesis and cardiovascular disease (CVD) risk stratification2. Dr. Makrilakis, et al 1 reported on their own recent findings that interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) in RA resulted in reduced chemerin concentrations, as well as decreased plasminogen activator inhibitor 1 levels (PAI-1)3 and arterial stiffness as estimated by the carotid-femoral pulse wave velocity (PWV)1; reductions in chemerin concentrations were associated with those of PAI-1 levels3 and decreases in carotid-femoral PWV1. In our investigation2, we had shown that not only excess was adiposity, but also disease activity and inflammatory markers were strongly related to chemerin concentrations. Taken together, our findings and those in the Makrilakis, et al study support the notion that chemerin may contribute to the reported link between inflammation and enhanced CVD risk in RA. Further, whereas greater … Address correspondence to Dr. P.H. Dessein, P.O. Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

Objective.We determined whether osteoprotegerin (OPG) concentrations are associated with established cardiovascular disease (CVD) among patients with rheumatoid arthritis (RA).Methods.OPG concentrations were measured by ELISA in 151 patients with RA (54 with CVD) and 62 age-matched control subjects without CVD. Established CVD was composed of documented ischemic heart disease, cerebrovascular disease, and peripheral artery disease.Results.In patients with RA, age, body mass index (BMI), rheumatoid factor (RF) positivity, anticyclic citrullinated peptide (anti-CCP) antibody positivity, and joint erosion status were associated with OPG concentrations [partial R (p) = 0.175 (0.03), −0.277 (0.0009), 0.323 (< 0.0001), 0.217 (0.008), and 0.159 (0.05), respectively]. Median (interquartile range) OPG concentrations increased from 6.38 (3.46–9.31) to 7.07 (5.04–10.65) and 8.64 (6.00–11.52) ng/ml in controls and patients with RA who had CVD and those who did not, respectively (p = 0.0002). Upon adjustment for age, sex, traditional risk factors, and BMI in mixed regression models, OPG concentrations remained lower in controls compared to patients with RA without CVD (p = 0.05) and in the latter compared to those with CVD (p = 0.03); the association of OPG concentrations with CVD among patients with RA also persisted after additional adjustment for RF and anti-CCP antibody positivity, and erosion status (p = 0.04).Conclusion.OPG concentrations are associated with disease severity and CVD prevalence in patients with RA. Whether consideration of OPG concentrations can improve CVD risk stratification in RA merits future longitudinal investigation.

To the Editor: Leptin is an adipokine that regulates appetite and energy expenditure1. Both high and low leptin production can further increase cardiovascular (CV) risk1. Leptin is also produced in inflamed joints and implicated in the pathophysiology of rheumatoid arthritis (RA)2. Whether leptin increases CV risk in RA is currently uncertain. Two studies reported a lack of association between leptin concentrations and carotid artery intima-media thickness (cIMT) in RA3,4. Leptin concentrations were also found to be unrelated to coronary artery classification scores in RA5. However, we recently reported an independent relationship between leptin concentrations and surrogate markers of early atherogenesis in young patients with RA2. Importantly, in the present context, carotid artery plaque is a more reliable indicator of atherosclerosis than cIMT6. In our present study, we examined the independent relationships of leptin concentrations with cIMT and plaque in 217 (112 black and 105 white) patients with RA. Because the production and effects of adipokines on CV risk depend on pathophysiological context1,2,7, we also determined whether the presence of conventional and nonconventional CV risk factors modified leptin concentrations and their associations with atherosclerosis. … Address correspondence to Prof. P.H. Dessein, P.O. Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

Rheumatoid arthritis (RA) enhances the risk of cardiovascular disease to a similar extent as diabetes. Whereas atherogenesis remains poorly elucidated in RA, traditional and nontraditional risk factors associate similarly and additively with CVD in RA. Current recommendations on CVD risk stratification reportedly have important limitations. Further, reported data on CVD and its risk factors derive mostly from data obtained in the developed world. An earlier epidemiological health transition is intrinsic to persons living in rural areas and those undergoing urbanization. It is therefore conceivable that optimal CVD risk stratification differs amongst patients with RA from developing populations compared to those from developed populations. Herein, we briefly describe current CVD and its risk factor profiles in the African black population at large. Against this background, we review reported data on CVD risk and its potential stratification amongst African black compared to white patients with RA. Routinely assessed traditional and nontraditional CVD risk factors were consistently and independently related to atherosclerosis in African white but not black patients with RA. Circulating concentrations of novel CVD risk biomarkers including interleukin-6 and interleukin-5 adipokines were mostly similarly associated with both endothelial activation and atherosclerosis amongst African black and white RA patients.

In the present study, we examined the potential impact of adiponectin on carotid ultrasound determined atherosclerosis in 210 (119 black and 91 white) RA patients in mixed regression models. Total adiponectin concentrations were smaller in patients with compared to those without the metabolic syndrome (MetS) defined waist criterion (median (range) = 6.47 (1.23–34.54) versus 8.38 (0.82–85.30) ng/mL,P=0.02, resp.); both total and high molecular weight (HMW) adiponectin concentrations were larger in patients with compared to those without joint deformities (7.97 (0.82–85.30) and 3.51 (0.01–35.40) versus 5.36 (1.29–19.49) and 2.34 (0.01–19.49) ng/mL,P=0.003and 0.02, resp.). Total and HMW adiponectin concentrations were associated with carotid artery plaque in patients with MetS waist (odds ratio (95% CI) = 0.87 (0.76–0.99) and 0.92 (0.85–0.99) per 1-standard deviation increment,P=0.02for both) and those without joint deformities (odds ratio (95% CI) = 0.94 (0.88–0.99) and 0.94 (0.89–0.99),P=0.03for both). Plaque prevalence was lower in patients without compared to those with joint deformities (23.4% versus 42.6,P=0.004in multivariable analysis). In RA patients with abdominal obesity or no clinically evident joint damage, adiponectin concentrations are reduced but nevertheless associated with decreased carotid atherosclerosis.

Background Carotid artery plaque as identified by ultrasound represents very high risk atherosclerosis. Objectives We determined the performance of cardiovascular disease (CVD) risk equations including the Systematic COronary Risk Evaluation (SCORE) and Framingham score in predicting plaque presence in patients with rheumatoid arthritis (RA). Methods A cohort of 330 cases was assembled amongst 451 Spanish patients that underwent CVD risk screening and carotid ultrasound. Applied exclusion criteria were established CVD, diabetes and moderate or severe chronic kidney disease. The findings were validated in 90 black and 97 white African RA patients. Results Carotid plaque was present in 162 (49.1%) of the Spanish patients. The SCORE and Framingham score were each strongly associated with plaque ( P P =0.003). The optimal cut-off value and corresponding sensitivity and specificity for the Framingham score and SCORE were 11.0, 64% and 81% and 0.5, 86% and 58%, respectively. Based on optimal cut-off values, a high Framingham score but not SCORE was associated with carotid plaque independent of age, sex, erythrocyte sedimentation rate and C-reactive protein concentrations. Whereas a conventional Framingham score value of ≥20 correctly classified only 25% as being at high CVD risk, this proportion increased to 64% in those with a Framingham score of >11; the percentage of patients without plaque incorrectly classified as being at high CVD risk increased from 17% in those with a Framingham score or ≥20 to only 23% in those with a Framingham score of >11.0. External validation produced similar results in white but not black Africans with RA. Conclusions In this study, the Framingham score outperformed the SCORE in predicting plaque presence in RA. Upon CVD risk stratification, a Framingham score of >11.0 comprises a measure that can reclassify about 40% of white RA patients without established CVD, chronic kidney disease or/and diabetes more accurately. Delineation of effective population specific CVD risk assessment strategies is needed in black African RA patients. Disclosure of Interest None declared

Background The role of impaired kidney function in enhanced atherogenesis associated with rheumatoid arthritis (RA) requires further elucidation. Objectives To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with RA. Methods We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. Results The CKD-EPI eGFR was 2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval)=2.19 (1.28-3.75), p=0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p=0.3), whereas the respective relationship was significant or borderline significant (p=0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. Conclusions Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients. Disclosure of Interest None declared

Background Whether TNF-related apoptosis-inducing ligand (TRAIL) impacts cardiovascular risk in rheumatoid arthritis (RA) is currently unknown. Objectives We examined the association of TRAIL concentrations with cardiovascular disease (CVD) in RA and, since osteoprotegerin (OPG) can act as a decoy receptor for TRAIL, whether TRAIL concentrations impact on the independent OPG level-atherosclerotic CVD relation that was recently documented in the present cohort (1). Methods TRAIL concentrations were assessed by ELISA in 151 RA patients of which 75 (49.7%) had CVD comprising ischemic heart disease (n=27), cerebrovascular accident (n=26), peripheral artery disease (n=9) or/and heart failure (HF) (n=27), and 62 controls. Results Mean RA duration was 12 years. In RA patients, C-reactive protein (CRP) levels and cholesterol-HDL cholesterol ratio related to TRAIL concentrations [partial R (p) = -0.222 (0.006) and 0.174 (p=0.04), respectively]. TRAIL concentrations were smaller in RA patients compared to controls (median (interquartile range) =80.2 (60.9-120.4) versus 130.4 (89.4-167.7) pg/ml, p Conclusions TRAIL concentrations are markedly reduced and associated with HF in established RA, this relationship being explained by CRP levels. OPG may directly enhance CVD risk in RA (1). References Lopez-Mejias, Ubilla B, Genre F, Corrales A, Hernandez JL, Ferraz-Amaro I, Tsang L, Llorca J, Blanco R, Gonzalez-Juanatey C, Gonzalez-Gay MA, Dessein PH. Osteoprotegerin concentrations relate independently to established cardiovascular disease in rheumatoid arthritis. J Rheumatol 2015;42:39-45. Disclosure of Interest None declared

Introduction We previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE. Methods A cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics. Results Carotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P 49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively. Conclusions Approximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.