Ahmed Solomon

Circulating Concentrations of the Novel Adipokine Chemerin Are Associated with Cardiovascular Disease Risk in Rheumatoid Arthritis

Objective. Depending on physiological context, the adipokine chemerin can reduce or enhance cardiovascular risk. We investigated whether chemerin concentrations represent cardiovascular disease risk in rheumatoid arthritis (RA). Methods. We assessed ELISA-determined chemerin concentrations and those of 4 early endothelial activation molecules as well as angiopoietin 2, which mediates angiogenesis and thereby contributes to advanced atherosclerosis, the common carotid artery intima-media thickness (cIMT), and carotid artery plaque by ultrasound in 236 patients (114 black and 122 white) with RA. Relationships were identified in potential confounder and mediator-adjusted mixed regression models. Results. Mean (SD) chemerin and median (interquartile range) angiopoietin 2 concentrations were 114 (35) ng/ml and 2560 (2044–3341) pg/ml, respectively; the mean (SD) cIMT was 0.708 (0.110) mm, and 40.3% of patients had plaque. Chemerin concentrations were not related to those of early endothelial activation molecules, but associated with those of angiopoietin 2 [β SE = 0.002 (0.0004), p < 0.0001] and plaque [OR 1.006 (95% CI 1.00–1.013), p = 0.05] in all patients. The presence of major conventional cardiovascular risk factors, generalized and abdominal obesity, and RA severity markers modified the independent chemerin-cardiovascular risk relations (interaction p < 0.05). Consequently, chemerin concentrations were associated with cIMT in those with but not without overweight or generalized obesity and abdominal obesity [β SE = 0.001 (0.0003), p = 0.005 and 0.001 (0.0001), p = 0.001 vs −0.001 (0.0004), p = 0.2 and −0.0002 (0.0004), p = 0.6, respectively], and with plaque in those without but not with generalized obesity [OR 1.008 (95% CI) 1.000–1.016, p = 0.03 vs 1.003 (0.990–1.017), p = 0.6, respectively]. The β (SE) for the chemerin-intima-media thickness relations in patients with overweight or generalized obesity and abdominal obesity were larger than in those without these characteristics (p < 0.0001 and = 0.04, respectively). Conclusion. Chemerin is associated with endothelial activation and atherosclerosis in RA. Adiposity influences the chemerin-atherosclerotic phenotype relations in RA.

Obesity and carotid atherosclerosis in African black and Caucasian women with established rheumatoid arthritis: a cross-sectional study

IntroductionReported findings on the relationship between adiposity and atherosclerotic cardiovascular disease (ACVD) risk in rheumatoid arthritis (RA) are contradictory and originate in developed populations. Approximately 80% of ACVD now occurs in developing countries. We aimed to ascertain the associations of clinical obesity measures with metabolic cardiovascular risk and atherosclerosis in African women with RA from a developing black and developed Caucasian population.MethodsThe associations of body mass index (BMI) as an indicator of overall adiposity and waist circumference and waist-to-height and waist-to-hip ratios as abdominal obesity indices with metabolic risk factors and high resolution B-mode ultrasound-determined carotid artery atherosclerosis were assessed in multivariate regression models in 203 African women with established RA; 108 were black and 95 Caucasian.ResultsBMI and waist-to-height ratio were higher in African black compared to Caucasian women (29.9 (6.6) versus 25.3 (4.9) kg/m2, P = 0.002 and 0.59 (0.09) versus 0.53 (0.08), P = 0.01, respectively). Interactions between population origin and anthropometric measures were not related to metabolic risk factors but were associated with atherosclerosis, independent of confounders and individual terms. In all patients, BMI was related to systolic and diastolic blood pressure but not with serum lipid concentrations whereas abdominal obesity indices were associated with serum lipid concentrations but not with blood pressure values; obesity measures that were associated with plasma glucose concentrations comprised BMI, waist circumference and waist-to-height ratio (P < 0.05 in multiple confounder adjusted analysis). In African Caucasian women, BMI was associated with common carotid artery intima-media thickness (standardized β (95% confidence interval (CI)) = 0.21 (0.03 to 0.38)) and waist-to-hip ratio with plaque (odds ratio (OR) (95% CI) = 1.83 (1.03 to 3.25) for one standard deviation (SD) increase). These relationships were independent of multiple non-metabolic risk factors and explained by metabolic risk factors. In African black women with RA, none of the obesity measures was related to atherosclerosis.ConclusionsObesity in women with RA from developing groups of black African descent does not as yet translate into atheroma. In Caucasian women with RA that belong to developed populations, BMI and waist-to-hip ratio should be considered in ACVD risk assessment.

Independent relationship between circulating resistin concentrations and endothelial activation in rheumatoid arthritis

Resistin is an adipokine that may contribute to the link between inflammation and cardiovascular disease.1 In rheumatoid arthritis (RA), resistin forms part of the inflammatory cascade and indeed colocalises with inflammatory cells in synovial tissue and upregulates cytokine production.2–6 Herein, we examined the associations of metabolic risk factors, systemic inflammation and disease characteristics with resistin concentrations as well as the independent relationship of resistin concentrations with endothelial activation in 217 African patients (112 black and 105 white patients) with established RA7 that form part of an ongoing study on cardiovascular risk.8 All patients were employing disease modifying agents for rheumatic disease that included tumour necrosis factor-α inhibition and rituximab in 3.7% and 0.5% of them. The study was approved by the Witwatersrand University Ethics Committee (Human Subjects) and each participant gave informed written consent. Concentrations of interleukin-6, a major circulating cytokine in …

Rheumatoid arthritis impacts on the independent relationships between circulating adiponectin concentrations and cardiovascular metabolic risk.

Adiponectin and leptin are likely involved in the pathophysiology of rheumatoid arthritis (RA) and therefore potential new therapeutic targets. Adiponectin inhibition could be expected to enhance cardiovascular metabolic risk. However, it is unknown whether RA changes the influence of adipokines on cardiovascular metabolic risk. We determined whether RA impacts on the independent relationships of circulating leptin and adiponectin concentrations with cardiovascular risk factors and carotid intima-media thickness (cIMT) in 277 black African subjects from a developing population; 119 had RA. RA impacted on the relationships of adiponectin concentrations with lipid concentrations and blood pressure, independent of confounders including adiposity (interaction P < 0.05). This translated into an association of adiponectin concentrations with more favorable lipid variables including HDL cholesterol (P = 0.0005), non-HDL cholesterol (P = 0.007), and triglyceride (P = 0.005) concentrations, total cholesterol-HDL cholesterol (P = 0.0002) and triglycerides-HDL cholesterol (P = 0.0003) ratios, and higher systolic (P = 0.0006), diastolic (P = 0.0004), and mean blood pressure (P = 0.0007) in RA but not non-RA subjects. Leptin was not associated with metabolic risk after adjustment for adiposity. The cIMT did not differ by RA status, and adipokine concentrations were unrelated to atherosclerosis. This study suggests that leptin and adiponectin inhibition may not alter overall cardiovascular risk and disease in RA.

The Carotid Artery Atherosclerosis Burden and Its Relation to Cardiovascular Risk Factors in Black and White Africans with Established Rheumatoid Arthritis: A Cross-sectional Study

Objective. Black Africans currently experience a distinctly low frequency of atherosclerotic cardiovascular disease. Whether this protection persists in those with rheumatoid arthritis (RA) is unknown. We compared the carotid atherosclerosis burden and its relationships with cardiovascular (CV) risk factors between Africans with RA from a developing black and developed CV population. Methods. We performed high resolution B-mode ultrasonography and assessed CV risk factors in 243 patients with established RA, of whom 121 were black and 122 white. Data were analyzed in age, sex, and healthcare center-adjusted regression models. Results. The mean ± SD common carotid intima-media thickness (cIMT) was 0.694 ± 0.097 mm in black and 0.712 ± 0.136 mm in white patients (adjusted p = 0.8). Plaque prevalence was also similar in black compared to white cases (35.5% and 44.3%, respectively; adjusted OR 0.83, 95% CI 0.32–2.20, p = 0.7). Interactions between population grouping and several CV risk factors were independently associated with cIMT and plaque. In stratified analysis, that is, in each population group separately, risk factors associated with cIMT or/and plaque comprised the systolic blood pressure (p = 0.02), serum cholesterol/high-density lipoprotein cholesterol ratio (p = 0.004), C-reactive protein concentrations (p = 0.01), and the presence of extraarticular manifestations (p = 0.01) in whites but, contrastingly, the Arthritis Impact Measurement Scales tension score (p = 0.04) and use of nonsteroidal antiinflammatory agent (p = 0.03) in black patients. The Framingham score was significantly associated with atherosclerosis only in whites (p < 0.0001). Conclusion. The carotid atherosclerosis burden is similar in black compared to white Africans with RA, but relationships between modifiable CV risk factors and atherosclerosis vary substantially among Africans with RA.

Marked independent relationship between circulating interleukin-6 concentrations and endothelial activation in rheumatoid arthritis

We examined the potential impact of conventional compared with nonconventional cardiovascular risk factors including interleukin-6 levels on endothelial activation in RA. Circulating soluble E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 concentrations were measured in 217 African patients (112 black and 105 white) with RA. In comprehensive confounder adjusted mixed regression models, 5 conventional and 4 nonconventional cardiovascular risk factors were associated (P = 0.05 to <0.0001) with endothelial activation. Interleukin-6 was the only risk factor related to each endothelial activation molecule and independently contributed by 18% and significantly more than other risk factors to the variation in overall endothelial activation as estimated by an SD (z) score of endothelial activation molecule concentrations. The independent interleukin-6-overall endothelial activation relationships were reproduced in various subgroups. Interleukin-6 concentrations relate consistently, markedly, and to a larger extent than other cardiovascular risk factors to endothelial activation in RA. Assessment of interleukin-6 concentrations may enhance cardiovascular risk stratification in RA.

Which Are the Determinants of Dyslipidemia in Rheumatoid Arthritis and Does Socioeconomic Status Matter in This Context

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death worldwide1. Although many genetic and environmental factors contribute to CVD, lipoproteins remain the pivotal agents in atherosclerosis1. Patients with rheumatoid arthritis (RA) experience a 2- to 3-fold increased risk for atherosclerotic CVD, a phenomenon that is likely attributable to unfavorable effects of cytokine-mediated high-grade inflammation on traditional risk factors such as insulin sensitivity and its direct adverse effects on the vasculature2. The ameliorations in traditional CV risk factor profiles3–5 and interleukin 6-related endothelial dysfunction6 upon disease activity suppression in RA support this paradigm. Considering the fundamental role of dyslipidemia in atherosclerosis in non-RA subjects prompts the question whether RA characteristics alter lipoprotein profiles. Such potential interactions have been the topic of numerous studies performed over the past 3 to 4 decades. As applies to other inflammatory conditions7, high-grade inflammation or disease activity in the context of RA results in a reduction in total and low-density lipoprotein (LDL) cholesterol and a more consistent and marked decrease in high-density lipoprotein (HDL) cholesterol, thereby increasing the atherogenic index, i.e., the total cholesterol/HDL cholesterol ratio3,4. Treatment with traditional disease modifying agents for rheumatic disease (DMARD) and glucocorticoids reverses these changes3,4, an effect that may be less consistent with tumor necrosis factor-α blockade8. The increase in total and LDL cholesterol with traditional DMARD therapy can be prevented by insulin sensitivity-enhancing dietary intervention3. Currently recommended treatment strategies generally comprise aggressive use of DMARD as soon as the disease is diagnosed. As a consequence, the typical RA patients may now no longer experience high-grade inflammation-induced dyslipidemia except during the time prior to seeking medical care. In this new era, then, do lipoprotein profiles … Address correspondence to Dr. P. Dessein, PO Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

Retinol Binding Protein 4 Concentrations Relate to Enhanced Atherosclerosis in Obese Patients with Rheumatoid Arthritis

Background Retinol binding protein 4 (RBP) enhances metabolic risk and atherogenesis. Whether RBP4 contributes to cardiovascular risk in rheumatoid arthritis (RA) is unknown. Methods We assessed RBP4 concentrations and those of endothelial activation molecules including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 by ELISA, and the common carotid artery intima-media thickness (cIMT) and carotid artery plaque by ultrasound in 217 (112 black and 105 white) patients with RA. Relationships were identified in potential confounder and mediator adjusted mixed regression models. Results RBP4 concentrations were associated with systolic and mean blood pressure, and those of glucose and E-selectin (partial R = −0.207 (p = 0.003), −0.195 (p = 0.006), −0.155 (p = 0.03) and −0.191 (p = 0.007), respectively in all patients); these RBP4-cardiovascular risk relations were mostly reproduced in patients with but not without adverse traditional or non-traditional cardiovascular risk profiles. RBP4 concentrations were not associated with atherosclerosis in all patients, but related independently to cIMT (partial R = 0.297, p = 0.03) and plaque (OR (95%CI) = 2.95 (1.31–6.68), p = 0.008) in those with generalized obesity, as well as with plaque in those with abdominal obesity (OR (95%CI) = 1.95 (1.12–3.42), p = 0.01). Conclusion In the present study, RBP4 concentrations were inversely associated with metabolic risk and endothelial activation in RA. This requires further investigation. RBP4 concentrations were related to enhanced atherosclerosis in patients with generalized or/and abdominal obesity.

Independent associations of total and high molecular weight adiponectin with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with rheumatoid arthritis: a cross-sectional study

IntroductionWhether adiponectin levels associate with atherogenesis in RA is uncertain. We examined the independent relationships of total and high molecular weight (HMW) adiponectin concentrations with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with RA.MethodsWe determined total and HMW adiponectin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), in 210 (119 black and 91 white) RA patients. Associations were determined in potential confounder and mediator adjusted mixed regression models.ResultsTotal and HMW adiponectin concentrations related similarly to metabolic risk factors and endothelial activation. In all patients, total and HMW adiponectin concentrations associated paradoxically with high systolic, diastolic and mean blood pressure (partial R = 0.155 to 0.241, P ≤0.03). Ethnic origin did not impact on these relationships (interaction P ≥0.09). Total and HMW adiponectin concentrations associated with those of glucose in white and black patients respectively (partial R = -0.304, P = 0.006 and -0.246, P = 0.01). In black but not white participants, total and HMW adiponectin concentrations also related favorably to lipid profiles (partial R = 0.292 to 0.360, P ≤0.003 for HDL cholesterol concentrations, -0.269 to -0.299, P ≤0.006 for triglyceride concentrations and -0.302 to -0.390, P ≤0.002 for total-HDL cholesterol ratio) and the number of metabolic risk factors (partial R = -0.210 to -0.238, P ≤0.03). In white but not black patients, total and HMW adiponectin concentrations associated paradoxically with overall endothelial activation as estimated by a standard z-score of endothelial activation molecule concentrations (partial R = 0.262, P = 0.01 and 0.252, P = 0.02); in the respective models, the extent of effect of total and HMW adiponectin concentrations on endothelial activation was larger in white compared to black participants (standardized β (SE) = 0.260 (0.107) versus -0.106 (0.107), P = 0.01 and 0.260 (0.120) versus -0.100 (0.111), P = 0.02). The HMW-total adiponectin ratio related inconsistently to metabolic risk factors and not to endothelial activation.ConclusionIn this study, total and HMW adiponectin concentrations associated with increased blood pressure parameters, and in white patients additionally with endothelial activation. The potential mechanism(s) underlying these paradoxical relationships between adiponectin concentrations and cardiovascular risk in RA merit further investigation.

Risk Factor Profiles for Atherosclerotic Cardiovascular Disease in Black and Other Africans with Established Rheumatoid Arthritis

Objective. Black Africans reportedly experience a distinctly low risk for atherosclerotic cardiovascular disease (CVD). We investigated whether this protection was present among Africans with established rheumatoid arthritis (RA). Methods. We determined disparities in CVD risk factor profiles (major conventional: hypertension, dyslipidemia, smoking, and diabetes; other conventional: underweight, obesity, metabolic syndrome, chronic kidney disease, alcohol consumption, tension, depression, and body height; nonconventional: rheumatoid factor status and markers of inflammation) and arterial stiffness (brachial pulse pressure) between 291 black and 335 other (229 white, 64 Asian, and 42 mixed ancestry) consecutive Africans with RA in multivariable regression models. Results. After adjusting for demographic characteristics and healthcare sector attendance, black Africans had more prevalent hypertension (OR 1.76, p = 0.01) and diabetes (OR 1.90, p = 0.07), smoked less frequently (OR 0.12, p < 0.0001), and had concurrent lower total and high-density lipoprotein cholesterol concentrations that resulted in unaltered atherogenic indices (p = 0.2) than the other participants in the study. These findings translated into global scores for major conventional risk factor-mediated future CVD event rates that were not reduced in black patients. Proportions of individual metabolic syndrome components differed between black and other patients but their total numbers of metabolic risk factors (p = 0.4) and metabolic syndrome frequencies (OR 1.44, p = 0.1) were similar. Black ethnicity did not independently associate with rheumatoid factor status, markers of inflammation, and brachial pulse pressures. Conclusion. The overall conventional and nonconventional atherosclerotic CVD risk burdens and arterial stiffness were not reduced in black patients with RA. CVD risk should be assessed and managed independent of ethnic origin and epidemiological transition stage in RA.