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Open Access Research article

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

Patrick H Dessein1*, Angela J Woodiwiss1, Gavin R Norton1, Linda Tsang2 and Ahmed Solomon3

Author Affiliations

1 Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

2 Milpark Hospital, Johannesburg, South Africa

3 Department of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

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Arthritis Research & Therapy 2013, 15:R128  doi:10.1186/ar4308

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/15/5/R128


Received:21 April 2013
Accepted:28 August 2013
Published:20 September 2013

© 2013 Dessein et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Whether 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.

Methods

We 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.

Results

Total 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.

Conclusion

In 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.

Introduction

Human adiponectin was identified in 1999 as the most abundant gene product in white adipose tissue [1]. Circulating concentrations of this adipokine are reduced in obesity [1,2]. Adiponectin decreases free fatty acid production and enhances insulin sensitivity [3] and its circulating concentrations associate with reduced plasma glucose and serum triglyceride levels and increased high density lipoprotein cholesterol concentrations, decreased blood pressure and a lower risk of type 2 diabetes [2,4-8]. These effects of adiponectin would be expected to translate into reduced cardiovascular disease risk. Besides, adiponectin additionally improves vascular health directly by mechanisms that include reduced endothelial activation through inhibition of nuclear factor κB activation dependent endothelial adhesion molecule production [9] as well as the synthesis of endothelial monocyte chemoattractant protein-1 [10], a crucial molecule in early atherogenesis [11]. However, although an initial study revealed a reduced risk of myocardial infarction in relation to high adiponectin concentrations [12], a subsequent large prospective investigation and meta-analysis by Sattar and colleagues as reported in 2006, found no association with coronary heart disease risk [13]. Moreover, subsequent studies reported paradoxical positive relationships between adiponectin concentrations and cardiovascular disease risk in elderly subjects [14,15], patients with heart failure [14] or prevalent cardiovascular disease [16] and black Americans [17]. While among the different isoforms of adiponectin, it is particularly high molecular weight (HMW) adiponectin that confers the potential antidiabetic [18] and vascular protective activities [19] of adiponectin in the general population, a potential association with incident coronary heart disease was also not confirmed [20].

Adiponectin further modulates inflammatory and immune responses and was shown to be involved in the pathogenesis of rheumatoid arthritis (RA) [21-23]. Indeed, adiponectin induces gene expression and protein synthesis of many pro-inflammatory and pro-destructive molecules in several effector cells that participate in the pathophysiology of RA [24-27].

Our knowledge on the association of adiponectin levels with cardiovascular disease in RA is currently more limited [28-34]. Notably in this context, the presence of autoimmunity can alter the relationship between adipokines and cardiovascular disease risk [35-37]. Thus, Hahn and colleagues found that leptin administration enhanced pro-inflammatory high density lipoprotein scores as well as atherosclerosis in lupus prone but not non-immune mice [35]. Leptin concentrations also associated with cardiovascular risk in patients with lupus [36]. In addition, we recently documented that RA impacts on the relationships of total adiponectin concentrations with both lipid profiles and blood pressure among black Africans with RA [37]. Nevertheless, it remains unknown whether this finding represents either an ethnicity or disease specific effect among patients with RA. Importantly in the present context, genetic determinants of adiponectin levels [38] and adiponectin-cardiovascular disease relations in the general population differ by ethnic grouping [17,39].

In the present investigation, we examined the impact of population grouping on independent total and HMW adiponectin concentration-metabolic cardiovascular risk factor relationships and whether adiponectin levels associate with surrogate markers of enhanced early atherogenesis including soluble E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) [40-47], in both black and white patients.

Methods

Patients

The present investigation was conducted according to the principles outlined in the Helsinki declaration. The Committee for Research on Human Subjects of the University of Witwatersrand approved the protocol (approval number: M06-07-33 in RA subjects). Participants gave informed, written consent. The study design was previously described [48-51]. Briefly, 210 African patients (119 black and 91 white) that met the 1987 American College of Rheumatology and 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA [52,53] were enrolled at the Charlotte Maxeke Johannesburg Academic Hospital and Milpark Hospital [48-51]. All invited participants agreed to participate. Data were missing in fewer than 5% of any of the recorded characteristics.

Data on previously diagnosed established cardiovascular disease were derived by hospital record review.

Assessments

We recorded demographic features and smoking status. Height, weight and waist and hip circumference were measured using standard approaches. The body mass index (BMI) was calculated and abdominal obesity and fat distribution were estimated by waist circumference and waist-hip ratio, respectively [48]. We recorded disease duration and rheumatoid factor status. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28) [54]. C-reactive protein concentrations were determined using immunoturbidimetric methods. Standard laboratory blood tests of renal and liver function, hematological parameters, lipids and glucose were performed. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation [55]. Cardiovascular drugs included antihypertensive agents and glucose and lipid lowering drugs.

Among metabolic risk factors, hypertension was defined as an average systolic blood pressure ≥140 or/and diastolic blood pressure ≥90 mmHg or/and current use of antihypertensive medications. Dyslipidemia was diagnosed when the atherogenic index, that is, the cholesterol:high density lipoprotein (HDL) cholesterol ratio was >4 and proatherogenic non-HDL cholesterol concentrations were calculated by subtracting HDL cholesterol from total cholesterol concentrations [48-51,56-59]. Diabetes was identified as the use of glucose lowering agents or a fasting plasma glucose ≥7 mmol/l. We calculated the number of metabolic risk factors using the National Cholesterol Education Program defined metabolic syndrome (MetS) definitions for MetS blood pressure, HDL cholesterol, triglycerides and glucose [60].

We measured endothelial activation molecule concentrations including those of soluble E-selectin, VCAM-1, ICAM-1 and MCP-1 using a solid-phase sandwich enzyme linked immunosorbant assay (Quantikine®HS, R & D Systems, Inc., Minneapolis, MN, USA). Their lower detection limits were 0.009 ng/l, 0.6 ng/l, 0.096 ng/l and 5.0 pg/ml, respectively; their inter- and intra-assay coefficients of variation were 7.9 and 5.8, 7.0 and 3.1, 5.5 and 4.6 and 5.7 and 5.8, respectively.

Total and HMW adiponectin concentrations were measured using solid-phase sandwich enzyme-linked immunosorbant assays (ELISA) (Quantikine®HS, R&D Systems, Inc.). Their lower detection limits were 0.246 and 0.195 ng/ml respectively. The inter- and intra-assay coefficients of variation were 6.5 and 3.5% for total and 8.5 and 3.0% for high molecular weight adiponectin, respectively.

Data management and analysis

Dichotomous variables are expressed as proportions or percentages and continuous variables as mean (SD), or median (interquartile range) when non-normally distributed. Non-normally distributed characteristics were also logarithmically transformed prior to their inclusion in multivariable statistical analysis. An endothelial activation score was employed to provide a summary measure of endothelial activation and was calculated from SD (z) scores as follows: [z (selectin) + z (VCAM-1) + z (ICAM-1) + z (MCP-1)] [61].

Disparities in baseline characteristics, cardiovascular drug use, metabolic risk factors, endothelial activation molecule concentrations and adiponectin variables between African black and white patients with RA were assessed using the Student’s t-test, Mann–Whitney U test and univariate logistic regression analysis as appropriate.

The associations of age, sex and population grouping with adiponectin variables were assessed by entering the respective characteristics together in single mixed regression models. Associations of other baseline characteristics with adiponectin variables were evaluated in models with adjustment for all three demographic characteristics.

The independent relations of adiponectin variables with metabolic risk factors and early endothelial activation were assessed in demographic characteristic, glomerular filtration rate and waist circumference (potential confounders or/and determinants identified in previous analysis) and cardiovascular drug use adjusted mixed linear regression models. The impact of population grouping on the relations of adiponectin variables with metabolic risk factors and endothelial activation was assessed by adding an interaction term (population grouping (white = 1; black = 2) x adiponectin variable) to the models, and in stratified analysis, that is, in black and white participants separately.

Statistical computations were made using the GB Stat™ program (Dynamic Microsystems, Inc, Silver Spring, MD, USA) and SAS software, version 9.1 (The SAS Institute, Cary, NC, USA).

Results

Baseline characteristics, cardiovascular drug use, metabolic risk factors, endothelial activation and adiponectin variables in African black and white patients with RA

Table 1 shows that as compared to their white counterparts, black patients were more often women, smoked less frequently, had a higher BMI but lower waist-hip ratio, higher DAS28, C-reactive protein concentrations and glomerular filtration rate and used more conventional disease-modifying antirheumatic drugs (DMARDs) but no biologic agents; they experienced more prevalent hypertension, higher blood pressure values and differences in some of the recorded individual lipid variables but not in their cholesterol-HDL cholesterol and triglycerides-HDL cholesterol ratios, and used lipid lowering agents less often and oral glucose lowering drugs more frequently. The number of metabolic risk factors was larger in black compared with white patients. E-selectin concentrations were higher and those of ICAM-1 and MCP-1 lower in black compared to white participants; black patients had lower HMW adiponectin concentrations and, consequently, their HMW-total adiponectin ratio was numerically lower.

Table 1. Baseline characteristics, cardiovascular drug use, metabolic risk factors, surrogate markers of enhanced early atherogenesis and adiponectin variables in African black and white patients with rheumatoid arthritis

Total and high molecular weight adiponectin concentrations were highly correlated in all, black and white patients (R = 0.617 (P <0.0001), R = 0.801 (P <0.0001) and R = 0.478 (P <0.0001), respectively).

Only seven patients had previously diagnosed established cardiovascular disease that included one myocardial infarction (white), five cerebrovascular accidents (four white and one black) and one peripheral vascular disease (white).

Associations between baseline recorded characteristics and adiponectin variables in patients with RA

As given in Table 2, in confounder adjusted analysis, age associated with HMW adiponectin concentrations, female gender with those of both total and HMW adiponectin concentrations and black ethnicity with low HMW-total adiponectin ratios. Among the anthropometric measures, BMI and, to a larger extent, waist circumference associated with low total and HMW adiponectin concentrations. An inverse relationship between glomerular filtration rate and total adiponectin concentrations approached significance. In contrast to the findings in a recently reported investigation [34] that was performed among early untreated patients with RA, disease activity was unrelated to adiponectin concentrations in those with treated established disease. Smoking status was not associated with adiponectin concentrations and also not related to endothelial activation (data not shown).

Table 2. Associations between baseline characteristics and total* and high-molecular weight adiponectin concentrations* and high molecular weight-total adiponectin ratios in patients with rheumatoid arthritis

In separate models in which age, sex, glomerular filtration rate, cardiovascular drug use and waist circumference were adjusted for, black ethnicity was not related to both total and HMW adiponectin concentrations (P = 0.9 for both) but associated with low HMW-total adiponectin concentration ratios (P = 0.05). Further adjustment for hypertension, diabetes and established cardiovascular disease did not alter these results (P = 0.9, 0.9 and 0.06 for black ethnicity-total and HMW adiponectin concentrations and -HMW-total adiponectin ratio relations respectively). These results were also similar in separate models in which age, sex, waist circumference, glomerular filtration rate and the number of metabolic risk factors (see Table 1) were entered as potential confounders or mediators (P = 0.7, 0.5 and 0.06 for black ethnicity-total and high molecular adiponectin concentrations and -HMW-total adiponectin ratio relations, respectively).

Independent relations of adiponectin variables with metabolic risk factors and surrogate markers of enhanced early atherogenesis in patients with RA

Tables 3 and 4 show the demographic characteristic, glomerular filtration rate, cardiovascular drug use and waist circumference adjusted relations of adiponectin variables with metabolic risk factors and endothelial activation molecules in all patients. As given in Table 3, in all patients, total adiponectin concentrations were independently related to high systolic, diastolic and mean blood pressure and low total, low density lipoprotein (LDL) and non-HDL cholesterol and triglyceride concentrations, and low total-HDL cholesterol and triglycerides-HDL cholesterol ratios. Population grouping impacted on the total adiponectin-HDL cholesterol concentration, -total-HDL cholesterol ratio, -non-HDL cholesterol and -triglyceride concentration and triglyceride-HDL cholesterol ratio, -number of metabolic risk factors and -VCAM-1 concentration and -endothelial activation score relations. In stratified analysis, total adiponectin concentrations associated significantly with high blood pressure values as well favorable lipid parameters and low number of metabolic risk factors in black but not white patients; total adiponectin concentrations related to low glucose concentrations and large VCAM-1 and MCP-1 concentrations as well as large endothelial activation score in white but not black participants.

Table 3. Independent relations of total adiponectin concentrations* with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in African black and white patients with rheumatoid arthritis

Table 4. Independent relations of high molecular weight adiponectin concentrations* with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in African black and white patients with rheumatoid arthritis

As shown in Table 4, in all patients, HMW adiponectin concentrations were independently related to high systolic, diastolic and mean blood pressure and large HDL cholesterol concentrations, low total HDL cholesterol ratios and triglyceride concentrations, triglycerides-HDL cholesterol ratios, glucose concentrations and number of metabolic risk factors. Population grouping impacted on the HMW adiponectin-total cholesterol and -HDL cholesterol ratio, non-HDL cholesterol and triglyceride concentration, total-HDL cholesterol and triglycerides-HDL cholesterol ratio, glucose concentration and number of metabolic risk factors relations. In stratified analysis, HMW adiponectin concentrations associated significantly with high blood pressure values as well as favorable lipid parameters, low glucose concentrations and low number of metabolic risk factors in black but not white patients; HMW adiponectin concentrations related to large VCAM-1 and ICAM-1-1 concentrations as well as large endothelial activation score in white but not black participants.

As given in Additional file 1: Table S1, in all patients, HMW-total adiponectin ratio associated with high total cholesterol concentrations. Population grouping impacted on the HMW-total adiponectin ratio-total, LDL, non-HDL cholesterol and glucose concentration relations. In stratified analysis, HMW-total adiponectin ratio associated with low glucose concentrations in black but not white patients, and with large LDL-cholesterol concentrations in white but not back participants.

Additional file 1: Table S1. Independent relations of high molecular weight-total adiponectin ratio with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in African black and white patients with rheumatoid arthritis.

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Because population grouping did not impact on total and HMW adiponectin-blood pressure relations but the respective associations were not significant in white patients in stratified analysis (Tables 3 and 4), we further compared the extent of effect of total and HMW adiponectin on blood pressure parameters between black and white patients, in the respective models. As shown in Table 5, the extent of effect of total and HMW adiponectin on blood pressure parameters was similar in black compared with white patients.

Table 5. Comparison of extent of effect of total and high molecular weight adiponectin concentrations on blood pressure and surrogate markers of enhanced early atherogenesis between black and white patients with rheumatoid arthritis, in mixed regression models

By contrast and also as given in Table 5, except for the HMW-VCAM-1 relation (P = 0.09), the extent of effect of total and HMW adiponectin on surrogate markers of enhanced early atherogenesis in the respective models (Tables 2, 3 and 4) was larger in white compared to black patients.

Table 6 shows that the relations of total and HMW adiponectin concentrations with surrogate markers of enhanced early atherogenesis in white participants (Tables 3 and 4), is independent of not only potential confounders and/or determinants as identified in the present analysis (Table 2) but also of metabolic risk factors including the MetS defined HDL, triglycerides, blood pressure and glucose criteria [60] as well as smoking. Additional adjustment for C-reactive protein concentrations did also not materially alter these results (data not shown).

Table 6. Relations of total and high- molecular weight adiponectin concentrations with surrogate markers of enhanced early atherogenesis after further adjustment for the number of metabolic risk factors* and smoking in white patients with rheumatoid arthritis

Finally, our findings on total and HMW adiponectin-blood pressure relations (Tables 3 and 4) were materially unaltered upon further adjustment for potentially confounding RA characteristics comprising disease duration (cumulative inflammation), DAS28, C-reactive protein concentrations, rheumatoid factor status (disease severity) and the employed number of conventional DMARDs and biologic agent and prednisone use [62-65] (data not shown).

Discussion

In the present study, total and HMW adiponectin concentrations related to a similar extent to metabolic risk factors in RA, as was previously documented in the non-RA population [20]. We found two similarities and three disparities in adiponectin-cardiovascular risk relations in black compared to white patients with RA. The former comprised positive adiponectin-blood pressure variable and inverse adiponectin-glucose concentration associations, and the latter positive adiponectin-favorable lipid profile and overall number of metabolic risk factors relationships in black but not white patients as well as positive adiponectin-endothelial activation associations in white but not black participants.

Numerous experimental studies have documented the protective effects of adiponectin on obesity induced pathological conditions, including insulin resistance and enhanced atherogenesis [66]. Although an insulin sensitivity enhancing effect would be expected to reduce high blood pressure, direct effects of adiponectin on components of vascular tissue are considered more important in this context [66]. These comprise the activating effects of adiponectin on endothelial nitric oxide (NO) synthase and cyclooxygenase-2 leading to the production of NO and prostaglandin-I2 production, respectively, and the ability of adiponectin to promote macrophage polarization toward the anti-inflammatory phenotype, which results in reduced interleukin-6, tumor necrosis factor (TNF)-α and MCP-1 and increased arginase-1, interleukin-1 and macrophage N-acetyl-galactosamine specific lectin-1 by M1 and M2 macrophages, respectively [66]. Each of these processes improves endothelial function.

Patients with RA experience substantially increased risk for cardiovascular disease [67-72]. Over the recent past, paradoxical positive relations between adiponectin concentrations and cardiovascular risk were reported in non-RA populations at high risk of cardiovascular disease [14-17]. In this context, we recently also found for the first time a paradoxical positive association between total adiponectin concentrations and blood pressure parameters in African black RA but not non-RA subjects [37]. In the present investigation we assessed total and HMW adiponectin concentrations and comprehensively adjusted for potential mediating and confounding characteristics in our analysis. Our current finding of positive relations between both total and HMW adiponectin concentrations and each of three blood pressure variables that were further present to a statistically similar extent in black and white patients argues against our previous result [37] being spurious and supports the notion that these relationships may be RA specific. Additionally, we found paradoxical positive associations between total and HMW adiponectin concentrations and endothelial activation in white patients only and indeed, in the respective models, the extent of effect of adiponectin concentrations on surrogate markers of enhanced early atherogenesis was significantly larger in white compared to black study participants. Thus, this relationship was ethnic specific among patients with RA.

Importantly in this regard, not only do genetic loci associated with adiponectin levels differ in black compared with whites but also, in the Health ABC study, adiponectin concentrations associated independently with prevalent and incident coronary heart disease in black but not white non-RA Americans [17]. Taken together, the impact of ethnicity on the adiponectin-cardiovascular risk relation may be reversed in subjects with RA. Further, whereas white ethnicity associates with higher adiponectin concentrations among black and white non-RA Americans and this association is driven by visceral adiposity and metabolic risk factors [17,39], ethnicity was not related to adiponectin levels both before and after adjustment for waist circumference and metabolic risk factors in the present RA cohort. Congruent with our previous findings [37], our current results suggest that findings on adiponectin metabolism and its associations with cardiovascular risk as reported in the non-RA population should not be merely translated to the RA population.

Potential mechanisms underlying the reported paradoxical adiponectin-cardiovascular risk relations were recently comprehensively and elegantly proposed by Sattar [73]. Among six raised possibilities, an attractive option was that of reverse causality, whereby increased adiponectin concentrations represent a chronic or acute on chronic compensatory mechanism to counteract metabolic and vascular stress in subjects with acute coronary syndrome or heart failure [73]. Recommendations for investigations aimed at elucidating paradoxical adiponectin-cardiovascular risk relations were also given.

Total and HMW adiponectin concentrations were strongly interrelated in the present RA investigation but the HMW-total adiponectin ratio was inconsistently associated with metabolic risk factors. The HMW-total adiponectin ratio was also not related to endothelial activation.

The previously alluded to paradoxical relation between total adiponectin and coronary heart disease among non-RA black Americans was postulated to result from a decreased production of HMW relative to other adiponectin isoforms in this population group [17,39]. We indeed found that HMW adiponectin concentrations were lower in black compared to white patients and black ethnicity associated with a lower HMW-total adiponectin ratio in age and sex adjusted analysis. However, HMW adiponectin concentrations were also shown to be unrelated to incident coronary heart disease [20].

RA adipocytes and their surrounding macrophages produce adipokines that regulate systemic inflammation and the presence of a complex adipokine-mediated interaction among white adipose tissue, cardiovascular disease and chronic inflammatory disease like RA was previously proposed [74]. In this regard, in a series of white patients with severe RA undergoing anti-TNF-α infliximab therapy, high grade inflammation showed an independent negative correlation with circulating adiponectin concentrations whereas low adiponectin levels clustered with metabolic syndrome features including dyslipidemia and high plasma glucose concentrations that reportedly contribute to atherogenesis in RA [75]. However, adiponectin concentrations were not related to blood pressure in this study. In another series of non-diabetic and mostly non-obese patients with ankylosing spondylitis undergoing anti-TNF-α therapy, adiponectin concentrations related to insulin sensitivity and marginally to low BMI [76]. Taken together, these findings support a role of hypoadiponectinemia in cardiometabolic risk in chronic inflammatory rheumatic diseases. The present study shows that in RA, ethnicity and presumably genetic factors may modulate metabolic risk through mechanisms that include an effect mediated by adipokines.

Our study has strengths and limitations. We assessed both total and HMW adiponectin concentrations and the production of four endothelial activation molecules, which reportedly mediates the initial stages of atherosclerosis [40-43] and is inhibited by adiponectin [9-11]. Endothelial activation is markedly enhanced and associated with disease characteristics that further are strongly implicated in increased cardiovascular risk, and hence constitutes a promising tool in the elucidation of atherogenic mechanisms in RA [44-47]. Importantly, endothelial activation was not associated with disease activity variables in the present cohort of patients with established and treated RA [61]. The cross sectional design of the present investigation precludes drawing inferences on the direction of causality and our results need to be reproduced in a longitudinal study, preferably with the inclusion of cardiovascular event rates as an outcome variable. Alcohol intake and physical activity can associate with increased adiponectin concentrations [6]. Only 15.3% of patients in the present study consumed alcohol with a median of three units per week, alcohol consumption was not related to total and HMW adiponectin concentrations (P = 0.4 and 0.5) and its inclusion as an additional confounder in the models in Tables 3, 4, 5 and 6 did not alter our findings (data not shown). The same lack of relationships was also present with regard to physical activity [36] (data not shown). Finally, the relative role of genetic [38] versus environmental factors, including socioeconomic characteristics [6] in the ethnicity-adiponectin and adiponectin-cardiovascular risk relationships among patients of different population origin in RA, were not determined and merit further study.

Conclusions

In this study, adiponectin concentrations related inversely to those of glucose, and in black patients to favorable lipid profiles. These relationships are similar to those reported in the non-RA population. However, adiponectin concentrations also independently associated with increased blood pressure parameters, and in white patients additionally with enhanced endothelial activation. The possible mechanism(s) underlying these paradoxical relationships together with the concurrent presence of beneficial associations merit further investigation in order to determine the potential role of adiponectin in cardiovascular disease as well as its concentrations in cardiovascular disease risk stratification in RA.

Abbreviations

BMI: Body mass index; DAS28: Disease activity score in 28 joints; DMARDs: Disease-modifying antirheumatic drugs; ELISA: Enzyme-linked immunosorbant assay; GFR: Glomerular filtration rate; HDL: High density lipoprotein; HMW: High molecular weight; ICAM: Intercellular adhesion molecule; LDL: Low density lipoprotein; MCP: Monocyte chemoattractant protein; MetS: Metabolic syndrome; RA: Rheumatoid arthritis; RF: Rheumatoid factor; VCAM: Vascular cell adhesion molecule.

Competing interests

The authors declared that they have no competing interests.

Authors’ contributions

PHD contributed to the conception, design and data acquisition, performed the statistical analysis and drafted the manuscript. AJW and GRN contributed to the conception and design and analysis and interpretation of the data. LT contributed to the conception, design, data acquisition, management and analysis. AS contributed to the conception, design and data. All authors read and approved the final manuscript.

Acknowledgements

The study was supported by the South African Medical Research Council (grant number MRC2008_DES) and the National Research Foundation.

References

  1. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahasi T, Matsuzawa Y: Paradoxical decease of an adipose-specific protein, adiponectin, in obesity.

    Biochem Biophys Res Commun 1999, 425:560-564. OpenURL

  2. Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyanma M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T: Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population.

    Clin Sci (Lond) 2002, 103:137-142. OpenURL

  3. Shezad A, Iqbal W, Shezad O, Lee YS: Adiponectin: regulation of its production and its role in human diseases.

    Hormones 2012, 11:8-20. OpenURL

  4. Fantuzzi G, Mazzone T: Adipose tissue and atherosclerosis: exploring the connection.

    Arterioscler Thromb Vasc Biol 2007, 27:996-1003. OpenURL

  5. Tanida M, Shen J, Horri Y, Matsuda M, Kihara S, Funahashi T, Shimomura I, Sawai H, Fukuda Y, Matsuzawa Y, Nagai K: Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats.

    Exp Biol Med (Maywood) 2007, 232:390-397. OpenURL

  6. Wannamethee SG, Tchemova J, Whincup P, Lowe GD, Rumley A, Brown K, Cherry L, Sattar N: Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronary heart disease risk-related parameters.

    Int J Obes (Lond) 2007, 31:1089-1098. OpenURL

  7. Iwashima Y, Katuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahasi T, Rakugi H, Matsuzawa Y, Ogihara T: Hypoadiponectinemia is an independent risk factor for hypertension.

    Hypertension 2004, 43:1318-1323. OpenURL

  8. Li S, Shin HJ, Ding EL, van Dam RM: Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis.

    JAMA 2009, 302:179-188. OpenURL

  9. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway.

    Circulation 2000, 102:1296-1301. OpenURL

  10. Lam KS, Xu A: Adiponectin: protection of the endothelium.

    Curr Diab Rep 2005, 5:254-259. OpenURL

  11. Gu L, Okada Y, Clinton SK, Libby P, Rollins BJ: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.

    Mol Cell 1998, 2:275-281. OpenURL

  12. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB: Plasma adiponectin levels and risk of myocardial infarction in men.

    JAMA 2004, 291:1730-1737. OpenURL

  13. Sattar N, Wannamethee G, Sarwar N, Tchernova J, Cherry L, Michael Wallace A, Danesh J, Whincup PH: Adiponectin and coronary heart disease. A prospective study and meta-analysis.

    Circulation 2006, 114:623-629. OpenURL

  14. Wannamethee SG, Whincup PH, Lennon L, Sattar N: Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure.

    Arch Intern Med 2007, 167:1510-1517. OpenURL

  15. Kizer JR, Barzilay JI, Kuller LH, Gottdiener JS: Adiponectin and risk of coronary heart disease in older men and women.

    J Clin Endocrinol Metab 2008, 93:3357-3364. OpenURL

  16. Dekker JM, Funahashi T, Nijpels G, Pitz S, Stehouwer CDA, Snijder MB, Bouter LM, Matsuzawa Y, Shimomura L, Heine RJ: Prognostic value of adiponectin for cardiovascular disease and mortality.

    J Clin Endocrinol Metab 2008, 93:1489-1496. OpenURL

  17. Kanaya AM, Wassel Fyr C, Vittinghoff E, Havel PJ, Cesari M, Nicklas B, Harris T, Newman AB, Satterfield S, Cummings SR: Serum adiponectin and coronary heart disease risk in older black and white Americans.

    J Clin Endocrinol Metab 2006, 91:5044-5050. OpenURL

  18. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT: Adiponectin multimeric complexes and the metabolic syndrome trait cluster.

    Diabetes 2006, 55:249-259. OpenURL

  19. Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T, Matsuzawa Y: Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.

    Circulation Res 2004, 94:e27-e31. OpenURL

  20. Sattar N, Watt P, Cherry L, Ebrahim S, Smith GD, Lawlor DA: High molecular weight adiponectin is not associated with incident coronary heart disease in older women: a nested prospective case–control study.

    J Clin Endocrinol Metab 2008, 93:1846-1849. OpenURL

  21. Derdemezis CS, Voulgari PV, Drosos AA, Kiortsis DN: Obesity, adipose tissue and rheumatoid arthritis: coincidence or more complex relationship?

    Clin Exp Rheumatol 2011, 29:712-727. OpenURL

  22. Klaasen R, Herenius MM, Wijbrandts CA, de Jager W, van Tuyl LH, Nurmohamed MT, Prakken BJ, Gerlag DM, Tak PP: Treatment-specific changes in circulating adipocytokines: a comparison between tumour necrosis factor blockade and glucocorticoid treatment for rheumatoid arthritis.

    Ann Rheum Dis 2012, 71:1510-1516. OpenURL

  23. Peters MJ, Watt P, Cherry L, Welsh P, Henninger E, Kijkmans BA, McInnes IB, Nurmohamed MT, Sattar N: Lack of effect of TNF-alpha blockade therapy on circulating adiponectin levels in patients with autoimmune disease: results from two independent prospective studies.

    Ann Rheum Dis 2010, 69:1687-1690. OpenURL

  24. Krysiak R, Handzlik-Orlik G, Okopien B: The role of adipokines in connective tissue diseases.

    Eur J Nutrition 2012, 51:513-528. OpenURL

  25. Frommer KW, Schaffler A, Buchler C, Steinmeyer J, Rickert M, Rehart S, Brentano F, Gay S, Muller-Ladner U, Nermann E: Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis?

    Ann Rheum Dis 2012, 71:1724-1732. OpenURL

  26. Ehling A, Schaffler A, Herfarth H, Tamer IH, Anders S, Distler O, Paul G, Distler J, Gay S, Scholmerich J, Neumann E, Muller-Ladner U: The potential of adiponectin in driving arthritis.

    J Immunol 2006, 176:4468-4478. OpenURL

  27. Frommer KW, Zimmermann B, Meier FM, Schroder D, Heil M, Schaffler A, Buchler C, Steinmeyer J, Brentano F, Gay S, Muller-Ladner U, Neumann E: Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis.

    Arthritis Rheum 2010, 62:2886-2899. OpenURL

  28. Scotece M, Conde J, Gómez R, López V, Pino J, González A, Lago F, Gómez-Reino JJ, Gualillo O: Role of adipokines in atherosclerosis: interferences with cardiovascular complications in rheumatic diseases.

    Mediators Inflamm 2012, 2012:125458. OpenURL

  29. Ozgen M, Koca SS, Dagli N, Balin M, Ustundag B, Isik A: Serum adiponectin and vaspin levels in rheumatoid arthritis.

    Arch Med Res 2010, 41:457-463. OpenURL

  30. Gonzalez-Gay MA, Gonzalez-Juanatey C, Rodriguez-Rodriguez L, Miranda-Filloy JA, Martin J, Llorca J: Lack of association between adipokines and ghrelin and carotid intima-media thickness in patients with severe rheumatoid arthritis.

    Clin Exp Rheumatol 2011, 29:358-359. OpenURL

  31. Rho YH, Chung CP, Solus JF, Raggi P, Oeser A, Gebretsadik T, Shintani A, Stein CM: Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis.

    Arthritis Rheum 2010, 62:1259-1264. OpenURL

  32. Chen X, Lu J, Bao J, Guo J, Shi J, Wang Y: Adiponectin: a biomarker for rheumatoid arthritis?

    Cytokine Growth Factor Rev 2013, 24:83-89. OpenURL

  33. Gómez R, Conde J, Scotece M, Gómez-Reino JJ, Lago F, Gualillo O: What’s new in our understanding of the role of adipokines in rheumatic diseases?

    Nat Rev Rheumatol 2011, 7:528-536. OpenURL

  34. El-Hini SH, Mohamed FI, Hassan AA, Ali F, Mahmoud A, Ibraheem HM: Visfatin and adiponectin as novel markers for evaluation of metabolic disturbance in recently diagnosed rheumatoid arthritis patients.

    Rheumatol Int 2013, 33:2283-2289. OpenURL

  35. Hahn BH, Lourencco EV, McMahon M, Skaggs B, Le E, Anderson M, Likuni N, Lai CK, La Cava A: Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin.

    Lupus 2010, 19:913-917. OpenURL

  36. McMahon M, Skaggs BJ, Sahakian L, Grossman J, FitzGerald J, Ragavendra N, Charles-Schoeman C, Chemishof M, Gom A, Witztum JL, Wong WK, Weisman M, Wallace DJ, La Cava A, Hahn BH: High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

    Ann Rheum Dis 2011, 70:1619-1624. OpenURL

  37. Dessein PH, Norton GR, Badenhorst M, Woodiwiss AJ, Solomon A: Rheumatoid arthritis impacts on the independent relationships between circulating adiponectin concentrations and cardiovascular metabolic risk.

    Mediators Inflamm 2013, 2013:461849. OpenURL

  38. Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, Scott RA, Henneman P, Heid IM, Kizer JR, Lyytikäinen LP, Fuchsberger C, Tanaka T, Morris AP, Small K, Isaacs A, Beekman M, Coassin S, Lohman K, Qi L, Kanoni S, Pankow JS, Uh HW, Wu Y, Bidulescu A, Rasmussen-Torvik LJ, Greenwood CM, Ladouceur M, Grimsby J, Manning AK, Liu CT, et al.: Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

    PLoS Genet 2012, 8:e1002607. OpenURL

  39. Wassel Fyr CL, Kanaya AM, Cummings SR, Reich D, Hsueh W-C, Reiner AP, Harris TB, Moffett S, Li R, Ding J, Milijkovic-Gacic I, Ziv E: Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study.

    Hum Genet 2007, 121:615-624. OpenURL

  40. Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, Rifai N, Libby P, Creager MA, Ridker PM: Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis.

    Arterioscler Thromb Vasc Biol 1998, 18:1765-1770. OpenURL

  41. Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, Boerwinkle E: Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) study.

    Circulation 1997, 96:4219-4225. OpenURL

  42. Martinovic I, Abegunewardene N, Seul M, Vosseler M, Horstick G, Buerke M, Darius H, Lindemann S: Elevated monocyte chemoattractant protein-1 serum levels in patients at risk for coronary artery disease.

    Circ J 2005, 69:1484-1489. OpenURL

  43. Kusano KF, Nakamura K, Kusano H, Nishii N, Banba K, Ikeda T, Hashimoto K, Yamamoto M, Fujio H, Miura A, Ohta K, Morita H, Saito H, Emori T, Nakamura Y, Kusano I, Ohe T: Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis.

    Circ J 2004, 68:671-676. OpenURL

  44. Wållberg-Jonsson S, Cvetkovic JT, Sundqvist K-G, Lefvert AK, Rantapää-Dahlqvist A: Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis.

    J Rheumatol 2002, 29:875-882. OpenURL

  45. Dessein PH, Joffe BI, Singh S: Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis.

    Arthritis Res Ther 2005, 7:R634-R643. OpenURL

  46. Södergren A, Karp K, Boman K, Eriksson C, Lundström E, Smedby T, Söderlund L, Rantapää-Dahlqvist S, Wållberg-Jonsson S: Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness.

    Arthritis Res Ther 2010, 12:R158. OpenURL

  47. Rho YH, Chung CP, Oeser A, Solus J, Asanuma Y, Sokka T, Pincus T, Raggi P, Gebretsadik T, Shintani A, Stein CM: Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis.

    Arthritis Rheum 2009, 61:1580-1585. OpenURL

  48. Solomon A, Norton GR, Woodiwiss AJ, Dessein PH: Obesity and carotid atherosclerosis in African black and Caucasian women with established rheumatoid arthritis: a cross-sectional study.

    Arthritis Res Ther 2012, 14:R67. OpenURL

  49. Solomon A, Christian BF, Norton GR, Woodiwiss AJ, Dessein PH: Risk factor profiles for atherosclerotic cardiovascular disease in black and other Africans with established rheumatoid arthritis.

    J Rheumatol 2010, 37:953-960. OpenURL

  50. Dessein PH, Norton GR, Joffe BI, Abdool-Carrim AT, Woodiwiss AJ, Solomon A: Metabolic cardiovascular risk burden and atherosclerosis in African black and Caucasian women with rheumatoid arthritis: a cross-section study.

    Clin Exp Rheumatol 2013, 31:53-61. OpenURL

  51. Solomon A, Woodiwiss AJ, Abdool-Carrim AT, Stevens BA, Norton GR, Dessein PH: 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.

    J Rheumatol 2012, 31:53-61. OpenURL

  52. Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

    Arthritis Rheum 1988, 31:315-324. OpenURL

  53. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, et al.: 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

    Ann Rheum Dis 2010, 69:1580-1588. OpenURL

  54. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis.

    Arthritis Rheum 1995, 38:44-48. OpenURL

  55. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G: National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.

    Ann Intern Med 2003, 139:137-147. OpenURL

  56. Dessein PH, Christian BF, Solomon A: Which are the determinants of dyslipidemia in rheumatoid arthritis and does socioeconomic status matter in this regard?

    J Rheumatol 2009, 36:1357-1369. OpenURL

  57. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Cucimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM: Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.

    Eur Heart J 2003, 24:987-1003. OpenURL

  58. Toms TE, Panoulas VF, Douglas KM, Nightingale P, Smith JP, Griffiths H, Sattar N, Symmons DP, Kitas GD: Are lipid ratios less susceptible to change with systemic inflammation than individual lipid components in patients with rheumatoid arthritis?

    Angiology 2011, 62:167-175. OpenURL

  59. Ridker P, Rifai N, Cook NR, Bradwin G, Buring JE: Non-HDL cholesterol, apolipoprotein A-1 and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women.

    J Am Med Assoc 2005, 294:326-333. OpenURL

  60. Grundy SM, Cleeman JI, Daniels SR, Konato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F: Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heat, Lung, and Blood Institute Scientific Statement.

    Circulation 2005, 112:2735-2752. OpenURL

  61. Dessein PH, Norton GR, Woodiwiss AJ, Solomon A: Independent relationship between circulating resistin concentrations and endothelial activation in rheumatoid arthritis.

    Ann Rheum Dis 2013, 72:1586-1588. OpenURL

  62. Panoulas VF, Metsios GS, Pace AV, John H, Trehame GJ, Banks MJ, Kitas GD: Hypertension in rheumatoid arthritis.

    Rheumatology (Oxford) 2008, 47:1286-1298. OpenURL

  63. Dessein PH, Stanwix AE, Joffe BI: Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis.

    Arthritis Res 2002, 4:R5. OpenURL

  64. Dessein PH, Joffe BI, Stanwix AE: Effects of disease modifying agents and dietary intervention on insulin resistance and dyslipidemia in inflammatory arthritis: a pilot study.

    Arthritis Res 2002, 4:R12. OpenURL

  65. Dessein PH, Joffe BI: Suppression of interleukin-6 concentrations is associated with decreased endothelial activation in rheumatoid arthritis.

    Clin Exp Rheumatol 2006, 24:161-167. OpenURL

  66. Ohashi K, Ouchi N, Matsuzawa Y: Adiponectin and hypertension.

    Am J Hypertens 2011, 24:263-269. OpenURL

  67. Kaplan MJ: Cardiovascular complications of rheumatoid arthritis: assessment, prevention, and treatment.

    Rheum Dis Clin North Am 2010, 36:405-426. OpenURL

  68. Stametelopoulos KS, Kitas GD, Papamichael CM, Chryssohoou E, Kyrkou K, Georgiopoulos G, Protogerou A, Panoulas VF, Sandoo A, Tentolouris N, Mavrikakis M, Sfikakis PP: Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study.

    Arterioscler Thromb Vasc Biol 2009, 29:1702-1708. OpenURL

  69. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J: Rheumatoid arthritis: a disease associated with accelerated atherogenesis.

    Semin Arthritis Rheum 2005, 35:8-17. OpenURL

  70. Dessein PH, Joffe BI: When is a patient with rheumatoid arthritis at risk for cardiovascular disease?

    J Rheumatol 2006, 33:201-203. OpenURL

  71. Gabriel SE, Crowson CS: Risk factors for cardiovascular disease in rheumatoid arthritis.

    Curr Opin Rheumatol 2012, 24:171-176. OpenURL

  72. John H, Kitas G: Inflammatory arthritis as a novel risk factor for cardiovascular disease.

    Eur J Intern Med 2012, 23:575-579. OpenURL

  73. Sattar N, Nelson SM: Adiponectin, diabetes, and coronary heart disease in older persons: unraveling the paradox.

    J Clin Endocrinol Metab 2008, 93:3299-3301. OpenURL

  74. Ferraz-Amaro I, Gonzalez-Juanatay C, Lopez-Mejias R, Riancho-Zarrabeitia L, Gonzalez-Gay MA: Metabolic syndrome in rheumatoid arthritis.

    Mediators Inflamm 2013, 2013:710928. OpenURL

  75. Gonzalez-Gay MA, Llorca J, Garcia-Unzueta MT, Gonzalez-Juanatay C, De Matias JM, Martin J, Redelinghuys M, Woodiwiss AJ, Norton GR, Dessein PH: High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis.

    Clin Exp Rheumatol 2008, 26:596-603. OpenURL

  76. Miranda-Filloy JA, Lopez-Mejias R, Gnre F, Carnero-Lopez B, Ochoa R, Diaz de Teran T, Gonzalez-Juanatay C, Blanco R, Llorca J, Gonzalez-Gay MA: Adiponectin and resistin serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

    Clin Exp Rheumatol 2013, 31:365-371. OpenURL