Skip Navigation


Rheumatology Advance Access originally published online on July 21, 2007
Rheumatology 2007 46(9):1466-1470; doi:10.1093/rheumatology/kem159
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
46/9/1466    most recent
kem159v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Panoulas, V. F.
Right arrow Articles by Kitas, G. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Panoulas, V. F.
Right arrow Articles by Kitas, G. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of serum uric acid with cardiovascular disease in rheumatoid arthritis

V. F. Panoulas1,2, H. J. Milionis2, K. M. J. Douglas1, P. Nightingale3, M. D. Kita1, R. Klocke1, M. S. Elisaf2 and G. D. Kitas1,*

1Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands, UK, 2Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece and 3Wolfson Computer Laboratory, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

*Correspondence to: Professor George D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Pensnett Road, Dudley, West Midlands, DY1 2HQ, UK. E-mail: gd.kitas{at}dgoh.nhs.uk; g.d.kitas{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Patient recruitment and...
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Elevated serum uric acid (SUA) levels have been associated with cardiovascular disease (CVD) in the general population. Rheumatoid arthritis (RA) is not thought to associate with high SUA but is characterized by increased CVD morbidity and mortality. We aimed to explore a potential association of SUA with CVD in RA patients and to evaluate whether such an association is present when the traditional CVD risk factors are taken into account.

Methods. 400 consecutive RA patients were recruited in this cross-sectional study and had all traditional CVD risk factors and SUA assessed. The association of SUA levels with other variables was assessed using bivariate correlations. Subsequent binary logistic models with appropriate adjustments were used to test the independence of the association between SUA and CVD.

Results. SUA levels were significantly higher in RA patients with CVD (RA + CVD) compared with RA patients without CVD (RA – CVD) (5.68 ± 1.81 mg dl–1 vs 5.06 ± 1.41 mg dl–1, P = 0.001). After adjusting for CVD risk factors, physical function (health assessment questionnaire, HAQ) and use of diuretics and/or statins the association between SUA and CVD in RA patients remained significant [Odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.04–1.79, P = 0.025]. Compared with subjects with SUA levels in the lowest quintile (<3.86 mg dl–1), those within the highest quintile (≥6.38 mg dl–1) had a 6-fold increase in the odds of having CVD (adjusted OR 6.46, 95% CI 1.66–25.05, P = 0.007).

Conclusions. This cross-sectional study suggests that SUA may be independently associated with CVD in RA patients. This needs to be confirmed in prospective studies.

KEY WORDS: Rheumatoid arthritis, Uric acid, Cardiovascular disease, Association


   Introduction
Top
 Abstract
 Introduction
Patient recruitment and...
 Results
 Discussion
 Acknowledgements
 References
 
Rheumatoid arthritis (RA) is associated with excess cardiovascular morbidity and mortality [1, 2]. There is growing evidence that cardiovascular disease (CVD) manifested as acute myocardial infarction (MI), sudden death, stroke or heart failure (HF) is highly prevalent in RA [3]. The Nurses Health Study demonstrated that the relative risk of MI in women with RA is twice that of those without RA [2], after adjusting for physical activity and use of drugs such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Recent studies [4, 5] showed also a higher risk of unrecognized MIs and sudden death, and a lower likelihood of angina symptoms in RA patients, thus indicating a different pattern of clinical expression of CVD in rheumatoid patients. This pattern may include different pain perception and generalized hyposensitivity to myocardial ischaemia [6]. The increased prevalence and spurious manifestation of CVD disease in RA patients renders the identification of additional CVD risk factors in this disease particularly important.

Conventional reversible CVD risk factors, including hypertension (HT) [7], smoking [8], obesity [9], dyslipidaemia [10] and insulin resistance [11] are more frequently encountered among RA patients than in the general population, but the CVD burden in RA cannot be fully explained by this. Therefore, non-traditional risk factors such as chronic inflammation have been implicated in the increased CV burden of RA patients [12].

Uric acid is a metabolic product of purine metabolism that may function as an antioxidant [13], thus protecting the vasculature from reactive oxygen species (ROS). However, it can also be a mediator of endothelial dysfunction, vascular smooth cell proliferation and low-grade inflammation, all precursors of HT and CVD [14]. Therefore, it is possible that SUA may contribute to, rather than protect against, the development of CVD. Recent evidence demonstrates that SUA is linked to CVD in the general population [14], but it remains controversial whether this association is independent of other risk factors [15, 16].

RA is not traditionally associated with hyperuricaemia [17]. Patients with concomitant gout and RA are only rarely encountered and often reported as interesting cases in the literature [18]. It is not surprising, therefore, that with the exception of a single study [19], the potential association of SUA levels with CVD in RA has not been investigated in any detail. In the present study, we aimed to explore a potential association of UA with CVD in patients with RA and to evaluate whether such an association is independent or mediated through traditional CVD risk factors. Furthermore, we wanted to estimate in this population at what levels SUA appears to exert deleterious effects on the cardiovascular system.


   Patient recruitment and characteristics
Top
 Abstract
 Introduction
 Patient recruitment and...
Results
 Discussion
 Acknowledgements
 References
 
400 consecutive patients with RA meeting retrospective application of the 1987 revised ACR criteria [20], attending routine outpatient clinics at the Department of Rheumatology of the Dudley Group of Hospitals, UK, were enrolled in this cross-sectional, one-centre study. The study had local Research Ethics Committee and Research and Development approval and all participants gave their written informed consent according to the Declaration of Helsinki. Basic demographics and clinical characteristics of the study population are shown in Table 1.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographic, clinical and laboratory characteristics of the study population

 
Clinical assessments
All participants underwent a thorough baseline evaluation including a detailed review of their medical history and hospital records, physical examination and contemporary assessments of height, weight, body mass index (BMI), body composition (using the TANITA Body Composition Analyzer BC-418), current disease activity score (DAS28) [21] and physical function using the Health Assessment Questionnaire (HAQ) [22]. All medications were recorded in detail, including low-dose aspirin, anti-hypertensives and oral daily prednisolone. Blood pressure (BP) was the mean of three measurements taken from the right arm with an appropriately sized cuff using a Criticare 506DXN machine (Systems Inc) with the patient seated. The presence of HT was defined as a systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg and/or the use of anti-hypertensive medications according to the British Hypertension Society/NICE guidelines [23, 24]. RA patients were classified as having CVD (RA + CVD) if they had a positive history of any of the following: MI, stroke or transient ischaemic attack (TIA), peripheral vascular disease (PVD), angioplasty, coronary artery bypass grafting (CABG) or if they had a positive Rose questionnaire [25] on assessment. Patients were defined as being diabetic when fasting serum glucose levels were >7 mmol/l and/or oral hypoglycaemic medication or insulin was used. Number of pack-years of smoking was recorded and patients were separated in three different groups: current smokers, ex-smokers and never smoked. Alcohol consumption was recorded as number of units consumed per week in those patients who admitted to drinking more than the maximum recommended weekly levels of 21 and 14 units for males and females, respectively.

Laboratory determinations
Venous blood was collected in the fasting state on the same day and a wide range of tests were performed. All biochemical tests were carried out in the Biochemistry Laboratory of Russells Hall Hospital, Dudley Group of Hospitals NHS Trust, UK. Blood samples were drawn for routine biochemistry in Z Serumsep, Clot Activator Vacuette® tubes, greiner bio-one. Samples were spun at 4500g for 5 min and the serum pipetted out for further testing. Routine tests were carried out on the same day and serum for insulin was frozen at –40°C until assay. Uric acid, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs) and glucose were measured using the Vitros® 5, 1 FS chemistry system (www.orthoclinical.com). (SUA is reported in mg dl–1; to convert SUA levels from mg dl–1 to µmol l–1 multiply by 59.48.)

Renal function was assessed by estimated glomerular filtration rate (GFR) using the six-variable Modification of Diet in Renal Disease (MDRD) equation [26], [estimated GFR = 170 x (creatinine)–0.999 x (age)–0.176 x (serum urea nitrogen)–0.170 x (albumin)+0.318 x (0.762 if patient female)]. Insulin resistance was evaluated from fasting glucose and insulin using the Homeostasis Model Assessment of Insulin Resistance (HOMA IR) [27] and the Quantitative Insulin sensitivity Check Index (QUICKI) [28].

Statistical analysis
The Kolmogorov–Smirnov test was used to evaluate whether each parameter followed a Gaussian distribution. All values are expressed as mean ± standard deviation (S.D.), median (25th–75th percentile values) or percentages as appropriate. Comparisons were performed by Student's t-test, Mann–Whitney U-test and chi-square test for normally distributed, not normally distributed and categorical variables, respectively.

Pearson correlation and Spearman rho coefficients were used to describe the bivariate relationship of SUA with other parameters.

Univariate and multivariate logistic regression analysis controlling for age, sex, uric acid, hypertension status, number of smoking pack-years, total cholesterol, QUICKI, BMI, HAQ, use of diuretic and use of statin, was utilized to identify the independence of the association of SUA with CVD in RA patients.

Significance was set at a value of P < 0.05. All analyses were carried out using SPSS 13.0 (SPSS Inc, Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Patient recruitment and...
 Results
Discussion
 Acknowledgements
 References
 
Of the total of 400 patients, 108 (27%) were men and 292 (73%) were women. The mean age was 61.55 ± 12.02 years. The cohort consisted almost exclusively (96%) of Caucasians (reflecting the local demographic split). Most patients (87.5%) were on disease-modifying anti-rheumatic drugs (DMARDs), with the most widely used (56.3%) being methotrexate (MTX). Only eight (2%) of the total number of patients assessed in this study admitted to drinking more than the recommended maximum weekly levels of 21 and 14 units for males and females, respectively; none of them were hyperuricaemic, their uric acid levels were not significantly different to the rest of the population and they were not over-represented in the RA ± CVD or RA – CVD groups. Due to this, alcohol intake was not included as a factor in the subsequent analysis.

Mean SUA levels were 5.18 mg dl–1 (range 2.1–13.13 mg dl–1); 37 (9.3%) patients (6 men and 31 women) were hyperuricaemic as defined by UA levels >8.41 mg dl–1 for males and >6.73 mg dl–1 for females (Table 1). Seventy-eight patients (19.5%) had CVD: 38 (9.5%) had a positive Rose questionnaire, 28 (7%) had suffered an MI, 17 (4.3%) had had a stroke, 11 (2.8%) had undergone angioplasty, 9 (3.3%) CABG surgery and 13 (3.3%) had documented PVD.

SUA levels were significantly higher in RA + CVD compared with RA – CVD (5.68 ± 1.81 mg dl–1 vs 5.06 ± 1.41 mg dl–1, P = 0.001). Males had significantly higher SUA levels than females (6.02 ± 1.36 mg dl–1 vs 4.87 ± 1.45 mg dl–1, P < 0.001). CVD was significantly more prevalent in those within the highest SUA quintile (≥6.38 mg dl–1) compared with those in the lowest SUA quintile (<3.86 mg dl–1), (34.2% vs 13.9%, P = 0.003).

Patients with RA + CVD had a higher CVD risk factor load compared with patients with RA – CVD (Table 1): they had a higher prevalence of hypertension (85.9 vs 67.8%, P = 0.002), were heavier smokers (10.0 vs 2.75 pack-years, P = 0.032) and were more prone to be insulin resistant as reflected by HOMA IR (2.76 vs 1.79, P < 0.001) or QUICKI (0.33 vs 0.35, P < 0.001). Physical function was worse (HAQ 2.0 vs 1.375, P < 0.001) and extra-articular features more common (78.2 vs 64.6%, P = 0.022) in RA + CVD compared with RA – CVD.

In bivariate analysis, SUA levels correlated significantly with TGs ({rho} = 0.24, P < 0.001), HDL ({rho} = –0.140, P = 0.005), male sex ({rho} = 0.37, P < 0.001), presence of HT ({rho} = 0.259, P < 0.001), use of furosemide ({rho} = 0.162, P = 0.001) or thiazide diuretics ({rho} = 0.244, P < 0.001), BMI (r = 0.172, P = 0.001), renal function [full MDRD (r = –0.451, P < 0.001)] and parameters of glucose metabolism/insulin resistance: glucose ({rho} = 0.19, P < 0.001), insulin ({rho} = 0.28, P < 0.001), HOMA IR ({rho} = 0.29, P < 0.001) and QUICKI ({rho} = –0.29, P < 0.001).

SUA levels were associated with the likelihood of having CVD both before and after adjustment for all possible confounders arising from the above bivariate correlations. In logistic regression (Table 2) with dependent variable the presence of CVD, crude OR was 1.29/1 mg dl–1 SUA increase (95% CI 1.1–1.52, P = 0.002). After adjusting for age, gender, HT, BMI, Total Cholesterol, smoking pack-years, QUICKI, HAQ, RA disease duration, use of diuretics and statins, the association between SUA and CVD in RA patients remained significant (OR = 1.36, 95% CI 1.039–1.79, P = 0.025). The adjusted Nagelkerke R2 of the model was 0.48.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Odds ratios for cardiovascular disease per 1 mg/dl increase in SUA in RA patients

 
Compared with subjects with SUA levels in the lowest quintile, those within the highest quintile had a 3.21-time increase in the odds of having CVD (95% CI 1.46–7.06, P = 0.004; Table 3). This association also remained strong after adjustment for potential confounders (OR 6.46, 95% CI 1.66–25.05, P = 0.007).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Univariate and multivariate analyses of the association between SUA quintiles and CVD in RA patients

 

   Discussion
Top
 Abstract
 Introduction
 Patient recruitment and...
 Results
 Discussion
Acknowledgements
 References
 
In this cross-sectional observational study, SUA levels were found to be associated with the presence of CVD in RA patients. This association remained significant even after adjustment for traditional CVD risk factors such as hypertension, smoking pack-years, total cholesterol, obesity and insulin resistance indices, as well as other potential confounders, such as renal function, use of drugs and RA disease severity, suggesting that SUA may be independently associated with CVD. This was further reinforced by the finding that RA patients within the highest SUA quintile were six times more likely to have CVD, compared with those within the lowest SUA quintile (OR 6.46, 95% CI 1.66–25.05, P = 0.007).

The cross-sectional, observational character of the present study is an obvious limitation: it cannot provide proof of causality or independence in the associations found and any interpretations can only be made with caution. It can, however, serve for hypothesis-generation, which can be further investigated in prospective studies designed specifically for the purpose. Another possible limitation of our study could be the lack of detailed data on alcohol consumption.

In the general population, the relationship between elevated SUA levels and the presence of, risk for, or death from CVD has been extensively investigated. In many studies, the significant association between SUA and CVD has been lost after adjusting for classical CVD risk factors [16, 29–32]. In others the significant independent association of SUA and CVD applied only to women [33], whereas in some [15, 34, 35], the significance was retained even after adjustment for potential confounders. The National Health and Nutrition Examination Survey [15], a national US observational study on 5926 subjects, suggested that uric acid is an independent, significant factor for CVD, even after adjustment for the traditional risk factors, age, race and use of diuretics. This association and its potentially significant implications obviously remain somewhat controversial; reasons for these discrepancies include important differences in study designs, populations and outcomes assessed.

In our study, SUA levels showed significant bivariate associations with several classical risk factors, including HT and metabolic factors, such as dyslipidaemia and insulin resistance. HT is highly prevalent in RA patients [7, 36], and may be a strong indirect link between SUA and CVD: induced mild hyperuricemia in rats has been shown to cause hypertension and salt sensitivity [37], while in humans, many studies have shown the relationship between SUA and HT [38, 39]. New onset essential HT in adolescents is also associated with an elevated UA (UA > 5.5 mg/dl) in the vast majority (90%) of cases, whereas it is present only in 30% of subjects with secondary HT and is rare in white-coat and normotensive adolescents [40]. In the present RA cohort, SUA correlated also with a variety of metabolic abnormalities, such as lipids and insulin resistance indices, which, together with hypertension, constitute the basic components of the metabolic syndrome. Recent studies demonstrate an increased prevalence of the metabolic syndrome in RA [41], and it has been proposed that hyperinsulinaemia stimulates UA reabsorption in the proximal tubule [42]. It is, therefore, possible that SUA, even within the normal range, serves as a surrogate marker of the dysmetabolic state associated with the metabolic syndrome, and may be marking out RA patients with increased CVD risk. Indeed, in the general population, Short et al [43]. demonstrated that SUA levels above 5.2 mg/dl were associated with 3.5-fold increased odds (OR = 3.5, 95% CI 1.0–11.9) for CV death and major clinical events in high-risk patients with prevalent coronary artery disease. This result is mirrored closely in our study in those RA patients who were within the highest SUA quintile (≥6.8 mg/dl).

In the present study, however, as in some of the general population studies, SUA appeared to have an independent association with the presence of CVD, after correction for most of the above factors. SUA has been suggested to be able to lead directly to CVD, by causing endothelial dysfunction and low-grade inflammation [44]. A recent study from Khosla et al. [45] has shown a decreased serum nitric oxide in hyperuricaemic rats, which is reversible by lowering SUA levels using allopurinol. In the same study, SUA impaired nitric oxide generation in cultured endothelial cells, implying that hyperuricaemia induces endothelial dysfunction, the beginning of the cardiovascular continuum [46]. After urate uptake into human vascular smooth cells there is a rapid phosporylation of the ERK1/2 and MAP kinases followed by the activation of the nuclear transcription factors NF-kB and AP-1 [47]. Transcription factor activation can lead to increased expression of cyclo-oxygenase-2 (COX-2) and thromboxane A2 (TXA2) [48]. Increased TXA2 may then lead to the production of platelet-derived growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-1), which can induce smooth muscle proliferation and monocyte/macrophage infiltration, respectively. MCP-1 is one of the central chemokines involved in vascular disease and atherosclerosis [49]. SUA can also stimulate human mononuclear cells to produce interleukin-1ß, interleukin-6 and tumour necrosis factor-{alpha} (TNF-{alpha}) [50], all of which have a well-established contribution to the pathways leading to vascular disease [51]. These may be collectively reflected in the levels of the acute-phase protein CRP, which has emerged as an important predictor of MI, stroke and vascular death [52]. Stimulation by UA leads in vitro to significantly increased CRP production in human vascular cells, providing a possible link between elevated SUA and CRP (and the systemic inflammatory response) in patients with CVD.

In conclusion, this study has demonstrated a potential independent association between SUA levels and CVD in patients with RA. The possible pathogenic mechanisms and potential clinical use of SUA as an early biomarker of future CVD events in this group of patients needs to be further investigated in prospective studies.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patient recruitment and...
 Results
 Discussion
 Acknowledgements
References
 
This study was funded by the Dudley Group of Hospitals R&D Directorate cardiovascular programme grant. The Department of Rheumatology is in receipt of infrastructure support from the Arthritis Research Campaign (grant number: 17682). V.F.P. is supported by a PhD scholarship from Empirikion Institute, Athens, Greece.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patient recruitment and...
 Results
 Discussion
 Acknowledgements
 References
 

  1. Wolfe F, Freundlich B, Straus V. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol (2003) 30:36–40.[Abstract/Free Full Text]
  2. Solomon D, Karlson E, Rimm E, Cannuscio C, Mandl M. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation (2003) 107:1303–7.[Abstract/Free Full Text]
  3. del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by classical risk factors. Arthritis Rheum (2001) 44:2737–45.[CrossRef][Web of Science][Medline]
  4. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum (2005) 52:402–11.[CrossRef][Web of Science][Medline]
  5. Banks MJ, Pace AV, Kitas GD. Acute coronary syndromes present atypically and recur more frequently in rheumatoid arthritis than matched controls [abstract]. Arthritis Rheum (2001) 44:S53.
  6. Sheifer SE, Manolio TA, Gersh BJ. Unrecognized myocardial infarction. Ann Intern Med (2001) 135:801–11.[Abstract/Free Full Text]
  7. Erb N, Pace AV, Douglas KMJ, Banks MJ, Kitas GD. Risk assessment for coronary heart disease in rheumatoid arthritis and osteoarthritis. Scand J Rheumatol (2004) 33:293–9.[CrossRef][Web of Science][Medline]
  8. Criswell LA, Merlino LA, Cerhan JR, et al. Cigarette smoking and the risk of rheumatoid arthritis amongst postmenopausal women: results from the Iowa Women's Health Study. American J Med (2006) 112:465–71.
  9. Symmons DPM, Bankhead C, Harrison BJ, Brennan P, Barrett EM, Scott DG. Blood transfusion, smoking and obesity as risk factors for development of rheumatoid arthritis: results from a primary care based incident case-control study in Norfolk, England. Arthritis Rheum (1997) 40:1955–61.[Web of Science][Medline]
  10. Situnayake RD, Kitas G. Dyslipidaemia and rheumatoid arthritis. Ann Rheum Dis (1997) 56:341–2.[Free Full Text]
  11. Dessein PH, Joffe BI, Stanwix A, Botha AS, Moomal Z. The acute phase response does not fully predict the presence of insulin resistance and dyslipidaemia in inflammatory arthritis. J Rheumatol (2002) 29:462–6.[Abstract/Free Full Text]
  12. Dessein PH, Joffe BI. When is a patient with rheumatoid arthritis at risk for cardiovascular disease? J Rheumatol (2006) 33:201–3.[Free Full Text]
  13. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis (2000) 148:131–9.[CrossRef][Web of Science][Medline]
  14. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertens (2003) 41:1183–90.[Abstract/Free Full Text]
  15. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA (2000) 283:2404–10.[Abstract/Free Full Text]
  16. Brand FN, McGee DL, Kannel WB, Stokes J III, Castelli WP. Hyperuricemia as a risk factor of coronary heart disease: the Framingham Study. Am J Epidemiol (1985) 121:11–18.[Abstract/Free Full Text]
  17. Atdjian M, Fernandez-Madrid F. Coexistence of chronic tophaceous gout and rheumatoid arthritis. J Rheumatol (1981) 8:989–92.[Web of Science][Medline]
  18. Modesto dos Santos V, Cezar BF, Barbosa ER, Carvalho FR. Coexistent gout and rheumatoid arthritis: a case report. Br J Hosp Med (Lond) (2005) 66:704–5.[Medline]
  19. Dessein PH, Joffe BI, Veller MG, et al. Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J Rheumatol (2005) 32:435–42.[Abstract/Free Full Text]
  20. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[Web of Science][Medline]
  21. 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. Arthrit Rheum (1995) 38:44–8.[Web of Science][Medline]
  22. Kirwan JR, Reeback JS. Stanford health assessment questionnaire modified to assess disability in British patients with rheumatoid arthritis. Br J Rheumatol (1986) 25:206–9.[Abstract/Free Full Text]
  23. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens (2004) 18:139–85.[CrossRef][Web of Science][Medline]
  24. National Collaborating Centre for Chronic Conditions. Hypertension: management of hypertension in adults in primary care: partial update (2006) London: Royal College of Physicians.
  25. Heyden S, Bartel AG, Tabesh E, et al. Angina pectoris and the Rose questionnaire. Arch Intern Med (1971) 128:961–4.[Abstract/Free Full Text]
  26. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med (1999) 130:461–70.[Abstract/Free Full Text]
  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia (1985) 28:412–9.[CrossRef][Web of Science][Medline]
  28. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab (2000) 85:2402–10.[Abstract/Free Full Text]
  29. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart (1997) 78:147–53.[Abstract/Free Full Text]
  30. Sakata K, Hashimoto T, Ueshima H, Okayama A. Absence of an association between serum uric acid and mortality from cardiovascular disease: NIPPON DATA 80, 1980–1994. National integrated projects for prospective observation of non-communicable diseases and its trend in the aged. Eur J Epidemiol (2001) 17:461–8.[CrossRef][Web of Science][Medline]
  31. Persky VW, Dyer AR, Idris-Soven E, et al. Uric acid: a risk factor for coronary heart disease? Circulation (1979) 59:969–77.[Abstract/Free Full Text]
  32. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med (1999) 131:7–13.[Abstract/Free Full Text]
  33. Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I epidemiologic follow-up study. Am J Epidemiol (1995) 141:637–44.[Abstract/Free Full Text]
  34. Lehto S, Niskanen L, Ronnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke (1998) 29:635–9.[Abstract/Free Full Text]
  35. Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertens (1999) 34:144–50.[Abstract/Free Full Text]
  36. McEntegart A, Capell HA, Creran D, Rumley A, Woodward M, Lowe GD. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatol (2001) 40:640–4.[Abstract/Free Full Text]
  37. Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertens (2001) 38:1101–6.[Abstract/Free Full Text]
  38. Alper AB Jr, Chen W, Yau L, Srinivasan SR, Berenson GS, Hamm LL. Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertens (2005) 45:34–8.[Abstract/Free Full Text]
  39. Sundstrom J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertens (2005) 45:28–33.[Abstract/Free Full Text]
  40. Feig DI. Uric acid and hypertension in adolescents. Semin Nephrol (2005) 25:32–8.[Web of Science][Medline]
  41. Karvounaris SA, Sidiropoulos PI, Papadakis JA, et al. Metabolic syndrome is common among middle-to-older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross-sectional, controlled, study. Ann Rheum Dis (2007) 66:28–33.[Abstract/Free Full Text]
  42. Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens (1996) 9:746–52.[CrossRef][Web of Science][Medline]
  43. Short RA, Johnson RJ, Tuttle KR. Uric acid, microalbuminuria and cardiovascular events in high-risk patients. Am J Nephrol (2005) 25:36–44.[CrossRef][Medline]
  44. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet (1990) 335:765–74.[CrossRef][Web of Science][Medline]
  45. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int (2005) 67:1739–42.[CrossRef][Web of Science][Medline]
  46. Schmieder RE. Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? J Hypertens Suppl (2006) 24:S31–5.[Medline]
  47. Kanellis J, Watanabe S, Li JH, Kang DH, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertens (2003) 41:1287–93.[Abstract/Free Full Text]
  48. Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol (2002) 13:2888–97.[Abstract/Free Full Text]
  49. Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell (1998) 2:275–81.[CrossRef][Web of Science][Medline]
  50. Kang DH, Seoh Y, Yoon K-1. A possible link between hyperuricemia and systemic inflammatory reaction as a mechanism of endothelial dysfunction in chronic renal failure. (2002) 13. American Society of Nephrology 35th Annual Meeting and Scientific Exposition. 466A.
  51. Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (2005) 108:205–13.[CrossRef][Web of Science][Medline]
  52. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med (2004) 350:1387–97.[Abstract/Free Full Text]
Submitted 2 March 2007; revised version accepted 18 May 2007.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Ann Rheum DisHome page
V F Panoulas, S N Nikas, J P Smith, K M J Douglas, P Nightingale, H J Milionis, G J Treharne, T E Toms, M D Kita, and G D Kitas
Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis
Ann Rheum Dis, November 1, 2008; 67(11): 1550 - 1556.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
V. F. Panoulas, G. S. Metsios, A. V. Pace, H. John, G. J. Treharne, M. J. Banks, and G. D. Kitas
Hypertension in rheumatoid arthritis
Rheumatology, September 1, 2008; 47(9): 1286 - 1298.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
V. F. Panoulas, K. M. J. Douglas, A. Stavropoulos-Kalinoglou, G. S. Metsios, P. Nightingale, M. D. Kita, M. S. Elisaf, and G. D. Kitas
Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis
Rheumatology, January 1, 2008; 47(1): 72 - 75.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
46/9/1466    most recent
kem159v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Panoulas, V. F.
Right arrow Articles by Kitas, G. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Panoulas, V. F.
Right arrow Articles by Kitas, G. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?