Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors
© Hettema et al.; licensee BioMed Central Ltd. 2008
Received: 13 December 2007
Accepted: 25 April 2008
Published: 25 April 2008
Several systemic autoimmune diseases are associated with an increased prevalence of atherosclerosis which could not be explained by traditional risk factors alone. In systemic sclerosis (SSc), microvascular abnormalities are well recognized. Previous studies have suggested an increased prevalence of macrovascular disease as well. We compared patients with SSc to healthy controls for signs of early atherosclerosis by measuring intima-media thickness (IMT) of the common carotid artery in relation to traditional risk factors and markers of endothelial activation.
Forty-nine patients with SSc, of whom 92% had limited cutaneous SSc, and 32 healthy controls were studied. Common carotid IMT was measured by using B-mode ultrasound. Traditional risk factors for cardiovascular disease were assessed and serum markers for endothelial activation were measured.
In patients with SSc, the mean IMT (median 0.69 mm, interquartile range [IQR] 0.62 to 0.79 mm) was not significantly increased compared with healthy controls (0.68 mm, IQR 0.56 to 0.75 mm; P = 0.067). Also, after correction for the confounders age, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol (P = 0.328) or using a different model taking into account the confounders age, HDL cholesterol, and history of macrovascular disease (P = 0.474), no difference in IMT was present between SSc patients and healthy controls. Plaques were found in three patients and not in healthy controls (P = 0.274). In patients, no correlations were found between maximum IMT, disease-related variables, and markers of endothelial activation. Endothelial activation markers were not increased in SSc patients compared with controls.
SSc is not associated with an increased prevalence of early signs of atherosclerosis.
Systemic sclerosis (SSc) is a generalized connective tissue disorder characterized by fibrosis of the skin and internal organs and widespread vascular lesions. The pathogenesis of the vasculopathy is not fully understood, but a viral trigger, immune reactions to viral or environmental factors, reperfusion injury, or antiendothelial antibodies may all be involved . Also, angiogenesis is insufficient or defective [2, 3]. Most attention has been given to microvascular disease in SSc, but previous studies have suggested an increased prevalence of macrovascular disease as well [4, 5].
In other autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Wegener granulomatosis, a significantly increased prevalence of atherosclerosis has been described [6–10]. Atherosclerosis nowadays is considered an inflammatory disease in which endothelial cell dysfunction is strongly implicated in its pathogenesis , in part related to traditional risk factors like smoking and dyslipidemia. Because of the increased cardiovascular morbidity and mortality in the aforementioned autoimmune diseases, attention has been given to the presence and treatment of cardiovascular risk factors. Despite increased mortality rates in SSc (partly due to cardiac involvement), cardiovascular risk factors and the presence of macrovascular disease have been emphasized less [12, 13]. In this study, we assessed signs of early atherosclerosis by measuring intima-media thickness (IMT) of the common carotid artery (CCA) in patients with SSc and healthy controls. In addition, we related the outcome to traditional risk factors and markers of endothelial activation.
Materials and methods
Consecutive patients with SSc, according to the American College of Rheumatology criteria , attending our outpatient clinic were included. Patients were subclassified in subsets as defined by LeRoy and colleagues [15, 16]. Forty-nine patients were included. Pregnancy was an exclusion criterion. Healthy subjects were included in this study as controls. Ethical approval for the study was obtained from the Medical Ethical Committee of the University Medical Center Groningen (University of Groningen, Groningen, The Netherlands). Informed consent was obtained from each participant.
Data were obtained from all subjects with respect to traditional risk factors for cardiovascular disease (CVD), including body mass index (BMI), smoking status, diabetes, blood pressure, lipid levels, and family history of CVD (considered positive if first-degree relatives suffered from CVD before 60 years of age).
In patients with SSc, we assessed disease-related factors as possible determinants of macrovascular disease. To assess disease activity, the preliminary European Scleroderma Study Group (EScSG) activity index (a score ranging from 0 to 10) was used. A score higher than 3 denotes active disease [17, 18]. Also, the revised preliminary SSc severity scale (Medsger severity scale), a measure of activity, damage, and severity, was used. This scale is a nine-organ disease severity scale in which for each organ system a score of 0 to 4 is applied, with 0 being normal and 4 denoting end-stage organ involvement . We also recorded statin use, cumulative prednisolone dose, and current or former use of immunosuppressive agents.
Measurements of intima-media thickness
B-mode ultrasonography was used to measure the common carotid IMT. Measurements were limited to the CCA and not extended to other segments. The prevalence of increased IMT and/or plaques is substantially higher in the carotid bulb or internal carotid artery (ICA), but the intended quantitative comparison between SSc patients and controls may be hindered by including these segments. An Acuson 128XP ultrasound device with a 7 MHz linear array transducer (Acuson Corporation, now part of Siemens Medical Solutions USA, Inc., Malvern, PA, USA) was used for measuring IMT in all patients and controls, as described before [7, 20]. With the subjects in the supine position, the left CCA wall segment was scanned from a lateral transducer position and recorded on s-VHS tape. The CCA wall segment was defined as 1 cm proximal to the carotid bifurcation. The far wall of the left common artery was assessed at three different positions. Off-line video analysis, using a previously described image analysis program , was performed by one reader unaware of patient or control group data or characteristics. The highest IMT value found in this segment was considered to be the maximum IMT, and the mean of three measurements in this segment was considered to be the mean IMT.
Lipid levels were measured by routine techniques. Additional serum and plasma samples for determination of markers of endothelial activation were stored at -20°C until analysis. Serum levels of vascular cell adhesion molecule-1 (s-VCAM-1) (R&D Systems Europe Ltd, Abingdon, UK) and thrombomodulin (TM) (Diaclone, Besançon, France) were measured according to the manufacturers' instructions. Serum was used to determine C-reactive protein (CRP) and plasma was used to determine von Willebrand factor (vWF) using in-house enzyme-linked immunosorbent assays, as described before .
Values are expressed as mean ± standard deviation when variables were normally distributed and as median with interquartile range (IQR) (25th to 75th percentile) in case of a non-normal distribution. Because the number of patients with diffuse cutaneous SSc (dSSc) was low in our patient group, subset analysis could not be performed. Differences between patients and controls were assessed by Student t test, Mann-Whitney U test, and χ2 test (Pearson chi-square or Fisher exact test) as appropriate. Linear regression was used to assess the relationship between IMT and the different groups (SSc patients and healthy controls). An unadjusted analysis in which no corrections were made for possible confounders and an adjusted analysis in which corrections were made for possible confounders are presented. The variables were entered manually. The level of significance for the association between group and outcome variable was set at a P value of less than 0.05. The variables age, gender, BMI, and smoking were also studied as potential effect modifiers in the relationship of interest. The correlation between maximum IMT and disease-related factors and endothelial markers was assessed by Spearman rank correlation coefficient since maximum IMT was non-normally distributed. All analyses were carried out with the Statistical Package of Social Science, version 12.1. for Windows (SPSS Inc., Chicago, IL, USA).
Characteristics of patients and controls
Traditional risk factors in systemic sclerosis patients and healthy controls
Patients (n = 49)
Controls (n = 32)
55.4 ± 11.6
50.9 ± 10.1
Male gender, number (percentage)
Body mass index, kg/m2
23.7 ± 2.9
24.0 ± 2.9
Pack years for smokers, number (percentage)
Diabetes mellitus, number (percentage)
Hypertension treated with antihypertensive agents, number (percentage)
Blood pressure, mm Hg
5.22 ± 1.00
5.53 ± 1.06
3.02 ± 0.85
3.06 ± 1.08
Lipid-lowering drugs, number (percentage)
Simvastatin, number (mean dose in milligrams)
Atorvastatin, number (mean dose in milligrams)
Rosuvastatin, number (mean dose in milligrams)
Family history of cardiovascular disease, number (percentage)
Cardiovascular history, number (percentage)
Peripheral vascular disease
C-reactive protein, mg/L
Characteristics of patients with systemic sclerosis
N = 49
Systemic sclerosis subset, number (percentage)
Diffuse cutaneous systemic sclerosis
Limited cutaneous systemic sclerosis
Disease duration, years
Raynaud phenomenon duration, years
Antibody, number (percentage)
Scl70 (topoisomerase 1)
Antinuclear antibodies, not specified
EScSG disease activity index
Medsger severity scale score
Modified Rodnan skin score
Prednisolone use, number (percentage)
Cumulative prednisolone dose, grams
Immunosuppressive agents, number (percentage)
Former or current users
Linear regression analysis for risk factors for mean intima-media thickness of the left common carotid artery in systemic sclerosis patients and healthy controls
Group (controls, patients)
95% confidence interval
Linear regression analysis unadjusted and adjusted for risk factors for maximum intima-media thickness of the left common carotid artery in systemic sclerosis patients and healthy controls
Group (controls, patients)
95% confidence interval
Endothelial activation markers
This study did not show differences in the IMT of the CCA and prevalence of plaques between patients with SSc and healthy controls, suggesting no increased prevalence of early atherosclerotic macrovascular disease in SSc. Also, no correlations were found between IMT, disease-related factors, and markers of endothelial activation. Traditional risk factors, like increasing age and dyslipidemia, accounted for increased IMT values in SSc patients and controls.
After the first reports suggesting an increased prevalence of macrovascular involvement in SSc, several studies have been performed in the last decade using IMT of the carotid artery as a marker of early atherosclerosis. Lekakis and colleagues , Kaloudi and colleagues , and Bartoli and colleagues [24, 25] found strongly increased IMT values in the CCA in SSc patients compared with controls. In these studies, mean IMT values were markedly higher than in our patients whereas mean age was comparable. It is not known whether patient groups in studies by Kaloudi and colleagues  and Bartoli and colleagues [24, 25] are from overlapping cohorts since these studies were performed in the same center and published in the same period. A larger percentage of diffuse cutaneous systemic sclerosis (dcSSc) subtype was present in these studies compared with our study, although Kaloudi and colleagues  found no significant differences between mean IMT between subtypes. On the other hand, our results are in agreement with those of Cheng and colleagues [26, 27] and Szucs and colleagues , who found no differences in IMT values in SSc patients compared with controls. Apart from a younger age and a larger percentage of dcSSc subtype in the study by Cheng and colleagues , age was comparable, as were IMT values. No difference was present in IMT values between subsets in this study either . In view of this findings and given the small number of patients with dcSSc in our study, we did not perform a subset analysis. Overall, these discrepancies between studies in the presence of early atherosclerosis as measured by common carotid IMT in SSc patients might be explained by methodological differences, such as patients included in the study and comorbidity.
In our SSc patients, lipid levels and statin use were statistically different from healthy controls. After correction for the strongest confounders in our model, no differences were seen in IMT values between SSc patients and healthy controls. Although statin use was no confounder in our model, a meta-analysis showed that statin therapy is efficient in decreasing the rate of carotid atherosclerosis progression in the long term . Otherwise, statins may have a potential benefit in preventing endothelial dysfunction in SSc patients .
Treatment with immunosuppressive agents, especially corticosteroids, influences the atherogenic process. Corticosteroids are considered to have atherogenic properties , like azathioprine , whereas for hydroxychloroquine  and methotrexate , a protective effect against atherosclerosis has been described. Otherwise, immunosuppressive therapy with prednisolone, cyclophosphamide, or hydroxychloquine was associated with the absence of plaques in patients with SLE . It is difficult to establish whether the observed associations between immunosuppressive agents and atherosclerosis are due to the immunosuppressive agents themselves or to their effect on the activity of the autoimmune disease. In our study, 49% were former or current users of immunosuppressive agents. No association was found between maximum IMT and cumulative prednisolone dose and use of other immunosuppressive agents.
Markers of inflammation, such as CRP, are related to the risk of cardiovascular and peripheral vascular disease. Increased levels of CRP are associated with increased risk of symptomatic disease [34, 35]. In our population, CRP levels were significantly elevated compared with healthy controls. The CRP levels we found might have been associated with future coronary events [34, 35], but we found no association between CRP and IMT values. This can be explained by the study design. Our study was not designed to find a relationship between CRP and risk of CVD, and we did not exclude other conditions that could explain elevated CRP levels, like intercurrent infections. Otherwise, in SSc patients, besides elevations due to infection, no significant elevations of CRP levels are seen .
Surprisingly, we did not find elevated levels of endothelial activation markers. Our population of SSc patients was heterogeneous with respect to disease duration. The typical patient had inactive disease. Most inflammation is expected in the early stages of the disease or in patients with active disease. Also, by using the Medsger severity scale, we could not find an association between macrovascular disease and the severity of SSc. This might explain the absence of increased levels of endothelial activation markers. All these data point to the absence of premature atherosclerosis in SSc.
Our results might be an underestimation of atherosclerosis in SSc patients and controls. Besides the possible explanations as stated above, our patients were suffering predominantly from lcSSc, in which inflammation is not always present . However, when IMT values were analyzed in subsets, other authors did not find differences in these values between subsets [23, 26]. Furthermore, we used IMT values of the CCA. This segment is commonly evaluated in our laboratory as it can be approached easily and measurements on this segment are reproducible. Using the same protocol as described here, we found increased IMT values in patients with SLE . However, atherosclerotic lesions appear later in the CCA than in the ICA or bulb, but these latter two segments are more difficult to visualize . Also, it can be difficult to assess whether IMT of the CCA represents atherosclerosis or vascular hypertrophy . Although other noninvasive markers of early changes in the arterial wall are available (such as arterial wall thickening and stiffening), carotid IMT has been used more frequently and has been found to be a strong predictor of future vascular events [40, 41].
IMT of the CCA is not increased in patients with SSc compared with controls, either when uncorrected or corrected for traditional risk factors. So, SSc seems not to be associated with increased early atherosclerotic macrovascular disease. It seems that, although SSc is characterized by endothelial dysfunction, this is reflected mainly in microvascular disease.
body mass index
common carotid artery
diffuse cutaneous systemic sclerosis
European Scleroderma Study Group
erythrocyte sedimentation rate
internal carotid artery
limited cutaneous systemic sclerosis
systemic lupus erythematosus
vascular cell adhesion molecule-1
von Willebrand factor.
- Kahaleh MB, LeRoy EC: Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity. 1999, 31: 195-214.View ArticlePubMedGoogle Scholar
- LeRoy EC: Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am. 1996, 22: 675-694. 10.1016/S0889-857X(05)70295-7.View ArticlePubMedGoogle Scholar
- Mackiewicz Z, Sukura A, Povilenaité D, Ceponis A, Virtanen I, Hukkanen M, Konttinen YT: Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin. Clin Exp Rheumatol. 2002, 20: 641-646.PubMedGoogle Scholar
- Ho ML, Veale D, Eastmond C, Nuki G, Belch J: Macrovascular disease and systemic sclerosis. Ann Rheum Dis. 2000, 59: 39-43. 10.1136/ard.59.1.39.PubMed CentralView ArticlePubMedGoogle Scholar
- Veale DJ, Collidge TA, Belch JJF: Increased prevalence of symptomatic macrovascular disease in systemic-sclerosis. Ann Rheum Dis. 1995, 54: 853-855.PubMed CentralView ArticlePubMedGoogle Scholar
- Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJF: Rheumatoid arthritis and macrovascular disease. Rheumatology. 2003, 42: 292-297. 10.1093/rheumatology/keg083.View ArticlePubMedGoogle Scholar
- De Leeuw K, Sanders JS, Stegeman C, Smit A, Kallenberg CG, Bijl M: Accelerated atherosclerosis in patients with Wegener's granulomatosis. Ann Rheum Dis. 2005, 64: 753-759. 10.1136/ard.2004.029033.PubMed CentralView ArticlePubMedGoogle Scholar
- Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, Côte R, Grover SA, Fortin PR, Clarke AE, Senécal JL: Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001, 44: 2331-2337. 10.1002/1529-0131(200110)44:10<2331::AID-ART395>3.0.CO;2-I.View ArticlePubMedGoogle Scholar
- Wallberg-Jonsson S, Ohman M, Rantapaa-Dahlqvist S: Which factors are related to the presence of atherosclerosis in rheumatoid arthritis?. Scand J Rheumatol. 2004, 33: 373-379. 10.1080/03009740410010308.View ArticlePubMedGoogle Scholar
- Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N, Jara LJ, Abu-Shakra M, Meroni PL, Sherer Y: Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005, 112: 3337-3347. 10.1161/CIRCULATIONAHA.104.507996.View ArticlePubMedGoogle Scholar
- Ross R: Atherosclerosis – An inflammatory disease. N Engl J Med. 1999, 340: 115-126. 10.1056/NEJM199901143400207.View ArticlePubMedGoogle Scholar
- Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D: Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003, 48: 2246-2255. 10.1002/art.11073.View ArticlePubMedGoogle Scholar
- Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, Medsger TA, Lucas M, Michet CJ, Kuwana M, Yasuoka H, Hoogen van den F, Te Boome L, van Laar JM, Verbeet NL, Matucci-Cerinic M, Georgountzos A, Moutsopoulos HM: Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med. 2005, 118: 2-10. 10.1016/j.amjmed.2004.04.031.View ArticlePubMedGoogle Scholar
- Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic-sclerosis (scleroderma). Arthritis Rheum. 1980, 23: 581-590. 10.1002/art.1780230510.View ArticleGoogle Scholar
- LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F: Scleroderma (systemic-sclerosis) – classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.PubMedGoogle Scholar
- LeRoy EC, Medsger TA: Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001, 28: 1573-1576.PubMedGoogle Scholar
- Valentini G, Della Rossa A, Bombardieri S, Bencivelli W, Silman AJ, D'Angelo S, Cerinic MM, Belch JF, Black CM, Bruhlmann P, Czirják L, De Luca A, Drosos AA, Ferri C, Gabrielli A, Giacomelli R, Hayem G, Inanc M, McHugh NJ, Nielsen H, Rosada M, Scorza R, Stork J, Sysa A, Hoogen van den FH, Vlachoyiannopoulos PJ: European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. Ann Rheum Dis. 2001, 60: 592-598. 10.1136/ard.60.6.592.PubMed CentralView ArticlePubMedGoogle Scholar
- Valentini G, Bencivelli W, Bombardieri S, D'Angelo S, Della Rossa A, Silman AJ, Black CM, Czirjak L, Nielsen H, Vlachoyiannopoulos PG: European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis. 2003, 62: 901-903. 10.1136/ard.62.9.901.PubMed CentralView ArticlePubMedGoogle Scholar
- Medsger TA, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W: Assessment of disease severity and prognosis. Clin Exp Rheumatol. 2003, 21: S42-S46.PubMedGoogle Scholar
- Blaauw J, van Pampus MG, van Doormaal JJ, Fokkema MR, Fidler V, Smit AJ, Aarnoudse JG: Increased intima-media thickness after early-onset preeclampsia. Obstet Gynecol. 2006, 107: 1345-1351.View ArticlePubMedGoogle Scholar
- Selzer RH, Hodis HN, Kwong-Fu H, Mack WJ, Lee PL, Liu CR, Liu CH: Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis. 1994, 111: 1-11. 10.1016/0021-9150(94)90186-4.View ArticlePubMedGoogle Scholar
- Lekakis J, Mavrikakis M, Papamichael C, Papazoglou S, Economou O, Scotiniotis I, Stamatelopoulos K, Vemmos C, Stamatelopoulos S, Moulopoulos S: Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud's phenomenon. Am Heart J. 1998, 136: 905-912. 10.1016/S0002-8703(98)70137-1.View ArticlePubMedGoogle Scholar
- Kaloudi O, Basta G, Perfetto F, Bartoli F, Del Rosso A, Miniati I, Conforti ML, Generini S, Guiducci S, Abbate R, Pignone A, Castellani S, Livi R, De Caterina R, Matucci-Cerinic M: Circulating levels of Nepsilon-(carboxymethyl)lysine are increased in systemic sclerosis. Rheumatology (Oxford). 2007, 46: 412-416. 10.1093/rheumatology/kel076.View ArticleGoogle Scholar
- Bartoli F, Angotti C, Fatini C, Conforti ML, Guiducci S, Blagojevic J, Melchiorre D, Fiori G, Generini S, Damjanov N, Rednic S, Pignone A, Castellani S, Abbate R, Matucci Cerinic M: Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis. Rheumatology (Oxford). 2007, 46: 772-775. 10.1093/rheumatology/kel433.View ArticleGoogle Scholar
- Bartoli F, Blagojevic J, Bacci M, Fiori G, Tempestini A, Conforti ML, Guiducci S, Miniati I, Di Chicco M, Del Rosso A, Perfetto F, Castellani S, Pignone A, Cerinic MM: Flow-mediated vasodilation and carotid intima-media thickness in systemic sclerosis. Ann N Y Acad Sci. 2007, 1108: 283-290. 10.1196/annals.1422.030.View ArticlePubMedGoogle Scholar
- Cheng KS, Tiwari A, Boutin A, Denton CP, Black CM, Morris R, Hamilton G, Seifalian AM: Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology (Oxford). 2003, 42: 1299-1305. 10.1093/rheumatology/keg371.View ArticleGoogle Scholar
- Cheng KS, Tiwari A, Boutin A, Denton CP, Black CM, Morris R, Seifalian AM, Hamilton G: Differentiation of primary and secondary Raynaud's disease by carotid arterial stiffness. Eur J Vasc Endovasc Surg. 2003, 25: 336-341. 10.1053/ejvs.2002.1845.View ArticlePubMedGoogle Scholar
- Szucs G, Tímár O, Szekanecz Z, Dér H, Kerekes G, Szamosi S, Shoenfeld Y, Szegedi G, Soltész P: Endothelial dysfunction precedes atherosclerosis in systemic sclerosis. Relevance for prevention of vascular complications. Rheumatology (Oxford). 2007, 46: 759-762. 10.1093/rheumatology/kel426.View ArticleGoogle Scholar
- Kang S, Wu Y, Li X: Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis. Atherosclerosis. 2004, 177: 433-442. 10.1016/j.atherosclerosis.2004.08.005.View ArticlePubMedGoogle Scholar
- Kuwana M: Potential benefit of statins for vascular disease in systemic sclerosis. Curr Opin Rheumatol. 2006, 18: 594-600. 10.1097/01.bor.0000245720.02512.3e.View ArticlePubMedGoogle Scholar
- Petri M, Lakatta C, Magder L, Goldman D: Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med. 1994, 96: 254-259. 10.1016/0002-9343(94)90151-1.View ArticlePubMedGoogle Scholar
- Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello A, Gilburd B, Corbanese S, Patnaik M, Zampieri S, Peter JB, Favaretto E, Iaccarino L, Sherer Y, Todesco S, Pauletto P: Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2003, 62: 1071-1077. 10.1136/ard.62.11.1071.PubMed CentralView ArticlePubMedGoogle Scholar
- Roman MJ, Shanker B, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003, 349: 2399-2406. 10.1056/NEJMoa035471.View ArticlePubMedGoogle Scholar
- Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK: C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J. 2002, 144: 233-238. 10.1067/mhj.2002.124054.View ArticlePubMedGoogle Scholar
- Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH: Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998, 97: 425-428.View ArticlePubMedGoogle Scholar
- Kucharz EJ, Grucka-Mamczar E, Mamczar A, Brzezinska-Wcislo L: Acute-phase proteins in patients with systemic sclerosis. Clin Rheumatol. 2000, 19: 165-166. 10.1007/s100670050039.View ArticlePubMedGoogle Scholar
- Valentini G, Silman AJ, Veale D: Assessment of disease activity. Clin Exp Rheumatol. 2003, 21: S39-S41.PubMedGoogle Scholar
- De Leeuw K, Freire B, Smit AJ, Bootsma H, Kallenberg CG, Bijl M: Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Lupus. 2006, 15: 675-682. 10.1177/0961203306069972.View ArticlePubMedGoogle Scholar
- Poredos P: Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis. Vasc Med. 2004, 9: 46-54. 10.1191/1358863x04vm514ra.View ArticlePubMedGoogle Scholar
- Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J: Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens. 2002, 20: 159-169. 10.1097/00004872-200202000-00001.View ArticlePubMedGoogle Scholar
- Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M: Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007, 115: 459-467. 10.1161/CIRCULATIONAHA.106.628875.View ArticlePubMedGoogle Scholar
This article is published under license to 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.