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Pone.0044668 1.6

Early Vascular Alterations in SLE and RA Patients—A Steptowards Understanding the Associated CardiovascularRisk Maria Jose´ Santos1,2*, Diana Carmona-Fernandes1, Helena Canha˜o1,3, Jose´ Canas da Silva2, Joa˜o 1 Rheumatology Research Unit, Instituto de Medicina Molecular da Faculdade de Medicina de Lisboa, Lisbon, Portugal, 2 Rheumatology Department, Hospital Garcia de Orta, Almada, Portugal, 3 Rheumatology and Metabolic Bone Diseases Department, Hospital de Santa Maria, Lisbon, Portugal, 4 Cardiology Department, Hospital Accelerated atherosclerosis represents a major problem in both systemic lupus erythematosus (SLE) and rheumatoidarthritis (RA) patients, and endothelial damage is a key feature of atherogenesis. We aimed to assess early endothelialchanges in SLE and RA female patients (127 SLE and 107 RA) without previous CV events. Biomarkers of endothelial cellactivation (intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (TM),and tissue factor (TF)) were measured and endothelial function was assessed using peripheral artery tonometry. Reactivehyperemia index (RHI), an indicator of microvascular reactivity, and augmentation index (AIx), a measure of arterial stiffness,were obtained. In addition, traditional CV risk factors, disease activity and medication were determined. Women with SLEdisplayed higher sICAM-1 and TM and lower TF levels than women with RA (p = 0.001, p,0.001 and p,0.001, respectively).
These differences remained significant after controlling for CV risk factors and medication. Serum levels of vascularbiomarkers were increased in active disease and a moderate correlation was observed between sVCAM-1 levels and lupusdisease activity (rho = 0.246) and between TF levels and RA disease activity (rho = 0.301). Although RHI was similar across thegroups, AIx was higher in lupus as compared to RA (p = 0.04). Also in active SLE, a trend towards poorer vasodilation wasobserved (p = 0.06). In conclusion, women with SLE and RA present with distinct patterns of endothelial cell activationbiomarkers not explained by differences in traditional CV risk factors. Early vascular alterations are more pronounced in SLEwhich is in line with the higher CV risk of these patients.
Citation: Santos MJ, Carmona-Fernandes D, Canha˜o H, Canas da Silva J, Fonseca JE, et al. (2012) Early Vascular Alterations in SLE and RA Patients—A Step towardsUnderstanding the Associated Cardiovascular Risk. PLoS ONE 7(9): e44668. doi:10.1371/journal.pone.0044668 Editor: Songtao Shi, University of Southern California, United States of America Received May 28, 2012; Accepted August 6, 2012; Published September 4, 2012 Copyright: ß 2012 Santos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by a grant from Fundac¸a˜o para a Cieˆncia e a Tecnologia, Portugal (PIC/IC/82920/2007). The funders had no role in studydesign, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
in regulating vascular tonus and permeability. Under basalconditions ECs express molecules such as thrombomodulin Chronic systemic inflammation predisposes to accelerated (TM), which prevent platelet aggregation and the activation of atherosclerosis, a risk that is well known in systemic lupus the clotting cascade. Further platelet inhibition is achieved as a erythematosus (SLE) and in rheumatoid arthritis (RA) patients result of nitric oxide (NO) synthesis, a major vascular relaxant with [1]. Subclinical vascular lesions develop long before atherosclerosis anti-inflammatory and anti-proliferative properties. During the becomes clinically evident, and they progress more rapidly in SLE inflammatory process, ECs undergo changes characterized by [2] and RA [3] than in the general population. Traditional enhanced expression of adhesion molecules, increased transen- cardiovascular (CV) risk factors do not fully explain this enhanced dothelial permeability, and loss of antithrombotic properties [11].
risk, and the disease itself is considered an independent CV risk Pro-inflammatory cytokines suppress TM expression and promote factor [1]. In addition, the potential contribution of genetic its cleavage and release into circulation [12]. In addition, they variants to the development of atherosclerosis in RA patients has induce the expression of tissue factor (TF), a procoagulant been recently highlighted [4,5]. However, the reported magnitude molecule absent from the surface of the intact ECs [13], shifting of the CV risk is several times higher in SLE than in RA [6–9], the balance towards a prothrombotic state. Furthermore, damaged and the reason for this divergence is still incompletely understood.
endothelium loses its ability to produce vasodilators, thus adding to Endothelial damage is considered the first step in the the vascular injury. Endothelial dysfunction is potentially a pathogenesis of atherosclerosis. It correlates with disease progres- reversible disorder. Indeed, in patients with active RA, the sion and predicts CV events in the general population [10]. The infusion of infliximab, a chimeric antibody against TNF, has been importance of endothelial cells (ECs) for vascular health is found to improve biomarkers of endothelial activation [14] and highlighted by its crucial role in maintaining blood fluidity and transiently ameliorate endothelial function[15].
September 2012 | Volume 7 | Issue 9 | e44668 In vivo, vascular function can be examined non-invasively by Quantification of soluble vascular biomarkers and quantifying biomarkers of endothelial activation/damage, by measuring the ability of endothelium to release NO in response Measurements were performed using commercial enzyme- to various stimuli or by assessing arterial wall stiffness [16].
linked immunosorbent assay (ELISA) based methods according Previous data indicate impaired endothelial function both in SLE to the manufacturers’ instructions. The Human sICAM-1 [17] and in RA patients [18] when compared to non-inflammatory FlowCytomix Simplex Kit and the Human sVCAM-1 FlowCyto- controls. Nevertheless it is unclear whether the magnitude of early mix Simplex Kit (Bender MedSystems GmbH, Vienna, Austria) vascular changes is similar in these two diseases.
were used for quantification of adhesion molecules, both using the Given the clinical and pathophysiological particularities of SLE FlowCytomix TM Technology. Serum levels of TM were measured and RA, we hypothesize that endothelial function is differently using the Human Thrombomodulin ELISA Kit (Cell Sciences H, disturbed in these two patient groups, which could explain the Canton, MA, USA) and serum levels of TF were quantified using different CV risk. Thus, the major aim of our study was to the AssayMax Human Tissue Factor ELISA kit (Assaypro, St compare endothelial cell function between SLE and RA as assessed by the measurement of soluble vascular biomarkers andby endothelial function testing, taking into account the presence of traditional CV risk factors and systemic inflammation.
Endothelial function was assessed by peripheral artery tonom- etry (PAT). PAT is a noninvasive operator-independent method that evaluates changes in pulse wave amplitude before and after reactive hyperemia. The inter-day variability of this technique inour department is 11% (data not published). The exam was Consecutive SLE and RA women fulfilling the ACR classifica- performed using the EndoPAT 2000 device (Itamar Medical Ltd, tion criteria and free of clinically manifest CV disease were Cesarea, Israel) as described elsewhere [22] and by assessors recruited from the rheumatology clinics of Hospital Garcia de blinded to the clinical diagnosis. Briefly, patients were placed in a Orta, Almada, and Hospital de Santa Maria, Lisbon, between quiet room, in supine position, with a specially designed finger April 2009 and October 2010. A control group of women without probe on the index finger of each hand, and a pressure cuff placed systemic inflammatory diseases was also recruited from the local on one arm. Patients were recommended to refrain from smoking community and evaluated in the same period. Participants were and drinking coffee or tea during the previous 24 hours and not to excluded if they were pregnant, breastfeeding, had impaired renal eat for at least 6 hours preceding the exam. PAT was continuously function (defined as serum creatinine .1.5 mg/dl), or had measured during a 10-minute baseline period, for 5 minutes after documented ischemic heart disease (previous infarction, revascu- the pressure cuff was inflated to suprasystolic pressure and for 10 larization surgery, angina, or heart failure), cerebrovascular additional minutes following the release of upper arm occlusion.
disease (stroke or transient ischemic attack) or symptomatic Pressure changes reflecting pulse amplitude were transmitted to a peripheral artery disease. The study was approved by the Ethics computer and reactive hyperemia index (RHI) was calculated as Committee of both hospitals and was conducted in accordance the ratio of PAT signal amplitude after cuff deflation divided by with the principles stated in the Declaration of Helsinki. All the amplitude of baseline signal, adjusted for fluctuations in the participants gave written informed consent.
magnitude of the signal in the contralateral finger [22].
Augmentation index (AIx) was calculated from the mean PAT waveform of the baseline period dividing the amplitude of the Demographic data, disease characteristics, current medication, second systolic peak by the difference between the second and the and CV risk profile including blood pressure, serum lipids, fasting glycemia, smoking habits, and body mass index (BMI) wereobtained. Patients were diagnosed with hypertension if the measured blood pressure was repeatedly $140/90 mm/Hg or if Continuous variables are expressed as means with standard they used antihypertensive medication. The diagnosis of diabetes deviations and categorical variables as the number of affected was made if fasting glucose level was $126 mg/dl, or if patients individuals and proportion of the total. Bivariate comparisons of were under pharmacological treatment. Participants were classi- SLE and RA patients were made using Student T-tests, Mann- fied as obese if BMI was $30 Kg/m2. Disease activity was Whitney, Kruskal-Wallis or x2 tests, as appropriate.
evaluated using the SLE Disease Activity Index 2000 (SLEDAI The levels of vascular biomarkers, as well as RHI and AIx, were 2K), [19] and in RA patients 28 joints were examined for compared between SLE and RA patients first as crude means tenderness and swelling, and the 4 variable disease activity score using the Mann Whitney test, followed by analysis of covariance (DAS28) was calculated using erythrocyte sedimentation rate [20].
(ANCOVA) to adjust for significant and clinically relevant baseline Disease activity was stratified according to the cutoffs of each covariates. Likewise, in order to assess the effect of disease activity instrument [20,21]: remission (SLEDAI 2K = 0 for SLE or on vascular biomarkers, RHI and AIx, comparisons between DAS28,2.6 for RA patients), low disease activity ($1 SLEDAI remission and active disease were performed.
2K,4, in the case of SLE, or $2.6 DAS28#3.2, in the case of Correlation between disease activity and endothelial cell RA), and active disease (SLEDAI 2K$4 or DAS28.3.2, for SLE function was studied separately in SLE and RA using Spearman correlation coefficient and partial correlations to control for age, Fasting blood samples were obtained before any other disease duration, cardiovascular risk factors and medication.
procedures for measurement of glucose, uric acid, lipids (total Statistical analysis was performed assuming a 5% significance cholesterol, high density lipoprotein (HDL) cholesterol, low density level and using SPSS 17 for Windows.
lipoprotein (LDL) cholesterol, and triglycerides), inflammatorymediators (C-reactive protein (CRP) and fibrinogen) and solublevascular biomarkers (sICAM-1, sVCAM-1, TM, and TF).
September 2012 | Volume 7 | Issue 9 | e44668 compared to RA (16% vs 11%; p = 0.04), indicating increasedarterial wall stiffness in these patients. This increase remained In total 127 women with SLE and 107 with RA, were included statistically significant after controlling for differences in baseline in the study. A control group of 124 women, mean age 46.9613.7 years, 98% Caucasian, and 52% postmenopausal wasalso evaluated as reference. Demographic and clinical character- Disease activity and endothelial function istics of SLE and RA patients are shown in Table 1. SLE women Patients presented a broad range of disease activity. The mean were younger and had shorter disease duration (8.466.5 years) SLEDAI 2K was 3.4664.5 (range 0 to 21) and the mean DAS28 compared to women with RA (10.767.3 years, p = 0.01). All lupus was 4.1961.4 (range 1.70 to 7.54). Disease was in remission in patients were ANA positive and 89% of RA patients were positive 41% of SLE and in 17% of RA cases. 39% of SLE patients either for IgM RF or for anti-citrullinated protein antibodies. The presented moderate/high active disease defined as a SLEDAI use of antimalarials and aspirin was more common in lupus, while 2K$4, and 72% of RA had moderate/high active disease more RA patients received methotrexate. Serum concentration of according to the DAS28 definition. Except for prednisolone fibrinogen was higher in SLE (SLE 3266147 mg/dl vs RA dosage, which was significantly higher in active SLE and active 2766101 mg/dl; p = 0.01), but CRP levels were similar in both RA than in remission, demographic characteristics, CV risk profile groups (SLE 1.1663.2 mg/dl vs 1.0662.5 mg/dl; p = 0.75).
and medication was comparable in quiescent and active disease.
Overall, serum levels of vascular biomarkers were elevated Vascular biomarkers and endothelial function as assessed when disease was active, being statistically significant the differences in sICAM-1, TM and TF levels between active and A distinct pattern of soluble ECs biomarkers was identified in quiescent SLE and in sICAM-1 and TF levels between active RA SLE and in RA. While sICAM-1 and TM levels were significantly higher, TF was lower in lupus than in RA patients (Figure 1).
sVCAM-1 showed a significant Spearman and partial correla- Differences in sICAM-1, TM and TF remained significant after tion with lupus disease activity measured by the SLEDAI (rho adjustment for covariates (Table 2).
0.246 and 0.361; p = 0.007 and p,0.001 respectively) and TM Reactive hyperemia was similar in SLE (RHI = 2.13560.686), levels correlated with DAS28 (rho 0.301 and 0.250; p = 0.002 and in RA (RHI = 2.19460.810) and in the control population p = 0.005). In SLE patients there was also a significant correlation (2.09060.579), while AIx was significantly higher in SLE as between sVCAM-1, TM, TF and ESR (rho 0.246, 0.323 and0.263; p = 0.01, p = 0.001 and p = 0.01, respectively) and betweenserum TM levels and CRP (rho 0.315; p = 0.001). No significant Table 1. Demographic and clinical characteristics of SLE and correlation was found in RA patients between ESR or CRP and A trend toward lower RHI was observed in active SLE (1.80660.16) as compared with remission (2.24960.13; p = 0.06), but no significant correlation was observed between RHI, AIx andSLEDAI or DAS28.
In this comparative study we found distinct patterns of soluble vascular biomarkers in SLE and in RA female patients free from clinically evident CV disease. Lupus patients presented higher serum sICAM-1 and TM levels, while TF was elevated in RA patients. These findings are relevant for understanding the pathophysiology of the increased CV risk in SLE and RA patients, as cell adhesion molecules may represent a link between inflammation and atherosclerosis. In fact, not only are VCAM-1and ICAM-1 highly expressed on the endothelium overlaying atherosclerotic lesions [23,24], but an increased serum concentra- tion of these molecules is also related to CV risk factors [25] and incident myocardial infarction [26]. In particular, high serum levels of ICAM-1 represent an independent risk factor for atherosclerosis and a predictor of future CV events [26,27]. Inaddition, we observed significantly increased levels of vascular biomarkers in active disease. These observations are in line with previous studies demonstrating that inflammatory mediators, including TNF, IL-6, interferon-gamma (INFc) [28], IL-18 [29], but also MCP-1 and MIF [30], upregulate endothelial cell adhesion molecule expression. The fact that SLE patients exhibit higher sICAM-1 and also higher fibrinogen concentrations may berelevant in the initiation and progression of atherosclerosis.
Results are presented as means (SD) or number of affected individuals and (%).
Indeed, ICAM-1 serves as a binding site for fibrinogen and SLE – systemic lupus erythematosus; RA – rheumatoid arthritis; CV- promotes adhesion and transendothelial migration of leukocytes cardiovascular; HDL – high density lipoprotein; LDL – low density lipoprotein, ns [31], an important early step in inflammatory vascular disease. We – non significant.
doi:10.1371/journal.pone.0044668.t001 did not find any difference in VCAM-1 serum levels among the September 2012 | Volume 7 | Issue 9 | e44668 Figure 1. Serum concentrations of vascular biomarkers in SLE and RA patients and non-inflammatory controls. sICAM-1– solubleintercellular adhesion molecule; sVCAM-1 – soluble vascular cell adhesion molecule; RHI–reactive hyperemia index; Aix – augmentation index; SLE –systemic lupus erythematosus; RA – rheumatoid arthritis.
doi:10.1371/journal.pone.0044668.g001 studied groups. In animal models, VCAM-1 expression is the control population and the relationship to atherosclerosis is considered a major early event in the atherosclerotic process uncertain [34,35]. Nevertheless, very recently sVCAM-1 was [32], and increased sVCAM-1 levels have been reported in lupus identified as an independent predictor of overall and cardiovas- nephritis [33]. However, in RA and SLE patients without renal or vascular disease, serum concentrations of VCAM-1 are similar to Table 2. Vascular biomarkers and results of PAT assessment in SLE and RA, after controlling for baseline covariates.
Adjusted for CV risk factors, disease duration and Results are presented as estimated marginal means (SE).
*Adjusted for the following covariates: age, disease duration, total cholesterol, HDL, LDL, triglycerides, aspirin, hydroxychloroquine, methotrexate use, and prednisolonedose.
1RHI and AIx results refer to 87 women with SLE and 75 with RA.
sICAM-1 – soluble intercellular adhesion molecule; sVCAM-1 – soluble vascular cell adhesion molecule; TM – thrombomodulin; TF – tissue factor; RHI – reactivehyperemia index; AIx – augmentation index.
doi:10.1371/journal.pone.0044668.t002 September 2012 | Volume 7 | Issue 9 | e44668 diseases remains uncertain [44–46]. Similarly, the improvement Table 3. Vascular biomarkers and endothelial function in following anti-rheumatic medication is not universally supported by the available literature [18]. Using PAT, we did not find anysignificant differences in RHI neither between patients and controls, nor between SLE and RA. RHI quantifies changes inpulse wave amplitude in response to reactive hyperemia, a measure of microvascular function. In the general population RHI is an independent predictor of adverse cardiac events [47], but its predictive value in rheumatic diseases has not beenestablished. The fact that we have included only females without previous CV events and normal renal function (relatively low risk population) may in part account for the comparable RHI found in patients and controls. In fact, only in more active SLE cases did RHI show a reduction. The follow up of these patients will allowus to ascertain the predictive value of RHI measured by PAT for Results are expressed as estimated marginal means (SE) adjusted for the development of CV event in SLE and RA patients.
prednisolone dose.
*RHI and AIx results refer to 87 women with SLE and 75 with RA.
Lupus patients presented higher AIx than RA patients and this SLE – systemic lupus erythematosus; RA – rheumatoid arthritis; sICAM-1 – difference remained significant after controlling for covariates. In soluble inter-cellular adhesion molecule; sVCAM-1 – soluble vascular cell apparently healthy subjects arterial stiffness is an independent adhesion molecule; TM – thrombomodulin; TF – tissue factor; RHI – reactive predictor of coronary heart disease and stroke [48], but the hyperemia index; AIx – augmentation index.
doi:10.1371/journal.pone.0044668.t003 predictive value of AIx in rheumatic diseases is unknown.
Cardiovascular risk factors and disease related features contribute There is growing evidence supporting the relationship between to arterial stiffening in SLE [49] and RA [50]. Shang et al found a inflammation and thrombotic complications of atherosclerosis correlation between carotid AIx and SLEDAI [51]. Increased (atherothrombosis). Interestingly, TM expression, a molecule with arterial stiffness was also associated with RA disease activity in anti-coagulant properties, is reduced during the inflammatory some, but not all, studies [18]. Increased AIx in SLE women process [12], and increased soluble TM levels probably indicate probably indicates a worse vascular condition.
EC injury. Together with increased TF, which is an initiator of the Taken together, our observations add to the evidence that the extrinsic coagulation cascade, this environment may raise the pathogenesis of atherosclerosis associated with inflammation may thrombogenic activity of plasma and contribute to cardiovascular differ in SLE and RA. Additionally, we found more pronounced events. Higher levels of TF in RA patients as compared to SLE early vascular changes in lupus patients, and when the disease is patients might be explained by the contribution of TNF to its active, which is in line with the higher risk for CV events expression [37]. Nevertheless, serum levels of adhesion molecules, TM, and TF may not accurately translate endothelial functionalexpression of these molecules, which is a limitation of our work.
A further effect of proinflammatory cytokines on EC is the inhibition of NO synthesis leading to endothelial dysfunction. In We would like to thank Mrs Ce´lia Monteiro for her help with PAT the general population, impaired endothelial function is a critical early step in the development of atherosclerosis [38] and predictsthe progression of structural arterial disease independently of conventional CV risk factors [39,40]. However, studies of Conceived and designed the experiments: MJS HC JEF VG. Performed endothelial function in inflammatory rheumatic diseases depicted the experiments: MJS DC-F. Analyzed the data: MJS HC JEF JCS VG.
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