George Konstantonis

Subclinical atherosclerosis in Systemic Lupus Erythematosus: Comparable risk with Diabetes Mellitus and Rheumatoid Arthritis☆

OBJECTIVE Although a high risk of subclinical atherosclerosis has been reported in Systemic Lupus Erythematosus (SLE), it is not adequately compared with that observed in other rheumatic and non-rheumatic high-cardiovascular (CVD) risk diseases, such as Rheumatoid Arthritis (RA) and Diabetes Mellitus (DM). Our objective was to evaluate the relative risk (RR) of subclinical atherosclerosis in SLE, RA and DM patients compared to healthy controls, and examine potential associations with traditional and disease-related CVD risk factors in SLE. METHODS We examined for atherosclerotic plaques 460 individuals (92% female) without CVD history, using carotid and femoral artery ultrasound: 115 SLE patients and matched 1:1 for age and gender RA, DM, and control subjects. Multivariate models were used to determine relative risk estimates for the number of atherosclerotic plaques in patient groups versus controls, and associations of plaques with traditional CVD and disease-related factors in SLE. RESULTS A nearly two-fold higher number of atherosclerotic plaques in the carotid and femoral arteries was detected in each of SLE, RA and DM groups compared to controls, after adjusting for the effect of traditional CVD risk factors (RR=1.80, 95% CI 1.05-3.08, p=0.033, RR=1.90 (1.11-3.26), p=0.019, RR=1.93 (1.14-3.28), p=0.015, respectively). In SLE patients, the number of atherosclerotic plaques was associated with age (p<0.001), smoking (p=0.016), hypertension (p=0.029), and cumulative corticosteroid dose (p=0.007). CONCLUSION The relative risk of subclinical atherosclerosis in SLE was comparable to that found in RA and DM, indicating that SLE patients merit a similar diligence in CVD risk assessment and management measures.

Subclinical Atherosclerosis Is Not Accelerated in Patients with Ankylosing Spondylitis with Low Disease Activity: New Data and Metaanalysis of Published Studies.

Objective. Chronic inflammatory rheumatic diseases are associated with accelerated atherosclerosis, but data in ankylosing spondylitis (AS) are limited and the relative contribution of inflammation versus classical cardiovascular (CV) risk factors remains a matter of controversy. We addressed this in an original study and a metaanalysis of previous studies. Methods. Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy [intima-media thickness (IMT), cross-sectional area], and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity, were examined in consecutive nondiabetic, CV disease (CVD)-free patients with AS. Healthy individuals carefully matched 1:1 with patients for age, sex, smoking habits, hyperlipidemia, and hypertension served as controls. A metaanalysis of original studies that examined subclinical atherosclerosis in patients with AS versus controls with comparable CVD risk factors was also performed. Results. Carotid and femoral atheromatic plaques were slightly less prevalent compared with controls in a contemporary cohort consisting of 67 patients with AS (82% men), aged 47.5 ± 12.5 years (mean ± SD), with a median disease duration of 12 years and a Bath AS Disease Activity Index (BASDAI) of 1.8 (interquartile range 0.4–3.6), of whom 66% were receiving anti-tumor necrosis factor (TNF) treatment. Carotid hypertrophy and stiffness, as well as aortic stiffness, were similar between patients and their matched controls. Metaanalysis of all published studies revealed a significantly increased carotid IMT, but not plaque burden, in AS versus controls. Notably, however, increased IMT was not evident in studies involving patients with low disease activity (mean BASDAI < 4) or in those studies that included > 50% of patients treated with anti-TNF. Conclusion. Low AS disease activity is not associated with accelerated atherosclerosis.

The Keith-Wagener-Barker and Mitchell-Wong grading systems for hypertensive retinopathy: association with target organ damage in individuals below 55 years.

Background: The usefulness of the hypertensive retinopathy classification by Keith–Wagener–Barker (KWB) in clinical practice remains controversial. The simplified Mitchell–Wong grading, combining the two initial KWB’ grades in one stage, is proposed as an alternative method; both systems are poorly validated regarding their association with target organ damage. Objective: In a population free of cardiovascular disease and diabetes, we aimed to investigate the interobserver and intraobserver agreement of both grading systems, their association with aortic stiffness, carotid hypertrophy or plaques and the role of age and sex on this association. Methods: Digital retinal images were obtained and graded – according to both classifications – by two independent and blinded observers; aortic stiffness (carotid-femoral pulse wave velocity, m/s) and common carotid hypertrophy (cross-sectional area, mm2) or plaques were assessed by tonometry and ultrasound, respectively. Results: From the gradable retinal photos obtained by 200 eyes of 107 consecutive patients (age: 54 ± 13 years, 51% men, 79% hypertensive patients) and after adjustments for confounders, the intraobserver and interobserver level of agreement was as following: KWB 88/64% and Mitchell–Wong 91/71%, respectively; exclusively in younger, not older, individuals aortic stiffness, carotid hypertrophy, but not plaques, were significantly associated with both systems, independently from confounders; no differences regarding target organ damage were found between stages 1 and 2 of KWB. Conclusion: Detecting early signs of hypertensive retinopathy may be of value in young individuals; the Mitchell–Wong seems preferable to the KWB classification system only for reasons of simplifying clinical practice.

The Additive Value of Femoral Ultrasound for Subclinical Atherosclerosis Assessment in a Single Center Cohort of 962 Adults, Including High Risk Patients with Rheumatoid Arthritis, Human Immunodeficiency Virus Infection and Type 2 Diabetes Mellitus

Background Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). Objective/Methods To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. Results Subclinical atheromatosis - defined as local plaque presence in at least on arterial bed - was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17 - 2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14 - 3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. Conclusion RA and HIV accelerate predominantly carotid than femoral. A “two windows” carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk.

Carotid and femoral atherosclerosis in antiphospholipid syndrome: Equivalent risk with diabetes mellitus in a case–control study

BACKGROUND Antiphospholipid syndrome (APS) may carry a worse prognosis for vascular complications when co-existing with subclinical atherosclerosis; however, the association between the two conditions remains ambiguous. METHODS We evaluated ultrasonographic markers of subclinical atherosclerosis in carotid and femoral arteries of 86 patients with thrombotic APS [43 primary APS (PAPS), 43 systemic lupus erythematosus-associated APS (SLE/APS)], 86 patients with diabetes mellitus (DM) and 86 healthy controls, individually matched for age and gender, and investigated their associations with traditional and disease-related factors in APS. RESULTS Carotid plaques were found in 28% of PAPS, 23% of SLE/APS, and 30% of DM patients versus 9% of controls (p = 0.006). Femoral plaques were found in 33% of PAPS, 19% of SLE/APS, 20% of DM, and 9% of controls (p = 0.032). Multivariate regression-derived relative risk estimates for atherosclerotic plaques in any location were 2.72 for PAPS, 2.63 for SLE/APS, and 1.98 for DM (p = 0.004, 0.009, and 0.032 respectively), after adjusting for age, gender, hypertension, dyslipidemia, smoking, BMI, and family history of coronary disease. Among patients with APS, atherosclerotic plaques were associated with the number of traditional CVD risk factors in both PAPS (RR = 2.75, p < 0.001) and SLE/APS (RR = 1.84, p < 0.001), and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS. CONCLUSIONS Patients with PAPS and SLE/APS have a nearly 2.5-fold risk of atherosclerotic plaques in carotid and femoral arteries compared to healthy controls, similar to DM patients. Atherosclerotic plaques are associated with the number of traditional risk factors in both APS and SLE/APS, and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS.

Phenotypes of office systolic blood pressure according to both brachial and aortic measurements: frequencies and associations with carotid hypertrophy in 1861 adults.

Background/aim: Aortic SBP (aSBP) associates with arterial damage more consistently than brachial SBP (bSBP). However, it is unknown how often aSBP is normal in the presence of elevated bSBP, and vice versa; if SBP phenotyping on the basis of bSBP and aSBP cut-off values improves cardiovascular risk stratification. We tested the frequency of four office SBP phenotypes: type I (both normal bSBP and aSBP); type II (high bSBP but normal aSBP); type III (normal bSBP but high aSBP), and type IV (both high bSBP and aSBP), the probability of each phenotype to be associated with increased arterial damage, using type Ia (i.e. normal bSBP and low-normal aSBP) as reference. Methods: In 1861 participants (age: 54 years, 49.1% men), we measured simultaneously bSBP, aSBP, and carotid cross-sectional wall area with ultrasound. Results: Depending on the applied cut-off values, type II and type III phenotypes represented together 5–11% of the population (0.9–3.4 and 1.8–10.3%, respectively) and type IV around 20%. Subgroups with phenotypes, Ib (i.e. normal bSBP and high-normal aSBP), II, III, and IV had gradually significantly higher probability (by 1.37–1.91, 2.3–3.3, 3.3–8.9 times, and 4.18–6.25, respectively) to present elevated carotid artery cross-sectional wall area compared with the reference group, even after adjustment for DBP and other confounders. Conclusions: Type II (i.e. isolated high bSBP) and type III (i.e. isolated high aSBP) office SBP phenotypes were common and had intermediate level (between types I and IV) of arterial damage.

Progression of subclinical atherosclerosis in systemic lupus erythematosus versus rheumatoid arthritis: the impact of low disease activity

Objectives The progression of subclinical atherosclerosis in SLE and RA has not been comparatively assessed. We sought to investigate the impact of low disease activity and other disease-related factors on atherosclerosis progression in SLE vs RA. Methods We performed a 3-year follow-up carotid and femoral artery ultrasound in 101 patients with SLE, 85 with RA and 85 controls after a baseline examination in 115 SLE and 1:1 age- and gender-matched RA patients and controls. We used logistic regression to compare atherosclerosis progression (new plaque development) between SLE and RA vs controls, and assess determinants of progression in SLE patients with different lupus low disease activity state (LLDAS) durations, adjusting for disease-related factors, antihypertensives, antiplatelets, statins and the Systemic Coronary Risk Evaluation 10-year cardiovascular risk. Results The odds ratio (OR) of plaque progression vs controls was significantly higher in SLE (OR = 2.81, P = 0.043), but not in RA (OR = 2.22, P = 0.109). Results were similar in patients with low disease activity (88% of SLE, 74% of RA). Multivariate determinants of progression in SLE included antiphospholipid antibodies (OR = 2.00, P = 0.043) and Systemic Coronary Risk Evaluation (OR = 2.87, P = 0.019) for all patients, and additionally cumulative corticosteroid dose during follow-up (OR = 1.38, P = 0.013) and disease duration (OR = 1.20, P = 0.022) for patients in LLDAS over entire follow-up. Results were similar for patients with shorter LLDAS durations (>75% or >50% of follow-up). Conclusion Plaque progression is accelerated in SLE regardless of disease activity, and is associated with antiphospholipid antibodies and the Systemic Coronary Risk Evaluation. In LLDAS, cumulative corticosteroid dose and disease duration are additional determinants of progression.

PS4:68 Carotid and femoral atherosclerosis in antiphospholipid syndrome: equivalent risk with diabetes mellitus in a case-control study

Background Antiphospholipid syndrome (APS) may carry a worse prognosis for vascular complications when co-existing with subclinical atherosclerosis, however, the association between the two conditions remains ambiguous. Methods We evaluated ultrasonographic markers of subclinical atherosclerosis in carotid and femoral arteries of 86 patients with thrombotic APS (43 primary APS (PAPS), 43 systemic lupus erythematosus-associated APS [SLE/APS]), 86 patients with diabetes mellitus (DM) and 86 healthy controls, individually matched for age and gender, and investigated their associations with traditional and disease-related factors in APS. Results Carotid plaques were found in 28% of PAPS, 23% of SLE/APS, and 30% of DM patients versus 9% of controls (p=0.006). Femoral plaques were found in 33% of PAPS, 19% of SLE/APS, 20% of DM, and 9% of controls (p=0.032). Multivariate regression-derived relative risk estimates for atherosclerotic plaques in any location were 2.72 for PAPS, 2.63 for SLE/APS, and 1.98 for DM (p=0.004, 0.009, 0.032 respectively), after adjusting for age, gender, hypertension, dyslipidemia, smoking, BMI, and family history of coronary disease. Among patients with APS, atherosclerotic plaques were associated with the number of traditional CVD risk factors in both PAPS (RR=2.75, p<0.001) and SLE/APS (RR=1.84, p<0.001), and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS. Conclusions Patients with PAPS and SLE/APS have a nearly 2.5-fold risk of atherosclerotic plaques in carotid and femoral arteries compared to healthy controls, similar to DM patients. Atherosclerotic plaques are associated with the number of traditional risk factors in both APS and SLE/APS, and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS.Abstract PS4:68 Table 1 Baseline characteristics of study participants and vascular ultrasonagraphic findings by disease groupAbstract PS4:68 Table 2 Relative risk of increased atherosclerotic plaque numbers conferred by participant disease group versus controls, after adjusting for the effect of traditional CV risk factorsAbstract PS4:68 Table 3 Relative risk conferred by ASP-related factors for increased number of subclinical atherosclerotic plaques in the carotid and ferroral arteries, corresponding 95% confidence intervals (CI), and p-values for interaction between each APS-related factor and APS type

Predictors of morbidity and mortality in early systemic sclerosis: Long-term follow-up data from a single-centre inception cohort

OBJECTIVES To determine predictors of morbidity and mortality in systemic sclerosis (SSc) in a long-term follow-up of an inception cohort of early SSc patients. METHODS We evaluated clinical manifestations, laboratory and lung function tests at disease onset as predictors of morbidity and mortality in 3rd, 6th and 9th year in SSc patients recruited within 12 months of disease onset. RESULTS A total of 115 SSc patients (97 women, mean age 48.1 ± 13.5 years, 54 diffuse subtype) were included. In multivariate regression analysis, predictors at disease onset for the presence of pulmonary fibrosis in 6th year of follow-up were diffuse subtype (OR: 4.4, p = 0.033), digital ulcers (OR: 7.9, p = 0.014) and esophageal involvement (OR: 4.79, p = 0.038). Arrythmias at disease onset predicted pulmonary hypertension (OR: 6.05, p = 0.022), while age (OR: 1.12, p = 0.002) and anti-Scl70 (OR: 4.3, p = 0.038) predicted arrhythmias in 6th year. During a follow-up of 101.8 ± 48.5 months, 23/115 patients died. Cox proportional hazard models analysis revealed 6 independent predictors of mortality present at disease onset: age at disease onset (45-59 years (HR: 3.0, p = 0.098), ≥60 years (HR: 4.3, p = 0.073), male gender (HR: 3.63, p = 0.025), diffuse subtype (HR: 2.83, p = 0.095), pulmonary fibrosis (HR: 3.7, p = 0.032), echocardiography-diagnosed pulmonary hypertension (HR = 7.49, p = 0.008) and DLCO < 60% (HR: 3.17, p = 0.035). Mortality rates at 3 and 6 years were 14% and 24% for patients with 3 independent predictors and 46% and 53% for patients with 4-6 predictors, respectively. CONCLUSION Clinical phenotypes at disease onset may predict morbidity and mortality in SSc and guide treatment decisions.

PS 05-57 24-HOUR AORTIC BLOOD PRESSURE VARIABILITY IS BETTER ASSOCIATED WITH CAROTID INTIMAL-MEDIAL THICKNESS AND CROSS-SECTIONAL AREA THAN BRACHIAL BLOOD PRESSURE VARIABILITY: THE SAFAR STUDY

Objective: We aim to investigate whether 24-hour (24-h) aortic blood pressure variability (BPV) is better associated with carotid intima-media thickness (CIMT) and cross-sectional area (CCSA)than 24-h brachial BPV. Design and Method: 445 consecutive individuals (aged 54.0 ± 13.0 years, 57.1% men) referred for consultation on hypertension underwent brachial and aortic 24-h ambulatory blood pressure monitor with a validated device (Mobil-O-Graph NG apparatus, Germany). The average real variability (ARV) and time-weighted standard deviation (wSD) of 24-h systolic BP were calculated. The internal and external lumen diameters and IMT of bilateral common carotid arteries were measured by ultrasonography. CCSA was calculated by carotid lumen diameters. Averages of bilateral CIMT and CCSA were used for the analysis. Results: In the univariate analysis, brachial and aortic BPVs all significantly correlated with CIMT and CCSA (P < 0.001, Table 3). In the multiple regression analysis after adjustment for confounders, AVRs and wSDs in both brachial and aortic were associated with CIMT, but no difference was found between brachial and aortic BPVs. CCSA was only significantly associated with aortic wSD. In the multiple logistic regression analysis as shown in Figure 2, CIMT > 900 &mgr;m was significantly and independently associated with aortic ARV and wSD (OR = 1.33; 95% CI: 1.02–1.74; OR = 1.58; 95% CI: 1.16–2.15; respectively), but not with brachial ARV or wSD. CCSA > 90th percentile was significantly and independently associated with aortic ARV (OR = 1.41; 95% CI: 1.02–1.96), rather than brachial ARV. No association was found between CCSA > 90th percentile and wSDs. In ROC curve analysis, aortic wSD identified CIMT > 900 &mgr;m and CCSA > 90th percentile better than brachial wSD (AUC: 0.72 VS. 0.69, P = 0.046; 0.72 VS. 0.68, P = 0.01; respectively), no difference was found between aortic and brachial ARVs. Conclusions: Although brachial and aortic 24-h systolic BPVs were both significantly associated with CIMT and CCSA, the 24-h aortic systolic BPV was superior to brachial systolic BPV in the identification of arterial damage.