Patients

The study was conducted in accordance with the Declaration of Helsinki and guidelines of the local ethics committee of the Ruhr-University Bochum (separate ethics approval was not needed for this retrospective study according to the local ethics committee regulations). All data analyzed are based on routine clinical examination; no patient underwent additional examination procedure for the purpose of this study. Written informed consent was obtained from all patients for the use of clinical and duplexsonography data, and the use of blood samples for observational research purposes.

Ultrasound examination

Baseline ultrasound examinations of carotid and femoral arteries of all 190 SLE and SSc patients were performed by two experienced investigators (JS and SMW) at the Department of Nephrology and Rheumatology, Marienhospital Herne, University of Bochum using the Siemens Acuson Sequoia 512 Ultrasound system (Siemens Medical Solutions, Erlangen, Germany) equipped with an 8 L5 linear transducer. Examinations were performed at 8.0 MHz for extracranial carotid and femoral arteries in several longitudinal and transversal section views to assess IMT and to identify atherosclerotic plaques (B-mode and color-coded duplexsonography). To avoid interobserver bias and because sonography examiners were not blinded for diagnosis in the routine clinical setting, the recorded anonymous images were evaluated only by one investigator (MF) without knowledge of patient data and characteristics.

Carotid artery assessment of intima-media thickness and atherosclerotic plaques

We documented the mean of six IMT measurements at the far wall of the CCA over a 1 cm long segment, 1 to 2 cm proximal to carotid bifurcation for both sides. We compared the power of left and right IMT values and documented a mean IMT of the CCA as the mean of 12 measurements among both sides. The areas of plaque were not included in the IMT assessment. Because the term pathologic intima-media thickening (pIMT) for assessment in the CCA is widely used but not well defined, we compared three different definitions of pIMT: a European version (pIMT > 0.9 mm) [24], a German version (men 40 to 70 years old, pIMT > 1.0 mm; women 40 to 54 years old, pIMT > 0.85 mm and 55 to 70 years old, pIMT > 1.0 mm) [25], and an Atherosclerosis Risk in Communities (ARIC) version, defined by the 90th percentile for different age and sex groups out of the ARIC cohort [26]. To apply the most sensitive definition of pIMT, a patient was diagnosed to have pIMT of the CCA when the left or right IMT CCA fulfilled these conditions (even when the mean of left and right IMT CCA was lower). Additionally, a focal thickening of intima-media that did not fulfill the definition of plaque might have fulfilled the definition of pIMT.

We screened the arteries for carotid plaques in common, internal and external carotids. According to the Mannheim cIMT consensus, a plaque was defined as a focal thickening of intima-media >0.5 mm or 50% of surrounding intima-media into the arterial lumen, or a focal thickening >1.5 mm [27].

Femoral artery assessment of intima-media thickness and atherosclerotic plaques

Analog to the assessment of mean IMT of the CCA, the mean IMT of the common femoral artery (CFA) was calculated as the mean of 12 IMT measurements at the far wall of the CFA (six at each side). Plaques were investigated with respect to the common, proximal superficial and deep femoral artery on both sides. Because femoral artery IMT measurement is not routinely performed, normal or rather pathologic IMT values as well as a definition of plaque are not given particularly for femoral arteries. Femoral artery plaque was thus defined similar to carotid artery plaque as a focal thickening of intima-media >0.5 mm or 50% of surrounding intima-media into the arterial lumen, or a focal thickening >1.5 mm [27]. In addition, we used and compared the definitions of pIMT and atherosclerotic plaque as given for carotid arteries with the findings at the femoral arteries.

Assessment of traditional cardiovascular risk factors for atherosclerosis

The assessed traditional risk factors for atherosclerosis were age, sex, body mass index, arterial hypertension, diabetes mellitus, smoking (current or former and pack-years), dyslipidemia and family history of cardiovascular disease. Blood pressure levels were evaluated as the mean of left and right brachial artery measurements after at least 5 minutes of rest or (whenever possible) by 24-hour outpatient blood pressure measurement. Hypertension was defined by blood pressure >140/90 mmHg or use of antihypertensive drugs. In cases when a calcium channel blocker was prescribed for secondary Raynaud phenomenon, we did not rate this as antihypertensive drug use, except if arterial hypertension was documented previously and the calcium antagonist was given to treat hypertension and Raynaud phenomenon at the same time. Dyslipidemia was defined by elevated plasma cholesterol (>200 mg/dl for age 18 to 29 years; >220 mg/dl for age 30 to 40 years; >240 mg/dl for age >40 years), plasma low-density lipoprotein cholesterol (>160 mg/dl) and/or plasma triglyceride (>200 mg/dl) levels, or use of lipid-lowering drugs such as HMG co-inhibitors [28]. Plasma high-density lipoprotein cholesterol levels were assessed as a protective vascular factor.

Assessment of potential nontraditional and disease-related determinants for atherosclerosis

We evaluated the following nontraditional and disease-related determinants as potential risk factors associated with accelerated atherosclerosis: in SLE patients, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index score (SLEDAI) [29] and disease damage was assessed by the Systemic Lupus International Collaborating Clinics damage index score (SLICC) [30]. In SSc patients we evaluated the modified Rodnan skin score [31]. Organ involvement was recorded including Raynaud phenomenon, pulmonary hypertension, coronary heart disease and peripheral arterial vascular disease (defined by obstructive vessel disease with claudicatio intermittens). We also assessed family history of connective tissue diseases, disease duration since diagnosis and age at diagnosis.

Previous immunosuppressive treatment was determined, such as use of prednisolone (duration of treatment, mean daily dose in the last 5 years and cumulative dose), hydroxychloroquine (HCQ), azathioprine (AZA) and cyclophosphamide (CYP) (duration of treatment and cumulative dose, if applicable). Sufficient data for duration of corticosteroid (CS) treatment were given in 96.8% of patients and for cumulative CS dose in 92.4% of patients. For duration of use and cumulative dose of HCQ, AZA and CYP, data were adequate in 99.5%, 98.4% and 99.5% of patients, respectively.

Routine laboratory assessment included C3c and C4c as disease activity markers for SLE patients, as well as C-reactive protein. Renal function was given by the glomerular filtration rate (Mayo formula). For analysis of the potential role of different autoantibodies, blood samples of all patients were tested by standard immunofluorescence test using Hep2 cells for antinuclear antibodies and by enzyme-linked immunosorbent assay (Euroimmune, Lübeck, Germany) for the following autoantibodies: double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Sm, C1q, SS-A, SS-B, U1RNP, Pm-Scl, RNP, RIP-PP, nucleosomes, centromeres, Scl-70 and antiphospholipid antibodies (cardiolipin IgG and IgM, β₁-glycoprotein-1 IgG and IgM, lupus anticoagulans).

Follow-up assessment of cardiovascular events

Patients were followed up by routine clinical visits at the Department of Dermatology, Venerology, and Allergology, University of Bochum. To compare the predictive value of pIMT, carotid and femoral artery plaques for CVEs, a review of patient records until December 2011 (5 years after baseline of the last included patient) was performed. CVEs were defined as coronary events (new angina pectoris or myocardial infarct requiring treatment), cerebrovascular events (transient ischemic attack or stroke), peripheral arterial vascular events (claudicatio intermittens, ischemic pain due to embolization) or death related to cardiovascular disease.

Statistical methods

Comparison of baseline carotid and femoral artery duplexsonography results in systemic sclerosis patients

Comparison of carotid and femoral artery definitive atherosclerosis (plaques) in systemic sclerosis patients

A total of 84 carotid artery plaques and 90 femoral artery plaques were detected in 59 SSc patients. Thirty-five carotid artery plaques were found in 27 patients (30%) on the left side compared with 49 plaques in 36 patients (40%) on the right side (P = 0.123). The distribution of carotid artery plaques according to the CCA, the region of the bulb, ICA and ECA is shown in Figure 1. In 9 to 18 patients (10 to 20%) carotid plaques would not have been detected if carotid ultrasound examination was limited to one side.

Forty-three femoral artery plaques were found in 36 patients (40%) on the left side and 47 plaques in 39 patients (43.3%) on the right side (P = 0.646). In 8 to 23 patients (8.9 to 25.6%) the plaques would have been missed if femoral ultrasound examination was limited to one side. Twenty-six patients (28.9%) had atherosclerotic plaques in only one of the four vascular territories. The overall frequency of carotid and femoral artery plaques was not different (50% vs. 52.2%; P = 0.845), but the plaque distribution varied in individual patients: in 12 patients (13.3%), plaque was only located at the carotid arteries; in 14 patients (15.6%), plaque was observed isolated at femoral arteries. In approximately every sixth to seventh patient, atherosclerosis would not have been detected if routine ultrasonography was limited to the carotid arteries.

Association of potential risk factors with intima-media thickness and atherosclerotic plaques in systemic sclerosis patients

Comparison of baseline carotid and femoral artery duplexsonography results in SLE patients

Association of potential risk factors with intima-media thickness and atherosclerotic plaques in SLE patients

Longitudinal analysis of cardiovascular events during follow-up in SSc and SLE patients

Overall, follow-up data of CVEs were available for 78/90 (87%) SSc patients and 51/100 (51%) SLE patients. During the observational period of in a total 650.1 person-years (mean 60.5 months, median 65.5 months, range 8 to 82 months), 24 CVEs were recorded in 19 out of 129 patients (15%): 13 events in 11/78 (14%) SSc patients (coronary events, n = 7; peripheral arterial vascular events, n = 3; death related to cardiovascular disease, n = 3) and 11 CVEs in 8/51 (16%) SLE patients (coronary events, n = 5; cerebrovascular events, n = 3; peripheral arterial vascular events, n = 3). The incidence of CVEs was 13 per 388.5 person-years (IDR = 3.35 per 100 person-years) in SSc patients and 11 per 261.6 person-years (IDR = 4.2 per 100 person-years) in SLE patients. Six patients (five SSc and one SLE) died due to other causes (one after stem cell transplantation, one severe pneumonia, one lung embolism, one breast cell cancer, one suicide, one unknown cause).

According to pathologic IMT of the CCA, only 7/19 (36.8%) patients with CVEs had pIMT according to the European definition (>0.9 mm), only 4/19 (21.1%) patients would meet the ARIC definition, and merely 2/19 (10.5%) patients the German definition of pathologic IMT.

According to the presence of plaque, CVEs were distributed as follows: 18 CVEs were observed within 183.75 person-years of follow-up (IDR = 9.8 per 100 person-years) in 15 out of 40 patients (37.5%) that had both carotid and femoral artery plaques; three CVEs per 200.6 person-years (IDR = 1.5 per 100 person-years) occurred in 2/37 (5.4%) patients that had only carotid (1/19, 5.2%) or only femoral artery plaques (1/18, 5.6%); and three CVEs per 265.75 person-years (IDR = 1.1 per 100 person-years) in 2/52 patients (3.8%) that had neither carotid nor femoral artery plaques. The incidence rate of CVEs during follow-up was thus significantly higher in patients with carotid and femoral artery plaque compared with patients with only carotid or only femoral artery plaque (rate ratio = 6.55, 95% CI = 1.9 to 22.2, P = 0.003) or compared with patients without atherosclerotic plaque (rate ratio = 8.68, 95% CI = 2.6 to 29.5, P < 0.001) (Figure 2). Patients with only carotid plaque or only femoral plaque were not at higher risk compared with patients without plaque (rate ratio = 1.32, 95% CI = 0.3 to 6.6, P = 0.731).

Analysis of time to first CVE revealed that SSc and SLE patients with coexistent carotid and femoral artery plaque are at higher risk (Figure 3A,B). Results from univariate analysis of potential predictors of CVEs during follow-up in SSc and SLE patients are presented in Table 8.

Intima-media thickness as surrogate marker of atherosclerosis in the general population

Measurement of intima-media thickening in the CCA is a widespread accepted surrogate marker for subclinical atherosclerosis [32, 33], although the clinical importance for the individual patient was recently challenged in the general population [34, 35]. Although the assessment of both IMT and atherosclerotic plaques is recommended for epidemiological trials studying cardiovascular disease, it is important to keep in mind that IMT not only represents subclinical atherosclerosis but is also influenced by nonatherosclerotic remodeling [27]. Presence of plaque is of overriding importance in reflecting cardiovascular risk [36, 37].

What is the rationale to determine a fixed definition of pathological increased intima-media thickness?

Although the term pathologic IMT is widely used, it is not well defined. According to the guidelines of the European Society of Cardiology, pIMT is defined as a focal IMT >0.9 mm, regardless of gender [24]. Different cutoff values were reported in several studies, ranging between IMT ≥1.0 mm and ≥1.18 mm for prediction of CVEs [38–40]. However, a fixed definition does not take regard of an increase in IMT with older age and differences between men and women, which is well documented in large studies [26]. For the German population only one small study reports reference values with respect to age and gender for pIMT: a cIMT > 1.0 mm in men 40 to 70 years old, cIMT > 0.85 mm in women 40 to 54 years old and cIMT > 1.0 mm in women 55 to 70 years old were defined as pIMT [25].

In SLE patients, Thompson and colleagues evaluated a mean IMT progression rate of 0.011 mm/year, which was comparable with the IMT progression rate in controls [4]. These rates also seem comparable with the rate of mean IMT progression in healthy controls evaluated in the large ARIC study of approximately 0.01 mm/year [26]. In our cohort, with respect to the results of baseline linear regression analysis, carotid IMT increased slightly less with 0.007 mm and 0.006 mm per age year in SSc and SLE patients, respectively. For that reason, in addition to the fix definition of pIMT given by the European Society of Cardiology [24], we also used an age-adjusted and sex-adjusted definition of pIMT for the German population [25], and calculated an "ARIC definition" for pIMT, defined by the 90th percentile of a large cohort from the ARIC study [26].

Is carotid intima-media thickness measurement a useful parameter for atherosclerosis assessment in SSc and SLE patients?

Previous studies in SSc and SLE patients showed a marked heterogeneity in IMT results, raising the question of whether IMT measurement is generally useful in these disease entities. Two recent meta-analyses reported a moderate statistically significant increased IMT in SSc and SLE patients compared with healthy controls [1, 2]. However, the clinical relevance of these findings is questionable because the "thickened" IMT of SSc and SLE patients seems to be within the range of normal values, and the mean IMT of controls was surprisingly low in some studies (and none of these studies analyzed the predictive value for CVEs). Moreover, most of the included studies in these meta-analyses primarily searched for a difference in IMT in the CCA, but atherosclerotic plaques at the bulb, ICA and ECA were not evaluated. Additionally, it is unclear whether other studies were not published because they also primarily focused on cIMT without looking for plaques and found no difference in cIMT (publication bias).

In our study we were able to show in both SSc and SLE patients that atherosclerotic plaques frequently occur without a thickened intima-media, regardless of how the definition of pIMT was applied. Our observed frequency of atherosclerotic plaques is consistent with studies of larger patient cohorts in SSc [10, 12, 15] and SLE [3–5].

The currently largest case–control study in 111 SSc patients by Nordin and colleagues reported a 48% frequency of plaques in patients compared with 41% in controls [10], but the prevalence of atherosclerotic plaques in SSc might have been underestimated when ultrasound examination did not include the ICA and ECA and by application of an unusual definition of plaque as IMT >1 mm and 100% increase of IMT compared with the adjacent wall. In contrast, Lukjanowicz and colleagues reported an increased frequency of atherosclerotic plaques in 25 of 62 SSc patients (40.3%) compared with no plaques in 30 healthy controls, also without any signs of intima-media thickening in SSc patients, which supports our observations (results published as abstract, details of ultrasound examination are unknown) [11, 12].

In SLE patients, Roman and colleagues (n = 197) [3], Thompson and colleagues (n = 217) [4] and Anania and colleagues (n = 114) [5] reported a frequency of 37 to 43% carotid artery plaques compared with 15 to 30% in healthy controls, and found no difference [4, 5] or even a lower cIMT [3] in SLE patients. In large studies without comparison with healthy controls, Manzi and colleagues (n = 175) [41] and Kao and colleagues (n = 392) [20] have observed carotid plaques in 30 to 40% of SLE patients.

Carotid atherosclerosis is thus frequent and may have been previously underestimated in both connective tissue diseases, when only cIMT was measured. An extension of carotid ultrasound examination distal to the CCA segment for plaque assessment is highly recommended, because the majority of plaques are localized distant to the CCA (only ~5% of plaques) at the region of the bulb (~40%), ICA (~45%) and ECA (~10%). Additionally, the use of a common definition of atherosclerotic plaque would be desirable to achieve comparable results between further studies [27].

Is carotid intima-media thickness measurement a useful parameter for prediction of cardiovascular events in SSc and SLE patients?

In general, the discrepancy between manifest atherosclerotic plaques and the absence of intima-media thickening raises the question of whether IMT measurement is useful in clinical routine care of SSc and SLE patients. With respect to clinically relevant atherosclerosis (that is, predictive of CVEs), IMT measurement was not as useful as detection of plaques for predicting CVEs in our cohort. Even if patients with incident CVEs have a higher baseline cIMT, as observed in a one large cohort of SLE patients (0.80 vs. 0.64 mm) [20], they would not have been identified as at risk of CVEs in routine clinical care if this increase does not fulfill the definition of pathologic IMT. Moreover, in accordance with our results, this large cohort study by Kao and colleagues in SLE patients revealed that assessment of plaques is more important than measurement of IMT for risk prediction of incident CVEs (HR 4.26 vs. 1.35, respectively). In SSc patients, large cohort studies of CVEs including atherosclerotic plaque assessment are lacking. Our data suggest that in SSc patients the detection of atherosclerotic plaques but not IMT is of clinical relevance in predicting CVEs as well.

Is additive femoral artery sonography useful to evaluate atherosclerosis and to identify SSc and SLE patients at risk of cardiovascular events?

Our results of plaque localization, representing differences between left and right sides as well as carotid and femoral artery plaque presence, underline the results of Belcaro and colleagues [16], who showed the necessity of bilateral carotid and femoral artery examination to estimate the presence of atherosclerosis accurately (in accordance with carotid arteries, the evaluation of atherosclerotic plaques seems to be more useful than the evaluation of IMT in femoral arteries). Furthermore, in concordance with the results of Belcaro and colleagues [16], the combined assessment of carotid and femoral artery plaques predicted significantly more CVEs during follow-up than the measurement of only one vascular segment. With respect to confounder-adjusted hazards, patients with coexistent carotid and femoral artery plaque had an approximate HR of 6 in contrast to patients with only carotid or only femoral artery plaque as well as in contrast to patients without plaque. In comparison, Kao and colleagues observed a HR of 4.3 for carotid plaque predictive of "hard" CVEs in SLE patients [20] but did not assess the femoral arteries. In our cohort of SSc and SLE patients, if we did not account for coexistent femoral artery atherosclerosis, we would have estimated a confounder-adjusted HR of 3.5 for carotid plaque predictive of CVEs (data shown in Additional file 3). The risk of CVEs by presence of carotid artery plaque would thus have been overestimated in patients without plaque and underestimated in patients with unknown coexistence of femoral artery plaque. Taken together, additional screening of the femoral artery is very useful to identify SSc and SLE patients at high risk.

Association of atherosclerosis with traditional and nontraditional cardiovascular risk factors, immunosuppressive medications and SSc and SLE specific variables

In SLE, previous studies have reported several traditional cardiovascular risk factors such as age, male sex, arterial hypertension, obesity, dyslipidemia and family history, but also disease-related factors such as disease duration, disease activity, damage score, renal involvement and prednisolone use to be associated with atherosclerosis [3, 4, 42–53]. There is still a controversial debate as to whether accelerated atherosclerosis is or is not a feature of SSc [8, 9]. However, in studies indicating a higher prevalence of atherosclerosis in SSc, an association with age, arterial hypertension, triglyceride levels, smoking, disease duration and cumulative CS dosage was observed [10, 54, 55]. In our cohort in univariate analysis, age, male gender, postmenopausal status in women, arterial hypertension, dyslipidemia and nicotine pack-years were associated with atherosclerotic plaques. Moreover, the presence of plaque was associated with a higher age at diagnosis, but not with disease duration in both patient groups. There was no association with illness-specific activity and damage scores such as the Systemic Lupus Erythematosus Disease Activity Index and the Systemic Lupus International Collaborating Clinics damage index in SLE, or the modified Rodnan Skin Score in SSc patients. Notably, age was the strongest factor associated with CCA and CFA IMT. Furthermore, postmenopausal status correlated with CCA IMT, and nicotine pack-years with CFA IMT, whereas other cardiovascular risk or disease-related factors did not. In multiple logistic regression analysis, age and nicotine pack-years were independently associated with atherosclerotic plaque occurrence over all patients. Additionally, in SSc patients the cumulative prednisolone dose was associated with atherosclerotic plaque, supporting the idea that prednisone use may be a deteriorating factor for atherosclerosis in SSc [55]. In SLE patients, corticosteroids have shown to increase cardiovascular risk factors such as arterial hypertension and body weight, whereas HCQ leads to a decrease of serum cholesterol levels [56]. Moreover, CYP, HCQ and CS use seem to be associated with a lower frequency of atherosclerotic plaque in SLE patients [49]. However, in our smaller cohort we found no significant differences in CYP, HCQ or CS medication between SLE patients with or without atherosclerotic plaque.

Interestingly, in multivariate analysis AZA use seemed to be associated with atherosclerotic plaques in SLE patients. AZA was recently found to be associated with an increased cIMT in pediatric SLE patients [47] and with vascular events in adult SLE patients [57]. Because of the limited number of SLE patients available for follow-up analysis in our cohort we were not able to analyze AZA as contributing risk factor for CVEs.

Association of autoantibodies with atherosclerosis in SSc and SLE

High titers of antinuclear antibodies were found to be associated with coronary atherosclerosis [58]. In our cohort, current or former ANA were not associated with IMT, and neither were with the presence of atherosclerotic plaque. Antiphospholipid antibodies are supposed to activate endothelial cells and are hence suspected to accelerate the atherosclerosis process [59], and different other autoantibodies were reported to correlate with cardiovascular disease in SLE. Roman and colleagues found anti-Sm, anti-RNP and anticardiolipin antibodies significantly more often in SLE patients without compared with those with carotid artery plaque [49]. Similarly, other studies reported that Sm antibodies may have cardioprotective effects and were less often observed in SLE patients with coronary atherosclerosis or carotid artery plaque [52, 60]. In our cohort, we found no difference in atherosclerotic plaque frequency between SLE patients with or without anti-Sm or anticardiolipin antibodies. Recently, dsDNA antibodies were suggested to contribute to noncalcified coronary plaque [44]. In contrast, in our cohort dsDNA antibodies were found less frequently in patients with atherosclerotic plaques in univariate analysis, but were not confirmed in multivariate analysis (which can be explained by the fact that dsDNA antibodies occurred more often in older SLE patients in our cohort). Surprisingly, in multivariate analysis absence of the less disease-specific ssDNA antibodies did qualify as a statistically significant independent predictor for atherosclerotic plaque in SLE patients. We found no confounder that can explain this unexpected finding; this observation may be verified in further studies.

Atherosclerosis was found more often in anti-centromere antibody-positive SSc patients [10], and coronary artery calcification less often in anti-SCL70 antibody-positive SSc patients [61]. Coronary flow reserve was reported to be lower in diffuse cutaneous SSc patients [62], perhaps due to microvascular involvement rather than atherosclerosis [8]. In SSc patients of our cohort, atherosclerosis was also found more often in the limited than diffuse cutaneous subtype, hence centromere antibody was found more often and SCL70 antibody less often in patients with atherosclerotic plaque. However, these findings in our cohort were due to the older age of patients with centromere antibodies compared with patients with Scl-70 antibodies; after adjustment for age there was no statistically significant difference (data not shown).

Limitations of the study

Whether the number of patients with plaque from the SSc and SLE patients was high enough to build two separate logistic regression models with a suitable number of events per variable, it was not for Cox regression and the analysis of both diseases was combined to ensure at least five patients with CVEs per variable [63, 64]. We are confident that this combined analysis was feasible because we did not observe a significant difference in the frequency or distribution of atherosclerotic plaque nor in the incidence of CVEs between SSc and SLE patients. However, we were not able to differentiate potential risk factors for CVEs between SSc and SLE patients.

The higher follow-up rate of SSc patients (87%) than SLE patients (51%) might be explained by the inclusion of SSc patients in the German network for SSc. Because the loss of follow-up in SLE patients (49%) could have biased our findings, we analyzed whether risk factors for CVEs were more or less prevalent in SLE patients without follow-up: SLE patients available for follow-up analysis had at baseline a slightly shorter disease duration (mean 5 years vs. 6 years), no difference in SLICC damage index score (median 2 vs. 2) and a slightly higher SLEDAI (median 12 vs. 8) compared with patients without follow-up. Baseline coronary heart disease was prevalent in 3/51 (5.9%) SLE patients available versus 6/49 (12.2%) SLE patients nonavailable for follow-up, male sex in 4/51 (7.8%) versus 9/49 (18.4%) and coexistence of carotid and femoral artery plaques in 12/51 (23.5%) versus 13/49 (26.5%) patients, respectively. SLE patients without follow-up were thus most probably at a slightly higher risk for CVEs and we might have underestimated the true incidence of CVEs in SLE patients. On the other hand, the incidence of CVEs in our SLE cohort was higher compared with previous larger cohort studies of SLE patients [18–20]. This difference might be based on unequal study populations, due to a varying definition of CVEs, and patients without follow-up may have been more likely than those without development of CVEs or who died due to other causes (in this scenario we might have overestimated the "true" incidence of CVEs in SLE patients).

However, besides these limitations our study primarily focused on the value of duplexsonography evaluation and demonstrated the uselessness of IMT measurement in contrast to plaque assessment and highlighted the value of additive femoral artery screening for assessment of atherosclerosis and to identify SSc and SLE patients at high risk of incident CVEs. Larger prospective studies are required to estimate the "true" incidence of CVEs and to evaluate further potential risk factors for CVEs, particularly in SSc patients.