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 [22
], Kaloudi and colleagues [23
], and Bartoli and colleagues [24
] 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 [23
] and Bartoli and colleagues [24
] 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 [23
] 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
] and Szucs and colleagues [28
], 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 [27
], age was comparable, as were IMT values. No difference was present in IMT values between subsets in this study either [26
]. 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 [29
]. Otherwise, statins may have a potential benefit in preventing endothelial dysfunction in SSc patients [30
Treatment with immunosuppressive agents, especially corticosteroids, influences the atherogenic process. Corticosteroids are considered to have atherogenic properties [31
], like azathioprine [32
], whereas for hydroxychloroquine [31
] and methotrexate [9
], 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 [33
]. 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
]. 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
], 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 [36
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 [37
]. However, when IMT values were analyzed in subsets, other authors did not find differences in these values between subsets [23
]. 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 [38
]. However, atherosclerotic lesions appear later in the CCA than in the ICA or bulb, but these latter two segments are more difficult to visualize [39
]. Also, it can be difficult to assess whether IMT of the CCA represents atherosclerosis or vascular hypertrophy [40
]. 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