Micro- and Macro-Vascular Disease in Systemic Sclerosis and Very Early SSc (VEDOSS): Results from a Monocentric Observational Study

<b>Background</b>: Systemic sclerosis (SSc) is characterized by endothelial dysfunction leading to progressive vascular injury and fibrosis. While microvascular involvement is well established as an early disease feature, macrovascular disease has been historically underrecognized and poorly investigated in very early disease stages. Integrated assessments across the SSc spectrum, including very early diagnosis of systemic sclerosis (VEDOSS), remain limited. <b>Methods</b>: In this cross-sectional observational study, patients with established SSc, VEDOSS, and primary Raynaud's phenomenon (PRP) were prospectively enrolled between October 2023 and April 2025. Participants underwent comprehensive microvascular and macrovascular evaluation, including nailfold videocapillaroscopy, multisegmental arterial Doppler ultrasound (carotid, aortic, and lower limb districts), flow-mediated dilation, and measurement of endothelial biomarkers (vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and circulating endothelial cells (CECs)). Traditional cardiovascular risk was estimated using Systematic Coronary Risk Estimation 2 (SCORE2). <b>Results</b>: Sixty-two female subjects were included (34 SSc, 14 VEDOSS, and 14 PRP). Microvascular abnormalities followed the expected disease continuum, with capillaroscopic changes present in 57% of VEDOSS and 91% of SSc patients. Although SCORE2 estimates and carotid intima-media thickness were comparable across groups, macrovascular abnormalities were more frequent in SSc (52.9%) and VEDOSS (50%) compared with PRP (21.4%). VCAM-1, ICAM-1, and CEC levels were significantly increased in SSc compared with PRP, whereas no significant differences were observed between VEDOSS and PRP. <b>Conclusions</b>: These findings support a unified micro- and macro-vascular disease model in SSc and demonstrate that macrovascular involvement is detectable already in the VEDOSS phase. Conventional cardiovascular risk scores underestimate the true vascular burden, highlighting the need for disease-specific risk stratification tools integrating vascular imaging and endothelial biomarkers.