Our multi-tier study including an aptamer-based analysis and a validation on independent cohorts supports the alterations in different biomarkers to reflect abnormal extracellular matrix formation, angiogenesis, vascular remodeling, and immune cell recruitment and function, which recapitulate the fundamental pathogenic aspects of SSc and some of the proposed biomarkers (Ang2, IL-22BP, and TPSB2) require a detailed discussion. Here, TPSB2 is linked to systemic sclerosis.