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Introduction The high mortality rate and irreversible progression of systemic sclerosis (SSc) underscore the critical importance of early recognition and diagnosis. Previous studies have showed that some patients exhibit signs of organ dysfunction during the Very Early Diagnosis of SSc (VEDOSS) stage, even before meeting the formal classification criteria. Based on these findings, our study focuses on the antibody-positive phase (preSSc), employing multi-omics approaches to investigate the pathophysiological changes from the antibody-positive phase, through the oligosymptomatic stage, and ultimately to the point at which classification criteria are met, in order to identify patients at high risk of rapid progression as early as possible.Material and Methods This study utilized samples from the Renji Scleroderma Longitudinal Cohort (Renji-SLOC). PreSSc was defined as the presence of SSc-specific antibodies (ACA, ATA, or ARA) in the absence of any other clinical manifestations. We included proteomic data from 17 preSSc, 13 VEDOSS, and 112 SSc patients, as well as PBMC RNA data from 20 preSSc, 29 VEDOSS, and 122 SSc patients for analysis. Proteomic data were collected using a QE-HF mass spectrometer, while RNA sequencing was performed using the NovaSeq X Plus platform.Results Differential analysis revealed significant overlap in the differentially expressed proteins and RNA between preSSc and VEDOSS compared to healthy controls (HC) with those between SSc and HC (66/270 proteins, p<0.05, FC>1; 199/323 RNA, p<0.05, FC>2). This suggests that some pathological changes associated with SSc may already be present during the antibody-positive stage. However, the manifestations of SSc remain unique, with 107/270 proteins and 51/323 RNA showing distinct patterns. Reactome pathway enrichment analysis of the commonly upregulated proteins identified early activation of innate immunity, coagulation pathways, and extracellular matrix organization. Additionally, Gene Ontology (GO) functional enrichment analysis of the commonly upregulated RNA indicated that multiple immune-related pathways are activated during the preSSc and VEDOSS stages.Conclusions Some SSc-related changes in proteins and RNA occur as early as the antibody-positive phase, prior to the VEDOSS stage. However, these changes do not follow a linear or stepwise progression. Early identification of antibody-positive and VEDOSS patients is critial for effective monitoring and timely intervention, potentially preventing or slowing disease progression.Abstract OC.43 Figure 1