Multiomics landscape of systemic sclerosis: from autoantibody-positivity to established disease.

Objectives

Systemic sclerosis (SSc) is a progressive autoimmune disease in which pathogenic processes may begin before clinical onset. We aimed to characterise molecular alterations across the spectrum from the asymptomatic SSc-specific autoantibody-positive (SSAP) phase through very early diagnosis of SSc (VEDOSS) to established SSc using integrated multiomics profiling.

Methods

In this multiomics study, we performed peripheral blood mononuclear cell transcriptomics and plasma proteomics in healthy controls, SSAP, VEDOSS, and limited and diffuse SSc. Differential expression, expression-pattern analysis across clinical groups, and functional enrichment were conducted to evaluate group-associated molecular features. Connectivity Map (CMap) analysis was used to prioritise hypothesis-generating perturbagens linked to early and persisting transcriptional signatures.

Results

A continuous molecular gradient was observed from health to established SSc, with SSAP and VEDOSS occupying intermediate molecular states. Immune dysregulation, particularly innate immune activation and type I interferon signalling, was detectable at the SSAP stage and showed higher activity across the ordered clinical groups. Plasma proteomics identified circulating protein markers related to vascular injury and extracellular matrix remodelling across the clinical groups. CMap analysis prioritised Janus kinase (JAK) inhibitors and phosphodiesterase inhibitors as hypothesis-generating perturbagens linked to early disease-associated programmes.

Conclusions

Molecular abnormalities associated with SSc are detectable before overt clinical disease. Multiomics profiling identifies circulating immune, vascular-associated, and profibrotic molecular features across the SSc disease severity spectrum and provides a framework for molecular characterisation and risk stratification.