Stratification according to autoantibody status in systemic sclerosis reveals distinct molecular signatures.

Objectives: Systemic sclerosis (SSc) is a heterogeneous disease, complicating its management. Its complexity and the insufficiency of clinical manifestations alone to delineate homogeneous patient groups further challenge this task. However, autoantibodies could serve as relevant markers for the pathophysiological mechanisms driving the disease. Identifying specific immunological mechanisms based on patients' serological statuses might facilitate a deeper understanding of the diversity of the disease.

Methods: A cohort of 206 patients with SSc enrolled in the PRECISESADS cross-sectional study was examined. Patients were stratified based on their anti-centromere (ACA) and anti-SCL70 (SCL70) antibody statuses. Comprehensive omics analyses including transcriptomic, flow cytometric, cytokine and metabolomic data were analysed to characterise the differences between these patient groups.

Results: Patients with SCL70 antibodies showed severe clinical features such as diffuse cutaneous sclerosis and pulmonary fibrosis and were biologically distinguished by unique transcriptomic profiles. They exhibit a pro-inflammatory and fibrotic signature associated with impaired tissue remodelling and increased carnitine metabolism. Conversely, ACA-positive patients exhibited an immunomodulation and tissue homeostasis signature and increased phospholipid metabolism.

Conclusions: Patients with SSc display varying biological profiles based on their serological status. The findings highlight the potential utility of serological status as a discriminating factor in disease severity and suggest its relevance in tailoring treatment strategies and future research directions.