Circulating extracellular vesicles in the context of interstitial lung disease related to systemic sclerosis: A scoping literature review

Background: Interstitial lung disease (ILD) is a significant cause of disability and mortality in systemic sclerosis (SSc), where lung fibrosis stems from the interaction of cells within the epithelial, endothelial, interstitial, and immune cell compartments. Extracellular vesicles (EVs) are particles released by cells capable of transferring functionally active molecules, playing a crucial role in intercellular communication. This scoping review aims to identify and map existing evidence about the role of EVs as biomarkers or pathophysiological actors in SSc-ILD. It also retrospectively assesses the compliance of published articles with the current reporting guidelines established by the International Society of Extracellular Vesicles (ISEV). Methods: This scoping review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The searches were conducted up until 31 May 2023, with no restrictions on the starting year. Results: Out of 778 publications identified and screened, 9 references were selected. The eligible studies collectively involved a total of 539 SSc patients, with 220 patients presenting with ILD, as demonstrated by highresolution computed tomography. The studies largely focused on the quantitative assessment of EVs through flow cytometry, primarily concerning larger EVs. The studies primarily focused on the association of EV features with vascular complications, with fibrotic pulmonary involvement typically explored as a secondary finding. The evaluated patients' clinical characteristics were significantly heterogeneous across the studies as well as the association of EV features with the evidence of ILD but none of them longitudinally investigated the relationships with SSc-ILD prognosis. Adherence of these exploratory studies to ISEV reporting guidelines in terms of EV nomenclature, reporting of pre-analytic variables, and qualitative verification of EV separation products was incomplete. Conclusions: The evidence concerning the clinical association of EV features is limited and conflicting. The interpretation of available data is substantially biased due to patient selection tailored for vascular complications, heterogeneity of separation methodology, and a lack of validation procedures.