The role of the pulmonary microenvironment in driving Systemic Sclerosis (SSc) to Systemic Sclerosis-Interstitial Lung Disease (SSc-ILD) transition

Objective A common complication in systemic sclerosis (SSc) is the development of SSc-associated interstitial lung disease (SSc-ILD), which has poor prognosis and high mortality rates. The pulmonary microenvironment may include mediators involved in disease pathogenesis that could be targets for new therapies to reduce SSc-to-SSc-ILD transition. Here, we aimed to identify soluble mediators in bronchoalveolar lavage fluid (BALF) that would differentiate SSc-ILD from SSc only patients through a systematic review. Methods Using a pre-registered study protocol, two databases (Web of Science, PubMed) were screened for publications between 2000-2024 in adult patients (keywords "Systemic sclerosis AND biomarker AND (lung lavage OR bronchoalveolar lavage)"). Mediators were meta-analysed (RevMan) and functionally enriched pathways identified (STRING-DB/G:Profiler). Results Screening identified 20 (out of 82) publications for inclusion into the systematic review; with qualitative synthesis (n=12) and meta-analyses (n=5). 30 different mediators were identified, 17 were available for SSc versus SSc-ILD comparison. Mediators showed a strong interconnectedness and were clustered into 3 groups: those released from tertiary granules (predominately extracellular matrix remodelling function), with chemokine receptor binding or antioxidant function. Conclusion Due to the limited number of studies, we were unable to perform a meta-analysis on mediators between SSc and SSc-ILD, highlighting the need for further studies. However, our review strongly highlights the involvement of the pulmonary epithelium in SSc-ILD, contributing to positive feedback between injured epithelial cells and fibroblast activation/fibrosis. Further research into the role of the epithelium is needed to identify novel mechanisms leading to SSc-ILD that could serve as novel pharmacological targets.