The Role of the Pulmonary Microenvironment in Driving Transition From Systemic Sclerosis to Systemic Sclerosis–Associated Interstitial Lung Disease

Rosabel Rodríguez Rodríguez, Julia Malitska, Susan Sultani, Nazia Chaudhuri, Guillermo López–Campos, Koray N. Potel, Steven O’Reilly, Bettina C. Schock

2025

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DOI 10.3899/jrheum.2025-0322
Data confidence 70 medium
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Abstract

OBJECTIVE: A common complication in systemic sclerosis (SSc) is the development of SSc-associated interstitial lung disease (SSc-ILD), which has poor prognosis and a high mortality rate. 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 that would differentiate patients with SSc-ILD from those with SSc only through a systematic review. METHODS: Using a preregistered study protocol, 2 databases (Web of Science, PubMed) were screened for publications between 2000 and 2024 in adult patients (keywords "systemic sclerosis AND biomarker AND [lung lavage OR bronchoalveolar lavage]"). Mediators were metaanalyzed (RevMan) and functionally enriched pathways identified (STRING-DB/G:Profiler). RESULTS: Screening identified 20/82 publications for inclusion into the systematic review, with qualitative syntheses (n = 12) and metaanalyses (n = 5). Thirty different mediators were identified, 17 were available for SSc vs SSc-ILD comparison. Mediators showed strong interconnectedness and were clustered into the following 3 groups: (1) those released from tertiary granules (predominately involved in remodeling of extracellular matrix), (2) those with chemokine receptor binding, and (3) those with antioxidant function. CONCLUSION: Due to the limited number of studies, we were unable to perform a metaanalysis 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.