Lung function trajectories across the systemic sclerosis disease spectrum: identification of GDF15 as a key serum biomarker and driver of disease progression

Systemic sclerosis (SSc) is a chronic multisystem autoimmune disease characterised by immune dysregulation, microvascular dysfunction, and progressive fibrosis of the skin and internal organs. SSc-associated interstitial lung disease (SSc-ILD) is the leading cause of disease-related mortality, but its clinical course is highly heterogeneous. While many patients remain stable, a subset develop progressive pulmonary fibrosis with accelerated decline in lung function. Identifying individuals at risk of progression remains a major clinical challenge.
Current monitoring relies on pulmonary function testing and imaging, which often detect disease only after clinically meaningful impairment has occurred. There is therefore increasing interest in circulating biomarkers that may enable earlier detection of disease activity and prediction of lung function decline.
This thesis integrates longitudinal clinical phenotyping with high-throughput proteomic analysis to investigate early pulmonary disease progression in SSc. Pulmonary function, symptom burden, and functional disability were characterised across the disease spectrum, including very early disease (VEDOSS). Using two independent VEDOSS cohorts, subclinical loss of lung function was demonstrated prior to overt clinical disease.
Serum proteomic profiling identified circulating proteins associated with progressive lung function decline and demonstrated that proteomic signatures can discriminate individuals at risk of rapid progression. The candidate biomarker growth differentiation factor-15 (GDF15) was validated in a prospectively recruited cohort using enzyme-linked immunosorbent assay (ELISA). Functional experiments further demonstrated that GDF15 induces epithelial-to-mesenchymal transition-associated molecular changes in lung epithelial cells.
Together, these findings demonstrate that early pulmonary involvement is detectable prior to overt clinical disease and highlight the potential of integrated biomarker-based approaches to improve risk stratification and enable earlier, more personalised intervention in SSc.