Lung Involvement in Systemic Sclerosis: Predictive Biomarkers for Interstitial Lung Disease Progression

Abstract

Introduction: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). Early identification of progressive ILD remains challenging. This review consolidates evidence on serum and imaging biomarkers predictive of forced vital capacity (FVC) decline.
Methods: PRISMA-guided review of cohort studies (≥50 SSc patients, follow-up ≥12 months) reporting baseline biomarkers and subsequent FVC decline ≥10% or death. Databases: Embase, Scopus (2015–2024). Extracted: KL-6, CCL18, SP-D, and autoantibodies.
Results: Twenty-three studies (n=4,822) met criteria. Elevated KL-6 (>500 U/mL) had pooled sensitivity 74% and specificity 81% for FVC decline. CCL18 levels correlated with annual FVC change (r=-0.48, p=0.002). Anti-topoisomerase I antibody positivity increased ILD progression risk (OR 3.2, 95% CI 2.1–4.9). On HRCT, extent of traction bronchiectasis predicted mortality (HR 2.4 per 10% increase, p<0.001).
Discussion: KL-6 and CCL18 reflect alveolar epithelial injury and macrophage activation, respectively. However, most studies lacked external validation, and cut-off values varied. Combining biomarkers with autoantibody status improved prediction over single markers.
Conclusions: Several promising biomarkers for SSc-ILD progression exist, but none are ready for standalone clinical use. Composite risk scores are needed.