Diagnostic and Prognostic Significance of Circulating Galectin-9 in Connective Tissue Disease-Associated Interstitial Lung Disease

Background and objectives: Interstitial lung disease (ILD) is the main cause of morbidity and mortality in patients with connective tissue disease (CTD). Therefore, effective biomarkers for diagnosis and predicting progression of CTD-ILD could be significant. Galectin-9 (Gal-9) has been reported to be associated with autoimmune diseases. Here, this study aims to investigate the role of circulating Gal-9 in the diagnosis and progression monitoring in patients with CTD-ILD. Methods: A total of 128 patients with CTD-ILD, 101 patients with CTD and 52 healthy controls were enrolled in this study. Serum Gal-9 levels were measured by enzyme-linked immunosorbent assay, and its correlation with clinical indices in patients with CTD-ILD were assessed using Spearman’s analysis. Receiver operating characteristic (ROC) analysis was applied to measure the diagnostic accuracy of Gal-9 in patients with CTD-ILD. Kaplan-Meier analysis was performed to assess the progression of ILD in patients with CTD-ILD with high and low baseline levels of serum Gal-9. Results: Serum Gal-9 levels were significantly higher in CTD-ILD patients than either CTD patients or healthy controls (median 18.3 ng/mL vs. 9.3 ng/mL vs. 7.6 ng/mL). Serum Gal-9 levels showed a significantly positive correlation with serum inflammatory indexes and Krebs von den Lungen-6 (KL-6), as well as lung computed tomography scores and reduced pulmonary function in patients with CTD-ILD (all p  < 0.05). Additionally, serum Gal-9 exhibited moderate diagnostic ability to identify the presence of ILD in patients with CTD. Intriguingly, longitudinal study revealed a significant reduction in serum Gal-9 levels after treatment in patients with CTD-ILD (35.0 ng/mL vs. 17.3 ng/mL, p  = 0.0012). Furthermore, patients with CTD-ILD with a baseline serum Gal-9 level of ≥ 10.45 ng/mL experienced a higher percentage of ILD progression than those with a level of < 10.45 ng/mL over a two-year follow-up (36.4% vs. 0.0%). Conclusions: Serum Gal-9 could serve as a potential circulating indicator for both the presence and severity of ILD, and it may also have prognostic significance in predicting ILD progression in patients with CTD.