Serum Complement C3 as a Biomarker for Predicting Diffusing Capacity of the Lung for Carbon Monoxide‑defined Severity in Connective Tissue Disease‑associated Interstitial Lung Disease

Serum Complement C3 as a Biomarker for Predicting Diffusing Capacity of the Lung for Carbon Monoxide‑defined Severity in Connective Tissue Disease‑associated Interstitial Lung Disease

Objectives: Reliable biomarkers for assessing disease severity in connective tissue disease‑associated interstitial lung disease (CTD‑ILD) remain not well established. This study aimed to identify potential severity biomarkers by correlating them with diffusing capacity of the lung for carbon monoxide (DLCO), a measure highly sensitive to early interstitial and vascular abnormalities. Methods: We conducted a retrospective chart review of patients with CTD‑ILD at Kaohsiung Chang Gung Memorial Hospital, Taiwan, from 2016 to 2025. Patients were included if their diagnosis was confirmed by the high‑resolution computed tomography or through multidisciplinary discussion. We collected clinical data, laboratory values, image results, and pulmonary function test results. Biomarker associations were evaluated using logistic regression and their optimal cutoff values were established with receiver operating characteristic (ROC) curve analysis. Results: Among 97 patients reviewed, 91 met inclusion criteria. Seventy‑three patients were eligible for severity analysis based on DLCO, stratified into normal/mild (n = 20) and moderate/severe (n = 53) groups. Lower serum complement C3 levels were significantly associated with increased disease severity (105.87 vs. 121.39 mg/dL; P = 0.01), whereas C4 levels showed no significant difference (P = 0.37). Logistic regression confirmed that lower C3 was a significant predictor of moderate/severe disease (odds ratio: 0.96, 95% confidence interval 0.93‑0.99, P = 0.02). Furthermore, ROC analysis demonstrated that C3 has good predictive value for severity, with an AUC of 0.704 (P = 0.005). Conclusions: Serum complement C3 is a promising biomarker for assessing severity in CTD‑ILD. The observed C3/C4 discrepancy suggests that the alternative complement pathway may play a primary role in the immune‑mediated injury affecting gas exchange. To translate this into clinical practice, further studies are necessary to validate its prognostic value.