To analyze the relationship between serum levels of glycan antigen 6 (KL-6) and pulmonary surfactant protein D (SP-D) in patients with connective tissue disease-related interstitial lung disease (CTD-ILD) and the diagnosis and severity of chest high-resolution computed tomography (HRCT), in order to investigate their clinical significance.

A total of 221 patients with CTD admitted to our hospital from January 2022 to December 2025 were retrospectively enrolled, comprising 81 patients with CTD-ILD and 140 patients with CTD alone. Based on whether they had received anti-CTD medication within the preceding 3 months, the patients were stratified into the following subgroups: the untreated CTD-ILD group 39 cases and the treated CTD-ILD group 42 cases; the untreated CTD group 70 cases and the treated CTD group 70 cases. Enzyme linked immunosorbent assay was used to measure serum KL-6 and SP-D levels. The diagnostic efficacy of serum KL-6 and SP-D were evaluated to predict CTD-ILD using binary logistic regression and receiver operating characteristic (ROC) curves. Spearman correlation analysis was used to explore the relationship between KL-6, SP-D and pulmonary function and HRCT scores.

Compared with the CTD group, the serum levels of KL-6 [855.39 (419.03, 1 281.28) U/ml vs. 182.71 (138.83, 231.68)U/ml], SP-D[64.56(61.10, 68.36) ng/ml vs. 49.27 (46.94, 52.50)ng/ml], and red blood cell distribution width-standard deviation (RDW-SD) [48.30(45.00, 51.40) fL vs. 44.40 (42.00, 48.10) fL] were significantly higher in the CTD-ILD group (P<0.05). Multivariate logistic regression analysis demonstrated that SP-D (OR=1.085, P<0.001), KL-6 (OR=1.009, P<0.001), and RDW-SD (OR=1.061, P=0.014) were independent risk factors for the development of CTD-ILD. ROC curve analysis indicated that the combination of KL-6, SP-D, and RDW-SD yielded the optimal predictive performance for CTD-ILD. The areas under the curve in the untreated and treated groups were 0.975 and 0.951, respectively, with corresponding sensitivity and specificity reaching 100.00% and 94.31% in the untreated group, and 76.89% and 95.12% in the treated group. Spearman correlation analysis showed that in both treated and untreated CTD-ILD patients, KL-6 and SP-D were significantly negatively correlated with pulmonary function parameters (r=-0.618~-0.278, P<0.05), and positively correlated with HRCT scores (untreated group: r=0.356 and 0.478; treated group: r=0.331 and 0.412; all P<0.05).

KL-6 and SP-D could be more promising biomarkers for diagnosing CTD-ILD and assessing its severity, and their diagnostic value is not affected by CTD disease subtypes and drug interference.