Gradient elevation of serum CYFRA21-1 and its synergy with KL-6 for risk stratification in rheumatoid arthritis-associated interstitial lung disease

Objective This study aimed to assess the clinical value of cytokeratin 19 fragment (CYFRA21-1) and its correlation with Krebs von den Lungen-6 (KL-6) in stratifying the severity of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods Data were retrospectively collected from 178 patients with rheumatoid arthritis (RA) admitted to our hospital between November 2024 and September 2025. The classification of patients into subgroups was based on chest high-resolution computed tomography (HRCT) findings, with 82 without interstitial lung disease (ILD), 53 with mild ILD, and 43 with advanced ILD. Serum KL-6 levels were measured using a latex agglutination assay, and the levels of tumor markers were determined by chemiluminescent immunoassay. Results Serum CYFRA21-1 levels were significantly higher in both the RA-mild ILD and RA-advanced ILD groups compared with the RA-no ILD group (2.10 ng/mL vs. 1.90 ng/mL, q = 0.024; 3.70 ng/mL vs. 1.90 ng/mL, q < 0.001). Multivariate analysis demonstrated that CYFRA21-1 was an independent risk factor for RA-mild ILD [odds ratio (OR) = 1.711, 95% confidence interval (CI) = 1.160–2.523, p = 0.007] and RA-advanced ILD (OR = 4.819, 95% CI = 2.942–7.892, p < 0.001). KL-6 and CYFRA21-1 showed strong negative correlations with predicted forced vital capacity (FVC% pred), with correlation coefficients decreasing to −0.877 and −0.763 in the advanced ILD group, their positive correlation progressively increased with disease severity ( r = 0.453–0.649). Furthermore, receiver operating characteristic (ROC) curve analysis indicated that CYFRA21-1 had diagnostic value for both RA-ILD (mild + advanced) and RA-advanced ILD. The area under the ROC curve (AUC) of CYFRA21-1 in RA-ILD was 0.73 ( p < 0.001; sensitivity = 61.86%; specificity = 78.05%), while that in RA-advanced ILD was 0.88 ( p < 0.001; sensitivity = 84.09%; specificity = 78.05%). Conclusion CYFRA21-1 exhibited graded expression and a positive correlation with KL-6, serving as a valuable serum biomarker for risk stratification and severity assessment in RA-ILD.