Spectrum of autoantibodies and other serological parameters in connective tissue disease–associated interstitial lung disease patients

Background Connective tissue disease–associated interstitial lung disease (CTD-ILD) is a major cause of morbidity and mortality in autoimmune disorders, yet detailed serological characterization remains limited in Indian cohorts. Objective This study aimed to evaluate and compare demographic, radiological, autoantibody, and serum profiles between CTD-ILD and non-CTD-ILD patients from Western India and to delineate hospitalization patterns and mortality outcomes among CTD-ILD patients. Methods This single-centre, cross-sectional study enrolled 200 patients with ILD ( n = 90 with CTD-ILD and n = 110 with non-CTD-ILD) from a tertiary care centre who were evaluated on a clinico-radiological basis. Antinuclear antibodies and ANA subspecificities were assessed using indirect immunofluorescence and a line blot assay. Serological parameters were quantified using ELISA and multiplex bead-based assays. Results CTD-ILD patients were significantly younger (49 vs. 57 years; p 0.001) and predominantly female (80.0% vs. 59.1%; p = 0.002). NSIP predominated in CTD-ILD (51.1%), whereas UIP predominated in non-CTD-ILD (46.4%; p 0.001). On multivariable analysis, younger age (aOR = 0.954; p 0.001), female sex (aOR = 2.709; p = 0.023), NSIP (aOR = 6.155; p = 0.001), and UIP (aOR = 8.877; p 0.001) were independent predictors of CTD-ILD. ANA positivity was higher in CTD-ILD (70.0% vs. 54.5%; p = 0.025), with a predominance of high-titre ANA (81.0%, ≥1:160) and a speckled IFA pattern. The nucleolar pattern was significantly more prevalent in the CTD-ILD group (11.1%; p = 0.010). Disease-specific autoantibody enrichment was observed as follows: anti-SSA/Ro and AMA-M2 in RA-ILD, anti-RNP/Sm in MCTD-ILD, and anti-Scl-70 in SSc-ILD. Anti-MDA5 ( p = 0.001), LDH ( p = 0.019), and pro-inflammatory cytokines TNF-α, IFN-γ, IL-4, and IL-22 were significantly elevated in CTD-ILD, whereas MMP7 levels were lower ( p = 0.025). TNF-α, IL-22, and IL-4 remained independent predictors in the multivariable analysis. Among CTD-ILD patients, 20.0% required hospitalization, with significantly higher in-hospital mortality in admitted patients (27.8% vs. 4.2%; p = 0.007) than in non-admitted CTD-ILD patients. Conclusion CTD-ILD patients demonstrated distinct demographic, radiological, autoantibody, and serological profiles compared to non-CTD-ILD patients, characterized by elevated anti-MDA5, LDH, and pro-inflammatory cytokines alongside lower MMP7 levels, reflecting an immune-driven rather than fibrosis-dominant pathobiology. These findings contribute to bridging the knowledge gap in the serological characterization of CTD-ILD in Indian cohorts.