Sex-specific Phenotypes and Outcomes in Non‑ipf Interstitial Lung Disease: Results from the INSIGHTS‑ILD Registry

Background. Sex-related differences in interstitial lung disease (ILD) phenotypes are well recognized, but it remains unclear whether sex itself independently influences outcomes in non-idiopathic pulmonary fibrosis (non-IPF) ILD once comorbidities, lung function, and treatment are considered. Methods. In the prospective INSIGHTS-ILD registry (data cut 17 September 2025), we compared men and women with non-IPF ILD using descriptive analyses and Cox models with prespecified adjustment steps: Model A (age, comorbidity count, smoking), Model B (A + forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]), and Model C (B + antifibrotic therapy). Prespecified subgroup analyses included age strata (≤55 and >55 years) and ILD entities. Longitudinal FVC and DLCO trajectories were assessed over 24 months. Results. Among 883 patients (483 men, 400 women), exposures and disease entities differed significantly by sex: men reported more occupational/environmental exposures and had higher rates of fibrotic idiopathic interstitial pneumonia, whereas women more frequently had autoimmune-related ILD and a family history of ILD. Men had a higher comorbidity burden and more often received antifibrotic therapy at baseline. Survival was shorter in men (HR 1.51; 95% CI 1.03–2.21), but this association disappeared after adjustment in Model A (HR 1.04; 0.65–1.68), Model B (HR 1.03; 0.61–1.74), and Model C (HR 1.04; 0.62–1.77). Progression-free survival and transplant-free survival showed no consistent sex-related differences. Longitudinal FVC and DLCO declines were modest and largely parallel in both sexes, with no significant between-group differences. Findings were similar across age groups and ILD entities. Conclusion. Men and women with non-IPF ILD differ in exposures, phenotypes, and comorbidities, but after accounting for these factors, sex is not an independent predictor of survival or functional progression. Risk assessment should therefore primarily be based on objective disease characteristics rather than sex alone.