Protective Effects of Apolipoprotein A and High-Density Lipoprotein Cholesterol Against Interstitial Lung Disease in Rheumatoid Arthritis: The Mediating Role of Systemic Inflammation

Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality in patients with rheumatoid arthritis (RA). Dysregulated lipid metabolism is associated with the progression of both RA and ILD. However, its relationship with the risk of ILD in the RA population remains uncertain. This study aimed to determine the association between lipid traits and incident ILD in an RA population, as well as the mediating role of systemic inflammation. This prospective cohort study included 4229 UK Biobank participants with RA and no baseline ILD. Cox proportional-hazards models were used to investigate the association between six lipid traits and ILD risk. Systemic inflammation was estimated using the INFLA-score. Generalized structural equation modeling was employed to investigate the mediating effect of the INFLA-score on the relationship between lipid traits and ILD incidence. After a mean follow-up of 14.736 years, 152 incident ILD cases were recorded. High serum levels of apolipoprotein A (ApoA) and high-density lipoprotein cholesterol (HDL-C) were independent protective factors against incident all-cause ILD in RA, associated with a 61.5% and 51.3% risk reduction in ILD per standard deviation (SD) increase in ApoA and HDL-C, respectively (ApoA: HR 0.385, 95% CI 0.189–0.783, p = 0.008; HDL: HR 0.487, 95% CI 0.280–0.847, p = 0.011). These associations were more pronounced in males, relatively young patients and ever-smokers. Systemic inflammation accounted for 88.5% of the association with ApoA and 63.6% with HDL-C, respectively. Elevated ApoA and HDL-C were independently associated with a lower risk of incident all-cause ILD in RA. The associations appear to be largely driven by low-grade systemic inflammation.