Systemic autoimmune rheumatic diseases (SARDs), including rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases, are associated with increased risk of interstitial lung diseases (ILD), but the underlying biological mechanisms remain poorly understood. We evaluated whether circulating proteins may mediate the association between SARDs and incident ILD in a prospective cohort.

Among the 52,996 participants with Olink plasma proteomic data, 49,338 were analyzed after excluding 3,658 people with prevalent non-SARDs autoimmune diseases or ILD. SARDs and ILD were defined using International Classification of Diseases and self-reported data. Cox proportional hazards models estimated hazard ratios adjusted for age, sex, ethnicity, assessment center, education, smoking, alcohol use, and body mass index. Mediation effects were assessed using generalized structural equation models (GSEM) with Weibull survival functions across 2,922 z-scored proteins. Significant proteins were further analyzed using Ingenuity Pathway Analysis (IPA) to identify biological pathways.

Of 49,338 participants, 1,095 individuals (female 76%) had SARDs at baseline. During a median follow-up of 12.7 years, 533 incident ILD occurred. SARDs were associated with a higher ILD incidence compared to participants without autoimmune diseases at baseline (HR: 4.60, 95% CI: 3.44-6.16). After Bonferroni correction in GSEM, 392 proteins were significant, with percentage mediated ranging from 1.5% to 29.6%. IPA of the proteins showed enrichment of cytokine-mediated inflammatory signaling, leukocyte adhesion and diapedesis, and extracellular matrix/fibrotic remodeling pathways. Predicted upstream regulators included TNF, TGFB1, IFNG, IL1B, and IL6.

These findings suggest that the association between SARDs and incident ILD may be partly explained by broad alterations in inflammatory, leukocyte trafficking, and tissue remodeling proteins, highlighting pathways for future mechanistic studies.