Objective:

To characterize transcriptomic profiles of RA-ILD lung tissue using single-cell RNA sequencing and understand the role of macrophage and fibroblast subpopulations in RA-ILD and its relationship to IPF.

Approach:

• Sample Processing: Fresh lung tissue samples from RA-ILD patients and controls were processed using poly(A) capture–based scRNA-seq, while archived specimens were analyzed using Flex scRNA-seq, allowing for comparative analysis of different sample types.

Key Findings:

• RA-ILD is associated with significant morbidity and mortality, rivaling cardiovascular disease.
• Up to 30% of RA patients exhibit subclinical ILD without significant symptoms.
• Machine learning tools identified protein mediators that distinguish RA-ILD from RA without ILD.
• A composite biomarker profile linked to IPF was elevated in some individuals with subclinical RA-ILD.
• Single-cell RNA sequencing revealed shared macrophage-fibroblast interactions promoting pulmonary fibrosis.

Interpretation:

The study provides insights into the immunopathogenesis of RA-ILD, focusing on macrophage and fibroblast interactions in disease progression.

Limitations:

• Potential restricted translocation of protein mediators from lung tissue to systemic circulation.
• Confounding factors from proinflammatory/profibrotic mediators originating from other tissues in RA.

Conclusion:

The findings enhance understanding of the molecular mechanisms underlying RA-ILD and its similarities with IPF.