Circulating Activin A and Follistatin-like Proteins in Rheumatoid Arthritis with Interstitial Lung Disease: A Cross-Sectional Comparative Study.

Background/Objectives: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) represents one of the major contributors to morbidity and mortality in Rheumatoid arthritis (RA), yet its underlying molecular mechanisms remain incompletely defined. Activin A, a member of the transforming growth factor-β (TGF-β) superfamily, has emerged as a key regulator of inflammation, fibroblast activation, and tissue remodeling. However, its role in RA patients with interstitial lung disease (ILD) has not been fully elucidated. We aimed to investigate circulating levels of Activin A, Follistatin-Like Protein-1 (FSTL1), and Follistatin-Like Protein-3 (FSTL3) in patients with RA, RA-ILD, idiopathic pulmonary fibrosis (IPF), and healthy controls and explore their associations with disease activity and pulmonary function parameters. Methods: This cross-sectional study included 90 participants: healthy controls (n = 20), RA (n = 25), RA-ILD (n = 21), and IPF (n = 24). Serum biomarkers were quantified using validated enzyme-linked immunosorbent assays (ELISAs). Clinical characteristics, inflammatory markers, disease activity indices, and pulmonary function tests were recorded. Group comparisons and correlation analyses were performed using appropriate parametric and non-parametric statistical methods. Results: Circulating Activin A levels were progressively increased from controls to RA, RA-ILD, and IPF, with significantly higher concentrations in all disease groups relative to controls. FSTL1 levels were significantly reduced in RA-ILD patients compared with RA and controls, while FSTL3 levels were markedly elevated in IPF. Activin A did not correlate with disease activity indices or pulmonary function parameters, whereas FSTL1 correlated positively with diffusing capacity of the lungs for carbon monoxide and disease duration, and FSTL3 showed an inverse association with lactate dehydrogenase. Conclusions: Activin A may be associated with the fibroinflammatory burden in both RA-ILD and IPF. The observation of altered circulating levels of Follistatin-like proteins-key regulatory molecules with multifaceted biological functions-suggests that the underlying pathogenesis is complex and governed by tightly regulated, interconnected signaling pathways.