LOXHD1 and RHOB Expression by Monocytes Predicts Progressive Systemic Sclerosis associated Interstitial Lung Disease.

Objective: A leading cause of death among scleroderma (SSc) patients, interstitial lung disease (ILD) remains challenging to prognosticate. The discovery of biomarkers that accurately determine which patients would benefit from close monitoring and aggressive therapy would be an essential clinical tool. We aimed to identify genes signatures that would predict progressive ILD.

Methods: We compared previously identified serum biomarkers, bulk peripheral blood mononuclear cells (PBMC) RNA gene expression (39 progressive SSc-ILD, and 43 stable SSc-ILD), and single-cell RNA gene expression of PBMC (13 progressive SSc-ILD, 14 stable SSc-ILD, and 6 control subjects).

Results: In previous studies, male sex, KL-6, and CRP were predictors of progressive disease. Monocyte expression of LOXHD1 and RHOB strongly predicted progression, suggesting a key role in immune dysregulation. LOXHD1 and related genes were enriched in the inflammatory gene networks, which may support monocyte associated inflammation. RHOB was consistently upregulated in both CD14+ and CD16+ monocytes across single-cell and bulk RNA data, underscoring robust association with progressive disease. In contrast, ATXN2L was downregulated in progressive, suggesting dysregulation of cellular stress responses. Additionally, S100A12, CHI3L1 and MMP9, previously linked to tissue remodeling, were again associated with progression in bulk RNA-seq and previous microarray studies, reinforcing their role in fibrosis.

Conclusion: With several potential biomarkers of progressive disease, the next step includes validation in larger, multicenter cohorts for use in clinical decision-making.