Spatial single cell RNA sequencing of cutaneous lupus reveals distinct tissue level changes with anifrolumab treatment

Summary: Abstract Body: Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease with no FDA-approved therapies. Anifrolumab, a monoclonal antibody targeting the type I interferon receptor, has shown promise in treating systemic lupus erythematosus, and emerging data suggest it may be highly effective in CLE. However, the molecular and cellular mechanisms underlying its effects on CLE remain incompletely understood. This study utilizes spatial transcriptomics and single-cell RNA sequencing to explore the impact of anifrolumab on gene expression and cellular composition in CLE-affected skin. Skin biopsies from uninvolved skin (n=2), discoid lupus erythematosus (DLE, n=4), and pre- and post-anifrolumab therapy samples (n=6) were analyzed. Spatial transcriptomics revealed distinct gene expression profiles across different skin compartments, with principal component analysis demonstrating that post-therapy samples shifted towards gene expression profiles characteristic of uninvolved skin. Differential gene expression analysis highlighted compartment-specific changes following anifrolumab treatment, including downregulation of inflammatory keratins (KRT6C, KRT16, KRT17) in the epidermis and upregulation of extracellular matrix genes (COL1A1, COL3A1) in the dermis. Vascular regions showed decreased expression of chemokines CXCL10 and CXCL11. Interferon-stimulated genes were downregulated across all compartments, confirming the on-target effects of anifrolumab. Notably, IFNAR1 expression increased post-treatment, particularly in the epidermis and vasculature, suggesting a potential loss of negative feedback regulation. Integration of single-cell RNA sequencing data revealed a reduction in T and B cell frequencies in lesional skin post-therapy. These findings offer novel insights into the molecular and cellular effects of anifrolumab in CLE, demonstrating its potential to restore skin homeostasis by modulating gene expression and immune cell composition. Ruoyi Jiang¹, Jeff Gelhausen^{1, 2} 1. Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States. 2. Department of Dermatopathology, Yale University School of Medicine, New Haven, CT, United States. Adaptive and Auto-Immunity