Spatial mapping of rheumatoid arthritis synovial niches reveals a LYVE1+ macrophage network associated with response to therapy

OBJECTIVES: Despite advances in rheumatoid arthritis (RA) treatment, a significant proportion of patients fail to achieve adequate remission. The dynamic cellular and architectural changes within the synovium that underpin therapeutic success remain poorly understood. This study aimed to unravel the synovial landscape during effective RA treatment, identifying key cellular networks and molecular pathways associated with remission. METHODS: We performed high-dimensional imaging mass cytometry on synovial tissues from healthy controls, patients with osteoarthritis, and patients with early RA longitudinally before and after 6 months of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) therapy. Findings were validated using whole-tissue RNA-sequencing and immunofluorescence in larger patient cohorts, and integrated with ligand-receptor analyses from public single-cell RNA-seq datasets and in vitro functional coculture assays. RESULTS: macrophages demonstrated a regulatory, anti-inflammatory phenotype in vitro, contrasting with proinflammatory myeloid cells. CONCLUSIONS: macrophage network as a pivotal component of synovial homeostasis and its restoration as a hallmark of clinical remission. These findings unveil novel cellular and molecular targets, paving the way for more active therapeutic strategies.