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: Our deep spatial profiling pinpointed a critical LYVE1+CD206+tissue-resident macrophage network, localised within perivascular niches alongside fibroblasts and vascular cells. This homeostatic network was disrupted in active RA but restored in patients responding well to csDMARDs. This restoration correlated with the re-establishment of specific cell-cell interactions and was governed by distinct molecular pathways, including chemokines, annexins, and TAM (TYRO3, AXL, MERTK) receptors. Functionally, LYVE1+ macrophages demonstrated a regula-tory, anti-inflammatory phenotype in vitro, contrasting with proinflammatory myeloid cells. Conclusions: This study provides an unprecedented spatial and dynamic blueprint of the RA syn-ovium's response to therapy. We identify the LYVE1+ macrophage network as a pivotal compo-nent 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.