From Systemic Autoimmunity to the Local Immune Niche of the Synovium: New Insights into the Development of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is commonly regarded as a chronic inflammatory autoimmune disease driven by systemic immune dysregulation. However, this view does not fully explain why inflammation preferentially localizes to the synovium, or why patients differ in local inflammatory burden, structural damage, and treatment response. Recent advances in synovial biopsy, single-cell transcriptomics, spatial omics, and multimodal imaging have shifted attention toward the tissue-level mechanisms of RA. Current evidence suggests that RA develops through a continuous interaction between systemic autoimmunity and local synovial lesion formation. Systemic autoimmune abnormalities provide the initiating background for disease development, whereas the transition to persistent clinical synovitis appears to require the establishment and stabilization of a local synovial immune niche; however, current evidence does not support this niche as a sufficient cause of RA in isolation. Within this niche, stromal cells, myeloid cells, adaptive immune populations, vascular remodeling, extracellular matrix reorganization, and metabolic adaptation interact to sustain local inflammation. As these local programs consolidate, the lesion may shift from an inflammation-maintaining state to a destructive niche that promotes bone erosion, cartilage injury, and persistent remodeling at the bone-cartilage-synovium interface. In parallel, RA research and therapeutic strategies are moving beyond inflammation control alone toward a framework centered on local lesion formation, dominant pathogenic networks, and tissue stratification. Synovial tissue profiling, lesion-driven precision stratification, and multimodal integrative assessment may offer a more direct basis for predicting treatment response and guiding precision therapy. This review summarizes the key mechanisms linking systemic autoimmunity, local synovial immune niche formation, and structural damage in RA, and discusses the implications of these advances for future research and treatment strategies.