Mapping the synovial immune ecosystem in rheumatoid arthritis: cellular cartography and pathotype-guided immune restoration.

Rheumatoid arthritis (RA) is not a uniform inflammatory pannus. It is a spatially organized, stage-dependent synovial immune ecosystem. Cellular cartography resolves synovitis into lymphoid, myeloid, stromal, and neuroimmune niches that track erosive disease, fibroproliferation, and pain-dominant states. Ecosystem state can differ between joints and shift over time, explaining a key paradox: inflammation may fall while relapse risk or pain persists. Longitudinally, RA evolves from preclinical immune dysregulation with mucosal priming to joint niche consolidation, then to refractory states reinforced by inflammatory memory, stromal imprinting, and neuroimmune sensitization. This argues for biomarkers that report dominant niche drivers and memory programs, not only inflammatory load. Therapies should be phase-matched and niche-targeted, combining stromal or neuroimmune modulation with immune-reset platforms such as T-cell engagers and CAR-T.