TNF and rheumatoid arthritis: As the first responders in RA joints, macrophages represent the earliest and most abundant immune cells in affected synovium (22), where they drive pathology through multiple mechanisms: production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 (23), chemokines such as Chemokine (C-C motif) ligand 2 (CCL2), and tissue-destructive metalloproteinases (MMP-3, MMP-12) (24).