TNF and rheumatoid arthritis: In particular, the combined positivity to RF and ACPA in RA patients was associated with an increased level of pro-inflammatory cytokines and C-reactive protein, which was hypothesized to be a consequence of the amplifying effect of RF on tumour necrosis factor (TNF) production triggered by ACPA [45] whereby ACPA interacts with citrullinated protein to form immune complexes (ICs) which activates the complement system, recruits, and activates immune cells, thereby triggering the production of proinflammatory cytokines [46].