Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint destruction, which affects approximately 0.5–1.0% of the adult population.

The vagus nerve has a pivotal role in modulating inflammation through the cholinergic anti-inflammatory pathway (CAP) to suppress the production of proinflammatory cytokines (e.g. TNF-alpha) by macrophages, and indirectly via the splenic coeliac ganglion. TNF-a is a central pathophysiological mediator in RA and is the target of monoclonal antibodies. 

The inhibition of the cytokine leads to release of acetylcholine from the distal vagus nerve. a7-Nicotinic acetylcholine (a7nAChR), receptors expressed on cytokine-producing macrophages, monocytes, and in the synovium of patients with RA, are activated by acetylcholine. Acetylcholine binds to the receptors and through downstream processing. inhibits nuclear factor-kappa beta activation and other proinflammatory factors.

In patients with RA, vagal tone is inversely associated with disease activity and can predict treatment response, thus, CAP represents a therapeutic target in RA using neuro-immunomodulatory approaches directed at the vagus nerve (Drewes et al., 2020).