Cholinergic anti-inflammatory pathway and vagus nerve stimulation in rheumatoid arthritis

To integrate mechanistic and clinical evidence on vagal regulation of immunity via the cholinergic anti-inflammatory pathway, linking neural and inflammatory signaling in rheumatoid arthritis (RA). It highlights how reduced vagal tone contributes to disease onset and progression and frames neuromodulation as a rationale for adjunctive therapeutic strategies.

Preclinical and clinical data demonstrate that vagal efferent activity modulates immune responses through noradrenergic circuits and activation of α7-nicotinic-acetylcholine-receptors on immune cells, inhibiting NF-κB nuclear translocation and reducing pro-inflammatory cytokines. This neuroimmune axis interacts with the hypothalamic-pituitary-adrenal axis and the microbiome, supporting an integrated model of inflammation. Vagus nerve stimulation (VNS) has been associated with reductions in inflammatory markers and clinically meaningful improvements in patients with RA. Implantable VNS has demonstrated efficacy and has received regulatory approval for moderate-to-severe RA refractory to disease-modifying antirheumatic drugs; however, the available evidence remains limited and requires confirmation in larger and more diverse populations. Noninvasive approaches show favorable safety profiles but heterogeneous efficacy and currently lack regulatory approval for immune-mediated diseases.

VNS represents a promising adjunct to conventional immunosuppressive therapy for RA. Further well-designed trials are needed to standardize stimulation protocols, and define optimal strategies for clinical implementation.