Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 29; pp. 8284 - 8289
• Main Authors: Koopman, Frieda A., Chavan, Sangeeta S., Miljko, Sanda, Grazio, Simeon, Sokolovic, Sekib, Schuurman, P. Richard, Mehta, Ashesh D., Levine, Yaakov A., Faltys, Michael, Zitnik, Ralph, Tracey, Kevin J., Tak, Paul P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.07.2016
• Subjects: Adult; Aged; Animal models; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - therapy; Autoimmune diseases; Biological Sciences; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - blood; Cytokines - immunology; Epilepsy - therapy; Female; Humans; Male; Middle Aged; Pain management; Rheumatoid arthritis; TNF inhibitors; Toxins; Transcutaneous electrical nerve stimulation-TENS; Vagus Nerve Stimulation; vagus nerve; cytokines; inflammatory reflex; tumor necrosis factor; rheumatoid arthritis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1605635113

Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.