title: Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.
abstract: 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.
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Frieda A
authors.initials: FA
authors.lastname: Koopman
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
authors.forename: Sangeeta S
authors.initials: SS
authors.lastname: Chavan
authors.affiliation: University Clinical Hospital, Mostar 88000, Bosnia and Herzegovina;
authors.forename: Sanda
authors.initials: S
authors.lastname: Miljko
authors.affiliation: Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia;
authors.forename: Simeon
authors.initials: S
authors.lastname: Grazio
authors.affiliation: Sarajevo University Clinical Center, Sarajevo 71000, Bosnia and Herzegovina;
authors.forename: Sekib
authors.initials: S
authors.lastname: Sokolovic
authors.affiliation: Department of Neurosurgery, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: P Richard
authors.initials: PR
authors.lastname: Schuurman
authors.affiliation: Department of Neurosurgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030;
authors.forename: Ashesh D
authors.initials: AD
authors.lastname: Mehta
authors.affiliation: SetPoint Medical Corporation, Valencia, CA91355.
authors.forename: Yaakov A
authors.initials: YA
authors.lastname: Levine
authors.affiliation: SetPoint Medical Corporation, Valencia, CA91355.
authors.forename: Michael
authors.initials: M
authors.lastname: Faltys
authors.affiliation: SetPoint Medical Corporation, Valencia, CA91355.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zitnik
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; P.P.Tak@amc.uva.nl.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D004827:Epilepsy / Q000628:therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055536:Vagus Nerve Stimulation
chemical_list: D016207:Cytokines
keywords: cytokines; inflammatory reflex; rheumatoid arthritis; tumor necrosis factor; vagus nerve