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Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis
Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved June 1, 2016 (received for review April 18, 2016)

Significance
Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients.
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.
Footnotes
↵1Present address: Department of Medicine, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
↵2Present address: Department of Rheumatology, Ghent University, 9000 Ghent, Belgium.
↵3Present address: Research & Development, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
- ↵4To whom correspondence should be addressed. Email: P.P.Tak{at}amc.uva.nl.
Author contributions: F.A.K., S.S.C., S.M., S.G., S.S., P.R.S., A.D.M., Y.A.L., M.F., R.Z., K.J.T., and P.P.T. designed research; F.A.K., S.S.C., S.M., S.G., S.S., P.R.S., A.D.M., Y.A.L., R.Z., K.J.T., and P.P.T. performed research; F.A.K., S.S.C., S.M., S.G., S.S., P.R.S., A.D.M., Y.A.L., M.F., R.Z., K.J.T., and P.P.T. analyzed data; and F.A.K., S.S.C., S.M., S.G., S.S., P.R.S., A.D.M., Y.A.L., M.F., R.Z., K.J.T., and P.P.T. wrote the paper.
Conflict of interest statement: M.F., Y.A.L., and R.Z. are employees of and equity holders in SetPoint Medical Corporation. K.J.T. is an equity holder in and has received consulting fees from SetPoint Medical Corporation. S.M., S.G., S.S., P.R.S., and P.P.T. received research grants from SetPoint Medical Corporation to support the clinical study reported here. P.P.T. has received consulting fees from SetPoint Medical Corporation and is currently an employee of GlaxoSmithKline, which holds an equity interest in SetPoint Medical Corporation.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1605635113/-/DCSupplemental.
Freely available online through the PNAS open access option.