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Research Article

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

Frieda A. Koopman, Sangeeta S. Chavan, Sanda Miljko, Simeon Grazio, Sekib Sokolovic, P. Richard Schuurman, Ashesh D. Mehta, Yaakov A. Levine, Michael Faltys, Ralph Zitnik, Kevin J. Tracey, and Paul P. Tak
PNAS first published July 5, 2016; https://doi.org/10.1073/pnas.1605635113
Frieda A. Koopman
aAmsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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Sangeeta S. Chavan
bLaboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
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Sanda Miljko
cUniversity Clinical Hospital, Mostar 88000, Bosnia and Herzegovina;
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Simeon Grazio
dClinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia;
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Sekib Sokolovic
eSarajevo University Clinical Center, Sarajevo 71000, Bosnia and Herzegovina;
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P. Richard Schuurman
fDepartment of Neurosurgery, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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Ashesh D. Mehta
gDepartment of Neurosurgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030;
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Yaakov A. Levine
hSetPoint Medical Corporation, Valencia, CA91355
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Michael Faltys
hSetPoint Medical Corporation, Valencia, CA91355
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Ralph Zitnik
hSetPoint Medical Corporation, Valencia, CA91355
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Kevin J. Tracey
bLaboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
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Paul P. Tak
aAmsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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  • For correspondence: P.P.Tak@amc.uva.nl
  1. Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved June 1, 2016 (received for review April 18, 2016)

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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.

  • vagus nerve
  • rheumatoid arthritis
  • inflammatory reflex
  • tumor necrosis factor
  • cytokines

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.

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Vagus nerve suppression of cytokines in humans
Frieda A. Koopman, Sangeeta S. Chavan, Sanda Miljko, Simeon Grazio, Sekib Sokolovic, P. Richard Schuurman, Ashesh D. Mehta, Yaakov A. Levine, Michael Faltys, Ralph Zitnik, Kevin J. Tracey, Paul P. Tak
Proceedings of the National Academy of Sciences Jul 2016, 201605635; DOI: 10.1073/pnas.1605635113

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Vagus nerve suppression of cytokines in humans
Frieda A. Koopman, Sangeeta S. Chavan, Sanda Miljko, Simeon Grazio, Sekib Sokolovic, P. Richard Schuurman, Ashesh D. Mehta, Yaakov A. Levine, Michael Faltys, Ralph Zitnik, Kevin J. Tracey, Paul P. Tak
Proceedings of the National Academy of Sciences Jul 2016, 201605635; DOI: 10.1073/pnas.1605635113
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