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, Paul P. Tak

Research output: Contribution to journalArticleAcademicpeer-review

631 Citations (Scopus)

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
Original languageEnglish
Pages (from-to)8284-8289
JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume113
Issue number29
DOIs
Publication statusPublished - 2016

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