Evidence map›Paper›PMID 27382171›Full record

Trial reportProceedings of the National Academy of Sciences of the United States of America2016

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 and 2 more

9 registry-linked trialsOpen access · bronzeAbstract readClinical TrialMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 9 registered trials, which are not on this map. Cited by 564 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
564citing papers in PubMed, 4 pooled it
50.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01552941 nacompletednot on this map

Pilot Study of the Safety and Efficacy of Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Using an Active Implantable Vagal Nerve Stimulation Device in Patients With Rheumatoid Arthritis

TypeinterventionalSponsorSetPoint Medical CorporationRan2011 to 2014Enrolled18ConditionsRheumatoid ArthritisArmsCyberonics VNS System
NCT03548116 naunknown statusnot on this mapstarted 2018, after this paper: background citation

Biological Effects of Ultrasound Insonification of the Spleen

TypeinterventionalSponsorJohn PelleritoRan2018 to 2022Enrolled137ConditionsHealthy VolunteerArmsUltrasound, Sham Ultrasound
NCT04100486 enrolling by invitationnot on this mapstarted 2019, after this paper: background citation

A Pilot Study to Quantify the Autonomic Nervous System Balance in Healthy, Able-Bodied Individuals

TypeobservationalSponsorNorthwell HealthRan2019 to 2027Enrolled48ConditionsAutonomic Dysfunction, Autonomic Imbalance, Autonomic Nervous System Diseases, Vagus Nerve Autonomic DisorderArmsStanding-Squatting-Standing Test, Deep Breathing Test, Cold Pressor Test, Cold Face Test, Valsalva Maneuver
NCT04343963 phase2 / phase3unknown statusnot on this mapstarted 2020, after this paper: background citation

Pyridostigmine in Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2 Infection

TypeinterventionalSponsorInstituto Nacional de Ciencias Medicas y Nutricion Salvador ZubiranRan2020 to 2021Enrolled436ConditionsCOVID-19, SARS-CoV-2ArmsPyridostigmine Bromide, Placebo
NCT04368156 nacompletednot on this mapstarted 2020, after this paper: background citation

A Prospective, Randomized, Controlled Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms (SAVIOR)

TypeinterventionalSponsorCarlos TorneroRan2020 to 2021Enrolled110ConditionsCovid-19ArmsgammaCore® (Vagus nerve stimulation)
NCT04413747 naunknown statusnot on this mapstarted 2020, after this paper: background citation

Yoga- Based Breathing for Vagus Nerve Stimulation as Home-care Adjuvant Treatment Against Burden COVID-19

TypeinterventionalSponsorHealth Ricerca e Sviluppo S.R.L.Ran2020 to 2021Enrolled1,000ConditionsCoronavirus Infection, Cytokine Storm, Mental DisorderArmsmorning Yoga-based breathing support, pre_lunch Yoga-based breathing support, pre_dinner Yoga-based breathing support
NCT04514627 nacompletednot on this mapstarted 2020, after this paper: background citation

Neuromodulation With Percutaneous Electrical Nerve Field Stimulation for Adults With COVID-19

TypeinterventionalSponsorOlive View-UCLA Education & Research InstituteRan2020 to 2022Enrolled55ConditionsCOVID-19ArmsAuricular percutaneous neurostimulation
NCT05457907 nacompletednot on this mapstarted 2023, after this paper: background citation

Ultrasound Therapy Effects to Modulate the Inflammatory Reflex

TypeinterventionalSponsorStanford UniversityRan2023 to 2023Enrolled19ConditionsHealthyArmsUltrasound device
NCT05743530 naunknown statusnot on this mapstarted 2023, after this paper: background citation

Effect of Perioperative Neurostimulation in Patients Undergoing Whipple Operation (Pancreaticoduodenectomy) on Acute Postsurgical Inflammatory Response [ENSWAPI-trial]

TypeinterventionalSponsorMedical University of GrazRan2023 to 2025Enrolled90ConditionsPancreaticoduodenectomyArmsTENS - transcutaneous electrical nerve stimulation, Placebo
3 · Its place in the literature

Who cites it

564 citing papers in PubMed, 4 syntheses or guidelines pooled it, 995 citations in OpenAlex.

  1. Pooled it
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  14. Article
  15. Diabetic Autonomic Neuropathy and Impaired Inflammatory Reflex.Endocrinology, diabetes & metabolism · 2026
    Review
  16. Review
  17. Transcutaneous auricular vagus nerve stimulation improves dysautonomia in patients with hypermobile Ehlers-Danlos syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Article
  18. Article
  19. Review
  20. Review

504 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 8 institutions in 4 countries.

Frieda A KoopmanAmsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
Sangeeta S ChavanLaboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
Sanda MiljkoUniversity Clinical Hospital, Mostar 88000, Bosnia and Herzegovina;
Simeon GrazioClinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia;
Sekib SokolovicSarajevo University Clinical Center, Sarajevo 71000, Bosnia and Herzegovina;
P Richard SchuurmanDepartment of Neurosurgery, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
Ashesh D MehtaDepartment of Neurosurgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030;
Yaakov A LevineSetPoint Medical Corporation, Valencia, CA91355.
Michael FaltysSetPoint Medical Corporation, Valencia, CA91355.
Ralph ZitnikSetPoint Medical Corporation, Valencia, CA91355.
Kevin J TraceyLaboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY 11030;
Paul P TakAmsterdam 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.
Alta Bates Summit Medical Center · USAcademic Medical Center · NLFeinstein Institute for Medical Research · USHofstra University · USSisters of Charity Hospital · HRUniversity Clinical Hospital Mostar · BAUniversity of Amsterdam · NLUniversity of Sarajevo · BA

Funding

Molecular Basis of Bioelectronic MedicineR35GM118182 · NIGMS · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · PI TRACEY, KEVIN J · 2016 to 2025
$7.3M
6 · The paper itself

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.

Indexed as

Vagus Nerve StimulationAdultAgedArthritis, RheumatoidCytokinesEpilepsyFemaleHumansMaleMiddle AgedCytokinescytokinesinflammatory reflexrheumatoid arthritistumor necrosis factorvagus nerve

Identifiers

PMID27382171
PMCPMC4961187
OpenAlexW2469268362

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

and 3 more above

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.