Transcutaneous auricular vagus nerve stimulation versus sham stimulation in patients with erosive hand osteoarthritis (ESTIVAL): a randomised, multicentre, double-blind, sham-controlled trial. - 2025
Transcutaneous auricular vagus nerve stimulation versus sham stimulation in patients with erosive hand osteoarthritis (ESTIVAL): a randomised, multicentre, double-blind, sham-controlled trial.
[en] [en] BACKGROUND: Erosive hand osteoarthritis is a painful and inflammatory disease without effective treatments. In this study we aimed to investigate the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) compared with sham stimulation in patients with inflammatory erosive hand osteoarthritis.
METHODS: ESTIVAL was a multicentre, randomised, double-blind, sham-controlled trial done in 18 French hospital centres (two secondary and 16 tertiary centres). Adults (aged ≥18 years), fulfilling the American College of Rheumatology criteria for hand osteoarthritis with at least one erosive interphalangeal joint and ultrasound-confirmed synovitis were randomly assigned (1:1), stratified by site, using centralised web-based randomisation with computer-generated allocation, to receive either daily 20-min taVNS (VAGUSTIM, Schwa Medico, Rouffach, France) or sham stimulation (sham group; no electrical current) for 12 weeks. The primary endpoint was change in hand pain on a visual analogue scale (VAS) from baseline to week 12. Safety was assessed by recording adverse events and serious adverse events at each visit using a standardised form completed by investigators. The primary outcome and safety were analysed in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT04520516, and is completed. No individuals with lived experience of hand osteoarthritis were involved in the design or conduct of the study.
FINDINGS: Between April 8, 2021, and March 29, 2022, 148 patients were enrolled in the study and 142 (96%) were randomly assigned (73 [51%] to the taVNS group and 69 [49%] to the sham group). Overall, the mean age was 66·5 years (SD 8·4), 125 (88%) of 142 participants were female, and 17 (12%) were male. At week 12, 63 (86%) of 73 participants in the taVNS group and 64 (93%) of 69 participants in the sham group provided primary outcome data. Median change in VAS hand pain was -16·0 mm (IQR -32·0 to 5·0) in the taVNS group versus -6·0 mm (-27·0 to 7·0) in the sham group, giving an adjusted between-group difference of -10·0 mm (95% CI -23·0 to 2·0; p=0·22) at week 12; the primary endpoint was not met. No serious adverse events occurred. Adverse events were reported by 22 (30%) of 73 participants in the taVNS and 16 (23%) and 69 participants in the sham group, with no emerging safety concerns.
INTERPRETATION: In participants with erosive hand osteoarthritis, taVNS was safe and well tolerated. Although the primary endpoint was not met, the consistent pain reduction observed in patients with greater synovial inflammation suggests that taVNS merits further investigation in this erosive hand osteoarthritis population.
FUNDING: French Ministry of Health.
Disciplines :
Orthopedics, rehabilitation & sports medicine
Author, co-author :
Courties, Alice; AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France
Tuffet, Sophie; Sorbonne Université, AP-HP Hôpital Saint-Antoine, Service de Pharmacologie Clinique et Plateforme de Recherche Clinique de l'Est Parisien (URCEST, CRB, CRC), Paris, France
Cormier, Grégoire; CHD Vendée-site de la roche sur Yon, Service de Rhumatologie, La Roche-sur-Yon, France
Roux, Christian H; CHU Pasteur 2, Service de Rhumatologie, University Cote d'Azur, Nice, France
Ornetti, Paul; CHU François-Mitterrand, Service de Rhumatologie, Dijon, France
Pers, Yves-Marie; IRMB, University of Montpellier, INSERM, CHU Montpellier, Clinical immunology and osteoarticular diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France
Gottenberg, Jacques-Éric; Hôpital Hautepierre- Hôpitaux Universitaires de Strasbourg, Service de Rhumatologie, Strasbourg, France
Lespessailles, Eric; CHR d'Orleans, Service de Rhumatologie, Orléans, France
Chapurlat, Roland; INSERM UMR_S 1033, Hôpital Edouard Herriot, PMO: Association Prévention des Maladies Osseuses, Lyon, France
Arniaud, Denis; Hôpital Saint-Joseph Marseille Service de Rhumatologie, Marseille, France
Rannou, François; Université Paris Cité, INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs (T3S), Campus Saint-Germain-des-Prés, Paris, France
Wendling, Daniel; CHU Besançon, Service de Rhumatologie, Besançon, France
Eymard, Florent; AP-HP Henri Mondor, Service de Rhumatologie, Créteil, France
Mathieu, Sylvain; Université Clermont Auvergne, CHU Gabriel Montpied, Service de Rhumatologie, INSERM, Neuro-Dol, Clermont-Ferrand, France
Richette, Pascal; Université de Paris, AP-HP Lariboisière, Service de Rhumatologie, Paris, France
Saraux, Alain; Université de Bretagne Occidentale (Univ Brest), Department of Rheumatology, CHU Brest, INSERM (U1227), LabEx IGO, Brest, France
Marotte, Hubert; Université Jean Monnet Saint-Étienne, CHU Saint-Étienne, Service de Rhumatologie, Mines Saint-Etienne, INSERM, SAINBIOSE U1059, Saint-Etienne, France
Poursac, Nicolas; CHU Bordeaux, Service de Rhumatologie Bordeaux, France
Rat, Anne-Christine; CHU de Caen, Service de Rhumatologie 14000, Caen, France, COMETE, Inserm, PFRS, Caen Normandie University, Caen, France
Bastard, Jean-Philippe; AP-HP, Hôpitaux Universitaires Henri Mondor, Département de biochimie-pharmacologie, Créteil, France
Fellahi, Soraya; AP-HP, Hôpitaux Universitaires Henri Mondor, Département de biochimie-pharmacologie, Créteil, France
Henrotin, Yves ; Université de Liège - ULiège > Département des Sciences de l'activité physique et de la réadaptation > Pathologie générale et physiopathologie - Techniques particulières de kinésithérapie
Minssen, Lise; AP-HP Hôpital Saint-Antoine, Service de Radiologie, Paris, France
Deprouw, Camille; AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France
Nguyen, Christelle; Université Paris Cité, INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs (T3S), Campus Saint-Germain-des-Prés, Paris, France
Touati, Amel; Sorbonne Université, AP-HP Hôpital Saint-Antoine, Service de Pharmacologie Clinique et Plateforme de Recherche Clinique de l'Est Parisien (URCEST, CRB, CRC), Paris, France
Bérard, Laurence; Sorbonne Université, AP-HP Hôpital Saint-Antoine, Service de Pharmacologie Clinique et Plateforme de Recherche Clinique de l'Est Parisien (URCEST, CRB, CRC), Paris, France
Rousseau, Alexandra; Sorbonne Université, AP-HP Hôpital Saint-Antoine, Service de Pharmacologie Clinique et Plateforme de Recherche Clinique de l'Est Parisien (URCEST, CRB, CRC), Paris, France
Simon, Tabassome; Sorbonne Université, AP-HP Hôpital Saint-Antoine, Service de Pharmacologie Clinique et Plateforme de Recherche Clinique de l'Est Parisien (URCEST, CRB, CRC), Paris, France
Maheu, Emmanuel; AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France
Berenbaum, Francis; AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France
Sellam, Jérémie; AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France. Electronic address: jeremie.sellam@aphp.fr
Transcutaneous auricular vagus nerve stimulation versus sham stimulation in patients with erosive hand osteoarthritis (ESTIVAL): a randomised, multicentre, double-blind, sham-controlled trial.
Haugen IK, Englund M, Aliabadi P, et al. Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study. Ann Rheum Dis 2011; 70: 1581–86.
Kloppenburg M, Kroon FP, Blanco FJ, et al. 2018 update of the EULAR recommendations for the management of hand osteoarthritis. Ann Rheum Dis 2019; 78: 16–24.
Verbruggen G, Veys EM. Numerical scoring systems for the anatomic evolution of osteoarthritis of the finger joints. Arthritis Rheum 1996; 39: 308–20.
Marshall M, Watt FE, Vincent TL, Dziedzic K. Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management. Nat Rev Rheumatol 2018; 14: 641–56.
Sellam J, Maheu E, Crema MD, et al. The DIGICOD cohort: a hospital-based observational prospective cohort of patients with hand osteoarthritis—methodology and baseline characteristics of the population. Joint Bone Spine 2021; 88: 105171.
Kroon FPB, Kortekaas MC, Boonen A, et al. Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial. Lancet 2019; 394: 1993–2001.
Wang Y, Jones G, Keen HI, et al. Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial. Lancet 2023; 402: 1764–72.
Wittoek R, Verbruggen G, Vanhaverbeke T, Colman R, Elewaut D. RANKL blockade for erosive hand osteoarthritis: a randomized placebo-controlled phase 2a trial. Nat Med 2024; 30: 829–36.
Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 2017; 46: 927–42.
Courties A, Berenbaum F, Sellam J. Vagus nerve stimulation in musculoskeletal diseases. Joint Bone Spine 2021; 88: 105149.
Yakunina N, Kim SS, Nam E-C. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation 2017; 20: 290–300.
Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA 2016; 113: 8284–89.
Genovese MC, Gaylis NB, Sikes D, et al. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. Lancet Rheumatol 2020; 2: e527–38.
Courties A, Deprouw C, Maheu E, et al. Effect of transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: results from a pilot trial. J Clin Med 2022; 11: 1087.
Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357: 1191–94.
Courties A, Deprouw C, Rousseau A, et al. Transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: protocol for the randomised, double-blind, sham-controlled ESTIVAL trial. BMJ Open 2022; 12: e056169.
Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957; 16: 494–502.
Haugen IK, Østergaard M, Eshed I, et al. Iterative development and reliability of the OMERACT hand osteoarthritis MRI scoring system. J Rheumatol 2014; 41: 386–91.
Kloppenburg M, Maheu E, Kraus VB, et al. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis. Osteoarthritis Cartilage 2015; 23: 772–86.
Bellamy N, Campbell J, Haraoui B, et al. Dimensionality and clinical importance of pain and disability in hand osteoarthritis: Development of the Australian/Canadian (AUSCAN) Osteoarthritis Hand Index. Osteoarthr Cartil 2002; 10: 855–62.
Bossenger NR, Lewis GN, Rice DA, Shepherd D. The autonomic and nociceptive response to acute exercise is impaired in people with knee osteoarthritis. Neurobiol Pain 2023; 13: 100118.
Choi S-E, Xu H, Kang J-H, et al. Elevated resting heart rate is associated with increased radiographic severity of knee but not hand joints. Sci Rep 2021; 11: 23697.
Courties A, Do A, Leite S, et al. The role of the non-neuronal cholinergic system in inflammation and degradation processes in osteoarthritis. Arthritis Rheumatol 2020; published online July 8. https://doi.org/10.1002/art.41429.
Aoyagi K, Rivas E, Shababi R, et al. Safety and preliminary efficacy of transcutaneous auricular vagus nerve stimulation on chronic knee pain: A pilot trial. Osteoarthr Cartil Open 2024; 7: 100545.
Chan E, Mani AR. Assessing the therapeutic potential of vagus nerve stimulation in autoimmune diseases: a systematic review. Physiol Rep 2025; 13: e70230.
Tracey KJ. Reflex control of immunity. Nat Rev Immunol 2009; 9: 418–28.
Tarn J, Legg S, Mitchell S, Simon B, Ng W-F. The effects of noninvasive vagus nerve stimulation on fatigue and immune responses in patients with primary Sjögren's syndrome. Neuromodulation 2019; 22: 580–85.
Aranow C, Atish-Fregoso Y, Lesser M. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis 2020; published online Nov 3. https://doi.org/10.1136/annrheumdis-2020-217872.
Hein E, Nowak M, Kiess O, et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm 2013; 120: 821–27.
Palmer S, Domaille M, Cramp F, et al. Transcutaneous electrical nerve stimulation as an adjunct to education and exercise for knee osteoarthritis: a randomized controlled trial. Arthritis Care Res 2014; 66: 387–94.
