Vagus nerve stimulation as a novel treatment for systemic lupus erythematous: study protocol for a randomised, parallel-group, sham-controlled investigator-initiated clinical trial, the SLE-VNS study

Amanda Hempel Zinglersen, Ida Lynghøj Drange, Katrine Aagaard Myhr, Andreas Fuchs, Mogens Pfeiffer-Jensen, Christina Brock, Søren Jacobsen, Amanda Hempel Zinglersen, Ida Lynghøj Drange, Katrine Aagaard Myhr, Andreas Fuchs, Mogens Pfeiffer-Jensen, Christina Brock, Søren Jacobsen

Abstract

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. SLE is treated with immunosuppressants with suboptimal efficacy and high risk of serious side effects. Patients with SLE have increased risk of mortality, organ damage and debilitating treatment-resistant fatigue. Autonomic nervous system dysfunction (AD) is present in approximately half of the patients and may promote autoimmunity by weakening the vagally mediated anti-inflammatory reflex. Recent studies suggest that transcutaneous vagus nerve stimulation (tVNS) has few side effects and beneficial effects on fatigue, pain, disease activity and organ function. This study investigates whether adjuvant tVNS improves measures of fatigue (primary end point), AD, clinical disease activity, inflammation, pain, organ function and quality of life.Hence, this study will contribute to the understanding of AD as a potentially important precursor of fatigue, disease activity, progression and complications in SLE, and how tVNS mechanistically may attenuate this. As adjuvant tVNS use may reduce the need for traditional immunosuppressive therapy, this trial may prompt a shift in the treatment of SLE and potentially other autoimmune disorders.

Methods and analysis: Eighty-four patients with SLE with fatigue and AD will be randomised 1:1 to active or sham tVNS in this double-blinded parallel-group study. In period 1 (1 week), participants will receive a 4 min tVNS 4 times daily and report on fatigue daily. After a 2-week pause, period 2 (8 weeks) will entail tVNS twice daily and participants will report on fatigue, pain and disease activity weekly. Secondary end points will be assessed before and after each period and after 1 week in period 2.

Ethics and dissemination: The study is approved by the Danish Medical Research Ethical Committees (case no: 2120231) and results will be published in international peer-reviewed journals.

Trial registration number: NCT05315739.

Keywords: immunology; neurophysiology; rheumatology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Overview of the systemic lupus erythematosus (SLE)-vagus nerve stimulation (VNS) study.

References

    1. Kaul A, Gordon C, Crow MK, et al. . Systemic lupus erythematosus. Nat Rev Dis Primers 2016;2:16039. 10.1038/nrdp.2016.39
    1. Jacobsen S, Petersen J, Ullman S, et al. . Mortality and causes of death of 513 Danish patients with systemic lupus erythematosus. Scand J Rheumatol 1999;28:75–80. 10.1080/030097499442522
    1. Barber MRW, Hanly JG, Su L, et al. . Economic evaluation of damage Accrual in an international systemic lupus erythematosus inception cohort using a multistate model approach. Arthritis Care Res 2020;72:1800–8. 10.1002/acr.24092
    1. Tench CM, McCurdie I, White PD, et al. . The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology 2000;39:1249–54. 10.1093/rheumatology/39.11.1249
    1. Zonana-Nacach A, Roseman JM, McGwin G, et al. . Systemic lupus erythematosus in three ethnic groups. VI: factors associated with fatigue within 5 years of criteria diagnosis. LUMINA Study Group. lupus in minority populations: nature vs nurture. Lupus 2000;9:101–9. 10.1191/096120300678828046
    1. Booth S, Price E, Walker E. Fluctuation, invisibility, fatigue - the barriers to maintaining employment with systemic lupus erythematosus: results of an online survey. Lupus 2018;27:2284–91. 10.1177/0961203318808593
    1. Petrocchi V, Visintini E, De Marchi G, et al. . Patient experiences of systemic lupus erythematosus: findings from a systematic review, Meta-Summary, and Meta-Synthesis. Arthritis Care Res 2021. 10.1002/acr.24639. [Epub ahead of print: 16 Jun 2021].
    1. Oglesby A, Shaul AJ, Pokora T. Adverse event burden, resource use, and costs associated with immunosuppressant medications for the treatment of systemic lupus erythematosus: a systematic literature review. Int J Rheumatol 2013;2013:347520. 10.1155/2013/347520
    1. Al Sawah S, Zhang X, Zhu B, et al. . Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins lupus cohort. Lupus Sci Med 2015;2:e000066. 10.1136/lupus-2014-000066
    1. Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: remission and low disease activity state. Rheumatology 2020;59:v19–28. 10.1093/rheumatology/keaa420
    1. Zinglersen AH, Iversen KK, Leffers HCB, et al. . Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus. Lupus Sci Med 2021;8:e000507. 10.1136/lupus-2021-000507
    1. Sander C, Hildebrandt H, Schlake H-P, et al. . Subjective cognitive fatigue and autonomic abnormalities in multiple sclerosis patients. Front Neurol 2017;8:475. 10.3389/fneur.2017.00475
    1. Nahman-Averbuch H, Granovsky Y, Sprecher E, et al. . Associations between autonomic dysfunction and pain in chemotherapy-induced polyneuropathy. Eur J Pain 2014;18:47–55. 10.1002/j.1532-2149.2013.00349.x
    1. Provan SA, Olstad DS, Solberg EE, et al. . Evidence of reduced parasympathetic autonomic regulation in inflammatory joint disease: a meta-analyses study. Semin Arthritis Rheum 2018;48:134–40. 10.1016/j.semarthrit.2017.11.010
    1. Di Franco M, Paradiso M, Riccieri V, et al. . Autonomic dysfunction and microvascular damage in systemic sclerosis. Clin Rheumatol 2007;26:1278–83. 10.1007/s10067-006-0492-y
    1. Kim J-S, Lee S-H, Oh Y-S, et al. . Arterial stiffness and cardiovascular autonomic dysfunction in patients with Parkinson's disease. Neurodegener Dis 2017;17:89–96. 10.1159/000450613
    1. Spallone V. Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J 2019;43:3–30. 10.4093/dmj.2018.0259
    1. Jin J, Wang W, Zhu L. Cardiovascular autonomic neuropathy is an independent risk factor for left ventricular diastolic dysfunction in patients with type 2 diabetes. Biomed Res Int 2017;2017:3270617. 10.1155/2017/3270617
    1. Weinrauch L, et al. . Relationship between autonomic function and progression of renal disease in diabetic proteinuria clinical correlations and implications for blood pressure control. Am J Hypertens 1998;11:302–8. 10.1016/S0895-7061(97)00472-X
    1. McIntire LK, McKinley RA, Goodyear C, et al. . Cervical transcutaneous vagal nerve stimulation (ctVNS) improves human cognitive performance under sleep deprivation stress. Commun Biol 2021;4:634. 10.1038/s42003-021-02145-7
    1. Tarn J, Legg S, Mitchell S, et al. . The effects of noninvasive vagus nerve stimulation on fatigue and immune responses in patients with primary Sjögren's syndrome. Neuromodulation 2019;22:580–5. 10.1111/ner.12879
    1. Courties A, Deprouw C, Maheu E, et al. . Transcutaneous auricular stimulation of the vagus nerve for erosive hand osteoarthritis an open label pilot study. Osteoarthritis Cartilage 2020;28:S360. 10.1016/j.joca.2020.02.562
    1. Frøkjaer JB, Bergmann S, Brock C, et al. . Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. Neurogastroenterol Motil 2016;28:592–8. 10.1111/nmo.12760
    1. Gaul C, Diener H-C, Silver N, et al. . Non-Invasive vagus nerve stimulation for prevention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 2016;36:534–46. 10.1177/0333102415607070
    1. Puledda F, Goadsby PJ. An update on non-pharmacological neuromodulation for the acute and preventive treatment of migraine. Headache 2017;57:685–91. 10.1111/head.13069
    1. Zhang Y, Popovic ZB, Bibevski S, et al. . Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2:692–9. 10.1161/CIRCHEARTFAILURE.109.873968
    1. Meregnani J, Clarençon D, Vivier M, et al. . Anti-Inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci 2011;160:82–9. 10.1016/j.autneu.2010.10.007
    1. Brock C, Brock B, Aziz Q, et al. . Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha. Neurogastroenterol Motil 2017;29:e12999. 10.1111/nmo.12999
    1. Rasmussen SE, Pfeiffer-Jensen M, Drewes AM, et al. . Vagal influences in rheumatoid arthritis. Scand J Rheumatol 2018;47:1–11. 10.1080/03009742.2017.1314001
    1. 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 U S A 2016;113:8284–9. 10.1073/pnas.1605635113
    1. Brock C, Rasmussen SE, Drewes AM. Vagal nerve Stimulation-Modulation of the anti-inflammatory response and clinical outcome in psoriatic arthritis or ankylosing spondylitis. Mediators Inflamm 2021;2021:9933532. 10.1155/2021/9933532
    1. Drewes AM, Brock C, Rasmussen SE, et al. . Short-Term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study. Scand J Rheumatol 2021;50:20–7. 10.1080/03009742.2020.1764617
    1. Bonaz B, Sinniger V, Pellissier S. Anti-Inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol 2016;594:5781–90. 10.1113/JP271539
    1. Dasari TW, Gabor F, Csipo T, et al. . Non-Invasive neuromodulation of vagus activity improves endothelial function in patients with heart failure with reduced ejection fraction: a randomized study. J Card Fail 2018;24:S59–60. 10.1016/j.cardfail.2018.07.266
    1. Chapleau MW, Rotella DL, Reho JJ, et al. . Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2016;311:H276–85. 10.1152/ajpheart.00043.2016
    1. Zhou L, Filiberti A, Humphrey MB, et al. . Low-Level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction. Exp Physiol 2019;104:28–38. 10.1113/EP087351
    1. Stavrakis S, Elkholey K, Morris L, et al. . Neuromodulation of inflammation to treat heart failure with preserved ejection fraction: a pilot randomized clinical trial. J Am Heart Assoc 2022;11:e023582. 10.1161/JAHA.121.023582
    1. Silberstein SD, Mechtler LL, Kudrow DB, et al. . Non-Invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 2016;56:1317–32. 10.1111/head.12896
    1. Goadsby PJ, de Coo IF, Silver N, et al. . Non-Invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018;38:959–69. 10.1177/0333102417744362
    1. Grazzi L, Tassorelli C, de Tommaso M, et al. . Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial. J Headache Pain 2018;19:98. 10.1186/s10194-018-0928-1
    1. Diener H-C, Goadsby PJ, Ashina M, et al. . Non-Invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled premium trial. Cephalalgia 2019;39:1475–87. 10.1177/0333102419876920
    1. Okdahl T, Bertoli D, Brock B, et al. . Study protocol for a multicentre, randomised, parallel group, sham-controlled clinical trial investigating the effect of transcutaneous vagal nerve stimulation on gastrointestinal symptoms in people with diabetes complicated with diabetic autonomic neuropathy: the DAN-VNS study. BMJ Open 2021;11:e038677. 10.1136/bmjopen-2020-038677
    1. Aringer M, Costenbader K, Daikh D, et al. . 2019 European League against Rheumatism/American College of rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151–9. 10.1136/annrheumdis-2018-214819
    1. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288–91.
    1. Gladman D, Ginzler E, Goldsmith C, et al. . The development and initial validation of the systemic lupus international collaborating Clinics/American College of rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9. 10.1002/art.1780390303
    1. Raymond K, Park J, Joshi AV, et al. . Patient experience with fatigue and qualitative Interview-Based evidence of content validation of the FACIT-Fatigue in systemic lupus erythematosus. Rheumatol Ther 2021;8:541–54. 10.1007/s40744-021-00292-1
    1. Barbacki A, Petri M, Aviña-Zubieta A, et al. . Fatigue measurements in systemic lupus erythematosus. J Rheumatol 2019;46:1470–7. 10.3899/jrheum.180831
    1. Petri MA, Martin RS, Scheinberg MA, et al. . Assessments of fatigue and disease activity in patients with systemic lupus erythematosus enrolled in the phase 2 clinical trial with blisibimod. Lupus 2017;26:27–37. 10.1177/0961203316654767
    1. Sletten DM, Suarez GA, Low PA, et al. . Compass 31: a refined and abbreviated composite autonomic symptom score. Mayo Clin Proc 2012;87:1196–201. 10.1016/j.mayocp.2012.10.013
    1. Karlson EW, Daltroy LH, Rivest C, et al. . Validation of a systemic lupus activity questionnaire (SLAQ) for population studies. Lupus 2003;12:280–6. 10.1191/0961203303lu332oa
    1. Ward MM, Marx AS, Barry NN. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J Rheumatol 2000;27:664–70.
    1. Safikhani S, Gries KS, Trudeau JJ, et al. . Response scale selection in adult pain measures: results from a literature review. J Patient Rep Outcomes 2017;2:40. 10.1186/s41687-018-0053-6
    1. Ware J, Kosinski M, Keller SD. A 12-Item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34:220–33. 10.1097/00005650-199603000-00003
    1. Spallone V, Bellavere F, Scionti L, et al. . Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis 2011;21:69–78. 10.1016/j.numecd.2010.07.005
    1. Gulichsen E, Fleischer J, Ejskjaer N, et al. . Screening for diabetic cardiac autonomic neuropathy using a new handheld device. J Diabetes Sci Technol 2012;6:965–72. 10.1177/193229681200600430
    1. Brock C, Jessen N, Brock B, et al. . Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in type 1 diabetes mellitus. Diabet Med 2017;34:1428–34. 10.1111/dme.13421
    1. Casellini CM, Parson HK, Richardson MS, et al. . Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther 2013;15:948–53. 10.1089/dia.2013.0129
    1. Spallone V, Ziegler D, Freeman R, et al. . Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–53. 10.1002/dmrr.1239
    1. Ackermans PAJ, Solosko TA, Spencer EC, et al. . A user-friendly integrated monitor-adhesive patch for long-term ambulatory electrocardiogram monitoring. J Electrocardiol 2012;45:148–53. 10.1016/j.jelectrocard.2011.10.007
    1. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task force of the European Society of cardiology and the North American Society of pacing and electrophysiology. Circulation 1996;93:1043–65.
    1. Touma Z, Gladman DD, Ibañez D, et al. . Systemic lupus erythematosus disease activity index 2000 Responder Index-50 enhances the ability of SLE Responder index to identify responders in clinical trials. J Rheumatol 2011;38:2395–9. 10.3899/jrheum.110550
    1. Jesus D, Matos A, Henriques C, et al. . Derivation and validation of the SLE disease activity score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019;78:365–71. 10.1136/annrheumdis-2018-214502
    1. Petri M, Genovese M, Engle E, et al. . Definition, incidence, and clinical description of flare in systemic lupus erythematosus. A prospective cohort study. Arthritis Rheum 1991;34:937–44. 10.1002/art.1780340802
    1. Wells G, Becker J-C, Teng J, et al. . Validation of the 28-joint disease activity score (DAS28) and European League against rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68:954–60. 10.1136/ard.2007.084459
    1. Arendt-Nielsen L, Andresen T, Malver LP, et al. . A double-blind, placebo-controlled study on the effect of buprenorphine and fentanyl on descending pain modulation: a human experimental study. Clin J Pain 2012;28:623–7. 10.1097/AJP.0b013e31823e15cb
    1. Lang RM, Badano LP, Mor-Avi V, et al. . Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of echocardiography and the European association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–71. 10.1093/ehjci/jev014
    1. Jiang B, Liu B, McNeill KL, et al. . Measurement of pulse wave velocity using pulse wave Doppler ultrasound: comparison with arterial tonometry. Ultrasound Med Biol 2008;34:509–12. 10.1016/j.ultrasmedbio.2007.09.008
    1. Chojnowski MM, Felis-Giemza A, Olesińska M. Capillaroscopy - a role in modern rheumatology. Reumatologia 2016;54:67–72. 10.5114/reum.2016.60215
    1. Goligher EC, Pouchot J, Brant R, et al. . Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus. J Rheumatol 2008;35:635–42.
    1. Aranow C, Atish-Fregoso Y, Lesser M, et al. . 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 2021;80:203–8. 10.1136/annrheumdis-2020-217872

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren