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Vagus nerve stimulation as a therapeutic option in inflammatory rheumatic diseases

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Abstract

The vagus nerve forms intricate neural connections with an extensive number of organs, particularly the digestive system. The vagus nerve has a pivotal role as a fundamental component of the autonomic nervous system, exhibiting an essential effect. It establishes a direct link with the parasympathetic system, consequently eliciting the synaptic release of acetylcholine. Recent studies have revealed the potential anti-inflammatory function of the vagus nerve. The activation of the hypothalamic system through the stimulation of vagal afferents is fundamentally involved in regulating inflammation. This activation process leads to the production of cortisol. The other mechanism, defined as the cholinergic anti-inflammatory pathway, is characterized by the involvement of vagal efferents. These fibers release the neurotransmitter acetylcholine at particular synaptic connections, involving interactions with macrophages and enteric neurons. The mechanism under consideration is ascribed to the α-7-nicotinic acetylcholine receptors. The fusion of acetylcholine receptors is responsible for the restricted secretion of inflammatory mediators by macrophages. A potential mechanism for anti-inflammatory effects involves the stimulation of the sympathetic system through the vagus nerve, leading to the control of immunological responses within the spleen. This article offers an extensive summary of the present knowledge regarding the therapeutic effectiveness of stimulating the vagus nerve in managing inflammatory rheumatic conditions based on the relationship of inflammation with the vagus nerve. Furthermore, the objective is to present alternatives that may be preferred while applying vagus nerve stimulation approaches.

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References

  1. Hilz MJ (2022) Transcutaneous vagus nerve stimulation—a brief introduction and overview. Auton Neurosci 243:103038. https://doi.org/10.1016/j.autneu.2022.103038

    Article  PubMed  Google Scholar 

  2. Jacobson A, Yang D, Vella M, Chiu IM (2021) The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunol 14:555–565. https://doi.org/10.1038/s41385-020-00368-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Mikami Y, Tsunoda J, Kiyohara H, Taniki N, Teratani T, Kanai T (2022) Vagus nerve-mediated intestinal immune regulation: therapeutic implications of inflammatory bowel diseases. Int Immunol 34:97–106. https://doi.org/10.1093/intimm/dxab039

    Article  PubMed  CAS  Google Scholar 

  4. Seifert O, Baerwald C (2023) Stimulation of the vagus nerve as a therapeutic principle. Z Rheumatol. https://doi.org/10.1007/s00393-023-01398-3

    Article  PubMed  PubMed Central  Google Scholar 

  5. Li S, Qi D, Li JN, Deng XY, Wang DX (2021) Vagus nerve stimulation enhances the cholinergic anti-inflammatory pathway to reduce lung injury in acute respiratory distress syndrome via STAT3. Cell Death Discov 7:63. https://doi.org/10.1038/s41420-021-00431-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wu Z, Zhang X, Cai T, Li Y, Guo X, Zhao X, Wu D, Li Z, Zhang L (2023) Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: an open double-blind, sham-controlled, pilot study. Brain Stimul 16:507–514. https://doi.org/10.1016/j.brs.2023.02.008VNS

    Article  PubMed  Google Scholar 

  7. Wang X, Ding Q, Li T, Li W, Yin J, Li Y, Li Y, Zhuang W (2023) Application of vagus nerve stimulation on the rehabilitation of upper limb dysfunction after stroke: a systematic review and meta-analysis. Front Neurol 14:1189034. https://doi.org/10.1007/s00393-023-01398-310.3389/fneur.2023

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bonaz B, Sinniger V, Pellissier S (2019) Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions. Cold Spring Harb Perspect Med 9:a034199. https://doi.org/10.1101/cshperspect.a034199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Longo S, Rizza S, Federici M (2023) Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes. Acta Diabetol 60:1007–1017. https://doi.org/10.1007/s00592-023-02088-x

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bonaz B, Sinniger V, Pellissier S (2021) Therapeutic potential of vagus nerve stimulation for inflammatory Bowel diseases. Front Neurosci 15:650971. https://doi.org/10.3389/fnins.2021.650971

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fang YT, Lin YT, Tseng WL, Tseng P, Hua GL, Chao YJ, Wu YJ (2023) Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications. Front Aging Neurosci 15:1173987. https://doi.org/10.3389/fnagi.2023.1173987

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kressel AM, Tsaava T, Levine YA, Chang EH, Addorisio ME, Chang Q, Burbach BJ, Carnevale D, Lembo G, Zador AM, Andersson U, Pavlov VA, Chavan SS, Tracey KJ (2020) Identification of a brainstem locus that inhibits tumor necrosis factor. Proc Natl Acad Sci USA 117:29803–29810. https://doi.org/10.1073/pnas.2008213117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Olofsson PS, Katz DA, Rosas-Ballina M, Levine YA, Ochani M, Valdés-Ferrer SI, Pavlov VA, Tracey KJ, Chavan SS (2012) α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol Med 18:539–543. https://doi.org/10.2119/molmed.2011.00405

    Article  PubMed  CAS  Google Scholar 

  14. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409–1417. https://doi.org/10.1007/s00296-011-1999-3

    Article  PubMed  Google Scholar 

  15. Nussinovitch N, Livneh A, Katz K, Langevitz P, Feld O, Nussinovitch M, Volovitz B, Lidar M, Nussinovitch U (2011) Heart rate variability in familial Mediterranean fever. Rheumatol Int 31:39–43. https://doi.org/10.1007/s00296-009-1214-y

    Article  PubMed  Google Scholar 

  16. Gezer HH, Erdem Gürsoy D, Acer Kasman S, Duruöz MT (2022) Assessment of autonomic dysfunction with the COMPASS-31 and its relationship with disease activity and cardiovascular risks in patients with psoriatic arthritis. Rheumatol Int 42:1539–1548. https://doi.org/10.1007/s00296-022-05110-7

    Article  PubMed  CAS  Google Scholar 

  17. Janse van Rensburg DC, Ker JA, Grant CC, Fletcher L (2012) Autonomic impairment in rheumatoid arthritis. Int J Rheum Dis 15:419–426. https://doi.org/10.1111/j.1756-185X.2012.01730.x

    Article  PubMed  Google Scholar 

  18. Ingegnoli F, Buoli M, Antonucci F, Coletto LA, Esposito CM, Caporali R (2020) The link between autonomic nervous system and Rheumatoid arthritis: from bench to bedside. Front Med 7:589079. https://doi.org/10.3389/fmed.2020.589079

    Article  Google Scholar 

  19. Holman AJ, Ng E (2008) Heart rate variability predicts anti-tumor necrosis factor therapy response for inflammatory arthritis. Auton Neurosci 143:58–67. https://doi.org/10.1016/j.autneu.2008.05.005

    Article  PubMed  CAS  Google Scholar 

  20. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 113:8284–8289. https://doi.org/10.1073/pnas.1605635113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Drewes AM, Brock C, Rasmussen SE, Møller HJ, Brock B, Deleuran BW, Farmer AD, Pfeiffer-Jensen M (2021) 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 50:20–27. https://doi.org/10.1080/03009742.2020.1764617

    Article  PubMed  CAS  Google Scholar 

  22. Marsal S, Corominas H, José de Agustín J et al (2021) Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study. Lancet Rheumatol 3:E262–E269. https://doi.org/10.1016/S2665-9913(20)30425-2

    Article  CAS  Google Scholar 

  23. Baker MC, Kavanagh S, Cohen S, Matsumoto AK, Dikranian A, Tesser J, Kivitz A, Alataris K, Genovese MC (2023) A randomized, double-blind, sham-controlled, clinical trial of auricular vagus nerve stimulation for the treatment of active Rheumatoid Arthritis. Arthritis Rheumatol. https://doi.org/10.1002/art.42637

    Article  PubMed  Google Scholar 

  24. Tłustochowicz M, Brzozowska M, Wierzba W, Raciborski F, Kwiatkowska B, Tłustochowicz W, Jacyna A, Marczak M, Kisiel B, Śliwczyński A (2020) Prevalence of axial spondyloarthritis in Poland. Rheumatol Int 40:323–330. https://doi.org/10.1007/s00296-019-04482-7

    Article  PubMed  Google Scholar 

  25. Zhang Y, Hu L, Liao S, Wang Y, Ji X, Liu X, Huang F, Zhu J (2023) Bibliometric analysis of publications on enthesitis in spondyloarthritis in 2012–2021 based on web of science core collection databases. Rheumatol Int 43:173–182. https://doi.org/10.1007/s00296-022-05227-9

    Article  PubMed  CAS  Google Scholar 

  26. Kocyigit BF, Sagtaganov Z, Yessirkepov M, Akyol A (2023) Assessment of complementary and alternative medicine methods in the management of ankylosing spondylitis, rheumatoid arthritis, and fibromyalgia syndrome. Rheumatol Int 43:617–625. https://doi.org/10.1007/s00296-022-05267-1

    Article  PubMed  CAS  Google Scholar 

  27. Brock C, Rasmussen SE, Drewes AM, Møller HJ, Brock B, Deleuran B, Farmer AD, Pfeiffer-Jensen M (2021) Vagal nerve stimulation-modulation of the anti-inflammatory response and clinical outcome in Psoriatic Arthritis or Ankylosing Spondylitis. Mediators Inflamm 2021:9933532. https://doi.org/10.1155/2021/9933532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ramkissoon CM, Güemes A, Vehi J (2021) Overview of therapeutic applications of non-invasive vagus nerve stimulation: a motivation for novel treatments for systemic lupus erythematosus. Bioelectron Med 7:8. https://doi.org/10.1186/s42234-021-00069-5

    Article  PubMed  PubMed Central  Google Scholar 

  29. Milovanović B, Stojanović L, Milićevik N, Vasić K, Bjelaković B, Krotin M (2010) Cardiac autonomic dysfunction in patients with systemic lupus, rheumatoid arthritis and sudden death risk. Srp Arh Celok Lek 138:26–32. https://doi.org/10.2298/sarh1002026m

    Article  PubMed  Google Scholar 

  30. Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B (2021) 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 80:203–208. https://doi.org/10.1136/annrheumdis-2020-217872

    Article  PubMed  CAS  Google Scholar 

  31. Davies K, Ng WF (2021) Autonomic nervous system dysfunction in primary Sjögren’s syndrome. Front Immunol 12:702505. https://doi.org/10.3389/fimmu.2021.702505

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Newton JL, Frith J, Powell D, Hackett K, Wilton K, Bowman S, Price E, Pease C, Andrews J, Emery P, Hunter J, Gupta M, Vadivelu S, Giles I, Isenberg D, Lanyon P, Jones A, Regan M, Cooper A, Moots R, Sutcliffe N, Bombardieri M, Pitzalis C, McLaren J, Young-Min S, Dasgupta B, Griffiths B, Lendrem D, Mitchell S, Ng WF, UK primary Sjögren’s syndrome registry (2012) Autonomic symptoms are common and are associated with overall symptom burden and disease activity in primary Sjogren’s syndrome. Ann Rheum Dis 71:1973–1979. https://doi.org/10.1136/annrheumdis-2011-201009

    Article  PubMed  Google Scholar 

  33. Qin L, Zhang Y, Yang X, Luo Q, Wang H (2022) Cardiac involvement in primary Sjӧgren’s syndrome. Rheumatol Int 42:179–189. https://doi.org/10.1007/s00296-021-04970-9

    Article  PubMed  Google Scholar 

  34. Ng WF, Bowman SJ, Griffiths B, UKPSSR study group (2011) United Kingdom Primary Sjogren’s Syndrome Registry—a united effort to tackle an orphan rheumatic disease. Rheumatology 50:32–39. https://doi.org/10.1093/rheumatology/keq240

    Article  PubMed  Google Scholar 

  35. Ng WF, Stangroom AJ, Davidson A, Wilton K, Mitchell S, Newton JL (2012) Primary Sjogrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure. QJM 105:1191–1199. https://doi.org/10.1093/qjmed/hcs172

    Article  PubMed  PubMed Central  Google Scholar 

  36. Tarn J, Legg S, Mitchell S, Simon B, Ng WF (2019) The effects of noninvasive vagus nerve stimulation on fatigue and immune responses in patients with primary Sjögren’s syndrome. Neuromodulation 22:580–585. https://doi.org/10.1111/ner.12879

    Article  PubMed  Google Scholar 

  37. Tarn J, Evans E, Traianos E, Collins A, Stylianou M, Parikh J, Bai Y, Guan Y, Frith J, Lendrem D, Macrae V, McKinnon I, Simon BS, Blake J, Baker MR, Taylor JP, Watson S, Gallagher P, Blamire A, Newton J, Ng WF (2023) The effects of noninvasive vagus nerve stimulation on fatigue in participants with primary Sjögren’s syndrome. Neuromodulation 26:681–689. https://doi.org/10.1016/j.neurom.2022.08.461

    Article  PubMed  Google Scholar 

  38. Rodrigues GD, Carandina A, Scatà C, Bellocchi C, Beretta L, da Silva Soares PP, Tobaldini E, Montano N (2022) Sympatho-vagal dysfunction in systemic sclerosis: a follow-up study. Life 13:34. https://doi.org/10.3390/life13010034

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zlatanovic M, Tadic M, Celic V, Ivanovic B, Stevanovic A, Damjanov N (2017) Cardiac mechanics and heart rate variability in patients with systemic sclerosis: the association that we should not miss. Rheumatol Int 37:49–57. https://doi.org/10.1007/s00296-016-3618-9

    Article  PubMed  Google Scholar 

  40. Rodrigues GD, Tobaldini E, Bellocchi C, Santaniello A, Caronni M, Severino A, Froldi M, Beretta L, da Silva Soares PP, Montano N (2019) Cardiac autonomic modulation at rest and during orthostatic stress among different systemic sclerosis subsets. Eur J Intern Med 66:75–80. https://doi.org/10.1016/j.ejim.2019.06.003

    Article  PubMed  Google Scholar 

  41. Bellocchi C, Carandina A, Della Torre A, Turzi M, Arosio B, Marchini M, Vigone B, Scatà C, Beretta L, Rodrigues GD, Tobaldini E, Montano N (2023) Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis. RMD Open 9:e003265. https://doi.org/10.1136/rmdopen-2023-003265

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goggins E, Mitani S, Tanaka S (2022) Clinical perspectives on vagus nerve stimulation: present and future. Clin Sci (Lond) 136:695–709. https://doi.org/10.1042/CS20210507

    Article  PubMed  Google Scholar 

  43. Courties A, Berenbaum F, Sellam J (2021) Vagus nerve stimulation in musculoskeletal diseases. Joint Bone Spine 88:105149. https://doi.org/10.1016/j.jbspin.2021.105149

    Article  PubMed  Google Scholar 

  44. Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, Majid A (2018) Safety and tolerability of transcutaneous vagus nerve stimulation in humans; a systematic review. Brain Stimul 11:1225–1238. https://doi.org/10.1016/j.brs.2018.08.010

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physical Medicine and Rehabilitation, University of Health Sciences, Adana Health Practice and Research Center, Adana, Turkey

    Burhan Fatih Kocyigit

  2. Department of Neurology, Psychiatry, Neurosurgery and Rehabilitation, South Kazakhstan Medical Academy, Shymkent, Kazakhstan

    Meirgul I. Assylbek

  3. Department of Social Health Insurance and Public Health, South Kazakhstan Medical Academy, Shymkent, Kazakhstan

    Meirgul I. Assylbek

  4. Medical Center ‘’Mediker’’, Shymkent, Kazakhstan

    Meirgul I. Assylbek

  5. Physiotherapy and Rehabilitation Application and Research Center, Hasan Kalyoncu University, Gaziantep, Turkey

    Ahmet Akyol

  6. Department of Biology and Biochemistry, South Kazakhstan Medical Academy, Shymkent, Kazakhstan

    Ruslan Abdurakhmanov & Marlen Yessirkepov

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  1. Burhan Fatih Kocyigit
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  2. Meirgul I. Assylbek
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  3. Ahmet Akyol
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  4. Ruslan Abdurakhmanov
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  5. Marlen Yessirkepov
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BFK drafted the initial version and performed searches through bibliographic databases. All co-authors contributed substantially to the concept and revisions. They approved the final version for submission.

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Correspondence to Burhan Fatih Kocyigit.

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Kocyigit, B.F., Assylbek, M.I., Akyol, A. et al. Vagus nerve stimulation as a therapeutic option in inflammatory rheumatic diseases. Rheumatol Int 44, 1–8 (2024). https://doi.org/10.1007/s00296-023-05477-1

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