Vagus nerve stimulation in rheumatic diseases: linking autonomic nervous system regulation, inflammation, and clinical outcomes

Zou et al. confirmed the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) in regulating cardiac function, obesity, glucose metabolism, gastrointestinal motility, and immune function [ 50 ]. Similarly, Yu Wang et al. reported a beneficial effect of taVNS in patients suffering from epilepsy and depression [ 51 ]. Another important therapeutic application of taVNS is in the treatment of migraine, where a significant reduction in the frequency of migraine attacks was observed following stimulation [ 52 ]. In a study conducted by Dong Wu et al., taVNS was shown to significantly alleviate symptoms of Ménière’s disease, leading the authors to conclude that it should be considered a supportive therapy for this condition [ 53 ]. TaVNS has also been shown to influence the gut microbiome and may exert anti-inflammatory effects. Three studies have investigated the relationship between taVNS and the gut microbial composition [ 54 – 56 ]. In the study by Mion et al., no significant changes in the fecal calprotectin concentration, a biomarker of intestinal inflammation, were observed after taVNS, although participants ( n = 12) reported a marked improvement in gastrointestinal symptoms over six months [ 54 ]. In a trial by Bora et al., female patients with irritable bowel syndrome (IBS) ( n = 20) underwent taVNS for four weeks, which resulted in a reduction in pain and disability. Moreover, responders to therapy presented greater microbial diversity and a greater abundance of Blautia than nonresponders did [ 55 ]. Similarly, Castillo et al. conducted an observational study in 17 women with IBS who underwent four weeks of transcutaneous electrical auricular field stimulation. The results revealed significant reductions in pain, disability, and catastrophizing, as well as beneficial modulation of carbohydrate degradation and long-chain fatty acid synthesis pathways [ 56 ]. These findings suggest that taVNS may modulate the gut microbiota composition and activity, thus influencing the gut–brain axis and contributing to pain and inflammation reduction. This mechanism may be particularly relevant in patients with spondyloarthropathies. However, these results require replication in larger cohorts and further validation through well-designed clinical trials. Future studies should aim to standardize taVNS protocols, including stimulation parameters such as frequency, intensity, and duration, to enable better comparability between studies and facilitate meta-analytical evaluations.

To date, most studies have been conducted on small patient cohorts, with no standardized and often short stimulation and follow-up periods. There was considerable heterogeneity in stimulation parameters, particularly regarding frequency settings, and a lack of unified research methodology. Investigations have focused on various aspects of VNS efficacy assessment; however, beyond measuring inflammatory markers, pain intensity, or disease activity, few studies have evaluated functional outcomes or other comorbid disease manifestations. Additionally, information regarding analgesic use or the need for healthcare services was rarely reported.

The results of studies evaluating the efficacy of vagus nerve stimulation in selected rheumatic diseases are summarized in Table  1 . Table 1 Summary of studies on vagus nerve stimulation Author Disease Type of stimulation Frequency [Hz] Number of patients Follow-up period Results Inflammatory rheumatic diseases Koopman [ 19 ] Rheumatoid arthritis Invasive – electrode implanted in the left vagus nerve at the cervical level 10 17 84 days Significant reduction in DAS-28 CRP (from 6.05 ± 0.18 at baseline to 4.16 ± 0.39 on day 42). Significant decrease in TNF levels (from 2900 ± 566 pg/ml at baseline to 1776 ± 342 pg/ml on day 42) Baker [ 36 ] Rheumatoid arthritis Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) 20 113 12 weeks Reduction in DAS28-CRP: −0.95 ± 0.16 for active stimulation and − 0.66 ± 0.16 for sham stimulation Reduction in HAQ-DI: −0.19 ± 0.06 for active stimulation and − 0.02 ± 0.06 for sham stimulation Marsal [ 37 ] Rheumatoid arthritis Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) 20 30 12 weeks Significant reduction in DAS28-CRP (5.3 at baseline and 3.9 after 12 weeks). Reduction in HAQ-DI (1.6 at baseline and 1.1 after 12 weeks). ACR20 response achieved in 16 patients (53%), ACR50 in 10 patients (33%), and ACR70 in 5 patients (17%). Tesser [ 38 ] Rheumatoid arthritis Invasive – electrode implanted in the left vagus nerve at the cervical level 10 242 3 months ACR20 response was achieved by 35.2% of arm 1 (stimulation) and by 24.2% of arm 2. The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P  = 0.0209, 95% confidence interval (CI) = 0.6, 23.1 Drewes [ 39 ] Rheumatoid arthritis Non-invasive transcutaneous cervical vagus nerve stimulation, bilateral 25 36 5 days In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02) In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone ( p  = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02) Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs. 4.9 ± 3 linear vagal scale, p = 0.03) Cardiac vagal tone was negatively associated with DAS28-CRP ( r  = −0.37, p = 0.03) Brock [ 40 ] Ankylosing spondylitis; Psoriatic arthritis Non-invasive transcutaneous cervical vagus nerve stimulation, bilateral 25 20 patients with AS 20 patients with PsA 5 days PsA group: Reduction in ASDAS (2.22 at baseline and 2.03 on day 5) Reduction in CRP (3.23 mg/L at baseline and 2.59 mg/L on day 5) Increase in TNF-α (1.65 pg/mL at baseline and 1.81 pg/mL on day 5) AS group: No statistically significant changes in DAS28-CRP, ASDAS, or CRP Reduction in cytokines: IFN-γ (4.36 vs. 3.76) IL-8 (3.83 vs. 3.03) IL-10 (0.46 vs. 0.42) Tarn [ 41 ] Sjögren’s syndrome Non-invasive transcutaneous cervical vagus nerve stimulation 25 40 54 days Significant reduction after 56 days of stimulation in the active group in the following scales: PRO-F-Physician: p  = 0.02 PRO-F-Mental: p  = 0.02 fVAS: p  = 0.04 Alpha reactivity showed a significant negative correlation with fVAS in the active group: p  < 0.01. IL-6 in the sham group: median increase of 452 pg/ml IL-6 in the active group: median decrease of 168 pg/ml No statistically significant differences were observed in HRV or muscle bioenergetics Jensen [ 26 ] Systemic lupus erythematosus, Rheumatoid arthritis Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) 25 47 patients with RA 5 patients with SLE Single session Patients after DB: an increase in all HRV parameters by 17–31% following stimulation. Patients after taVNS: an increase in all HRV parameters by 18–25% Aranow [ 42 ] Systemic lupus erythematosus Non-invasive transcutaneous auricular stimulation of the left vagus nerve 30 18 4 days of stimulation, 12 days of follow-up Reduction in median VAS score to − 5.35 after taVNS vs. 0.15 after SS Reduction in fatigue reflected by an increase in median FACIT-F score to 12.00 after taVNS vs. − 2.00 after SS Reduction in median swollen joints [%]: 100.00 after taVNS vs. 14.29 after SS Reduction in median tender joints [%]: 98.49 Non-inflammatory rheumatic disease Lommano [ 43 ] Fibromyalgia Non-invasive transcutaneous auricular stimulation of the left vagus nerve 20 25 28 days Reduction in FIQR score: 69.12 ± 17.58 before taVNS vs. 62.24 ± 19.19 after taVNS. Improvement in autonomic function in the following domains: Orthostatic symptoms: 21.60 ± 13.61 before vs. 16.08 ± 11.61 after taVNS Vasomotor symptoms: 1.96 ± 1.74 before vs. 1.58 ± 1.55 after taVNS Pupillomotor symptoms: 3.54 ± 1.10 before vs. 3.19 ± 1.06 after taVNS Other symptoms showed no statistically significant differences. Improvement in PDQ: 23.08 ± 5.33 before vs. 21.20 ± 6.05 after taVNS Improvement in CSS-9: 30.32 ± 3.35 before vs. 29.16 ± 3.42 after taVNS Neves [ 44 ] Fibromyalgia Manual acupuncture stimulation of the auricular branch of the vagus nerve (aVNS), left or right ear Manual acupuncture stimulation 51 4 weeks of stimulation, 12 weeks of follow-up No statistically significant differences were found between the right-sided and left-sided aVNS groups aVNS-L produced consistent immunomodulatory effects, including decreased IL-1β and TNF-α levels, and increased IL-4, IL-10 Akkurt [ 45 ] Fibromyalgia Non-invasive transcutaneous auricular stimulation of the left or bilateral vagus nerve 25 40 11 sessions of stimulation, 2 weeks of follow-up No significant differences were observed between groups except for FIQ and BAI on day 28 ( p  = 0.002-0.008) Both groups showed significant within-group improvements in VAS ( r  = 0.87–0.94;  p  < 0.001), BDI ( r  = 0.46–0.71;  p  < 0.001), FIQ ( r  = 0.95–0.99;  p  < 0.001), and BAI ( r  = 0.69–0.94;  p  < 0.001) scores HRV parameters showed no significant between-group differences, with small effect sizes ( r  < 0.15) Courties [ 46 ] Osteoarthritis Non-invasive transcutaneous auricular stimulation of the left vagus nerve 25 142 12 weeks 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) Elsehrawy [ 47 ] Osteoarthritis Non-invasive transcutaneous auricular stimulation of the left vagus nerve. 25 68 weeks Reduction in VAS: median 8.0 before taVNS, 4.0 after taVNS Improvement in PPT of the right knee joint: median 22.00 before, 30.00 after Improvement in PD-Q: median 18.50 before, 8.0 after Improvement in DN4: median 4.0 before, 1.0 after Improvement in KOOS: median 26.50 before, 67.0 after Aoyagi [ 48 ] Osteoarthritis Non-invasive transcutaneous auricular stimulation of the vagus nerve 25 30 Single session Compared to baseline, knee pain was reduced by 1.27 (95% CI, -1.74, -0.80) immediately after and by 1.87 (-2.33, -1.40) 15 min after tVNS; CPM improved by 0.11 (0.04, 0.19) and 0.07 (-0.01, 0.15); and HF improved by 213.29 (-0.38, 426.96) and 234.17 (20.49, 447.84). PPT and TS were not changed after tVNS Summary of studies on vagus nerve stimulation Significant reduction in DAS-28 CRP (from 6.05 ± 0.18 at baseline to 4.16 ± 0.39 on day 42). Significant decrease in TNF levels (from 2900 ± 566 pg/ml at baseline to 1776 ± 342 pg/ml on day 42) Reduction in DAS28-CRP: −0.95 ± 0.16 for active stimulation and − 0.66 ± 0.16 for sham stimulation Reduction in HAQ-DI: −0.19 ± 0.06 for active stimulation and − 0.02 ± 0.06 for sham stimulation Significant reduction in DAS28-CRP (5.3 at baseline and 3.9 after 12 weeks). Reduction in HAQ-DI (1.6 at baseline and 1.1 after 12 weeks). ACR20 response achieved in 16 patients (53%), ACR50 in 10 patients (33%), and ACR70 in 5 patients (17%). In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02) In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone ( p  = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02) Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs. 4.9 ± 3 linear vagal scale, p = 0.03) Cardiac vagal tone was negatively associated with DAS28-CRP ( r  = −0.37, p = 0.03) PsA group: Reduction in ASDAS (2.22 at baseline and 2.03 on day 5) Reduction in CRP (3.23 mg/L at baseline and 2.59 mg/L on day 5) Increase in TNF-α (1.65 pg/mL at baseline and 1.81 pg/mL on day 5) AS group: No statistically significant changes in DAS28-CRP, ASDAS, or CRP Reduction in cytokines: IFN-γ (4.36 vs. 3.76) IL-8 (3.83 vs. 3.03) IL-10 (0.46 vs. 0.42) Significant reduction after 56 days of stimulation in the active group in the following scales: PRO-F-Physician: p  = 0.02 PRO-F-Mental: p  = 0.02 fVAS: p  = 0.04 Alpha reactivity showed a significant negative correlation with fVAS in the active group: p  < 0.01. IL-6 in the sham group: median increase of 452 pg/ml IL-6 in the active group: median decrease of 168 pg/ml No statistically significant differences were observed in HRV or muscle bioenergetics Patients after DB: an increase in all HRV parameters by 17–31% following stimulation. Patients after taVNS: an increase in all HRV parameters by 18–25% Reduction in median VAS score to − 5.35 after taVNS vs. 0.15 after SS Reduction in fatigue reflected by an increase in median FACIT-F score to 12.00 after taVNS vs. − 2.00 after SS Reduction in median swollen joints [%]: 100.00 after taVNS vs. 14.29 after SS Reduction in median tender joints [%]: 98.49 Reduction in FIQR score: 69.12 ± 17.58 before taVNS vs. 62.24 ± 19.19 after taVNS. Improvement in autonomic function in the following domains: Orthostatic symptoms: 21.60 ± 13.61 before vs. 16.08 ± 11.61 after taVNS Vasomotor symptoms: 1.96 ± 1.74 before vs. 1.58 ± 1.55 after taVNS Pupillomotor symptoms: 3.54 ± 1.10 before vs. 3.19 ± 1.06 after taVNS Other symptoms showed no statistically significant differences. Improvement in PDQ: 23.08 ± 5.33 before vs. 21.20 ± 6.05 after taVNS Improvement in CSS-9: 30.32 ± 3.35 before vs. 29.16 ± 3.42 after taVNS No statistically significant differences were found between the right-sided and left-sided aVNS groups aVNS-L produced consistent immunomodulatory effects, including decreased IL-1β and TNF-α levels, and increased IL-4, IL-10 No significant differences were observed between groups except for FIQ and BAI on day 28 ( p  = 0.002-0.008) Both groups showed significant within-group improvements in VAS ( r  = 0.87–0.94;  p  < 0.001), BDI ( r  = 0.46–0.71;  p  < 0.001), FIQ ( r  = 0.95–0.99;  p  < 0.001), and BAI ( r  = 0.69–0.94;  p  < 0.001) scores HRV parameters showed no significant between-group differences, with small effect sizes ( r  < 0.15) Reduction in VAS: median 8.0 before taVNS, 4.0 after taVNS Improvement in PPT of the right knee joint: median 22.00 before, 30.00 after Improvement in PD-Q: median 18.50 before, 8.0 after Improvement in DN4: median 4.0 before, 1.0 after Improvement in KOOS: median 26.50 before, 67.0 after Available clinical evidence indicates that vagus nerve stimulation (VNS) may have beneficial effects on selected clinical and inflammatory outcomes in rheumatic diseases; however, the consistency and magnitude of these effects vary across studies. The most consistent evidence supporting the efficacy of VNS has been observed in rheumatoid arthritis (RA). Both invasive and non-invasive VNS have demonstrated improvements in disease activity and reductions in patient-reported symptoms. In the study by Koopman et al., invasive VNS reduced DAS28-CRP and TNF-α levels. Similarly, the study by Marsal et al. demonstrated reductions in DAS28-CRP and HAQ-DI, with ACR20, ACR50, and ACR70 responses observed in 53%, 33%, and 17% of participants, respectively [ 19 , 36 ]. The study by Baker et al. also demonstrated reductions in both DAS28-CRP and HAQ-DI in the stimulation group compared with the placebo group [ 37 ]. More recent evidence from a larger randomized trial of invasive VNS also demonstrated a significantly higher ACR20 response rate in the stimulation group than in the control group [ 38 ]. Additional evidence was provided by Drewes et al., who demonstrated that short-term non-invasive cervical VNS reduced DAS28-CRP, CRP, and interferon-γ levels in patients with high disease activity. Interestingly, baseline cardiac vagal tone was lower in patients with high disease activity and was negatively associated with DAS28-CRP, further supporting a potential relationship between autonomic regulation and inflammatory disease activity [ 39 ]. Collectively, these findings support the potential clinical relevance of VNS in RA; however, differences in stimulation protocols, study designs, and treatment duration limit direct comparisons between studies. In the study by Brock et al., patients with psoriatic arthritis (PsA) demonstrated reductions in ASDAS and CRP, whereas patients with ankylosing spondylitis (AS) did not show statistically significant differences in ASDAS, DAS28-CRP, or CRP. However, patients with AS demonstrated a marked response in terms of reductions in pro-inflammatory cytokine levels [ 40 ]. This discrepancy suggests that biological and clinical responses to VNS do not necessarily occur in parallel and may vary depending on the underlying disease and the outcome assessed. Similar discrepancies between clinical outcomes, autonomic nervous system measures, and pro-inflammatory cytokine levels can be observed in Sjögren’s syndrome and systemic lupus erythematosus (SLE). In the study by Tarn et al., patients with Sjögren’s syndrome reported reductions in fatigue, disease symptoms, and interleukin-6 levels following stimulation compared with sham stimulation. However, no statistically significant differences were observed in HRV parameters [ 41 ]. Conversely, a study including patients with RA and SLE demonstrated significant improvements in HRV parameters following VNS, suggesting that autonomic modulation may occur independently of changes in clinical disease symptoms [ 26 ]. The study by Arnow et al. in patients with SLE also demonstrated beneficial effects of VNS on fatigue, pain, and joint tenderness [ 42 ]. Overall, these findings suggest that HRV assessment may provide useful information regarding the autonomic response to VNS; however, early changes in HRV may not necessarily correlate with clinical symptoms. Further studies with longer follow-up periods are needed to determine whether changes in HRV may subsequently translate into improvements in the clinical status of patients. This raises the possibility that HRV may serve as a prognostic marker reflecting the organism’s capacity and potentially inflammatory regulation. Thus, abnormalities in HRV parameters may indicate an increased susceptibility to disease development, whereas improvements in HRV may reflect an enhanced capacity to reduce inflammation and improve clinical outcomes. Studies investigating osteoarthritis (OA) and fibromyalgia suggest that VNS may potentially reduce pain, improve functional status and selected autonomic symptoms, and decrease pro-inflammatory cytokine levels [ 43 – 47 ]. However, discrepancies have also been observed in these conditions, as the study by Courties et al. did not demonstrate a statistically significant difference in VAS scores between the stimulation and placebo groups [ 48 ]. The direction of the effects induced by vagus nerve stimulation (VNS) most likely depends on the selected frequency and other stimulation parameters. The optimal and commonly used frequency range for reducing cytokine production appears to be approximately 10 Hz. This approach is frequently applied across various inflammatory disease models and may most effectively activate the vagus nerve’s anti-inflammatory mechanisms. The use of higher frequencies may influence the central autonomic network, leading to beneficial clinical effects such as pain modulation, disease activity suppression, a reduction in fatigue, and even an improvement in bone density. Interestingly, several studies have shown that even with stimulation frequencies of 20 Hz or higher, cytokine levels in the blood are reduced, although in some cases, no statistically significant changes are observed. In the treatment of drug-resistant epilepsy and major depressive disorder, the best therapeutic outcomes of VNS are typically achieved with frequencies of 25–30 Hz. However, to confirm these assumptions, further high-quality studies are needed to compare the efficacy of VNS across different stimulation parameters. Additional research is also necessary to elucidate the specific anti-inflammatory and analgesic mechanisms, which are likely parameter dependent [ 49 ].

Vagus nerve stimulation (VNS) appears to be a promising alternative or adjunctive therapeutic approach for the management of inflammation, pain, and fatigue in patients with rheumatic and musculoskeletal diseases. The extent of VNS efficacy is dependent on the stimulation parameters applied. Low-frequency stimulation, approximately 10 Hz, appears to exert the most pronounced anti-inflammatory effects. In contrast, higher frequencies in the range of 20–25 Hz likely act via afferent vagal fibers and may contribute to the reduction in pain and fatigue. However, before VNS can be routinely implemented in clinical practice, further research is needed. It is essential to increase sample sizes, conduct multicenter studies across diverse populations, standardize stimulation parameters, and further elucidate the mechanisms of action and the differential effects of various stimulation frequencies on the vagus nerve. Additionally, potential adverse effects should be systematically identified and characterized.

Possible clinical implications include the need for further studies involving large patient cohorts, long-term follow-up, placebo-controlled designs, and homogeneous methodologies, as well as the need to standardize stimulation parameters and clinical endpoints. Research exploring the potential use of VNS as an adjunctive therapy in RMDs is promising. However, these findings require confirmation in larger, more homogeneous cohorts with long-term, placebo-controlled follow-up and consistent methodological approaches. Furthermore, future studies should aim to standardize taVNS protocols, including stimulation parameters such as frequency, intensity, and duration, to improve comparability across studies and facilitate meta-analyses.

A literature search was conducted from January through August 22, 2026, using PubMed/MEDLINE, with an additional search performed in the Directory of Open Access Journals (DOAJ) to identify potentially relevant open-access publications and ensure that the review reflected the most recent evidence available as of August 2026.No publication date restrictions were applied. The search was limited to articles published in English. The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to vagus nerve stimulation and rheumatic diseases. The following search strategy was used: (“Vagus Nerve Stimulation” [MeSH Terms] OR “vagus nerve stimulation “[Title/Abstract] OR “transcutaneous vagus nerve stimulation” [Title/Abstract] OR “transcutaneous auricular vagus nerve stimulation” [Title/Abstract] OR “transcutaneous cervical vagus nerve stimulation” [Title/Abstract] OR taVNS [Title/Abstract] OR tVNS [Title/Abstract]) AND (“Rheumatic Diseases” [MeSH Terms] OR “rheumatic disease” [Title/Abstract] OR “rheumatic diseases” [Title/Abstract] OR “Arthritis, Rheumatoid” [MeSH Terms] OR “rheumatoid arthritis” [Title/Abstract] OR “Spondylitis, Ankylosing” [MeSH Terms] OR “ankylosing spondylitis” [Title/Abstract] OR “Spondylarthritis” [MeSH Terms] OR spondyloarthritis [Title/Abstract] OR “Arthritis, Psoriatic” [MeSH Terms] OR “psoriatic arthritis” [Title/Abstract] OR “Lupus Erythematosus, Systemic” [MeSH Terms] OR “systemic lupus erythematosus” [Title/Abstract] OR “Sjogren’s Syndrome” [MeSH Terms] OR “Sjögren’s syndrome” [Title/Abstract] OR “Osteoarthritis” [MeSH Terms] OR osteoarthritis [Title/Abstract] OR “Fibromyalgia” [MeSH Terms] OR fibromyalgia [Title/Abstract]). The updated search identified 143 records. After applying the English-language filter, 140 records remained for screening. Titles and abstracts were screened for relevance, followed by full-text assessment of potentially eligible publications. Publications reporting follow-up or extension data from previously reported patient cohorts were evaluated in relation to the original study and were not considered independent clinical studies when they involved the same study population. Following title and abstract screening and subsequent full-text assessment, 15 original clinical studies were included in the final review. Inclusion criteria: Original human studies evaluating invasive or non-invasive forms of vagus nerve stimulation in patients with rheumatic diseases were considered eligible. Studies were included if they investigated inflammatory or immunological outcomes, autonomic nervous system-related outcomes, and/or clinically relevant outcomes associated with vagal neuromodulation, including disease activity, pain, fatigue, and physical function. Particular attention was given to studies assessing inflammatory biomarkers and cytokines, measures of autonomic nervous system activity, including heart rate variability (HRV), and clinical indicators of inflammatory disease activity. Randomized and non-randomized clinical trials, sham-controlled studies, pilot studies, proof-of-concept studies, feasibility studies, and single-arm clinical studies were eligible for inclusion. Both invasive and non-invasive approaches to vagus nerve stimulation were considered. Exclusion criteria: Animal and in vitro studies, systematic and narrative reviews, meta-analyses, study protocols, commentaries, editorials, letters to the editor, and case reports were excluded. Studies unrelated to rheumatic diseases or not involving vagus nerve stimulation were also excluded.

According to the EULAR European Manifesto 2024–2029, “Promoting a European Response to the Health and Socio-Economic Challenges of Rheumatic and Musculoskeletal Diseases (RMDs)” , these disorders affect approximately 120 million Europeans. Rheumatic and musculoskeletal diseases (RMDs) represent one of the leading causes of disability in the European Union, accounting for more than 50% of the total disability burden across EU member states [ 1 ]. RMDs are broadly categorized into inflammatory and noninflammatory conditions. Inflammatory diseases primarily include autoimmune disorders, such as inflammatory arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthropathies (SpA), connective tissue diseases (e.g., systemic lupus erythematosus), and vasculitides. Noninflammatory RMDs are common conditions affecting a large portion of the population and include osteoarthritis, osteoporosis, fibromyalgia, and chronic back pain. Both groups significantly impair quality of life and contribute to considerable disability. Inflammatory RMDs, in particular, are associated with severe comorbidities such as cardiovascular disease, diabetes, and psychiatric disorders as well as increased mortality and in some cases, life-threatening complications. Consequently, there is a pressing need for therapeutic interventions that effectively reduce inflammation and pain in RMDs. Despite significant advances in pharmacotherapy for inflammatory diseases, its control remains insufficient in a substantial proportion of patients. Therefore, interest in developing complementary or alternative therapeutic strategies to support or enhance existing pharmacological treatments is increasing. The development of autoimmune diseases, including rheumatologic conditions, is frequently correlated with autonomic nervous system (ANS) dysfunction, which is characterized by sympathetic overactivity and reduced parasympathetic function [ 2 ]. A key component of the parasympathetic system is the vagus nerve (VN). Increasing scientific evidence indicates that proper vagal function plays an essential role in activating anti-inflammatory pathways [ 3 ]. Thus, supporting impaired parasympathetic activity through vagus nerve stimulation may help modulate ANS function and trigger anti-inflammatory processes [ 4 ]. The balance and activity of both autonomic branches can be assessed through heart rate variability (HRV) analysis. The autonomic nervous system (ANS) is divided into two branches: the sympathetic and parasympathetic systems. Its primary role is the involuntary regulation of internal organ function, which operates largely beyond conscious control. However, visceral innervation is not its sole function. The ANS also regulates and integrates the activity of internal organs by coordinating their function with the endocrine system, emotional responses, behavior, and external environmental stimuli. This integration enables the body and nervous system to react. and adapt to both external and internal environmental changes. Proper functioning of these two ANS branches, as well as maintaining a dynamic equilibrium between them, is essential for achieving homeostasis in the human body. Balanced sympathetic and parasympathetic activity allows organisms to adapt effectively to constantly changing internal and external conditions and is fundamental for maintaining overall health. The sympathetic nervous system (SNS) is activated in situations requiring intense physical or mental activity. It stimulates multiple organ systems, excluding the gastrointestinal tract, and is often described as the “fight-or-flight” system due to its heightened activation during stress. Sympathetic impulses are transmitted through short, unmyelinated preganglionic fibers that synapse onto myelinated postganglionic fibers within the paravertebral and prevertebral ganglia. In contrast, the parasympathetic nervous system (PNS) predominates during rest and sleep, promoting regenerative and restorative processes. Its long, unmyelinated preganglionic fibers travel along spinal and cranial nerves III, VII, IX, and X, with synapses occurring near the target visceral organs via short, myelinated postganglionic fibers [ 5 , 6 ]. A key component of the parasympathetic branch is the tenth cranial nerve, the vagus nerve (VN). Recent scientific reports increasingly suggest that vagal dysfunction, as well as overall ANS dysregulation, is correlated with the manifestation of autoimmune disorders [ 2 , 3 , 7 ]. Jiaqi Lv et al. described the importance of cholinergic anti-inflammatory pathways and their interactions with the autonomic and immune systems. Acetylcholine, the primary neurotransmitter of the vagus nerve, can modulate immune cell activity, thereby exerting. anti-inflammatory effects. Consequently, the vagus nerve plays crucial roles in both the development. and regulation of autoimmune and inflammatory diseases [ 4 , 8 , 9 ]. The vagus nerve (VN), or cranial nerve X, is the longest cranial nerve and serves as a crucial communication pathway between the central nervous system (CNS) and the body through the innervation of major internal organs. The VN is a mixed nerve, composed of approximately 20% efferent (motor) and 80% afferent (sensory) fibers. It represents the primary component of the parasympathetic nervous system (PNS) [ 10 , 11 ]. A particularly important structure within the VN pathway is the dorsal vagal complex (DVC), which is located. in the lower portion of the brainstem. The DVC comprises the nucleus tractus solitarius (NTS), the area postrema (AP), and the dorsal motor nucleus of the vagus (DMN), with most vagal sensory inputs terminating at neurons within the NTS. Owing to its anatomical position, the NTS can integrate both emotional and physiological signals. It receives direct sensory input from vagal afferent fibers, serving as the primary relay point for signals traveling from the body to the brain as well as descending signals from higher cortical regions. Thus, the DVC plays a central role in the integration of autonomic, endocrine, and limbic responses [ 12 ]. The efferent fibers of the vagus nerve originate in the DMN and project to target organs, innervating the heart, lungs, liver, pancreas, kidneys, adrenal glands, and gastrointestinal tract from the esophagus through the stomach and small intestine to the splenic flexure of the colon. The afferent fibers, specifically visceral sensory fibers, collect information from the thoracic and abdominal regions and transmit it via the inferior (nodose) ganglion. of the vagus nerve to the medulla oblongata, passing through the lateral portion of the olive and forming synapses in the nucleus tractus solitarius (NTS) and the area postrema (AP), both of which are closely interconnected with the dorsal motor nucleus of the vagus nerve (DMN). These visceral signals are further relayed to the hypothalamus, amygdala, and cerebral cortex [ 10 , 12 , 13 ]. Research indicates that the NTS receives approximately 95% of projections from vagal afferent fibers, projecting onward to multiple regions of the forebrain, limbic system, and brainstem. This neuroanatomical organization underscores the central integrative role of the dorsal vagal complex in coordinating autonomic, endocrine, and emotional responses [ 13 ]. A notable example of visceral information transfer through vagal afferents is indirect modulation of the hypothalamic‒pituitary‒adrenal (HPA) axis. The NTS projects to the paraventricular nucleus (PVN) of the hypothalamus, which serves as the primary regulator of the HPA axis. In response to signals indicating elevated cytokine levels, stress, or tissue injury transmitted via the VN, the PVN increases the release of corticotropin-releasing hormone (CRH). Elevated CRH levels subsequently stimulate the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which in turn activates the adrenal cortex to produce glucocorticoids, primarily cortisol, which is commonly referred to as the stress hormone. As cortisol levels increase, the activation of glucocorticoid receptors triggers a negative feedback mechanism, suppressing further HPA axis activity. Therefore, proper parasympathetic (vagal) activity exerts an inhibitory effect on the HPA axis, reducing cortisol production, alleviating physiological stress, and lowering proinflammatory cytokine levels in the body [ 14 – 16 ]. In a study conducted by O’Keane et al. on a group of patients with chronic depression, a significant decrease in adrenocorticotropic hormone (ACTH) levels was observed following vagus nerve stimulation [ 17 ]. Other researchers, in their analysis involving healthy individuals, demonstrated a significant effect of metyrapone on reducing heart rate variability (HRV). Metyrapone, an inhibitor of cortisol synthesis, induced an increase in ACTH secretion and activation of the hypothalamic‒pituitary‒adrenal (HPA) axis. This finding indicates that pharmacological activation of the HPA axis contributes to a reduction in vagal tone [ 18 ]. In addition to the afferent vagal fibers that influence HPA axis function, a second anti-inflammatory pathway, the cholinergic anti-inflammatory pathway (CAP), is mediated through the activation of efferent vagal fibers [ 15 ]. The anti-inflammatory effects of this mechanism result from two primary processes that ultimately lead. to the binding of acetylcholine to α7-nicotinic receptors on the surface of macrophages, thereby inhibiting the production of proinflammatory cytokines. In the first mechanism, increasing levels of inflammatory cytokines stimulate afferent vagal fibers, transmitting this information to the nucleus tractus solitarius (NTS). The signal is then relayed to the dorsal motor nucleus of the vagus (DMN), from which efferent fibers project to target organs. Acetylcholine, which is released as a neurotransmitter of the vagus nerve, directly modulates macrophage activity, suppressing cytokine production [ 3 , 4 , 8 , 19 ]. In the second mechanism, the efferent fibers of the vagus nerve communicate with the splenic nerve at the level of the celiac (solar) plexus, where the primary neurotransmitter is norepinephrine. Norepinephrine stimulates the spleen to induce T lymphocytes that produce acetylcholine. Acetylcholine then binds to α7-nicotinic receptors located on the surface of macrophages, thereby inhibiting the production of proinflammatory cytokines [ 3 , 4 , 8 , 19 ]. The mechanisms described above provide the basis for research into the anti-inflammatory effects of transcutaneous vagus nerve stimulation (tVNS). Heart rate variability (HRV) is a measure used to assess the functioning of the autonomic nervous system (ANS), specifically reflecting the balance or imbalance between its sympathetic and parasympathetic branches. HRV is calculated from electrocardiographic (ECG) recordings by measuring the time intervals (in milliseconds) between consecutive R peaks in the QRS complex (RR intervals). Under normal physiological conditions, the time between successive heartbeats varies. The greater these variations are, the greater the adaptability and functional integrity of the autonomic nervous system. Conversely, a constant RR interval indicates a reduced adaptive capacity of the ANS to changing internal and external conditions. The root mean square of successive differences (RMSSD), the square root of the mean of the squares of differences between successive RR intervals, reflects parasympathetic (vagal) activity. Higher RMSSD values (i.e., greater HRV) indicate better autonomic flexibility and vagal tone, whereas low RMSSD values suggest sympathetic dominance and diminished regenerative capacity, which may result from stress or disease. Reference RMSSD values vary slightly according to the patient’s age. One of the consequences of reduced parasympathetic activity is impaired regulation of inflammatory processes [ 20 , 21 ]. A comprehensive HRV analysis includes the following parameters: PNS index – assessment of parasympathetic nervous system activity, calculated on the basis of: ((Mean RR, RMSSD (root mean square of successive differences), SD1 index). SNS index - assessment of sympathetic nervous system activity, calculated on the basis of the following: (Mean HR (heart rate), Baevsky’s stress index, SD2 index). LF (low frequency) - the spectral peak within the low-frequency band, influenced by both sympathetic and parasympathetic activity. HF (High Frequency) - the spectral peak within the high-frequency band, reflecting exclusively parasympathetic activity. The LF/HF ratio - is used as an approximate indicator of the balance between sympathetic and parasympathetic modulation of the heart [ 22 , 23 ]. PNS index – assessment of parasympathetic nervous system activity, calculated on the basis of: ((Mean RR, RMSSD (root mean square of successive differences), SD1 index). SNS index - assessment of sympathetic nervous system activity, calculated on the basis of the following: (Mean HR (heart rate), Baevsky’s stress index, SD2 index). LF (low frequency) - the spectral peak within the low-frequency band, influenced by both sympathetic and parasympathetic activity. HF (High Frequency) - the spectral peak within the high-frequency band, reflecting exclusively parasympathetic activity. The LF/HF ratio - is used as an approximate indicator of the balance between sympathetic and parasympathetic modulation of the heart [ 22 , 23 ]. Studies conducted by Yajing Wei et al. and Bellocchi et al. demonstrated that chronic autoimmune inflammatory diseases are associated with autonomic nervous system disfunction with a strong correlation between ANS dysfunction and inflammation. The authors emphasized that maintaining a dynamic balance between sympathetic and parasympathetic activity is vital for homeostasis and inflammatory control [ 2 , 24 ]. Disruptions of this balance have been observed in conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis and even endometriosis [ 3 , 25 – 29 ]. Patients with ankylosing spondylitis (AS) frequently exhibit ANS dysfunction, often reflected in reduced heart rate variability (HRV). Low HRV values indicate impaired autonomic adaptability to changing internal and external conditions, typically characterized by sympathetic overactivity and parasympathetic (vagal) hypoactivity [ 28 – 30 ]. A study conducted by Halman et al. reported a correlation between reduced parasympathetic activity in RA patients and poorer therapeutic response to anti-TNF treatment. The authors suggested that HRV analysis might serve as a potential predictor of treatment response [ 31 ]. Furthermore, Erelund et al. confirmed the presence. of autonomic dysfunction and abnormal HRV parameters in RA patients, characterized by sympathetic dominance and vagal attenuation. The longitudinal five-year follow-up revealed no significant correlation between HRV changes and disease activity progression. These findings raise an important question: are autonomic disturbances a consequence of the disease process, or do they predispose individuals. to its development? Addressing this question requires further long-term prospective studies [ 32 ]. An interesting observation was reported by Grimshalm et al., who demonstrated the presence of choline acetyltransferase (ChAT) on the synovial membrane in patients with RA and advanced knee osteoarthritis. ChAT is an enzyme involved in the synthesis of acetylcholine, the main neurotransmitter of the cholinergic anti-inflammatory pathway, which is mediated, among other processes, by the vagus nerve [ 33 ]. The least invasive and one of the most effective forms of vagus nerve stimulation is transcutaneous auricular vagus nerve stimulation (taVNS). Several types of electrodes designed for taVNS are commercially available; however, according to studies by Yakunin et al., the most effective approach involves the use of an earphone-shaped electrode that precisely targets the cymba conchae region of the auricle. This configuration enables stimulation of the auricular branch of the vagus nerve. Functional magnetic resonance imaging (fMRI) studies have demonstrated that stimulation at the cymba conchae most effectively activates the locus coeruleus and the nucleus tractus solitarius (NTS) of the vagus nerve, suggesting that this region represents the most promising site for taVNS application [ 13 ]. The electrode is connected to a TENS-type electrical stimulator. The stimulation parameters should be individually adjusted according to each patient’s needs; however, the frequency should not exceed 50 Hz. By modulating the stimulation frequency, it is possible to selectively influence either the afferent or efferent fibers of the vagus nerve. Available studies indicate that stimulation at a frequency of approximately 10 Hz produces the most pronounced anti-inflammatory effects [ 3 , 19 , 34 ]. Given its diverse physiological effects on the vagus nerve, transcutaneous auricular stimulation has demonstrated high efficacy across multiple clinical conditions. The method is currently utilized both in European Union countries and in the United States. In the U.S., taVNS has been officially approved by the Food and Drug Administration (FDA) as a treatment for epilepsy and treatment-resistant depression [ 35 ].