You are here

  • Home
  • Archive
  • Volume 9, Issue 3
  • Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis

Article Text

Article menu

Download PDFPDF

Systemic sclerosis
Original research
Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis
  1. Chiara Bellocchi1,2,3,
  2. Angelica Carandina1,3,
  3. Alice Della Torre1,3,
  4. Massimiliano Turzi1,4,
  5. Beatrice Arosio1,
  6. Maurizio Marchini1,
  7. Barbara Vigone2,3,
  8. Costanza Scatà1,3,
  9. Lorenzo Beretta2,3,
  10. Gabriel Dias Rodrigues1,
  11. Eleonora Tobaldini1,3 and
  12. Nicola Montano1,3
  1. 1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
  2. 2Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  3. 3Department of Internal Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
  4. 4Buzzi Children’s Hospital, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
  1. Correspondence to Nicola Montano; nicola.montano{at}unimi.it

Abstract

Objective Systemic sclerosis (SSc) is an autoimmune disease with health-related quality of life (HRQoL) high impairment. Pain is of paramount importance to be targeted by therapeutical approaches. Our study aim was to perform an add-on device-based non-invasive neuromodulatory treatment through transcutaneous auricular vagal nerve stimulation (tVNS) in patients with SSc, assessing its effects on pain as primary endpoint and on inflammation, cardiovascular autonomic control and HRQoL.

Methods Thirty-two patients with SSc were enrolled based on reported pain assessed through Numeric Rating Scale (NRS). Twenty-one (90% with limited cutaneous SSc) completed a randomised, cross-over, patient-blind trial, in which interventional and active control were used in random order for 4 weeks, interspersed with 4 weeks washout. NRS, Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Item4 for pain interference, heart rate variability (HRV), serum cytokines and HRQoL questionnaires (Health Assessment Questionnaire, Patient Health Questionnaire-9, University of California, Los Angeles Gastrointestinal Tract, Pittsburgh Sleep Quality Index) were assessed at baseline, at T1 (after 1 month of tVNS or active control), at T2 (after washout) and at T3 (after 1 month of active control or tVNS). T-test for paired data and Wilcoxon signed-rank test for non-normally distributed parameters were performed to compare the effect of tVNS and active control.

Results NRS pain was significantly reduced by tVNS and not by active control (Mean±SD: −27.7%±21.3% vs −7.7%±26.3%, p=0.002). Interleukin-6 was downregulated in tVNS versus active control (p=0.029). No significant differences were observed in tVNS versus active control for PROMIS-29 Item4, QoL scales and HRV with both spectral and symbolic analyses.

Conclusion tVNS demonstrated to be a safe and non-invasive add-on tool to reduce pain in SSc.

  • systemic sclerosis
  • immune system diseases
  • autoimmune diseases

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003265

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?

    • Systemic sclerosis (SSc) is one of the systemic autoimmune diseases with the most severe impact on quality of life, among several causes, chronic pain. The transcutaneous auricular vagal nerve stimulation (tVNS) was proved to reduce pain in other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus.

    WHAT DOES THIS STUDY ADD?

    • This is the first randomised, controlled, cross-over, patient-blind trial to perform non-invasive neuromodulatory treatment through tVNS in patients with SSc.

    • tVNS demonstrated to be a safe and non-invasive add-on tool to reduce chronic pain in patients with SSc.

    • We observed a decrease of interleukin-6 serum levels after tVNS use, further investigations are needed.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study adds important information on analgesic effects of tVNS in autoimmune diseases and confirms its high safety profile.

    Introduction

    Systemic sclerosis (SSc) is a systemic autoimmune disease characterised by microvascular disfunction, autoantibody production and widespread fibrosis of skin and internal organs. Due to its complexity, SSc is one of the systemic autoimmune diseases with the highest quality-of-life impairment, chronic pain, dramatic progressive organ damage1 2 and high standardised mortality ratio (3.5). Pain affects about 83% of patients with SSc, mostly due to digital ulcers and inflammatory joint involvement.3–6 Pain affects routine daily activities and is related to the development of sleep disturbances and depressive mood.7

    Recent clinical trials proposed a new non-invasive neuromodulation technique, the transcutaneous auricular vagal nerve stimulation (tVNS), to reduce inflammatory pain in autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), showing promising results.8–11 VNS is a non-pharmacological treatment already used for decades in the treatment of refractory epilepsy, uncontrolled migraine and depression.12–14 tVNS positive impact on pain and inflammation could be related to its effects on the parasympathetic branch of the autonomic nervous system (ANS).15 Interestingly, evidence shows that ANS contributes to the control of both the innate and adaptive immunity preserving the homeostasis of the immune responses.16 Namely, the parasympathetic branch has an immunosuppressive and regulatory effect, known as ‘the cholinergic anti-inflammatory pathway’,17 mediated by the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) on macrophages and T cells. When ANS balance is lost, due to a sympathetic-mediated beta-adrenergic activation, a state of immune over-reaction together with an excess of inflammation predominates, as demonstrated in sepsis preclinical mice models, in chronic autoimmune diseases18 19 and in COVID-19.20

    A cardiovascular sympatho-vagal imbalance, namely a predominant sympathetic and a reduced parasympathetic modulation, was reported in several autoimmune diseases including inflammatory bowel diseases, RA, SLE and SSc as well, especially in those patients with more severe fibrosis and long disease duration.21–23

    Based on the above premises, here we aimed to apply tVNS as a non-invasive device-based treatment in patients with SSc to assess its effect on pain and, as secondary outcomes, on inflammation, cardiovascular autonomic control and health-related quality of life (HRQoL) measures.

    Materials and methods

    Population

    For the present randomised, controlled cross-over trial, we enrolled 32 consecutively adult patients with SSc with moderate-to-severe chronic pain from the Scleroderma Unit of Internal Medicine, Immunology and Allergology Department (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) between March 2019 and January 2022. All patients fulfilled the 2013 American College of Rheumatology/European league against rheumatism (ACR/EULAR) classification criteria for SSc.24 Patients included were reporting chronic pain (Numeric Rating Scale score (NRS) ≥6) with at least one type of SSc-related pain (eg, joint pain or pain from active ulcers) within the month prior to enrolment. The absence of a stable sinus rhythm on the ECG, ongoing therapy with beta-blocker drugs, presence of clinically significant rheumatic diseases other than SSc, recent hospitalisation (<6 months), active infection, vagotomy, presence of implantable devices (cochlear implants, deep brain stimulators, implanted vagal stimulators, cardiac pacemakers) and pregnancy were all exclusion criteria. We did not consider a limit to disease duration nor to the amount of limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc) to be included in the study.

    Study procedures

    A randomised, controlled, AB×BA cross-over trial was performed. Patients were randomly assigned with a 1:1 ratio to the interventional arm with tVNS (25 Hz, arm A) on the cymba concha or to the active control group(1 Hz, arm B) on the cymba concha for 4 not consecutive hours/day for 4 weeks. Each group shifted to the opposite arm after a washout period of 4 weeks. The study was conducted in single-blind for the patients.

    Baseline assessment (T0) included the assessment of pain during the last week through NRS, 10 min ECG and respiratory activity recording during resting conditions, blood sample collection and the administration of questionnaires for the evaluation of five domains, such as pain interference, functional disability, gastrointestinal symptoms, sleep quality and depressive symptoms. In addition to T0 assessment, three other experimental evaluation sessions (T1, T2, T3) were performed after the first 4 weeks of treatment, after the washout period and after the last 4 weeks of treatment, respectively (figure 1).

    Figure 1
    Figure 1

    Study design. Participants were enrolled in a randomised, controlled, AB×BA cross-over study. tVNS, transcutaneous auricular vagal nerve stimulation.

    Stimulation

    The stimulation parameters included a duty cycle of 30 s on and 30 s off in order to not irritate the skin and a pulse width of 250 μs. The stimulation frequency was 25 Hz for real stimulation and 1 Hz for active control. The device was portable and patients performed the tVNS or the active control for 4 non-consecutive hours/day for 4 weeks at home. Two titan electrodes located in a structure similar to an earphone were to be placed on the cymba conchae of the left ear (real tVNS), an area 100% innervated by the auricular branch of the vagus nerve. Electrode pads were used with electrode contact spray to facilitate the electrical conduction as well as the patient comfort. The intensity range of the device spread from 0.2 mA to 5 mA. The stimulation intensity was set by each patient based on the personal minimum intensity required to perceive electrical stimulation described as a pricking or tingling sensation on the skin without discomfort. The active control with 1 Hz stimulation was necessary to ensure blinding due to the cross-over design of the study. As a matter of fact, the other parameters were maintained in order to elicit the same sensation evoked by real tVNS (eg, tingling sensation).

    This type of device allowed close monitoring of patient compliance. As a matter of fact, it was possible to access the history of the stimulations performed on the last day, on the last week and on the last month. The device recorded the percentage of effective stimulation, evaluated through the correct contact between the electrode and the skin, performed with respect to the 4 hours per day as per protocol. A compliance threshold of 85% of total stimulation time was set for inclusion in the final analysis.

    Pain assessment

    The pain perceived in the last week was assessed at each time point (T0–T3) through the NRS. Patients were asked to rate the pain experienced in the last week using whole numbers on a scale from 0 to 10, where 0 represents ‘no pain’ and 10 represents ‘the worst pain possible’.25 A reduction of approximately two points or a reduction of approximately 30% of the NRS score from the baseline value represents a clinically important difference.26 The interference of pain with daily activities was assessed through the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Short Form v2.0 Pain Interference 4a. This questionnaire is composed by 4 items with 5-point Likert-type scales.

    Health-related quality of life

    The HRQoL was investigated through four main domains and corresponding questionnaires: functional disability, gastrointestinal symptoms, depressive symptoms and sleep quality. Functional disability was quantified through the Health Assessment Questionnaire (HAQ). The score range is between 0, indicating no functional disability, and 3, severe functional disability.27 The presence and severity of gastrointestinal symptoms were assessed through the University of California at Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 instrument (UCLA GIT 2.0). The UCLA GIT 2.0 questionnaire contains 34 items, organised into seven subscales: reflux, distention/bloating, diarrhoea, faecal soilage, constipation, emotional well-being and social functioning.28 The total UCLA GIT 2.0 score is calculated by averaging all subscales, except the one for constipation, and ranges from 0 to 2.83, higher scores indicating more severe symptomatology and worse HRQoL.29 The presence of depressive symptoms was assessed through the Patient Health Questionnaire-9 (PHQ-9). The score ranges from 0 to 27 and a PHQ-9 score ≥10 has a sensitivity of 88% and a specificity of 88% for major depression.30 The sleep quality was evaluated using the questionnaire Pittsburgh Sleep Quality Index (PSQI). We considered the global score of the test, which has a possible range of 0–21 points.31 A global score higher than 5 is considered as an indicator of relevant sleep disturbances.

    Cardiovascular autonomic control assessment

    ECG and respiratory recordings were performed at rest, in supine position with spontaneous breathing, for 10 min at each time point (T0–T3). All participants were informed to avoid taking food and caffeine in the 2 hours preceding the recording session. All measurements were performed in a quiet temperature-controlled room (between 20°C and 24°C). ECG (lead II) and respiratory activity were recorded using an ad hoc telemetric system device (LAB3, Marazza, Monza, Italy).

    The heart rate variability (HRV) analysis was performed off-line to evaluate the cardiovascular autonomic modulation. Linear spectral analysis and non-linear symbolic analysis were performed through a specific software (Heart Scope II, AMPS, ITA) on the R-R time series derived from the ECG signals. One segment of 250±50 beats at rest without artefacts was selected from the R-R time series. The autoregressive model was applied to identify the spectral power in the low-frequency band (LF, bounded between 0.04 and 0.15 Hz), an index of sympathetic modulation and baroceptive activity, and in the high-frequency band (HF, bounded between 0.15 and 0.40 Hz), an index of parasympathetic modulation which is synchronous with respiratory activity in case of normal free breathing (9–24 breaths/min).32–34 The LF and HF components were expressed in normalised units (LFnu and HFnu) to represent the relative amount of each component compared with the total power of the HRV spectrum.33 The algorithm also calculates the LF/HF ratio, which is considered an index of the sympatho-vagal balance.35 36

    The symbolic analysis was performed on the same segments in order to evaluate non-reciprocal changes of sympathetic and parasympathetic modulation.7 23 37–39 The R-R time series was converted into three beats patterns: (1) 0V, patterns with no variation, all three symbols are equal; (2) 2LV, patterns with two like variations, all symbols are different from the previous one and they are in ascending or descending order and (3) 2UV, patterns with two unlike variations, all symbols are different from the previous one but not in a consequent order. The percentage of the patterns 0V is a marker of cardiac sympathetic modulation and 2UV or 2LV are markers of cardiac vagal modulation.40

    Plasma biomarkers analysis

    The plasmatic concentrations (pg/mL) of interleukin (IL)-6, IL-10, IL-1β, interferon-γ, tumour necrosis factor-α (TNF-α), tumour necrosis factor receptor 1, brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, triggering receptor expressed on myeloid cells 2, neurofilament light chain were quantified using the Simple Plex Ella (Ella) (ProteinSimple, Bio-Techne, Minneapolis, Minnesota, USA), an automated immunoassay platform that allows the rapid quantitation of analytes from a single disposable microfluidic cartridge.

    Statistical analysis

    Data were analysed using SPSS Statistics V.27 (IBM, Armonk, New York, USA). The Shapiro-Wilk test was performed to evaluate the normal distribution of the data. Results were expressed as absolute frequency, relative frequency, means and SD or median and IQR. The two-way Analysis of Variance for repeated measure was performed to compare the two baseline periods (T0 and T2) considering Time (T0 vs T2) as within subject factor and treatment schedule assigned by randomisation (A×B or B×A) as between subject factor. To compare the effect of tVNS and active control, the relative percent change (∆rel%) post-treatment with tVNS or with active control (T1 or T3) from baseline (T0 or T2) of NRS score, questionnaire scores and HRV indices was calculated [∆rel%=(post-baseline)/baseline*100]. The Student’s t-test for paired data was performed to compare the effect of tVNS and of active control on normally distributed parameters. The Wilcoxon signed-rank test was used to compare the effect of tVNS and of active control on non-normally distributed parameters. The χ2 test was performed to evaluate differences between the number of patients who experienced a clinically significant reduction in pain after tVNS and the number of patients who experienced a clinically significant reduction in pain after active control. A p value <0.05 was considered statistically significant.

    Results

    A total of 35 eligible consecutive patients were identified within our centre. Two patients refused to participate, and one patient did not tolerate tVNS even at the lowest intensity due to local ear skin discomfort. Thirty-two patients were randomised to start tVNS (arm A) or active control (arm B). Overall, 11 were dropouts: 7 of them due to logistical problems related to the pandemic occurrence, 3 due to the time commitment of the treatment and 1 due to hospitalisation. Four out of 11 patients dropped out before T1 evaluation, 4 patients were lost at the end of the washout and 3 patients dropped out before T3 evaluation. Out of 32 patients, 21 of them completed the study, 19 (90%) had a lcSSc and 2 (10%) had a dcSSc. Two patients were excluded from HRV analysis due to the presence of many artefacts during the ECG recordings. We reported the patient enrolment flowchart in figure 2.

    Figure 2
    Figure 2

    Flowchart of patient enrolment. HRV, heart rate variability.

    Baseline clinical and demographic features of the 21 patients with SSc that completed the study are listed in table 1. Patients continued their usual treatments during the trial, specifically 6 were under immunosuppressive therapies, 16 on calcium channel blockers and low dose aspirin for the control of Raynaud Phenomenon. None of the patients were on angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers nor under complementary therapies (such as cognitive-behaviour therapy, hypnosis).

    View this table:
    Table 1

    Baseline demographic and clinical description of the enrolled patients

    Enrolment assessment (T0) versus post-washout assessment (T2)

    All patients had at least one type of SSc-related pain (eg, joint pain or pain from active ulcers). At baseline (T0), 11 patients had moderate (NRS=6–7) chronic pain while 10 patients had severe (NRS ≥8) chronic pain. The most frequently reported pain was joint pain (17/21, 81%), 5 out of 21 patients had active ulcers (24%), 4 patients suffered from recurrent migraine (19%), 2 patients also had fibromyalgia (10%). As regard to the other aspects of the HRQoL, 7 out of 21 patients presented significant depressive symptoms (PHQ-9 score >10) and 13 out of 21 patients presented significant sleep impairment (PSQI total score >5) at the enrolment.

    The statistical analysis revealed no differences between the intensity of pain assessed at the two baseline timepoints: enrolment (T0) and post-washout session (T2). Depressive symptoms were more severe at the enrolment (T0) than post-washout assessment (T2) regardless randomisation (see online supplemental table 1).

    The statistical analysis did not show significant differences in the HRV indexes (see online supplemental table 2) between the two baselines (T0 vs T2). Also, the inflammatory profile between tVNS and active control at T0 and T2 is shown in online supplemental table 3.

    Effects of tVNS

    tVNS resulted in a significant reduction of chronic pain levels from baseline than active control (figure 3, mean±SD: −27.7%±21.3% vs −7.7%±26.3%, p=0.002).

    Figure 3
    Figure 3

    Relative mean percent change of chronic pain assessed by NRS score after active control and tVNS; *p<0.05. NRS, Numeric Rating Scale; tVNS, transcutaneous auricular vagal nerve stimulation.

    Moreover, tVNS achieved a clinically significant reduction in chronic pain with a ∆NRS of two points (mean±SD: −2.0±1.6). This result was not reached by the active control (mean±SD: −0.5±1.8). Thirteen patients achieved a pain reduction of at least two NRS points after tVNS, while only five patients achieved a pain reduction of at least two NRS points after active control (p=0.029).

    As reported in table 2, tVNS did not determine significant effects on the other aspects of HRQoL. In particular, there was no difference between the relative changes after tVNS and after active control in pain interference with daily activities (assessed through PROMIS-29 Item 4a), functional disability, gastrointestinal symptoms, depressive symptoms and sleep quality.

    View this table:
    Table 2

    Comparison between relative changes from baseline (T0 or T2) after tVNS and after active control of pain and HRQoL features

    The relative changes of HRV indexes from baseline (T0 or T2) determined by tVNS and active control did not show significant differences as reported in table 3.

    View this table:
    Table 3

    Comparison between relative changes from baseline (T0 or T2) after tVNS and after active control of HRV indexes

    Finally, tVNS determined a significant reduction of plasma IL-6 levels, not present after active control (median −17.1%, IQR (−33.6%; 16.2%) vs median 39.6%, IQR (−10.1%; 287.7%)). The other inflammatory parameters did not show any significant differences between the post-tVNS and post-active control changes, as shown in table 4.

    View this table:
    Table 4

    Comparison between relative changes from baseline (T0 or T2) after tVNS and after active control of inflammatory profile

    Discussion

    The major finding of this randomised cross-over clinical trial is that non-invasive tVNS was able to significantly reduce chronic pain in patients affected by SSc. Moreover, a reduction in IL-6 levels post-tVNS treatment was observed.

    Similar findings had already been reported in patients with SLE and RA.10 11 41 42 Indeed, in a recent randomised, double-blind, controlled trial, Aranow et al showed a reduction of pain and plasma levels of substance P, a neurotransmitter associated with inflammation and pain, in patients with SLE treated with tVNS for four consecutive days.10 Moreover, tVNS was well tolerated and no significant side effects were reported. At difference, authors did not find a direct effect on serum inflammatory cytokines, nor a sustained tVNS effect over time, maybe due to the short period of treatment.10 Furthermore, another study conducted on patients with RA with high disease activity, showed effects of VNS, applied transcutaneously to the cervical vagus nerve, in reducing both pain and inflammatory biomarkers, thus supporting an anti-inflammatory effect of tVNS.41 Other studies using different VNS type of electrodes and stimulation pattern showed a decrease of inflammation in patients with RA and IBD,42 43 and a recent study41 reported a reduction of inflammatory biomarkers and fatigue in patients with Sjogren’s Syndrome.

    We analysed serum levels of several cytokines finding a significant decrease of IL-6 levels following tVNS, while no decrease was observed after active control. Interestingly, IL-6 is an acute phase response inducer and its serum levels in SSc correlate with acute phase proteins, such as TNF-α and high sensitive C reactive protein.44 IL-6 role in SSc is well documented, promoting a T-helper 2 driven fibrosis at lung and skin level.45 Preclinical studies showed that the vagus nerve directly influences inflammation through the cholinergic anti-inflammatory pathway suppressing macrophage production of TNF-α and IL-6 through the α7 subunit of nAChR.46 Certain systemic pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are involved in the process of peripheral pain sensitisation47 and it could be speculated that the reduction in chronic pain might be due to a downregulation of the sensitising inflammatory stimulus. However, other than IL-6, the several inflammatory markers tested in the present study did not show a significant serum level reduction following tVNS, thus further larger and mechanistic studies are needed to support an anti-inflammatory effect of tVNS in patients. Alternatively, the analgesic effect of tVNS could also be consequent to a direct effect on brainstem autonomic regulatory pathways. The stimulation of the auricular branch of vagus nerve can modulate the activity of nucleus tractus solitarius which has main afferent projections to the locus coeruleus that regulate pain threshold.48,49

    Pain, especially chronic one, is known to be related to a decrease of HRQoL and to sleep disturbances in SSc.7 Furthermore, the gastrointestinal (GI) tract is affected in about 90% of patients with SSc and in physiologic conditions ANS balances the GI motility and its normal stress response.50 51 However, while in the present study we observed a direct tVNS effect on pain measured through the NRS, no difference between effective and active control was observed relating to HRQoL and sleep quality scales, nor GI symptoms as assessed through the UCLA GIT 2.0. In addition, cardiovascular autonomic modulation, assessed by HRV indexes, did not show differences after stimulation. These results could be due to a longer treatment duration needed to assess substantial clinical change in these three domains also, it has to be acknowledged that the high disease duration (mean of 17 years) of the patients enrolled represent a higher disease associated organ damage more difficult to reverse thus consequently with difficulties in improving HRQoL. Cardiovascular autonomic alterations are known to be present in patients with SSc, and they seem to be associated with clinical features such as disease duration, skin involvement and anti-topoisomerase autoantibody positivity.52 Due to the long disease history and disease severity of the present cohort, it is possible to hypothesise that the duration of tVNS treatment was not enough to induce a change in cardiovascular autonomic control. Further studies with a longer and chronic tVNS application are needed to evaluate the possibility of restoring the sympathovagal balance.

    Our study showed as a strength the cross-over trial design, which ensured solidity of the statistical results. We demonstrated also that tVNS is a safe non-invasive therapeutical option, since no adverse event has been observed during interventional stimulation. Also, to the best of our knowledge, this was the first study applying a neuromodulation technique to treat chronic pain in SSc.

    We acknowledge several limitations for the present study. First, a limited sample size, mainly due to patients’ dropouts related to the intercurrent pandemic situation was an important limit. Second, the majority of SSc included in the trial had a lcSSc subset with a long disease duration and further studies including higher numbers of dcSSc and a shorter disease duration have to be performed. Third, tVNS is still lacking of a gold standard pattern of stimulation, in terms of time length of the treatment and stimulation parameters, thus results should not be extrapolated to different stimulation patterns.

    Conclusion

    In conclusion, our data support the use of tVNS as a non-invasive tool for the treatment of chronic pain in patients with SSc, as well as in other systemic autoimmune diseases. The tVNS effect on IL-6 observed in the present SSc cohort is worthy to be further investigated on larger cohorts.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants. All the patients signed a written informed consent. The study was approved by the local ethics committee Comitato Etico Milano Area 2 (approval ID: 821_2021).

    Acknowledgments

    To GILS Gruppo Italiano per la lotta alla Sclerodermia.

    References

    1. ↵
      1. Volkmann ER,
      2. Andréasson K,
      3. Smith V
      . Systemic sclerosis. Lancet 2023;401:304–18. doi:10.1016/S0140-6736(22)01692-0
      OpenUrl
    2. ↵
      1. Elhai M,
      2. Meune C,
      3. Avouac J, et al
      . Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology 2012;51:1017–26. doi:10.1093/rheumatology/ker269
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Jaeger VK,
      2. Distler O,
      3. Maurer B, et al
      . Functional disability and its predictors in systemic sclerosis: a study from the Desscipher project within the EUSTAR group. Rheumatology (Oxford) 2018;57:441–50. doi:10.1093/rheumatology/kex182
      OpenUrlPubMed
    4. ↵
      1. Park EH,
      2. Strand V,
      3. Oh YJ, et al
      . Health-related quality of life in systemic sclerosis compared with other rheumatic diseases: a cross-sectional study. Arthritis Res Ther 2019;21:61. doi:10.1186/s13075-019-1842-x
    5. ↵
      1. Bassel M,
      2. Hudson M,
      3. Taillefer SS, et al
      . Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian national survey. Rheumatology (Oxford) 2011;50:762–7. doi:10.1093/rheumatology/keq310
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Schieir O,
      2. Thombs BD,
      3. Hudson M, et al
      . Prevalence, severity, and clinical correlates of pain in patients with systemic sclerosis. Arthritis Care Res 2010;62:409–17. doi:10.1002/acr.20108 Available: http://doi.wiley.com/10.1002/acr.v62%3A3
      OpenUrlCrossRefWeb of Science
    7. ↵
      1. Carandina A,
      2. Bellocchi C,
      3. Dias Rodrigues G, et al
      . Cardiovascular autonomic control, sleep and health related quality of life in systemic sclerosis. Int J Environ Res Public Health 2021;18:2276. doi:10.3390/ijerph18052276
    8. ↵
      1. Koopman FA,
      2. van Maanen MA,
      3. Vervoordeldonk MJ, et al
      . Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med 2017;282:64–75. doi:10.1111/joim.12626
      OpenUrlCrossRefPubMed
    9. ↵
      1. Ramkissoon CM,
      2. Güemes A,
      3. Vehi J
      . Overview of therapeutic applications of non-invasive Vagus nerve stimulation: a motivation for novel treatments for systemic lupus erythematosus. Bioelectron Med 2021;7:8. doi:10.1186/s42234-021-00069-5
    10. ↵
      1. Aranow C,
      2. Atish-Fregoso Y,
      3. 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. doi:10.1136/annrheumdis-2020-217872
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. Marsal S,
      2. Corominas H,
      3. de Agustín JJ, et al
      . Non-invasive Vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study. Lancet Rheumatol 2021;3:e262–9. doi:10.1016/S2665-9913(20)30425-2 Available: https://www.sciencedirect.com/science/article/pii/S2665991320304252
      OpenUrl
    12. ↵
      1. Franzini A,
      2. Messina G,
      3. Marras C, et al
      . Hamilton rating scale for Depression-21 modifications in patients with vagal nerve stimulation for treatment of treatment-resistant depression: series report. Neuromodulation 2008;11:267–71. doi:10.1111/j.1525-1403.2008.00174.x
      OpenUrlPubMed
    13. ↵
      1. Chakravarthy K,
      2. Chaudhry H,
      3. Williams K, et al
      . Review of the uses of vagal nerve stimulation in chronic pain management. Curr Pain Headache Rep 2015;19:54. doi:10.1007/s11916-015-0528-6
    14. ↵
      1. Xie H,
      2. Ma J,
      3. Ji T, et al
      . Efficacy of Vagus nerve stimulation in 95 children of drug-resistant epilepsy with structural etiology. Epilepsy Behav 2023;140:109107. doi:10.1016/j.yebeh.2023.109107
    15. ↵
      1. Ingegnoli F,
      2. Buoli M,
      3. Antonucci F, et al
      . The link between autonomic nervous system and rheumatoid arthritis: from bench to bedside. Front Med 2020;7:589079. doi:10.3389/fmed.2020.589079
      OpenUrlPubMed
    16. ↵
      1. Bellocchi C,
      2. Carandina A,
      3. Montinaro B, et al
      . The interplay between autonomic nervous system and inflammation across systemic autoimmune diseases. Int J Mol Sci 2022;23:2449. doi:10.3390/ijms23052449
    17. ↵
      1. Tracey KJ
      . The inflammatory reflex. Nature 2002;420:853–9. doi:10.1038/nature01321
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Rosas-Ballina M,
      2. Ochani M,
      3. Parrish WR, et al
      . Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in Endotoxemia. Proc Natl Acad Sci U S A 2008;105:11008–13. doi:10.1073/pnas.0803237105
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Pongratz G,
      2. Straub RH
      . The sympathetic nervous response in inflammation. Arthritis Res Ther 2014;16:504. doi:10.1186/s13075-014-0504-2
    20. ↵
      1. Al-Kuraishy HM,
      2. Al-Gareeb AI,
      3. Qusti S, et al
      . Covid-19-induced Dysautonomia: A menace of sympathetic storm. ASN Neuro 2021;13:17590914211057635. doi:10.1177/17590914211057635
    21. ↵
      1. Bonaz B,
      2. Sinniger V,
      3. Pellissier S
      . The Vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract. Front Immunol 2017;8:1452. doi:10.3389/fimmu.2017.01452
    22. ↵
      1. Maule S,
      2. Quadri R,
      3. Mirante D, et al
      . Autonomic nervous dysfunction in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA): possible pathogenic role of Autoantibodies to autonomic nervous structures. Clin Exp Immunol 1997;110:423–7. doi:10.1046/j.1365-2249.1997.4501466.x
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Rodrigues GD,
      2. Carandina A,
      3. Scatà C, et al
      . Sympatho-vagal dysfunction in systemic sclerosis: A follow-up study. Life 2022;13:34. doi:10.3390/life13010034
      OpenUrl
    24. ↵
      1. van den Hoogen F,
      2. Khanna D,
      3. Fransen J, et al
      . 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European League against rheumatism collaborative initiative. Ann Rheum Dis 2013;72:1747–55. doi:10.1136/annrheumdis-2013-204424
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Hartrick CT,
      2. Kovan JP,
      3. Shapiro S
      . The Numeric rating scale for clinical pain measurement: A ratio measure Pain Pract 2003;3:310–6. doi:10.1111/j.1530-7085.2003.03034.x
      OpenUrlCrossRefPubMed
    26. ↵
      1. Farrar JT,
      2. Young JP,
      3. LaMoreaux L, et al
      . Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149–58. doi:10.1016/S0304-3959(01)00349-9
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. Krishnan E,
      2. Sokka T,
      3. Häkkinen A, et al
      . Normative values for the health assessment questionnaire disability index: Benchmarking disability in the general population: normative values for the HAQ disability index. Arthritis Rheum 2004;50:953–60. doi:10.1002/art.20048
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Khanna D,
      2. Hays RD,
      3. Maranian P, et al
      . Reliability and validity of the University of California, Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument. Arthritis Rheum 2009;61:1257–63. doi:10.1002/art.24730 Available: http://doi.wiley.com/10.1002/art.v61%3A9
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Khanna D,
      2. Furst DE,
      3. Maranian P, et al
      . Minimally important differences of the UCLA scleroderma clinical trial consortium gastrointestinal tract instrument. J Rheumatol 2011;38:1920–4. doi:10.3899/jrheum.110225
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Kroenke K,
      2. Spitzer RL,
      3. Williams JBW
      . The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16:606–13. doi:10.1046/j.1525-1497.2001.016009606.x
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Curcio G,
      2. Tempesta D,
      3. Scarlata S, et al
      . Validity of the Italian version of the Pittsburgh sleep quality index (PSQI). Neurol Sci 2013;34:511–9. doi:10.1007/s10072-012-1085-y
      OpenUrlCrossRefPubMed
    32. ↵
      1. Hayano J,
      2. Yuda E
      . Pitfalls of assessment of autonomic function by heart rate variability. J Physiol Anthropol 2019;38:3. doi:10.1186/s40101-019-0193-2
    33. ↵
      1. Montano N,
      2. Porta A,
      3. Cogliati C, et al
      . Heart rate variability explored in the frequency domain: A tool to investigate the link between heart and behavior. Neurosci Biobehav Rev 2009;33:71–80. doi:10.1016/j.neubiorev.2008.07.006
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      1. Thomas BL,
      2. Claassen N,
      3. Becker P, et al
      . Validity of commonly used heart rate variability markers of autonomic nervous system function. Neuropsychobiology 2019;78:14–26. doi:10.1159/000495519
      OpenUrl
    35. ↵
      1. Shaffer F,
      2. McCraty R,
      3. Zerr CL
      . n.d. A healthy heart is not A metronome: an integrative review of the heart’s anatomy and heart rate variability. Front Psychol;5. doi:10.3389/fpsyg.2014.01040 Available: http://journal.frontiersin.org/article/10.3389/fpsyg.2014.01040/abstract
    36. ↵
      1. Electrophysiology TF of the ES of C the NA
      . Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–65. doi:10.1161/01.CIR.93.5.1043
      OpenUrlFREE Full Text
    37. ↵
      1. Zamunér AR,
      2. Shiffer D,
      3. Barbic F, et al
      . Mechanical Somatosensory stimulation decreases blood pressure in patients with Parkinson’s disease. J Hypertens 2019;37:1714–21. doi:10.1097/HJH.0000000000002084
      OpenUrl
    38. ↵
      1. Carandina A,
      2. Lazzeri G,
      3. Rodrigues GD, et al
      . Dysautonomia in Parkinson’s disease: impact of Glucocerebrosidase gene mutations on cardiovascular autonomic control. Front Neurosci 2022;16:842498. doi:10.3389/fnins.2022.842498
    39. ↵
      1. Rodrigues GD,
      2. Tobaldini E,
      3. Bellocchi C, et al
      . Cardiac autonomic modulation at rest and during orthostatic stress among different systemic sclerosis Subsets. Eur J Intern Med 2019;66:75–80. doi:10.1016/j.ejim.2019.06.003
      OpenUrl
    40. ↵
      1. Porta A,
      2. Tobaldini E,
      3. Guzzetti S, et al
      . Assessment of cardiac autonomic modulation during graded head-up tilt by symbolic analysis of heart rate variability. Am J Physiol Heart Circ Physiol 2007;293:H702–8. doi:10.1152/ajpheart.00006.2007
      OpenUrlCrossRefPubMedWeb of Science
    41. ↵
      1. Drewes AM,
      2. Brock C,
      3. 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. doi:10.1080/03009742.2020.1764617
      OpenUrlPubMed
    42. ↵
      1. Koopman FA,
      2. Chavan SS,
      3. 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. doi:10.1073/pnas.1605635113
      OpenUrlAbstract/FREE Full Text
    43. ↵
      1. Bonaz B,
      2. Sinniger V,
      3. Hoffmann D, et al
      . Chronic Vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil 2016;28:948–53. doi:10.1111/nmo.12792 Available: http://doi.wiley.com/10.1111/nmo.2016.28.issue-6
      OpenUrlCrossRefPubMed
    44. ↵
      1. Ohtsuka T
      . Serum Interleukin-6 level is reflected in elevated high-sensitivity C-reactive protein level in patients with systemic sclerosis. J Dermatol 2010;37:801–6. doi:10.1111/j.1346-8138.2010.00883.x
      OpenUrlCrossRefPubMed
    45. ↵
      1. Sato S,
      2. Hasegawa M,
      3. Takehara K
      . Serum levels of Interleukin-6 and Interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 2001;27:140–6. doi:10.1016/s0923-1811(01)00128-1
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      1. Andersson U,
      2. Tracey KJ
      . Reflex principles of immunological homeostasis. Annu Rev Immunol 2012;30:313–35. doi:10.1146/annurev-immunol-020711-075015
      OpenUrlCrossRefPubMedWeb of Science
    47. ↵
      1. Zhang JM,
      2. Cytokines J
      . Inflammation and pain. Int Anesthesiol Clin 2007.
    48. ↵
      1. Ludwig M,
      2. Wienke C,
      3. Betts MJ, et al
      . Current challenges in reliably targeting the noradrenergic locus coeruleus using transcutaneous auricular vagus nerve stimulation (tavns). Autonomic Neuroscience 2021;236:102900. doi:10.1016/j.autneu.2021.102900 Available: https://www.sciencedirect.com/science/article/pii/S1566070221001302
      OpenUrlPubMed
    49. ↵
      1. Llorca-Torralba M,
      2. Borges G,
      3. Neto F, et al
      . Noradrenergic locus coeruleus pathways in pain modulation. Neuroscience 2016;338:93–113. doi:10.1016/j.neuroscience.2016.05.057
      OpenUrl
    50. ↵
      1. DiRenzo D,
      2. Russell J,
      3. Bingham CO, et al
      . The relationship between autonomic dysfunction of the gastrointestinal tract and emotional distress in patients with systemic sclerosis. J Clin Rheumatol 2021;27:11–7. doi:10.1097/RHU.0000000000001144
      OpenUrl
    51. ↵
      1. Cerinic MM,
      2. Generini S,
      3. Pignone A, et al
      . The nervous system in systemic sclerosis (scleroderma). clinical features and Pathogenetic mechanisms. Rheum Dis Clin North Am 1996;22:879–92. doi:10.1016/s0889-857x(05)70306-9
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      1. Masini F,
      2. Galiero R,
      3. Pafundi PC, et al
      . Autonomic nervous system dysfunction correlates with Microvascular damage in systemic sclerosis patients. J Scleroderma Relat Disord 2021;6:256–63. doi:10.1177/23971983211020617
      OpenUrl

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • CB and AC contributed equally.

    • Contributors AC, CB, BA and LB analysed the data. CB and AC wrote and revised the manuscript. AC, CB, ADT and MT worked on the clinical database. AC, CB, ADT, MT, BV, BA, MM, CS and GDR collected data and assisted with the analysis. AC, ADT, MT, CS and GDR performed cardiovascular autonomic control assessment. AC, CB, NM and ET elaborated the conception and study design. All authors of the present manuscript contributed to the general conception of the work and to the analysis and interpretation of data. All authors revised critically the manuscript and approve the final version, guaranteeing accuracy and integrity of any part of the work. NM

      is the guarantor of the study with full responsibility for the work and the conduct of the study.

    • Funding This study was partially funded by Gruppo Italiano per la lotta alla Sclerodermia (GILS) (Bando giovani ricercatori 2018 to Dr CB) and by Italian Ministry of Health, Current research IRCCS (RC 2023 193 01 to NM).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.