ObjectiveSystemic 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.MethodsThirty-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.ResultsNRS 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.ConclusiontVNS demonstrated to be a safe and non-invasive add-on tool to reduce pain in SSc.