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

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. SLE is treated with immunosuppressants with suboptimal efficacy and high risk of serious side effects. Patients with SLE have increased risk of mortality, organ damage and debilitating treatment-resistant fatigue. Autonomic nervous system dysfunction (AD) is present in approximately half of the patients and may promote autoimmunity by weakening the vagally mediated anti-inflammatory reflex. Recent studies suggest that transcutaneous vagus nerve stimulation (tVNS) has few side effects and beneficial effects on fatigue, pain, disease activity and organ function. This study investigates whether adjuvant tVNS improves measures of fatigue (primary end point), AD, clinical disease activity, inflammation, pain, organ function and quality of life. Hence, this study will contribute to the understanding of AD as a potentially important precursor of fatigue, disease activity, progression and complications in SLE, and how tVNS mechanistically may attenuate this. As adjuvant tVNS use may reduce the need for traditional immunosuppressive therapy, this trial may prompt a shift in the treatment of SLE and potentially other autoimmune disorders. METHODS AND ANALYSIS: Eighty-four patients with SLE with fatigue and AD will be randomised 1:1 to active or sham tVNS in this double-blinded parallel-group study. In period 1 (1 week), participants will receive a 4 min tVNS 4 times daily and report on fatigue daily. After a 2-week pause, period 2 (8 weeks) will entail tVNS twice daily and participants will report on fatigue, pain and disease activity weekly. Secondary end points will be assessed before and after each period and after 1 week in period 2. ETHICS AND DISSEMINATION: The study is approved by the Danish Medical Research Ethical Committees (case no: 2120231) and results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05315739

Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus

Objectives Cardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs). In patients with SLE, we aimed to determine the characteristics of CAN and if CAN associates with health-related quality of life (HRQoL).Methods Patients with SLE and healthy controls (HCs) were CAN tested with 5 min HRV and three CARTs to determine parameters reflecting parasympathetic and mixed sympathetic–parasympathetic function. Subjects were classified as having no, early or definitive CAN by having none, one or more than one abnormal CART, respectively. HRQoL as determined by the Short Form 12 (SF-12) was assessed in SLE.Results Of 111 patients with SLE, 92 answered the SF-12 and 54 were matched with 54 HCs for characterisation of CAN. Definitive CAN was present in 24.1% (95% CI 15% to 37%) patients with SLE and 1.9% (95% CI 0.3% to 9.8%) HCs (OR 16.8, 95% CI 2.1 to 133.8, p=0.008). The corresponding prevalences of any CAN were 53.7% (95% CI 41% to 66%) and 22.6% (95% CI 13% to 35%). SLE patients with definitive CAN showed signs of mixed sympathetic–parasympathetic dysfunction, whereas patients without CAN primarily presented with impaired parasympathetic activity. Signs of parasympathetic as well as sympathetic–parasympathetic dysfunction were associated with low physical SF-12 component score (all: β>0.211, p<0.05). The mental SF-12 component score was not associated with any CAN indices.Conclusions CAN was a frequent finding in SLE and associated to self-report on impaired physical HRQoL. Even patients without CAN showed signs of impaired parasympathetic function compared with controls