A cluster of type II interferon-regulated genes associates with disease activity in patients with systemic lupus erythematosus.

Upregulation of interferon-regulated genes (IRGs), denoted IFN signature, in peripheral blood has been used as an indirect measure of IFN pathway activation in patients with systemic lupus erythematosus (SLE). However, it has not been determined, which IFN signatures that optimally reflect clinical disease activity. In this study, we determined an IFN signature based on the expression of 128 IRGs in whole blood from 34 SLE patients in a cross-sectional (CS) study, 11 with active lupus nephritis followed longitudinally (LS) and 15 healthy controls. Blood samples were collected in PAXgene tubes and RNA was extracted and purified using a PAXgene blood RNA kit (Qiagen). Gene expression was measured using the NanoString nCounter Gene Expression platform. The CS SLE patients with higher disease activity displayed thrice as many upregulated IRGs (n = 46) as the rest. These IRGs clustered in three groups, consisting of IRGs known to be predominantly stimulated by type I (gene cluster K1) and type II (gene clusters K2 and 3) IFNs. SLEDAI-2K scores associated with the K2 and K3 gene scores (ß = 0.372 and ß = 0.419, both p < 0.015) but not with K1. In the longitudinal study, the mean SLEDAI-2K score decreased after an average follow-up of 360 days (ß = -2.08, P = 5.09 × 10-12). The mean K1, K2 and K3 gene scores did not change over time, however longitudinal changes in SLEDAI-2K and K3 scores were associated (ß = 0.814, p = 0.007). This study validates the presence of type I IRG subsets that do not associate with disease activity in SLE patients. The novel finding in this study is the association between a type II IRG subset and disease activity. Both findings may have significant implications for choosing IRGs defining clinically relevant IFN signatures.

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: ß>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.

Neuromuscular Electrical Stimulation Preserves Leg Lean Mass in Geriatric Patients.

AIM: This study aimed to examine changes in lean mass during hospitalization in geriatric patients and the effect of muscle activation by neuromuscular electrical stimulation. METHODS: Thirteen patients (69-94 yr) at a geriatric ward completed tests at hospital admission (days 2-3) and discharge (days 8-10). One leg received daily stimulation of the knee extensors, whereas the other leg served as a control leg. Lean mass was evaluated by dual-energy x-ray absorptiometry scans and muscle thickness by ultrasound scans. Muscle biopsies were collected from both legs at admission and discharge in nine patients and analyzed for fiber size, satellite cell number, and activation and expression of genes associated with muscle protein synthesis and breakdown, connective tissue, and cellular stress. RESULTS: The relative decline in leg lean mass and midthigh region lean mass was larger in the control (-2.8% ± 1.5%) versus the stimulated leg (-0.5% ± 1.4%, P < 0.05). Although there were no changes in fiber size or satellite cell number, the mRNA data revealed that, compared with control, the stimulation resulted in a downregulation of myostatin (P < 0.05) and a similar trend for MAFbx (P = 0.099), together with an upregulation of Collagen I (P < 0.001), TenascinC (P < 0.001), CD68 (P < 0.01), and Ki67 (P < 0.05) mRNA. CONCLUSION: These findings demonstrate a moderate decline in leg lean mass during a hospital stay in geriatric patients, whereas leg lean mass was preserved with daily neuromuscular electrical muscle activation. At the cellular level, the stimulation had a clear influence on suppression of atrophy signaling pathways in parallel with a stimulation of connective tissue and cellular remodeling processes.

Can electrical stimulation enhance effects of a functional training program in hospitalized geriatric patients?

BACKGROUND: Hospitalization of older medical patients may lead to functional decline. This study investigated whether simultaneously applied neuromuscular electrical stimulation (NMES) can enhance the effects of a functional training program in hospitalized geriatric patients. METHOD: This was a quasi-randomized controlled trial in geriatric hospitalized patients (N = 16, age = 83.1 ±â€¯8.1 years, mean ±â€¯SD). The patients performed a simple and time efficient chair-stand based functional exercise program daily, either with (FT + NMES, N = 8) or without (FT, N = 8) simultaneous NMES to the knee extensor muscles. Physical function was assessed at day 2 and 6-10 of the hospitalization with the De Morton Mobility Index (DEMMI), a 30-second chair stand test (30 s-CST) and a 4-meter gait speed test (4 m-GST). Additionally, the pooled results of training from the two training groups (TRAINING, N = 16) was compared to a similar historical control-group (CON, N = 48) receiving only standard-care. RESULTS: Eight patients were assigned to FT, 12 to FT+NMES with 4 dropouts during intervention. During the 6-10 days of hospitalization, both groups improved in all functional measures (p < 0.05), but with no difference between groups (p > 0.05). The training sessions within the FT+NMES-group were more time consuming (~11 vs ~7 min) and entailed higher levels of discomfort than FT-training sessions. Compared to standard-care, training resulted in significantly larger improvements in the 30 s-CST (TRAINING: +3.8 repetitions; CON: +1.4 repetitions, p < 0.01), but not in the DEMMI-test and the 4 m-GST. CONCLUSION: A short-duration daily functional training program improves chair stand performance in hospitalized geriatric patients, with no additional effect of simultaneous electrical muscle stimulation.