Does stress response axis activation differ between patients with autoimmune disease and healthy people?

Many studies have shown that patients with autoimmune disease present a hypoactive hypothalamic-pituitary-adrenal (HPA) axis, but the results are controversial. Our objective was to study differences in stress response axis activity between patients with autoimmune disease and healthy people. The study sample consisted of 97 women divided into four groups: 37 healthy women (HW), 21 with systemic lupus erythematosus (SLE), 21 with Sjögren's syndrome (SS), and 18 with systemic sclerosis (SSc). After being exposed to a stress task, participants' skin conductance and salivary cortisol levels were measured in order to assess their response to psychological stress. Diurnal cortisol concentrations were assessed by measuring salivary cortisol in samples collected five times over one day. In addition, self-administered questionnaires were used to assess psychological variables. A time × group interaction effect was found (p = 0.003) in salivary cortisol secretion in response to stressful challenge. The healthy group presented normal activation, the SS and SLE groups showed no activation, and the SSc group presented a similar activation pattern to the HW group, except at the time of recovery. Total cortisol production (AUCg) was higher in the SSc group than in the HW group (p = 0.001). Differences were also observed in the cortisol AUCg collected over one day between healthy women and patients with SLE (p = 0.004) as well as with SSc (p = 0.001): women with SLE and SSc presented higher total hormone production than healthy women. Patients with autoimmune disease present a different HPA axis response, which may contribute to the harmful effects of stress in these diseases.

Sclerostin as a biomarker of cardiovascular risk in women with systemic lupus erythematosus.

Cardiovascular disease is one of the main causes of death in patients with systemic lupus erythematosus (SLE). On the other hand, sclerostin is a reliable and early biomarker of vascular calcification. This study aimed to estimate the association between sclerostin and two markers of cardiovascular risk, carotid atherosclerotic plaque (CP) and carotid-femoral pulse wave velocity (PWV), in women with SLE. The presence of CP (determined by carotid artery ultrasound) and PWV were measured in 68 women with SLE and preserved renal function. None of the participants had a history of cardiovascular disease. Serum levels of sclerostin were determined using the ELISA method. Other factors associated with increased cardiovascular risk were also measured. The association between sclerostin, CP and PWV was assessed using Receiver Operating Characteristic (ROC) curves and multivariate regression models. The area under the ROC curve was 0.785 (95% confidence interval [CI] 0.662-0.871) for CP and 0.834 (95% CI 0.729-0.916) for dichotomized PWV. After adjusting for other cardiovascular risk factors, it was found that a 10-units increase in sclerostin values was associated with a 44% increase in the odds of CP (95% CI 1-105), but no adjusted association was observed between sclerostin and PWV. Predictive models included age (for both outcomes), hypertension, Framingham risk score and C-reactive protein (for PWV), but not sclerostin. Sclerostin is associated with the presence of CP in women with SLE. Further research should confirm its possible role as a biomarker of cardiovascular risk in these patients.

Effects of 12-week aerobic exercise on patient-reported outcomes in women with systemic lupus erythematosus.

PURPOSE: To evaluate the effects of aerobic exercise on patient-reported outcomes (PROs) in women with systemic lupus erythematosus (SLE), and whether changes in cardiorespiratory fitness (CRF) mediate the changes in PROs. METHODS: A total of 58 women with SLE were assigned to either an exercise group (EG; n = 26) or a control group (CG; n = 32) in this non-randomized clinical trial. The EG comprised 12 weeks of aerobic exercise (2 sessions/week) between 40%-75% of the individual's heart rate reserve. At baseline, and at week 12, CRF (Bruce test) and PROs were assessed including psychological stress (Perceived Stress Scale), sleep quality (Pittsburg Sleep Quality Index), fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory), and quality of life (36-item Short-Form Health Survey). RESULTS: In comparison to the CG, the EG showed a significant reduction in general fatigue (mean difference (MD) -2.86 units; 95%CI -5.70 to -0.01; p = 0.049), physical fatigue (MD -4.33 units; 95%CI -7.02 to -1.65; p = 0.002) and a non-significant reduction of reduced motivation (MD - 1.29 units; 95%CI -2.60 to 0.03; p = 0.055). There were no significant between-group differences in the changes in psychological stress, sleep quality, depressive symptoms, quality of life, or other fatigue dimensions (all p > 0.05). Changes in CRF mediated the effects of the exercise intervention on general fatigue by 53.8%. CONCLUSION: The results suggest that 12 weeks of progressive aerobic exercise might improve relevant dimensions of fatigue in women with SLE, despite the absence of effects on other PROs. Improvements in CRF seem to mediate the effect of exercise on general fatigue.Implications for rehabilitationAerobic exercise could be safely introduced in rehabilitation programs for inactive patients with SLE with mild disease activity.Including physical activity recommendations as part of rehabilitation could improve relevant aspects of fatigue in women with SLE.When rehabilitation aims at reducing fatigue, cardiorespiratory fitness improvements derived from physical activity might enhance benefits.

Physical Fitness Attenuates the Impact of Higher Body Mass and Adiposity on Inflammation in Women With Systemic Lupus Erythematosus.

Aims: Higher body mass and adiposity represent independent contributors to the systemic low-grade inflammatory state often observed in patients with systemic lupus erythematosus (SLE). This study assessed the role of physical fitness in the association of body mass and adiposity with inflammation in women with SLE. Methods: A total of 77 women with SLE were included in this cross-sectional study. We obtained body mass index, waist-to-height ratio, and body fat percentage as indicators of body mass and adiposity. Inflammation was assessed through Serum levels of C-reactive protein, interleukin 6, and leptin. Cardiorespiratory fitness was assessed with the 6-minute walk test, range of motion with the back-scratch test, and muscular strength with handgrip dynamometry. Results: Cardiorespiratory fitness attenuated the association of both body mass index and body fat percentage with interleukin 6 (all, P<0.05). Range of motion attenuated the association of body mass index with interleukin 6 (P<0.05) and the association of body fat percentage with C-reactive protein (P<0.05). These interactions indicated that higher fitness was associated with a lower increase in inflammation per unit increase of body mass or adiposity. Muscular strength showed a non-significant trend to attenuate the association of body fat percentage with interleukin 6 (P=0.057) but potentiated the association of body fat percentage with leptin (P<0.05). Conclusion: These findings suggest that higher levels of cardiorespiratory fitness and range of motion might attenuate the impact of higher body mass and adiposity on inflammation in women with SLE. The role of muscular strength requires further investigation.

Relative Handgrip Strength as Marker of Cardiometabolic Risk in Women with Systemic Lupus Erythematosus.

This study aimed to examine the association of relative handgrip strength (rHGS) with cardiometabolic disease risk factors in women with systemic lupus erythematosus (SLE). METHODS: Seventy-seven women with SLE (mean age 43.2, SD 13.8) and clinical stability during the previous six months were included. Handgrip strength was assessed with a digital dynamometer and rHGS was defined as absolute handgrip strength (aHGS) divided by body mass index (BMI). We measured blood pressure, markers of lipid and glucose metabolism, inflammation (high sensitivity C-reactive protein [hs-CRP]), arterial stiffness (pulse wave velocity [PWV]), and renal function. A clustered cardiometabolic risk index (z-score) was computed. RESULTS: Pearson's bivariate correlations revealed that higher rHGS was associated with lower systolic blood pressure (SBP), triglycerides, hs-CRP, PWV, and lower clustered cardiometabolic risk (rrange = from -0.43 to -0.23; all p < 0.05). Multivariable linear regression analyses adjusted for age, disease activity (SLEDAI), and accrual damage (SDI) confirmed these results (all p < 0.05) except for triglycerides. CONCLUSIONS: The findings suggest that higher rHGS is significantly associated with lower cardiometabolic risk in women with SLE.

Heart Rate Variability in Women with Systemic Lupus Erythematosus: Association with Health-Related Parameters and Effects of Aerobic Exercise.

Abnormal heart rate variability (HRV) has been observed in patients with systemic lupus erythematosus (SLE). In a combined cross-sectional and interventional study approach, we investigated the association of HRV with inflammation and oxidative stress markers, patient-reported outcomes, and the effect of 12 weeks of aerobic exercise in HRV. Fifty-five women with SLE (mean age 43.5 ± 14.0 years) were assigned to either aerobic exercise (n = 26) or usual care (n = 29) in a non-randomized trial. HRV was assessed using a heart rate monitor during 10 min, inflammatory and oxidative stress markers were obtained, psychological stress (Perceived Stress Scale), sleep quality (Pittsburg Sleep Quality Index), fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory), and quality of life (36-item Short-Form Health Survey) were also assessed. Low frequency to high frequency power (LFHF) ratio was associated with physical fatigue (p = 0.019). Sample entropy was inversely associated with high-sensitivity C-reactive protein (p = 0.014) and myeloperoxidase (p = 0.007). There were no significant between-group differences in the changes in HRV derived parameters after the exercise intervention. High-sensitivity C-reactive protein and myeloperoxidase were negatively related to sample entropy and physical fatigue was positively related to LFHF ratio. However, an exercise intervention of 12 weeks of aerobic training did not produce any changes in HRV derived parameters in women with SLE in comparison to a control group.

Association between homocysteine levels and arterial stiffness in women with systemic sclerosis.

OBJECTIVES: The purpose of this study was to evaluate homocysteine (Hcy) serum levels in women with systemic sclerosis (SSc) compared with healthy controls and to examine possible associations between Hcy and markers of arterial stiffness. METHODS: A cross-sectional study was performed at a single hospital between November 2017 and May 2019: 62 women with SSc and 62 age- and sex-matched healthy controls were enrolled. Pulse wave velocity (PWV) was measured non-invasively along the carotid-femoral arterial segment. Serum Hcy was analysed using immunonephelo-metric method. RESULTS: There was a significant difference in Hcy serum levels between SSc female patients and healthy controls (11.9±3.3 vs. 10.3±2.3 µmol/ml, p=0.002). Serum levels of Hcy were positively correlated with PWV (r=0.28, p<0.05), brain natriuretic peptide (BNP) (r=0.36, p<0.05) and disease duration (r=0.38, p<0.05), within the SSc group. In addition, in the linear regression model, higher Hcy concentrations were associated with higher PWV [ß=0.74 95% CI (0.085, 1.394); p=0.027], BNP [ß=0.04 95% CI (0.014, 0.072); p=0.004] and disease duration [ß=0.18 95% CI (0.070, 0.300); p=0.002]. In multiple linear regression model adjusting for covariants, Hcy remained positively related to the PWV [ß=0.033 95% CI (0.003, 0.062); p=0.031]. CONCLUSIONS: Our findings revealed a positive correlation between Hcy serum levels and PWV, which indicates that high levels of Hcy may predispose to the development of vascular stiffness in patients with SSc.

Sleep quality and clinical and psychological manifestations in women with mild systemic lupus erythematosus activity compared to women with fibromyalgia: A preliminary study.

Objectives: This study analyzed sleep quality in fibromyalgia (FM) and systemic lupus erythematosus (SLE) and explored its relationship with other clinical and psychological manifestations.Methods: Twenty women with FM, 19 women with SLE and 22 healthy women participated in the study. Subjective sleep quality, fatigue, pain, depression and anxiety were evaluated with self-reports, and objective sleep measures were obtained with actigraphy. Comparisons were analyzed with Chi-square, Kruskal-Wallis's H and Mann-Whitney's U tests. Relationships between measurements were analyzed with Spearman's correlation coefficients.Results: Subjective sleep quality was altered in the FM and SLE groups compared to the control group (15.53 ± 3.27, 8.47 ± 3.20, 4.91 ± 2.79, p < .05, respectively). FM and SLE patients reported higher levels of pain (22.65 ± 9.87, 10.21 ± 9.93, 2.30 ± 3.096, p < .05), fatigue (4.67 ± 0.37, 3.59 ± 3.04, 2.33 ± 0.59, p < .05) and depressive symptoms (9.90 ± 3.78, 4.53 ± 3.04, 4.17 ± 3.95, p < .05) than controls, respectively. Worse subjective quality of sleep was associated with higher pain intensity and more depressive symptoms in FM and SLE. Actigraphy measures showed that FM patients spent more time in bed than subjects in the remaining groups.Conclusion: Sleep deterioration is related to more pain and depressive symptoms in FM and SLE. Addressing sleep disturbances may improve not only sleep quality but also depressive symptoms and pain.

Physical Fitness and Body Composition in Women with Systemic Lupus Erythematosus.

Background and objectives: Higher physical fitness is associated with a more favorable weight and body composition in the general population, although this association has not been studied in patients with systemic lupus erythematosus (SLE). The aim of the present study was to examine the association of different components of physical fitness with body composition in women with SLE with mild disease activity. Materials and Methods: This cross-sectional study included 77 women with SLE (43.2 ± 13.8 years old) and clinical stability during the previous 6 months. Body composition (including body mass index (BMI), fat mass index (FMI), waist circumference, waist-to-height ratio and waist-to-hip ratio) was assessed using a stadiometer, an anthropometric tape, and a bioimpedance device. Physical fitness included cardiorespiratory fitness (Siconolfi step test and 6 min walk test), muscular strength (handgrip strength test as upper body measure and 30 s chair stand as lower body measure), and flexibility (back-scratch test). Participants with a fitness level equal or above the median of the study sample were categorized as "fit" and those below the median were categorized as "unfit". Linear regression assessed the association of physical fitness with body composition parameters. Results: Cardiorespiratory fitness and upper body muscular strength were negatively associated with BMI, FMI, waist circumference, and waist-to-height ratio (all, p < 0.05). Lower body muscular strength and flexibility were negatively related to FMI, waist circumference, waist-to-height ratio, and waist-to-hip ratio (all, p < 0.05). These relationships were still significant after controlling for age, disease duration, accrual damage, and SLE activity. Overall, fit patients presented significantly lower values in all body composition parameters compared to unfit patients (all, p < 0.05). Conclusions: The main findings of the present study suggest that physical fitness is inversely associated with body composition in women with SLE. Given the cross-sectional nature of this study, future clinical trials should study the causal pathways underlying these relationships.

Thrombotic microangiopathy in a patient with eosinophilic granulomatosis with polyangiitis: case-based review.

The correct diagnosis, classification and therapeutic management of thrombotic microangiopathies (TMA) continue to be a challenge for the clinician. We report a rare case of eosinophilic granulomatosis with polyangiitis (EGPA) as a trigger for complement-mediated TMA in a 57-year-old man who was successfully treated with corticoids, cyclophosphamide and therapeutic plasma exchange. Additionally, we review few other cases reported in the literature and the pathophysiological pathway of association between TMA and EGPA. We found that the mutual relationships between the inflammation triggered by vasculitis, the exacerbated complement activation, together with hypereosinophilia and endothelial damage seem to be the key in explaining the connection between both entities. We suggest that an understanding of the multi-causal nature of TMAs is crucial for the correct diagnosis and treatment of these patients.

Association between non-dipper hypertension and vitamin D deficiency in women with systemic lupus erythematosus.

OBJECTIVES: Blood pressure (BP) physiologically declines more than 10% at night. Subjects who do not experience this drop are classified as non-dippers. They have a higher risk of cardiovascular diseases (CVD). Vitamin D deficiency and non-dipper pattern have been associated in the general population. Patients with systemic lupus erythematosus (SLE) are more likely to have vitamin D deficiency, a non-dipper pattern and CVD. We aimed to evaluate a possible relationship between vitamin D deficiency and non-dipper pattern in patients with SLE. METHODS: Using 24-hour ambulatory BP monitoring, 77 women with SLE were divided into dippers and non-dippers. 25-hydroxyvitamin D (25(OH)D) levels were compared between both groups. A multivariate analysis was used to determine which variables were independently associated with non-dipper pattern. RESULTS: 62% of patients were non-dippers. They had lower levels of 25(OH)D than dippers (19.4±8.9 vs. 25.9±10.1 ng/ml, p=0.005). Patients with lower 25(OH)D levels were more likely to be non-dippers (OR 3.7, 95%CI 1.2-11.4; p=0.025). The nocturnal decline of mean BP correlated with levels of 25(OH)D (r=0.227, p=0.047). Night-time systolic, diastolic and mean BP inversely correlated with the levels of 25(OH)D (r=-0.274, p=0.016; r=-0.238, p=0.037, and r=-0.260, p=0.022, respectively), but only night- time systolic BP remained significant after adjustment for age and body mass index (r=-0.228, p=0.049). 25(OH)D levels and the use of mycophenolate were found to be independently associated with non-dipper pattern in SLE patients. CONCLUSIONS: Vitamin D deficiency may contribute to the development of a non-dipper pattern in patients with SLE.

Effects of 12-week Aerobic Exercise on Arterial Stiffness, Inflammation, and Cardiorespiratory Fitness in Women with Systemic LUPUS Erythematosus: Non-Randomized Controlled Trial.

This study assessed the effect of 12-week aerobic exercise on arterial stiffness (primary outcome), inflammation, oxidative stress, and cardiorespiratory fitness (secondary outcomes) in women with systemic lupus erythematosus (SLE). In a non-randomized clinical trial, 58 women with SLE were assigned to either aerobic exercise (n = 26) or usual care (n = 32). The intervention comprised 12 weeks of aerobic exercise (2 sessions × 75 min/week) between 40⁻75% of the individual's heart rate reserve. At baseline and at week 12, arterial stiffness was assessed through pulse wave velocity (PWV), inflammatory (i.e., high-sensitivity C-reactive protein [hsCRP], tumor necrosis factor alpha [TFN-α], and inteleukin 6 [IL-6]) and oxidative stress (i.e., myeloperoxidase [MPO]) markers were obtained from blood samples, and cardiorespiratory fitness was assessed (Bruce test). There were no between-group differences in the changes in arterial stiffness (median PWV difference -0.034, 95% CI -0.42 to 0.36 m/s; p = 0.860) or hsCRP, TNF-α, IL-6, and MPO (all p > 0.05) at week 12. In comparison to the control group, the exercise group significantly increased cardiorespiratory fitness (median difference 2.26 minutes, 95% CI 0.98 to 3.55; p = 0.001). These results suggest that 12 weeks of progressive treadmill aerobic exercise increases cardiorespiratory fitness without exacerbating arterial stiffness, inflammation, or oxidative stress in women with SLE.

Association of a rare variant of the TNFSF13B gene with susceptibility to Rheumatoid Arthritis and Systemic Lupus Erythematosus.

A rare variant (BAFF-var) of the tumor necrosis factor superfamily 13b (TNFSF13B) gene has been recently associated with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The aim of this study was to investigate the association between TNFSF13B BAFF-var and susceptibility to rheumatoid arthritis (RA) and replicate that association in SLE. 6,218 RA patients, 2,575 SLE patients and 4,403 healthy controls from three different countries were included in the study. TNFSF13B BAFF-var was genotyped using TaqMan allelic discrimination assay. PLINK software was used for statistical analyses. TNFSF13B BAFF-var was significantly associated with RA (p = 0.015, OR = 1.21, 95% CI = 1.03-1.41) in the Spanish cohort. A trend of association was observed in the Dutch (p = 0.115) and German (p = 0.228) RA cohorts. A meta-analysis of the three RA cohorts included in this study revealed a statistically significant association (p = 0.002, OR = 1.24, 95% CI = 1.10-1.38). In addition, TNFSF13B BAFF-var was significantly associated with SLE in the Spanish (p = 0.001, OR = 1.41, 95% CI = 1.14-1.74) and the German cohorts (p = 0.030, OR = 1.86, 95% CI = 1.05-3.28), with a statistically significant p-value obtained in the meta-analysis (p = 0.0002, OR = 1.46, 95% CI = 1.09-2.32). The results obtained confirm the known association of TNFSF13B BAFF-var with SLE and, for the first time, demonstrate that this variant contributes to susceptibility to RA.