Objective To comprehensively assess associations of site-specific CD4+-T-cell hypomethylation of the CD40-Ligand gene ( CD40L) with disease activity of women with systemic lupus erythematosus (SLE). Methods CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4+-T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. Results 60 female SLE patients participated in the study (age 45.7 ± 11.1 years, disease duration 17.0 ± 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (β = −40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (β = −30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (β = 15.0, p = 0.046, adjusted p = 0.8). Conclusion Site-specific hypomethylation of the CD40L promotor in CD4+-T-cells show associations with disease activity in female SLE patients.
Objective Hypomethylation of CD40-ligand (CD40L) in T-cells is associated with increased disease activity in systemic lupus erythematosus (SLE). We therefore investigated possible associations of dietary methyl donors and products with CD40L methylation status in SLE. Methods Food frequency questionnaires were employed to calculate methyl donor micronutrients in 61 female SLE patients (age 45.7 ± 12.0 years, disease duration 16.2 ± 8.4 years) and compared to methylation levels of previously identified key DNA methylation sites (CpG17 and CpG22) within CD40L promotor of T-cells using quantitative DNA methylation analysis on the EpiTYPER mass spectrometry platform. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Linear regression modelling was used. P values were adjusted according to Benjamini & Hochberg. Results Amongst the micronutrients assessed (g per day), methionine and cysteine were associated with methylation of CpG17 (β = 5.0 (95%CI: 0.6-9.4), p = 0.04; and β = 2.4 (0.6-4.1), p = 0.02, respectively). Methionine, choline, and cysteine were additionally associated with the mean methylation of the entire CD40L (β = 9.5 (1.0-18.0), p = 0.04; β = 1.6 (0.4-3.0), p = 0.04; and β = 4.3 (0.9-7.7), p = 0.02, respectively). Associations of the SLEDAI with hypomethylation were confirmed for CpG17 (β=-32.6 (-60.6 to -4.6), p = 0.04) and CpG22 (β=-38.3 (-61.2 to -15.4), p = 0.004), but not the mean methylation of CD40L. Dietary products with the highest impact on methylation included meat, ice cream, white bread, and cooked potatoes. Conclusions Dietary methyl donors may influence DNA methylation levels and thereby disease activity in SLE.
Objective This study aimed to assess polyunsaturated fatty acid (PUFA) status and association with systemic inflammation and fish consumption in systemic lupus erythematosus (SLE). Methods Parameters of PUFA status including the proportion of omega-6 and -3 fatty acids in highly unsaturated fatty acids (omega-6%, omega-3%), essential fatty acids linoleic acid (LA) and alpha-linolenic acid (ALA), the omega-6 PUFA arachidonic acid (ARA) and the sum of key omega-3 PUFA eicosapentaenoic acid+docosahexaenoic acid (omega-3 status) were measured by gas chromatography in 68 SLE patients (88.2% female, aged 45.7±12.5 years). Associations with serum CRP, disease activity, damage and fish consumption were assessed by linear regression modelling adjusted for age, sex and body mass index. Associations are reported in terms of regression coefficients (β). Results Omega-6 PUFA were associated with higher CRP: omega-6% (β = 0.052, p = 0.02), the ratio of LA/ALA (β = 0.007, p = 0.02) and ARA (β = 0.308, p = 0.001). Conversely, omega-3% was associated with lower CRP (β = −0.051, p = 0.02). Increased dietary PUFA consumption from fish (g/day) was linked to a higher omega-3 status (β = 2.21, p = 0.02) and lower self-reported damage (Brief Index of Lupus Damage; β = −3.22, p = 0.02). Conclusions Omega-3 and omega-6 fatty acid status differentially reflect systemic inflammation in SLE and are linked to fish consumption.
Background Contrast-induced nephropathy (CIN) is a major adverse event in patients undergoing coronary angiography. The Mehran risk model is the gold-standard for CIN risk prediction. However, its performance in comparison to more contemporary National Cardiovascular Data Registry-Acute Kidney Injury (NCDR-AKI) risk models remains unknown. We aimed to compare both in this study. Methods and results Predictions of Mehran and NCDR-AKI risk models and clinical events of CIN and need for dialysis were assessed in a total of 2067 patients undergoing coronary angiography with or without percutaneous coronary intervention. Risk models were compared regarding discrimination (receiver operating characteristic analysis), net reclassification improvement (NRI) and calibration (graphical and statistical analysis). The NCDR risk model showed superior risk discrimination for predicting CIN (NCDR c-index 0.75, 95% CI 0.72–0.78; vs. Mehran c-index 0.69, 95% CI 0.66–0.72, p < 0.01), and continuous NRI (0.22; 95% CI 0.12–0.32; p < 0.01) compared to the Mehran model. The NCDR risk model tended to underestimate the risk of CIN, while the Mehran model was more evenly calibrated. For the prediction of need for dialysis, NCDR-AKI-D also discriminated risk better (c-index 0.85, 95% CI 0.79–0.91; vs. Mehran c-index 0.75, 95% CI 0.66–0.84; pNCDRvsMehran < 0.01), but continuous NRI showed no benefit and calibration analysis revealed an underestimation of dialysis risk. Conclusion In German patients undergoing coronary angiography, the modern NCDR risk model for predicting contrast-induced nephropathy showed superior discrimination compared to the GRACE model while showing less accurate calibration. Results for the outcome ‘need for dialysis’ were equivocal. Graphic abstract
Objective To assess whether a healthy lifestyle is associated to beneficial effects on various systemic lupus erythematosus (SLE) health domains. Methods In a cross-sectional study, Mediterranean Diet Adherence Score (MEDAS), physical activity energy expenditure (PAEE), and smoking status were assessed by questionnaires, along with clinical parameters and various health domains including Systemic Lupus Disease Activity Score (SLEDAI), Depression Scale (CES-D), Fatigue Severity (FSS), functional status (FFbH), physical and mental quality of life (PCS, MCS). Lifestyle choices were assessed with respect to health domains by linear regression modeling. Additionally, SLE patients with a healthy lifestyle (MEDAS ≥ 4, ≥ 1 h sport per week, no smoking) were compared to those without by Wilcoxon’s signed-rank test. Results 49 of 145 SLE patients (44.3 ± 31.7 years, 87.6% female) followed a healthy lifestyle and showed a higher physical quality of life (β = 4.5 (95%-CI 1.5–7.9) p = 0.01), lower depression (β = −5.0 (−8.2 to −0.2) p = 0.02) and lower fatigue (β = −0.8 (−1.5 to −0.2) p = 0.01) independently of SLE disease activity. Furthermore, dsDNA-antibodies were lower (146 ± 540 vs 266 ± 146 U/mL, p = 0.049). In a more detailed analysis, physical activity had the highest impact on the various health domains when compared to smoking or diet adherence, which was consistent even after adjusting for multiple potential confounders. Each 1,000 kcal of weekly PAEE was associated to a 1.8 (0.9–2.6) point increase in the PCS ( p = 0.0001), a 0.2 (0.03–0.4) point decrease in the CES-D ( p = 0.01) and a 2.8 (1.2–4.4) point increase in the FFbH ( p = 0.0006). Conclusion A healthy lifestyle, especially physical activity is associated with beneficial effects including quality of life, depression and fatigue in SLE.
Aims Absolute treatment effects—i.e. numbers needed to treat (NNTs)—of novel antidiabetic drugs for cardiovascular outcomes have not been comprehensively evaluated. We aimed to perform a meta‐analysis of digitalized individual patient outcomes to display and compare absolute treatment effects. Methods and results Individual patient time‐to‐event information from Kaplan–Meier plots of cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints from cardiovascular outcome trials (CVOTs) evaluating dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, and sodium glucose transporter 2 (SGLT2) inhibitors vs. placebo were digitalized using WebPlotDigitizer 4.2 and the R code of Guyot et al .; Weibull regression models were generated, validated, and used to estimate NNT for individual trials; random‐effects meta‐analysis generated Meta‐NNT with 95% confidence intervals. Sixteen CVOTs reported time‐to‐event information (14 in primary diabetes and 2 in primary heart failure populations). Thirteen studies including 96 860 patients were meta‐analysed for CM : At the median follow‐up of 30 months, Meta‐NNTs were 178 (64 to ∞ to −223) for DPP‐4 inhibitors, 261 (158 to 745) for GLP‐1 receptor agonists, and 118 (68 to 435) for SGLT2 inhibitors. Ten studies including 96 128 patients were meta‐analysed for HHF : At the median follow‐up of 29 months, estimated Meta‐NNTs were −644 (229 to ∞ to −134) for DPP‐4 inhibitors, 441 (184 to ∞ to −1100) for GLP‐1 receptor agonists, and 126 (91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective for HHF in primary heart failure populations [Meta‐NNT 25 (19 to 39)] vs. primary diabetes populations [Meta‐NNT 233 (167 to 385)] at 16 months of follow‐up. Conclusions We found only modest treatment benefits of GLP‐1 receptor agonists and SGLT2 inhibitors for CM and HHF in primary type 2 diabetes mellitus populations. In primary heart failure populations, SGLT2 inhibitor benefits were substantial and comparable in efficacy to established heart failure medication.
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