Low-density granulocytes and monocytes as biomarkers of cardiovascular risk in systemic lupus erythematosus.

OBJECTIVE: The aim was to evaluate the most relevant cell populations involved in vascular homeostasis as potential biomarkers of SLE-related cardiovascular disease (CVD). METHODS: Low-density granulocytes (LDGs), monocyte subsets, endothelial progenitor cells, angiogenic T (Tang) cells, CD4+CD28null and Th1/Th17 lymphocytes and serum cytokine levels were quantified in 109 SLE patients and 33 controls in relationship to the presence of subclinical carotid atheromatosis or cardiovascular disease. A second cohort including 31 recent-onset SLE patients was also included. RESULTS: Raised monocyte and LDG counts, particularly those LDGs negative for CD16/CD14 expression (nLDGs), in addition to the ratios of monocytes and nLDGs to high-density lipoprotein-cholesterol (HDLc) molecules (MHR and nLHR, respectively), were present in SLE patients with traditional risk factors or subclinical atheromatosis but not in those who were CV-free, thus revealing their value in the identification of patients at risk of CVD, even at the onset of disease. Accordingly, nLDGs were correlated positively with carotid intima-media thickness (cIMT) and with inflammatory markers (CRP and IL-6). A bias towards more differentiated monocyte subsets, related to increased IFN-α and IL-17 serum levels, was also observed in patients. Intermediate monocytes were especially expanded, but independently of their involvement in CVD. Finally, CD4+CD28null, Th17 and Th1 lymphocytes were increased, with CD4+CD28null and Th17 cells being associated with cIMT, whereas endothelial progenitor and Tang cell levels were reduced in all SLE patients. CONCLUSION: The present study highlights the potential use of MHR and nLHR as valuable biomarkers of CVD risk in SLE patients, even at diagnosis. The increased amounts of nLDGs, monocytes, Th17 and senescent-CD28null subsets, coupled with reduced pro-angiogenic endothelial progenitor cells and Tang cells, could underlie the development of atheromatosis in SLE.

Comparison of the Birmingham Vasculitis Activity Score and the Five-Factor Score to Assess Survival in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Study of 550 Patients From Spain (REVAS Registry).

OBJECTIVE: To compare the accuracy of the Birmingham Vasculitis Activity Score (BVAS), version 3, and the Five Factor Score (FFS), version 1996 and version 2009, to assess survival in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: A total of 550 patients with AAV (41.1% with granulomatosis with polyangiitis, 37.3% with microscopic polyangiitis, and 21.6% with eosinophilic granulomatosis with polyangiitis), diagnosed between 1990 and 2016, were analyzed. Receiver operating characteristic (ROC) curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores. RESULTS: Overall mortality was 33.1%. The mean ± SD BVAS at diagnosis was 17.96 ± 7.82 and was significantly higher in nonsurvivors than in survivors (mean ± SD 20.0 ± 8.14 versus 16.95 ± 7.47, respectively; P < 0.001). The mean ± SD 1996 FFS and 2009 FFS were 0.81 ± 0.94 and 1.47 ± 1.16, respectively, and were significantly higher in nonsurvivors than in survivors (mean ± SD 1996 FFS 1.17 ± 1.07 versus 0.63 ± 0.81 [P < 0.001] and 2009 FFS 2.13 ± 1.09 versus 1.15 ± 1.05 [P < 0.001], respectively). Mortality rates increased according to the different 1996 FFS and 2009 FFS categories. In multivariate analysis, BVAS, 1996 FFS, and 2009 FFS were significantly related to death (P = 0.007, P = 0.020, P < 0.001, respectively), but the stronger predictor was the 2009 FFS (hazard ratio 2.9 [95% confidence interval 2.4-3.6]). When the accuracy of BVAS, 1996 FFS, and 2009 FFS to predict survival was compared in the global cohort, ROC analysis yielded area under the curve values of 0.60, 0.65, and 0.74, respectively, indicating that 2009 FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001 and when assessing the 1-year, 5-year, and long-term mortality. Correlation among BVAS and 1996 FFS was modest (r = 0.49; P < 0.001) but higher than between BVAS and the 2009 FFS (r = 0.28; P < 0.001). CONCLUSION: BVAS and FFS are useful to predict survival in AAV, but the 2009 FFS has the best prognostic accuracy at any point of the disease course.

IgM anti-phosphorylcholine antibodies associate with senescent and IL-17+ T cells in SLE patients with a pro-inflammatory lipid profile.

OBJECTIVE: The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE. METHODS: Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls. RESULTS: IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (ß= -0.252; P = 0.002), high-density lipoprotein (HDL; ß = 0.271; P = 0.001), low-density lipoprotein (LDL; ß= -0.192; P = 0.017) and glucocorticoid treatment (ß= -0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (ß = 0.194; P = 0.028) and SLEDAI (ß = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: ß = -0.455, P = 0.001; Th17: ß= -0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines. CONCLUSION: The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role.

Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis.

OBJECTIVE: To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model. PATIENTS AND METHODS: The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017. RESULTS: The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (P<.001), mixed microbiological infections (P=.02), and more than 1 infection (P=.01) and glucocorticoid monotherapy (P=.02). According to univariate analyses, platelets of less than 100,000/mm3 (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death. CONCLUSION: The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.

Serum Levels of Anti-PON1 and Anti-HDL Antibodies as Potential Biomarkers of Premature Atherosclerosis in Systemic Lupus Erythematosus.

The present study aimed to evaluate the possible role of immunoglobulin G (IgG) antibodies against high-density lipoproteins (HDL) and paraoxonase 1 (PON1) as possible biomarkers of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). To this end, levels of these autoantibodies, PON1 activity and total antioxidant capacity were quantified in serum samples from 198 SLE patients, 100 healthy controls (HC) and 42 non-autoimmune individuals with traditional cardiovascular risk factors. PON1 rs662 polymorphism was analysed in a subgroup of patients and controls. Subclinical CVD were determined by Doppler ultrasound in 118 SLE patients and 30 HC, analysing carotid intima-media thickness (IMT) and blood flow parameters in internal carotid, middle cerebral and basilar arteries. Serum levels of both anti-HDL and anti-PON1 antibodies were increased in SLE patients compared with HC (p < 0.001); however, only anti-PON1 antibodies, in addition to disease activity, were significant predictors of the impaired PON1 function in SLE (ß = -0.143, p = 0.045). Conversely, anti-HDL antibodies were associated with higher risk of CVD (odds ratio: 3.69; p = 0.012) and lower HDL levels at disease onset (ρ = -0.324, p = 0.044). Finally, anti-PON1 antibodies were associated with carotid IMT in SLE (ß = 0.201, p = 0.008) and inversely related to cranial arteries blood flow velocities in patients with clinical and subclinical CVD (all p < 0.001). In sum, these findings allowed us to propose serum levels of anti-PON1 and anti-HDL antibodies as potential early biomarkers of endothelial damage and premature atherosclerosis in SLE, thus constituting useful therapeutic targets for the prevention of future CVD in these patients.

Circulating microparticle subpopulations in systemic lupus erythematosus are affected by disease activity.

BACKGROUND: Immune cells under chronic inflammation shed microparticles (MPs) that could fuel the inflammatory responses and atherosclerosis typically presented in systemic lupus erythematosus (SLE). This study analyzes total and subset-specific MPs from SLE patients and their possible influence on clinical features, leukocyte activation and serum cytokines. METHODS: Total MPs and those derived from platelets, endothelial cells, monocytes, granulocytes and T-cells were quantified in plasma of 106 SLE patients and 33 healthy controls by flow cytometry. MP amounts were analyzed according to clinical manifestations, blood leukocyte populations and circulating cytokines (IFNα, TNFα, IL-10, BLyS, IL-17, IL-1ß, CXCL10, CCL-2, CCL3, leptin). Finally, the in vitro effect of SLE-isolated MPs on the leukocyte activation status was analyzed. RESULTS: Total circulating MPs in SLE patients were related to increased disease duration and the presence of cardiovascular disease. Furthermore, patients displayed increased counts of MPs from platelets, monocytes and T-lymphocytes, especially in SLE patients with disease activity or with TNFαhigh-profile. Accordingly, MPs were associated with increased expression of activation markers in blood T-cells and monocytes. Finally, analyses propose a role of glucocorticoids in MPs generation and leukocyte activation since both fresh and cultured T-cells under this treatment presented higher IL-10 and CD25 production. CONCLUSIONS: The altered profile of subset-specific SLE-MPs was influenced by the disease activity and altered status of leukocyte native cells, also associated with a TNFαhigh-profile. TRANSLATIONAL RESULTS: SLE patients, especially those with disease activity, displayed increased counts of MPs derived from platelets, monocytes and T-lymphocytes, which were more frequently found in TNFαhigh-type patients. The origin of such SLE-MP subsets seems to be related to the over-activated status of T-cells and monocytes characteristic of these patients. Ex vivo and in vitro analyses propose a role of glucocorticoids in the generation of circulating MPs and leukocyte activation in SLE patients.

Encefalitis límbica: una entidad hasta ahora poco conocida / Limbic encephalitis: a poorly known disease

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Senescent profile of angiogenic T cells from systemic lupus erythematosus patients.

The chronic inflammatory environment associated with systemic lupus erythematosus can lead to an accelerated immunosenescence responsible for the endothelial damage and increased cardiovascular risk observed in these patients. The present study analyzed two populations with opposite effects on vascular endothelium, angiogenic T cells and the senescent CD4(+)CD28(null) subset, in 84 systemic lupus erythematosus patients and 46 healthy controls. Also, 48 rheumatoid arthritis patients and 72 individuals with traditional cardiovascular risk factors participated as disease controls. Phenotypic characterization of CD28(+) and CD28(null) cells was performed by analyzing markers of senescence (CCR7, CD27, CD57) and cytotoxicity (CD56, perforin, granzyme B, IFN-γ). IL-1ß, IL-6, IL-8, IL-10, IL-12, IL-17A, IFN-α, IFN-γ, TNF-α, B lymphocyte stimulator, and GM-CSF serum levels were analyzed in systemic lupus erythematosus patients and healthy controls. CD4(+)CD28(null) cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28(null)-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28(+)-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28(null)-angiogenic T cell subset with inflammatory, rather than protective, effects could be present.

Influencia del tratamiento con nitratos intravenosos en la mortalidad precoz de pacientes con insuficiencia cardiaca aguda. Estudio NITRO-EAHFE / Influence of intravenous nitrate treatment on early mortality among patients with acute heart failure. NITRO-EAHFE Study

Introducción y objetivos. La evidencia sobre la influencia pronóstica de los nitratos intravenosos en pacientes con insuficiencia cardiaca aguda es escasa. El objetivo del estudio es determinar la influencia de este tratamiento en mortalidad precoz y reconsulta. Métodos. Estudio de cohortes, multicéntrico, prospectivo de pacientes con insuficiencia cardiaca aguda en servicios de urgencias en 2 periodos (mayo de 2009 y noviembre-diciembre de 2011). Se incluyó pacientes con presión arterial sistólica > 110 mmHg agrupados en función de si recibieron nitroglicerina intravenosa o no. Las variables objetivo fueron mortalidad a 3, 7, 14 y 30 días y reconsulta a 30 días. Para determinar la influencia pronóstica del tratamiento se realizó un propensity score mediante regresión logística. Resultados. De 4.897 individuos se incluyeron 3.178. Fallecieron a 30 días 308 (9,7%) y reconsultaron 465 (17%). La edad media era de 79,5 ± 10,0 años y 796 (25%) recibieron nitratos intravenosos. Tras emparejarlos quedaron 685 individuos en cada grupo. La hazard ratio de los nitratos para mortalidad a 30 días fue 1,21 (intervalo de confianza del 95%, 0,87-1,70) y para reconsulta 0,93 (intervalo de confianza del 95%, 0,71-1,22). Los resultados fueron similares para la mortalidad a 3, 7 y 14 días (hazard ratio = 1,05 [intervalo de confianza del 95%, 0,56-1,96], hazard ratio = 1,20 [intervalo de confianza del 95%, 0,74-1,94] y hazard ratio = 1,23 [intervalo de confianza del 95%, 0,82-1,84], respectivamente). En presencia de edema de pulmón hipertensivo, el grupo de nitratos mostró una hazard ratio de 0,88 (intervalo de confianza del 95%, 0,47-1,63) para mortalidad a 30 días. Conclusiones. Los nitratos intravenosos no influyen en mortalidad precoz ni en reconsulta en pacientes con insuficiencia cardiaca aguda (AU)

Introduction and objectives. There is little evidence on the prognostic influence of intravenous nitrates in patients with acute heart failure. Our purpose was to determine the influence of this treatment on early mortality and new visits. Methods. Prospective, multicenter cohort study of patients with acute heart failure in an emergency room during 2 periods (May 2009 and November-December 2011). Patients with systolic blood pressure > 110 mmHg were included, grouped according to whether they received intravenous nitroglycerin or not. Endpoints were mortality at 3, 7, 14, and 30 days and new visits at 30 days. The propensity score was estimated by logistic regression to determine the prognostic influence of the treatment. Results. We included 3178 of 4897 individuals. A total of 308 (9.7%) had died within 30 days and 465 (17%) attended new visits. The mean (standard deviation) age was 79.5 (10.0) years, and 796 (25%) patients received intravenous nitrates. After matching, there were 685 individuals in each group. The hazard ratio for 30-day mortality with nitrates was 1.21 (95% confidence interval, 0.87-1.70) and was 0.93 for new visits (95% confidence interval, 0.71-1.22). The results were similar for mortality at 3, 7, and 14 days (hazard ratio = 1.05 [95% confidence interval, 0.56-1.96], hazard ratio = 1.20 [95% confidence interval, 0.74-1.94], and hazard ratio = 1.23 [95% confidence interval, 0.82-1.84], respectively). In the presence of hypertensive pulmonary edema, the nitrates group showed a hazard ratio of 0.88 (95% confidence interval, 0.47-1.63) for 30-day mortality. Conclusions. Intravenous nitrates do not influence early mortality or new visits in patients with acute heart failure (AU)

Influence of Intravenous Nitrate Treatment on Early Mortality Among Patients With Acute Heart Failure. NITRO-EAHFE Study.

INTRODUCTION AND OBJECTIVES: There is little evidence on the prognostic influence of intravenous nitrates in patients with acute heart failure. Our purpose was to determine the influence of this treatment on early mortality and new visits. METHODS: Prospective, multicenter cohort study of patients with acute heart failure in an emergency room during 2 periods (May 2009 and November-December 2011). Patients with systolic blood pressure > 110mmHg were included, grouped according to whether they received intravenous nitroglycerin or not. Endpoints were mortality at 3, 7, 14, and 30 days and new visits at 30 days. The propensity score was estimated by logistic regression to determine the prognostic influence of the treatment. RESULTS: We included 3178 of 4897 individuals. A total of 308 (9.7%) had died within 30 days and 465 (17%) attended new visits. The mean (standard deviation) age was 79.5 (10.0) years, and 796 (25%) patients received intravenous nitrates. After matching, there were 685 individuals in each group. The hazard ratio for 30-day mortality with nitrates was 1.21 (95% confidence interval, 0.87-1.70) and was 0.93 for new visits (95% confidence interval, 0.71-1.22). The results were similar for mortality at 3, 7, and 14 days (hazard ratio = 1.05 [95% confidence interval, 0.56-1.96], hazard ratio = 1.20 [95% confidence interval, 0.74-1.94], and hazard ratio = 1.23 [95% confidence interval, 0.82-1.84], respectively). In the presence of hypertensive pulmonary edema, the nitrates group showed a hazard ratio of 0.88 (95% confidence interval, 0.47-1.63) for 30-day mortality. CONCLUSIONS: Intravenous nitrates do not influence early mortality or new visits in patients with acute heart failure.

Analysis of two autoimmunity genes, IRAK1 and MECP2, in giant cell arteritis.

OBJECTIVES: The Xq28 region, containing IRAK and MECP2, represent a common susceptibility locus for a high number of autoimmune diseases. Our aim in the present study was to evaluate the influence of the IRAK1 and MECP2 autoimmunity-associated genetic variants in the giant cell arteritis (GCA) susceptibility and its clinical subphenotypes. METHODS: We analysed a total of 627 female biopsy-proven GCA patients and 1,520 female healthy controls of Spanish Caucasian origin. Two polymorphisms, rs1059702 and rs17345, located at IRAK1 and MECP2, respectively, were genotyped using TaqMan® allelic discrimination assays. RESULTS: No association with any of the analysed polymorphisms was evident when genotype and allele frequencies were compared between GCA patients and controls (rs1059702: allelic p-value=0.699, OR=0.96, CI 95% 0.80-1.17; rs17435: allelic p-value=0.994, OR=1.00, CI 95% 0.84-1.19). Likewise, the subphenotype analysis yield similar negative results. CONCLUSIONS: We have assessed for the first time the possible role of IRAK1 and MECP2 autoimmune disease-associated polymorphisms in GCA. Our data suggest that IRAK1 rs1059702 and MECP2 rs17435 genetic variants do not play a significant role in GCA susceptibility or severity.