Impact of cardiovascular risk factors in antiphospholipid syndrome: an observational study from the Spanish national registry.

OBJECTIVES: To determine the burden and impact of cardiovascular risk factors (CRF) in antiphospholipid syndrome (APS) patients. METHODS: Analysis of the patients diagnosed with APS identified in the Spanish Hospital Discharge Database between 2016 and 2017. We analysed the admissions due to arterial (ATE) and venous thromboembolic events (VTE) and evaluated the incidence and the attributed risk of each CRF. RESULTS: 5424 admissions in patients diagnosed with APS were identified. 64.6% were women and the mean age was 54.6. The mortality rate was 3.1%. Overall, 35.8% of patients had hypertension, 14% were diabetic, 21.7% hypercholesterolaemic, 9.9% obese and 26.7% smokers. Thromboembolic events (67.9% arterial and 32.1% venous) accounted for 11.9% of admissions and 7.1% of deaths. Male sex (OR 1.83, 95% CI 1.41-2.21), cholesterol (OR 1.25, 95% CI 1.01-1.54) and smoking (OR 1.49, 95% CI 1.22-1.81) were independently associated with thromboembolic events. Meanwhile, patients with ATE were older (57 vs. 54.1 years p=0.033), and presented more secondary APS (17.1% vs. 10.6%, p=0.034), hypertension (47.7% vs. 33.5%, p=0.001), diabetes (16.9% vs. 9.6%, p=0.017), cholesterol (34.3% vs. 17.8%, p<0.001) and smoking habit (41.2% vs. 24%, p<0.001) when compared with VTE. Risk factors independently associated with ATE events were male sex (OR=1.61, 95% CI=1.30-2.03), hypertension (OR=1.30, 95% CI=1.03-1.64), cholesterol (OR=1.51, 95% CI=1.18-1.94) and smoking habit (OR=1.84, 95% CI=1.47-2.32), while VTE events were determined by male sex (OR=2.06, 95% CI=1.53-2.77) and obesity (OR=1.61, CI=1.02-2.52). CONCLUSIONS: Thromboembolic events in APS were in part determined by a high prevalence of CRF. The identification of distinct profiles may allow us to undertake a more personalised approach to reduce thromboembolic events and to individualise anticoagulant and antiplatelet therapy.

Individualizing mechanical ventilation: titration of driving pressure to pulmonary elastance through Young's modulus in an acute respiratory distress syndrome animal model.

BACKGROUND: Mechanical ventilation increases the risk of lung injury (VILI). Some authors propose that the way to reduce VILI is to find the threshold of driving pressure below which VILI is minimized. In this study, we propose a method to titrate the driving pressure to pulmonary elastance in an acute respiratory distress syndrome model using Young's modulus and its consequences on ventilatory-induced lung injury. MATERIAL AND METHODS: 20 Wistar Han male rats were used. After generating an acute respiratory distress syndrome, two groups were studied: (a) standard protective mechanical ventilation: 10 rats received 150 min of mechanical ventilation with driving pressure = 14 cm H2O, tidal volume < 6 mL/kg) and (b) individualized mechanical ventilation: 10 rats received 150 min of mechanical ventilation with an individualized driving pressure according to their Young's modulus. In both groups, an individualized PEEP was programmed in the same manner. We analyzed the concentration of IL-6, TNF-α, and IL-1ß in BAL and the acute lung injury score in lung tissue postmortem. RESULTS: Global driving pressure was different between the groups (14 vs 11 cm H2O, p = 0.03). The individualized mechanical ventilation group had lower concentrations in bronchoalveolar lavage of IL-6 (270 pg/mL vs 155 pg/mL, p = 0.02), TNF-α (292 pg/mL vs 139 pg/mL, p < 0.01) and IL-1ß (563 pg/mL vs 131 pg/mL, p = 0.05). They presented lower proportion of lymphocytes (96% vs 79%, p = 0.05) as well as lower lung injury score (6.0 points vs 2.0 points, p = 0.02). CONCLUSION: In our model, individualization of DP to pulmonary elastance through Young's modulus decreases lung inflammation and structural lung injury without a significant impact on oxygenation.

In vitro radiosensitization by eribulin in human cancer cell lines.

Background: The objective was to to determine the radiosensitizing properties of eribulin and the potential mechanisms of radiosensitization in cervical (HeLa) and pharyngeal (FaDu) cancer cell lines. Materials and methods: Cytotoxicity was evaluated by the crystal violet method. The 10% and 50% inhibitory concentration (IC10, IC50) for 24-hour drug exposure were determined. The surviving fraction at 2 Gy (SF2) and the sensitizer enhancement ratio (SER) were calculated from radiation cell survival curves in the presence or absence of eribulin. Combination index (CI) was calculated to determine if there is a true synergistic interaction between eribulin and irradiation. Cell cycle changes were assessed by propidium iodide staining and flow cytometry. Apoptotic cells were detected by annexin V and TUNEL-assay. Results: Mean IC50s and IC10s were 1.58 nM and 0.7 nM and 0.7 nM and 0.27 nM for HeLa and FaDu cells, respectively. Radiosensitization was observed in both lines with a SER up to 2.71 and 2.32 for HeLa and FaDu cells, respectively. A true synergistic effect was showed with a CI of 0.82 and 0.76 for HeLa and FaDu cells, respectively. Eribulin induced significant G2/M cell arrest and marked apoptosis. Irradiation combined with 3 nM eribulin increased the apoptotic response to radiation in Hela cells. Conclusion: Eribulin shows a true in vitro radiosensitizing effect in HeLa and FaDu cells by inducing significant G2/M phase arrest. In HeLa, the enhancement radiation-induced apoptosis could be an additional mechanism of radiosensitization. Further studies are needed to evaluate the clinical benefits of concurrent eribulin and radiotherapy as a novel therapeutic strategy for cancer.

Inflammatory-Related Clinical and Metabolic Outcomes in COVID-19 Patients.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection elicits inflammatory manifestations that relate with a "cytokine storm." OBJECTIVE: The aim of this research was to assess the role of circulating interleukin 6 (IL-6) levels and other inflammatory markers in patients with coronavirus disease 2019 (COVID-19) on metabolic functions and accompanying clinical complications. Patients and Methods. A total of 165 patients diagnosed with COVID-19 pneumonia were examined for medical features and inflammatory markers such as blood IL-6, CRP, ferritin, LDH, neutrophil/lymphocyte index (NLI), D-Dimer, and Red Cell Distribution Width (RDW). Regression analyses concerning electronically collected medical data were adjusted by appropriate factors and confounding variables. Results. Plasma IL-6 determinations evidenced a consistent association with hospital stay days, Intensive Care Unit (ICU) admission, and mortality rates. Similar trends were found for other proinflammatory variables, where ferritin and NLI showed a remarkable value as surrogates. Hyperglycaemia and the Charlson Comorbidity Index Score were positively associated with the inflammatory response induced by the SARS-COV-2 infection. An unhealthy lifestyle such as smoking and alcoholic drinks consumption as well as excessive body adiposity influenced inflammatory-related outcomes in the screened patients. CONCLUSION: IL-6 together with other inflammatory biomarkers accompanied poor clinical and metabolic outcomes in COVID-19-infected patients. IL-6 may result in a suitable proxy to individually categorise patients in order to manage this infectious pandemic.

Decreased circulating endothelial progenitor cells as an early risk factor of subclinical atherosclerosis in systemic lupus erythematosus.

OBJECTIVE: Endothelial progenitor cells (EPCs) play an important role in vascular damage repair and it has been suggested that a decreased number of these cells is associated with increased subclinical atherosclerosis. Our study aim was to evaluate whether the number of circulating EPCs in patients with SLE is associated with subclinical atherosclerosis, the presence of cardiovascular (CV) risk factors and SLE-specific factors. METHODS: Forty-six female SLE patients were included. At the time of each patient's appointment, CV risk factors, SLE-specific factors and EPCs were assessed in peripheral blood by flow cytometry. Simultaneously, atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry, intima media thickness (IMT) and carotid plaque by B-mode US scanning. RESULTS: Patients were classificated according to PWV following the reference values adjusted by age and blood pressure published by the European Society of Cardiology. Patients with pathological values of PWV showed a significant decrease of circulating EPC percentage compared with normal PWV patients. Decreased EPC counts were also associated with certain risk factors, including hypertension, tobacco use, impaired glucose metabolism, and metabolic syndrome, and correlate with high levels of high-sensitivity CRP (hsCRP) or fibrinogen. The presence of carotid plaque and IMT measurement were unrelated with EPC quantification. CONCLUSION: Patients with a reduced percentage of EPCs showed pathological arterial stiffness and association with certain CV risk factors, suggesting that the measurement of circulating EPCs can be used as a biological marker to determine subclinical atherosclerosis in SLE.

Sarcoidosis and lymphoma mortality risk: An observational study from the Spanish National Registry.

Introduction: Patients with sarcoidosis have a lower survival rate than the general population, in part due to cardiovascular disease, infections and neoplasms. Our objective was to evaluate the impact of haematological neoplasms (HN) and lymphomas on sarcoidosis patient mortality in a nation-wide analysis conducted in Spain, a country with a population of 47 million. Methods: Retrospective and observational comparison of the HN related deaths in sarcoidosis patients and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of sarcoidosis on the risk of dying from each HN lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed. Results: In the period 2016 and 2019, 139,531 in-hospital deaths from neoplasms were certified in Spain (77 in patients with sarcoidosis). Patients with sarcoidosis died at younger age than the general Spanish population (72.9 vs 77.6, p<0.001). Sarcoidosis patients presented a higher mortality risk from HN (20.8% vs 8.9%, p=0.001, OR=2.64, 95% CI 1.52-4.59), attributable to the higher proportion of deaths from non-Hodgkin lymphoma (NHL), (9.2% vs 2.9%, p=0.006, OR= 3.33, 95% CI 1.53-7.25) from both B cell (6.6% vs 2.5%, p=0.044, OR= 2.62, 95% 1.06-6.5) and T/NK cell lineages (2.6% vs 0.3%, p=0.024, OR= 7.88, 95% CI 1.92-32.29) as well as HN with uncertain behavior and myeloproliferative disorders (2.6% vs 0.3%, p=0.018, OR= 11.88, 95% CI 2.88-49.02). The mean age of sarcoidosis patients who died from HN (63.6 vs 71.9, p=0.032) and non-Hodgkin lymphoma (56.9 vs 71, p=0.009) was lower than that of the general population. Conclusion: Patients with sarcoidosis present a higher risk of premature death from HN, including NHL from B, T/NK cell lineage and myeloproliferative disorders in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early-detection programs for these conditions should be investigated and considered carefully.

IgA Anti-ß2-Glycoprotein I Antibodies as Markers of Thrombosis and Severity in COVID-19 Patients.

Patients with COVID-19 may develop a hypercoagulable state due to tissue and endothelial injury, produced by an unbalanced immune response. Therefore, an increased number of thromboembolic events has been reported in these patients. The aim of this study is to investigate the presence of antiphospholipid antibodies (aPL) in COVID-19 patients, their role in the development of thrombosis and their relationship with the severity of the disease. In this retrospective study, serum samples from 159 COVID-19 patients and 80 healthy donors were analysed for the presence of aPL. A total of 29 patients (18.2%) and 14 healthy donors (17.5%) were positive for aPL. Nineteen COVID-19 patients (12%) but no healthy donor presented a positive percentage of the IgA isotype aPL. IgA anti-ß2-glycoprotein I antibodies (anti-ß2GPI) were the most frequent type (6.3%) in patients but was not detected in any healthy donor. The positivity of this antibody was found to be significantly elevated in patients with thromboembolic events (25% vs. 5%, p = 0.029); in fact, patients with positive IgA anti-ß2GPI had an incidence of thrombosis over six times higher than those who had normal antibody concentrations [OR (CI 95%) of 6.67 (1.5-30.2), p = 0.014]. Additionally, patients with moderate-severe disease presented a higher aPL positivity than patients with mild disease according to the Brescia (p = 0.029) and CURB-65 (p = 0.011) severity scales. A multivariate analysis showed that positivity for IgA anti-ß2GPI is significantly associated with disease severity measured by CURB-65 [OR (CI 95%) 17.8 (1.7-187), p = 0.0016]. In conclusion, COVID-19 patients have a significantly higher positive percentage of the IgA isotype aPL than healthy donors. IgA anti-ß2GPI antibodies were the most frequently detected aPL in COVID-19 patients and were associated with thrombosis and severe COVID-19 and are thus proposed as a possible marker to identify high-risk patients.

Higher mortality risk from gynaecological neoplasms and non-Hodgkin's lymphoma in patients with systemic lupus erythematosus: an observational study from the Spanish National Registry.

OBJECTIVE: To evaluate the impact of the different types of neoplasms and lineages on mortality of patients with SLE. METHODS: Retrospective and observational comparison of the neoplasm-related deaths in patients with SLE and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of SLE on the risk of dying from each neoplasm lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed. RESULTS: During 2016-2019, 139 531 in-hospital deaths from neoplasms were certified in Spain (91 in patients with SLE). Patients with SLE presented a lower mortality rate from solid organ neoplasms, (80.2% vs 91.1%, OR 0.393), linked to their lower risk of colorectal carcinoma (1.1% vs 10.8%, OR 0.110). By contrast, gynaecological neoplasms presented a higher risk (8.8% vs 3%, OR 3.039) in the deceased patients with SLE, associated with the higher frequency of vulvar neoplasms (2% vs 0.2%, OR 14.767) and cervical carcinomas (3.3% vs 0.5%, OR 3.809). Haematological neoplasm-related deaths were also more prevalent in patients with SLE (19.8% vs 8.9%, OR 2.546), mostly attributable to the higher proportion of deaths due to non-Hodgkin's lymphoma (11% vs 2.9%, OR 4.060) of B cell lineage (9.9% vs 2.5%, OR 4.133). CONCLUSIONS: Patients with SLE present a higher risk of death from vulvar neoplasms, cervical carcinomas and B-cell non-Hodgkin's lymphoma in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early detection programmes for these conditions should be investigated and considered carefully.

Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Prevalence and impact of cerebrovascular risk factors in patients with giant cell arteritis: An observational study from the Spanish national registry.

OBJECTIVE: To assess the prevalence and impact of cerebrovascular risk factors (CRF) on cerebrovascular events (CVE) in patients with giant cell arteritis (GCA). METHODS: Analysis of the patients diagnosed with GCA identified in the Spanish Hospital Discharge Database between 2016 and 2018. RESULTS: 8,474 hospital admissions from patients diagnosed with GCA were identified. 3.4% of the admissions were motivated by CVE (stroke in 2.8% and transient ischemic attack in 0.6%). When compared with the admissions due to other causes, the patients who suffered from CVE presented a higher rate of male sex (36.2% vs 43.5%, p=0.007), hypertension (66.9% vs 74.4%, p=0.004), diabetes (27.6% vs 33.7%, p=0.016) and atherosclerosis (6.6% vs 10.2%, p=0.0.017). After adjustment, male sex (OR=1.35, 95% CI 1.06-1.72) and mainly hypertension (OR=1.44, 95% CI 1.11-1.90) were associated with a higher risk of CVE. CONCLUSION: Hypertension, along with male sex, was the strongest risk factor for cerebrovascular events in GCA patients. In these high-risk patients, antiplatelet therapy should be re-considered and evaluated in prospective studies.

Neutrophil ß1 adrenoceptor blockade blunts stroke-associated neuroinflammation.

BACKGROUND AND PURPOSE: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil ß1 adrenoceptors (ß1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that ß1AR blockade will improve stroke outcomes. EXPERIMENTAL APPROACH: Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective ß1AR blocker metoprolol (12.5 mg·kg-1 ) when injected i.v. 10 min before reperfusion. KEY RESULTS: Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1+ ). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via ß1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, ß1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates. CONCLUSIONS AND IMPLICATIONS: Our findings describe that ß1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored.

Usefulness of the hemogram as a measure of clinical and serological activity in systemic lupus erythematosus.

Background and objectives: Systemic Lupus Erythematosus (SLE) follow-up is based on clinical, and analytical parameters. We aimed to determine the differences between the Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR) and Red blood cell distribution width (RDW) between SLE patients and healthy controls and to assess their association with anemia status, classical inflammatory biomarkers and cytokines, disease activity, SLE related factors and treatment received for SLE. Methods: Seventy-seven patients with SLE according to 2012 SLICC criteria and 80 healthy controls were included. Patients with SLE were classified in SLE with anemia (SLE-a) and SLE without anemia (SLE-na). Statistical analysis between SLE patients and controls and the association of serological and clinical activity markers with proposed hematological indices among SLE patients were performed. Results: RDW, NLR and PLR, were significantly higher in SLE patients than in healthy control group (p < 0.001), in SLE-a patients as compared to SLE-na (p < 0.0001) and were significantly associated with hypocomplementemia (p < 0.05). PLR was higher in active patients measured by SLEDAI-2K score and with longer disease duration (p < 0.05). RDW was associated with serological activity of the patients (p < 0.05) and was correlated with SLEDAI-2K and SLICC/ACR scores, hsCRP, D-dimer, fibrinogen, IL-6 and TNF as well as with corticosteroids intake (p = 0.05). A logistic regression analysis confirmed that after adjustment by age and hemoglobin values, RDW presented linear correlation with IL-6 levels (Beta-coefficient = 0.369, p = 0.003). Conclusion: NLR, PLR and RDW values suggest SLE serological and clinical activity. Given their availability, these markers not only could be useful tools to identify and monitor active SLE patients but whose application should be considered in inflammatory pathologies orchestrated by IL-6 and TNF.

Red blood cell distribution width as a marker of hyperinflammation and mortality in COVID-19.

BACKGROUND: Red blood cell distribution width (RDW) could reflect interleukin-6 (IL-6) systemic activity since anisocytosis represents the inhibition of erythropoiesis, leaded by the hyperinflammatory background. Our objective was to analyze RDW performance to predict outcome in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). METHODS: Retrospective observational study including 173 patients with COVID-19-associated ARDS. Data was analyzed at hospital admission, inclusion in the TOCICOV Study (day 0), days 1, 3, 7 and 15 post-inclusion. RESULTS: Overall, 57% patients received tocilizumab. Overall mortality was 20.8%. RDW was higher in non-survivors compared to survivors at admission (13.53% vs. 14.35, P=0.0016), day 0 (13.60% vs. 14.42, P=0.026), day 3 (13.43% vs. 14.36, P<0.001) and day 7 (13.41% vs. 14.31, P=0.046), presenting better discrimination ability for mortality than other prognostic markers [area under the curve-receiver operating characteristic (AUC-ROC) =0.668 for admission RDW, 0.680 for day 0 RDW, 0.695 for day 3 RDW and 0.666 for day 7 RDW]. RDW values did not vary significantly according to tocilizumab treatment. When adjusted by hemoglobin and tocilizumab treatment, only RDW at admission, day 0, day 3 and C reactive protein (CRP) at day 0 and day 1 were associated with mortality (P<0.05). Only in non-tocilizumab treated patients, IL-6 levels at day 0 were correlated with day 3 RDW (r=0.733, P=0.004) and with day 3 CRP (r=0.727, P=0.022). Both parameters showed significant statistical correlation (r=0.255 for day 1 RDW and CRP in the overall cohort and r=0.358 for day 3 RDW and CRP in patients not treated with tocilizumab, P<0.015). CONCLUSIONS: RDW predicts COVID-19-associated ARDS mortality and reflects the hyperinflammatory background and the effects of cytokines such as IL-6, irrespective of tocilizumab treatment.

Serum cytokines to predict systemic lupus erythematosus clinical and serological activity.

We aimed to explore the role of interleukin (IL)-6, interferon-gamma (IFNγ), IL-10, and tumor necrosis factor (TNF) as predictors of systemic lupus erythematosus (SLE) clinical and serological activity, and their correlation with the treatment received. We performed a retrospective analysis of 77 patients with SLE according to the 2012 Systemic Lupus International Collaborative Clinics (SLICC) criteria. The outcomes were serological activity (SA), active disease (AD), complete remission (CR), the low-disease activity state (LDAS), and immunosuppressive treatment. SA was present in 17.1%, AD in 17.3%, CR in 13%, and LDAS in 64.9% of patients. IL-6 values were higher in patients in SA, in AD, in those receiving steroids alone, and in patients without CR or LDAS (p < 0.05). IFNγ was associated with anti-double stranded DNA (dsDNA) antibodies positivity and immunosuppression, whereas IL-10 values were higher in patients with CR (p < 0.05). The IL6-IFN product was able to predict anti-double stranded DNA (anti-dsDNA) antibodies positivity (area under the receiver operating characteristic curve [AUC-ROC] = 0.705, 95% confidence interval [CI] 0.563-0.847), SA (AUC-ROC = 0.720, 95% CI 0.542-0.899), AD (AUC-ROC = 0.701, 95% CI 0.520-0.882), steroid treatment (AUC-ROC = 0.751, 95% CI 0.622-0.879), and the absence of LDAS (AUC-ROC = 0.700, 95% CI 0.558-0.834). The IL6-IFN/IL10 ratio predicted AD (AUC-ROC = 0.742, 955 CI 0.540-0.944), steroid treatment (AUC-ROC = 0.721, 95% CI 0.572-0.870), and the absence of LDAS (AUC-ROC = 0.694, 95% CI 0.536-0.853). In conclusion, IL-6, IL-10, and IFNγ might help to assess SLE serological and clinical activity. Their combination in the IL-6-IFN product and the IL-6xIFN to IL-10 ratio results in novel tools to determine and predict SA, AD, and LDAS. Prompt detection of SLE activity might allow a rapid intervention to avoid established or chronic damage.

Impact of severe infections in SLE: an observational study from the Spanish national registry.

OBJECTIVE: Infections are a common complication of SLE. Our objective was to evaluate their causes and impact on the survival of patients with SLE. METHODS: Analysis of the admissions and death causes in patients diagnosed with SLE from the Spanish Hospital Discharge Database and the infection-related deaths of the Spanish population from the National Statistical Institute, between 2016 and 2018.Only infections recorded as the main diagnosis were analysed (severe or clinically relevant infection). RESULTS: Among 18 430 admissions in patients with SLE, disease activity was the cause of admission in 19% of all patients and infection in 15%. However, infection was the main cause of death (25%) while SLE activity was responsible for only 6% of deaths (p<0.001). Severe infection exceeded SLE as a cause of death for patients dying at ages between 40-59 (23% vs 4%, p<0.001), 60-79 (26% vs 6%, p<0.001) and older than 80 years (25% vs 6%, p<0.001). Infection was the cause of death in 8% of the Spanish population, a significantly lower rate when compared with patients with SLE (p<0.001). Compared with the general population, infections were the highest relative cause of death in patients with SLE, particularly at younger ages: 40% vs 3% for those below 20 years old (p<0.01), 33% vs 4% between 20 and 39 (p<0.001), 23% vs 5% between 40 and 59 (p<0.001), 26% vs 5% between 60 and 79 (p<0.001) and 25% vs 9% for those older than 80 years (p<0.001). CONCLUSION: Our nationwide study confirms that infections are the leading cause of death in SLE in Spain, with the highest proportion occurring in young patients with lupus compared with the general population of the same age range.

Systemic Autoimmune Diseases in Patients Hospitalized with COVID-19 in Spain: A Nation-Wide Registry Study.

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren's Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet's Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78−1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04−1.07), heart failure (OR = 1.67, 95% CI 1.10−2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05−1.59) and liver disease (OR = 1.97, 95% CI 1.13−3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis.

Trends in Hospital Admissions and Death Causes in Patients with Systemic Lupus Erythematosus: Spanish National Registry.

BACKGROUND: the admission and death causes of SLE patients might have changed over the last years. METHODS: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997-2000, 2001-2005, 2006-2010, and 2011-2015). RESULTS: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997-2000 to 31,977 in 2011-2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). CONCLUSIONS: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study.

INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study.

INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Calcium and vitamin D supplement intake may increase arterial stiffness in systemic lupus erythematosus patients.

OBJECTIVES: Low serum levels of 25-hydroxyvitamin D (25(OH)D) have been associated with a higher frequency of risk factors and cardiovascular disease. The aim of this study is to evaluate the association of 25(OH)D, cardiovascular risk factors, and subclinical atherosclerosis in systemic lupus erythematosus (SLE) patients. METHOD: Forty-seven female SLE patients were studied. Data collected included demographics, SLE activity, disease damage, cardiovascular risk factors, and markers of subclinical atherosclerosis. Patient treatments and vitamin D and calcium supplementation (VitD-Ca) were recorded. Vitamin D deficiency was defined as serum 25(OH)D < 50 nmol/l measured by ultra-high-performance liquid chromatography. Atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry and intima-media thickness (IMT) by B-mode ultrasound scanning. RESULTS: 61.7% of patients were vitamin D deficient with a mean level of 31.91 ± 10.21 nmol/l. Serum vitamin D concentration was significantly higher in the 23 patients taking VitD-Ca supplements than that in patients not supplemented (p = 0.004). No significant association was found between 25(OH)D serum levels and cardiovascular risk factors, disease activity, or different treatments for SLE. A significant positive correlation was found between 25(OH)D levels, PWV (p = 0.02), and IMT (p = 0.01); moreover, patients taking VitD-Ca supplements presented an increased arterial stiffness. CONCLUSION: Patients with arterial stiffness showed higher levels of serum vitamin D and most of them were on VitD-Ca supplements. Although prospective studies with a larger number of patients and follow-up are needed, our findings suggest that VitD-Ca supplementation may have effects on SLE patients' arterial stiffness.