Anti-dsDNA B-Cell ELISpot as a Monitoring and Flare Prediction Tool in SLE Patients.

Anti-dsDNA autoantibodies quantification and complement levels are widely used to monitor disease activity in systemic lupus erythematosus (SLE). However, better biomarkers are still needed. We hypothesised whether the dsDNA antibody-secreting B-cells could be a complementary biomarker in disease activity and prognosis of SLE patients. Fifty-two SLE patients were enrolled and followed for up to 12 months. Additionally, 39 controls were included. An activity cut-off (comparing active and non-active patients according to clinical SLEDAI-2K) was established for SLE-ELISpot, chemiluminescence and Crithidia luciliae indirect immunofluorescence tests (≥11.24, ≥374.1 and ≥1, respectively). Assays performances together with complement status were compared regarding major organ involvement at the inclusion and flare-up risk prediction after follow-up. SLE-ELISpot showed the best performance in identifying active patients. High SLE-ELISpot results were associated with haematological involvement and, after follow-up, with an increased hazard ratio for disease flare-up (3.4) and especially renal flare (6.5). Additionally, the combination of hypocomplementemia and high SLE-ELISpot results increased those risks up to 5.2 and 32.9, respectively. SLE-ELISpot offers complementary information to anti-dsDNA autoantibodies to evaluate the risk of a flare-up in the following year. In some cases, adding SLE-ELISpot to the current follow-up protocol for SLE patients can improve clinicians' personalised care decisions.

COVID-19 and the antiphospholipid syndrome.

Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic. Most COVID-19 patients are asymptomatic or have flu-like symptoms. However, around 15% of the patients may have severe disease, including unilateral or bilateral pneumonia with acute respiratory distress syndrome and progressive hypoxemia that may require mechanical ventilation assistance. A systemic inflammatory response syndrome occurs in the most severe forms of COVID-19, with multiorgan involvement which can be life threatening caused by a cytokine storm. Although what best characterizes COVID-19 are the manifestations of the respiratory system, it has been shown that it also acts at the cardiovascular level, producing coagulation abnormalities, which causes thrombotic events mainly in the arteries/arterioles, microcirculation and venous system, and potentially increased mortality risk. This multiorgan vascular disease overlaps with other known microangiopathies, such as thrombotic microangiopathy or paroxysmal nocturnal hemoglobinuria, where complement overactivation plays an important role in the pathophysiology of thrombosis. Furthermore, coagulopathy secondary to COVID-19 occurs in the context of an uncontrolled inflammatory response, reminiscent of APS, especially in its catastrophic form. This review summarizes the current knowledge regarding the relationship between COVID-19 and the APS.

Persistent Antiphospholipid Antibodies Are Not Associated With Worse Clinical Outcomes in a Prospective Cohort of Hospitalised Patients With SARS-CoV-2 Infection.

Objective: Patients with COVID-19 presented with an elevated prevalence of antiphospholipid antibodies (aPL) but the relationship with thrombosis is controversial. We analysed the persistence of aPL and their association with the clinical outcomes during hospitalisation in a cohort of COVID-19 patients. Patients and Methods: We conducted a prospective study including consecutive hospitalised patients with COVID-19 from Hospital Clínic of Barcelona between March 28th and April 22nd, 2020. Clinical outcomes during hospitalisation were thrombosis, intensive care unit (ICU) admission, and severe ventilatory failure. We determined both criteria and non-criteria aPL. Of note, in those patients with a positive result in the first determination, a second sample separated by at least 12 weeks was drawn to test the persistence of aPL. Results: One hundred and fifty-eight patients (59.5% men) with a mean age of 61.4 ± 14.9 years old were included. Thrombosis was present in 28 (17.7%) patients, severe respiratory failure in 47 (30.5%), and 30 (18.9%) patients were admitted to ICU. Sixteen (28.6%) patients were positive for the criteria aPL at both determinations and only two (3.6%) of them suffered from thrombosis during hospitalisations (both had aCL IgG). However, they presented with low titers of aCL. Of note, aPL were not related to thrombosis, ICU admission or severe respiratory failure. Conclusion: Although aPL were prevalent in our cohort of hospitalised COVID-19 patients and they were persistent in half of tested patients, most determinations were at low titers and they were not related to worse clinical outcomes.

Antigens and Antibodies of the Antiphospholipid Syndrome as New Allies in the Pathogenesis of COVID-19 Coagulopathy.

High prevalence of both criteria and extra-criteria antiphospholipid antibodies (aPL) has been reported in COVID-19 patients. However, the differences in aPL prevalence decreased when an age-matched control group was included. The association of aPL with thrombotic events in COVID-19 is very heterogeneous. This could be influenced by the fact that most of the studies carried out were conducted on small populations enriched with elderly patients in which aPL was measured only at a single point and they were performed with non-standardized assays. The few studies that confirmed aPL in a second measurement showed that aPL levels hardly changed, with the exception of the lupus anticoagulant that commonly reduced. COVID-19 coagulopathy is an aPL-independent phenomenon closely associated with the onset of the disease. Thrombosis occurs later in patients with aPL presence, which is likely an additional prothrombotic factor. B2-glycoprotein deficiency (mainly aPL antigen caused both by low production and consumption) is very common during the SARS-CoV2 infection and has been associated with a greater predisposition to COVID-19 complications. This could be a new prothrombotic mechanism that may be caused by the blockage of its physiological functions, the anticoagulant state being the most important.

Elevated plasma levels of epithelial and endothelial cell markers in COVID-19 survivors with reduced lung diffusing capacity six months after hospital discharge.

BACKGROUND: Some COVID-19 survivors present lung function abnormalities during follow-up, particularly reduced carbon monoxide lung diffusing capacity (DLCO). To investigate risk factors and underlying pathophysiology, we compared the clinical characteristics and levels of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or reduced DLCO 6 months after discharge. METHODS: Prospective, observational study. Clinical characteristics during hospitalization, and spirometry, DLCO and plasma levels of epithelial (surfactant protein (SP) A (SP-A), SP-D, Club cell secretory protein-16 (CC16) and secretory leukocyte protease inhibitor (SLPI)), and endothelial (soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and Angiopoietin-2) 6 months after hospital discharge were determined in 215 COVID-19 survivors. RESULTS: DLCO was < 80% ref. in 125 (58%) of patients, who were older, more frequently smokers, had hypertension, suffered more severe COVID-19 during hospitalization and refer persistent dyspnoea 6 months after discharge. Multivariate regression analysis showed that age ≥ 60 years and severity score of the acute episode ≥ 6 were independent risk factors of reduced DLCO 6 months after discharge. Levels of epithelial (SP-A, SP-D and SLPI) and endothelial (sICAM-1 and angiopoietin-2) markers were higher in patients with reduced DLCO, particularly in those with DLCO ≤ 50% ref. Circulating SP-A levels were associated with the occurrence of acute respiratory distress syndrome (ARDS), organizing pneumonia and pulmonary embolisms during hospitalization. CONCLUSIONS: Reduced DLCO is common in COVID-19 survivors 6 months after hospital discharge, especially in those older than 60 years with very severe acute disease. In these individuals, elevated levels of epithelial and endothelial markers suggest persistent lung damage.

Covid-19 coagulopathy and antiphospholipid syndrome

The presence of thrombotic events in COVID 19 patients has been described since the beginning of the pandemic, this association has been confirmed in most of the reported studies. Autopsy reports have shown that most thromboses are located in the lung, although they are also have been observed in other organs such as skin and kidneys. The SARS-CoV2 infection induces a generalized prothrombotic state, which is attributed to a combination of factors such as hypoxia, excess cellular apoptosis, and mainly by an overactivation of the immune system. Among immune-mediated prothrombotic situations, antiphospholipid syndrome (APS) stands out. Repeat thrombotic events are observed in APS in the presence of antiphospholipid antibodies (aPL). There are numerous studies that report high prevalence of aPL in patients with COVID-19 infection. However, the results showed discrepancies in the data on the prevalence of aPL, and its role in the pathogenesis of thrombosis in these patients. This could be due to the heterogeneity of the detection procedures for aPL or to transient elevations of non-pathogenic aPL levels in the context of infection. In this review we try to clarify the role of aPL in COVID-19 infection, trying to answer the question of whether it is a proper coagulopathy, or secondary to APS. Resumen La presencia de eventos trombóticos en los pacientes con covid-19 se describió desde el inicio de la pandemia, asociación que ha sido confirmada en la mayoría de los estudios reportados. Los informes de necropsias han puesto en evidencia que la mayoría de las trombosis se localiza en el pulmón, aunque también se han observado en otros órganos, como la piel y los riñones. La infección por SARS-CoV-2 induce un estado protrombótico generalizado que se atribuye a una conjunción de factores como la hipoxia, el exceso de apoptosis celular y, sobre todo, una hiperactivación del sistema inmune. Entre las situaciones protrombóticas inmunomediadas destaca el síndrome antifosfolipídico (SAF), en el cual se observan eventos trombóticos de repetición en presencia de anticuerpos antifosfolipídicos (AAF). Existen numerosos estudios que reportan una elevada prevalencia de AAF en los pacientes con infección por covid-19;sin embargo, los resultados muestran discordancias en los datos de prevalencia de AAF y su rol en la patogenia sobre la trombosis en estos pacientes, lo que que podría deberse a la heterogeneidad de los procedimientos de detección de los AAF o a elevaciones transitorias de los niveles de AAF no patogénicos en el contexto de la infección. En esta revisión se busca aclarar el papel de los AAF en la infección por covid-19, intentando responder a la pregunta de si se trata de una coagulopatía propia, o es secundaria a un SAF.

Beta-2-Glycoprotein-I Deficiency Could Precipitate an Antiphospholipid Syndrome-like Prothrombotic Situation in Patients With Coronavirus Disease 2019.

OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19) present coagulation abnormalities and thromboembolic events that resemble antiphospholipid syndrome (APS). This work has aimed to study the prevalence of APS-related antigens, antibodies, and immune complexes in patients with COVID-19 and their association with clinical events. METHODS: A prospective study was conducted on 474 adults with severe acute respiratory syndrome coronavirus 2 infection hospitalized in two Spanish university hospitals. Patients were evaluated for classic and extra-criteria antiphospholipid antibodies (aPLs), immunoglobulin G (IgG)/immunoglobulin M (IgM) anticardiolipin, IgG/IgM/immunoglobulin A (IgA) anti-ß2-glicoprotein-I (aß2GPI), IgG/IgM antiphosphatidylserine/prothrombin (aPS/PT), the immune complex of IgA aß2GPI (IgA-aß2GPI), bounded to ß2-glicoprotein-1 (ß2GPI) and ß2GPI levels soon after COVID-19 diagnosis and were followed-up until medical discharge or death. RESULTS: Prevalence of aPLs in patients with COVID-19 was as follows: classic aPLs, 5.8%; aPS/PT, 4.6%; IgA-aß2GPI, 15%; and any aPL, 21%. When patients were compared with individuals of a control group of a similar age, the only significant difference found was the higher prevalence of IgA-aß2GPI (odds ratio: 2.31; 95% confidence interval: 1.16-4.09). No significant differences were observed in survival, thrombosis, or ventilatory failure in aPL-positive versus aPL-negative patients. ß2GPI median levels were much lower in patients with COVID-19 (15.9 mg/l) than in blood donors (168.8 mg/l; P < 0.001). Only 3.5% of patients with COVID-19 had normal levels of ß2GPI (>85 mg/l). Low levels of ß2GPI were significantly associated with ventilatory failure (P = 0.026). CONCLUSION: ß2GPI levels were much lower in patients with COVID-19 than in healthy people. Low ß2GPI-levels were associated with ventilatory failure. No differences were observed in the COVID-19 evolution between aPL-positive and aPL-negative patients. Functional ß2GPI deficiency could trigger a clinical process similar to that seen in APS but in the absence of aPLs.

The impact of SARS-CoV-2 coronavirus infection in patients with systemic lupus erythematosus from a single center in Catalonia.

OBJECTIVE: To evaluate the incidence and characteristics of SARS-CoV-2 infection among patients with systemic lupus erythematosus (SLE) and to compare it to that described in the general population. METHODS: For 5 weeks, we carried out a cross-sectional study consisting of telephone interviews of SLE patients. We collected epidemiological data, symptoms suggesting COVID-19, results of nasopharyngeal swabs, and ongoing treatments. In those patients who required hospital admission, clinical, radiological, and laboratory features, and outcome were investigated. RESULTS: Four hundred patients with SLE completed the survey. Overall, 4 (1.00%, 95%CI 0.02-1.98) patients were classified as confirmed cases of COVID-19 and 26 (6.51%, 95%CI 4.08-8.94) as possible clinical cases. The incidence of confirmed cases in our series was similar to that of the Catalan population (1.00% versus 0.63%; p = 0.456), whereas the incidence of possible cases was higher in our series (6.51% versus 1.29%; p < 0.005). The only difference between SLE patients with confirmed and possible COVID-19 and those without was the percentage of patients who have had contact with a confirmed or possible case of COVID-19 (26.7% versus 9.2%; p = 0.003) CONCLUSIONS: The incidence of COVID-19 in SLE patients with inactive disease is low and, in our series, all cases with confirmed infection recovered. Key Points • In a cohort of SLE patients with stable and clinical inactive disease, the incidence of COVID-19 is low. • All SLE patients with confirmed SARS-CoV-2 infection recovered.

The Rheumatology Drugs for COVID-19 Management: Which and When?

INTRODUCTION: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. 'Repurposing' immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

Using machine learning to estimate the effect of racial segregation on COVID-19 mortality in the United States.

This study examines the role that racial residential segregation has played in shaping the spread of COVID-19 in the United States as of September 30, 2020. The analysis focuses on the effects of racial residential segregation on mortality and infection rates for the overall population and on racial and ethnic mortality gaps. To account for potential confounding, I assemble a dataset that includes 50 county-level factors that are potentially related to residential segregation and COVID-19 infection and mortality rates. These factors are grouped into eight categories: demographics, density and potential for public interaction, social capital, health risk factors, capacity of the health care system, air pollution, employment in essential businesses, and political views. I use double-lasso regression, a machine learning method for model selection and inference, to select the most important controls in a statistically principled manner. Counties that are 1 SD above the racial segregation mean have experienced mortality and infection rates that are 8% and 5% higher than the mean. These differences represent an average of four additional deaths and 105 additional infections for each 100,000 residents in the county. The analysis of mortality gaps shows that, in counties that are 1 SD above the Black-White segregation mean, the Black mortality rate is 8% higher than the White mortality rate. Sensitivity analyses show that an unmeasured confounder that would overturn these findings is outside the range of plausible covariates.

A multidisciplinary registry of patients with autoimmune and immune-mediated diseases with symptomatic COVID-19 from a single center.

BACKGROUND AND AIM: There is increasing interest regarding SARS-CoV-2 infection in patients with autoimmune and immune-mediated inflammatory diseases (AI/IMID) with some discrepancies in different cohorts about their risk and outcomes. The aim was to describe a multidisciplinary cohort of patients with AI/IMID and symptomatic SARS-CoV-2 infection in a single tertiary center and analyze sociodemographic, clinical, and therapeutic factors associated with poor outcomes. METHODS: A retrospective observational study was conducted from the 1st of March until May 29th, 2020 in a University tertiary hospital in Barcelona, Spain. Patients with an underlying AI/IMID and symptomatic SARS-CoV-2 infection were identified in our local SARS-CoV-2 infection database. Controls (2:1) were selected from the same database and matched by age and gender. The primary outcome was severe SARS-CoV-2 infection, which was a composite endpoint including admission to the intensive care unit (ICU), need for mechanical ventilation (MV), and/or death. Several covariates including age, sex, and comorbidities among others were combined into a multivariate model having severe SARS-CoV-2 as the dependent variable. Also, a sensitivity analysis was performed evaluating AID and IMID separately. RESULTS: The prevalence of symptomatic SARS-CoV-2 infection in a cohort of AI/IMID patients was 1.3%. Eighty-five patients with AI/IMID and symptomatic SARS-CoV-2 were identified, requiring hospitalization in 58 (68%) cases. A total of 175 patients admitted for SARS-CoV-2 (58 with AI/IMID and 117 matched-controls) were analyzed. In logistic regression analysis, a significant inverse association between AI/IMID group and severe SARS-CoV-2 (OR 0.28; 95% CI 0.12-0.61; p = 0.001), need of MV (OR 0.20; IC 95% 0.05-0.71; p = 0.014), and ICU admission (OR 0.25; IC 95% 0.10-0.62; p = 0.003) was found. CONCLUSIONS: Patients with AI/IMID who require admission for SARS-CoV-2 infection have a lower risk of developing severe disease, including the need to stay in the ICU and MV.