Urine levels of HMGB1 in Systemic Lupus Erythematosus patients with and without renal manifestations

INTRODUCTION: Lupus nephritis (LN) is a severe and frequent manifestation of systemic lupus erythematosus (SLE). Its pathogenesis has not been fully elucidated but immune complexes are considered to contribute to the inflammatory pathology in LN. High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different types of cells during activation and/or cell death and may act as a pro-inflammatory mediator, alone or as part of DNA-containing immune complexes in SLE. Urinary excretion of HMGB1 might reflect renal inflammatory injury. To assess whether urinary HMGB1 reflects renal inflammation we determined serum levels of HMGB1 simultaneously with its urinary levels in SLE patients with and without LN in comparison to healthy controls (HC). We also analyzed urinary HMGB1 levels in relation with clinical and serological disease activity. METHODS: The study population consisted of 69 SLE patients and 17 HC. Twenty-one patients had biopsy proven active LN, 15 patients had a history of LN without current activity, and 33 patients had non-renal SLE. Serum and urine levels of HMGB1 were both measured by western blotting. Clinical and serological parameters were assessed according to routine procedures. In 17 patients with active LN a parallel analysis was performed on the expression of HMGB1 in renal biopsies. RESULTS: Serum and urinary levels of HMGB1 were significantly increased in patients with active LN compared to patients without active LN and HC. Similarly, renal tissue of active LN patients showed strong expression of HMGB1 at cytoplasmic and extracellular sites suggesting active release of HMGB1. Serum and urinary levels in patients without active LN were also significantly higher compared to HC. Urinary HMGB1 levels correlated with SLEDAI, and showed a negative correlation with complement C3 and C4. CONCLUSION: Levels of HMGB1 in urine of SLE patients, in particular in those with active LN, are increased and correlate with SLEDAI scores. Renal tissue of LN patients shows increased release of nuclear HMGB1 compared to control renal tissue. HMGB1, although at lower levels, is, however, also present in the urine of patients without active LN. These data suggest that urinary HMGB1 might reflect both local renal inflammation as well as systemic inflammation

Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by a disturbed T-cell balance skewed towards effector T-cells, in particular Th17-cells. The novel cytokine interleukin-21 (IL-21) is suggested to be crucial for triggering T-cell responses towards IL-17 producing cells. Thus, we aimed to investigate the ability of T-cells to produce IL-21 and IL-17 in SLE patients. METHODS: Peripheral blood of 34 SLE patients and 18 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) and calcium ionophore (Ca-Io). Percentages of IL-21- and IL-17A expressing T-cells were analysed by flow cytometry. The expression levels of the transcription factors B-cell lymphoma-6 (BCL-6) and factors retinoid-related orphan receptor (ROR-γt) were assessed in T-cells by real-time RT-PCR and flow cytometry. Additionally, IL-21 receptor (IL-21R) expression on B- and T-cells of patients and HC was analyzed. RESULTS: Significantly increased percentages of IL-21 expressing CD4(+ )T-cells and CD8(+ )T-cells were found in SLE patients as compared to HC. The percentages of IL-21(+ )CD4(+ )T-cells and CD8(+ )T-cells correlated significantly with the percentages of IL-17A(+ )CD4(+ )T-cells and CD8(+ )T-cells, respectively. The relative expression of BCL-6 and ROR-γt did not differ between SLE patients and HC. IL-21R expression occurred mainly on B-cells and was not different comparing SLE patients and HC. CONCLUSIONS: This study demonstrates an increased proportion of IL-21(+ )T-cells in SLE patients correlating with the proportion of IL-17(+ )T-cells. This suggests a pivotal role of IL-21 in the pathogenesis of SLE

COVID-19 in cancer patients: clinical characteristics and outcome—an analysis of the LEOSS registry

Introduction Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. Patients and methods We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. Results In total, 435 cancer patients were included in our analysis. Commonest age category was 76–85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. Conclusion Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions

Covid-19 triage in the emergency department 2.0: how analytics and AI transform a human-made algorithm for the prediction of clinical pathways

The Covid-19 pandemic has pushed many hospitals to their capacity limits. Therefore, a triage of patients has been discussed controversially primarily through an ethical perspective. The term triage contains many aspects such as urgency of treatment, severity of the disease and pre-existing conditions, access to critical care, or the classification of patients regarding subsequent clinical pathways starting from the emergency department. The determination of the pathways is important not only for patient care, but also for capacity planning in hospitals. We examine the performance of a human-made triage algorithm for clinical pathways which is considered a guideline for emergency departments in Germany based on a large multicenter dataset with over 4,000 European Covid-19 patients from the LEOSS registry. We find an accuracy of 28 percent and approximately 15 percent sensitivity for the ward class. The results serve as a benchmark for our extensions including an additional category of palliative care as a new label, analytics, AI, XAI, and interactive techniques. We find significant potential of analytics and AI in Covid-19 triage regarding accuracy, sensitivity, and other performance metrics whilst our interactive human-AI algorithm shows superior performance with approximately 73 percent accuracy and up to 76 percent sensitivity. The results are independent of the data preparation process regarding the imputation of missing values or grouping of comorbidities. In addition, we find that the consideration of an additional label palliative care does not improve the results

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Urinary T cells in active lupus nephritis show an effector memory phenotype

Background Systemic lupus erythematosus (SLE) is accompanied by alterations in T cell homeostasis including an increased effector response. Migrated effector memory T cells (CD45RO(+) CCR7(-); T-EM) appear to be involved in tissue injury. The objective of this study was to investigate the distribution and phenotype of effector memory T cells in the peripheral blood (PB), and their presence in renal biopsies and urine of patients with SLE. The hypothesis that these T EM cells migrate to the kidney during active disease was tested. Methods A total of 43 patients with SLE and 20 healthy controls were enrolled. CD4(+)T(EM) cells and CD8(+)T(EM) cells were analysed in PB and urine using flow cytometric analysis. In 10 patients with active lupus nephritis a parallel analysis was performed on the presence of T EM cells in kidney biopsies. Results The percentage of circulating CD8(+)T(EM) cells in patients with SLE was significantly decreased versus healthy controls (33.9 +/- 18.3% vs 42.9 +/- 11.0%, p=0.008). In patients with active renal involvement (n=12) this percentage was further decreased to 30.4 +/- 15.9%, p=0.01. Analysis of the urinary sediment in active renal disease showed increased numbers of CD4(+)T cells (134 +/- 71 cells/ml) and CD8(+)T cells (287 +/- 220 cells/ml), respectively, while in healthy controls and patients without active renal disease almost no T cells were present. In all, 73.6 +/- 8.3% of urinary CD4(+)T cells and 69.3 +/- 26.0% of urinary CD8(+)T cells expressed the T EM phenotype. CD8(+) cells were also found in renal biopsies. Conclusions The data presented are compatible with the hypothesis that CD8(+) effector memory cells migrate from the PB to the kidney and appear in the urine during active renal disease in patients with SLE. These cells could serve as an additional marker of renal activity in patients with SLE

Disturbed Th1, Th2, Th17 and T-reg balance in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by disturbed T-cell homeostasis. Dysbalance of T-helper-cell (Th) subsets (Th1/Th2/Th17) and regulatory T-cells (T-regs) is suggested to contribute to the pathogenesis of SLE. Recent reports suggest functional deviation of T-regs in terms of producing IL-17A, a process that may be aberrant in SLE. Therefore, we analyzed these T-cell subsets in SLE to test the hypothesis that aberrant T-cell subset skewing is present in SLE-patients. We investigated simultaneously the intracellular cytokines IFN-gamma, IL-4 and IL-17A in CD4(+)T-cells as well as in T-regs. Skewing of T-cell subsets towards Th17 cells was observed in SLE-patients. Although the proportion of T-regs was similar between SLE-patients and healthy controls, the ability of T-regs to express IFN-gamma and IL17A was impaired in SLE-patients. Even in quiescent SLE-patients T-cell homeostasis is aberrant in terms of skewing towards IL-17 producing T-cells. (C) 2011 Elsevier Inc. All rights reserved.</p

Disturbed Th1, Th2, Th17 and T-reg balance in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by disturbed T-cell homeostasis. Dysbalance of T-helper-cell (Th) subsets (Th1/Th2/Th17) and regulatory T-cells (T-regs) is suggested to contribute to the pathogenesis of SLE. Recent reports suggest functional deviation of T-regs in terms of producing IL-17A, a process that may be aberrant in SLE. Therefore, we analyzed these T-cell subsets in SLE to test the hypothesis that aberrant T-cell subset skewing is present in SLE-patients. We investigated simultaneously the intracellular cytokines IFN-gamma, IL-4 and IL-17A in CD4(+)T-cells as well as in T-regs. Skewing of T-cell subsets towards Th17 cells was observed in SLE-patients. Although the proportion of T-regs was similar between SLE-patients and healthy controls, the ability of T-regs to express IFN-gamma and IL17A was impaired in SLE-patients. Even in quiescent SLE-patients T-cell homeostasis is aberrant in terms of skewing towards IL-17 producing T-cells. (C) 2011 Elsevier Inc. All rights reserved