Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development.

ABSTRACT: Antiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) are a major cause for acquired thrombophilia, but specific interventions preventing autoimmune aPL development are an unmet clinical need. Although autoimmune aPL cross react with various coagulation regulatory proteins, lipid-reactive aPL, including those derived from patients with COVID-19, recognize the endolysosomal phospholipid lysobisphosphatidic acid presented by the cell surface-expressed endothelial protein C receptor. This specific recognition leads to complement-mediated activation of tissue factor (TF)-dependent proinflammatory signaling and thrombosis. Here, we show that specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) prevents the prothrombotic effects of aPL derived from patients with COVID-19 in mice and the aPL-induced proinflammatory and prothrombotic activation of monocytes. The induction of experimental APS is dependent on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and NAPc2 suppresses monocyte endosomal reactive oxygen species production requiring the TF cytoplasmic domain and interferon-α secretion from dendritic cells. Latent infection with murine cytomegalovirus causes TF cytoplasmic domain-dependent development of persistent aPL and circulating phospholipid-reactive B1 cells, which is prevented by short-term intervention with NAPc2 during acute viral infection. In addition, treatment of lupus prone MRL-lpr mice with NAPc2, but not with heparin, suppresses dendritic-cell activation in the spleen, aPL production and circulating phospholipid-reactive B1 cells, and attenuates lupus pathology. These data demonstrate a convergent TF-dependent mechanism of aPL development in latent viral infection and autoimmune disease and provide initial evidence that specific targeting of the TF initiation complex has therapeutic benefits beyond currently used clinical anticoagulant strategies.

Lower uromodulin serum levels are associated with poorer prognosis in patients with cirrhosis and hepatorenal syndrome type 2.

Hepatorenal syndrome (HRS) is associated with a dismal prognosis in patients with cirrhosis, and therapeutic options are limited. Biomarkers to identify patients with poor response to therapy are urgently needed. This study aimed to evaluate the predictive value of serum levels of uromodulin (sUMOD) in patients with cirrhosis and HRS treated with terlipressin and albumin (T/A). In total, 156 patients [81 patients with HRS treated with T/A, 42 patients with cirrhosis without kidney injury, and 33 patients with cirrhosis with prerenal acute kidney injury (AKI)] were included. sUMOD levels were analyzed by ELISA. Patients with HRS were prospectively followed for the composite endpoint of hemodialysis-/liver transplantation-free survival (HD/LTx-free survival). Of the 81 patients with HRS, 40 had HRS type 1 and 41 type 2. In the cohort of patients with HRS treated with T/A, median sUMOD level was 100 ng/mL (IQR 64; 144). sUMOD differed significantly between patients with HRS compared with patients without AKI (P = 0.001) but not between patients with HRS and prerenal AKI (P = 0.9). In multivariable analyses, sUMOD levels in the lowest quartile were independently associated with a lower rate of complete response to T/A (OR 0.042, P = 0.008) and a higher risk for reaching the composite endpoint of HD/LTX-free survival (HR 2.706, P = 0.013) in patients with HRS type 2 treated with T/A. In contrast, sUMOD was not significantly associated with these outcomes in patients with HRS type 1. sUMOD may be a valuable biomarker for identifying patients with HRS type 2 treated with T/A to predict response and prognosis.NEW & NOTEWORTHY Biomarkers identifying patients with hepatorenal syndrome (HRS) and poor response to therapy are urgently needed. In this study, lower serum uromodulin (sUMOD) levels were associated with poorer response to therapy with terlipressin and albumin and consequently with poorer prognosis in patients with HRS type 2. In patients with HRS type 1, there was no association between sUMOD and poorer prognosis.

Constitutive knockout of interleukin-6 ameliorates memory deficits and entorhinal astrocytosis in the MRL/lpr mouse model of neuropsychiatric lupus.

BACKGROUND: Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE's pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice. METHODS: We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala. RESULTS: MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value < 0.1). Serum levels of IL-6 correlated with learning and memory performance (R2 = 0.58; p = 0.03), but not motivated behavior, in MRL/lpr mice. Compared to MRL/lpr IL-6 WT, IL-6 KO mice exhibited improved novelty preference on object placement (45.4% vs 60.2%, p < 0.0001) and object recognition (48.9% vs 67.9%, p = 0.002) but equivalent performance in tests for anxiety-like disease and depression-like behavior. IL-6 KO mice displayed decreased cortical expression of aif1 (microglia; p = 0.049) and gfap (astrocytes; p = 0.044). Correspondingly, IL-6 KO mice exhibited decreased density of GFAP + cells compared to IL-6 WT in the entorhinal cortex (89 vs 148 cells/mm2, p = 0.037), an area vital to memory. CONCLUSIONS: The inflammatory composition of MRL/lpr CSF resembles that of human NPSLE patients. Increased in the CNS, IL-6 is necessary to the development of learning and memory deficits in the MRL/lpr model of NPSLE. Furthermore, the stimulation of entorhinal astrocytosis appears to be a key mechanism by which IL-6 promotes these behavioral deficits.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.

OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.

Effects of undergraduate ultrasound education on cross-sectional image understanding and visual-spatial ability - a prospective study.

INTRODUCTION/AIM: Radiological imaging is crucial in modern clinical practice and requires thorough and early training. An understanding of cross-sectional imaging is essential for effective interpretation of such imaging. This study examines the extent to which completing an undergraduate ultrasound course has positive effects on the development of visual-spatial ability, knowledge of anatomical spatial relationships, understanding of radiological cross-sectional images, and theoretical ultrasound competencies. MATERIAL AND METHODS: This prospective observational study was conducted at a medical school with 3rd year medical students as part of a voluntary extracurricular ultrasound course. The participants completed evaluations (7-level Likert response formats and dichotomous questions "yes/no") and theoretical tests at two time points (T1 = pre course; T2 = post course) to measure their subjective and objective cross-sectional imaging skills competencies. A questionnaire on baseline values and previous experience identified potential influencing factors. RESULTS: A total of 141 participants were included in the study. Most participants had no previous general knowledge of ultrasound diagnostics (83%), had not yet performed a practical ultrasound examination (87%), and had not attended any courses on sonography (95%). Significant subjective and objective improvements in competencies were observed after the course, particularly in the subjective sub-area of "knowledge of anatomical spatial relationships" (p = 0.009). Similarly, participants showed improvements in the objective sub-areas of "theoretical ultrasound competencies" (p < 0.001), "radiological cross-section understanding and knowledge of anatomical spatial relationships in the abdomen" (p < 0.001), "visual-spatial ability in radiological cross-section images" (p < 0.001), and "visual-spatial ability" (p = 0.020). CONCLUSION: Ultrasound training courses can enhance the development of visual-spatial ability, knowledge of anatomical spatial relationships, radiological cross-sectional image understanding, and theoretical ultrasound competencies. Due to the reciprocal positive effects of the training, students should receive radiology training at an early stage of their studies to benefit as early as possible from the improved skills, particularly in the disciplines of anatomy and radiology.

A20 in Kidney Transplantation and Autoimmunity.

A20, the central inhibitor of NFκB, has multiple anti-inflammatory properties, making it an interesting target in kidney autoimmune disease and transplant biology. It has been shown to be able to inhibit inflammatory functions in macrophages, dendritic cells, T cells, and B cells in various ways, leading to less tissue damage and better graft outcomes. In this review, we will discuss the current literature regarding A20 in kidney transplantation and autoimmunity. Future investigations on animal models and in existing immunosuppressive therapies are needed to establish A20 as a therapeutic target in kidney transplantation and autoimmunity. Cell-based therapies, modified viruses or RNA-based therapies could provide a way for A20 to be utilized as a promising mediator of inflammation and tissue damage.

Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial.

BACKGROUND: Data on belimumab efficacy in patients with lupus nephritis (LN) according to diagnosis duration or induction therapy are limited. Post hoc analyses of the phase 3, randomized, double-blind BLISS-LN study (GSK BEL114054; NCT01639339) were performed to assess belimumab efficacy on kidney-related outcomes in newly diagnosed and relapsed LN subgroups and according to the use of glucocorticoid (GC) pulses at induction. METHODS: BLISS-LN randomized 448 patients with active LN to monthly intravenous belimumab 10 mg/kg or placebo plus standard therapy. Post hoc analyses assessed primary efficacy renal response (PERR) and complete renal response (CRR) at week 104, time to kidney-related event or death and time to first LN flare from week 24 in newly diagnosed and relapsed patients and patients with/without GC pulses at induction. RESULTS: A greater proportion of patients achieved a PERR with belimumab versus placebo in the newly diagnosed {69/148 [46.6%] versus 55/148 [37.2%]; odds ratio [OR] 1.36 [95% confidence interval (CI) 0.85-2.20]} and relapsed [27/75 (36.0%) versus 17/75 (22.7%); OR 2.31 (95% CI 1.07-5.01)] subgroups. Similarly for CRR [newly diagnosed: 50/148 (33.8%) versus 36/148 (24.3%); OR 1.49 (95% CI 0.88-2.51) and relapsed: 17/75 (22.7%) versus 8/75 (10.7%); OR 3.11 (95% CI 1.16-8.31)]. The probability of kidney-related event or death, or LN flare was lower with belimumab versus placebo in both subgroups. Belimumab was associated with improved kidney outcomes versus placebo with or without GC pulses at induction. CONCLUSION: Data suggest consistent benefits of belimumab on kidney outcomes for newly diagnosed and relapsed patients, and irrespective of GC pulses at induction.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

Successful transplantation of four kidney grafts from two small pediatric donors with anuric acute renal failure into adult recipients.

BACKGROUND: Kidneys from infants with anuric acute kidney injury (AKI) only rarely get accepted for transplantation despite encouraging data that such kidneys can have very good long-term outcome. METHODS: We report the transplantation of four kidney grafts from two pediatric donors (3 and 4 years) with anuric acute kidney injury as single kidneys into four adult recipients. RESULTS: All grafts gained function within 14 days posttransplantation, only one recipient needed dialysis after transplantation. None of the recipients suffered from surgical complications. One month after transplantation, all recipients were free of dialysis. Estimated glomerular filtration rates (eGFR) 3 months after transplantation were 37, 40, 50, and 83 mL/min/1.73 m2 . eGFR increased further through month 6, reaching 45, 50, 58, and 89 mL/min/1.73 m2 . CONCLUSION: These cases highlight the feasibility of successful transplantation of single pediatric kidney grafts into adult recipients despite anuric AKI of the donor.

Case Report of Anti-Thrombogenicity.

BACKGROUND: The Toray Filtryzer™-NF is a new polymethyl methacrylate filter with improved hemocompatibility and reduced impact on platelet counts. OBJECTIVES: This suggests that, if necessary, a reduction in anticoagulation may be possible when dialysis is performed with the Toray Filtryzer™-NF. METHODS: In the following, we dialyzed 5 hemodialysis patients who had a contraindication to full anticoagulation postoperatively or after renal biopsy with the Filtryzer™-NF. RESULTS: A significant reduction in heparin administration was achieved, and in 1 patient, heparin substitution was completely omitted. Despite the significantly reduced heparin doses, no thrombosis of the system occurred during the hemodialysis. CONCLUSION: In conclusion, hemodialysis using the Toray Filtryzer™-NF is an effective alternative for patients at significantly increased risk of bleeding.

Efficient removal of antibodies to adeno-associated viruses by immunoadsorption.

BACKGROUND: Gene therapies based on adeno-associated viruses (AAV) are a therapeutic option to successfully treat monogenetic diseases. However, the influence of pre-existing immunity to AAV can compromise the application of AAV gene therapy, most notably by the presence of neutralizing antibodies (NAb) to AAV. METHODS: In the following study, we investigated to what extent the treatment by immunoadsorption (IA) would reduce the levels of human anti-AAV antibodies to AAV2 and AAV5. To that end, we screened blood sera from 40 patients receiving IA treatment because of underlying autoimmune disease or transplant rejection, with detectable AAV-antibodies in 23 patients (22 by NAb detection, and 1 additionally by anti-AAV5 ELISA analysis). RESULTS: Our results show that IA efficiently depleted anti-AAV2 NAb with a mean reduction of 3.92 ± 1.09 log2 titer steps (93.4%) after three to five single IA treatments, 45% of seropositive subjects had an anti-AAV2 titer below the threshold titer of 1:5 after the IA treatment series. Anti-AAV5 NAb were reduced to below the threshold titer of 1:5 in all but one of five seropositive subjects. Analysis of total anti-AAV5 antibodies by ELISA demonstrated an anti-AAV5 antibody reduction over the IA treatment series of 2.67 ± 1.16 log2 titer steps (84.3%). CONCLUSION: In summary, IA may represent a safe strategy to precondition patients with pre-existing anti-AAV antibodies to make this population eligible for an effective AAV-based gene therapy.

FoCUS cardiac ultrasound training for undergraduates based on current national guidelines: a prospective, controlled, single-center study on transferability.

INTRODUCTION: In emergency and critical-care medicine, focused cardiac ultrasound (FoCUS) is indispensable for assessing a patient's cardiac status. The aim of this study was to establish and validate a peer-to-peer-supported ultrasound course for learning FoCUS-specific skills during undergraduate studies at a German university. METHODS: A 1-day, 12 teaching units training course was developed for students in the clinical section of medical college, with content based on the current national guidelines. A total of 217 students participated in the study (97 in the course group and 120 in the control group). The course and the participants' subjective assessment of improved skills were evaluated using a questionnaire (7-point Likert scale; 7 = complete agreement and 1 = no agreement at all). Objective learning gains were assessed by tests before and after the course. These consisted of a test of figural intelligence (eight items) and a test of technical knowledge (13 items). RESULTS: The course participants experienced significant improvement (P < 0.001) from before to after the course, with a large effect size of η2part = 0.26. In addition, the course group had significantly better results (P < 0.001) than the control group in the post-test, with a medium to large effect size of η2part = 0.14. No significant differences (P = 0.27) were detected in the test section on figural intelligence. The evaluations showed that the participants had a high degree of satisfaction with the course approach, teaching materials, and tutors. There was also a positive increase in their subjective assessment of their own skills, including areas such as technical knowledge, ultrasound anatomy, and performance of the examination. CONCLUSION: The results of both the objective learning assessment and the subjective evaluations suggest that a FoCUS course originally intended for qualified physicians is equally suitable for students. With the development and provision of modern digital teaching media, even more students will be able to benefit from this approach in the future.

Undergraduate ultrasound training: prospective comparison of two different peer assisted course models on national standards.

BACKGROUND: A thorough knowledge of sonography is essential in clinical practice. Therefore, sonography training is increasingly incorporated into the medical school curriculum, entailing different course models. The question arises which model is most effective to convey sustained sonographic skills. METHODS: Two different peer-assisted learning (PAL) sonography course models were developed as part of a clinical prospective study. The course content was based on the national resident curriculum of the German Society for Ultrasound in Medicine (DEGUM). Model A consists of a 10-week course and model B of a two-day compact course. Each model entailed 20 teaching units (TU). A script was used to prepare for each unit. Two modified OSCE exams of the ultrasound skills (max = 50 points per exam) were performed during the last teaching unit to assess the competence level. For subjective self-assessment and model evaluation, a questionnaire with a 7-point Likert scale was employed. RESULTS: A total of 888 students of the 3rd year participated as part of a voluntary elective in the study (744 in model A and 144 in model B). In the exams, participants in model A (median 43 points) scored significantly higher than those in model B (median 39; p < 0.01). Participants in model A (mean 1.71 points) obtained significantly higher mean competency gain scores in subject knowledge than model B (mean 1.43 points; p < 0.01) participants. All participants were satisfied with the course concept (A: mean 1.68 vs. B: mean 1.78 points; p = 0.05), the teaching materials (A: mean 1.81 vs. B: mean 1.69 points; p = 0.52), and the tutor's didactic skills (A: mean 1.24 vs. B: mean 1.15 points; p < 0.05). CONCLUSION: These results suggest that sonography-specific competency may be obtained through different course models, with a model stretching over several weeks leading to a higher competence level. Further research should assess the long-term retention of the skills obtained in different models.

IL-34 and protein-tyrosine phosphatase receptor type-zeta-dependent mechanisms limit arthritis in mice.

Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis.

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.

Immunoadsorption and plasma exchange-Efficient treatment options for neurological autoimmune diseases.

BACKGROUND: Therapeutic plasma exchange (TPE) and immunoadsorption (IA) are first or second line treatment options in patients with neurological autoimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorders (NMSOD), chronic inflammatory demyelinating polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome), and autoimmune encephalitis. METHODS: In this prospective randomized controlled monocentric study, we assessed safety and efficacy of therapy with IA or TPE in patients with neurological autoimmune diseases. Treatment response was assessed using various neurological scores as well by measuring immunoglobulin and cytokine concentrations. Clinical outcome was evaluated by application of specific scores for the underlying diseases. RESULTS: A total of 32 patients were analyzed. Among these, 19 patients were treated with TPE and 13 patients with IA. IA and TPE therapy showed a comparable significant treatment response. In patients with MS and NMOSD, mean EDSS before and after treatment showed a significant reduction after treatment with IA. We observed a significant reduction of the pro-inflammatory cytokines IL-12, lL-17, IL-6, INF-γ, and tumor necrosis factor alpha during IA treatment, whereas this reduction was not seen in patients treated with TPE. CONCLUSIONS: In summary, both IA and TPE were effective and safe procedures for treating neurological autoimmune diseases. However, there was a trend towards longer therapy response in patients treated with IA compared to TPE, possibly related to a reduction in plasma levels of pro-inflammatory cytokines seen only in the IA-treated group.

Non-bacterial thrombotic endocarditis in a patient with pancreatic carcinoma.

Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that most often accompanies a malignant disease and involves a hypercoagulable state. We report the incidental finding of a rare case of an NBTE affecting the tricuspid valve in a patient with metastatic pancreatic carcinoma complicated by severe venous and arterial thromboembolisms.

Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. METHODS: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6-/- MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. RESULTS: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. CONCLUSION: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis.

OBJECTIVES: In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. METHODS: Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. RESULTS: Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. CONCLUSION: Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.