A lipid-protein autoimmunity target: Several autoimmune diseases, including systemic lupus erythematosus and primary antiphospholipid syndrome, are characterized by the presence of antiphospholipid antibodies (aPLs). These molecules can activate the complement and coagulation cascades, which contributes to pathologies such as thrombosis, stroke, and pregnancy complications. Müller-Calleja et al. found that endothelial protein C receptor (EPCR) in complex with lysobisphosphatidic acid (LBPA) is the cell-surface target for aPL and mediates its internalization (see the Perspective by Kaplan). aPL binding to EPCR-LBPA resulted in the activation of tissue factor–mediated coagulation and interferon-α production by dendritic cells. Interferon-α, in turn, fueled the expansion of B1a cells, which secrete aPLs. The specific blockade of this target in mice inhibited the development of aPL autoimmunity, offering hope for future therapies for these conditions. Science , this issue p. eaay1833 ; see also p. 1100

Introduction: Ultrasound diagnostics is an important examination method in everyday clinical practice, but student education is often inadequate for acquiring sufficient basic skills. Individual universities have therefore started integrating (extra)curricular training concepts into medical education. This study aimed to evaluate sustainable skills development through participation in peer-assisted ultrasound courses. Methods: From 2017, students in the clinical part of medical school could opt for extracurricular peer-assisted ultrasound courses. Depending on the format (10-week course/2-day compact course) these comprised 20 teaching units focusing on abdominal and emergency ultrasonography. Students attending compulsory workshops at the start of their practical year were enrolled in this study, allowing for a comparison between the study group (attended ultrasound course) and the control group (did not attend ultrasound course). Competency from two out of four practical exams (subjects: “aorta”, “gallbladder”, “kidney” and “lung”) was measured, and a theory test on the same subject areas (“pathology recognition”) was administered. Additional questions concerned biographical data, subjective competency assessment (7-point Likert scale), and “attitude to ultrasound training in the curriculum”. Results: Analysis included 302 participants in total. Ultrasound courses had been attended on average 2.5 years earlier (10-week course) and 12 months earlier (2-day compact course), respectively. The study group (n = 141) achieved significantly better results than the control group (n = 161) in the long-term follow-up. This applies both to practical exams (p < 0.01) and theory tests (p < 0.01). After course attendance, participants reported a significantly higher subjective assessment of theoretical (p < 0.01) and practical (p < 0.01) ultrasound skills. Conclusions: Peer-assisted ultrasound courses can sustainably increase both theoretical and practical competency of medical students. This highlights the potential and need for standardised implementation of ultrasound courses in the medical education curriculum.

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.

Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation. In the 9-month interim analysis of this phase 3 trial, iptacopan, a complement factor B inhibitor, led to a significant reduction of 38.3% in the 24-hour urinary protein-to-creatinine ratio as compared with placebo and had an acceptable safety profile. In this phase 3 trial, we enrolled adults who had IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m² of body-surface area, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite supportive care. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily. The primary end point for the final analysis was the annualized total eGFR slope as estimated over a 24-month period. Secondary end points included a composite kidney-failure end point (i.e., a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 ml per minute per 1.73 m², the initiation of maintenance dialysis, receipt of kidney transplant, or death from kidney failure), assessed in a time-to-event analysis. Safety was also assessed. Among 477 patients included in the final analysis, 238 had been randomly assigned to iptacopan and 239 to placebo. The annualized total eGFR slope was -3.10 ml per minute per 1.73 m² per year with iptacopan, as compared with -6.12 ml per minute per 1.73 m² per year with placebo (difference, 3.02 ml per minute per 1.73 m² per year; 95% confidence interval [CI], 2.02 to 4.01; adjusted P<0.001). A composite kidney-failure end-point event occurred in 21.4% of the patients in the iptacopan group, as compared with 33.5% of those in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81; adjusted P = 0.003). The incidence of adverse events was 87.0% in the iptacopan group and 89.1% in the placebo group. Serious adverse events occurred in 12.2% of the patients who received iptacopan and in 11.7% of those who received placebo, and serious infections in 6.7% and 2.1%, respectively. No deaths occurred. Iptacopan therapy led to a significantly slower decline in kidney function than placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

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.

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.