The course and outcomes of Covid-19 in patients with anca-associated systemic vasculitis, receiving biological therapy (rituximab, mepolizumab): The results of the first 8 months of the pandemic
02 Mar 2021-Vol. 59, Iss: 1, pp 37-46
TL;DR: An analysis of the COVID-19 course and outcomes in AAV patients treated with rituximab or mepolizumab from one rheumatology center registry seems that B cell depletion, without reducing the risk of infection, may have a protective effect with regard to therisk of severe/catastrophic CO VID-19, which, however, can be insufficient in A AV patients.
Abstract: Objective. Currently, the issues of the effect of anti-B cell therapy or inhibitor of interleukin 5 on the risk of COVID-19 infecting and outcomes in patients with ANCA-associated vasculitis (AAV) has not been completely studied. We present an analysis of the COVID-19 course and outcomes in AAV patients treated with rituximab or mepolizumab from one rheumatology center registry. Methods. From November 11 to November 15, 2020, a cross-sectional study was conducted using telephone and online surveys, and information was collected from all 128 AAV patients treated with rituximab in V.A. Nasonova Research Institute of Rheumatology. Patients mean age was 51 (20–81) years, 61.7% were women. Granulomatosis with polyangiitis (GPA) was diagnosed in 58 patients, microscopic polyangiitis (MPA) – in 38, eosinophilic granulomatosis with polyangiitis (EGPA) – in 24 (including 54.2% of ANCA-negative cases), and AAV with uncertain nosological affiliation – in 8 patients. Due to the disease activity or a high risk of AAV recurrence during the pandemic rituximab was prescribed in 60/126 (47.6%) patients, and mepolizumab – in 6 cases. Results. In the spring of the pandemic (until May 2020), the incidence of COVID-19 in AAV patients treated with rituximab was 4.3%, the disease course was relatively favorable. All patients recovered. At month 3–6, antibodies to SARS-CoV-2 IgG persisted in only 1 out of 4 patients. Since September 2020, the incidence has increased 3-fold, with a more severe course of COVID-19. In total, in the period until November 11, 2020, COVID-19 was diagnosed in 17.2% (22/128); the mean age of patients was 55 (25–81) years; 54.5% were women. 21/22 patients were on rituximab therapy, 2 patients had mepolizumab therapy (including 1 case after previous rituximab therapy). COVID-19 incidence was lower in patients with GPA (15.5%) vs MPA and EGPA (21.1% and 20.8% respectively). The mortality rate was 13.6%, including 2 patients with MPA and 1 patient with GPA. When analyzing the 5-year survival rate according to the registry of AAV patients treated with rituximab, prognosis worsening was noted; in 2020 there were 3 deaths due to COVID-19, in the previous 5 years – only 2 deaths. Discussion. Taking into account the fact the mechanisms of AAV and severe COVID-19 are largely synergistic (primarily in the context of microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome as manifestation of the acute inflammatory syndrome), the activity of AAV can potentially contribute to the disease onset and a severe course of COVID-19. Given the previously published information on the use of rituximab during the COVID-19 pandemic for various diseases, it seems that B cell depletion, without reducing the risk of infection, may have a protective effect with regard to the risk of severe/catastrophic COVID-19, which, however, can be insufficient in AAV patients. Further analysis of COVID-19 cases in patients with AAV and other immuno-inflammatory rheumatic diseases is exceptionally important.
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01 Jan 2018
TL;DR: In this article, targeted anti-B-cell therapy that causes B-cell depletion in blood and target organs is effective in a wide range of immuno-inflammatory rheumatic diseases.
Abstract: Impaired B-cell immunological tolerance plays a central role in the pathogenesis of immuno-inflammatory rheumatic diseases (IIRD). B-cells link innate and acquired immunity: they express Toll-like receptors that respond to danger signals; act as antigen-presenting cells; induce an antigen-specific immune response; determine the development of immunological memory; and synthesize a wide range of cytokines that regulate (stimulate or suppress) an immune response and inflammation. In IIRD, there are metabolic and B-cellular signaling disturbances that lead to defects in B-regulatory, T-regulatory, follicular T-helper, and dendritic cells. B-cells synthesize organ-nonspecific and organspecific autoantibodies that are biomarkers for autoimmune diseases and play an important role in their immunopathogenesis. Anti-B-cell therapy that causes B-cell depletion in blood and target organs is effective in a wide range of IIRD. Its efficiency is determined by various mechanisms, such as suppression of pathogenic autoantibody synthesis; modulation of the function of B-cells (antigen presentation, cytokine synthesis, and costimulation), T-lymphocytes and dendritic cells. Further study of a strategy for targeted anti-B-cell therapy, mechanisms of action, and new targets is important for the progress of modern rheumatology to improve the treatment strategy of IIRD.
7 citations
05 Aug 2020
TL;DR: COVID-19 had a mild clinical course in patients with Agammaglobulinemia lacking B lymphocytes, whereas it developed aggressively in Common Variable Immune Deficiency.
Abstract:
Summary
COVID-19 had a mild clinical course in patients with Agammaglobulinemia lacking B lymphocytes, whereas it developed aggressively in Common Variable Immune Deficiency. Our data offer mechanisms for possible therapeutic targets.
2 citations
13 Apr 2022
TL;DR: In this paper , the authors presented the results of a combined analysis of literature data and own clinical observations regarding the safety and feasibility of using monoclonal anti-CD20 antibodies in the treatment of B-cell lymphoproliferative diseases during the COVID-19 pandemic.
Abstract: The review presents the results of a combined analysis of literature data and own clinical observations regarding the safety and feasibility of using monoclonal anti-CD20 antibodies in the treatment of B-cell lymphoproliferative diseases during the COVID-19 pandemic. The main points of the pathogenesis of the influence of monoclonal anti-CD20 antibodies on the course of COVID-19 are described. The current trends in the modification of the accepted algorithms of lymphoproliferative diseases therapy with the inclusion of monoclonal anti-CD20 antibodies are summarized, and the possibilities of specific prevention by vaccination against COVID-19 are also considered. Copyright © 2022 ABV-Press Publishing House. All rights reserved.
TL;DR: In this article , a case of moderate COVID-19 in a patient with granulomatosis with polyangiitis, who received anti-B cell therapy with rituximab (RTX) for a long time.
Abstract: Patients with ANCA-associated vasculitis (AAV) cause extreme alertness during the coronavirus disease 2019 (COVID-19) pandemic, associated with many factors: the initial damage to the respiratory system (upper respiratory tract, lungs) and kidneys, immunosuppressive treatments, difficult prognosis of COVID-19 with the risk of AAV exacerbation. We present a clinical case of а moderate COVID-19 in a patient with granulomatosis with polyangiitis, who received anti-B cell therapy with rituximab (RTX) for a long time. Coronavirus pneumonia developed one year after RTX, while B-lymphocyte depletion persisted. In order to achieve an adequate antiviral immune response and prevent hyperinflammation, treatment was carried out with antiviral drugs, anticoagulants, convalescent plasma, human normal immunoglobulin, and interleukin-6 antagonist tocilizumab. Possible predictors of severe COVID-19 in patients with AAV are discussed.
TL;DR: In this article , the authors evaluated the safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving rituximab (RTX), based on a prospective observational study.
Abstract: The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus; currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur").Objective – to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study.Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 – rheumatoid arthritis, 9 – Sjogren’s syndrome (SS), 4 – IgG4-related disease, 3 – systemic lupus erythematosus (SLE), 3 – dermatomyositis (DM), 2 – systemic scleroderma (SSD). Median age was 59 (19–82) years; male : female ratio – 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age – 45 (35–71) years; male : female ratio – 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions.Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV – 10, SS – 3, SSD – 2, SLE – 1, DM – 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1–2), there were no deaths. Good TC’s tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA – 3 MPA – 1, RA – 2, SLE – 1, IgG4-related disease – 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death.Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.
References
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TL;DR: The findings provide strong empirical support for the routine application of serological testing in the diagnosis and management of COVID-19 patients and offer vital clinical information during the course of SARS-CoV-2 infection.
Abstract: BACKGROUND: The novel coronavirus SARS-CoV-2 is a newly emerging virus. The antibody response in infected patients remains largely unknown, and the clinical value of antibody testing has not been fully demonstrated. METHODS: 173 patients with SARS-CoV-2 infection were enrolled. Their serial plasma samples (nâ
=â
535) collected during hospitalization were tested for total antibodies (Ab), IgM, and IgG against SARS-CoV-2. The dynamics of antibodies with disease progress were analyzed. RESULTS: Among 173 patients, the seroconversion rates for Ab, IgM, and IgG were 93.1%, 82.7%, and 64.7%, respectively. The reason for the negative antibody findings in 12 patients might be due to the lack of blood samples at the later stage of illness. The median seroconversion times for Ab, IgM, and then IgG were days 11, 12, and 4, respectively. The presence of antibodies wasâ
<40% among patients within 1 week of onset, and rapidly increased to 100.0% (Ab), 94.3% (IgM), and 79.8% (IgG) by day 15 after onset. In contrast, RNA detectability decreased from 66.7% (58/87) in samples collected before day 7 to 45.5% (25/55) during days 15-39. Combining RNA and antibody detection significantly improved the sensitivity of pathogenic diagnosis for COVID-19 (Pâ
<â
.001), even in the early phase of 1 week from onset (Pâ
=â
.007). Moreover, a higher titer of Ab was independently associated with a worse clinical classification (Pâ
=â
.006). CONCLUSIONS: Antibody detection offers vital clinical information during the course of SARS-CoV-2 infection. The findings provide strong empirical support for the routine application of serological testing in the diagnosis and management of COVID-19 patients.
2,223 citations
University of Paris1, French Institute of Health and Medical Research2, Rockefeller University3, National Institutes of Health4, University of Tartu5, Lyon College6, Tartu University Hospital7, Utrecht University8, Vita-Salute San Raffaele University9, Yale University10, Pasteur Institute11, Collège de France12, University of Amsterdam13, McGill University Health Centre14, Garvan Institute of Medical Research15, University of New South Wales16, Ghent University Hospital17, University of Barcelona18, University of Vic19, Catalan Institution for Research and Advanced Studies20, Science for Life Laboratory21, Karolinska University Hospital22, Howard Hughes Medical Institute23, Aarhus University24, Aarhus University Hospital25, University of Milano-Bicocca26, University of Lorraine27, Karolinska Institutet28, Haukeland University Hospital29, University of Bergen30, Canadian Real Estate Association31, University of Brescia32, University of Pavia33
TL;DR: A means by which individuals at highest risk of life-threatening COVID-19 can be identified is identified, and the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical CO VID-19 is tested.
Abstract: Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
1,913 citations
TL;DR: Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS, and a similar outbreak of Kawasaki-like disease is expected in countries involved in the SEMS epidemic.
1,851 citations
TL;DR: At least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state, and could suggest targets for specific intervention.
1,787 citations
TL;DR: It is shown that the functional exhaustion of cytotoxic lymphocytes is associated with SRAS-CoV-2 infection, which may break down antiviral immunity at an early stage, and the role of NKG2A has been identified to induce NK cell exhaustion in chronic viral infections.
Abstract: In December 2019, a novel coronavirus was first reported in Wuhan, China. It was named by the World Health Organization as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is responsible for coronavirus disease 2019 (COVID-19). Up to 28 February 2020, 79,394 cases have been confirmed according to China’s National Health Commission. Outside China, the virus has spread rapidly to over 36 countries and territories. Cytotoxic lymphocytes such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are necessary for the control of viral infection, and the functional exhaustion of cytotoxic lymphocytes is correlated with disease progression. However, whether the cytotoxic lymphocytes in patients infected with SARS-CoV-2 become functionally exhausted has not been reported. We showed that the total number of NK and CD8 T cells was decreased markedly in patients with SARS-CoV-2 infection. The function of NK and CD8 T cells was exhausted with the increased expression of NKG2A in COVID-19 patients. Importantly, in patients convalescing after therapy, the number of NK and CD8 T cells was restored with reduced expression of NKG2A. These results suggest that the functional exhaustion of cytotoxic lymphocytes is associated with SRAS-CoV-2 infection. Hence, SARS-CoV-2 infection may break down antiviral immunity at an early stage. SARS-CoV-2 has been identified as a genus β-coronavirus, and it shares 79.5% sequence homology with SARS-CoV. In our cohort of 68 COVID-19 patients admitted to The First Affiliated Hospital (Hefei) and Fuyang Hospital (Fuyang), both of which are part of Anhui Medical University in China, there were 55 cases of mild disease (MD) and 13 cases of severe disease (SD). Patients were aged 11–84 years, and the median age of patients was 47.13 years. The percentage of male patients was 52.94%. Consistent with previous studies, many patients had fever (80.88%), cough (73.53%), and sputum (32.36%) upon admission. The prevalence of other symptoms (e.g., headache, diarrhea) was relatively low (Supplementary Table 1). The clinical features of patients infected with SARS-CoV-2 was consistent with those reported by Chen and colleagues. Upon admission, the neutrophil count was remarkably higher in SD patients than in MD cases, whereas the lymphocyte count was significantly lower in SD cases than in MD cases. The concentration of total bilirubin, D-dimer, and lactate dehydrogenase in blood was higher in SD patients than that in MD patients. Levels of alanine aminotransferase and aspartate aminotransferase were slightly higher in SD cases than those in MD cases. Levels of albumin and hemoglobin were lower in SD patients than those in MD patients (Supplementary Table 2). Specifically, T cell and CD8 T cell counts were decreased significantly in MD and SD patients compared with those in healthy controls (HCs). The number of T cells and CD8 T cells was significantly lower in SD patients than that in MD cases. The counts of NK cells were reduced remarkably in SD patients compared with those in MD cases and HCs (Fig. 1a). As an inhibitory receptor, NKG2A has been demonstrated to induce NK cell exhaustion in chronic viral infections. Notably, NKG2A expression on NK and CD8 T cells results in functional exhaustion of NK and CD8 T cells. In patients infected with SARSCoV-2, NKG2A expression was increased significantly on NK and CD8 T cells compared with that in HCs (Fig. 1b). Next, to identify the role of NKG2A on the function of NK and CD8 T cells, levels of CD107a, interferon (IFN)-γ, interleukin (IL)-2, granzyme B, and tumor necrosis factor (TNF)-α were measured through staining of intracellular cytokines. We found lower percentages of CD107a NK, IFN-γ NK, IL-2 NK, and TNF-α NK cells and mean fluorescence intensity (MFI) of granzyme B NK cells in COVID-19 patients than those in HCs. Consistent with these findings, COVID-19 patients also showed decreased percentages of CD107a CD8, IFN-γCD8, and IL-2CD8 T cells and MFI of granzyme BCD8 T cells, compared with those in HCs (Fig. 1c). Taken together, these results suggest the functional exhaustion of cytotoxic lymphocytes in COVID-19 patients. Hence, SARS-CoV-2 may break down antiviral immunity at an early stage. In our setting, ~94.12% of patients were administered antiviral therapy (Kaletra®). Chloroquine phosphate was used in 7.35% of patients, and the proportion of patients treated with IFN was 64.71%. In addition, 48.53% patients received antibiotic treatment (Supplementary Table 3). Comparison of the total number of cytotoxic lymphocytes (including CTLs and NK cells) after therapy was carried out. The total number of T cells and NK cells recovered in the convalescent period in four of the five patients, and the total count of CTLs was restored in the convalescent period in three of the five patients (Fig. 1d). Hence, efficacious therapy was accompanied by an increased number of T cells, CTLs, and NK cells. Importantly, the percentage of NKG2A NK cells was decreased in the convalescent period compared with that before treatment among five patients. Similarly, five patients showed a decreased percentage of NKG2A CTLs in the convalescent period (Fig. 1e).
1,358 citations