scholarly journals B cell depletion in immune-mediated rheumatic diseases and coronavirus disease 2019 (COVID-19)

2021 ◽  
Vol 59 (4) ◽  
pp. 384-393
Author(s):  
E. L. Nasonov ◽  
A. S. Avdeeva
Keyword(s):  
B Cell ◽  
Rheumatic Diseases ◽  
Bacterial Infections ◽  
Human Monoclonal Antibody ◽  
Chimeric Mouse ◽  
Internal Organs ◽  
Irreversible Damage ◽  
Autoimmune Rheumatic Diseases ◽  
Number Of Factors ◽  
Immune Mediated

In patients with immune-mеdiated (autoimmune) rheumatic diseases (IMIRD), there are a number of factors (advanced age, uncontrolled inflammation, initially irreversible damage to internal organs, comorbid pathology, genetic and other factors) that can potentially lead to an increase in “sensitivity” to SARS-CoV -2 (severe acute respiratory syndrome coronavirus-2) and concomitant viral and bacterial infections, an increase in the risk of a severe course of COVID-19 (coronavirus disease 2019), a decrease in the effectiveness of therapy for both IMIRDs and COVID-19. An important area of pharmacotherapy for IMIRDs and other autoimmune diseases is associated with the use of anti-B-cell drugs, primarily rituximab (RTX), which is a chimeric (mouse/human) monoclonal antibody (mAb) to the CD20 antigen of B cells. At present, in Russia, the RTM biosimilar, acellbia (BIOCAD), is widely used, which is not inferior to RTX in terms of efficiency and safety. The problems of anti-B-cell therapy during the COVID-19 pandemic in relation to the risk of infection, severe course and insufficient effectiveness of vaccination against SARSCoV- 2 are considered. According to the recommendations of the Association of Rheumatologists of Russia, a more rigorous assessment of indications for induction and maintenance therapy of RTX therapy and harmonization of the timing of drug administration and vaccination is required.

scholarly journals A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Monica Balzarotti ◽  
Massimo Magagnoli ◽  
Miguel Ángel Canales ◽  
Paolo Corradini ◽  
Carlos Grande ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Chimeric Mouse ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Large B Cell

SummaryBackground BI 836826 is a chimeric mouse–human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.

B cell checkpoints in autoimmune rheumatic diseases

2019 ◽  
Vol 15 (5) ◽  
pp. 303-315 ◽  
Author(s):  
Samuel J. S. Rubin ◽  
Michelle S. Bloom ◽  
William H. Robinson
Keyword(s):  
B Cell ◽  
Rheumatic Diseases ◽  
Autoimmune Rheumatic Diseases

scholarly journals Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1332 ◽  
Author(s):  
Michie Imamura ◽  
Akihiro Mukaino ◽  
Koutaro Takamatsu ◽  
Hiroto Tsuboi ◽  
Osamu Higuchi ◽  
...  
Keyword(s):  
Autonomic Dysfunction ◽  
Rheumatic Diseases ◽  
Lupus Erythematosus ◽  
Acetylcholine Receptors ◽  
Case Reports ◽  
Pathophysiological Mechanism ◽  
Autoimmune Rheumatic Diseases ◽  
Immune Mediated ◽  
Autonomic Disturbance ◽  
Antibody Levels

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

scholarly journals Coronavirus disease 2019 (COVID-19) and immune-mediated inflammatory rheumatic diseases: at the crossroads of thromboinflammation and autoimmunity

2020 ◽  
Vol 58 (4) ◽  
pp. 353-367
Author(s):  
E. L. Nasonov ◽  
T. V. Beketova ◽  
T. M. Reshetnyak ◽  
A. M. Lila ◽  
L. P. Ananieva ◽  
...  
Keyword(s):  
Rheumatic Diseases ◽  
Complement System ◽  
Vascular Endothelial Cells ◽  
Basic Mechanism ◽  
Pathological Process ◽  
Human Organism ◽  
Inflammatory Rheumatic Diseases ◽  
Irreversible Damage ◽  
Immune Mediated ◽  
The Complement System

Inflammation and coagulation are key basic mechanism of protection against all potentially pathogenic mechanical and biological factors targeting human organism from inner and outer environment. On the other hand, uncontrolled inflammation results in hypercoagulation, inhibition of anticoagulation and alteration of mechanisms responsible for resolution of inflammation, while production of “procoagulant” mediators (thrombin, tissue factor and others), activation of platelets and of vascular endothelial cells maintains inflammation. All factors taken together serve as the basis for a pathological process called thromboinflammation or immunothrombosis. Currently thromboinflammation is considered in the broad sense as a universal pathogenetic mechanism of numerous widespread acute and chronic conditions, including immune-mediated (autoimmune) inflammatory rheumatic diseases, oftentimes complicated by severe irreversible damage to vital organs. Thromboinflammation gained specific attention during СОVID-19 (coronavirus disease 2019) pandemic, caused by SARS-Cov-2 (severe acute respiratory syndrome Coronavirus-2). COVID-19 is considered currently as systemic thromboinflammation syndrome, manifesting via generalized thrombosis of arterial and venous macro- and microvasculature, termed as COVID-19-coagulopathy. The paper discusses common pathogenetic coagulopathy mechanisms in COVID-19 and immune-mediated (autoimmune) inflammatory rheumatic diseases (IMRDs), associated with overproduction of antiphospholipid antibodies, activation of the complement system, and dis-regulated synthesis of proinflammatory cytokines, etc. Delineating the autoimmune subtype of thromboinflammation, identification of genetic (i.e., genes encoding the complement system and others) and molecular-biologic biomarkers associated with higher occurrence of COVID-19-coagulopathy are the most relevant undertakings for the current practice. Gaining insights into mechanisms of thromboinflammation and converting them into potential pharmacotherapies of IMDs would facilitate and accelerate the drafting of effective therapeutic strategies for COVID-19. 

scholarly journals Immune Axonal Neuropathies Associated With Systemic Autoimmune Rheumatic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Delia Tulbă ◽  
Bogdan Ovidiu Popescu ◽  
Emilia Manole ◽  
Cristian Băicuș
Keyword(s):  
Rheumatic Diseases ◽  
Rapid Progression ◽  
Treatment Protocols ◽  
Sensorimotor Polyneuropathy ◽  
Therapeutic Implications ◽  
Autoimmune Rheumatic Diseases ◽  
Vasa Nervorum ◽  
Immune Mediated ◽  
Night Sweats ◽  
Demyelinating Neuropathies

Immune axonal neuropathies are a particular group of immune-mediated neuropathies that occasionally accompany systemic autoimmune rheumatic diseases such as connective tissue dissorders and primary systemic vasculitides. Apart from vasculitis of vasa nervorum, various other mechanisms are involved in their pathogenesis, with possible therapeutic implications. Immune axonal neuropathies have highly heterogeneous clinical presentation and course, ranging from mild chronic distal sensorimotor polyneuropathy to severe subacute mononeuritis multiplex with rapid progression and constitutional symptoms such as fever, malaise, weight loss and night sweats, underpinning a vasculitic process. Sensory neuronopathy (ganglionopathy), small fiber neuropathy (sensory and/or autonomic), axonal variants of Guillain-Barré syndrome and cranial neuropathies have also been reported. In contrast to demyelinating neuropathies, immune axonal neuropathies show absent or reduced nerve amplitudes with normal latencies and conduction velocities on nerve conduction studies. Diagnosis and initiation of treatment are often delayed, leading to accumulating disability. Considering the lack of validated diagnostic criteria and evidence-based treatment protocols for immune axonal neuropathies, this review offers a comprehensive perspective on etiopathogenesis, clinical and paraclinical findings as well as therapy guidance for assisting the clinician in approaching these patients. High quality clinical research is required in order to provide indications and follow up rules for treatment in immune axonal neuropathies related to systemic autoimmune rheumatic diseases.

scholarly journals Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 435-445 ◽  
Author(s):  
ME Reff ◽  
K Carner ◽  
KS Chambers ◽  
PC Chinn ◽  
JE Leonard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Chinese Hamster Ovary Cells ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Target Cells ◽  
Chimeric Mouse ◽  
Variable Regions

Murine monoclonal antibody 2B8 specifically recognizes the CD20 phosphoprotein expressed on the surface of normal B lymphocytes and B- cell lymphomas. The light- and heavy-chain variable regions of 2B8 were cloned, after amplification by the polymerase chain reaction, into a cDNA expression vector that contained human IgG1 heavy chain and human kappa-light chain constant regions. High-level expression of chimeric- 2B8 antibody (C2B8) was obtained in Chinese hamster ovary cells. Purified C2B8 exhibited antigen binding affinity and human-tissue reactivity similar to the native murine antibody. In vitro studies showed the ability of C2B8 to bind human C1q, mediate complement- dependent cell lysis of human B-lymphoid cell lines, and lyse human target cells through antibody-dependent cellular cytotoxicity. Infusion of macaque cynomolgus monkeys with doses ranging from 1.6 mg/kg to 6.4 mg/kg resulted in greater than 98% depletion of peripheral blood (PB) B cells and 40% to 70% depletion of lymph node B cells. Recovery of PB B cells usually started at 2 weeks after treatment and required 60 to greater than 90 days to reach normal levels. As much as 95% depletion of B cells in peripheral lymph nodes and bone marrow was observed following weekly injections of 16.8 mg/kg antibody. No toxicity was observed in any of the animals. These results offer the possibility of using an “immunologically active” chimeric anti-CD20 antibody as an alternative approach in the treatment of B-cell lymphoma.

scholarly journals Iatrogenic antibody deficiency from B-cell targeted therapies in autoimmune rheumatic diseases

2019 ◽  
Vol 6 (1) ◽  
pp. e000337 ◽  
Author(s):  
Sonali Wijetilleka ◽  
David Jayne ◽  
Chetan Mukhtyar ◽  
Mohammed Yousuf Karim
Keyword(s):  
B Cell ◽  
Rheumatic Diseases ◽  
Targeted Therapies ◽  
Side Effect ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Antibody Deficiency ◽  
Significant Group ◽  
Autoimmune Rheumatic Diseases ◽  
Increased Risk ◽  
Mild Reduction

B-cell targeted therapies (BCTT) are now widely used in autoimmune rheumatic diseases, including SLE, antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. Early studies suggested that rituximab did not influence serum immunoglobulins. However, subsequently, with increased patient numbers, longer follow-up duration and many patients having received multiple BCTT courses, multiple subsequent studies have identified hypogammaglobulinaemia as a potential side effect. Patients developing hypogammaglobulinaemia appear to fit into two principal categories: the majority who develop transient, often mild reduction in immunoglobulins without increased infection and a much smaller but clinically significant group with a more sustained antibody deficiency, who display increased risk of infection. Monitoring immunoglobulin levels represents an opportunity for the early detection of hypogammaglobulinaemia, and the prevention of avoidable morbidity. In the two major studies, approximately 4%–5% of BCTT-treated patients required immunoglobulin replacement due to recurrent infections in the context of hypogammaglobulinaemia. Despite this, monitoring of immunoglobulins is suboptimal, and there remains a lack of awareness of hypogammaglobulinaemia as an important side effect.

scholarly journals Rituximab-Based Treatment, HCV Replication, and Hepatic Flares

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Evangelista Sagnelli ◽  
Mariantonietta Pisaturo ◽  
Caterina Sagnelli ◽  
Nicola Coppola
Keyword(s):  
B Cell ◽  
Parvovirus B19 ◽  
Human Monoclonal Antibody ◽  
Chimeric Mouse ◽  
Varicella Zoster ◽  
Hepatic Cells ◽  
B Virus ◽  
Life Threatening ◽  
A Cell ◽  
Hepatic Flare

Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only afewsmall studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

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