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      Emerging B-Cell Therapies in Systemic Lupus Erythematosus

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          Abstract

          Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease of unknown etiology, whose hallmark is the production of autoantibodies. B cells are promising targets for novel SLE therapies. In 2011, belimumab (Benlysta ®), a fully humanized monoclonal antibody inhibiting B-cell activation and proliferation, was the first medication in 50 years to be approved by the US Food and Drug Administration to treat adult SLE. This review discusses the current experience with B-cell-targeted therapies, including those targeting B-cell-surface antigens (rituximab, ocrelizumab, ofatumumab, obinutuzumab, obexelimab, epratuzumab, daratumumab), B-cell survival factors (belimumab, tabalumab, atacicept, blisibimod), or B-cell intracellular functions (ibrutinib, fenebrutinib, proteasome inhibitors), for the management of SLE. It focuses on ongoing clinical trials and real-world post-marketing use, where available, including their safety profiles, and concludes with our recommendations for B-cell-centric approaches to the management of SLE.

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          Most cited references 96

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          Systemic lupus erythematosus.

          Systemic lupus erythematosus is an autoimmune connective-tissue disorder with a wide range of clinical features, which predominantly affects women, especially from certain ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. Treatments range from antimalarial agents to corticosteroids and immunosuppressive agents. This Seminar draws attention to advances in the epidemiology, genetics, cardiovascular risks, lupus nephritis, CNS disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related and quality of life issues. New therapeutic approaches, such as biological agents and mycophenolate mofetil, will also be discussed.
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            The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.

            Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.
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              The BAFF/APRIL system in SLE pathogenesis.

              Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                tcrm
                tcriskman
                Therapeutics and Clinical Risk Management
                Dove
                1176-6336
                1178-203X
                14 January 2021
                2021
                : 17
                : 39-54
                Affiliations
                [1 ]Division of Rheumatology, Renaissance School of Medicine, Stony Brook University Medical Center , Stony Brook, NY, USA
                [2 ]Division of Pediatric Rheumatology, Steven and Alexandra Cohen Children Medical Center , New Hyde Park, NY, USA
                [3 ]Zucker School of Medicine at Hofstra/Northwell , Hempstead, NY, USA
                [4 ]Center for Autoimmune, Musculoskeletal, and Hematopoietic Diseases Research, Feinstein Institute for Medical Research , Manhasset, NY, USA
                Author notes
                Correspondence: Joyce S Hui-Yuen Division of Pediatric Rheumatology, Steven and Alexandra Cohen Children Medical Center , 1991 Marcus Avenue, Suite M100, New Hyde Park, NY11040, USATel +1 516.472.3700Fax +1 516.472.3752 Email jhuiyuen@nshs.edu
                Article
                252592
                10.2147/TCRM.S252592
                7814238
                © 2021 Bag-Ozbek and Hui-Yuen.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 0, Tables: 4, References: 98, Pages: 16
                Funding
                Funded by: No specific funding;
                No specific funding was received to carry out the work described in this manuscript.
                Categories
                Review

                Medicine

                epratuzumab, rituximab, belimumab, novel b-cell therapies, treatment, systemic lupus erythematosus

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