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Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
In 2010, the FDA guidelines indicated a need for change in study design for SLE therapies, emphasizing the need for a candidate SLE drug to meet its primary end point in two well-controlled trials that demonstrate superiority. Shortly thereafter, in 2011, after over fifty years, a drug solely for SLE was introduced to the market. Belimumab (BEL) is a recombinant human IgG-1γ monoclonal antibody. Phase 3 clinical trials (BLISS) have demonstrated that BEL, along with standard therapy (MMF or CYC), results in higher response rates as measured by the Systemic Lupus Erythematosus Responder Index (SRI) when compared to placebo and standard therapy at week 52. There seemed to be a dose-dependent relationship, with patients who received 10 mg/kg intravenously experiencing greater responses than those with placebo in all three components of SRI, while patients who received only 1 mg/kg exhibited significantly greater response in only two of the three components (specifically, physician global assessment [PGA] and SELENA-SLEDAI).64 However, this study excluded patients with acute, severe lupus nephritis. Post hoc analysis did indicate decreased proteinuria and renal flares in the study group, suggesting some renal benefit from BEL.65
Connective Tissue Disorders
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Laura Atzori, Caterina Ferreli, Franco Rongioletti
Management: Among systemic agents, antimalarials (e.g., hydroxychloroquine 400 mg/daily) remain a first-line treatment. Short courses of corticosteroids are sometimes necessary to control flares. Oral retinoids and some immunosuppressive treatments, including methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil, are alternative therapies. Anti-BlyS antibody belimumab has demonstrated a good responder index and has recently been approved in SLE. Topical treatment with corticosteroids or calcineurin inhibitors is considered adjuvant treatment.
B
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Combination strategies for lupus nephritis: facts and controversies
Published in Expert Review of Clinical Immunology, 2023
B-lymphocyte stimulator (BLyS), or B-cell-activating factor (BAFF), belongs to the TNF ligand superfamily and is essential for maturation, survival, proliferation, and immunoglobulin class switching of B cells [53]. BLyS binds to any of the three receptors on B cells, namely transmembrane activator and calcium modulator ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF-receptor (BAFF-R). Belimumab is a fully humanized monoclonal antibody against soluble trimeric BLyS and hinders its binding to the receptors. Belimumab reduces the number of peripheral CD20+ B cells, which are mainly of the naïve, transitional, and activated B cell phenotypes [54]. Pre-switched memory B cells and plasmablasts show a delayed reduction but post-switched memory B cells are not affected.
Is chronic pain as an autoimmune disease?
Published in Canadian Journal of Pain, 2022
The pregnancy compensation hypothesis explains why the incidence of autoimmunity is higher in females than in males. In addition, it has recently been shown that females express higher epidermal levels of a putative transcriptional co-factor, vestigial-like family member 3 (VGLL3), independent of biological age and gonadal hormone regulation.73 VGLL3 exhibits female-specific nuclear localization, which suggests that it is implicated to play a key role in sexually dimorphic transcriptional regulation of its target genes. Knockdown of VGLL3 in vitro results in decreased expression of select female-biased immune transcripts, including BAFF (B cell–activating factor, also known as B-lymphocyte stimulator and TNFSF13B). This is the target of belimumab, the only biologic treatment that is currently used to treat systemic lupus erythematosus.74 Similarly, males with this autoimmune condition demonstrate upregulated expression and nuclear localization of VGLL3 in their inflamed epidermis.73 Interestingly, skin-directed overexpression of Vgll3 in female mice causes systemic autoimmunity, with symptoms similar to those observed in patients with systemic lupus erythematosus.75 B-cell expansion, autoantibody production, and immune complex deposition are shown to ultimately contribute to tissue damage. They are all found to be engaged, with upregulated BAFF occurring as a consequence of overexpressed Vgll3 in females, further demonstrating it as a driver of sex-specific autoimmunity.75
Investigational drugs for the treatment of kidney transplant rejection
Published in Expert Opinion on Investigational Drugs, 2022
Lukas K van Vugt, Maaike R Schagen, Annelies de Weerd, Marlies EJ Reinders, Brenda CM de Winter, Dennis A Hesselink
Belimumab is a humanized, monoclonal, anti-B lymphocyte stimulator (BLyS) immunoglobulin (Ig) G1-antibody. Its mechanism of action is to bind members of the tumor necrosis factor (TNF) receptor superfamily, which prevents binding with BLyS (Figure 1). Three TNF receptors are identified as a binding site for BLyS: BAFF-R (BR3; B cell-activating factor-receptor), TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B-cell maturation antigen) [42,43]. BLyS (also known as BAFF; B-cell activating factor) is a cytokine of the TNF ligand family. BLyS is expressed in B cell lineage cells and on various other cell types (monocytes, dendritic cells, and bone marrow stromal cells) [44–46]. Binding of belimumab to the TNF receptor prevents the survival, maturation and activation of B lymphocytes and their differentiation into plasma cells. Moreover, it prevents stimulation of T lymphocyte-dependent and -independent antibody responses and T lymphocyte co-stimulation [47–50]. Belimumab is currently licensed for use in patients with systemic lupus erythematosus [51], where high circulating levels of BLyS result in an abnormally high pathogenic antibody production and autoimmune disease [52].