Objective
To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids.

Methods
Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52.

Results
Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti–double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group.

Conclusion
Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.34359

Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study†

Objective

Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.



Methods

A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.



Results

Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/μl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t-test). This improvement persisted for 12 months, despite the absence of a significant change in anti–double-stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level ≥100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.



Conclusion

Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20430

B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin9s lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

/pdf/the-innate-mononuclear-phagocyte-network-depletes-b-4ry5o2ityh.pdf

The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

The invention provides humanized and chimeric anti-CD20 antibodies for treatment of CD20 positive malignancies and autoimmune diseases.

Immunoglobulin variants and uses thereof

In vertebrates, serum antibodies are an essential component of innate and adaptive immunity and immunological memory They also can contribute significantly to immunopathology Their composition is the result of tightly regulated differentiation of B lymphocytes into antibody-secreting plasma blasts and plasma cells The survival of antibody-secreting cells determines their contribution to the immune response in which they were generated and to long-lasting immunity, as provided by stable serum antibody levels Short-lived plasma blasts and/or plasma cells secrete antibodies for a reactive immune response Short-lived plasma blasts can become long-lived plasma cells, probably by competition with preexisting plasma cells for occupation of a limited number of survival niches in the body, in a process not yet fully understood Limitation of the number of long-lived plasma cells allows the immune system to maintain a stable humoral immunological memory over long periods, to react to new pathogenic challenges, and to adapt the humoral memory in response to these antigens

Maintenance of serum antibody levels

In recent years, advances in our understanding of the regulation of the immune system have enabled the identification of cellular and molecular targets that could potentially affect the pathogenesis of many autoimmune diseases. In particular, the demonstration that B lymphocytes could play a central role in pathogenesis suggests that their elimination may be a highly beneficial therapeutic goal in a variety of diseases. Hybridoma antibody technology has been applied as a first step toward developing such specific agents. One of the initial applications of this technology was the characterization of the surface molecules on lymphocytes, to enable the discrimination of each type of lymphocyte. These early studies identified CD20 as a specific marker for B cells (1). CD20 has been found to be highly expressed on the surface of pre–B lymphocytes as well as on both resting and activated mature B lymphocytes, whereas it is not expressed by hematopoietic stem cells, pro–B cells, or other normal tissues (Figure 1). However, despite extensive investigation, the role of CD20 in B cell physiology has remained a mystery; there is no known natural ligand, and CD20-knockout mice are without a discernible immunologic phenotype (2). From the characterization of its encoding gene, CD20 has been predicted to be a 33–37-kd membraneassociated phosphoprotein, with a structure of 4 transmembrane regions, a 44–amino acid extracellular loop, and cytoplasmic Nand C-termini (3). Based on structural homologies, CD20 has been postulated to function as a calcium channel subunit (for review, see ref. 4), which may explain the finding that ligation of CD20 can affect B cell activation, differentiation, and cell cycle progression from the G1 to the S phase (5,6). Important for its use as a therapeutic target, binding of CD20 does not modulate its expression or result in substantial internalization. CD20 is also not shed, and there are no other known membrane or secreted analogs to interfere with its use for B cell targeting (7). In recent reports, the properties of different monoclonal antibodies against human CD20 have been investigated (8). The clinical potential of CD20-targeted therapy derives, in large part, from the unexpected finding that treatment with an antibody to CD20 induces the death of B lymphocytes, even without the need to conjugate the antibody to a toxin. The best-exploredmechanism has been the properties of rituximab (trade name Rituxan), a chimeric monoclonal antibody specific for human CD20, comprising the variable regions of a murine anti-human CD20 B cell hybridoma fused to human IgGand -constant regions (9) (see Figure 1). Rituximab has a binding affinity for human CD20 of 8 nM. The clearance of B cells is, in part, mediated through induction of complement-mediated activities and triggering of antibody-dependent cellular cytotoxicity. This latter activity is dependent on interactions with cellular receptors for the IgG1-constant regions (i.e., Fc receptors), especially Fc receptor type IIIa, which is expressed on a variety of cells including phagocytic cells (10). Rituximab has also been shown to directly trigger intracellular pathways for apoptotic B cell death that involve the activation of phospholipase C , interruption of the signal transducer and activator of transcription 3/interleukin-6 pathway, down-regulation of c-myc, and up-regulation of the proapoptosis molecule Bax, a member of the Bcl-2 family (11,12). This sequence of molecular events results in the activation of Supported by grants AI-40305, AR-47360, and AI-46637 from the NIH, and a grant from the Alliance for Lupus Research. Gregg J. Silverman, MD, Stuart Weisman, MD: University of California, San Diego. Address correspondence and reprint requests to Gregg J. Silverman, MD, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail: gsilverman@ucsd.edu. Submitted for publication September 16, 2002; accepted in revised form January 28, 2003.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.10947

Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Stuart Weisman

Author Tools

Chat about Author

Papers

Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy