ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 1753

A Rheumatoid Factor Paradox: Inhibition of Rituximab-Induced Complement Dependent Cytotoxicity of B Cells

Jonathan D. Jones1, Irene Shyu2, Marianna M. Newkirk3 and William F. C. Rigby2, 1Rheumatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 2Rheumatology, Dartmouth-Hitchcock Med Ctr, Lebanon, NH, 3Medicine, McGill University Health Centr, Montreal, QC, Canada

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: autoantibodies, rheumatoid arthritis (RA) and rituximab

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Title: B-cell Biology and Targets in Autoimmune Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose:  

Rheumatoid factor (RF) is an autoantibody directed against the Fc portion of IgG antibodies.  It is found in ~80% of patients with rheumatoid arthritis (RA). It has been postulated that RF potentiates immune complex disease in RA by enhanced fixation of complement. Rituximab (RTX), an antibody targeting CD20 on B cells, exhibits increased efficacy in seropositive patients with refractory RA.  We hypothesized that this improved efficacy was due to the ability of RF to­­ enhance the ability of RTX to mediate complement dependent cytotoxicity, leading to enhanced synovial depletion of B cells.

Methods:

We developed a model assay system of RTX to mediate complement dependent cytotoxicity (CDC) using the Daudi human B cell line modified to grow in serum-free media. CDC was determined by propidium iodide staining 30 minutes after combining Daudi cells with RTX 10 μg/ml and human sera (1%; as a source of complement) from healthy donors and patients. The effect of RF on RTX-CDC was determined by the following methods:  i) Comparison of CDC by RF+ sera vs RF- sera; ii) Addition of monoclonal IgA or IgM RF to seronegative sera; iii) Mixing studies of RF+ and RF- sera. 

Results:

In the presence of 1% human sera, RTX resulted in rapid (minutes) and profound (>50%) Daudi cell death. This effect was complement dependent as proven by a lack of Daudi cell death by RTX in serum free media, heat-inactivated serum, and C5 deficient serum.  A surprising variation in the ability of human sera to mediate RTX-CDC was observed. The mean percent of RTX-CDC ranged from healthy donors 54% (n=15), RF+ RA patients 47% (n=40), RF- RA patients 88% (n=15), non-RA patients 83% (n=15). Remarkably, sera with an IgM RF >250 IU/ml resulted in a mean CDC of 13% compared to sera with IgM RF 9-100 IU/ml having a mean CDC of 74%.  A similar effect of increasing IgA RF concentration was seen but was not as profound an effect as IgM RF.  Mixing of RF+ sera with RF- sera demonstrated the reduced RTX-CDC, indicating the presence of an inhibitor. The identity of RF as the inhibitory factor was demonstrated by the ability of either purified monoclonal IgM RF or monoclonal IgA RF added to RF- sera to mediate near complete inhibition of CDC at concentrations of 50 μg/ml and 10 μg/ml, respectively.  The inhibitory effect of RF could be blocked by excess IgG.  In addition, we observed that RF did not alter RTX binding to CD20 on B cells.  Therefore, we conclude that RF blocks the ability of early complement components to be recruited to the IgG Fc portion of RTX.

Conclusion:

Contrary to our original hypothesis, RF inhibits RTX induced CDC in vitro. Thus, the enhanced efficacy of RTX in seropositive RA patients cannot be easily attributed to modulation of B cell depletion through CDC. This result is surprising given the roles of RF in immune complex clearance and complement activation. Not only does this generate a new set of insights into the biologic role of RF, it indicates that high RF levels may potentially modulate the efficacy of any therapeutic monoclonal antibody.


Disclosure:

J. D. Jones,
None;

I. Shyu,
None;

M. M. Newkirk,
None;

W. F. C. Rigby,
None.

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-rheumatoid-factor-paradox-inhibition-of-rituximab-induced-complement-dependent-cytotoxicity-of-b-cells/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology