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: 0512

Co-stimulatory Blockade Causes Targeted Quantitative and Clonotypic Contractions in Extrafollicular B-cell Subsets in Seropositive RA Patients

Jasmine Shwetar1, William Rigby2, Sladjana Skopelia-Gardner3, Abhimanyu Armarnani1, Kelly Ruggles1 and Gregg Silverman1, 1NYU Grossman School of Medicine, New York, NY, 2Dartmouth-Hitchcock, Norwich, VT, 3Dartmouth Hitchcock Medical Center, Hanover, NH

Meeting: ACR Convergence 2024

Keywords: Anti-ACPA, B-Cell Targets, Biologicals, rheumatoid arthritis, T Cell

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

Date: Saturday, November 16, 2024

Title: RA – Treatment Poster I

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Of all approved biologic therapies, other than anti-CD20 depletion only CTLA4-Ig/abatacept treatment reduces levels of pathologic autoantibodies. Herein, our primary goal has been to elucidate the effect of co-stimulatory blockade on the representation of lymphocytes and determine if there are shifts in clonal dynamics associated with clinical response.

Methods: Biologic-naïve patients with seropositive RA were enrolled, and received the standard IV regimen of abatacept, which was then discontinued after the month 5 infusion. Clinical evaluation and biospecimen collection were performed at baseline, 3, 6, and 9 months or when a flare occurred. In addition to routine clinical lab testing, autoantibody responses were evaluated in including CCP3. PBMCs were interrogated at a single cell level for high-dimensional surface phenotype and transcriptomic profiles, by Expanded Cellular Indexing of Transcriptomes and Epitopes (eCITE) sequencing.

Results: 16/18 RA patients that completed 5 months of abatacept treatment, had complete clinical responses based on CDAI, mirrored by reductions in serum RF and ACPA levels (not shown). Single-cell analyses of 7 patients demonstrated treatment-induced increases in naïve CD4+ T cells, and reductions in regulatory T cells, and CD8+ effector memory cells (Fig.1&2). Treatment was also associated with significant reductions of CD19+sIgD-CD27- (DN2) B cells, CD19+CD69+IgM+IgD+ activated Naïve (aNav) B cells and antibody-secreting cells (ASC) that are linked to pathologic autoimmune B-cell responses (not shown).

In the subject with the greatest number of single CD19+ B cells, antibody gene usage was examined, which demonstrated a remarkable expansion of an unique B-cell clonotypic set, as identical VH and VL were found in 21 different B cells (Fig 3), distributed across IgM+IgD- pre-switch memory, CD69+IgM+IgD+ activated naïve (aNav) and CD27-CD11c+Tbet+ DN2 detected across all four sampled timepoints. Most were identified as preswitch memory, which was numerically greatest at baseline (Fig3), then decreased after 3treatment, and then expanded at the time of flare (Fig 3C), yet absent in transitional, naïve, post-switch DN1 and DN4 subsets and ASC. VH genes were closest to VH3-33*04  DH6-13*01 JH3*02, with 7 silent and 6 replacement (including a single CDR) mutation. Vk genes was closest to Vk3-15*01 Jk1*01 with 1 silent and 5 replacement (including a single CDR) mutations. As a recombinant IgM, there was strong binding to CCP3 peptide used for clinical diagnosis,  citrullinated α-enolase, as well autoreactivity for nucleosome and Sm antigen (not shown), reflecting the broad breach in clonal immune tolerance.

Conclusion: Complete clinical response to abatacept in RA was associated with quantitative reductions in extrafollicular; aNav, DN2, preswitch memory, and ASC, as well as reductions in the B-cell clonotypic expansion in these subsets, as identified by surface phenotype and transcriptomic profiles. Our findings are consistent with abatacept causing preferential therapeutic effects on extrafollicular B cells that include DN2 cells, recently implicated as major RA-associated autoantibody producers in rheumatoid joints.

Supported in part by funds from BMS.

Supporting image 1

Figure 1. UMAP clustering for T cell subsets in 7 individual seropositive RA patients, characterized from 55,497 single mononuclear cells. These data demonstrated that CD4+ regulatory T cells (Tregs) nadired at 3 months after treatment, whereas CD8+ effector memory cells dropped to the lowest levels in clinical responders after 6 months of treatment (not shown).

Supporting image 2

Figure 2. Distribution of characteristic transcripts of -cell subsets. UMAP is shown in Fig1.

Supporting image 3

Figure 3. Representation of B cells expressing VH: VL of clonotype in Patient 1, overtime. A) UMAP distribution of B cell subsets. B) Location of 21 distinct B cells expressing identical clonotype 1 VH and VL gene rearrangements. These overlie transcriptomic signatures of pre-switch memory, aNav and DN2 subsets. C) Representation of clonotype 1 B cells at sequential time points of samplings are indicated HTO 1 (baseline), HTO 2 (after 3 months of treatment), HTO3 (after 6 months), and HTO4 (time of disease flare after medication withdrawal). Clonotypic B cells are not found within the transitional, naïve, post-switch DN1, DN4 subsets or ASC.


Disclosures: J. Shwetar: None; W. Rigby: None; S. Skopelia-Gardner: None; A. Armarnani: None; K. Ruggles: None; G. Silverman: NYU, 10.

To cite this abstract in AMA style:

Shwetar J, Rigby W, Skopelia-Gardner S, Armarnani A, Ruggles K, Silverman G. Co-stimulatory Blockade Causes Targeted Quantitative and Clonotypic Contractions in Extrafollicular B-cell Subsets in Seropositive RA Patients [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/co-stimulatory-blockade-causes-targeted-quantitative-and-clonotypic-contractions-in-extrafollicular-b-cell-subsets-in-seropositive-ra-patients/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/co-stimulatory-blockade-causes-targeted-quantitative-and-clonotypic-contractions-in-extrafollicular-b-cell-subsets-in-seropositive-ra-patients/

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