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: 1439

The EP4 Receptor Antagonist CR6086 Is More Effective Than Classical NSAID and DMARD Treatment in a Murine Model of Arthritis and in Human RA Synovial Explants

Marije I. Koenders1, Monique M. Helsen1, Birgitte Walgreen1, Wim B. van den Berg1, Gianfranco Caselli2, Ornella Letari2 and Peter M. van der Kraan1, 1Experimental Rheumatology, Radboud university medical center, Nijmegen, Netherlands, 2Rottapharm Biotech, Monza, Italy

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Animal models, DMARDs, naproxen, prostaglandins and rheumatoid arthritis, treatment

  • Tweet
  • Email
  • Print
Session Information

Date: Monday, November 14, 2016

Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: CR6086 is a novel small molecule acting as a potent and selective antagonist of the prostaglandin E2 (PGE2) receptor EP4 subtype (EP4 receptor). Recent studies have shown that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs) and T cell differentiation, and may therefore play a key role in the altered immune response observed in autoimmune diseases such as rheumatoid arthritis (RA). The objectives of this study were: (1) to evaluate the efficacy and immunomodulatory effects of systemic treatment with CR6086 in comparison to classical NSAID or DMARD treatment on experimental arthritis in mice; (2) to confirm the efficacy of EP4 receptor targeting in a translational setting using human RA synovial tissue.

Methods: In female C57Bl/6 mice, antigen-induced arthritis (AIA) was elicited by two immunizations with methylated bovine serum albumin (mBSA) as an antigen in Freund’s complete adjuvant, and subsequently by intra-articular injection with mBSA into the right knee joint. Treatment was started two hours after the onset of arthritis, in 6 treatment groups: CR6086 (20 or 60 mg/kg/day), Naproxen (60 mg/kg/day), Dexamethasone (5 mg/kg/day), Etanercept (10 mg/kg every other day) or vehicle control. The effects of treatment were studied in vivo by 99mTechnetium measurements to detect joint swelling in the arthritic knee joint. At day 7 of treatment, mice were sacrificed and joints were isolated for histological analysis of inflammation and destruction. Synovial tissue was collected at day 3 to assess local cytokine and chemokine production by Luminex, and synovial gene expression by RT-QPCR. Furthermore, synovial explants of RA patients were cultured ex vivo in the presence or absence of CR6086 (300nM), Etanercept (10 µg/mL), or Tofacitinib (300nM), and the effect on spontaneous cytokine and chemokine production was analyzed by Luminex.

Results: Treatment with the EP4 receptor antagonist CR6086 significantly and dose-dependently reduced antigen-induced arthritis, as scored by macroscopic and histological scoring. Interestingly, CR6086 at 60 mg/kg/day was more effective than Naproxen, a classical NSAID, in reducing clinical inflammation scores and histological joint pathology. Furthermore, CR6086 at this dose was as effective as Dexamethasone in reducing histological inflammation, and even more potent in protecting from severe bone erosions. Regarding the immunomodulatory actions of CR6086, our study showed that CR6086 treatment reduced cytokines like IL-1beta, IL-17A, and to a lesser extent IL-6 and IFNgamma. The ex vivo experiment with human synovial tissue showed a beneficial, inhibitory effect of CR6086 on spontaneous secretion of cytokines and chemokines by synovial explants in two RA donors. In these two “responders”, a comparable inhibitory effect of Etanercept was observed, whereas Tofacitinib was clearly less effective than CR6086.

Conclusion: These findings provide support for the potential therapeutic effects of the EP4 receptor antagonist CR6086 in RA patients, and point to the PGE2-EP4 receptor pathway as a rational target for the development of novel DMARDs with immunomodulatory and anti-inflammatory properties.


Disclosure: M. I. Koenders, None; M. M. Helsen, None; B. Walgreen, None; W. B. van den Berg, None; G. Caselli, Rottapharm Biotech, 3; O. Letari, Rottapharm Biotech, 3; P. M. van der Kraan, None.

To cite this abstract in AMA style:

Koenders MI, Helsen MM, Walgreen B, van den Berg WB, Caselli G, Letari O, van der Kraan PM. The EP4 Receptor Antagonist CR6086 Is More Effective Than Classical NSAID and DMARD Treatment in a Murine Model of Arthritis and in Human RA Synovial Explants [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-ep4-receptor-antagonist-cr6086-is-more-effective-than-classical-nsaid-and-dmard-treatment-in-a-murine-model-of-arthritis-and-in-human-ra-synovial-explants/. Accessed .
  • Tweet
  • Email
  • Print

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-ep4-receptor-antagonist-cr6086-is-more-effective-than-classical-nsaid-and-dmard-treatment-in-a-murine-model-of-arthritis-and-in-human-ra-synovial-explants/

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