Background/Purpose: Discovery of the essential role of S1P signaling in regulating lymphocyte trafficking led to the development of S1P receptor modulators for the treatment of autoimmune disorders such as multiple sclerosis and ulcerative colitis. Cenerimod, a selective S1P1 receptor modulator, has shown positive results in preclinical models of SLE, systemic sclerosis, and Sjögren’s syndrome^1-3 and two phase 2 trials in SLE. Recruitment is ongoing for two Phase 3 clinical trials investigating 4 mg cenerimod for the treatment of adults with SLE (OPUS; NCT05648500 & NCT05672576). We examined the potential of cenerimod to modulate the progression of rheumatoid arthritis (RA) in multiple preclinical murine models.⁴

Methods: Cenerimod was orally administered as therapeutic or prophylactic treatment in RA rodent models. In the mBSA-DTH model, C57BL6/J mice were immunized with mBSA/CFA before antigen challenge. Pristane-induced arthritis (PIA) and adjuvant-induced arthritis (AIA) were induced in rats by CFA or pristane challenge, respectively. Disease development was monitored by measuring edema formation. Relevant biomarkers such as cellular changes, autoantibody development, and chemokine secretion were measured in plasma, inflamed tissue, and draining lymph nodes.

Results: In the mBSA-DTH model, cenerimod significantly reduced joint swelling and limited the production of autoantibodies and pro-inflammatory chemokines in the joints. Furthermore, analysis of the draining lymph nodes revealed a novel effect of cenerimod treatment in mitigating the migration of dendritic cells. Similarly, proliferation and cytokine secretion by effector T cells were blunted by S1P1 receptor modulation, which may be a direct consequence of reduced dendritic cell lymph node homing and hence, antigen presentation. In the rat PIA model, therapeutic cenerimod treatment decreased paw inflammation by inhibiting leukocyte influx to the site of inflammation. In the AIA model, low-dose cenerimod treatment limited joint inflammation to the same degree as low-dose corticosteroid treatment with dexamethasone, without displaying negative effects on body weight.

Conclusion: Cenerimod is highly efficacious in several murine RA models by preventing antigen transport, by reducing the release of pro-inflammatory cytokines & chemokines, and by inhibiting lymphocyte egress to the circulation. In particular, the reduction of dendritic cell migration suggests cenerimod may modulate antigen presentation, which could have implications for the treatment of autoimmune diseases. Our findings suggest that cenerimod can effectively disrupt multiple nodes of a vicious circle of pathogenesis associated with rheumatic diseases like RA. Combining these novel results with published data, we propose that S1P1 receptor modulation has potential to provide clinical benefit to patients with arthritis who currently lack satisfactory treatment options.

REFERENCES 1. Strasser DS et al. RMD Open 2020;6(2):e001261. 2. Kano M et al. Sci Rep 2019;9:658. 3. Gerossier E et al. Arthritis Res Ther 2021;23:289. 4. Hoyler T et al. Doi: 10.1136/annrheumdis-2023-eular.879

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/successful-treatment-of-rheumatoid-arthritis-in-mice-using-cenerimod-a-selective-modulator-of-the-s1p1-receptor-demonstrates-the-potential-benefits-of-s1p1-receptor-immunomodulation-for-rheumatic-di/