Background/Purpose: The activated C5a-fragment of complement factor C5 is a potent pro-inflammatory effector molecule that chemo-attracts and activates myeloid cells such as neutrophils, monocytes, and macrophages. C5a levels are elevated in rheumatoid arthritis (RA) synovial fluids, and C5a receptor (C5aR)–expressing cells infiltrate RA synovial tissues. Currently, a Novo Nordisk clinical trial is investigating the potential of an anti-C5aR antibody as a treatment for RA. Because C5a and C5aR-expressing cells are found also in affected joints of collagen-induced arthritis (CIA) mice, we investigated whether a blocking anti-mC5aR antibody is efficacious in inhibiting disease progression in already established arthritis in the CIA model. Furthermore, an analysis of the mechanism of action in the therapeutic CIA model qualified a number of peripheral and locally produced biomarkers with translational potential for future verification of anti-C5aR treatments effects in human trials.

Methods: DBA/1 mice were immunized s.c. with collagen type II in complete Freund’s adjuvant at day 0 and received a boost immunization at day 21. Therapeutic s.c. treatment with an anti-mC5aR mAb was initiated in mice with already established arthritis. Mice were sacrificed after two weeks of treatment (0.5 mg/mouse three times a week) or 48 hours after one single treatment. TNFα inhibition was used as reference treatment. Blood samples were analysed by flow cytometry for cell type and activation state. Cytokine and chemokine profiles were obtained on blood samples and paw homogenates.    

Results: Anti-mC5aR treatment was able to halt disease development. Histopathology and serum MMP-3 levels confirmed the clinical treatment effect. In comparison to treatment with a TNFa inhibitor or control antibody, peripheral blood neutrophils from anti-mC5aR treated mice exhibited significantly reduced CD11b expression after two weeks of treatment, indicating reduced activation. The numbers of circulating neutrophils were reduced in both the anti-TNFα and anti-mC5aR treated groups. The CD11b expression was reduced 48 hours after one single anti-mC5aR treatment. Cytokine and chemokine profiles showed significant impact on local inflammatory mediators in the paw, such as IL-6, KC, MCP-1, and MIP-2 already 48 hours after a single anti-mC5aR treatment but not after a single treatment with a TNFα inhibitor. Anti-mC5aR had no impact on the level of anti-collagen type II antibodies.

Conclusion: The data suggest that C5aR blockade has a rapid effect on joint inflammation by down-regulation of pro-inflammatory mediators. This may be due to a direct effect on infiltrating myeloid cells, as C5a induces cytokine and chemokine release by macrophages and other cells. The effect on the circulating neutrophil number and activation stage indicate also a peripheral effect on target cells, suggesting that leukocyte activation and recruitment may also be targeted by C5aR blockade. The effects on peripheral cells may be used as biomarkers in human clinical trials. In conclusion, mechanistic data from the CIA model suggest that C5aR blockade is a potential novel treatment for arthritis that may elicit rapid clinical effects on both infiltrating and peripheral leukocytes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peripheral-and-local-effects-of-anti-c5ar-treatment-in-the-collagen-induced-arthritis-model/