...CR2-fH substantially reduced disease activity and joint damage...

An inhibitor of the alternative pathway (AP) of complement activation reduces clinical disease activity and joint damage in an animal model of inflammatory arthritis, according to new research by Banda et al. published in The Journal of Immunology.

The role of the complement system, and in particular the AP, in the pathogenesis of rheumatoid arthritis is unclear. As previously shown by the same investigators in genetically modified mice, the AP is required for the induction of collagen antibody-induced arthritis (CAIA), a model of disease that mimics the effector phase of immune-complex-induced arthritis. The present study was undertaken to explore the role of the major circulating AP inhibitor, factor H, in this disease model.

A recombinant AP inhibitor comprising complement receptor 2 and factor H (CR2–fH) was administered systematically in order to target sites of inflammation in mice with CAIA. Intraperitoneal injection of 250 µg or 500 µg CR2-fH at 0 and 3 days post-induction substantially reduced disease activity scores and signs of joint damage at day 10, in comparison with control-treated mice. Levels of C3 deposition in the synovium and cartilage were also lower in CR2-fH-treated mice, which suggests local effects of the recombinant inhibitor. The higher dose of CR2-fH decreased expression of tumor necrosis factor and increased expression of interleukin-10 in the knee joints of CAIA mice.

Experiments in vitro demonstrated that CR2-fH inhibits only the AP of complement activation, with no marked effects on the classical or leptin pathways. Furthermore, CR2-fH was a more-potent inhibitor of the AP than monoclonal antibodies against factor B and C5.

“We show that, despite the high levels of endogenous serum factor H (around 500 µg/ml), this protein must not be sufficiently able to bind to the cartilage and block the AP,” says lead investigator V. Michael Holers. “Using a method to deliver a supplementary amount of factor H specifically to the joint, we seem to bypass this inherent failure of the normal complement regulatory system.”

Further studies will aim to clarify how the complement system is dysregulated in arthritis.