New data demonstrate that the C5a-C5aR axis is important in the onset of inflammation and may be driving the infiltration of inflammatory cells into synovial fluid in both psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Thus, C5a or C5aR may be a promising target for treatment.
One of the major effector molecules in the complement system is C5a, the split product of complement C5. This molecule is highly proinflammatory and acts on C5a-receptor (C5aR) positive cells. This includes granulocytes, monocytes, subsets of macrophages, dendritic cells, and mast cells. Expression on T cells is still debated.
Danish researchers hypothesized that the C5a-C5aR axis plays a major role in initiating and/or maintaining inflammatory joint diseases such as RA and PsA. They published their findings in PLoS One.1
The aim of the study was to investigate the role of C5a and C5aR in RA and PsA with respect to both expression and function. The study included 30 patients with active RA and 10 patients with active PsA. Nineteen patients with active osteoarthritis (OA) were also included for comparison. These patients all gave fasting blood samples, Patient-Reported General Health was assessed, and synovial fluid was aspirated from an affected joint under ultrasound guidance. A healthy control group of 30 age- and sex-matched subjects was also recruited.
Researchers performed immunohistochemical analyses on synovial tissue samples from joint replacement patients with RA, PsA, and OA. They also performed analyses on synovectomy biopsies from patients with RA.
The results indicate that the C5a-C5aR axis is important in the onset of inflammation and in driving the influx of immune cells into the synovium in both RA and PsA.
In synovial samples from joint replacement, infiltrating C5aR-positive (C5aR+) cells were found in 80% of patients with RA, 100% of patients with PsA, and 73% of patients with OA. No C5aR+ cells were infiltrating the synovium from non-inflammatory controls. In synovial biopsies obtained by synovectomy, C5aR+ cells were present in 100% of patients with RA.
In synovial fluids from RA and PsA patients, all neutrophils and monocytes expressed C5aR. In RA patients, neutrophil and monocytes constituted on average 37% and 9% of the cells in the synovial fluid. In PsA patients, neutrophils and monocytes constituted on average 58% and 7% of the cells in the synovial fluid.
While OA patients were considered the best non-inflammatory controls available, neutrophils and monocytes were constituted on average 5% and 9% in the synovial fluid. These findings suggest low inflammation is likely to be present and questions OA as a non-inflammatory control for the others. However, C5a levels in patients with RA or PsA were still found to be significantly elevated compared with levels in patients with OA.
Implications for future treatment
The findings support a role for the involvement of the C5a-C5aR axis in the pathogenesis of RA. While an oral C5aR antagonist, PMX53, was investigated in a small clinical trial of patients with RA with no effect on clinical score, it can be speculated that the doses were too low.
For PsA, researchers obtained results similar to those obtained for RA patients. In PsA patients, C5a titers were increased in synovial fluid. However, a larger study is warranted to substantiate these conclusions in PsA.
In addition, researchers determined that OA is not a valid non-inflammatory model when comparing arthritic diseases due to a varying inflammatory profile.
In summary, the C5a-C5aR axis is important in the onset of inflammation and driving the influx of immune cells into the synovium in both RA and PsA. "C5a or C5aR may be a promising treatment target in both diseases," researchers conclude.
This study was supported by an unrestricted grant to the Parker Institute from the OAK Foundation.
1. Hornum L, Hansen AJ, Tornehave D, et al. C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid. PLoS One. 2017;12(12):e0189017. doi: 10.1371/journal.pone.0189017.