Presently, the most effective treatment for rheumatoid arthritis in humans is TNFα neutralisation.32,33,34,35,36,37,38
However, 30–40% of patients with rheumatoid arthritis are resistant to anti‐TNFα therapy, suggesting that in a proportion of patients the disease is TNFα‐independent. In SCW arthritis mice, only joint inflammation is TNFα‐dependent whereas joint destruction is not blocked by TNFα antagonists.21
We have investigated the anti‐inflammatory and chondroprotective efficacy of GM‐CSF neutralisation in the SCW arthritis model in an attempt to identify a treatment that could potentially be effective in cases of TNFα‐independent destructive disease. We have used a rat anti‐mouse GM‐CSF neutralising mAb and shown that it has a high binding affinity for recombinant mouse GM‐CSF and equally high cytokine‐neutralising potential. Our results show a significant dose‐related anti‐inflammatory activity of GM‐CSF neutralisation by mAb 22E9 as measured by the uptake of a radiolabelled molecule into knees, a validated test for quantification of joint swelling.29
The suppression of joint swelling by 22E9 was seen on days 1 and 2 after arthritis induction and was comparable to the anti‐inflammatory effect observed with dexamethasone treatment. GM‐CSF neutralisation by mAb 22E9 was clearly superior to TNFα neutralisation by Enbrel at the same protein concentration (300 μg) showing that the two anti‐inflammatory approaches have different modes of action in the SCW model. Apparently, GM‐CSF neutralisation did not act via inhibition of TNFα production but rather via inhibition of other mediators of inflammation.
Many pathogenic features of arthritis rely on the accumulation of inflammatory cells in the joints and the local release of proinflammatory mediators such as cytokines and chemokines, inducing more immune cells to the site of disease. This leads to further increased inflammation, even higher levels of proinflammatory cytokines and destructive enzymes in joints, and ultimately to cartilage and bone destruction.39
One of the major constituents of articular cartilage is aggrecan, a large aggregating chondroitin sulphate proteoglycan. Its loss from cartilage is one of the major causes for cartilage destruction in arthritis.40,41
GM‐CSF neutralisation significantly reduced the number of inflammatory cells in the synovium of diseased knees, as did neutralisation of TNFα. However, although efficacious at decreasing cell influx, neutralisation of TNFα had no effect on proteoglycan loss, showing that in this model cartilage proteoglycan loss is independent of TNFα21
and probably mediated by factors produced by cells already present in the joint. By contrast, GM‐CSF neutralisation was remarkably efficacious at decreasing proteoglycan loss showing a chondroprotective therapeutic activity. Published studies have shown that in several models of arthritis one of the main cytokines controlling cartilage destruction is IL1β.21,42,43,44
One possible mechanism of the cartilage protective activity of GM‐CSF neutralisation could be by reduction of local levels of IL1β. Indeed, GM‐CSF neutralisation by 22E9 decreased levels of IL1β in joints whereas TNFα neutralisation had no effect on IL1β levels, thereby providing a possible explanation for the differential chondroprotective effect of both treatments. GM‐CSF treatment had no effect on local levels of other mediators such as the chemokines RANTES and KC or IL6, supporting the predominant role for IL1β in cartilage destruction.
Increased levels of GM‐CSF have been found in rheumatoid arthritis synovium12,13
and synovial fluid,14
suggesting that this cytokine may play a role in the pathogenesis of the disease. Exogenous administration of GM‐CSF to patients with rheumatoid arthritis or Felty's patients and CIA mice also increased disease severity.17,18,19
By contrast, in the absence of GM‐CSF, such as in GM‐CSF knock‐out mice, susceptibility to arthritis is reduced16
and treatment of CIA arthritic mice with anti‐GM‐CSF mAb decreased disease severity.15
Our findings in another experimental model of rheumatoid arthritis support the hypothesis that GM‐CSF may represent a novel therapeutic target for arthritis. Together with our study in the fully TNFα‐independent chronic SCW arthritis model in which treatment was started on week 3 of disease induction (Plater‐Zyberk et al, submitted), our data support the fact that neutralisation of GM‐CSF is a potential treatment that would not only decrease inflammation but additionally protect cartilage from destruction possibly also in TNFα‐independent disease.