antagonist in lapine monoarticular arthritis . Antifibrotic action of interleukin-1 receptor

Objective-To determine if the administration ofinterleukin-l receptor antagonist (IL-Ira) to animals with established antigen induced arthritis had any beneficial effects on the synovitis and cartilage destruction. Methods-Antigen induced arthritis was induced in New Zealand White rabbits, and after two weeks IL-Ira was administered every six hours over a 72 hour period. Animals were then killed and joint tissues examined for the degree of synovitis, synovial fibrosis, and cartilage damage. Results-The response of the arthritis to the treatment was minor in terms of joint swelling, leucocyte accumulation, or cartilage proteoglycan loss. However, the synovial fibrosis was not only halted by administration of IL-Ira, but reversed. The inflamed synovial linings of IL-Ira treated animals showed a significant loss of synovial collagen content and a reappearance of the synovial fat spaces which are prominent in the normal synovial lining. Conclusion-This study shows that IL-Ira has potent antifibrotic activity and suggests the use of this agent for the reversal of the fibroproliferative process which is so important in the pathology of rheumatoid arthritis. Division of Biochemistry, Kennedy Institute of Rheumatology, Bute Gardens, London W6 7DW, United Kingdom J Lewthwaite T E Hardingham Maxillofacial Surgery Research Unit, Eastman Dental Institute for Oral Health Care Sciences, University ofLondon, 256 Gray's Inn Road, London WCIX 8LD, United Kingdom S Blake B Henderson Synergen Inc, 1885 33rd Street, Boulder, Colorado 80301, USA R C Thompson Correspondence to: Professor Brian Henderson. Accepted for publication 13 February 1995 (Ann Rheum Dis 1995; 54: 591-596) The synovitis associated with rheumatoid arthritis is also accompanied by a profound proliferative and fibrotic response which can clearly be seen when the joint is opened at surgery. The rheumatoid synovial lining becomes enlarged, growing over and into the articular cartilage, and normally forms a mass of villous processes which protrude into the joint space. This fibroproliferative response is one of the complex processes that leads to the destruction of articular cartilage and subchondral bone in this disease.' Cytokines and growth factors are likely to be involved in this synovial fibroproliferative response, but there are a number of problems in defining their precise role. Most human rheumatoid synovium available for study comes from patients at the end stage of disease, by which time the fibroproliferative response is likely to be much less active. It is only in recent years that agents specifically inhibiting cytokine synthesis or function have become available for clinical evaluation. It is possible to test hypotheses concerning the role of cytokines and growth factors in synovial fibroproliferation by use of animal models of rheumatoid arthritis. One model that has been used extensively and which mimics the synovial fibroproliferative response of rheumatoid arthritis is antigen induced arthritis in the rabbit.2" Induction of arthritis produces a swift proliferative response in many of the resident cell populations2 5 which is associated with the accumulation of leucocytes in the synovial subintima.3 A striking finding is the rapid increase in collagen content of the inflamed synovial lining.6 Two members of the interleukin (IL)-l family, IL-la and IL-1iB, are potent proinflammatory molecules with the capacity to stimulate mesenchymal cells, including synovial fibroblasts, to proliferate and produce increased levels of connective tissue macromolecules.7 Thus it is possible that, by blocking the activity of IL-1, one could inhibit this fibroproliferative response in the inflamed synovial lining. The specific blockade of IL-1 is now possible by utilising the third member of the IL1 family-interleukin1 receptor antagonist. This protein has the capacity to bind to the type I IL1 receptor without triggering an agonist response, and thus functions as a receptor antagonist.7 8 It can therefore be used to identify pathology caused specifically by this cytokine. Previously, we have shown that the intravenous administration of IL-lra is effective in inhibiting the synovitis and cartilage proteoglycan loss caused by the intra-articular injection of IL-1.9 In a subsequent study, we found that IL-lra had no inhibitory effect on swelling, leucocyte accumulation or cartilage proteoglycan loss when administered to rabbits with acute antigen induced arthritis.'0 These results suggest that IL1 is not a major mediator of the induction phase of this experimental lesion. In terms of the management of rheumatoid arthritis, it is obviously of more interest to determine what effect inhibitors such as IL-Ira have on the established disease. Therefore, in the present study we have examined the effects of administering IL-lra to rabbits in which disease had been induced two weeks earlier. At this stage the joints are chronically inflamed and there are marked fibroproliferative changes in the inflamed synovial lining.2 6 591 group.bmj.com on June 11, 2017 Published by http://ard.bmj.com/ Downloaded from