The effects of interferon-beta treatment on synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis

Objective. Interferon-beta (IFN beta) treatment is emerging as a potentiall y effective form of therapy in various immune-mediated conditions. This stu dy evaluated the effects of IFN beta therapy on the cell infiltrate, cytoki ne profile, and expression of metalloproteinase 1 (MMP-1) in synovial tissu e from patients with rheumatoid arthritis (RA). To further assess the mecha nism of action, in vitro experiments were conducted to determine the effect s of IFN beta on the production of MMP-1, MMP-3, tissue inhibitor of metall oproteinases 1 (TIMP-1), and prostaglandin E-2 (PGE(2)) by human fibroblast -like synoviocytes (FLS). Methods. Eleven patients were treated for 12 weeks with purified natural fi broblast IFN beta (Frone; Ares-Serono, Geneva, Switzerland) subcutaneously 3 times weekly with the following dosages: 6 million IU (n = 4), 12 million IU (n = 3), and 18 million IU (n 4). Synovial biopsy specimens were obtain ed by needle arthroscopy at 3 time points: directly before and at 1 month a nd 3 months after initiation of treatment. Immunohistologic analysis was pe rformed using monoclonal antibodies specific for the following phenotypic m arkers and mediators of joint inflammation and destruction: CDS, CD38, CD68 , CD55, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 b eta), IL-6, MMP-1, and TIMP-1. In addition, we measured the production of M MP-1, MMP-3, TIMP-1, and PGE, by RA FLS and dermal fibroblasts in the prese nce and absence of IFN beta. Results. A statistically significant reduction in the mean immunohistologic scores for CD3+ T cells and the expression of MMP-1 and TIMP-1 at 1 month, CD38+ plasma cells and the expression of IL-6 at 3 months, and the express ion of IL-1 beta at both 1 and 3 months was observed in synovial tissue aft er IFN beta treatment. The scores for CD68+ macrophages and TNF alpha expre ssion also tended to decrease, but the differences did not reach statistica l significance. The in vitro experiments revealed inhibition of MMP-1, MMP- 3, and PGE(2) production by RA FLS, whereas TIMP-1 production was only slig htly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts. Conclusion. The changes in synovial tissue after IFN beta treatment and the in vitro data support the view that IFN beta therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflam mation and destruction. Larger well-controlled studies are warranted to sho w the efficacy of IFN beta treatment for RA.