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

• Published in: Arthritis and rheumatism 2000-02, Vol.43 (2), p.270-274
• Main Authors: Smeets, Tom J. M., Dayer, Jean M., Kraan, Maarten C., Versendaal, Johannes, Chicheportiche, Rachel, Breedveld, Ferdinand C., Tak, Paul P.
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - therapeutic use; Adult; Aged; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Dinoprostone - biosynthesis; Diseases of the osteoarticular system; Female; Fibroblasts - metabolism; Humans; Immunohistochemistry; Inflammatory joint diseases; Interferon-beta - therapeutic use; Male; Matrix Metalloproteinase 1 - biosynthesis; Matrix Metalloproteinase 1 - drug effects; Matrix Metalloproteinase 3 - biosynthesis; Matrix Metalloproteinase 3 - drug effects; Medical sciences; Metalloendopeptidases - biosynthesis; Middle Aged; Synovial Membrane - chemistry; Synovial Membrane - cytology; Synovial Membrane - metabolism; Synovitis - drug therapy; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/1529-0131(200002)43:2<270::AID-ANR5>3.0.CO;2-H

Objective Interferon‐β (IFNβ) treatment is emerging as a potentially effective form of therapy in various immune‐mediated conditions. This study evaluated the effects of IFNβ therapy on the cell infiltrate, cytokine profile, and expression of metalloproteinase 1 (MMP‐1) in synovial tissue from patients with rheumatoid arthritis (RA). To further assess the mechanism of action, in vitro experiments were conducted to determine the effects of IFNβ on the production of MMP‐1, MMP‐3, tissue inhibitor of metalloproteinases 1 (TIMP‐1), and prostaglandin E2 (PGE2) by human fibroblast‐like synoviocytes (FLS). Methods Eleven patients were treated for 12 weeks with purified natural fibroblast IFNβ (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 obtained by needle arthroscopy at 3 time points: directly before and at 1 month and 3 months after initiation of treatment. Immunohistologic analysis was performed using monoclonal antibodies specific for the following phenotypic markers and mediators of joint inflammation and destruction: CD3, CD38, CD68, CD55, tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), IL‐6, MMP‐1, and TIMP‐1. In addition, we measured the production of MMP‐1, MMP‐3, TIMP‐1, and PGE2 by RA FLS and dermal fibroblasts in the presence and absence of IFNβ. 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 expression of IL‐1β at both 1 and 3 months was observed in synovial tissue after IFNβ treatment. The scores for CD68+ macrophages and TNFα expression also tended to decrease, but the differences did not reach statistical significance. The in vitro experiments revealed inhibition of MMP‐1, MMP‐3, and PGE2production by RA FLS, whereas TIMP‐1 production was only slightly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts. Conclusion The changes in synovial tissue after IFNβ treatment and the in vitro data support the view that IFNβ therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflammation and destruction. Larger well‐controlled studies are warranted to show the efficacy of IFNβ treatment for RA.