The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis.
OBJECTIVE
Interferon-beta (IFNbeta) treatment is emerging as a potentially effective form of therapy in various immune-mediated conditions. This study evaluated the effects of IFNbeta 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 IFNbeta 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 IFNbeta (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 alpha (TNFalpha), interleukin-1beta (IL-1beta), 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 IFNbeta.


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-1beta at both 1 and 3 months was observed in synovial tissue after IFNbeta treatment. The scores for CD68+ macrophages and TNFalpha 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 PGE2 production by RA FLS, whereas TIMP-1 production was only slightly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts.


CONCLUSIONS
The changes in synovial tissue after IFNbeta treatment and the in vitro data support the view that IFNbeta 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 IFNbeta treatment for RA.
Smeets
T J
TJ
Academic Medical Center, Amsterdam, The Netherlands.
Dayer
J M
JM
Kraan
M C
MC
Versendaal
J
J
Chicheportiche
R
R
Breedveld
F C
FC
Tak
P P
PP
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000187:drug effects; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000187:drug effects; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D008875:Middle Aged; D013583:Synovial Membrane / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D013585:Synovitis / Q000188:drug therapy*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D019715:Tissue Inhibitor of Metalloproteinase-1; D016899:Interferon-beta; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone