Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis - Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers
Mc. Kraan et al., Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis - Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers, ARTH RHEUM, 43(8), 2000, pp. 1820-1830
Objective. Leflunomide and methotrexate have proven to be efficacious in re
ducing joint inflammation and slowing destruction in clinical trials of pat
ients with rheumatoid arthritis (RA). This study was conducted to provide m
ore insight into the mechanism of action of these agents in synovial tissue
.
Methods. In a 2-center, prospective, randomized, double-blind clinical tria
l, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dos
e) and methotrexate (increased stepwise to 15 mg/week) treatment in patient
s,vith active RA, Paired synovial tissue biopsy samples were obtained by kn
ee arthroscopy at baseline and after 4 months of treatment. Frozen synovial
tissue sections were stained for macrophages (CD68), T cells (CD3), adhesi
on molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adh
esion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interle
ukin-1 beta [IL-1 beta]), matrix metalloproteinase 1 (MMP-1), and tissue in
hibitor of metalloproteinases 1 (TIMP-1).
Results. Paired synovial tissue sections were available in 35 patients (16
taking leflunomide, 19 taking methotrexate). Both drugs displayed equal cli
nical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexa
te-treated patients (53%) fulfilling the American College of Rheumatology 2
0% response criteria. Both compounds showed similar effects on synovial tis
sue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expressio
n were noted after 4 months of treatment. Both leflunomide- and methotrexat
e-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial
tissue. In the subset of patients fulfilling the 20% response criteria of
the American College of Rheumatology, a more pronounced reduction in the ex
pression of ICAM-1, VCAM-1, IL-1 beta, and MMP-1 was found compared with th
e nonresponders.
Conclusion. Leflunomide and methotrexate are clinically efficacious drugs t
hat interfere with mechanisms involved in joint inflammation and destructio
n of joint integrity.