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.
OBJECTIVE
Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue.


METHODS
In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor 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 clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-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 expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders.


CONCLUSIONS
Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.
Kraan
M C
MC
Department of Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Reece
R J
RJ
Barg
E C
EC
Smeets
T J
TJ
Farnell
J
J
Rosenburg
R
R
Veale
D J
DJ
Breedveld
F C
FC
Emery
P
P
Tak
P P
PP
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000378:metabolism*; D004311:Double-Blind Method; D006801:Humans; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077339:Leflunomide; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D011446:Prospective Studies; D013583:Synovial Membrane / Q000737:chemistry / Q000201:enzymology*; D013585:Synovitis / Q000150:complications / Q000201:enzymology*; D013810:Therapeutic Equivalency
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D007555:Isoxazoles; D008666:Metalloendopeptidases; D000077339:Leflunomide