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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.
Arthritis Rheum. 2000 Aug; 43(8):1820-30.AR

Abstract

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.

CONCLUSION

Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.

Authors+Show Affiliations

Department of Medicine, Academic Medical Center, Amsterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10943872

Citation

Kraan, M C., 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." Arthritis and Rheumatism, vol. 43, no. 8, 2000, pp. 1820-30.
Kraan MC, Reece RJ, Barg EC, 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. Arthritis Rheum. 2000;43(8):1820-30.
Kraan, M. C., Reece, R. J., Barg, E. C., Smeets, T. J., Farnell, J., Rosenburg, R., Veale, D. J., Breedveld, F. C., Emery, P., & Tak, P. P. (2000). 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. Arthritis and Rheumatism, 43(8), 1820-30.
Kraan MC, 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. Arthritis Rheum. 2000;43(8):1820-30. PubMed PMID: 10943872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kraan,M C, AU - Reece,R J, AU - Barg,E C, AU - Smeets,T J, AU - Farnell,J, AU - Rosenburg,R, AU - Veale,D J, AU - Breedveld,F C, AU - Emery,P, AU - Tak,P P, PY - 2000/8/16/pubmed PY - 2000/9/9/medline PY - 2000/8/16/entrez SP - 1820 EP - 30 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 43 IS - 8 N2 - 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. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/10943872/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_ L2 - https://doi.org/10.1002/1529-0131(200008)43:8<1820::AID-ANR18>3.0.CO;2-D DB - PRIME DP - Unbound Medicine ER -