Inhibitory effects of leflunomide therapy on the activity of matrixmetalloproteinase-9 and the release of cartilage oligomeric matrix protein in patients with rheumatoid arthritis.
OBJECTIVE
To determine the effects of the disease modifying antirheumatic drug (DMARD) leflunomide on the expression of the matrix metalloproteinase MMP-1 (collagenase) and the activity of MMP-9 that are believed to play a major role in cartilage destruction associated with inflammation in patients with rheumatoid arthritis (RA). Serum concentrations of cartilage oligomeric matrix protein (COMP) should offer promise for monitoring tissue degradation in the RA joints during a 6-month therapy with leflunomide.


METHODS
Thirty-six patients with RA meeting the ACR-criteria were recruited for the study in a multicentre trial. A dose of 20 mg leflunomide/day (after a 3-day 100 mg/day loading dose), an isoxazole derivate and inhibitor of the "de novo" pyrimidine synthesis, was administered for a study period of 6 months. MMP-1, the activity of MMP-9 and COMP values were measured in serum by enzyme immuno assay. The very sensitive acute phase protein serum amyloid A (SAA) was also determined by EIA. The measurements were performed before and after 3 and 6 months of leflunomide therapy.


RESULTS
High levels of active MMP-9, COMP and SAA were detected in the sera of the patients with RA prior to the start of the leflunomide therapy compared to normal control sera. A significant reduction of the MMP-9 activity levels was seen after 3 months immunomodulation with leflunomide and was maintained after 6 months (p < 0.01). The degradation marker COMP and the inflammation marker SAA decreased significantly after 6 months (p < 0.04, respectively p < 0.01). There was also an insignificant tendency of MMP-1 reduction in serum after 6 months.


CONCLUSIONS
This study demonstrated that a DMARD therapy with leflunomide can cause positive effects on cartilage degradation and inflammation achieving reductions in the acute phase protein SAA, the enzymatic attack of MMPs and the loss of the cartilage matrix component COMP.
Kullich
W C
WC
Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases, Saalfelden, Austria. lbirehab@salzburg.co.at
Mur
E
E
Aglas
F
F
Niksic
F
F
Czerwenka
C
C
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology; D015415:Biomarkers / Q000097:blood; D064236:Cartilage Oligomeric Matrix Protein; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008297:Male; D064235:Matrilin Proteins; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000032:analysis; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D007555:Isoxazoles; D064235:Matrilin Proteins; D000685:Serum Amyloid A Protein; C577553:TSP5 protein, human; D020780:Matrix Metalloproteinase 9; D000077339:Leflunomide