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Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis

I Tchetverikov^1,2, L R Lard², J DeGroot¹, N Verzijl¹, J M TeKoppele¹, F C Breedveld², T W J Huizinga², R Hanemaaijer¹

¹ TNO Prevention and Health, PO Box 2215, 2301 CE Leiden, The Netherlands
² Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands

Correspondence to:
Correspondence to:
Dr R Hanemaaijer, TNO Prevention and Health, PO Box 2215, 2301 CE, Leiden, The Netherlands; R.Hanemaaijer{at}pg.tno.nl

Objective: To analyse the relation between systemic levels of pro-MMP-3, -8, and -9 matrix metalloproteinase (MMP) activity in ₂ macroglobulin (₂M)/MMP complexes and the progression of joint destruction in patients with recent onset rheumatoid arthritis (RA).

Methods: 109 patients with RA of recent onset were entered into this longitudinal study. Patients were followed up for two years; clinical data, blood samples, and radiographs were obtained at baseline and at 1 and 2 years. Serum levels of MMPs were measured by sandwich ELISA and MMP activity assays.

Results: During the two years joint damage progressed from 0 to 10 (median Sharp score, p<0.001). Stable levels of pro-MMP-3 and a significant decrease in the levels of pro-MMP-8 and -9 and ₂M/MMP complexes were seen throughout the two years. Regression analysis showed that serum pro-MMP-3 levels at disease onset were independently associated with the progression of joint damage (B=0.7, 95% CI 0.3 to 1.1, p=0.001). Based on the rate of joint destruction, patients were divided into two subgroups: patients with mild and severe joint damage progression. The pro-MMP-3 levels were significantly higher in the group with severe compared with mild disease at all times. Levels of pro-MMP-8 and -9 were decreased in both groups, whereas ₂M/MMP complex levels decreased in the group with mild disease only.

Conclusion: Serum levels of the MMPs studied are associated with disease activity, but serum pro-MMP-3 levels at the onset of disease are also predictive of joint damage progression.

Keywords: matrix metalloproteinases; rheumatoid arthritis; joint damage

Abbreviations: ACR, American College of Rheumatology; ₂M, ₂ macroglobulin; CI, confidence interval; CRP, C reactive protein; DAS, disease activity score; DMARD, disease modifying antirheumatic drug; EAC, early arthritis clinic; ELISA, enzyme linked immunosorbent assay; JDS, joint damage score; MMP, matrix metalloproteinase; RA, rheumatoid arthritis; RF, rheumatoid factor; SE, shared epitope; SF, synovial fluid; TIMP, tissue inhibitor of matrix metalloproteinase

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