Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: relationship to radiological progression and inflammation in early rheumatoid arthritis. A prospective 5-year study

Objective. To assess how serum concentrations of some cytokines, proteases and their inhibitors and cartilage oligomeric matrix protein (COMP) relate to the evolution of clinical disease and joint damage in early rheumatoid arthritis (RA). Methods. Annual assessment was performed in 24 RA patients subdivided into thrice groups according to disease severity as determined by the radiological progression rate. All patients were followed for 5 yr after inclusion. Functional status, Larsen's radiographic index in hands and feet (joint damage score, JDS) and C-reactive protein (CRP) were assessed annually and compared with interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1Ra), promatrix metalloproteinase 3 (proMMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1) and COMP. which were determined by specific immunological tests. Results. The median JDS was initially between 4.5 and 7. During the study time the progression of JDS was 1 (median) for patients with slow progression, 33 for patients with intermediate progression and 62 for patients with rapid progression. Changes in CRP and proMMP-3 concentrations over time differed significantly between the groups, but no significant difference was observed for IL-1Ra, TIMP-1 or COMP. ProMMP-3 was closely related to CRP at each time point. IL-6 correlated significantly with CRP at the last four annual follow-up examinations. CRP and proMMP-3 correlated with JDS at the last two or three examinations and the combined levels of these markers over 5 yr correlated significantly with joint damage progression (Spearman rank correlation 0.73 and 0.74 respectively). IL-1Ra showed a weak negative correlation with JDS, and COMP tended to correlate with JDS only at the start. The initial proMMP-3 concentration was the only significant variable predicting rapidly developing joint damage, but the predictive value was low. Conclusions. ProMMP-3 correlated closely at all time points with CRP, but gave little or no additional clinical information regarding inflammation or radiographic progression, IL-1Ra and TIMP-1 showed weaker, acute-phase-like variation, which may reflect pathogenic agonist inhibitor imbalance in the evolution of RA. COMP, in contrast, did not reflect the inflammatory CRP-related component of the disease or the destructive aspect in this study.