Association of circulating levels of MMP-8 with mortality from respiratory disease in patients with rheumatoid arthritis

Introduction: Matrix metalloproteinases (MMPs) are implicated in the destruction of the joint and have been shown to be strongly associated with inflammation in rheumatoid arthritis (RA). Circulating MMPs have also been associated with cardiovascular disease in the general population, and are predictive of cardiovascular mortality. The purpose of the present study was to determine whether circulating levels of MMPs are predictive of mortality in RA. Methods: A multiplex suspension array system (Luminex (R)) was used to measure levels of MMPs (1, 2, 3, 8 and 9) in sera taken at recruitment of RA patients (n = 487) in a study of factors associated with mortality in RA. Patients were tracked on the National Health Service Central Register for notification of death, and the relationship between baseline MMP levels and mortality was analysed using Cox proportional hazards regression analysis. Results: At the time of follow-up, 204/486 patients had died, of which 94 (46.1%) had died of circulatory diseases, 49 of malignancy (24.0%), and 42 (20.6%) of respiratory diseases. In a stepwise analysis which included all MMPs, only MMP-8 was significantly associated with all cause mortality (P = 0.0007, 0.6% hazard ratio increase per ng/ml). No association was found between MMP levels and mortality due to circulatory disease or malignancy. However MMP-8 levels were strongly associated with mortality due to respiratory disease (P < 0.0001, 1.3% hazard ratio increase per ng/ml). The association with respiratory disease related mortality remained highly significant in multivariate models which included smoking as well as markers of severity and disease activity such as rheumatoid factor, nodular disease, and C-reactive protein (CRP). Conclusions: The serum level of MMP-8 is a strong predictor of mortality in RA, especially that due to respiratory disease. This finding is consistent with increased activation of neutrophils in RA and identifies serum MMP-8 as a useful marker for increased risk of premature death.