Leflunomide and methotrexate reduce levels of activated matrix metalloproteinases in complexes with alpha(2) macroglobulin in serum of rheumatoid arthritis patients

Objective: To analyse the effects of leflunomide and methotrexate treatment on matrix metalloproteinase (MMP) activity levels in alpha(2) macroglobulin/MMP (alpha M-2/ MMP) complexes in the systemic circulation of rheumatoid arthritis (RA) patients. Methods: A total of 102 RA patients from a prospective, double-blind, randomised clinical trial comparing leflunomide and methotrexate were selected; clinical data and blood samples were collected at baseline, at 4 months and at 1 year. Serum MMP activity levels in alpha M-2 were quantified using low molecular weight fluorogenic substrates, indicating the proportion of activated MMPs that were not inhibited by specific tissue inhibitors of MMP (TIMP). Results: Patients had active disease as shown by high disease activity score (DAS, mean of 6.9 and 7.0 for methotrexate and leflunomide patients respectively), which was reduced over the study period (4.2 and 5.2 respectively, p<0.001). In leflunomide-treated patients a significant reduction of MMP activity levels was observed as early as at the 4 months timepoint persisting thereafter, whereas in methotrexate-treated patients the reduction was seen at 1 year. Conclusion: The results show that systemic levels of activated MMPs are reduced in RA patients upon exposure to leflunomide or methotrexate.