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Leflunomide and methotrexate reduce levels of activated matrix metalloproteinases in complexes with α2 macroglobulin in serum of rheumatoid arthritis patients

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Author: Tchetverikov, I. · Kraan, M.C. · El, B. van · Hanemaaijer, R. · Groot, J. de · Huizinga, T.W.J.
Type:article
Date:2008
Source:Annals of the Rheumatic Diseases, 1, 67, 128-130
Identifier: 240571
doi: doi10.1136/ard.2006.067827
Keywords: Biology · Biomedical Research · alpha 2 macroglobulin · C reactive protein · leflunomide · matrix metalloproteinase · methotrexate · teriflunomide · tissue inhibitor of metalloproteinase 1 · analysis · blood sampling · clinical study · complex formation · controlled study · disease activity · drug activity · drug dose increase · drug effect · drug efficacy · drug exposure · loading drug dose · major clinical study · priority journal · protein blood level · quantitative analysis · rheumatoid arthritis · serum · systemic circulation · Aged · alpha-Macroglobulins · Antirheumatic Agents · Arthritis, Rheumatoid · Biological Markers · C-Reactive Protein · Down-Regulation · Enzyme Inhibitors · Female · Humans · Isoxazoles · Male · Matrix Metalloproteinases · Methotrexate · Middle Aged · Multiprotein Complexes · Phenylalanine · Statistics, Nonparametric · Thiophenes

Abstract

Objective: To analyse the effects of leflunomide and methotrexate treatment on matrix metalloproteinase (MMP) activity levels in a2 macroglobulin/MMP (α2M/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 α2M 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. Chemicals / CAS: alpha 2 macroglobulin, 95568-41-5; C reactive protein, 9007-41-4; leflunomide, 75706-12-6; methotrexate, 15475-56-6, 59-05-2, 7413-34-5; teriflunomide, 108605-62-5, 282716-73-8; tissue inhibitor of metalloproteinase 1, 140208-24-8; alpha-Macroglobulins; Antirheumatic Agents; batimastat, 130370-60-4; Biological Markers; C-Reactive Protein, 9007-41-4; Enzyme Inhibitors; Isoxazoles; leflunomide, 75706-12-6; Matrix Metalloproteinases, EC 3.4.24.-; Methotrexate, 59-05-2; Multiprotein Complexes; Phenylalanine, 63-91-2; Thiophenes