Abstract
In our article, we evaluated the regulatory effects of the infusions of rituximab, a monoclonal antibody directed against CD20+ B cells, on the serum matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in patients with active rheumatoid arthritis (RA) not responding to anti-tumor necrosis factor (anti-TNF) therapy. Twelve RA patients were planned to receive four infusions of 1,000 mg of rituximab at weeks 0, 2, 24 and 26. The therapy was combined with methotrexate (MTX) (20–30 mg/week). Seven patients were refractory to previously received infliximab, and five to etanercept. Serum concentrations of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase B (MMP-9) and TIMP-1 were measured by ELISA on weeks 0, 2, 12, 24, 36 and 52. Initial infusion of rituximab downregulated serum MMP-1 (p < 0.01), MMP-3 (p < 0.001), MMP-9 (p < 0.001) and TIMP-1 (p < 0.05) levels. Second drug administration caused even more remarkable reduction of measured MMPs (p < 0.001 in all cases) and TIMP-1 level (p < 0.01). These findings were accompanied by significantly decreased ratios of measured MMPs to TIMP-1. Next rituximab infusions on weeks 24 and 26 sustained the suppression of serum MMPs levels. Prior to the initial rituximab infusion, serum concentrations of studied MMPs and TIMP-1 significantly correlated with markers of RA activity such as disease activity score (DAS28) and CRP levels. Rituximab therapy, beside a rapid clinical improvement, reduced serum MMPs concentrations in RA patients refractory to anti-TNF treatment. Repeated infusions of rituximab maintained initial serum MMPs suppression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00296-014-3112-1) contains supplementary material, which is available to authorized users.
Highlights
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease from which suffer about 1 % of adult population [1]
Several studies revealed that Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), and especially the disturbances of the enzyme to inhibitor ratios, are involved in the degradation of the articular components in the course of RA [3, 6, 8]
Because MMPs production was proven to be under control of such cytokines such as tumor necrosis factor alpha (TNF-α), [5] anti-TNF drugs were suggested for RA therapy
Summary
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease from which suffer about 1 % of adult population [1]. Disease is characterized by an invasive and tissue destructive infiltrate of lymphocytes, macrophages and synoviocytes in the joint [2]. Matrix metalloproteinases (MMPs) produced by macrophages and synovial fibroblasts were shown to be involved in the articular tissues destruction [3,4,5]. The activity of MMPs is downregulated by tissue inhibitor of metalloproteinases (TIMPs), which neutralize MMPs. MMPs and TIMPs and especially their imbalance are supposed to be engaged in the process of the joint tissues remodeling in RA [6,7,8]. A monoclonal antibody directed against CD20+ B cells was developed to induce transient depletion of B cells which were shown to stimulate MMPs synthesis by macrophages and fibroblasts [5, 10, 11]. A monoclonal antibody directed against CD20+ B cells, showed significant improvements in disease
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