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Effect of etanercept on matrix metalloproteinases and angiogenic vascular endothelial growth factor: a time kinetic study
  1. A Aggarwal,
  2. S Panda,
  3. R Misra
  1. Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
  1. Correspondence to:
    Dr A Aggarwal

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Chronic synovitis in rheumatoid arthritis results in the formation of pannus that invades the joint cartilage and the underlying bone. Matrix metalloproteinases (MMPs) can degrade cartilage, bone, and connective tissue matrix.1 Of these matrix degrading enzymes, MMP-1 is the most important and is present in the synovial lining of patients with rheumatoid arthritis (RA).2 In synovial tissue, the level of tissue inhibitor of MMP (TIMP) is reduced, tilting the balance towards tissue destruction. The effect of soluble tumour necrosis factor receptor (sTNFr) on these mediators is not known, because the only study available had pooled data of patients treated with sTNFr alone and in combination with methotrexate.3

Angiogenesis is central to the maintenance of pannus and is controlled by many factors. Identification of vascular endothelial growth factor (VEGF) as the major angiogenic factor, demonstration of its presence in the synovial tissue of patients with RA,4 and suppression of collagen induced arthritis by its inhibitor suggest that it may have a role in the angiogenesis of RA.5 TNF up regulates the production of VEGF.6 No data are available on the effect of sTNFr on VEGF. Thus we studied the effect of sTNFr monotherapy on VEGF and MMPs in patients with RA.

Ten patients with RA (all women, nine seropositive, mean age 35.2 years, mean duration of disease 6.2 years)7 were studied. They received 25 mg of sTNFr (etanercept) twice weekly subcutaneously. No other disease modifying antirheumatic drugs were given. Plasma samples were collected at baseline and then weekly for the first 1 month and monthly thereafter for the next 3 months. Clinical assessment included 28 swollen joint count, 28 tender joint count, duration of early morning stiffness, physician’s and patient’s global assessment, and Health Assessment Questionnaire. VEGF, MMP-1, and TIMP were measured by sandwich enzyme linked immunosorbent assay (ELISA; R&D, Minneapolis, USA). C reactive protein was measured by turbidimetery. Non-parametric tests were used for correlation and intergroup comparison.

There was a good correlation between the levels of C reactive protein and those of VEGF (p<0.001) and MMP (p<0.002). After treatment the levels of MMP fell significantly (fig 1A) as compared with baseline values as early as 2 weeks after the start of treatment. The levels of TIMP-1 however remained unchanged (fig 1B). VEGF levels also fell but to a lesser degree (fig 1C). These effects paralleled changes in clinical parameters like tender joint count or swollen joint count (figs 1D and E).

Figure 1

 Box plot showing the percentage change at different times in patients treated with etanercept as compared with the baseline value in each patient (A) MMP-1; (B) TIMP-1; (C) VEGF; (D) 28 tender joint count; (E) 28 swollen joint count. o depicts outliers and * depicts extreme values. †p<0.05, ‡p<0.005. For values with †pcorr was not significant after Bonferroni’s correction.

MMPs cause tissue destruction because of their proteolytic abilities. Our data of more than 50% decrease in MMP-1 within 2 weeks of the start of treatment suggest that TNF blockade down regulates production of MMPs. Recently, sTNFr treatment has been shown to reduce MMP expression in the synovial membrane.3 Anti-TNF antibody has also been shown to have similar effect on MMPs.8 An ideal treatment will be one which increases levels of TIMP and reduces levels of MMP. Unfortunately, most data,3,8 including ours, show that TIMP levels are either not affected or are reduced to a smaller degree than MMPs with TNF blockade. Even this change is likely to tilt the balance in favour of TIMP and thus prevent action of MMPs and tissue damage.

As far as we know, our study is the first to demonstrate the effect of sTNFr on plasma VEGF in patients with RA, even though the effect was mild. Reduction in serum VEGF levels was also reported with the use of anti-TNF antibody.6 However, serum VEGF levels may be confounded by VEGF released by platelets, which may increase with the thrombocytosis of inflammation. Hence we measured plasma VEGF levels.

Thus sTNFr has significant and early effect on mediators of tissue damage.


This work was supported by a research grant to AA from the author’s institution. Etanercept was supplied by Wyeth Lederle Ltd as part of a multi-institutional study.