Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis.

Svein Olav Kolset,Trine Marita Reine,Morten Wang Fagerland,Tram Thu Vuong,Gunnbjørg Hjeltnes,Trond Jenssen,Stefan Agewall,Ivana Hollan,Knut Mikkelsen,Øystein Førre,Gia Deyab

doi:10.1371/journal.pone.0253247

Abstract

The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects joints, but can affect other organs and tissues including the circulatory system [1]
No other significant relationships were observed, neither in simple nor in multiple linear regression analyses. This is the first study to demonstrate that antirheumatic treatment is associated with decrease in serum syndecan-1 levels in RA patients
The well-known effect of antirheumatic treatment on Cardiovascular disease (CVD) might be partly due to its protective effect on endothelial glycocalyx (EG)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects joints, but can affect other organs and tissues including the circulatory system [1]. Cardiovascular disease (CVD), mainly due to atherosclerosis, is the main cause of increased mortality in RA. The pathogenesis of the accelerated atherosclerosis in RA is complex and has not been fully elucidated yet. Inflammation appears to play an important role. RA patients are predisposed to endothelial dysfunction (ED), which is the first and reversible stage of atherogenesis [2]. Early detection and therapeutic targeting of ED may be of a great clinical importance

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Conclusion