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

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.

Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment

“…Moreover, the demonstration that in our study the favourable effects on endothelial homeostasis seem to be at least partly independent of the reduction of systemic inflammation fits well with this hypothesis and confirms the results of recent in vitro and population-based studies [ 24 , 33 ]. In fact, in a cohort of patients with the CV risk profile, MTX therapy did not reduce the levels of some inflammatory cytokines, such as TNFα, IL-1β and IL-6 [ 46 ].…”

“…In particular, increased intracellular levels of adenosine by activation of adenosine monophosphate-protein kinase genes, reduction of inflammatory cytokines and oxidative stress, scavenging of free radicals and inhibition of neutrophil oxidative burst, as well as improvement of aortic thickening by acting on overexpression of endothelial cell beta-3 receptors, have been suggested as potential mechanisms in recent studies [ 28 – 32 ]. Interestingly, a significant reduction of serum syndeca-1 levels, reflecting an improvement of endothelial layer integrity, was observed following a 6-week MTX monotherapy in a small cohort of RA patients [ 33 ]. Taken together, these results suggest a protective, anti-inflammatory activity of MTX on endothelial layer integrity and function.…”

“…Taken together, these results suggest a protective, anti-inflammatory activity of MTX on endothelial layer integrity and function. However, the positive effect on endothelial homeostasis and the reduced risk of CV events in RA seem to be partly independent from MTX-induced improvement of disease activity, suggesting that alternative mechanisms may contribute to the improvement of endothelial function and reduction of CV risk [ 24 , 33 ]. The effect of MTX on biomarkers and cell subsets of endothelial damage and repair has been poorly explored.…”

Endothelial glycocalyx degradation is associated with acute lung injury and prognosis in septic patients

“…The excessive production of in ammatory factors is directly involved in vascular damage, glycocalyx shedding, and endothelial dysfunction in septic conditions [21]. Besides, Metalloproteinases (MMPs) and disintegrin and metalloproteinases (ADAM) are known to cleave syndecan1 directly from the endothelial cell membrane, which is activated during sepsis [22,23]. Studies have shown degradation of the endothelial glycocalyx facilitates the in ow of uid, including lots of protein and macromolecules into the alveolar space, and exacerbated pulmonary vascular permeability is associated with endothelial glycocalyx degradation under septic conditions [24,25].…”

Endothelial Glycocalyx Degradation in Critical Illness and Injury

“…Prophylactic administration of a TNF-α inhibitor ameliorated glycocalyx degradation in response to low-dose endotoxin in healthy volunteers (12), and a combination therapy of methotrexate and/or a TNF-α inhibitor in rheumatoid arthritis patients decreased syndecan-1 for greater than 6 weeks (122). However, whether TNF-α inhibition would be beneficial to the glycocalyx in the often more severe inflammation observed in critically ill patients is undetermined, although the history of TNF-α inhibition trials (123,124) in sepsis would suggest not.…”