TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis

Abstract

Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The present study investigated the effect of anti-tumor necrosis factor-α (anti-TNF-α) therapy in combination with methotrexate on plasma sGAG levels and serum markers of endothelial dysfunction. Among sGAG types, plasma chondroitin/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/H) were characterized using electrophoretic fractionation. Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and asymmetric dimethylarginine (ADMA) were measured by immunoassays. The measurements were carried out four times: at baseline and after 3, 9 and 15 months of anti-TNF-α therapy. All analyzed parameters, excluding ADMA, were significantly elevated in patients with RA before the implementation of biological therapy compared to healthy subjects. Performed anti-TNF-α treatment led to a successive decrease in HS/H levels toward normal values, without any effect on CS/DS levels in female RA patients. The treatment was also effective at lowering the serum levels of sVCAM-1, MCP-1, MMP-9 and ADMA. Moreover, a significant positive correlation was found between the circulating HS/H and the 28 joint disease activity score based on the erythrocyte sedimentation rate (DAS28-ESR, r = 0.408; p <0.05), MCP-1 (r = 0.398; p <0.05) and ADMA (r = 0.396; p <0.05) in patients before the first dose of TNF-α inhibitor. In conclusion, a beneficial effect of anti-TNF-α therapy on cell-surface heparan sulfate proteoglycans (HSPGs)/HS turnover and endothelial dysfunction was observed in this study. This was manifested by a decrease in blood HS/H levels and markers of endothelial activation, respectively. Moreover, the decrease in the concentration of HS/H in the blood of patients during treatment, progressing with the decline in disease activity, indicates that the plasma HS/H profile may be useful for monitoring the efficacy of anti-TNF-α treatment in patients with RA.

To explore the application of HMGB1, SII, S100A8 / A9 and MCP-1 in the diagnosis, condition monitoring and prognosis of rheumatoid arthritis

“…MCP-1 had the highest sensitivity, which may be related to the massive in ltration of its main chemotactic monocytes / macrophages into the joint cavity. HMGB1, SII, S100A8/A9 and MCP-1 were close to the classical indexes RF and Anti-CCP in AUC area, sensitivity, speci city and yoden index, and all of them have reached the medium diagnostic value, consistent with the ndings of A Szeremeta, et al [22] , it can assist RF and Anti-CCP and improve the diagnostic e ciency of RA patients.…”

“…M gernert et al [21] found that the expression of S100A8/A9 was different in different RA activities, which may be involved in the pathogenesis of RA. MCP-1 is an important factor in monocyte / macrophage mediated in ammatory process, which can recruit and chemotactic monocytes to penetrate into synovial tissue and differentiate into macrophages and osteoclasts, leading to the formation of synovial in ammatory environment, joint destruction, and the development of RA [22] .…”

Effects of Etanercept and Adalimumab on Serum Levels of Cartilage Remodeling Markers in Women with Rheumatoid Arthritis

“…Indeed, TNFαI therapy has been found to downregulate the levels of various MMPs in the serum of RA patients [ 40 , 41 , 42 , 43 , 44 , 45 ]. Additionally, in our previous studies [ 25 , 46 ], we documented the beneficial effects of TNF-α blockade on serum levels of MMP-9, as well as ADAMTS-4 and ADAMTS-5, in female RA patients. In the present study, we observed a statistically significant reduction in the serum concentration of MMP-3 in response to anti-TNF-α treatment.…”

Collagen in Orthopedics: From Molecules to Therapies

“…RA is characterized by several autoantigens including guanosine proteins, type II collagen, and circulating serum proteins. Autoantibodies like the rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) that are produced to counter these antigens serve as diagnostic markers of RA [22,54,56]. During disease progression, MMP-13 cleaves type II collagen, thus reducing its levels and leaving behind degradation products in the articular cartilage.…”