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Raynaud Phenomenon and the Vascular Disease in Scleroderma

Posted Sep 11 2009 4:56pm

Coagulation and Fibrinolysis
The status of the coagulation and fibrinolytic systems in systemic sclerosis is not well described. Mattuci-Cerinic et al. examined the coagulation/fibrinolysis system in 29 patients with systemic sclerosis. Significant activation of the coagulation system and reduction in fibrinolysis activities was noted. The conclusions in this study are in agreement with the histologic findings in systemic sclerosis, in which excessive fibrin deposits are commonly seen in association with thrombosis in the microvessels. Still, no controlled trial using anticoagulation or fibrinolytic enhancing therapy in systemic sclerosis has been accomplished to date.

Atherosclerosis and Hyperlipidemia
van Vugt et al. reported a higher than expected incidence of arteriosclerotic disease and hyperlipidemia in patients with primary Raynaud phenomenon who underwent upper extremity angiograms. Of 103 patients with primary Raynaud phenomenon, the angiograms were compatible with vasospasm in 42 patients, atherosclerotic vascular disease in 44 patients, peripheral embolism in eight patients, and vasculitis and Buerger disease in six patients. Moreover, 47% of patients had hyperlipidemia. The high frequency of atherosclerotic vascular disease in patients with Raynaud phenomenon noted in this study should serve as a reminder of the epidemic nature of atherosclerosis and should encourage the search for hyperlipidemia in patients with Raynaud phenomenon.

Endothelial Apoptosis
The bulk of published studies suggest a pathogenetic role for antiendothelial antibodies in systemic sclerosis. This conclusion was reinforced by Worda et al., who described the induction of endothelial apoptosis in the chicken model of systemic sclerosis (UCD-200) by directly transferring UCD-200 serum into normal chicken embryos. Binding of antiendothelial antibodies to the microvascular EC in the chorioallantoic membrane in association with EC apoptosis was unmistakably seen.

However, the cell and target antigen specificity of antiendothelial antibodies is still unknown. Moreover, standarized detection methods are badly needed. A new assay for antiendothelial antibodies that used indirect immunofluorescence technique with rodent lung preparations and fluorescinated human anti-IgG has been introduced. Positive testing was recorded in 42 of 45 patients with systemic sclerosis. It is not clear whether this method detects ANAs in addition to antiendothelial antibodies, because the reported staining patterns were nuclear or nucleolar in location. Moreover, it is not clear whether antiendothelial antibodies are truly endothelial-specific and whether they react with the same antigens. Indeed, Western blot analysis of EC protein extracts showed an average of 10 reacting bands in each antiendothelial antibody-positive serum, and in most examples, extracts from fibroblast reacted with antiendothelial antibodies, sometimes even more so than with EC.

Vasculogenesis and Angiogenesis
The vascular changes in systemic sclerosis affect predominantly the microcirculation and arterioles, with capillary necrosis and intimal proliferation of arterioles resulting in occlusion of blood vessels, decreased organ blood flow, and a state of progressive chronic organ ischemia. This underperfused state (ischemia, acidosis) should be a fertile ground for neoangiogenesis, but new capillaries are rare, and broad avascular areas are common, suggesting defective pathways in angiogenesis and vascular repair.

Konttinen et al. reported an immunohistochemical study of systemic sclerosis skin that showed rare and sporadic expression of αvβ3 integrin in the blood vessels, suggesting unsuccessful attempts at new vessel formation. The expression of αvβ3 integrin receptor is associated with VEGF-mediated angiogenesis and is used as a histologic marker for new vessel formation.

Circulating Endothelial Cells
The recent innovations in cell isolation and immunohistochemical evaluation allowed the isolation of circulating fully differentiated EC and bone marrow-derived endothelial progenitor cells. Del Papa et al. observed increased circulating EC and bone marrow-derived endothelial progenitors in 46 patients with systemic sclerosis. The circulating number of ECs correlated with the overall disease activity score and with pulmonary hypertension.

Gene Expression Profile in Systemic Sclerosis Skin
Analysis of general and cell type-specific gene expression patterns in systemic sclerosis skin demonstrated upregulation of genes related to endothelial cells (VE-cadherin, Thy 1, von Wilbrand factor, and CD31), B and T cells, and extracellular matrix. The upregulated genes were detected in involved and clinically uninvolved systemic sclerosis skin. It is interesting to note that histologic evidence for fibrosis was seen in clinically unaffected skin. Moreover, no clear differences in patterns of gene expression among fibroblasts derived from systemic sclerosis, morphia, and normal skin were noted, suggesting that fibroblasts in vitro are not a suitable starting sample for examining systemic sclerosis-specific gene expression patterns.

Therapeutic Interventions with Ascorbic Acid.

The hypothesis that a potent water-soluble antioxidant can reverse endothelial dysfunction was tested in 11 patients with systemic sclerosis and 10 healthy subjects.[28] The study was a double-blind, randomized, cross-over, placebo-controlled trial using 2 g ascorbic acid or placebo. No clear effect for ascorbic acid on endothelial-dependent vasodilatation was seen. The authors suggested that the use of different antioxidants or different dosing of ascorbic acid may be required to show beneficial effects for antioxidants on endothelial vasodilatory function.

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