Abnormal endothelial cell function in scleroderma and related conditions

Background Scleroderma renal crisis (SRC) and scleroderma-associated pulmonary hypertension are life-threatening complications of scleroderma which may be related to abnormal endothelial cell function. Objectives To explore whether endothelial cells are in a highly activated state in SRC, scleroderma-associated pulmonary hypertension, and scleroderma control patients, by measurement of soluble adhesion molecules shed by activated endothelial cells. To investigate the expression of thrombomodulin in scleroderma-associated pulmonary hypertension. To identify risk factors for SRC, and to investigate why some patients progress to end stage renal failure. To assess the effect of Iloprost on the outcome of SRC. To investigate the possibility that anti-endothelial cell antibodies contribute in the pathogenesis of SRC. Findings Measurements of the soluble adhesion molecules sVCAM-1, sICAM-1, and sE-selectin show clear evidence of endothelial cell activation in SRC. In contrast scleroderma-associated pulmonary hypertension was seen to develop without such evidence of endothelial cell activation. Plasma soluble thrombomodulin concentration is elevated in scleroderma-associated pulmonary hypertension but not in scleroderma control plasma. Patients with early diffuse scleroderma, who are anti-RNA polymerase I and III positive are at increased risk of SRC. Severity of renal impairment at presentation was the only factor clearly associated with a worse prognosis in scleroderma renal crisis. Iloprost therapy may improve outcome in SRC. Anti-endothelial cell antibodies do not appear to initiate vascular damage in SRC, but they may potentiate or prolong the period of vascular injury seen in this condition