iloprost and Scleroderma--Diffuse

Intravenous iloprost improves Raynaud's phenomenon (RP) and promotes healing of digital ulcers in systemic sclerosis (SSc; scleroderma). Despite a short half-life, its clinical efficacy lasts weeks. Endothelial adherens junctions, which are formed by VE-cadherin clustering between endothelial cells (ECs), regulate endothelial properties including barrier function, endothelial-to-mesenchymal transition (EndoMT), and angiogenesis. We undertook this study to investigate the hypothesis that junctional disruption contributes to vascular dysfunction in SSc, and that the protective effect of iloprost is mediated by strengthening of those junctions.. Dermal ECs from SSc patients and healthy controls were isolated. The effect of iloprost on ECs was examined using immunofluorescence, permeability assays, Matrigel tube formation, and quantitative polymerase chain reaction.. Adherens junctions in SSc were disrupted compared to normal ECs, as indicated by reduced levels of VE-cadherin and increased permeability in SSc ECs (P < 0.05). Iloprost increased VE-cadherin clustering at junctions and restored junctional levels of VE-cadherin in SSc ECs (mean ± SD 37.3 ± 4.3 fluorescence units) compared to normal ECs (mean ± SD 29.7 ± 3.4 fluorescence units; P < 0.05), after 2 hours of iloprost incubation. In addition, iloprost reduced permeability of monolayers, increased tubulogenesis, and blocked EndoMT in both normal and SSc ECs (n ≥ 3; P < 0.05). The effects in normal ECs were inhibited by a function-blocking antibody that prevents junctional clustering of VE-cadherin.. Our data suggest that the long-lasting effects of iloprost reflect its ability to stabilize adherens junctions, resulting in increased tubulogenesis and barrier function and reduced EndoMT. These findings provide a mechanistic basis for the use of iloprost in treating SSc patients with RP and digital ulcers.

Topics: Adherens Junctions; Antigens, CD; Cadherins; Capillary Permeability; Case-Control Studies; Cells, Cultured; Endothelial Cells; Epithelial-Mesenchymal Transition; Female; Humans; Iloprost; Male; Middle Aged; Neovascularization, Physiologic; Raynaud Disease; Scleroderma, Diffuse; Vasodilator Agents

The pathophysiology of both limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous SSc (dcSSc), representing two subtypes of an autoimmune disease of the connective tissue, is still enigmatic. Life-limiting, progressive fibrotic changes as a consequence of vasculopathy and autoimmunity are characteristic in varying extent for lcSSc and dcSSc. Previously, an increased IL-33 serum concentration in early phase SSc patients and an elevated tissue expression of its receptor, ST2L, on endothelial cells (EC) were described. While suggested as a biomarker for fibrotic diseases, for example liver fibrosis, the role of soluble ST2 (sST2) in the pathological processes and its contribution to vascular fibrosis in SSc has not been investigated. Here, we showed that sST2 is elevated in late phase limited cutaneous SSc (lcSSc) as compared to patients with shorter disease duration or with the diffuse subtype of SSc. We demonstrated that sST2, not IL-33, is significantly increased in serum of lcSSc patients with disease duration over 9 years. Soluble ST2 was not elevated in healthy controls or in SSc patients with early skin involvement or disease duration shorter than 9 years. Furthermore, we observed that sST2 serum levels were lowered by iloprost (prostacyclin) treatment. After 5 days of iloprost infusion, sST2 serum levels fell in 6 of 7 patients. Therefore, we not only like to propose sST2 as a biomarker for progressive vascular fibrosis, but moreover, suggest that the involvement of sST2 in the pathogenesis of lcSSc may be exploited therapeutically.

Topics: Adult; Aged; Autoimmune Diseases; Biomarkers; Disease Progression; Endothelial Cells; Female; Humans; Iloprost; Interleukin-33; Interleukins; Male; Middle Aged; Receptors, Somatostatin; Scleroderma, Diffuse; Scleroderma, Limited; Vasodilator Agents

To report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement.. In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5-1 ng/kg/min (6 hours per day, for 5 days every 6-8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased.. Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient.. This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.

Topics: Adult; Humans; Iloprost; Male; Raynaud Disease; Scleroderma, Diffuse; Vasodilator Agents