Endothelin-1 is a potent vasoconstrictor and binds to two receptors, ET-A and ET-B, which are variable expressed on endothelial cells, smooth muscle cells, and fibroblasts. Furthermore, endothelin-1 has been found to be released in vitro by scleroderma fibroblasts and could contribute to the development of dermal fibrosis in systemic sclerosis. Bosentan is a dual receptor antagonist, that competes with the binding of endothelin-1 to both receptors and has already been approved for the treatment of pulmonary arterial hypertension in Europe, the US, and some other countries. The purpose of this study is to evaluate the effect of bosentan treatment on skin fibrosis and functionality in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a polymorphic disorder with an unknown cause characterized by fibrosis of the skin, blood vessels, and visceral organs. The degree of skin involvement is a very important outcome measure in patients with this disease. The pathogenesis of SSc involves immunologic mechanisms, vascular damage, and excessive accumulation of extracellular matrix component in the skin. One reason for these changes is meant to be an increased release of endothelin-1, a peptide which has vasoconstrictor effects and possesses mitogenic activity on cultured vascular smooth muscle cells and fibroblasts, cell types that are involved in SSc pathogenesis. Interestingly, endothelin-1 levels are raised in patients with SSc and Raynaud´s disease, particularly, in the subset of patients with diffuse cutaneous SSc who have widespread dermal sclerosis. However, skin fibrosis in SSc is a poorly studied, rare condition for which there are no approved therapies. Bosentan is a dual endothelin receptor antagonist, that competes with the binding of endothelin-1 to both receptors (ET-A and AT-B). It was recently shown to be effective in the treatment of idiopathic as well as pulmonary arterial hypertension (PAH) in SSc, but it has also been proved in two multicenter randomized prospective placebo-controlled double-blind studies in Europe and the US (RAPIDS-1 and RAPIDS-2) that there is a beneficial effect of bosentan in preventing digital ulcers in these patients. Furthermore,it has been suggested that bosentan has also a positive effect on skin fibrosis. In this study, skin fibrosis will be measured using 20-MHz-ultrasound, the Rodnan Skin Score, and investigation of the fist closure of each patient during treatment with bosentan over 24 weeks.

Inclusion Criteria:

• Patients with systemic sclerosis (diffuse SSc, limited SSc)
• ACR criteria fulfilled
• Current areas of skin fibrosis due to SSc
• Women postmenopausal or negative pre-treatment pregnancy test as well as a reliable method of contraception during study treatment and for at least 3 months after study treatment termination
• Signed informed consent

Exclusion Criteria:

• Severe PAH or interstitial lung disease (WHO class III and IV)
• Skin fibrosis and digital ulcers (DUs) due to conditions other than SSc
• Systolic BP < 85 mmHg
• Hemoglobin concentration < 75% of the lower limit of the normal range
• AST and/or ALT values greater than 3 times the upper limit of normal
• Moderate to severe hepatic impairment
• Severe malabsorption, severe organ failure or any life threatening condition
• Breast feeding
• Treatment with any of the following drugs: glibenclamide (glyburide), cyclosporine A, and tacrolimus 1 week prior to study participation
• Treatment with parenteral prostanoids 3 months prior to study participation
• Treatment with inhaled, subcutaneous or oral prostanoids 1 month prior to registration
• Systemic antibiotics to treat infection of DUs 2 weeks prior to study participation
• Current treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction
• Patient with conditions that prevent compliance with the protocol or adhering to therapy
• Patient who received an investigational product within 1 month preceding screening
• Known hypersensitivity to bosentan or any of the excipients