Pharmacological treatment of digital ulcers in Systemic Sclerosis

The role of endothelin in the SS microangiopathy

Endothelin-1 (ET-1), a 21-amino acid peptide, is a potent vasoconstrictor, mainly produced by endothelial cells, that is found in high concen- trations in the skin as well as in lung, kidney, and plasma of patients with SSc.

Besides being a potent vasoconstrictor, ET-1 is a direct downstream target of transforming growth factor-1 (TGF-1) and it behaves as a profibrotic cytokine, stimu-lating fibroblast chemotaxis and proliferation and inducing procollagen and fibronectin synthesis. Further, increased circulating ET-1 levels have been observed in patients with diffuse SSc with widespread fibrosis and those with limited SSc and hypertensive disease, suggesting that soluble ET-1 levels may be a marker of vascular damage. Thus, ET-1 is suggested to contribute signifi- cantly to fibrogenesis, linking between vasculopathy and fibrosis, and the blockade of ET-1 signaling might lead to the reduction of fibrogenesis. Because ET-1 mediates its biological effects on fibro- blasts through endothelin A and B receptors (ETA/BR), there is growing evidence that antagonizing the interaction with these receptors might represent a possible strategy to downregulate the effects of ET-1 at least on the skin fibrosis of SSc disease.

Therapeutic approaches to reduce the appearance of new digital ulcers

There are several therapeutic approaches to improve RP or to reduce the appearance of new digital ulcers.



Bosentan, a dual ET-1 receptor anta- gonist, has been licensed to treat pulmonary hypertension and to prevent the onset of new digital ulcers in patients with SSc and history of digital ulcers.



Iloprost is a prostacyclin analog that blocks platelet aggregation and adhesion, dilates arterioles and venules, activates fibrinolysis, and reduces the release of oxygen-reactive species, reducing the effects of RP9. ET-1 receptor antagonism exerted over the long term in patients with SSc may interfere with the mechanisms inducing progressive microvascular damage such as capillary loss.

The combination of Bosentan and Iloprost significantly improves the skin microcirculation in Systemic Sclerosis

Studies have reported the longterm effects of ET-1 receptor antagonism on nailfold microvascular damage changes, as assessed by NVC analysis in patients with SSc who had digital ulcers. In particular, NVC revealed that treatment with the combination of bosentan with iloprost significantly increased the number of capillaries after 2 years of treatment.

No new digital ulcers were detected in the patients with SSc during longterm treatment with ET-1 receptor antagonist combined with iloprost,

The intensive longterm combination treatment with intravenous iloprost (5-day cycles, with 24-h continuous intravenous infusion, every 3 months) seems to further enhance the effects of the ET-1 receptor antagonism compared to the monotherapy.


Cutolo M, Zampogna G, Vremis L et al. Longterm effects of endothelin receptor antagonism on microvascular damage evaluated by nailfold capillaroscopic analysis in systemic sclerosis. J Rheumatol. 2013