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Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

Digital skin vasoconstriction on local cooling is exaggerated in primary Raynaud's phenomenon (RP) as compared with controls. A significant part of such vasoconstriction relies on the inhibition of the nitric oxide (NO) pathway. We tested the effect of the phosphodiesterase 5 (PDE5) inhibitor sildenafil, which potentiates the effect of NO, on skin blood flow. We recruited 15 patients with primary RP, performing local cooling without sildenafil (day 1), after a single oral dose of 50 mg (day 2), and after a dose of 100 mg (day 3). Skin blood flow, skin temperature, and arterial pressure were recorded, and data were expressed as cutaneous vascular conductance (CVC). Sildenafil at 100 mg, but not 50 mg, significantly lessened the cooling-induced decrease in CVC. It also increased resting CVC and skin temperature. These data suggest that 100 mg sildenafil improves digital skin perfusion during local cooling in primary RP. The benefit of sildenafil "as required" should be confirmed in a randomized, controlled trial.