Treprostinil Hydrogel Iontophoresis in Systemic Sclerosis‐Related Digital Skin Ulcers: A Safety Study

Abstract

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC 0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC 0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.

Rehabilitative interventions for ischaemic digital ulcers, pain, and hand functioning in systemic sclerosis: a prospective before-after study

“…This treatment increases the blood flow of the skin in the leg and foot compared to a placebo. Despite some minor local adverse events (e.g., erythema or burns), related to iontophoresis, this procedure has been shown to be safe and effective in the treatment of digital ulcers in patients with systemic sclerosis [ 21 ].…”

Esophageal Dysfunction in Systemic Sclerosis: An Update

“…In clinical trials, clonidine, as an α 2 agonist, improves esophageal peristalsis and the ability of the lower sphincter to contract [ 2 , 13 ]. Prostaglandin-related drugs that can increase blood flow, such as treprostinil, have been shown to significantly improve the blood flow of the local skin after ion introduction into the skin [ 70 ]. Fasudil can inhibit the RhoA/Rho kinase pathway, improve angiogenesis defects, increase circulating endothelial cells, dilate blood vessels, and contribute to the repair of esophageal vessels and the protection of endothelial cells [ 13 ].…”

“…In clinical trials, clonidine, as an a2 agonist, improves esophageal peristalsis and the ability of the lower sphincter to contract [2,13]. Prostaglandin-related drugs that can increase blood flow, such as treprostinil, have been shown to significantly improve the blood flow of the local skin after ion introduction into the skin [70].…”

Laser Speckle Contrast Analysis: Functional Evaluation of Microvascular Damage in Connective Tissue Diseases. Is There Evidence of Correlations With Organ Involvement, Such as Pulmonary Damage?

“…Systemic sclerosis is characterized by structural and functional vasculopathy, where the peripheral microvascular involvement may manifest as Raynaud's phenomenon (RP) and/or digital ulcers (DU) (Domsic et al, 2014;Gaillard-Bigot et al, 2014;Sebastiani et al, 2014;Sulli et al, 2014b;Lambrecht et al, 2016;Morales-Cárdenas et al, 2016;Trombetta et al, 2016;Smith et al, 2018;Frech and Murtaugh, 2019;Bruni et al, 2020;Guigui et al, 2020;Farina et al, 2021;Gigante et al, 2021;Suliman et al, 2021). Frequently, RP is the earliest morphological and functional manifestation of SSc vasculopathy (Domsic et al, 2014;Gaillard-Bigot et al, 2014;Sulli et al, 2014b;Lambrecht et al, 2016; -Cárdenas et al, 2016;Trombetta et al, 2016;Frech and Murtaugh, 2019;Guigui et al, 2020;Farina et al, 2021;Gigante et al, 2021;Suliman et al, 2021). RP, secondary to SSc (SRP), is also the most common presenting feature of the disease, it is observed in 95% of scleroderma patients (Wigley et al, 1990;Wigley and Flavahan, 2016;Bruni et al, 2018).…”