u-62840 and Skin-Ulcer

Digital ulcers (DU), defined as necrotic lesions located at distal digits or overlying bony prominences, occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). These lesions are extremely painful and lead to substantial functional disability. The pathogenesis of DU differs depending on their location. DU located at distal aspects of digits are thought to be related to tissue ischemia from several processes, including vasospasm secondary to Raynaud's phenomenon, intimal fibro-proliferation, and thrombosis of digital arteries. DU located over bony prominences, such as the phalangeal joints and elbows, are thought to be due to repetitive microtrauma and difficulty healing due to atrophic, avascular tissue overlying the joints. Management of DU include non-pharmacologic and pharmacologic modalities. This review summarizes the current available and investigational therapies for the treatment and prevention of DU in patients with SSc.

Topics: Anticoagulants; Epoprostenol; Fingers; Humans; Piperazines; Platelet Aggregation Inhibitors; Purines; Scleroderma, Systemic; Selective Serotonin Reuptake Inhibitors; Sildenafil Citrate; Skin Ulcer; Sulfones; Therapies, Investigational; Vasodilator Agents

Although there is abundant evidence of vascular perturbation from studies of peripheral blood in systemic sclerosis (SSc), there are few data about the ability to use biomarkers of vascular injury and growth factors to predict vascular outcomes and response to therapy. We sought to explore the association between candidate vascular biomarkers and digital ulcerations (DU) in a clinical trial context.. We examined 19 circulating vascular, angiogenic, and inflammatory biomarkers in 124 patients with scleroderma and DU who participated in a randomized controlled trial of oral treprostinil diolamine (ClinicalTrials.gov identifier NCT00775463). Correlation, regression, and random forest analyses were conducted to assess biomarker relationships in response to drug treatment.. Over the 20-week trial, 82 (66%) patients had their cardinal ulcer completely heal, 54 (44%) developed new ulcers, and 72 (58%) had complete healing of all ulcers; mean change in ulcer burden comparing week 20 with baseline was - 0.36 ± 1.70. Nineteen biomarkers were analyzed for their association and ability to predict clinical DU outcomes. After adjusting for multiple comparisons, no individual biomarker (baseline level, week 20 level, or change over time) was significantly associated with any of the clinical outcomes, suggesting that traditional vascular, angiogenic or inflammatory drivers are not predictive of ulcer fate.. The lack of strong response to any of the vascular, angiogenic, or inflammatory markers suggest that these pathways are not primary drivers in the development of DU clinical outcomes in a SSc population with prevalent DU.. • Currently we lack robust biomarkers to predict vascular outcomes or response to therapy in scleroderma patients with Raynaud's phenomenon.• Longitudinal assessment of vascular biomarkers in a clinical trial setting provides a unique opportunity to define biomarkers that predict vascular outcomes.• In a randomized controlled trial of oral treprostinil diolamine for treatment of scleroderma-associated digital ulcers, biomarkers involved in several vascular, inflammatory, and angiogenic pathways did not predict short-term clinical response to therapy or digital ulcer outcomes.• Further study of these and other biomarkers should be considered in Raynaud's clinical trials in scleroderma patients without prevalent digital ulcers.

Topics: Administration, Oral; Adult; Biomarkers; Epoprostenol; Female; Fingers; Humans; Male; Middle Aged; Raynaud Disease; Regression Analysis; Scleroderma, Systemic; Skin Ulcer

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

Topics: Administration, Cutaneous; Adult; Blood Circulation; Double-Blind Method; Epoprostenol; Female; Fingers; Foot; Healthy Volunteers; Humans; Hydrogels; Iontophoresis; Male; Middle Aged; Scleroderma, Systemic; Skin; Skin Temperature; Skin Ulcer; Toes; Young Adult

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.

Topics: Administration, Cutaneous; Adolescent; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Epoprostenol; Feasibility Studies; Female; Fingers; Humans; Iontophoresis; Male; Middle Aged; Regional Blood Flow; Scleroderma, Systemic; Skin; Skin Ulcer; Tissue Distribution; Young Adult

We performed a pilot trial of subcutaneous treprostinil for the treatment of digital ulcers in scleroderma. Of the 5 patients completing therapy, ulcer size significantly decreased and no new ulcers occurred on continuous therapy. Although effective, the high rate of injection site reactions may limit the utility of this therapy.

Topics: Adult; Epoprostenol; Female; Fingers; Humans; Injections, Subcutaneous; Male; Middle Aged; Scleroderma, Systemic; Skin Ulcer; Treatment Outcome

Prior studies investigating the efficacy of oral treprostinil to treat digital ulcers (DU) in systemic sclerosis (SSc)-associated Raynaud phenomenon have yielded conflicting results. In this investigation, we examined whether DU burden increased after patients withdrew from oral treprostinil that was administered during an open-label extension study.. A multicenter, retrospective study was conducted to determine DU burden in the year after withdrawal from oral treprostinil. DU burden 3-6 months (Time A) and > 6-12 months (Time B) after drug withdrawal was compared with DU burden at baseline, defined as the last day receiving drug in the open-label extension study, by a paired Student t test. Changes in DU burden while receiving drug in the open-label study were compared with changes in DU burden at Time B by a paired Student t test.. Fifty-one patients from 9 clinical sites were included for analysis. DU burden increased significantly from baseline (mean 0.47) to Time A (mean 2.1, p = 0.002, n = 23) and Time B (mean 1.45, p = 0.013, n = 30). Total DU burden decreased during oral treprostinil exposure (mean change -0.6) and then increased by Time B (mean change 1.05, p = 0.0027 for comparison, n = 30). In the year after drug withdrawal, many patients required vasodilator therapy and pain medications. Three patients were hospitalized for complications from DU, and 4 patients required surgery for DU.. Total DU burden increased significantly after discontinuation of oral treprostinil. These data provide supportive evidence of a beneficial effect of oral treprostinil for the vascular complications of SSc and suggest that further study is warranted.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Fingers; Humans; Male; Middle Aged; Raynaud Disease; Recurrence; Retrospective Studies; Scleroderma, Systemic; Skin Ulcer

We report a case of severe digital ulcerations associated with systemic sclerosis, successfully treated with treprostinil (Remodulin). There was improvement within days of the treatment initiation; complete healing was accomplished after 16 weeks of therapy. Patients with systemic sclerosis and peripheral small vessel disease have limited therapeutic options. Treprostinil is a prostacyclin analogue that can be delivered by subcutaneous infusion and is approved in the USA only for treatment of primary pulmonary hypertension. This report provides an impressive example of an alternative, complementary indication for the use of treprostinil.

Topics: Adult; Epoprostenol; Female; Fingers; Humans; Infusions, Parenteral; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Wound Healing