endothelin-1 and Skin-Ulcer

Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker.. To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.. Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients.. Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or >3).. The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups.. In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.. Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.. clinicaltrials.gov Identifiers: NCT01474109, NCT01474122.

Topics: Administration, Oral; Double-Blind Method; Endothelin-1; Female; Fingers; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Pyrimidines; Scleroderma, Systemic; Skin Ulcer; Sulfonamides

The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1

Topics: Adult; Aged; Aged, 80 and over; Arteries; Capillaries; Cytokines; Endothelin-1; Female; Fibrosis; Humans; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Raynaud Disease; Skin; Skin Ulcer; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha; Veins

To evaluate the presence of ET-1 in patients with scleroderma and its correlation with the level of disease activity; to verify if the levels of endothelin are associated with the clinical profile and autoantibodies of scleroderma, and even if there is an association with microvascular injury detected by nailfold capillaroscopy.. A total of 74 patients, 37 patients with scleroderma, the remaining being controls, were subjected to measurement of ET-1 by ELISA. Patients with scleroderma were evaluated through a questionnaire about characteristics of the disease and determination of autoantibodies. Disease severity was defined by the criteria of Medsger and microvascular disease was accessed through nailfold capillaroscopy.. Of the 37 patients with scleroderma, three (8.1%) were men and 34 (91.89%) women, with a mean age of 48.97 ± 13.36 years and mean disease duration of 42.54 ± 13, 35. The amounts of ET-1 in the controls was 0.41 to 5.65 pg / ml (median of 2.26 pg / ml) and, in the scleroderma group, from 0.41 to 8.82 pg / ml (median, 0.41 pg / ml), with p = 0.0007. There was no correlation with disease duration, patient age and the degree of skin involvement. No correlation was found between serum levels of ET-1 and disease severity (p = 0.13). Higher levels of ET-1 were observed in the form of overlap (1.49 to 6.82 pg / ml).. The levels of ET-1 in scleroderma were inferior to controls. There was no association of ET-1 levels with the variables studied.

Topics: Adolescent; Adult; Aged; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Humans; Male; Microscopic Angioscopy; Microvessels; Middle Aged; Skin Ulcer; Young Adult

To describe the effect of bosentan and its dual inhibition of endothelin-1 ETA and ETB receptors on digital ulcers in patients with systemic sclerosis (SSc).. Patients receiving bosentan for SSc-related digital ulcers were identified in eight centers, and their characteristics and follow-up were recorded.. Nine (six with diffuse and three with limited cutaneous forms of SSc) patients (median age: 54 years) had received bosentan for digital ulcers. Complete healing occurred in seven (median time to improvement: 4 weeks). Another experienced a significant decrease in the number of ulcers (from 22 to 5) in 8 weeks, while one had no improvement. After a median follow-up of 24.3 months, only one recurrence was observed. Raynaud phenomenon improved in all but one patient.. These data suggest that some patients may benefit from bosentan to treat digital ulcers. The short time to healing in these patients with rather chronic ulcers argues strongly in favor of its use. These results also strengthen the evidence that endothelin-1 plays an important role in the vascular manifestations of SSc.. Bosentan can be effective in the treatment of digital ulcers in some SSc patients with SSc, probably especially those involving substantial ischemia. Bosentan is not a first-line drug in this indication yet and must be carefully used by specialists in SSc. Forthcoming results from the international RAPIDS-2 study should clarify the indications for bosentan in the treatment of SSc-related digital ulcers.

Topics: Adult; Aged; Antibodies, Antinuclear; Bosentan; Endothelin-1; Female; Fingers; Follow-Up Studies; Humans; Ischemia; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Time Factors; Treatment Outcome