Longterm Treatment with Endothelin Receptor Antagonist Bosentan and Iloprost Improves Fingertip Blood Perfusion in Systemic Sclerosis

2014 ◽  
Vol 41 (5) ◽  
pp. 881-886 ◽  
Author(s):  
Maurizio Cutolo ◽  
Barbara Ruaro ◽  
Carmen Pizzorni ◽  
Francesca Ravera ◽  
Vanessa Smith ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Blood Perfusion ◽  
Progressive Increase ◽  
Digital Ulcers ◽  
Endothelin Receptor ◽  
Nailfold Videocapillaroscopy ◽  
Raynaud Phenomenon ◽  
Doppler Flowmetry ◽  
Longterm Treatment ◽  
Capillary Dilation

Objective.To evaluate the longterm effects of endothelin-1 (ET-1) antagonism on peripheral blood perfusion (PBP) in patients with systemic sclerosis (SSc).Methods.Twenty-six patients with SSc already receiving cyclic intravenous iloprost (ILO) for severe Raynaud phenomenon were enrolled. Thirteen patients continued the treatment for a further 3 years (ILO group) and 13 patients, because of the appearance of digital ulcers, received in addition bosentan (BOS; 125 mg twice/day) for 3 years (ILO + BOS group). Both PBP at fingertips and nailfold microangiopathy were evaluated yearly by laser Doppler flowmetry and nailfold videocapillaroscopy, respectively.Results.A progressive significant increase of PBP was observed in the ILO + BOS group during the 3 followup years (p = 0.0007, p = 0.0002, p = 0.01, respectively). In contrast, an insignificant progressive decrease of PBP was observed in the ILO group. Difference of perfusion between the PBP evaluations at basal temperature and at 36°C (to test capillary dilation capacity), was found progressively decreased during the 3-year followup only in the ILO group (p = 0.05, p = 0.26, p = 0.09, respectively). A progressive increase of nailfold capillary number was observed only in the ILO + BOS group after 2 and 3 years of followup (p = 0.05).Conclusion.Longterm treatment of SSc patients with ET-1 antagonism, in combination with ILO, seems to increase fingertip blood perfusion, as well as both capillary dilation capacity and number.

Longterm Effects of Endothelin Receptor Antagonism on Microvascular Damage Evaluated by Nailfold Capillaroscopic Analysis in Systemic Sclerosis

2012 ◽  
Vol 40 (1) ◽  
pp. 40-45 ◽  
Author(s):  
MAURIZIO CUTOLO ◽  
GIUSEPPE ZAMPOGNA ◽  
LAURA VREMIS ◽  
VANESSA SMITH ◽  
CARMEN PIZZORNI ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Capillary Number ◽  
Disease Duration ◽  
Progressive Increase ◽  
Endothelin Receptor ◽  
Nailfold Videocapillaroscopy ◽  
Microvascular Damage ◽  
Treatment Protocols ◽  
Longterm Treatment ◽  
Previous Group

Objective.Systemic sclerosis (SSc) is characterized by microvascular injury, fibrosis, and hypoxia of involved tissues. The vasoactive peptide endothelin-1 (ET-1) seems to be implicated in these events. Using nailfold videocapillaroscopy (NVC), we evaluated longterm effects of ET-1 antagonist treatment on nailfold microvascular damage in patients with SSc, over a 3-year followup period.Methods.Thirty patients with SSc (mean age 64 ± 5 yrs, mean disease duration 8 ± 1 yrs) were recruited during their programmed standard treatment protocols. At baseline (T0), 15 patients with SSc (mean age 63 ± 15 yrs, mean disease duration 7 ± 3 yrs), already receiving cyclic intravenous infusion of iloprost (5 continuous days, average 80 μg/day, every 3 mo), continued the treatment for a further 3 years (ILO group). The remaining 15 patients with SSc (mean age 68 ± 13 yrs, mean disease duration 8 ± 4 yrs), although they continued the same cyclic intravenous iloprost treatment as the previous group, also received bosentan 125 mg twice a day for 3 years (ILO+BOS group). Qualitative analysis (scleroderma patterns) and semiquantitative scoring of the microvascular damage were performed by validated routine NVC methods.Results.During followup, a statistically significant increase of capillary number was observed in the ILO+BOS group (p < 0.02), with a significant and progressive increase of angiogenesis (p < 0.01). In contrast, the ILO group showed a statistically significant decrease of capillary number (p < 0.05). After 3 years the number of capillaries was significantly higher in the ILO+BOS group than in the ILO group (p < 0.05). The score for giant capillaries decreased significantly in both groups of patients with SSc (p < 0.05).Conclusion.In this open study, longterm treatment with ET-1 receptor antagonist in combination with iloprost was found to interfere with progression of nailfold microvascular damage in patients with SSc, as assessed by NVC over a 3-year followup period.

Peripheral Blood Perfusion Correlates with Microvascular Abnormalities in Systemic Sclerosis: A Laser-Doppler and Nailfold Videocapillaroscopy Study

2010 ◽  
Vol 37 (6) ◽  
pp. 1174-1180 ◽  
Author(s):  
MAURIZIO CUTOLO ◽  
CARMELA FERRONE ◽  
CARMEN PIZZORNI ◽  
STEFANO SOLDANO ◽  
BRUNO SERIOLO ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Negative Correlation ◽  
Healthy Subjects ◽  
Blood Perfusion ◽  
Laser Doppler ◽  
Nailfold Videocapillaroscopy ◽  
Microvascular Damage ◽  
Local Skin ◽  
Doppler Flowmetry ◽  
Prostacyclin Analog

Objective.To investigate possible correlations between fingertip blood perfusion (FBP) status, assessed by laser Doppler flowmetry (LDF), and morphological microvascular abnormalities, detected by nailfold videocapillaroscopy (NVC), in patients with systemic sclerosis (SSc). The effects on FBP of intravenous (IV) treatment with the prostacyclin analog iloprost were also investigated.Methods.Thirty-four consecutive patients with SSc and 16 healthy subjects were evaluated. LDF was performed by analyzing blood perfusion at the fingertips in both hands. Patients with SSc were distributed into the appropriate NVC pattern of microangiopathy (early, active, and late). Iloprost was administered to inpatients with SSc by 24-hour IV infusion for 7 consecutive days (4 μg/h).Results.FBP was significantly lower in patients with SSc (p < 0.05) compared to controls. Heating of the LDF probe at 36°C induced a significant increase of FBP in all subjects (p < 0.001), but the slope of variation was significantly lower in patients with SSc compared to controls (p < 0.05). Patients with SSc showing the late NVC pattern of microangiopathy had significantly lower FBP than patients with the active and early NVC patterns (p < 0.05). A negative correlation was observed between FBP and NVC rating of the microvascular damage (p < 0.05). After iloprost treatment, a significant increase of FBP was observed in patients with SSc (p < 0.05).Conclusion.Patients with SSc show a decreased FBP partially reversible by local skin heating. The FBP correlated negatively with the extent of nailfold microvascular damage, and IV iloprost treatment increased the FBP.

scholarly journals Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis

2016 ◽  
Vol 43 (11) ◽  
pp. 2033-2041 ◽  
Author(s):  
Amelia Chiara Trombetta ◽  
Carmen Pizzorni ◽  
Barbara Ruaro ◽  
Sabrina Paolino ◽  
Alberto Sulli ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Clinical Outcomes ◽  
Capillary Number ◽  
Blood Perfusion ◽  
Diagnostic Tools ◽  
Synthetic Analog ◽  
Digital Ulcers ◽  
Doppler Flowmetry ◽  
Pulmonary Arterial ◽  
The Absolute

Objective.To quantify in patients with systemic sclerosis (SSc) the absolute nailfold capillary number/mm (the absolute number of capillaries, observable in the first row, in 1 mm per field) and fingertip blood perfusion (FBP) during longterm therapy with the endothelin receptor antagonist bosentan (BOSE) and the synthetic analog of prostacyclin PGI2 iloprost (ILO) by multiple diagnostic tools. Observed values were correlated with clinical outcomes.Methods.Thirty patients with SSc already receiving intravenous ILO (80 μg/day) for 5 continuous days (every 3 mos) were recruited in the clinic. Fifteen patients continued such treatment (ILO group), while in 15 patients BOSE (125 mg twice/day) was added (ILO + BOSE group) because of the onset of pulmonary arterial hypertension or digital ulcers (DU). The followup period was 4 years (T0–T4). Every year the following were evaluated: absolute nailfold capillary number/mm by nailfold videocapillaroscopy, FBP by laser Doppler flowmetry, DU incidence, DLCO, systolic pulmonary arterial pressure (sPAP), renal arterial resistive index, and other biomarkers. From T2 to T4, laser speckled contrast analysis was added. Nonparametric tests were used for statistical analysis.Results.Limited to the ILO + BOSE group, absolute capillary number/mm and FBP showed a progressive increase independently from other variables. In addition, during followup there was a significant reduction (80%) in the incidence of new DU, whereas DLCO and sPAP did not worsen.Conclusion.The study shows in patients with SSc with up to 4 years of combined therapy a progressive significant recovery in structure and function of microvasculature linked to improved clinical outcomes, independent of disease severity.

scholarly journals Capillaroscopy as an Outcome Measure for Clinical Trials on the Peripheral Vasculopathy in SSc—Is It Useful?

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Maurizio Cutolo ◽  
Alberto Sulli ◽  
Carmen Pizzorni ◽  
Vanessa Smith
Keyword(s):  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Outcome Measure ◽  
Digital Ulcers ◽  
Nailfold Videocapillaroscopy ◽  
Therapeutic Trials ◽  
Specific Serum ◽  
Pulmonary Arterial ◽  
Microvascular Impairment ◽  
Clinical Conditions

Peripheral microvascular impairment in systemic sclerosis (SSc) may be easily detected and scored in a safe noninvasive way by nailfold videocapillaroscopy (NVC). The paper highlights clinical conditions related to SSc in which NVC may represent an outcome measure of therapeutical interventions, by elaborating on their already assessed relationship with the NVC patterns and eventually scores. The 3 important biological/clinical conditions are: the positivity for SSc-specific serum autoantibodies, the presence of SSc skin digital ulcers (DUs) and of pulmonary arterial hypertension (PAH) SSc associated. In conclusion, to the question if capillaroscopy (NVC) may represent in SSc an outcome measure for clinical trials on the peripheral vasculopathy, based on the growing evidence and our detailed studies, the answer is positive. Recent therapeutic trials in SSc are confirming this role, and the experience is growing rapidly.

scholarly journals Raynaud Phenomenon in Systemic Sclerosis: Does Digital Thermal Monitoring Correlate to Specific Nailfold Videocapillaroscopy Abnormalities?

2020 ◽  
pp. jrheum.191371
Author(s):  
Julie Thomas ◽  
Mislav Radic ◽  
Jordan R. Tucker ◽  
Rebecca Overbury ◽  
Tracy M. Frech
Keyword(s):  
Systemic Sclerosis ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Clinical Care ◽  
Density Measurement ◽  
Nonparametric Tests ◽  
Reactivity Index ◽  
Thermal Monitoring ◽  
Nailfold Videocapillaroscopy ◽  
Raynaud Phenomenon

Objective Early diagnosis of systemic sclerosis (SSc) is imperative, and Raynaud phenomenon (RP) is an important component of progressive vasculopathy. Nailfold videocapillaroscopy (NVC) is a well-established tool that can quantify structural vascular abnormalities. Digital thermal monitoring (DTM) assesses microvascular functional dysfunction related to thermoregulation. In this study, we investigated the correlation of NVC patterns and DTM variables in patients with SSc. Methods Patients with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism criteria who consented and enrolled in the clinical care registry had NVC and DTM performed. For NVC, the number of capillaries (density), measurement of apical diameter (dimension), presence or absence of hemorrhages, and number of abnormal shapes were assessed to categorize 3 different qualitative patterns: early, active, and late. For DTM, Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery, and fingertip vascular function were assessed, and a vascular reactivity index (VRI) measurement was automated. Statistical evaluation was performed by nonparametric tests to assess the correlation of NVC and VRI. Results Thirty-one SSc subjects with interpretable NVC and DTM performed on the same day were included in the study. VRI was progressively higher in SSc patients with early, active, and late NVC patterns of microangiopathy (P < 0.0001). There was a significant negative correlation between VRI and microhemorrhages scores (r = –0.363, P = 0.044). Conclusion Our study suggests that more advanced vasculopathy correlates to reduced microvascular function as detected by DTM and more advanced structural abnormalities detected by NVC. NVC and DTM may provide different aspects of vasculopathy quantification and complement each other as investigative tools.

scholarly journals Successful Treatment with Bosentan of Lower Extremity Ulcers in a Scleroderma Patient

2013 ◽  
Vol 2013 ◽  
pp. 1-3 ◽  
Author(s):  
Alix Naert ◽  
Petra De Haes
Keyword(s):  
Molecular Weight ◽  
Systemic Sclerosis ◽  
Lower Extremity ◽  
Low Molecular Weight Heparin ◽  
Local Treatment ◽  
Low Molecular Weight ◽  
Digital Ulcers ◽  
Endothelin Receptor ◽  
Vasodilator Therapy ◽  
Scleroderma Patient

Digital ulcers are a well-known problem in patients with systemic sclerosis. Lower extremity ulcers are less prevalent but are also a challenging and underestimated complication of the disease causing important pain and morbidity. Bosentan, an oral dual endothelin receptor antagonist, has been shown to be effective in preventing digital ulcers in patients with systemic sclerosis. A few recent observations showed the efficacy of bosentan for accelerating the healing of nondigital ulcers in scleroderma patients. This report deals with a 48-year-old patient with systemic sclerosis who developed painful ulcers on the left ankle and hallux. The ulcers were refractory to a combination of vasodilator therapy with a calcium antagonist and several courses of intravenous prostanoids, low molecular weight heparin, aspirin, simvastatin, and intensive local treatment. Bosentan treatment showed spectacular healing of the ulcers already after 4 months of therapy. This case supports the previous few observations of accelerating wound healing of lower extremity ulcers in systemic sclerosis patients with bosentan treatment.

scholarly journals Microvascular damage evaluation in systemic sclerosis: the role of nailfold videocapillaroscopy and laser techniques

Reumatismo ◽  
2017 ◽  
Vol 69 (4) ◽  
pp. 147 ◽  
Author(s):  
B. Ruaro ◽  
A. Sulli ◽  
V. Smith ◽  
C. Pizzorni ◽  
S. Paolino ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Peripheral Blood ◽  
Imaging Technique ◽  
Blood Perfusion ◽  
Clinical Aspects ◽  
Damage Evaluation ◽  
Nailfold Videocapillaroscopy ◽  
Microvascular Damage ◽  
Laser Technologies

Microvascular damage and a decrease in peripheral blood perfusion are typical features of systemic sclerosis (SSc) with serious clinical implications, not only for a very early diagnosis, but also for disease progression. Nailfold videocapillaroscopy is a validated and safe imaging technique able to detect peripheral capillary morphology, as well as to classify and to score any nailfold abnormalities into different microangiopathy patterns. Capillaroscopic analysis is now included in the ACR/EULAR classification criteria for SSc. The decrease in peripheral blood perfusion is usually associated with microvascular damage in SSc, which may be studied by different methods. Several of these make use of safe laser technologies. This paper focuses on these new clinical aspects to assess SSc microvascular impairment.

Paradoxical Reaction of Raynaud Phenomenon following the Repeated Administration of Lloprost in a Patient with Diffuse Cutaneous Systemic Sclerosis

2012 ◽  
Vol 46 (10) ◽  
pp. 1439-1439 ◽  
Author(s):  
Rebeca Iglesias Barreira ◽  
Belén Bardán García ◽  
Mónica Granero López ◽  
Iria Rodríguez Legazpi ◽  
Hortensia Álvarez Díaz ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Repeated Administration ◽  
Vascular Involvement ◽  
Digital Ulcers ◽  
Probability Scale ◽  
Paradoxical Reaction ◽  
Raynaud Phenomenon ◽  
Naranjo Probability Scale ◽  
Case Summary ◽  
Diffuse Cutaneous Systemic Sclerosis

Objective TO report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement. Case Summary In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5–1 ng/kg/min (6 hours per day, for 5 days every 6–8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased. Discussion Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient. Conclusions This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.

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