Ilenia Molinaro

Bosentan Improves Skin Perfusion of Hands in Patients with Systemic Sclerosis with Pulmonary Arterial Hypertension

Objective. Our aim was to investigate effects of bosentan on hand perfusion in patients with systemic sclerosis (SSc) with pulmonary arterial hypertension (PAH), using laser Doppler perfusion imaging (LDPI). Methods. We enrolled 30 SSc patients with PAH, 30 SSc patients without PAH, and 30 healthy controls. In SSc patients and healthy controls at baseline, skin blood flow of the dorsum of the hands was determined with a Lisca laser Doppler perfusion imager. The dorsal surface of the hands was divided into 3 regions of interest (ROI). ROI 1 included 3 fingers of the hand from the second to the fourth distally to the proximal interphalangeal finger joint. ROI 2 included the area between the proximal interphalangeal and the metacarpophalangeal joint. ROI 3 included only the dorsal surface of the hand without the fingers. LDPI was repeated in SSc patients and controls after 4, 8, and 16 weeks of treatment. In SSc patients, nailfold videocapillaroscopy and Raynaud Condition Score (RCS) were performed at baseline and at 4, 8, and 16 weeks. Results. SSc patients with PAH enrolled in the study received treatment with bosentan as standard care for PAH. In these patients with PAH, after 8 and 16 weeks of treatment, bosentan improved minimum, mean, and maximum perfusion and the perfusion proximal-distal gradient. Bosentan seems to be most effective in patients with the early and active capillaroscopic pattern than in patients with the late pattern. Bosentan improved skin blood flow principally in the ROI 1 compared to the ROI 2 and ROI 3. Bosentan restored the perfusion proximal-distal gradient in 57% of SSc patients with the early capillaroscopic pattern. No significant differences from baseline were observed in the RCS in SSc patients with PAH. Conclusion. Bosentan improved skin perfusion in SSc patients with PAH, although it did not ameliorate symptoms of Raynaud’s phenomenon. Skin blood perfusion increased in SSc patients with PAH, particularly in the skin region distal to the proximal interphalangeal joint, and in patients with the early/active capillaroscopic pattern. Double-blind randomized clinical trials are needed to evaluate the effects of bosentan on skin perfusion of SSc patients without PAH and with active digital ulcers.

In systemic sclerosis macrovascular damage of hands digital arteries correlates with microvascular damage

OBJECTIVE To assess morphology and blood flow of the proper palmar digital arteries (PPDA) by color Doppler ultrasonography (CDUS) and its relationship with nailfold videocapillaroscopy (NVC), skin blood perfusion and digital arteries pulsatility of hands in SSc patients and healthy controls. METHODS CDUS, NVC, laser Doppler perfusion imaging (LDPI) and photoplethysmography (PPG) were performed in 36 systemic sclerosis (SSc) patients and 20 healthy controls. RESULTS CDUS was pathologic in 69% of patients with SSc and in none of healthy controls (p<0.0001). SSc patients with low vascular damage (early capillaroscopic pattern) have a normal morphology of PPDA, but the blood flow, evaluated by peak systolic velocity (PSV) and end diastolic velocity (EDV), is reduced and vascular resistance, measured by resistive index (RI) and pulsatility index (PI), increased. At this stage the LDPI mean perfusion and digital artery pulsatility, evaluated by PPG, were reduced. The US changes appear with microvascular damage progression (active and late capillaroscopic patterns), while the PPDA blood flow progressively decreases (PSV and EDV decreased, RI and PI increased). The macrovascular damage correlates with disease duration. Anti-topoisomerase I represents an independent predictive factor for macrovascular damage. We not observed any association between digital ulcer history, pulmonary fibrosis and US findings. CONCLUSION PPDA blood flow dysfunction is already present in early disease. Structural macrovascular damage progresses with worsening of SSc microangiopathy.

Laser Doppler perfusion imaging in systemic sclerosis impaired response to cold stimulation involves digits and hand dorsum

OBJECTIVES To assess by Laser Doppler perfusion imaging (LDPI) skin blood perfusion of hands in patients with SSc and primary RP (PRP) at baseline and after cold stimulation (CS). In SSc patients, the associations between skin perfusion and nailfold video capillaroscopy (NVC) patterns were also evaluated. METHODS Forty patients with SSc, 38 patients with PRP and 32 healthy controls were recruited. Skin blood flow of the hands was detected by Lisca Laser Doppler Perfusion Imager at baseline and after CS. Further laser Doppler scanning was performed for each hand at 0 (T(1)), 3 (T(2)), 7 (T(3)) and 15 min (T(4)). RESULTS Baseline mean perfusion is significantly (P < 0.000 l) lower in SSc patients than in healthy controls. In SSc patients, mean perfusion is reduced after CS (P < 0.0001) and skin flow recovery (significant difference between T(0) and T(4), P < 0.0001) is incomplete. In SSc patients with low vascular damage (early and active capillaroscopic groups), the abnormal microvascular response to CS involves only the digits, while the perfusion of hands dorsum is normal. With the progression of vascular damage (late capillaroscopic groups), the abnormal microvascular response to CS also appears in the hand dorsum skin. In PRP patients, baseline hand perfusion is very low and the skin flow recovery after CS is absent (P < 0.05). CONCLUSION In early SSc, the thermoregulation of finger skin is impaired, but only in advanced stages of microangiopathy does the skin of the hand dorsum show a vasomotor control failure.

The combination of laser Doppler perfusion imaging and photoplethysmography is useful in the characterization of scleroderma and primary Raynaud's phenomenon.

Objective: To investigate simultaneously skin perfusion and digital artery pulsatility of hands in patients with primary Raynauds phenomenon (PRP) and systemic sclerosis (SSc). Methods: In 100 SSc patients, 92 PRP patients, and 80 healthy controls, perfusion and digital artery pulsatility of the hands were investigated by laser Doppler perfusion imaging (LDPI) and photoplethysmography (PPG), respectively. Results: Both the mean value of mean perfusion and the mean value of sphygmic wave amplitude were lower (p < 0.0001) in the PRP group than in the SSc group, and also in the SSc group compared with the healthy controls. A positive correlation (r = 0.95) was found between the mean value of mean perfusion and the mean value of sphygmic wave amplitude. A homogeneous perfusion distribution pattern was present in 95% of the healthy controls, 93% of the PRP patients, and 4% of the SSc patients. PPG shows a homogeneous pattern in 95% of the healthy controls, 93% of the PRP patients, and 28% of the SSc patients. LDPI and PPG showed a positive concordance (p < 0.05) in homogeneous pattern evaluation. In the SSc patients, no correlation (r = 0.38) was observed between the mean value of sphygmic wave amplitude and the mean value of mean perfusion of each finger. Conclusion: LDPI and PPG can provide useful information in distinguishing patients with PRP and SSc, although nailfold videocapillaroscopy (NVC) is the best method for analysing microvascular damage in rheumatic diseases.

Intrarenal Hemodynamic Parameters Correlate with Glomerular Filtration Rate and Digital Microvascular Damage in Patients with Systemic Sclerosis

OBJECTIVES To evaluate intrarenal arterial stiffness by Doppler ultrasound and examine the correlation between renal Doppler indices, glomerular filtration rate, and digital microvascular damage in systemic sclerosis patients. METHODS Thirty systemic sclerosis patients and 30 healthy controls were enrolled in this study. Doppler indices of intrarenal arterial stiffness, peak systolic flow velocity, end diastolic flow velocity, resistive index, pulsative index, and systolic/diastolic (S/D) ratio were measured on the interlobar artery of both kidneys. Glomerular filtration rate was measured using Tc(99m) diethylenetriamine pentaacetic acid (DTPA). Equation 7 from the Modification of Diet in Renal Disease was used to estimate glomerular filtration rate. Nailfold videocapillaroscopy findings were classified as early, active, and late patterns. RESULTS The intrarenal arterial stiffness, evaluated by Doppler indices, was higher in systemic sclerosis patients than healthy controls. In systemic sclerosis patients pulsative index (r = -0.69), resistive index (r = -0.75), and S/D ratio (r = -0.74) showed a negative correlation with measured glomerular filtration rate (P < 0001). High correlation (P = 0008) was observed between measured and estimated glomerular filtration rate (r = 0.55). Pulsative index, resistive index, and S/D ratio significantly increased with progression of capillaroscopic damage. Conversely, measured glomerular filtration rate significantly decreased with capillaroscopic damage progression. CONCLUSIONS Doppler indices of intrarenal arterial stiffness are noninvasive diagnostic tests to evaluate renal damage in SSc patients. Intrarenal arterial stiffness and glomerular filtration rate correlate with capillaroscopic microvascular damage.

Evaluation of Chronic Kidney Disease Epidemiology Collaboration equation to estimate glomerular filtration rate in scleroderma patients

OBJECTIVE Renal involvement in SSc is often subclinical and chronic kidney disease (CKD) develops, with slow worsening of glomerular filtration rate (GFR). The present investigation was undertaken in order to study how well the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) correlates with measured GFR (mGFR) in a group of SSc patients with serum creatinine (sCr) in the normal range. METHODS Forty-one scleroderma patients (37 females and 4 males) with a median age of 46 years were enrolled. GFR was measured using technetium-99 m DTPA (Tc-99 m DTPA). The modified Cockroft-Gault formula, 4- and 7-variable Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations were used for estimated GFR (eGFR). RESULTS mGFR showed a median value of 84 ml/min (range 32.8-121.2 ml/min). Seven patients had reduced GFR (<60 ml/min), 19 had GFR within 60-90 ml/min and 15 had GFR >90 ml/min. The results showed mild correlation between the BSA-modified Cockroft-Gault and mGFR (P > 0.05), mild statistically significant correlation with 4-variable MDRD (P < 0.05), high statistically significant correlation with 7-variable MDRD (P = 0.01), but the greatest correlation was obtained using CKD-EPI (P = 0.002). No correlation with age, disease duration or subset of disease was found. CONCLUSIONS In scleroderma patients with normal sCr value, CKD-EPI is a useful formula to assess GFR.

Long-term N-acetylcysteine therapy in systemic sclerosis interstitial lung disease: A retrospective study

Systemic sclerosis (SSc) is associated with interstitial lung diseases. The primary endpoints of this study were changes between baseline and month 24 in single-breath carbon monoxide diffusing capacity (DLco). The secondary endpoints were: vital capacity (VC), forced expired volume in 1 sec (FEV1), total lung capacity (TLC), scores of high resolution computed tomography (HRCT) of the chest, number of adverse effects. In this study, we retrospectively investigated data from SSc patients who had undergone therapy with high-dose intravenous N-acetylcysteine (NAC) at a dosage of 15 mg/Kg/h for 5 consecutive hours every 14 days. After NAC therapy median values of DLco (69.5% vs 77.7%), VC (99% vs 101.3%) and TLC (93% vs 98.3%) significantly increased. We did not observed any significant changes from baseline in FEV1 value and HRTC score. The improvement in lung function was more evident in SSc patients without radiological signs of pulmonary fibrosis than in patients with pulmonary fibrosis. In SSc patients with mild-moderate pulmonary fibrosis intravenous NAC administration slows the rate of deterioration of DLco, VC and TLC. In conclusion, this retrospective study demonstrates that long-term therapy with intravenous NAC ameliorates pulmonary function tests in SSc patients.

Erectile Dysfunction, Endothelium Dysfunction, and Microvascular Damage in Patients with Systemic Sclerosis

INTRODUCTION Erectile dysfunction (ED) prevalence in men with systemic sclerosis (SSc) is high and can be considered a manifestation of endothelium damage. AIM This study aims to correlate ED with endothelial dysfunction and digital vascular damage in SSc patients. MAIN OUTCOME MEASURES The main outcome measures were erectile function, Doppler indices of cavernous arteries, flow-mediated dilation (FMD), capillaroscopic damage, skin perfusion, and digital pulsatility. METHODS In 23 SSc patients, erectile function was investigated using the International Index of Erectile Function-5 (IIEF-5). Doppler indices of cavernous arteries, peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were measured at the penoscrotal junction before and after pharmacostimulation with 20 mg prostaglandin E1. FMD and nailfold videocapillaroscopy (NVC) were used to evaluate endothelial dysfunction and capillaroscopic damage. Skin perfusion and digital sphygmic waves were measured by laser Doppler perfusion imaging (LDPI) and digital photoplethysmography (PPG), respectively. RESULTS IIEF-5 score was reduced in 83% of patients. PSV was reduced in 96%, while EDV was increased in 48% of patients. A positive correlation was observed between IIEF-5 score and FMD (r = 0.71, P < 0.0001) and between the former and PSV (r = 0.76, P < 0.0001). A negative correlation was observed between EDV and FMD (r = -0.509, P < 0.01). FMD and Doppler indices were reduced with capillaroscopic damage progression. A positive correlation exists between LDPI perfusion and IIEF-5 score (r = 0.743, P < 0.0001) and between the former and PSV (r = 0.714, P < 0.0001), while a negative correlation is observed between LDPI perfusion and EDV (r = -0.677, P < 0.0001). A positive correlation exists between PPG pulsatility and IIEF-5 score (r = 0.752, P < 0.0001) and between the former and PSV (r = 0.747, P < 0.0001), while negative correlation is observed between PPG pulsatility and EDV (r = -0.689, P < 0.0001). CONCLUSION In SSc patients, ED correlates with endothelial dysfunction and digital microvascular damage.

Clitoral blood flow in systemic sclerosis women: correlation with disease clinical variables and female sexual dysfunction

OBJECTIVES The objectives of this study were to investigate clitoral blood flow in SSc women compared with healthy controls and to correlate it with microvascular damage and disease clinical variables. We also evaluated the correlation between clitoral blood flow and sexual dysfunction. METHODS Twenty-two SSc women and 20 healthy controls matched for sex and age were enrolled in this study. Baseline Doppler indices of the clitoral artery were measured. Peak systolic velocity, end diastolic velocity, resistive index (RI), pulsatile index (PI) and systolic/diastolic (S/D) ratio were measured. The female sexual function index (FSFI) was used to assess sexual function. RESULTS The RI and S/D ratio were higher (P < 0.0001) in SSc women compared with healthy controls. The PI, RI and S/D ratio increased with progression of capillaroscopic damage. The RI and S/D ratio were higher (P < 0.01) in women with digital ulcers than in women without digital ulcers. No correlation exists between Doppler indices of the clitoral artery and age or clinical variables of disease. The FSFI was reduced in 7 (32%) of 22 SSc women. A negative correlation was observed between both the FSFI and RI (R = -0.74, P < 0.0001) and the S/D ratio (R = -0.68, P < 0.0001). A negative correlation exists between the RI and all domains of the FSFI score except for desire. CONCLUSION Clitoral blood flow was reduced in SSc women compared with healthy controls. Clitoral blood flow was reduced in SSc women with digital ulcers and it correlated with capillaroscopic damage progression. A negative correlation exists between the RI and S/D ratio and all domains of the FSFI score except for desire.

The Different Photoplethysmographic Patterns Can Help to Distinguish Patients With Primary and Sclerodermic Raynaud Phenomenon

Introduction:The aim of this study is to investigate pulsatility of digital arteries of hands by means of photoplethysmography (PPG) in patients with primary Raynaud phenomenon (PRP) and systemic sclerosis (SSc) and to compare the results with those obtained in healthy controls. Methods:One hundred five patients with SSc, 96 patients with PRP and 85 healthy controls were recruited in this study. Nailfold videocapillaroscopy and PPG were performed in healthy controls and patients. In patients with SSc, the capillaroscopic pattern was classified as early, active and late group pattern. A baseline PPG was recorded simultaneously in all 10 fingers of the hands. The photoplethysmographic curves were evaluated for morphology and amplitude of sphygmic wave. Results:In healthy controls group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc and 2 subsets of disease. Conclusion:PPG represents a technique noninvasive to evaluate simultaneously in all 10 fingers of hands digital arteries pulsatility. PPG improves the evaluation of vascular damage in patients with primary and sclerodermic RP.