Objective: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database.Methods: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile.Results: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% Cl 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% Cl 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% Cl 0.34-3.56.Conclusion: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of sderoderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. (C) 2015 Elsevier Inc. All rights reserved.

Patients with systemic sclerosis (SSc; scleroderma) are at high risk for the development of ischemic digital ulcers (DUs), which occur in 35–60% of SSc patients. The aim of this study was to assess the correlation between intrarenal arterial stiffness and DUs in SSc patients and to evaluate the prognostic value of Doppler indices to predict new DU occurrence.

To the Editor: Two variants of laser Doppler monitoring exist to evaluate digital blood flow: laser Doppler imaging (LDI) and laser Doppler flowmetry (LDF). The first technique uses a scanning method with a distant light source and detector, while the second uses optical fibers to carry the light to and from the tissue. As a result, LDF measures the microcirculatory blood flow through a very small volume of tissue, whereas LDI scans a larger tissue area. LDF continuously measures skin blood perfusion; because of the scanning time, LDI cannot measure it continuously1. We address the relationship between digital blood flow and capillaroscopic damage in patients with systemic sclerosis (SSc). Table 1 outlines the main studies. View this table: Table 1. Main studies of laser Doppler monitoring and capillaroscopy to evaluate microvascular damage in patients with systemic sclerosis (SSc). Using LDI, Correa, et al found lower digital blood flow in 44 patients with SSc compared with healthy controls at baseline and after cold stimulus2. No correlation was found between functional … Address correspondence to Prof. Salsano; E-mail: felice.salsano{at}uniroma1.it

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.

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.

Systemic sclerosis (SSc) is a multisystem autoimmune disease of unknown etiology characterized by inflammation, autoantibody production, and fibrosis. It predominantly affects women, this suggesting that female sex hormones such as estrogens may play a role in disease pathogenesis. However, up to date, the role of estrogens in SSc has been scarcely explored. The activity of estrogens is mediated either by transcription activity of the intracellular estrogen receptors (ER), ERα and ERβ, or by membrane-associated ER. Since the presence of autoantibodies to ERα and their role as estrogen agonists interfering with T lymphocyte homeostasis were demonstrated in other autoimmune diseases, we wanted to ascertain whether anti-ERα antibodies were detectable in sera from patients with SSc. We detected anti-ERα antibody serum immunoreactivity in 42% of patients with SSc (30 out of 71 analyzed). Importantly, a significant association was found between anti-ERα antibody values and key clinical parameters of disease activity and severity. Fittingly, anti-ERα antibody levels were also significantly associated with alterations of immunological features of SSc patients, including increased T cell apoptotic susceptibility and changes in T regulatory cells (Treg) homeostasis. In particular, the percentage of activated Treg (CD4(+)CD45RA(-) FoxP3(bright)CD25(bright)) was significantly higher in anti-ERα antibody positive patients than in anti-ERα antibody negative patients. Taken together our data clearly indicate that anti-ERα antibodies, probably via the involvement of membrane-associated ER, can represent: i) promising markers for SSc progression but, also, ii) functional modulators of the SSc patients' immune system.

Digital ulcers (DUs) and gangrene are common skin manifestations of connective tissue diseases, especially systemic sclerosis. Raynaud's phenomenon (RP) is an almost universal manifestation of systemic sclerosis, with 95% of all patients being affected, and resulting in DUs in approximately 30% of the patients each year. Although RP may be present in approximately 25-50% of the patients, DUs are relatively rare in systemic lupus erythematosus (SLE) and never present as an initial manifestation of disease. In this case report DUs appear as the initial manifestation of SLE in a young woman with a capillaroscopic scleroderma pattern and elevated systolic pulmonary arterial pressure.

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 microvasculare 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. (C) 2011 Elsevier Inc. All rights reserved.

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. (C) 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:815-821

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 prevalence of erectile dysfunction (ED) in men with systemic sclerosis (SSc) can be considered a manifestation of endothelium damage. Aim of the study is to investigate ED in SSc patients by color Doppler ultrasound examination and to correlate it with disease severity and digital vascular damage.In 20 males SSc patients blood flow velocity in the cavernous artery was determined with Duplex ultrasonography. Naifold videocapillaroscopy, Sexual Health Inventory for Men (SHIM) and Medsger Disease Severity Scale (DSS) were performed. Arteriogenic ED was defined by the presence of a reduced peak systolic velocity (PSVs), while diastolic velocity (EDV) and the resistive index (RI) were estimated to evaluate venocclusive dysfunction. SSc patients are classified by capillaroscopic pattern and vascular domain of DSS into two groups: low vascular damage (early or active capillaroscopic pattern and score of vascular domain of DSS≤2) and high vascular damage (late capillaroscopic pattern and score of vascular domain of DSS≥3).In all SSc patients a reduction of SHIM is present (mean 13.5±6.3). Patients with less vascular damage have a significantly (p<0.001) higher score of SHIM than patients with greater vascular damage (19.2±2.4 vs 7.9±2.7). No significant difference (p>0.5) between the two groups of vascular damage was found in PSVs. Venocclusive dysfunction was present only (p<0.001) in the group with high vascular damage.We can assert that there is a relationship between SSc vascular digital damage and ED.

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.

We investigated in systemic sclerosis (SSc) patients the T cell homeostasis and its relationship with the clinical course of the disease. Distribution of peripheral T cell subsets, thymic output, lymphocyte proliferation and apoptosis were analyzed by flow cytometry or ELISA. Age inappropriate levels of naive CD4+ T cells and thymic output were observed. Proliferation of CD4+ T cells, lymphocyte apoptosis and CD4+ regulatory T (Treg) cell frequency were significantly higher than those observed in controls and significantly correlated with clinical phenotypes and clinical progression parameters i.e., diffusing capacity of the lung for carbon monoxide (DLCO) and disease activity. These data indicate that the evaluation of the T cell homeostasis can represent a valuable prognostic tool for SSc patients and it is useful to distinguish between limited and diffuse phenotypes. A therapeutic intervention targeted at reversing T cell homeostasis abnormalities would therefore potentially be helpful in counteracting disease progression.

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.

Objective. To investigate capillary morphology and skin blood flow of dorsal hands by nailfold videocapillaroscopy (NVC) and laser Doppler perfusion imaging (LDPI), respectively, in patients with primary Raynaud’s phenomenon (PRP) and systemic sclerosis (SSc) and to compare the results with those obtained in healthy controls. Methods. The study group consisted of 142 patients with SSc, 88 patients with PRP, and 147 healthy controls. NVC was performed in all the groups examined. In patients with SSc the capillaroscopic pattern was classified as early, active, or late group pattern. A baseline skin blood flow determination of the dorsum of the subject’s hands was acquired through a low-energy 670 nm Lisca Laser Doppler Perfusion Imager. Results. In the healthy controls the perfusion distribution pattern was homogeneous, with a proximal-distal perfusion gradient. In patients with PRP, the perfusion distribution pattern was homogeneous, but the proximal-distal perfusion gradient was absent. Finally, in patients with SSc the perfusion distribution pattern was dyshomogeneous and a proximal-distal gradient was absent. The minimum perfusion, mean perfusion, maximum perfusion, and standard deviation, calculated as variation by means of each measurement site, were significantly different in all the groups examinated. Conclusion. NVC represents the best method to analyze microvascular damage in rheumatic diseases. LDPI improves the evaluation of vascular damage in patients with SSc. The LDPI and the capillaroscopic images fully matched the definition of the various stages of vascular digital damage in SSc.

Objective. To evaluate the presence of celiac disease in patients with systemic sclerosis (SSc). The association of autoimmune diseases with celiac disease has been reported, but few publications deal with the combination of SSc and celiac disease. Methods. We investigated the presence of anti-tissue transglutaminase (anti-tTG) antibodies and serum antiendomysial antibodies (anti-EMA) in 50 patients with SSc. All subjects were on a gluten-containing diet. Duodenal mucosa histology and biopsy culture were performed in anti-tTG-positive patients; anti-EMA and IgA, IgG1 anti-tTG were detected in culture supernatants. Results. The incidence of celiac disease in patients with SSc was found to be 8%. Serum anti-tTG antibody-positive results were detectable in 5 out of 50 patients with SSc, but only in 4 of them was the diagnosis confirmed by histological results (Marsh classification). Conclusion. Our data show an increased prevalence of celiac disease in patients with SSc.

Aim: To evaluate resistance index (RI) changes in renal artery after N -acetylcysteine infusion in patients with systemic sclerosis. Methods: In an open-label study 40 patients with systemic sclerosis (SSc) were treated with N -acetylcysteine (NAC) iv infusion over 5 consecutive hours, at a dose of 0.015 g·kg −1 ·h −1 . Renal haemodynamic effects were evaluated by color Doppler examination before and after NAC infusion. Results: NAC infusion significantly reduced RI in a group of sclerodermic patients with early/active capillaroscopic pattern, modified Rodnan Total Skin Score (mRTSS) <14 and mild-moderate score to the vascular domain of Medsger Scleroderma Disease Severity Scale (DSS). RI increased after NAC infusion in patients with late capillaroscopic pattern, mTRSS>14 and severe-end stage score to the vascular domain of DSS. In patients with reduction of RI after NAC infusion, diffusion capacity for carbon monoxide mean value was significantly higher than in those patients with an increase of RI. No significant differences in renal blood flow were found between patients with different subsets of SSc. Conclusion: In patients with low disease severity NAC ameliorates vascular renal function.

N-Acetylcysteine is useful in the short-term treatment of severe Raynaud's phenomenon and digital ulcers (DU) in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 3 years) in a prospective study of a cohort of 50 consecutive patients with SSc who received N-acetylcysteine (NAC) infusional therapy every 2 weeks. We observed a reduction of DU/patient/year (4.5 +/- 3.1 vs 0.81 +/- 0.79) and DU ulcer visual analog scale (VAS; 6.88 +/- 2.62 vs 3.20 +/- 1.80), a decrease of the Raynaud's phenomenon (RP) number attacks (7.18 +/- 3.87 vs 3 +/- 1.92), and RP VAS (6.24 +/- 1.92 vs 3.62 +/- 1.48). In this study, we did not observe serious adverse events in patients. Minor side effects were flushing (two patients) and headache (one patient). NAC infusion was generally well tolerated, and nobody had to discontinue the treatment. In conclusion, long-term therapy with NAC, in patients with SSc, has a durable effectiveness on ischemic ulcers and Raynaud's phenomenon.