Increased Intrarenal Arterial Stiffness May Predict the Occurrence of New Digital Ulcers in Systemic Sclerosis

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1 Arthritis Care & Research Vol. 66, No. 9, September 2014, pp DOI /acr , American College of Rheumatology ORIGINAL ARTICLE Increased Intrarenal Arterial Stiffness May Predict the Occurrence of New Digital Ulcers in Systemic Sclerosis EDOARDO ROSATO, BIAGIO BARBANO, ANTONIETTA GIGANTE, ILENIA MOLINARO, SILVIA QUARTA, SIMONETTA PISARRI, ANTONIO AMOROSO, ROSARIO CIANCI, AND FELICE SALSANO Objective. 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. Methods. Seventy unselected, consecutive patients with SSc (58 women and 12 men, mean SD age years) were enrolled. In all patients, Doppler ultrasound examination was performed. The following Doppler indices of intrarenal stiffness were measured: peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI), pulsatile index (PI), and systolic/diastolic ratio (S/D). Results. In total, 30 (42%) of 70 patients experienced new DUs. RI, S/D, and PI were significantly higher in SSc patients with new DUs than in SSc patients without new DUs. The receiver operating characteristic (ROC) curves demonstrated a good accuracy of new DU prediction for RI (0.94, P < ), S/D (0.92, P < ), and PI (0.88, P < ). Conversely, the ROC curve showed no performance for PSV (0.58, P > 0.05) and EDV (0.28, P > 0.05). Using a cutoff value of 0.70 for RI and 3.25 for S/D, the positive predictive value was 90.6% and 92.9%, respectively. Conclusion. We can conclude that Doppler indices of intrarenal stiffness are reliable markers of new DU occurrence. Doppler indices could be used in association with the capillaroscopic and clinical findings or serologic tests for the identification of patients at high risk of developing DUs. INTRODUCTION Systemic sclerosis (SSc; scleroderma) is an autoimmune disease characterized by endothelial dysfunction and fibrosis of the skin and internal organs. Endothelial dysfunction, microvascular damage, and macrovascular damage are the hallmarks of SSc (1,2). Patients with SSc are at high risk for the development of ischemic digital ulcers (DUs), which occur in 35 60% of SSc patients (3). The early detection of patients with a high risk of developing DUs could allow a preventive treatment of these complications, with a reduction of morbidity and social costs. The capillaroscopic skin ulcer risk index Edoardo Rosato, MD, PhD, Biagio Barbano, MD, Antonietta Gigante, MD, Ilenia Molinaro, MD, Silvia Quarta, MD, Simonetta Pisarri, MD, Antonio Amoroso, MD, Rosario Cianci, MD, Felice Salsano, MD: Sapienza University of Rome, Rome, Italy. Address correspondence to Edoardo Rosato, MD, PhD, Sapienza University of Rome, Department of Clinical Medicine, Clinical Immunology Unit, Viale dell Università 37, Rome, Italy. edoardo.rosato@uniromal.it. Submitted for publication June 3, 2013; accepted in revised form February 4, (CSURI) may represent a novel tool with the ability to predict the development of DUs in SSc patients (4). Chronic renal vasculopathy is frequent in SSc patients, while scleroderma renal crisis (SRC) has been reported in 10% of SSc patients. Increased arterial stiffness is known to be associated with sclerodermic kidney dysfunction. It is known that Doppler renal ultrasound is a useful and noninvasive diagnostic tool to evaluate intrarenal arterial stiffness. In SSc patients, renal Doppler ultrasound is especially useful in both subclinical renal damage and SRC (5). Rosato et al demonstrated that intrarenal hemodynamic parameters correlate with glomerular filtration rate (GFR) and digital microvascular damage in SSc (6). Moreover, the indices are also useful in monitoring SRC and evaluating the response to specific drugs (7). The aim of this study was to asses a correlation between intrarenal arterial stiffness and DUs in SSc patients and to evaluate the prognostic value of Doppler indices to predict new DU occurrence. SUBJECTS AND METHODS Subjects. Enrolled in this study were 70 consecutive patients with SSc (58 women and 12 men, mean SD ages 1380

2 Intrarenal Arterial Stiffness and Digital Ulcers 1381 Significance & Innovations Doppler indices of intrarenal arterial stiffness were increased in patients with systemic sclerosis. Doppler indices of intrarenal arterial stiffness were higher in systemic sclerosis patients with digital ulcers than in systemic sclerosis patients without digital ulcers. Doppler indices of intrarenal stiffness were reliable markers of new digital ulcer occurrence. Table 1. Epidemiologic and clinical features of the SSc patients* Value Sex, men/women 58/12 Age, years Disease duration, years Raynaud s phenomenon duration, years dcssc/lcssc 39/31 SSc-specific autoantibodies, no. (%) Anti topoisomerase I 38 (54) Anticentromere 25 (36) None 7 (10) Patients with digital ulcer history, no. (%) 46 (65) Patients with new digital skin ulcers, no. (%) 30 (42) No. of digital ulcers/patient Capillaroscopic pattern, no. (%) Early 27 (38.6) Active 25 (35.7) Late 18 (25.7) * Values are the mean SD unless indicated otherwise. SSc systemic sclerosis; dcssc diffuse cutaneous SSc; lcssc limited cutaneous SSc years). All patients met the preliminary American College of Rheumatology criteria for the classification of SSc (8). The mean SD duration of Raynaud s phenomenon (RP) and mean SD duration of disease were years and years, respectively. Overall, 31 patients had limited cutaneous SSc (lcssc) and 39 had diffuse cutaneous SSc (dcssc), as defined by LeRoy et al (9). Table 1 shows the epidemiologic and clinical features of the SSc patients. Patients with obstructive kidney disease and renal artery stenosis and those with microscopic or macroscopic hematuria, abnormal urinary sediment, SRC, history of glomerulonephritis or nephroureterolithiasis, antiphospholipid-associated nephropathy, coexistent myeloperoxidase antineutrophil cytoplasmic autoantibody associated glomerulonephritis, dilated renal pelvis or atrophied kidney on ultrasonography, overt proteinuria, or elevated serum creatinine concentration ( 106 moles/liter) were excluded. Patients with a history of uncontrolled systemic hypertension, hyperlipidemia, cardiac failure, cardiac valve diseases (insufficiency or stenosis of aortic and mitralic valve), hepatic failure, diabetes mellitus, cerebrovascular diseases, peripheral vascular diseases, and coagulopathy were excluded, and smokers and pregnant or breastfeeding women were also excluded. All SSc patients underwent treatment with calciumchannel blockers (nifedipine 30 mg/day). At the time of Doppler examination, 27 patients were receiving prostanoid therapy and 18 were receiving bosentan. No studies have demonstrated an influence of bosentan on Doppler indices of interlobar arteries. Our data did not show any influence of bosentan on intrarenal Doppler indices. None of the patients were treated with immunosuppressive agents (e.g., cyclophosphamide or mycophenolate mofetil). After Doppler examination, the patients were examined for the appearance of new DUs after 3, 6, 9, and 12 months of followup without any changes in previous treatments. Thirty healthy controls were also recruited (26 women and 4 men, mean SD ages years). The subjects written consent was obtained according to the Declaration of Helsinki and the study was approved by the Ethics Committee of Sapienza University. Doppler ultrasound. SSc patients and healthy controls were placed for at least 15 minutes before the Doppler ultrasound examination in a temperature-controlled room at C. The size of the left and right kidneys and the flow in the aorta and renal arteries were evaluated to detect a morphologic abnormality or renal artery stenosis. During the measurements, the patients were supine and held their breath. Doppler ultrasound examinations were performed by the same senior nephrologist blinded to the clinical features of the patient (RC). Renal Doppler ultrasound was performed using a Toshiba Aplio Ultrasound System SSA- 790 equipped with a convex 3.5-MHz probe. Renal Doppler flow was obtained in 3 different interlobar arteries of both kidneys (mesorenal, superior, and inferior pole), guided by color-flow mapping. The Doppler gate width was kept small, and the angle of insonation was maintained at 60. We used an anterior approach for detecting the renal artery origin and an oblique, lateral approach for the intermediate tract and intrarenal vessels. No aliasing was allowed in the interlobar arteries while the following parameters were measured: peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI), pulsatile index (PI), and systolic/diastolic ratio (S/D). RI was calculated as (peak systolic frequency shift minimum diastolic frequency shift)/peak systolic frequency shift and the PI was calculated as (peak systolic frequency shift minimum diastolic frequency shift)/mean frequency shift. The PSV and EDV are expressed as cm/second. The mean value of 3 measurements of interlobar arteries from each kidney was calculated. For each patient, Doppler ultrasound parameters were calculated as the mean of measurements of both kidneys. While performing the renal Doppler examination, the operator evaluated the heart function. The Doppler examination was not performed in SSc patients and healthy controls with arrhythmia or tachycardia or bradycardia. Weighted kappa was used to evaluate the intrarater reliability by the same observer. The kappa values for RI and S/D were and 0.965, respectively. The intrapatient

3 1382 Rosato et al Table 2. Doppler indices of SSc patients and healthy controls* SSc patients Healthy controls PSV, cm/second EDV, cm/second PI RI S/D * Values are the mean SD. SSc systemic sclerosis; PSV peak systolic velocity; EDV end diastolic velocity; PI pulsatile index; RI resistive index; S/D systolic/diastolic ratio. coefficient of variation for RI and S/D measurement was 1.2% and 1.3%, respectively. Calcium-channel blocker therapy was discontinued 72 hours before the Doppler ultrasound. Patients receiving iloprost therapy underwent Doppler examination the day before the next infusion (6,7). Estimated GFR. According to a previous study, GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation, which expressed as a single equation is GFR 141 min(serum creatinine/, 1) max (serum creatinine/, 1) Age (if female) (if black), where 0.7 for females and 0.9 for males, for females and for males, and min indicates the minimum of serum creatinine/ or 1 and max indicates the maximum of serum creatinine/ or 1 (10). Nailfold videocapillaroscopy (NVC). NVC was performed with a videocapillaroscope (Pinnacle Studio Version 8) equipped with a 500 optical probe. The nailfold of the second, third, fourth, and fifth finger was examined in each patient. According to Cutolo et al, the patterns identified within the SSc pattern included early, active, and late (11). DUs. The DUs were classified according to Amanzi et al as follows: DUs derived from digital pitting scar (DPS), pure DUs, DUs derived from calcinosis, and DUs derived from gangrene (12). Statistical analysis. All of the results were expressed as the mean and SD. Commercial software (SPSS, version P 20.0) was used for statistical analysis. The coefficient of skewness and the coefficient of kurtosis were used to evaluate normal distribution of data. Multivariate analysis was applied for the estimation of the relationship of Doppler indices with clinical features (e.g., age and duration of disease). A receiver operating characteristic (ROC) curve analysis was performed to analyze the prognostic accuracy of each Doppler index in regard to ulcer development. Group comparisons were made by Student s unpaired 2-tailed t-test. Pearson s product-moment correlation coefficient (r) was used to test for an association between numerical variables. Chi-square test or Fisher s exact test, as appropriate, was used to compare categorical variables. Relative risk (RR) and 95% confidence intervals (95% CIs) are reported. Comparisons between the 3 NVC patterns were by nonparametric Kruskal-Wallis test and the data were expressed as the median and range. P values less than 0.05 were considered significant. RESULTS PSV did not show a significant difference (P 0.05) between SSc patients and healthy controls (mean SD versus cm/second). EDV was significantly (P 0.001) lower in SSc patients than healthy controls (mean SD versus cm/second). PI (mean SD versus ), RI (mean SD versus ), and S/D (mean SD versus ) were significantly higher in SSc patients than in healthy controls (Table 2). In SSc patients, no statistical correlations were observed between Doppler indices (PSV, EDV, RI, PI, and S/D) and age, subset of disease, and SSc-specific autoantibodies. PSV, EDV, and PI showed no statistically significant (P 0.05) correlation with estimated GFR. Estimated GFR was correlated with other Doppler indices, including RI (r 0.31, P 0.01) and S/D (r 0.35, P 0.01). In 3 capillaroscopic groups of SSc patients, no significant differences of PSV and EDV were observed. PI, RI, and S/D significantly increased with the progression of capillaroscopic damage (Table 3). The principal features of SSc patients with or without new DUs are shown in Table 4. Within 12 months since the Doppler ultrasound, 30 (42%) of 70 patients experienced new DUs. The new DUs were more frequent (P 0.05) in patients with dcssc (30%) than in patients with lcssc (12.9%). The occurrence of new DUs was higher Table 3. Doppler indices of 3 capillaroscopic groups* Healthy controls, mean SD Early Active Late P PSV, cm/second ( ) 32.6 ( ) 33 ( ) 0.05 EDV, cm/second ( ) 10.6 ( ) 8.5 ( ) 0.05 PI ( ) 1.33 ( ) 1.67 ( ) RI ( ) 0.69 ( ) 0.73 ( ) S/D ( ) 3.23 ( ) 3.71 ( ) * Values are the median (range) unless otherwise indicated. P was calculated in 3 capillaroscopic patterns. PSV peak systolic velocity; EDV end diastolic velocity; PI pulsatile index; RI resistive index; S/D systolic/diastolic ratio.

4 Intrarenal Arterial Stiffness and Digital Ulcers 1383 Table 4. Clinical features of SSc patients with or without new DUs* Patients with new DUs Patients without new DUs DU history Yes 29 (41.4) 17 (24.3) No 1 (1.4) 23 (32.9) Subset dcssc 21 (30.0) 18 (25.7) lcssc 9 (12.9) 22 (31.4) Autoantibodies Anti topoisomerase I 19 (27.1) 18 (25.7) Others 11 (15.7) 22 (31.4) Capillaroscopy Early 1 (1.4) 26 (37.1) Active 14 (20.0) 11 (15.7) Late 15 (21.4) 3 (4.3) * Values are the number (percentage). SSc systemic sclerosis; DUs digital ulcers; dcssc diffuse cutaneous SSc; lcssc limited cutaneous SSc. (P 0.05) in patients with anti topoisomerase I antibodies (27.1%) than in patients with other autoantibodies (15.7%). The new DU occurrence was higher (P ) in SSc patients with DU history (41.4%) than in SSc patients without DU history (1.4%). New DUs were more frequent (P ) in patients with active and late capillaroscopic pattern than in patients with early capillaroscopic pattern (Table 4). We observed 119 new DUs in SSc patients: 52 DPS (43.7%), 62 pure DUs (52.1%), 4 DUs derived from calcinosis (3.4%), and 1 DU derived from gangrene (0.8%). We did not observe any correlation between DU subset and intrarenal Doppler indices. For treatments, 2 (66.6%) of 3 patients treated with bosentan developed new DUs, 6 (50%) of 12 patients treated with intravenous iloprost developed new DUs, and 11 (73%) of 15 patients treated with bosentan and intravenous iloprost developed new DUs. When comparing patients with and without new DUs, we observed significant differences in many Doppler indices; RI, S/D, and PI were significantly higher in SSc patients with new DUs than in SSc patients without new DUs. Therefore the PI, RI, and S/D were significantly (P ) higher in SSc patients without DUs than healthy controls (Table 5). RI (mean SD versus ), S/D (mean SD versus ), and PI (mean SD versus ) were significantly (P ) higher in SSc patients with DU history than in SSc patients without DU history. No significant differences of PSV and EDV were observed in SSc patients with DU history and without DU history. The ROC curves demonstrated a good accuracy of new DU prediction for RI (0.94, P [95% CI ]), S/D (0.92, P [95% CI ]), and PI (0.88, P [95% CI ]). Conversely, the ROC curve showed no performance for PSV (0.58, P 0.05 [95% CI ]) and EDV (0.28, P 0.05 [95% CI ]). Using a cutoff value of 0.70, the positive predictive value of RI was 90.6% (95% CI %). An RI 0.70 was present in 27 of 30 patients with new DUs. The negative predictive value was 92.8% (95% CI %), and only 3 of 42 patients with an RI 0.70 experienced new DUs. The association between new DUs and RI was confirmed by RR calculation (13.5 [95% CI ], P ). Using a cutoff value of 3.25, the positive predictive value of S/D was 92.9% (95% CI %). An S/D 3.25 was present in 26 of 30 patients with new DUs. The negative predictive value was 90.58% (95% CI %), and only 4 of 42 patients with an S/D 3.25 experienced new DUs. The association between new DUs and S/D was confirmed by RR calculation (17.3 [95% CI ], P ). DISCUSSION In this study, we demonstrated that intrarenal arterial stiffness was increased in SSc patients and was correlated with capillaroscopic damage. Additionally, estimated GFR correlated with some Doppler indices (RI and S/D). Conversely, the SSc patients with increased intrarenal stiffness showed an increased risk of DU occurrence. Previous studies have shown that chronic renal vasculopathy seems to be the main pathogenic mechanism of all SSc renal manifestations, including SRC. In the early stage of SSc renal damage, resistance indices increase and GFR is normal or slightly reduced. This initial reduction of GFR is linked more with a reduced blood inflow in intrarenal vessels than with a reduced glomerular filtration capacity. With the progression of intrarenal vascular damage, GFR is further reduced. In the late stage, the deterioration of GFR is due to both the further reduction of blood inflow of intrarenal arteries and the glomerular injury (6,7,13). Table 5. Doppler indices of SSc patients with or without new DUs* SSc patients with new DUs (n 30) SSc patients without new DUs (n 40) P PSV, cm/second EDV, cm/second PI RI S/D * Values are the mean SD. SSc systemic sclerosis; DUs digital ulcers; PSV peak systolic velocity; EDV end diastolic velocity; PI pulsatile index; RI resistive index; S/D systolic/diastolic ratio.

5 1384 Rosato et al Many of the severe internal organ complications of SSc are vascular. Intimal hyperplasia, endothelial dysfunction, and occlusive vasculopathy are ubiquitous features of SSc. These vascular lesions are the underlying basis of important clinical syndromes in SSc, including RP, DUs, pulmonary arterial hypertension, and SRC (14,15). The DU pathogenesis is believed to include many of the hallmark processes of critical tissue ischemia, such as impaired afferent vasomotion, endothelial dysfunction, microvascular disruption, intimal hyperplasia, reduced venous drainage, increased local platelet activation, and increased leukocyte adherence. Endothelin 1 (ET-1) showed a key role in the pathogenesis of SSc-associated DUs. Plasma ET-1 concentrations are increased in patients with SSc. Previous randomized, double-blind, placebocontrolled trials demonstrated that bosentan, an oral ET receptor antagonist, reduced new DU occurrence (3). Patients with SSc are at high risk for the development of ischemic DUs, which occur in 35 60% of patients with SSc. In our study groups, the incidence of new DUs was 42%. Our data do not differ much from those of the study by Steen et al. The majority (58%) of the 2,080 Pittsburgh patients had experienced a DU during their course of SSc, and one-third (32%) of all patients with SSc have had persistent DUs (persistent or recurrent ulcers for at least 6 months). However, no serologic or clinical markers have been proven safe in predicting the new DU occurrence. Many authors have tried to identify markers that may be predictive for the development of new DUs (16). The early occurrence and high frequency of DU complications are especially seen in patients with dcssc and/or antitopoisomerase antibodies. Male patients with early onset SSc, more severe skin fibrosis, impaired diffusing capacity for carbon monoxide, and anti topoisomerase I are most likely to exhibit prior or current DUs (17,18). Avouac et al identified high placental growth factor serum levels and low circulating endothelial progenitor cell counts as predictors of new DUs in SSc. This highlights the critical role of angiogenesis in this vascular outcome. These markers may improve DU risk stratification and therefore allow earlier therapeutic intervention (19). DU occurrence was associated with capillaroscopic damage. Cutolo et al demonstrated that skin DUs seemed to be associated with the late NVC pattern, characterized by avascular areas (severe capillary loss) (20). Sebastiani et al demonstrated that the proposed CSURI may represent a novel tool with the ability to predict the development of DUs in SSc patients. The development and validation of new outcome measures may facilitate the recognition of patients at high risk of developing DUs and may improve the monitoring of vascular complications and treatments (4). In our study group, Doppler indices (RI, S/D, and PI) were increased in SSc patients with new DUs compared to patients without new DUs. In addition, the subclinical renal vasculopathy seemed correlated to digital vascular damage; in fact, estimated GFR correlated with RI and S/D. Doppler indices of intrarenal arterial stiffness, particularly RI, showed a good accuracy of new DU predictions. Indeed, RI, S/D, and PI showed a good association with new DU occurrence. Ultrasound plays a crucial role in the assessment of organ involvement in SSc and vasculitides. Ultrasound measures promise reproducible and objective scores of disease activity and extension. Ultrasound reveals early pathognomonic abnormalities and may help start early treatment (21). The color Doppler measurement of RI at the level of the interlobar artery has been proposed as an indicator for differential diagnosis between acute and chronic nephropathies; for example, the ratio was higher in acute pathologies with vascular and tubulointerstitial involvement, but not in those with glomerular involvement. RI and S/D were advanced as useful parameters for quantifying the alterations in renal blood flow that may occur with renal disease (22). In lupus nephritis, RI correlated significantly with creatinine level, chronicity index, and presence of interstitial disease. Only RI and chronicity index were statistically significant predictors of a poor renal outcome (23). We can suppose that intrarenal stiffness is a manifestation of microvascular and vascular damage in SSc patients. Previous studies have demonstrated a correlation between microvascular digital damage and renal vascular damage (6). In addition, response to vasodilatator drugs correlated with intrarenal arterial Doppler indices (24,25). Because Doppler indices are an easy tool to use, we can assume that they could be used in association with the capillaroscopic and clinical findings or serologic tests in the identification of patients at high risk of developing DUs. We can conclude that Doppler indices of intrarenal stiffness are reliable markers of new DU occurrence. Therefore, larger studies are needed to confirm our preliminary data. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Rosato had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Rosato, Barbano, Gigante, Pisarri, Amoroso, Cianci, Salsano. Acquisition of data. 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