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Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients
Microvascular Research 115 (2018) 28–33
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Microvascular Research journal homepage: www.elsevier.com/locate/ymvre
Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients
MARK
B. Ruaroa,⁎, A. Sullia, C. Pizzornia, S. Paolinoa, V. Smithb, E. Alessandria, A.C. Trombettaa, J. Alsheyyaba, M. Cutoloa a Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, IRCCS Policlinico San Martino, Genova, Italy b Department of Rheumatology, Ghent University Hospital, Department of Internal Medicine, Ghent University, Ghent, Belgium
A R T I C L E I N F O
A B S T R A C T
Keywords: Systemic sclerosis Laser speckle contrast analysis Skin high-frequency ultrasound Nailfold videocapillaroscopy Peripheral blood perfusion Dermal thickness Nailfold microangiopathy
Objective: To identify possible correlations between skin blood perfusion (BP) and dermal thickness (DT) in different skin areas of systemic sclerosis (SSc) patients. Methods: Sixty-two SSc patients, according to 2013 EULAR/ACR criteria, and 62 healthy subjects (CNT) were enrolled. Skin BP was analysed by laser speckle contrast analysis (LASCA) at the level of dorsum of the middle phalanx of the third fingers, dorsal aspect of the hands and zygoma. DT was assessed by both skin high frequency ultrasound (US) and modified Rodnan skin score (mRSS) in the same above reported areas. All patients were studied also by nailfold videocapillaroscopy (NVC) to assess the proper pattern of microvascular damage (“Early”, “Active”, or “Late”). Results: At the level of finger dorsum a statistically significant negative correlation was observed in SSc patients between skin BP and both ultrasound-DT (p = 0.0005 r = 0.43) and mRSS (p = 0.0007 r = 0.42), but not at the level of hand dorsum and zygoma. No statistically significant correlation was present between skin BP and ultrasound-DT at any level in CNT. In detail, SSc patients, compared to CNT, showed a statistically significant lower BP only at level of fingers (median PU 72.6 vs 136.1 respectively, p < 0.0001) and a statistically significant higher ultrasound-DT at the level of dorsum of 3th finger bilaterally (median mm 0.9 vs 0.7, p < 0.0001), dorsum of hands (median mm 0.9 vs 0.7, p < 0.0001) and zygoma (median mm 0.8 vs 0.7, p < 0.0001). A significant positive correlation between ultrasound-DT and mRSS was observed in SSc patients at level of the three areas (dorsum of fingers p < 0.0001 r = 0.51; dorsum of hands p = 0.03 r = 0.27; zygoma p = 0.0001 r = 0.45). A progressive decrease of skin BP and increase of ultrasound-DT was found correlated with the progression of the severity of NVC patterns. Conclusions: This study demonstrates for the first time in SSc patients a significant inverse relationship between skin BP, measured by LASCA, and DT, evaluated by both US and mRSS, at the level of dorsum of the middle phalanx of the third fingers.
1. Introduction Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease, characterized by typical clinical cutaneous alterations that include peripheral microangiopathy and decreased skin blood perfusion (BP), as well as increased dermal thickness (DT) (Gabrielli et al., 2009; Cutolo et al., 2010a; Barbano et al., 2017; Hesselstrand et al., 2008). The morphological impairment of peripheral microcirculation may precede the other symptoms by many years, is a predictive factor for SSc progression, and may be assessed and classified by nailfold
videocapillaroscopy (NVC) (Burmester et al., 2017; Cutolo et al., 2010a; Smith et al., 2010, 2016; Ingegnoli et al., 2013a,b). Although NVC permits the observation of the column of red blood cells moving inside the capillaries, the blood flow cannot be quantified in standard conditions (Mugii et al., 2009). Conversely, laser speckle contrast analysis (LASCA) is a method to quantify BP at level of different skin areas, such as face and hands, and a recent study demonstrated a very good inter-rater reliability of BP measurements by LASCA (Ruaro et al., 2014; Della Rossa et al., 2013; Lambrecht et al., 2016).
⁎ Corresponding author at: Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, n° 6, 16132 Genova, Italy. E-mail address: [email protected] (B. Ruaro).
http://dx.doi.org/10.1016/j.mvr.2017.08.004 Received 24 July 2017; Received in revised form 18 August 2017; Accepted 19 August 2017 Available online 20 August 2017 0026-2862/ © 2017 Elsevier Inc. All rights reserved.
–
3/25
–
4/13
–
–
63.0 (20)
59.0 (19)
69.5 (23)
–
65.0 (21,5)
62.0 (21)
–
SSc vs CNT statistical signific. Early (#15) median (IQR)
Active (#19) median (IQR)
29
Late (#28) median (IQR)
E vs L statistical signific.
lcSSc (#45) median (IQR)
dcSSc (#17) median (IQR)
lcSSc vs dcSSc statistical signific.
2/43
2/17
1/14
6/56
66.0 (16.5)
SSc (#62) median (IQR)
5/57
64.0 (16)
Sex (males/ females)
CNT (#62) median (IQR)
Age (years)
–
9.0 (8)
7.0 (5)
–
13.7 (9)
7.0 (5)
4.0 (3)
–
–
7.0 (6)
4.0 (3)
–
7.5 (6)
4.0 (3)
1.8 (1.5)
–
5.0 (4)
–
– 8.5 (7)
SSc duration (years)
RP duration (years)
–
3/1/13
32/3/10
–
11/2/15
13/0/6
11/2/2
–
35/4/23
–
ANA IIF-pattern (centr/ spec/spec + nucl)
–
12/2/6
9/1/11
–
14/1/3
5/2/3
2/0/11
–
21/3/17
–
ENA (Scl70/ RNAP/neg)
79.6/51.0/133.1 (25.2/ 24.1/59.3) 63.9/44.2/121.5 (34.0/ 13.4/41.6) p = 0.02/0.4/0.7
88.7/57.4/135.5 (24.0/ 24.0/58.5) 67.5/51.0/137.2 (42.4/ 18.0/26.5) 60.7/46.6/121.3 (31.7/ 15.8/39.4) p < 0.0001/=0.06/=0.2
136.1/49.6/126.2 (55.8/ 20.0/41.6) 72.6/48.4/131.9 (35.1/ 20.0/35.3) p < 0.0001/=0.3/=0.3
BP (PU) fingers/hands/face
p = 0.002/0.028/0.0002
1.1/0.9/0.9 (0.3/0.2/0.1)
p = 0.0015/=0.0003/ < 0.0001 0.9/0.9/0.9 (0.1/0.2/0.1)
1.0/1.0/0.9 (0.3/0.3/0.1)
0.9/0.9/0.9 (0.2/0.2/0.1)
0.8/0.8/0.8 (0.1/0.1/0.1)
p < 0.0001 for all areas
0.9/0.9/0.8 (0.3/0.2/0.2)
0.7/0.7/0.7 (0.1/0.1/0.1)
DT (millimetres) fingers/ hands/face
p = 0.0002/0.0001/ 0.0001
3.0/1.0/1.0 (1.0/0.0/0.0)
2.0/0/0 (1.0/0.0/0.0)
< 0.0001 for all areas
3/1/1 (1.0/1.0/1.0)
2/0/0 (1.5/0.0/0.0)
1/0/0 (1.0/0.0/0.0)
–
2.0/0.0/0.0 (2.0/1.0/1.0)
–
mRSS (score) fingers/ hands/face
Table 1 Clinical findings in systemic sclerosis (SSc) patients and healthy subjects (CNT). (RP = Raynaud's phenomenon; ANA = antinuclear antibodies; IIF = indirect immunofluorescence; centr = centromeric, spec = speckled; spec + nucl = speckled + nucleolar, ENA = extractable nuclear antigens: Scl70 = anti-topoisomerase autoantibodies, RNAP = anti RNA polymerase III autoantibodies, neg = ENA negative, BP = skin blood perfusion; DT = dermal thickness (ultrasound evaluation); mRSS = modified Rodnan skin score; Early, Active, Late = patterns of microangiopathy at nailfold videocapillaroscopy; lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; PU = perfusion units; # = number of cases; IQR = interquartile range).
B. Ruaro et al.
Microvascular Research 115 (2018) 28–33
Microvascular Research 115 (2018) 28–33
B. Ruaro et al.
Recent studies reported the utility of high frequency skin ultrasound (US) for early identification of skin involvement in SSc patients (Hesselstrand et al., 2008; Sulli et al., 2014a). In a previous investigation we checked local BP by laser Doppler flowmetry, in a single point of fingertip of SSc patients, and DT, measured at level of finger dorsum (Sulli et al., 2014a). The aim of this study was to identify possible correlations between two main clinical features of SSc, the decrease of skin BP and the increase of DT, using LASCA, modified Rodnan skin score (mRSS) and high frequency skin US at the level of dorsum of fingers, dorsum of hands and zygoma.
2. Methods 2.1. Patients Sixty-two SSc patients (6 males and 56 females, mean age 64 ± 11 SD years) were enrolled. Demographic and clinical data are reported in Table 1. SSc patients met either the ACR/EULAR criteria for SSc or the Le Roy's criteria for the classification of early SSc (van den Hoogen et al., 2013; LeRoy and Medsger, 2001). Patients gave written informed consent and the study was conducted according to the ethical standard of Good Clinical Practice. All SSc patients were taking aspirin (average dosage 100 mg/day) at the time of the study. Other concomitant treatments included: proton pump inhibitors (used by #52 patients), antihypertensive drugs (#14 patients), endothelin-1 receptor antagonists (average dosage 125 mg twice/day: #5 patients), cyclosporine (average dosage 150 mg/day: #10 patients), methotrexate (average dosage 7.5 mg/week: #11 patients). Prostanoids and endothelin-1 receptor antagonists, if used, were temporarily withdrawn one month before instrumental assessments. LASCA, US and NVC were performed the same day in all SSc patients. LASCA and US were also performed in 62 healthy subjects (CNT) similar to SSc patients about age and sex (see Table 1 for demographic data).
Fig. 1. Example of laser speckle contrast analysis (LASCA) evaluated in a SSc patient (A) and in an healthy subject (B).
2.4. Skin high frequency ultrasound (US) Several studies have reported the utility and reliability of high frequency ultrasound (US) in order to quantify dermal thickness (Ch'ng et al., 2013; Moore et al., 2003; Kaloudi et al., 2010). Therefore, high frequency US was performed in both SSc patients and healthy subjects to evaluate DT (ultrasound-DT) in the same body areas tested with the mRSS. The average value was recorded in millimetres (mm) (MyLab 25 ultrasound system equipped with an 18 MHz, Esaote, Genoa, Italy). The use of a high frequency probe offers considerably better resolution, allowing both the distinction between dermis and subcutaneous fat and the measurement of skin thickness. The same operator performed the US in all subjects, with an intra-operator reproducibility of 95% as reported in our previous study (Sulli et al., 2014a).
2.2. Laser speckle contrast analysis (LASCA) Skin BP was analysed by LASCA technique (Pericam PSI, Perimed, Milan, Italy) at the level of dorsal aspect of the whole hands and face, in both SSc patients and healthy subjects as previously described (Ruaro et al., 2014; Della Rossa et al., 2013). Different regions of interest (ROIs) were created at the level of dorsum of middle phalanx of third finger bilaterally (ROI = circle area of 1 cm of diameter, placed in the middle of the phalanx), dorsum of both hands (ROI = oval area of 5 × 3 cm, placed between head and basis of the metacarpal bones), and zygoma (ROI = circle area of 3 cm of diameter) (see Fig. 1). The average BP from the two dorsal areas of fingers, dorsum of the hands and zygoma was calculated by summing the perfusion values of the two sides (right and left) and then dividing the final value by two. The BP was quantified as perfusion units (PU) (Ruaro et al., 2016).
2.5. Nailfold videocapillaroscopy (NVC) All patients were assessed by nailfold videocapillaroscopy (NVC), (equipped with a 200 × contact lens, connected to image analysis software - Videocap, DS MediGroup, Milan, Italy) in order to score the severity of microangiopathy and to classify it within the proper pattern of microvascular damage (“Early”, “Active”, or “Late”) (Smith et al., 2010; Sulli et al., 2008; Pizzorni et al., 2017). The technical parameters were standardized as previously reported (Smith et al., 2010; Sulli et al., 2008).
2.3. Modified Rodnan skin score (mRSS) The mRSS is the validated method to evaluate the severity of skin involvement and to classify, in routine clinical practice, patients with either limited cutaneous SSc (lcSSc) or diffuse cutaneous skin involvement (dcSSc) (Kaldas et al., 2009; Czirják et al., 2007). The mRSS was used to evaluate DT at the level of the dorsum of the middle phalanx of the third fingers, dorsum of hands and zygoma bilaterally, in SSc patients, as reported in the literature, and the average score for fingers, hands and zygoma was calculated (Kaldas et al., 2009; Czirják et al., 2007).
2.6. Statistical analysis Statistical analysis was carried out by parametric procedures, and confirmed by nonparametric tests. Mann-Whitney U test were performed to compare unpaired groups of variables, and Kruskal-Wallis 30
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Fig. 2. Correlation between nailfold microangiopathy extent, peripheral blood perfusion (BP), and dermal thickness evaluated by both high frequency ultrasound (ultrasound-DT) and modified Rodnan skin score (mRSS). (CI = confidence interval).
microangiopathy in all the three areas (Table 1). Similarly, the mRSS was found progressively higher in patients with “Early”, “Active” and “Late” patterns of microangiopathy (Table 1). Finally, patients with dcSSc showed higher ultrasound-DT and mRSS, as well as lower BP, than patients with lcSSc (Table 1).
test was used to compare continuous variables with nominal variables with more than two levels. Multiple and linear regression along with Spearman rank correlation tests were employed to search for possible relationships between variables. The p values lower than 0.05 were considered statistically significant. Results are given as, median and interquartile range (IQR).
4. Discussion 3. Results This study demonstrates, for the first time in SSc patients, a relationship between skin BP (measured by LASCA) and DT (evaluated by both US and mRSS) at the level of dorsum of middle phalanx of third finger. Interesting, no statistically significant correlation was observed between skin BP and DT at the level of dorsum of hands and zygoma, confirming our previous data (Della Rossa et al., 2013; Sulli et al., 2014b). Furthermore, BP values of both hand dorsum and zygoma were found similar in SSc patients and healthy subjects, possibly being that these areas are mainly served by macro-circulation vessels, and therefore usually spared by the Raynaud's phenomenon and associated pathological changes (Cutolo et al., 2017). The gradual decrease of skin BP present at level of fingers was found associated with the progression of the microcirculatory damage, as reflected by the NVC patterns of microangiopathy (“Early, “Active” and “Late”) (Barbano et al., 2017; Ruaro et al., 2014; Della Rossa et al., 2013; Sulli et al., 2014a). This observation confirm the results previously reported that the reduction of BP correlates with the progression of the structural/morphological microvessel damage (Cutolo et al., 2010b, 2016; Trombetta et al., 2016a). In addition, SSc patients show statistically significant higher ultrasound-DT and mRSS values at level of dorsum of the middle phalanx of third finger, dorsum of hand, and zygoma than healthy subjects (Moore et al., 2003; Sulli et al., 2017). A significant positive correlation between US and mRSS was confirmed (Sulli et al., 2014a, 2017; Moore et al., 2003). Of note, present results show that the severity of the nailfold microvessel damage, evaluated by NVC, correlates positively with DT, as detected by both high frequency US and mRSS, and negatively with skin BP.
Interestingly, a significant negative correlation was observed between skin BP and both ultrasound-DT (p = 0.0005, r = − 0.43) and mRSS (p = 0.0007; r = − 0.42) in SSc patients at the level of fingers. Whereas, no statistically significant correlation was found between skin BP and both ultrasound-DT (p = 0.17; r = 0.18) and mRSS (p = 0.88; r = 0.14) at level of dorsum of hands and zygoma (p = 0.64; r = 0.8, p = 0.14; r = 0.01 respectively) in SSc patients. In healthy subjects no statistically significant correlation was detected between skin BP and ultrasound-DT at the level of fingers (p = 0.57, r = 0.01), dorsum of hands (p = 0.46, r = 0.10) or zygomas (p = 0.57, r = 0.07) (Fig. 2). SSc patients showed a statistically significant lower BP at level of finger areas when compared with healthy subjects (median PU 72.6 vs 136.1 respectively, p < 0.0001). No statistically significant difference in BP values was observed between SSc and healthy subjects at the level of dorsum of hand (median PU 48.4 vs 49.6 respectively, p = 0.3) and zygoma (median PU 131.9 vs 126.2 respectively, p = 0.3) (Table 1). A gradual decrease of BP was observed at the level of the dorsum of fingers in patients with different progressive pattern of microangiopathy, “Early, “Active” and “Late” (Table 1). SSc patients showed a statistically significant higher ultrasound-DT than healthy subjects at the level of dorsum of finger areas (median mm 0.9 vs 0.7 mm, p < 0.0001), dorsum of hands (median mm 0.9 vs 0.7, p < 0.0001) and zygoma (median mm 0.8 vs 0.7, p < 0.0001) (Table 1). Interestingly, a statistically significant positive correlation was observed between ultrasound-DT and mRSS values in SSc patients at level of the three areas (dorsum of fingers p < 0.0001 r = 0.51; dorsum of hands p = 0.03 r = 0.27; zygoma p = 0.0001 r = 0.45) (Fig. 2). Additionally, also ultrasound-DT was found progressively higher in SSc patients with the “Early”, “Active” and “Late” NVC pattern of 31
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blood perfusion correlates with microvascular abnormalities in systemic sclerosis: a Laser-Doppler and nailfold videocapillaroscopy study. J. Rheumatol. 37, 1174–1180. Cutolo, M., Herrick, A.L., Distler, O., Becker, M.O., Beltran, E., Carpentier, P., et al., 2016. Nailfold videocapillaroscopic and other clinical risk factors for digital ulcers in systemic sclerosis: a multicenter, prospective cohort study. Arthritis Rheumatol. 68, 2527–2539. Cutolo, M., Ruaro, B., Smith, V., 2017. Macrocirculation versus microcirculation and digital ulcers in systemic sclerosis patients: macro-microcirculation and scleroderma. Rheumatology. http://dx.doi.org/10.1093/rheumatology/kex165. (Epub ahead of print). Czirják, L., Nagy, Z., Aringer, M., Riemekasten, G., Matucci-Cerinic, M., Furst, D.E., et al., 2007. The EUSTAR model for teaching and implementing the modified Rodnan skin score in systemic sclerosis. Ann. Rheum. Dis. 66, 966–969. 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Seventeen-point dermal ultrasound scoring system—a reliable measure of skin thickness in patients with systemic sclerosis. Rheumatology 42, 1559–1563. Mugii, N., Hasegawa, M., Hamaguchi, Y., Tanaka, C., Kaji, K., Komura, K., et al., 2009. Reduced red blood cell velocity in nailfold capillaries as a sensitive and specific indicator of microcirculation injury in systemic sclerosis. Rheumatology 48, 696–703. Pizzorni, C., Giampetruzzi, A.R., Mondino, C., Facchiano, A., Abeni, D., Paolino, S., et al., 2017. Nailfold capillaroscopic parameters and skin telangiectasia patterns in patients with systemic sclerosis. Microvasc. Res. 111, 20–24. Ruaro, B., Sulli, A., Alessandri, E., Pizzorni, C., Ferrari, G., Cutolo, M., 2014. Laser speckle contrast analysis: a new method to evaluate peripheral blood perfusion in systemic sclerosis patients. Ann. Rheum. Dis. 73, 1181–1185. Ruaro, B., Sulli, A., Smith, V., Paolino, S., Pizzorni, C., Cutolo, M., 2015. Short-term follow-up of digital ulcers by laser speckle contrast analysis in systemic sclerosis patients. Microvasc. Res. 101, 82–85. Ruaro, B., Sulli, A., Pizzorni, C., Paolino, S., Smith, V., Cutolo, M., 2016. Correlation between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients. Microvasc. Res. 105, 119–124. Shah, A.A., Schiopu, E., Hummers, L.K., Wade, M., Phillips, K., Anderson, C., et al., 2013. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res. Ther. 15, R54. Smith, V., Pizzorni, C., De Keyser, F., Decuman, S., Van Praet, J.T., Deschepper, E., et al., 2010. Reliability of the quantitative and semiquantitative nailfold videocapillaroscpy assessment in a systemic sclerosis cohort: a two-centre study. Ann. Rheum. Dis. 69, 1092–1096. 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Patients with lcSSc showed lower DT and higher skin BP than those with dcSSc. This is of interest because these results confirm the literature reporting that patients with lcSSc are likely to have less severe organ involvement than those with dcSSc, and SSc patients with littler organ involvement are likely to have lower nailfold microvessel damage as well as higher skin BP and lower DT (Cutolo et al., 2010a; Hesselstrand et al., 2008; Ruaro et al., 2014; Sulli et al., 2014a; Smith et al., 2013; Caramaschi et al., 2007). In conclusion, imaging is an important adjunct to quantify and follow the different aspects of microvascular damage in SSc. Both LASCA and skin US are safe and not invasive detection methods, and offer the possibility to record and quantify the results, therefore we suggest to consider both evaluations, at least at baseline in every early SSc patient. However, the possibility to quantify in SSc the therapeutic effects of different regimens by testing both LASCA and US together, represent an important option compared to their single use (Hesselstrand et al., 2008; Cutolo et al., 2010b; Shah et al., 2013; Ruaro et al., 2015; Trombetta et al., 2016b). Funding This study was supported by funding from the Research Laboratory and Academic Division of Rheumatology of the University of Genova, Italy. Disclosure statement The authors have declared no conflict of interest. Contributorship The manuscript has been seen and approved by all the authors that have given necessary attention to ensure the integrity of the work. Ethical approval Local internal review board approval. Acknowledgements The authors thank Barbara Wade, contract Professor at the University of Torino, for her linguistic advice. The authors thank Doctor Sara De Gregorio from the Division of Rheumatology, University of Genova, for the support in graphic reproduction. Barbara Ruaro is supported by a Grant from the Italian Society of Rheumatology 2015. Vanessa Smith is a Senior Clinical Investigator of the Research Foundation - Flanders (Belgium) (FWO) [1802915N]. All authors are members of the EULAR Study Group on Microcirculation in Rheumatic Diseases. References Barbano, B., Marra, A.M., Quarta, S., Gigante, A., Barilaro, G., Gasperini, M.L., et al., 2017. In systemic sclerosis skin perfusion of hands is reduced and may predict the occurrence of new digital ulcers. Microvasc. Res. 110, 1–4. Burmester, G.R., Bijlsma, J.W.J., Cutolo, M., McInnes, I.B., 2017. Managing rheumatic and musculoskeletal diseases - past, present and future. Nat. Rev. Rheumatol. 13, 443–448. Caramaschi, P., Canestrini, S., Martinelli, N., Volpe, A., Pieropan, S., Ferrari, M., et al., 2007. Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity. Rheumatology 46, 1566–1569. Ch'ng, S.S., Roddy, J., Keen, H.I., 2013. A systematic review of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. Int. J. Rheum. Dis. 16, 264–272. Cutolo, M., Sulli, A., Smith, V., 2010a. Assessing microvascular changes in systemic slerosis diagnosis and management. Nat. Rev. Rheumatol. 6, 578–587. Cutolo, M., Ferrone, C., Pizzorni, C., Soldano, S., Seriolo, B., Sulli, A., 2010b. Peripheral
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J. Rheumatol. 43, 2033–2041. van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S.R., Baron, M., Tyndall, A., et al., 2013. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747–1755.
Trombetta, A.C., Smith, V., Pizzorni, C., Meroni, M., Paolino, S., Cariti, C., et al., 2016a. Quantitative alterations of capillary diameter have a predictive value for development of the capillaroscopic systemic sclerosis pattern. J. Rheumatol. 43, 599–606. Trombetta, A.C., Pizzorni, C., Ruaro, B., Paolino, S., Sulli, A., Smith, V., Cutolo, M., 2016b. Effects of longterm treatment with Bosentan and Iloprost on nailfold absolute capillary number, fingertip blood perfusion, and clinical status in systemic sclerosis.
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Microvascular Research journal homepage: www.elsevier.com/locate/ymvre
Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients
MARK
B. Ruaroa,⁎, A. Sullia, C. Pizzornia, S. Paolinoa, V. Smithb, E. Alessandria, A.C. Trombettaa, J. Alsheyyaba, M. Cutoloa a Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, IRCCS Policlinico San Martino, Genova, Italy b Department of Rheumatology, Ghent University Hospital, Department of Internal Medicine, Ghent University, Ghent, Belgium
A R T I C L E I N F O
A B S T R A C T
Keywords: Systemic sclerosis Laser speckle contrast analysis Skin high-frequency ultrasound Nailfold videocapillaroscopy Peripheral blood perfusion Dermal thickness Nailfold microangiopathy
Objective: To identify possible correlations between skin blood perfusion (BP) and dermal thickness (DT) in different skin areas of systemic sclerosis (SSc) patients. Methods: Sixty-two SSc patients, according to 2013 EULAR/ACR criteria, and 62 healthy subjects (CNT) were enrolled. Skin BP was analysed by laser speckle contrast analysis (LASCA) at the level of dorsum of the middle phalanx of the third fingers, dorsal aspect of the hands and zygoma. DT was assessed by both skin high frequency ultrasound (US) and modified Rodnan skin score (mRSS) in the same above reported areas. All patients were studied also by nailfold videocapillaroscopy (NVC) to assess the proper pattern of microvascular damage (“Early”, “Active”, or “Late”). Results: At the level of finger dorsum a statistically significant negative correlation was observed in SSc patients between skin BP and both ultrasound-DT (p = 0.0005 r = 0.43) and mRSS (p = 0.0007 r = 0.42), but not at the level of hand dorsum and zygoma. No statistically significant correlation was present between skin BP and ultrasound-DT at any level in CNT. In detail, SSc patients, compared to CNT, showed a statistically significant lower BP only at level of fingers (median PU 72.6 vs 136.1 respectively, p < 0.0001) and a statistically significant higher ultrasound-DT at the level of dorsum of 3th finger bilaterally (median mm 0.9 vs 0.7, p < 0.0001), dorsum of hands (median mm 0.9 vs 0.7, p < 0.0001) and zygoma (median mm 0.8 vs 0.7, p < 0.0001). A significant positive correlation between ultrasound-DT and mRSS was observed in SSc patients at level of the three areas (dorsum of fingers p < 0.0001 r = 0.51; dorsum of hands p = 0.03 r = 0.27; zygoma p = 0.0001 r = 0.45). A progressive decrease of skin BP and increase of ultrasound-DT was found correlated with the progression of the severity of NVC patterns. Conclusions: This study demonstrates for the first time in SSc patients a significant inverse relationship between skin BP, measured by LASCA, and DT, evaluated by both US and mRSS, at the level of dorsum of the middle phalanx of the third fingers.
1. Introduction Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease, characterized by typical clinical cutaneous alterations that include peripheral microangiopathy and decreased skin blood perfusion (BP), as well as increased dermal thickness (DT) (Gabrielli et al., 2009; Cutolo et al., 2010a; Barbano et al., 2017; Hesselstrand et al., 2008). The morphological impairment of peripheral microcirculation may precede the other symptoms by many years, is a predictive factor for SSc progression, and may be assessed and classified by nailfold
videocapillaroscopy (NVC) (Burmester et al., 2017; Cutolo et al., 2010a; Smith et al., 2010, 2016; Ingegnoli et al., 2013a,b). Although NVC permits the observation of the column of red blood cells moving inside the capillaries, the blood flow cannot be quantified in standard conditions (Mugii et al., 2009). Conversely, laser speckle contrast analysis (LASCA) is a method to quantify BP at level of different skin areas, such as face and hands, and a recent study demonstrated a very good inter-rater reliability of BP measurements by LASCA (Ruaro et al., 2014; Della Rossa et al., 2013; Lambrecht et al., 2016).
⁎ Corresponding author at: Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, n° 6, 16132 Genova, Italy. E-mail address: [email protected] (B. Ruaro).
http://dx.doi.org/10.1016/j.mvr.2017.08.004 Received 24 July 2017; Received in revised form 18 August 2017; Accepted 19 August 2017 Available online 20 August 2017 0026-2862/ © 2017 Elsevier Inc. All rights reserved.
–
3/25
–
4/13
–
–
63.0 (20)
59.0 (19)
69.5 (23)
–
65.0 (21,5)
62.0 (21)
–
SSc vs CNT statistical signific. Early (#15) median (IQR)
Active (#19) median (IQR)
29
Late (#28) median (IQR)
E vs L statistical signific.
lcSSc (#45) median (IQR)
dcSSc (#17) median (IQR)
lcSSc vs dcSSc statistical signific.
2/43
2/17
1/14
6/56
66.0 (16.5)
SSc (#62) median (IQR)
5/57
64.0 (16)
Sex (males/ females)
CNT (#62) median (IQR)
Age (years)
–
9.0 (8)
7.0 (5)
–
13.7 (9)
7.0 (5)
4.0 (3)
–
–
7.0 (6)
4.0 (3)
–
7.5 (6)
4.0 (3)
1.8 (1.5)
–
5.0 (4)
–
– 8.5 (7)
SSc duration (years)
RP duration (years)
–
3/1/13
32/3/10
–
11/2/15
13/0/6
11/2/2
–
35/4/23
–
ANA IIF-pattern (centr/ spec/spec + nucl)
–
12/2/6
9/1/11
–
14/1/3
5/2/3
2/0/11
–
21/3/17
–
ENA (Scl70/ RNAP/neg)
79.6/51.0/133.1 (25.2/ 24.1/59.3) 63.9/44.2/121.5 (34.0/ 13.4/41.6) p = 0.02/0.4/0.7
88.7/57.4/135.5 (24.0/ 24.0/58.5) 67.5/51.0/137.2 (42.4/ 18.0/26.5) 60.7/46.6/121.3 (31.7/ 15.8/39.4) p < 0.0001/=0.06/=0.2
136.1/49.6/126.2 (55.8/ 20.0/41.6) 72.6/48.4/131.9 (35.1/ 20.0/35.3) p < 0.0001/=0.3/=0.3
BP (PU) fingers/hands/face
p = 0.002/0.028/0.0002
1.1/0.9/0.9 (0.3/0.2/0.1)
p = 0.0015/=0.0003/ < 0.0001 0.9/0.9/0.9 (0.1/0.2/0.1)
1.0/1.0/0.9 (0.3/0.3/0.1)
0.9/0.9/0.9 (0.2/0.2/0.1)
0.8/0.8/0.8 (0.1/0.1/0.1)
p < 0.0001 for all areas
0.9/0.9/0.8 (0.3/0.2/0.2)
0.7/0.7/0.7 (0.1/0.1/0.1)
DT (millimetres) fingers/ hands/face
p = 0.0002/0.0001/ 0.0001
3.0/1.0/1.0 (1.0/0.0/0.0)
2.0/0/0 (1.0/0.0/0.0)
< 0.0001 for all areas
3/1/1 (1.0/1.0/1.0)
2/0/0 (1.5/0.0/0.0)
1/0/0 (1.0/0.0/0.0)
–
2.0/0.0/0.0 (2.0/1.0/1.0)
–
mRSS (score) fingers/ hands/face
Table 1 Clinical findings in systemic sclerosis (SSc) patients and healthy subjects (CNT). (RP = Raynaud's phenomenon; ANA = antinuclear antibodies; IIF = indirect immunofluorescence; centr = centromeric, spec = speckled; spec + nucl = speckled + nucleolar, ENA = extractable nuclear antigens: Scl70 = anti-topoisomerase autoantibodies, RNAP = anti RNA polymerase III autoantibodies, neg = ENA negative, BP = skin blood perfusion; DT = dermal thickness (ultrasound evaluation); mRSS = modified Rodnan skin score; Early, Active, Late = patterns of microangiopathy at nailfold videocapillaroscopy; lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; PU = perfusion units; # = number of cases; IQR = interquartile range).
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Recent studies reported the utility of high frequency skin ultrasound (US) for early identification of skin involvement in SSc patients (Hesselstrand et al., 2008; Sulli et al., 2014a). In a previous investigation we checked local BP by laser Doppler flowmetry, in a single point of fingertip of SSc patients, and DT, measured at level of finger dorsum (Sulli et al., 2014a). The aim of this study was to identify possible correlations between two main clinical features of SSc, the decrease of skin BP and the increase of DT, using LASCA, modified Rodnan skin score (mRSS) and high frequency skin US at the level of dorsum of fingers, dorsum of hands and zygoma.
2. Methods 2.1. Patients Sixty-two SSc patients (6 males and 56 females, mean age 64 ± 11 SD years) were enrolled. Demographic and clinical data are reported in Table 1. SSc patients met either the ACR/EULAR criteria for SSc or the Le Roy's criteria for the classification of early SSc (van den Hoogen et al., 2013; LeRoy and Medsger, 2001). Patients gave written informed consent and the study was conducted according to the ethical standard of Good Clinical Practice. All SSc patients were taking aspirin (average dosage 100 mg/day) at the time of the study. Other concomitant treatments included: proton pump inhibitors (used by #52 patients), antihypertensive drugs (#14 patients), endothelin-1 receptor antagonists (average dosage 125 mg twice/day: #5 patients), cyclosporine (average dosage 150 mg/day: #10 patients), methotrexate (average dosage 7.5 mg/week: #11 patients). Prostanoids and endothelin-1 receptor antagonists, if used, were temporarily withdrawn one month before instrumental assessments. LASCA, US and NVC were performed the same day in all SSc patients. LASCA and US were also performed in 62 healthy subjects (CNT) similar to SSc patients about age and sex (see Table 1 for demographic data).
Fig. 1. Example of laser speckle contrast analysis (LASCA) evaluated in a SSc patient (A) and in an healthy subject (B).
2.4. Skin high frequency ultrasound (US) Several studies have reported the utility and reliability of high frequency ultrasound (US) in order to quantify dermal thickness (Ch'ng et al., 2013; Moore et al., 2003; Kaloudi et al., 2010). Therefore, high frequency US was performed in both SSc patients and healthy subjects to evaluate DT (ultrasound-DT) in the same body areas tested with the mRSS. The average value was recorded in millimetres (mm) (MyLab 25 ultrasound system equipped with an 18 MHz, Esaote, Genoa, Italy). The use of a high frequency probe offers considerably better resolution, allowing both the distinction between dermis and subcutaneous fat and the measurement of skin thickness. The same operator performed the US in all subjects, with an intra-operator reproducibility of 95% as reported in our previous study (Sulli et al., 2014a).
2.2. Laser speckle contrast analysis (LASCA) Skin BP was analysed by LASCA technique (Pericam PSI, Perimed, Milan, Italy) at the level of dorsal aspect of the whole hands and face, in both SSc patients and healthy subjects as previously described (Ruaro et al., 2014; Della Rossa et al., 2013). Different regions of interest (ROIs) were created at the level of dorsum of middle phalanx of third finger bilaterally (ROI = circle area of 1 cm of diameter, placed in the middle of the phalanx), dorsum of both hands (ROI = oval area of 5 × 3 cm, placed between head and basis of the metacarpal bones), and zygoma (ROI = circle area of 3 cm of diameter) (see Fig. 1). The average BP from the two dorsal areas of fingers, dorsum of the hands and zygoma was calculated by summing the perfusion values of the two sides (right and left) and then dividing the final value by two. The BP was quantified as perfusion units (PU) (Ruaro et al., 2016).
2.5. Nailfold videocapillaroscopy (NVC) All patients were assessed by nailfold videocapillaroscopy (NVC), (equipped with a 200 × contact lens, connected to image analysis software - Videocap, DS MediGroup, Milan, Italy) in order to score the severity of microangiopathy and to classify it within the proper pattern of microvascular damage (“Early”, “Active”, or “Late”) (Smith et al., 2010; Sulli et al., 2008; Pizzorni et al., 2017). The technical parameters were standardized as previously reported (Smith et al., 2010; Sulli et al., 2008).
2.3. Modified Rodnan skin score (mRSS) The mRSS is the validated method to evaluate the severity of skin involvement and to classify, in routine clinical practice, patients with either limited cutaneous SSc (lcSSc) or diffuse cutaneous skin involvement (dcSSc) (Kaldas et al., 2009; Czirják et al., 2007). The mRSS was used to evaluate DT at the level of the dorsum of the middle phalanx of the third fingers, dorsum of hands and zygoma bilaterally, in SSc patients, as reported in the literature, and the average score for fingers, hands and zygoma was calculated (Kaldas et al., 2009; Czirják et al., 2007).
2.6. Statistical analysis Statistical analysis was carried out by parametric procedures, and confirmed by nonparametric tests. Mann-Whitney U test were performed to compare unpaired groups of variables, and Kruskal-Wallis 30
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Fig. 2. Correlation between nailfold microangiopathy extent, peripheral blood perfusion (BP), and dermal thickness evaluated by both high frequency ultrasound (ultrasound-DT) and modified Rodnan skin score (mRSS). (CI = confidence interval).
microangiopathy in all the three areas (Table 1). Similarly, the mRSS was found progressively higher in patients with “Early”, “Active” and “Late” patterns of microangiopathy (Table 1). Finally, patients with dcSSc showed higher ultrasound-DT and mRSS, as well as lower BP, than patients with lcSSc (Table 1).
test was used to compare continuous variables with nominal variables with more than two levels. Multiple and linear regression along with Spearman rank correlation tests were employed to search for possible relationships between variables. The p values lower than 0.05 were considered statistically significant. Results are given as, median and interquartile range (IQR).
4. Discussion 3. Results This study demonstrates, for the first time in SSc patients, a relationship between skin BP (measured by LASCA) and DT (evaluated by both US and mRSS) at the level of dorsum of middle phalanx of third finger. Interesting, no statistically significant correlation was observed between skin BP and DT at the level of dorsum of hands and zygoma, confirming our previous data (Della Rossa et al., 2013; Sulli et al., 2014b). Furthermore, BP values of both hand dorsum and zygoma were found similar in SSc patients and healthy subjects, possibly being that these areas are mainly served by macro-circulation vessels, and therefore usually spared by the Raynaud's phenomenon and associated pathological changes (Cutolo et al., 2017). The gradual decrease of skin BP present at level of fingers was found associated with the progression of the microcirculatory damage, as reflected by the NVC patterns of microangiopathy (“Early, “Active” and “Late”) (Barbano et al., 2017; Ruaro et al., 2014; Della Rossa et al., 2013; Sulli et al., 2014a). This observation confirm the results previously reported that the reduction of BP correlates with the progression of the structural/morphological microvessel damage (Cutolo et al., 2010b, 2016; Trombetta et al., 2016a). In addition, SSc patients show statistically significant higher ultrasound-DT and mRSS values at level of dorsum of the middle phalanx of third finger, dorsum of hand, and zygoma than healthy subjects (Moore et al., 2003; Sulli et al., 2017). A significant positive correlation between US and mRSS was confirmed (Sulli et al., 2014a, 2017; Moore et al., 2003). Of note, present results show that the severity of the nailfold microvessel damage, evaluated by NVC, correlates positively with DT, as detected by both high frequency US and mRSS, and negatively with skin BP.
Interestingly, a significant negative correlation was observed between skin BP and both ultrasound-DT (p = 0.0005, r = − 0.43) and mRSS (p = 0.0007; r = − 0.42) in SSc patients at the level of fingers. Whereas, no statistically significant correlation was found between skin BP and both ultrasound-DT (p = 0.17; r = 0.18) and mRSS (p = 0.88; r = 0.14) at level of dorsum of hands and zygoma (p = 0.64; r = 0.8, p = 0.14; r = 0.01 respectively) in SSc patients. In healthy subjects no statistically significant correlation was detected between skin BP and ultrasound-DT at the level of fingers (p = 0.57, r = 0.01), dorsum of hands (p = 0.46, r = 0.10) or zygomas (p = 0.57, r = 0.07) (Fig. 2). SSc patients showed a statistically significant lower BP at level of finger areas when compared with healthy subjects (median PU 72.6 vs 136.1 respectively, p < 0.0001). No statistically significant difference in BP values was observed between SSc and healthy subjects at the level of dorsum of hand (median PU 48.4 vs 49.6 respectively, p = 0.3) and zygoma (median PU 131.9 vs 126.2 respectively, p = 0.3) (Table 1). A gradual decrease of BP was observed at the level of the dorsum of fingers in patients with different progressive pattern of microangiopathy, “Early, “Active” and “Late” (Table 1). SSc patients showed a statistically significant higher ultrasound-DT than healthy subjects at the level of dorsum of finger areas (median mm 0.9 vs 0.7 mm, p < 0.0001), dorsum of hands (median mm 0.9 vs 0.7, p < 0.0001) and zygoma (median mm 0.8 vs 0.7, p < 0.0001) (Table 1). Interestingly, a statistically significant positive correlation was observed between ultrasound-DT and mRSS values in SSc patients at level of the three areas (dorsum of fingers p < 0.0001 r = 0.51; dorsum of hands p = 0.03 r = 0.27; zygoma p = 0.0001 r = 0.45) (Fig. 2). Additionally, also ultrasound-DT was found progressively higher in SSc patients with the “Early”, “Active” and “Late” NVC pattern of 31
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Short-term follow-up of digital ulcers by laser speckle contrast analysis in systemic sclerosis patients. Microvasc. Res. 101, 82–85. Ruaro, B., Sulli, A., Pizzorni, C., Paolino, S., Smith, V., Cutolo, M., 2016. Correlation between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients. Microvasc. Res. 105, 119–124. Shah, A.A., Schiopu, E., Hummers, L.K., Wade, M., Phillips, K., Anderson, C., et al., 2013. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res. Ther. 15, R54. Smith, V., Pizzorni, C., De Keyser, F., Decuman, S., Van Praet, J.T., Deschepper, E., et al., 2010. Reliability of the quantitative and semiquantitative nailfold videocapillaroscpy assessment in a systemic sclerosis cohort: a two-centre study. Ann. Rheum. Dis. 69, 1092–1096. 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Patients with lcSSc showed lower DT and higher skin BP than those with dcSSc. This is of interest because these results confirm the literature reporting that patients with lcSSc are likely to have less severe organ involvement than those with dcSSc, and SSc patients with littler organ involvement are likely to have lower nailfold microvessel damage as well as higher skin BP and lower DT (Cutolo et al., 2010a; Hesselstrand et al., 2008; Ruaro et al., 2014; Sulli et al., 2014a; Smith et al., 2013; Caramaschi et al., 2007). In conclusion, imaging is an important adjunct to quantify and follow the different aspects of microvascular damage in SSc. Both LASCA and skin US are safe and not invasive detection methods, and offer the possibility to record and quantify the results, therefore we suggest to consider both evaluations, at least at baseline in every early SSc patient. However, the possibility to quantify in SSc the therapeutic effects of different regimens by testing both LASCA and US together, represent an important option compared to their single use (Hesselstrand et al., 2008; Cutolo et al., 2010b; Shah et al., 2013; Ruaro et al., 2015; Trombetta et al., 2016b). Funding This study was supported by funding from the Research Laboratory and Academic Division of Rheumatology of the University of Genova, Italy. Disclosure statement The authors have declared no conflict of interest. Contributorship The manuscript has been seen and approved by all the authors that have given necessary attention to ensure the integrity of the work. Ethical approval Local internal review board approval. Acknowledgements The authors thank Barbara Wade, contract Professor at the University of Torino, for her linguistic advice. The authors thank Doctor Sara De Gregorio from the Division of Rheumatology, University of Genova, for the support in graphic reproduction. Barbara Ruaro is supported by a Grant from the Italian Society of Rheumatology 2015. Vanessa Smith is a Senior Clinical Investigator of the Research Foundation - Flanders (Belgium) (FWO) [1802915N]. All authors are members of the EULAR Study Group on Microcirculation in Rheumatic Diseases. References Barbano, B., Marra, A.M., Quarta, S., Gigante, A., Barilaro, G., Gasperini, M.L., et al., 2017. In systemic sclerosis skin perfusion of hands is reduced and may predict the occurrence of new digital ulcers. Microvasc. Res. 110, 1–4. Burmester, G.R., Bijlsma, J.W.J., Cutolo, M., McInnes, I.B., 2017. Managing rheumatic and musculoskeletal diseases - past, present and future. Nat. Rev. Rheumatol. 13, 443–448. Caramaschi, P., Canestrini, S., Martinelli, N., Volpe, A., Pieropan, S., Ferrari, M., et al., 2007. Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity. Rheumatology 46, 1566–1569. Ch'ng, S.S., Roddy, J., Keen, H.I., 2013. A systematic review of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. Int. J. Rheum. Dis. 16, 264–272. Cutolo, M., Sulli, A., Smith, V., 2010a. Assessing microvascular changes in systemic slerosis diagnosis and management. Nat. Rev. Rheumatol. 6, 578–587. Cutolo, M., Ferrone, C., Pizzorni, C., Soldano, S., Seriolo, B., Sulli, A., 2010b. Peripheral
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J. Rheumatol. 43, 2033–2041. van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S.R., Baron, M., Tyndall, A., et al., 2013. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747–1755.
Trombetta, A.C., Smith, V., Pizzorni, C., Meroni, M., Paolino, S., Cariti, C., et al., 2016a. Quantitative alterations of capillary diameter have a predictive value for development of the capillaroscopic systemic sclerosis pattern. J. Rheumatol. 43, 599–606. Trombetta, A.C., Pizzorni, C., Ruaro, B., Paolino, S., Sulli, A., Smith, V., Cutolo, M., 2016b. Effects of longterm treatment with Bosentan and Iloprost on nailfold absolute capillary number, fingertip blood perfusion, and clinical status in systemic sclerosis.
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