Microvascular Research 105 (2016) 119124

Contents lists available at ScienceDirect

Microvascular Research
journal homepage: www.elsevier.com/locate/ymvre

Correlations between skin blood perfusion values and nailfold

capillaroscopy scores in systemic sclerosis patients
B. Ruaro a, A. Sulli a, C. Pizzorni a, S. Paolino a, V. Smith b, M. Cutolo a,
a
b

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino-IST, Genoa, Italy
Department of Rheumatology, Ghent University Hospital, Ghent University, Belgium

a r t i c l e

i n f o

Article history:
Received 11 January 2016
Revised 17 February 2016
Accepted 17 February 2016
Available online 18 February 2016
Keywords:
Systemic sclerosis
Blood perfusion
Laser speckle contrast analysis
Nailfold videocapillaroscopy

a b s t r a c t
Objectives: To correlate blood perfusion (BP) values assessed by laser speckle contrast analysis (LASCA) in
selected skin areas of hands and face with nailfold capillary damage scores in systemic sclerosis (SSc) patients.
Methods: Seventy SSc patients (mean SSc duration 6 5 years) and 70 volunteer healthy subjects were enrolled
after informed consent. LASCA was performed at different areas of the face (forehead, tip of nose, zygomas and
perioral region) and at dorsal and volar regions of hands. Microvascular damage was assessed and scored by
nailfold videocapillaroscopy (NVC) and the microangiopathy evolution score (MES) was calculated.
Results: SSc patients showed a signicantly lower BP than healthy subjects at ngertips, periungual areas and
palm of hands (p b 0.0001), but not at the level of face and dorsum of hands. A gradual decrease of BP at ngertips,
periungual and palm areas, was found in SSc patients with progressive severity of NVC patterns of microangiopathy (early, active, or late) (p b 0.01). A negative correlation was observed between MES and BP values, as
well as between loss of capillaries and BP, at the same areas (p b 0.001 and p b 0.01, respectively). Patients with
diffuse cutaneous SSc (dcSSc) showed lower BP than those with limited cutaneous SSc (p b 0.04).
Conclusions: LASCA detects a signicant reduction of BP only in those areas usually affected by Raynaud's
phenomenon (ngertips, periungual and palm areas), especially in dcSSc patients, and BP values signicantly
correlate with the nailfold capillaroscopy scores of microangiopathy.
2016 Published by Elsevier Inc.

Introduction
Systemic sclerosis (SSc) is characterized by early impairment of the
microvascular system and decreased peripheral blood perfusion together
with progressive tissue brosis (Cutolo et al., 2010a,b; Herrick, 2008;
Rosato et al., 2011).
Nailfold videocapillaroscopy (NVC) is a safe and validated technique
to assess and quantify morphological capillary alterations, while laser
speckle contrast analysis (LASCA) is a non-invasive method to evaluate
and quantify blood perfusion (BP) at different skin sites, especially in
SSc patients (Smith et al., 2010; Sulli et al., 2014a; Ruaro et al., 2014).
Compared to the limits of the contact and single point technique Laser
Doppler owmetry, LASCA allows analysis of BP on different and larger
skin areas of the body, with a more reproducible and safer non-contact
approach (i.e. face or legs) (Ruaro et al., 2014). Furthermore, LASCA is
less prone to movement artifacts.
Limited information is available about BP at specic body sites in SSc,
like either dorsum of hands or face, usually spared by Raynaud's
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: mcutolo@unige.it (M. Cutolo).

http://dx.doi.org/10.1016/j.mvr.2016.02.007
0026-2862/ 2016 Published by Elsevier Inc.

phenomenon, with the exception of nose (Cutolo et al., 2010b; Rosato

et al., 2011; Ruaro et al., 2014; Murray et al., 2006). The aim of this
study was to assess by LASCA the BP in different skin areas of hands
and face in SSc patients, and to search for correlations with nailfold
capillary damage extent as detected by NVC.
Patients and methods
During their regular followup, seventy consecutive SSc patients
(mean age 63 12 SD years, 63 women and 7 men, mean Raynaud's
phenomenon duration 12 11 years, mean SSc duration 6
5 years), according to the new ACR/EULAR criteria and 70 healthy
subjects (mean age 63 15 years, 62 women and 8 men), were
enrolled and after informed consent (van den Hoogen et al., 2013).
Assessments were carried out after a treatment-free period of at
least one month from prostanoids, calcium channel blockers, ACEinhibitors and endothelin-1 receptor antagonists, in order to avoid the
vasodilatory effects of treatments. All SSc patients at the time of analysis
were taking aspirin, as a practice in our center.
Complete medical history and clinical examination were recorded,
including the detection of either limited (lcSSc), or diffuse (dcSSc)
skin involvement. Patients with diabetes, arterial hypertension, or
other vascular diseases that could potentially interfere with peripheral

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B. Ruaro et al. / Microvascular Research 105 (2016) 119124

blood perfusion were excluded. Patients were asked not to either drink
coffee or smoke the day of the assessment.

Laser speckle contrast analysis (LASCA)

BP was analyzed by LASCA (Pericam PSI, Perimed, Jarfalla, Sweden)
in SSc patients and healthy subjects (Ruaro et al., 2014). The principle
of LASCA is that when laser light illuminates a tissue, it forms a speckle
pattern. Any such changes in the speckle pattern are recorded by a detector camera and analyzed by software. If the illuminated area is static,
then the speckle pattern is stationary. When there is movement in the
area, such as red blood cells in tissue, the speckle pattern will change
over time and appear blurred. The level of blurring (contrast) is analyzed and interpreted as blood perfusion.
Technical parameters e.g. working distance (14.314.8 cm), point
density (1386 1036), frame rate resolution (10 images/s), as well as
the width and height of the measurement area (12.5 14/15 cm)
were standardized for all subject evaluations. All subjects stayed in the
waiting room for 30 min at 2223 C before all the assessments.
BP was registered at the level of whole face and dorsal and volar
aspects of hands for 30 s, and the values were recorded as perfusion
units (PU).
After scan acquisition, regions of interest (ROI) were created at the
central area of ngertips and periungual areas from ngers II to V
bilaterally, palm and dorsum of both hands, as well as at the level of
the face (forehead, tip of nose, zygomas and perioral region) (see
Fig. 1 for ROI areas). The ROIs created al the level of periungual areas
include a portion of nail and a portion of periungual skin, in order to
evaluate blood perfusion in the same area where nailfold capillaroscopy
is performed.
The amplitude of the ROI area may be easily reproduced in order to
quantitate blood perfusion inside similar areas in all subjects;

furthermore, the assessment of mean BP of a large area by LASCA highly

reduces the variability and errors linked to repeated measurements.
The average BP from either ngertips or periungual areas was
calculated by summing the perfusion values of 8 ngers together and
then dividing the nal value by the number of ngers. Likewise, the
average BP from palm, dorsum of hands, and zygomas was calculated
by summing the perfusion values of the two sides (right and left)
together and then dividing the nal value by two. The same operator
(BR) performed the examination in all SSc patients and healthy subjects,
blind to NVC examination. There was a 95% reproducibility of the LASCA
assessment by evaluating the same patients two consecutive times, and
drawing new ROIs on the body areas.

Nailfold videocapillaroscopy (NVC)

NVC was performed in each patient to assess morphological microvascular damage using a videocapillaroscopy optical probe, equipped
with a 200 contact lens, connected to an image analysis software
(Videocap, DS Medica, Milan, Italy).
The same operator (CP) performed the NVC examination in all SSc
patients the same day of LASCA examination (blind to its results),
according to previously published methods (Cutolo et al., 2010a;
Smith et al., 2010; Sulli et al., 2012). Each capillary abnormality (including number of capillaries and angiogenic vessels) was scored by a
validated semi-quantitative rating scale by considering the average of
the eight ngers, and the appropriate NVC pattern of microangiopathy
was assigned to the SSc patients on the basis of their nailfold capillary
abnormalities: early NVC pattern (21 patients), active NVC pattern
(21 patients) or late NVC pattern (28 patients) (Smith et al., 2010;
Sulli et al., 2008, 2012). The microangiopathy evolution score (MES),
sum of three scores for loss of capillaries, disorganization of the
microvascular array and capillary ramications (range 09), was

Fig. 1. Laser speckle contrast analysis (LASCA) images of healthy subject (A) and systemic sclerosis patient (B) showing the regions of interest (ROI white circles) created at the level of
whole face, forehead, tip of nose, zygomas, perioral region, dorsum, periungual areas, palm and ngertips to evaluate blood perfusion. A1, B1 face; A2, B2 dorsum of hand; A3, B3 palm of
hand.

B. Ruaro et al. / Microvascular Research 105 (2016) 119124

also evaluated to assess the extent of the vascular damage (Sulli et al.,
2008).

121

than 0.05 was considered statistically signicant. The results are

reported as median and interquartile range [IQR].
Results

Statistical analysis
Statistical analysis was carried out by non-parametric tests. The
MannWhitney U test was performed to compare unpaired groups of
variables and the KruskalWallis test was used to compare continuous
variables with nominal variables with more than two levels. The Spearman rank correlation test was employed to search for any relationships
between variables, along with linear regression tests. Any p value lower

Clinical characteristics of SSc patients and healthy subjects are

reported in Table 1.
SSc patients showed a signicant lower median BP than healthy subjects at the level of ngertips (86 and 189 PU, respectively, p b 0.0001),
periungual areas (69 and 140 PU, respectively, p b 0.0001) and palm of
hands (77 and 111 PU, respectively, p b 0.0001) (see Table 1 for
interquartile ranges).

Table 1
Clinical characteristics of SSc patients and healthy subjects, along with statistical signicance of differences between groups.

Age
(years)
Sex
(m/f)
SSc duration
(years)

CNT
(#70)
Median
[IQR]
(min, max)

SSc
(#70)
Median
[IQR]
(min, max)

SSc vs CNT
Statistic. signic.

Early
(#21)
Median
[IQR]

Active
(#21)
Median
[IQR]

Late
(#28)
Median
[IQR]

E vs A vs L
Statistic. signic.

lcSSc
(#56)
Median
[IQR]

dcSSc
(#14)
Median
[IQR]

lcSSc vs dcSSc
Statistic. signic.

65
[24]
(31, 78)
8/62

64
[18]
(34, 77)
7/63

p = 0.86

64
[19]

59
[12]

69
[16]

p = 0.05

64
[18]

63
[18]

p = 0.68

2/19

2/19

3/25

3/53

4/10

5
[18]
(1, 19)
8
[11]
(1, 53)
4.5
[5]
(0, 9)
86
[28]
(32, 172)
77
[45]
(23, 183)
69
[44]
(24, 155)
51
[21]
(21, 98)
134
[46]
(29, 226)
112
[37]
(42, 217)
137
[54]
(47, 222)
145
[59]
(73, 316)
137
[56]
(72, 265)
9
[36]
18
[31]
17
[24]
26
[38]
4
59

2
[3]

4
[4]

7.5
[7]

p b 0.0001

4
[7]

6
[8]

p = 0.12

4
[8]

6
[8]

14
[18]

p = 0.001

8
[11]

7
[8]

p = 0.72

0.5
[1]

4.0
[1]

6.0
[1]

p b 0.0001

4
[5]

6
[3]

p = 0.0001

p b 0.0001

103
[58]

86
[18]

80
[45]

p = 0.004

88
[36]

77
[43]

p = 0.01

p b 0.0001

92
[50]

82
[37]

67
[40]

p = 0.017

85
[40]

60
[37]

p = 0.03

p b 0.0001

86
[35]

65
[52]

57
[44]

p = 0.007

78
[43]

57
[39]

p = 0.04

p = 0.06

58
[25]

48
[19]

48
[19]

p = 0.501

51
[20]

49
[21]

p = 0.70

p = 0.70

138
[41]

131
[39]

136
[66]

p = 0.939

131
[43]

145
[49]

p = 0.13

p = 0.33

116
[26]

101
[31]

123
[67]

p = 0.573

106
[33]

126
[57]

p = 0.12

p = 0.96

137
[52]

139
[36]

134
[60]

p = 0.920

133
[51]

141
[46]

p = 0.37

p = 0.28

146
[59]

155
[48]

142
[76]

p = 0.852

144
[58]

152
[49]

p = 0.47

p = 0.39

134
[64]

137
[44]

144
[50]

p = 0.924

134
[56]

145
[54]

p = 0.34

p b 0.0001

11
[38]
28
[39]
17
[39]
34
[41]
0
18

4
[28]
17
[34]
21
[26]
34
[42]
2
22

13
[23]
9
[20]
23
[15]
19
[29]
1
20

p = 0.070

3
[37]
27
[37]
10
[29]
34
[41]
3
31

17
[26]
8
[19]
20
[30]
11
[28]
1
29

p = 0.50

Raynaud's duration
(years)

MES

Fingertip BP (PU)

189
[70]
(45, 321)
111
[26]
(48, 232)
140
[54]
(42, 217)
50
[24]
(32, 150)
127
[34]
(84, 240)
106
[40]
(67, 234)
131
[42]
(62, 247)
126
[44]
(70, 316)
143
[48]
(89, 322)
78
[58]
90
[57]
49
[39]
61
[36]
3
60

Palm BP
(PU)
Periungual BP (PU)

Dorsum BP
(PU)
Whole face BP (PU)

Forehead BP (PU)

Tip of nose BP (PU)

Zygomas BP (PU)

Perioral region BP (PU)

BP difference
Fingertip-palm (PU)
BP difference
periungual-dorsum (PU)
BP difference
ngertip-periungual (PU)
BP difference
palm-dorsum (PU)
Smoking habitus
Coffee
habitus

p b 0.0001
p b 0.0001
p b 0.0001

p = 0.008
p = 0.350
p = 0.037

p = 0.01
p = 0.24
p = 0.04

CNT = healthy subjects. SSc = systemic sclerosis patients. E = Early pattern of nailfold microangiopathy. A = active pattern of nailfold microangiopathy. L = late pattern of nailfold
microangiopathy. lcSSc = limited cutaneous systemic sclerosis. dcSSc = diffuse cutaneous systemic sclerosis. MES = microangiopathy evolution score. BP = blood perfusion. PU =
perfusion units.

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B. Ruaro et al. / Microvascular Research 105 (2016) 119124

No signicant difference in BP values was observed between SSc and

healthy subjects at the level of dorsum of hands, whole face, as well as
different ROIs of the face (see Table 1 for details).
SSc patients showed a lower median difference of BP than healthy
subjects between ngertips and palm (9 and 78 PU, respectively,
p b 0.0001), periungual areas and dorsum (18 and 90 PU, respectively,
p = 0.0009), ngertips and periungual areas (17 and 49 PU, respectively, p b 0.0001), as well as palm and dorsum (26 and 61 PU, respectively,
p b 0.0001) (see Table 1 for details).
A signicant positive correlation was observed between ngertip BP
and periungual BP in both SSc patients and healthy subjects (p b 0.0001,
r = 0.70, for both), as well as between palm BP and ngertip BP
(p b 0.0001, r = 0.68, for both), dorsum BP and periungual BP (p =
0.0003 r = 0.43, and p = 0.05 r = 0.30, respectively), dorsum BP and

palm BP (p = 0.0008 r = 0.40 and p = 0.0001 r = 0.44, respectively)

(see Fig. 2).
Interestingly, a signicant decrease of BP at the level of ngertips
(p = 0.004), periungual areas (p = 0.007) and palms (p = 0.017),
was detected by LASCA in SSc patients with different progressive
severity NVC patterns of microangiopathy (early, active, or late)
(see Table 1). In particular, periungual BP was 86, 65 and 57 PU
respectively in early, active and late NVC patterns (p = 0.007).
Conversely, no statistically signicant difference of BP values was
observed between the three NVC patterns at the level of dorsum of
hands, whole face, as well as different ROIs of the face (see Table 1 for
details).
A signicant negative correlation was also observed between MES
and BP at the level of ngertip (r = 0.49, p b 0.0001), periungual

Fig. 2. Statistically signicant correlations between blood perfusion values (BP) at different skin sites in systemic sclerosis (SSc) patients and healthy subjects (CNT). Correlations between
microangiopathy evolution score (MES) and blood perfusions are also reported.

B. Ruaro et al. / Microvascular Research 105 (2016) 119124

(r = 0.40, p = 0.01), and palm areas (r = 0.35, p = 0.003) (see

Fig. 2). Of particular interest, a signicant negative correlation was
observed between number of capillaries and BP in above reported
areas (ngertip, periungual and palm) (p b 0.01).
Patients with dcSSc had signicantly lower median BP than those
with lcSSc at ngertips (77 and 88 PU respectively, p = 0.01),
periungual areas (57 and 78 PU, respectively, p = 0.04), and palm of
hands (60 and 85 PU, respectively, p = 0.03).
Conversely, no signicant difference of BP values was observed
between dcSSc and lcSSc at the level of dorsum of hands, whole face,
and different ROIs of the face.
Finally, patients with dcSSc had reduced number of capillaries and
increased severity of angiogenesis, as well as higher MES, than those
with lcSSc (median scores 6 and 4 respectively, p = 0.0001).
Discussion
This study reports, for the rst time in SSc patients, signicant
correlations between BP values in different body areas and nailfold
microangiopathy severity, as respectively detected by LASCA and NVC.
BP was found lower in SSc patients than in healthy subjects at ngertips, conrming previous results obtained by single laser Doppler
owmetry (Cutolo et al., 2010b, 2014; Ruaro et al., 2014; Sulli et al.,
2014b). In addition, this study showed lower BP in SSc patients than
in healthy subjects at the level of both periungual areas and palm of
hands, while no signicant difference of BP was observed at the level
of dorsum of hands and whole face, as well as different ROIs of the face.
Nevertheless, despite lacking of statistically signicant differences,
SSc patients showed higher median perfusion values than healthy subjects al the level of face ROIs. These skin regions are often sites of
teleangectases, which perfusion is notably high. If their presence may
inuence the average perfusion of a large skin area remain to be
understood.
A similar cohort of SSc patients was already included in a previous
preliminary report containing pilot study data on blood perfusion in different areas of hands and face in SSc patients, without capillaroscopy
evaluation (Sulli et al., 2014a). The data reported in the present study
come from a new set of data, different from the previous one, in
which LASCA and NVC were performed at the same time in a larger cohort of SSc patients, in order to detect also possible correlation between
functional and morphological evaluations.
Noteworthy was the negative correlation detected between NVC
microvascular damage scores and BP values, not only at ngertips, but
also at periungual areas where the NVC analysis showed low number
of capillaries and high MES.
In addition, SSc patients with a worse pattern for microvascular
damage and capillary loss (late NVC pattern) showed at ngertips,
periungual areas, and palm of hands a signicantly lower BP than patients with a less severe microangiopathy (early NVC pattern)
(Cutolo et al., 2010b; Ruaro et al., 2014; Sulli et al., 2014b).
In agreement with the above evidence, the negative correlation
observed between BP and MES, that includes also the increased
neo-angiogenesis (as signal of tissue hypoxia), supports a progressive
hypoperfusion related to capillary loss (Cutolo et al., 2010b; Sulli et al.,
2008; Smith et al., 2013; Ingegnoli et al., 2013).
The absence of correlation between BP values and nailfold microangiopathy extent at dorsum of hands and face areas, is in agreement with
the observed lack of BP value differences between SSc patients and
healthy subjects in these anatomical regions.
As matter of fact, BP values of both face and hand dorsum were
found similar in SSc patients and healthy subjects, possibly being that
these areas are mainly served by macrocirculation vessels, and therefore
are usually spared by the Raynaud's phenomenon.
Of note, the BP differences between ngertips and palm, periungual
areas and dorsum of hands, ngertips and periungual areas, palm and
dorsum of hands were found lower in SSc patients than in healthy

123

subjects. Furthermore, the BP difference between SSc patients and

healthy subjects was found particularly evident at the level of
periungual and ngertip areas. The greater hypoperfusion observed in
these areas, might support the higher risk and prevalence of local digital
ulcers in SSc patients, especially in patients with the late NVC pattern
(Cutolo et al., 2010a; Ingegnoli et al., 2013; Ennis et al., 2013).
Finally, patients with dcSSc showed lower BP at ngertips,
periungual and palm areas than those with lcSSc, as well as higher
MES. This observation, once again seems in agreement with previous
reports of earlier development of digital ulcers observed in SSc patients
with advanced capillaroscopic pattern of microangiopathy (late
pattern), and diffuse cutaneous skin involvement (Ingegnoli et al.,
2013; Guillevin et al., 2013).
In conclusion, this study demonstrates for the rst time that BP is
signicantly reduced in SSc patients only in those areas usually affected
by Raynaud's phenomenon (ngertips, periungual and palm areas), and
it correlates with the severity of nailfold microvascular damage, as
detected by LASCA and NVC respectively. This is particularly evident in
dcSSc patients, and might support the higher risk and prevalence of
digital ulcers in those areas.
Funding
This study was supported by funding from the Research Laboratory
and Academic Division of Rheumatology of the University of Genova,
Italy (UGE001-15).
Disclosure statement
The authors have declared no conict 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 institutional review board approval.
Acknowledgments
Authors are members of the EULAR Study Group on Microcirculation
in Rheumatic Diseases.
V. Smith is senior clinical investigator of the Research Foundation
Flanders (Belgium) (FWO).
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