Download High-frequency ultrasound of skin involvement in

Rheumatology 2008;47:84–87
doi:10.1093/rheumatology/kem307
High-frequency ultrasound of skin involvement in systemic sclerosis
reflects oedema, extension and severity in early disease
R. Hesselstrand, A. Scheja, M. Wildt and A. Åkesson
Objective. The aim was to compare skin assessment by palpation and by high-frequency ultrasound in patients with SSc with disease
duration <2 yrs.
Methods. Skin thickness and skin echogenicity were measured by 20 MHz ultrasound at five different anatomical sites in 106 individuals
within 2 yrs from the first non-Raynaud’s symptom and compared with the modified Rodnan skin score (mRss).
Results. The patients with short disease duration were characterized by high skin thickness and low skin echogenicity, which correlated
inversely, reflecting oedema. Patients with diffuse skin involvement displayed higher skin thickness and lower skin echogenicity than did
patients with limited skin involvement. The ultrasound measurements correlated to the local mRss from the corresponding anatomical region
and also to the total mRss. However, there was a considerable overlap in both skin thickness and skin echogenicity between different local
mRss at all five anatomical sites. Skin involvement of the chest could be detected earlier by ultrasound than by palpation.
Conclusion. In SSc patients with short disease duration, high-frequency ultrasound can identify the oedematous phase that may precede
palpable skin involvement and may thus be useful to identify patients with diffuse skin involvement very early in the disease process.
Ultrasound measurements also reflect the severity of the overall skin involvement.
KEY
WORDS:
Systemic sclerosis, Scleroderma, Ultrasound, Skin thickness, Skin echogenicity, Skin score.
high thickness represent oedema and the increased ECM
production is suggestive of early or aggressive skin disease [12].
High-frequency ultrasound offers a potential for quantitative
assessment of skin thickness and skin echogenicity in SSc. In a
longitudinal pilot study of 16 patients with early SSc and 16
controls, dcSSc patients but not lcSSc patients had higher skin
thickness and lower skin echogenicity than controls. Unlike
healthy individuals, these SSc patients displayed large variations
between different ultrasound measurements over time in the same
individual; during the follow-up, skin thickness decreased and skin
echogenicity increased. This study included five different anatomical sites and showed that high-frequency ultrasound had a very
low inter- and intra-observer variability except for inter-observer
variability of skin thickness of the phalanx that was 0.66 [13]. In a
study where all 17 sites of the Rss were examined by ultrasound,
the inter- and intra-observer variability for dermal thickness was
also very low [14].
The aim of this study was to compare the results of highfrequency ultrasound of the skin with a modified Rss (mRss) in
patients with SSc with disease duration of <2 yrs. In this large
study, we sought to confirm and expand the findings of our pilot
study [13] and focused on patients with short disease duration
since in these patients objective measurement of phase and degree
of skin involvement is particularly important.
Introduction
Systemic sclerosis (SSc, scleroderma) is characterized by fibrosis in
skin and internal organs, progressive vascular obliteration and the
production of auto antibodies [1]. The fibrotic process involves
cytokines, such as TGF-, that are released by a variety of
immune cells, including macrophages and T cells or platelets at
sites of vascular injury, continuously stimulating fibroblast
production of extracellular matrix (ECM) [2]. Studies of SSc
have been complicated by the heterogeneity and rareness of the
condition and the difficulty of discriminating between different
phases of the disease. In addition, the different components of the
disease have a discordant natural history. Skin involvement is
often ameliorated after reaching a peak within 3 yrs of disease,
whereas lung involvement typically worsens over time, especially if
untreated in the first years of disease [3–6].
The established method of skin assessment is the semiquantitative scoring (Rodnan skin score, Rss), introduced by
Rodnan in 1979, which is used worldwide with variations in
definitions of the score grades per anatomical site or number of
sites to score [7]. Despite its simplicity and usefulness, the Rss has
drawbacks. Difficulty in discriminating between hard, tight or
thick skin, as well as rather low sensitivity to change limit the
usefulness of Rss in short-term therapeutic studies. Fibrosis of the
skin can be assessed by palpation and its extent predicts both
internal organ involvement and survival [8]. SSc patients may be
subdivided into limited cutaneous SSc (lcSSc) and diffuse
cutaneous SSc (dcSSc), but there is an overlap in both serological
and clinical features between these two groups. The subdivision is
based on palpation but studies of skin biopsies [9], ultrasound [10]
and durometry [11] have shown signs of involvement of the
so-called uninvolved skin, suggesting that palpation underestimates the skin fibrosis.
Fibroblasts from patients with more rapid changes in skin
thickness and skin echogenicity as measured by ultrasound have
been shown to produce more ECM in vitro. Low echogenicity and
Subjects and methods
Subjects
In this retrospective study, we identified 106 patients with disease
duration <2 yrs in whom ultrasound examination was performed.
The study was approved by the local ethics committee. All subjects
met the ACR criteria for SSc [15]. The disease was classified as
dcSSc or lcSSc according to the extent of skin involvement [1].
Skin involvement was determined by the mRss with palpation of
17 anatomical sites (face, fingers, hands, forearms, upper arms,
chest, abdomen, thighs, legs and feet) and scoring on a 0–3 scale,
where 0 ¼ normal skin, 1 ¼ slight thickening, 2 ¼ moderate thickening and 3 ¼ hidebound skin sclerosis. The scores for all sites were
summed to give a total score, with a maximum possible score of
51 [16]. All subjects were examined by one of the four physicians in
Department of Rheumatology, Lund University Hospital, Lund, Sweden.
Submitted 28 May 2007; revised version accepted 17 October 2007.
Correspondence to: R. Hesselstrand, Department of Rheumatology, Lund
University Hospital, S-221 85 Lund, Sweden. E-mail: [email protected]
84
ß The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Skin ultrasound in SSc reflects oedema and severity
TABLE 1. Skin thickness (millimetres) measured by ultrasound
TABLE 2. Skin echogenicity (pixels) measured by ultrasound
Mean (S.D.)
lcSSc
Region
Phalanx
Hand
Forearm
Leg
Chest
Total
2.01
1.40
1.46
1.38
1.55
7.83
(0.43)
(0.28)
(0.26)
(0.26)
(0.25)
(1.11)
Mean (S.D.)
dcSSc
2.18
1.76
1.83
1.52
1.89
9.10
85
(0.38)
(0.41)
(0.41)
(0.33)
(0.40)
(1.38)
P
0.086
0.001
0.001
0.015
0.001
0.001
Reference values
1.08–1.96
0.92–1.32
1.00–1.60
0.94–1.66
0.96–1.92
5.39–7.71
lcSSc
Region
Phalanx
Hand
Forearm
Leg
Chest
Total
25.2
31.5
40.1
48.1
47.2
192
(8.45)
(9.94)
(9.24)
(9.19)
(8.57)
(36.5)
dcSSc
20.8
23.4
31.6
46.1
41.2
166
(6.38)
(10.5)
(9.69)
(9.44)
(9.43)
(32.6)
P
Reference values
0.015
0.001
0.001
0.446
0.007
0.003
17.9–44.3
22.3–46.3
28.6–49.8
34.4–58.0
32.6–-56.6
149.7–241.3
P indicates differences between lcSSc and dcSSc calculated using the Mann–Whitney U-test;
reference values derived from healthy female controls (mean 2 S.D.).
P indicates differences between lcSSc and dcSSc calculated using the Mann–Whitney U-test;
reference values derived from healthy female controls (mean 2 S.D.).
the scleroderma group trained to be concordant in the skin scoring
technique.
TABLE 3. Association between skin thickness and skin echogenicity measured by
ultrasound
Ultrasound
Skin thickness and skin echogenicity were measured with a highfrequency ultrasound scanner (Dermascan, Cortex Technology,
Denmark) in which a 20 MHz transducer was mounted. Two scans
were obtained of the tissue: a one-dimensional A mode image with
different echoes defining the interfaces between epidermis, dermis
and subcutis and a two-dimensional B mode image with different
colours reflecting the differing echogenicities of the skin. The
echogenicity in the dermal region was represented on an arbitrary
scale (0–255 pixels), where a low value represents high water
content and a high value represents low water content, and by
outlining a block of skin in which the mean echogenicity was
estimated for a selected region [13].
All measurements were made before noon and by the same
observer (M.W.) who performed and read the ultrasound
examinations. Five anatomical sites, selected in order to distinguish skin involvement in lcSSc and dcSSc and to monitor disease
development over time, were analysed—the dorsal aspect of the
mid portion of the proximal phalanx of the right second finger
(phalanx), the area (valley) between the metacarpophalangeal
joints II and III of the right hand (hand), the dorsal aspect of the
right forearm 3 cm proximal of the wrist (forearm), the lateral
aspect of the right leg 12 cm proximal of the ankle joint (leg) and
the sternum 2 cm distal from the upper part of the manubrium
(chest).
Study design
All patients were examined by mRss and by ultrasound to determine skin thickness and skin echogenicity. The ultrasound
examination was performed at the patients’ first visit to the
department during the time period of November 1994 to December
2004. Follow-up data until December 2005 were retrieved.
Statistics
Differences between groups were calculated using the Mann–
Whitney U-test. Associations between variables were analysed
using the Spearman’s correlation.
Results
Out of the 106 patients, 86% were females and 72% were
classified as lcSSc. Mean age (S.D.) at diagnosis was 49.2 (13.7) yrs
and the disease duration was estimated to be 0.93 (0.50) yrs. The
patients were followed for a mean (S.D.) of 3.91 (2.98) yrs.
Patients with dcSSc have more extensive skin involvement, but in
this study, examination by ultrasound revealed that patients with
dcSSc also had thicker skin on hand, forearm, leg and chest than
did patients with lcSSc, whereas the differences in skin thickness
on phalanx did not reach statistical significance (Table 1).
Thickness vs echogenicity
Phalanx
Hand
Forearm
Leg
Chest
Total
n
rS
P
101
104
104
103
103
96
0.42
0.68
0.52
0.41
0.46
0.47
0.001
0.001
0.001
0.001
0.001
0.001
TABLE 4. Association between the total and local modified Rodnan skin score and
skin thickness or skin echogenicity measured by ultrasound
Skin thickness and:
Phalanx
Hand
Forearm
Leg
Chest
Total
Total mRss
rS (P)
Local mRss
rS (P)
0.39
0.65
0.65
0.41
0.44
0.66
0.37
0.72
0.62
0.39
0.36
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
(0.001)
Skin echogenicity and:
Total mRss
rS (P)
0.37
0.43
0.44
0.18
0.24
0.37
(0.001)
(0.001)
(0.001)
(0.067)
(0.018)
(0.001)
Local mRss
rS (P)
0.40
0.47
0.46
0.25
0.27
(0.001)
(0.001)
(0.001)
(0.012)
(0.006)
Skin echogenicity differed between dcSSc and lcSSc patients on
phalanx, hand, forearm and chest, but not on leg (Table 2).
There was an inverse correlation between skin thickness and
skin echogenicity measured by ultrasound at all five sites
(Table 3), indicating that thicker skin is initially caused by
oedema. This correlation was strongest in the hand and least
pronounced in the leg.
There was a correlation between the total mRss and the
local skin thickness and skin echogenicity at the five examined
sites (Table 4), suggesting that ultrasound examination of
one site reflects total skin involvement. The ultrasound measurements tended to correlate closer to the total mRss in hand
and forearm, whereas the total mRss correlated less to skin
thickness in the phalanx and less to skin echogenicity in the leg.
Similar correlations were noticed between local mRss and
ultrasound examination of the corresponding anatomical region
(Table 4).
At all five anatomical sites, there was a considerable overlap in
both skin thickness and skin echogenicity between different local
mRss (example in Fig. 1). There were 10 patients who, by
palpation, had no skin involvement of the chest (mRss ¼ 0) but
had skin thickness greater than mean 2 S.D. for controls (women
>1.92 and men >2.0 mm) measured by ultrasound. Four of those
were classified as dcSSc at all investigations because of skin
involvement of upper arms or thighs (one had a renal crisis
at entry), four were classified as having lcSSc at all investigations
(two had pulmonary arterial hypertension at entry) and two
patients were initially classified as having lcSSc but later evolved
86
R. Hesselstrand et al.
FIG. 1. Skin thickness and skin echogenicity at hand, forearm and chest measured by ultrasound in 106 SSc patients with disease duration <2 yrs in relation to the local
mRss at the corresponding site. Box plots represent the 25 and 75th percentile of measures, the median (line in box) and the minimum and maximum values (whiskers).
Dotted lines represent reference values defined as mean 2 S.D. derived from healthy female individuals.
into dcSSc. Thus, ultrasound examination may predict the
transition from lcSSc to dcSSc.
Discussion
A novel finding in this study is the strong inverse relationship
between skin thickness and skin echogenicity measured by
ultrasound in patients with SSc and disease duration <2 yrs
(Table 3). This relationship implies that the oedema that occurs
early in disease results in both increased skin thickness and
decreased skin echogenicity; therefore, ultrasound may be useful
in ascertaining whether a patient is truly in the early oedematous
phase. This relationship disappears when the oedematous phase is
replaced by the indurative phase since skin thickness decreases
and skin echogenicity increases during serial measurements [13].
This large study also confirms the findings in our previous
pilot study in which skin thickness measured by ultrasound
was increased in patients with dcSSc compared with lcSSc
patients [13].
The mRss has been used for diagnosis as well as inclusion
criteria and end-points in therapeutic trials. The identification
of patients in the oedematous phase is of importance for
therapeutic studies since such patients are probably more likely
to respond to intervention. Ultrasound measurements may
facilitate improved patient selection, whereas other measures of
outcome such as the durometer, functional scales and biomarkers
may be more suitable as end-points. In addition, ultrasound
measurements may help in the early identification of patients with
dcSSc, as the two patients in the present study classified as lcSSc
with skin thickness >2 mm at the chest measured by ultrasound
later were classified as dcSSc.
The close relationship between the local ultrasound findings
and the total mRss is intriguing (Table 4). The severity of skin
involvement at a specific anatomical site measured by ultrasound
thus corresponds to the total skin involvement by palpation.
This finding is further supported by the ultrasound differences
between lcSSc and dcSSc. Patients with dcSSc have a more
widespread skin involvement, but this study also shows a higher
skin thickness and a lower skin echogenicity at the involved areas
(Tables 1 and 2).
The present ultrasound data indicate differences between
various anatomical regions (Table 3). Of the five sites we have
Skin ultrasound in SSc reflects oedema and severity
used, the correlation between skin thickness and skin echogenicity
was weakest at the phalanx and the leg. Inter-observer variability
has previously been shown to be slightly higher in measurements
of skin thickness of the phalanx [13, 17]. This may be caused by
the difficulties of obtaining a perpendicular picture, especially in
patients with slender fingers, where the probe may slide sideways.
Furthermore, oedema of the leg is a frequent finding that may
have causes unrelated to SSc. Given that ultrasound is a timeconsuming, but objective, method, there may be ways to simplify
the examinations. Skin thickness and skin echogenicity at hand
and forearm gave the most reliable and useful information and
may be selected to assess the severity of skin involvement. In
addition, ultrasound of the chest, thighs or upper arms could be
performed to identify lcSSc individuals with high skin thickness,
who may evolve into dcSSc.
The mRss is the established method for assessing skin
involvement in SSc. However, there is a considerable overlap in
skin thickness measured by ultrasound in patients with different
mRss, even in the outermost range of 0 or 3 (example in Fig. 1).
This does not necessarily imply a weakness of either the
ultrasound technique or the skin scoring technique but rather
that mRss does not only reflect skin thickness but also skin
consistency and that ultrasound is an important complement in
the evaluation of skin involvement in SSc. A patient may thus
score a ‘0’ on mRss but have high skin thickness if the skin is soft
and oedematous but may score a ‘2’ on mRss but have normal
skin thickness if the skin is hard, a finding possible to confirm by
durometry.
This study is limited by the retrospective and single-centre
design. Furthermore, serial measurements are needed to know
whether the change in skin thickness or echogenicity also relates to
changes in mRss.
In conclusion, we have found that in SSc patients with short
disease duration, high-frequency ultrasound is useful to identify
the oedematous phase, detect skin involvement early if the
diagnosis is uncertain and assess the severity of overall skin
involvement.
Rheumatology key messages
In SSc patients with short disease duration, skin ultrasound may
help to:
identify the oedematous phase
detect skin involvement early
assess the severity of overall skin involvement.
87
Acknowledgements
Funding: This study was supported by grants from the Medical
Faculty of the University of Lund, the Swedish Rheumatism
Association, Gustaf V’s 80 yrs Fund, the Österlund Foundation
and the Koch Foundation.
Disclosure statement: The authors have declared no conflicts of
interest.
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