A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?
A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?
He Liu 0 1
Yong Hou 1
Qing-li Zhu 0 1
Dong Xu 1
Liang Wang 0 1
Jian-chu Li 0 1
Yu- xin Jiang 0 1
Qian Wang 1
Meng-tao Li 1
Feng-chun Zhang 1
Xiao-feng Zeng 1
0 Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing , China , 2 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing , China
1 Editor: Masataka Kuwana, Keio University , JAPAN
To evaluate the usefulness of skin ultrasound and acoustic radiation force impulse (ARFI) quantification in diffuse cutaneous systemic sclerosis (dcSSc).
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: YH received the funding, the National
Natural Science Foundation of China (81671614),
the website: www.nsfc.gov.cn/. YH contributed in
the study design, data collection and analysis,
decision to publish, and preparation of the
Competing interests: The authors have declared
that no competing interests exist.
Patients and methods
28 patients with dcSSc, and 15 age gender matched normal controls were recruited. Skin
echogenicity, thickness, and ARFI quantification were measured by ultrasound at 17 sites
corresponding to the modified Rodnan skin score (mRSS) in each participant. Compared
with controls, skin echogenicity of dcSSc patients was classified into isoechoic, hypoechoic,
and hyperechoic. The skin thickness, ARFI quantification and mRSS were compared
between isoechoic, hypoechoic, hyperechoic and controls.
In patients with dcSSc, the skin thickness increased as the echogenicity changed on the
order of isoechoic, hypoechoic and hyperechoic. ARFI quantification was significantly higher
in hyperechoic than isoechoic (p<0.001). The mRSS were significantly higher in
hyperechoic and/or hypoechoic than isoechoic. For isoechoic patients and healthy controls, the
skin echogenicity or thickness was no significant different, however, the ARFI quantification
was significantly higher in isoechoic than controls.
Skin ultrasound is feasible for assessing the skin involvement in dcSSc. Skin echogenicity
correlates with skin thickness, stiffness, and mRSS. ARFI quantification may be more
sensitive to detect skin changes, compared with skin echogenicity and thickness.
Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder of unknown aetiology,
which may involve the skin and internal organs to varying degrees and with different courses.
The extent of skin involvement correlates with survival and prognosis [
]. Ultrasound has
been demonstrated to be a reliable tool to measure skin thickness, echogenicity, and stiffness,
and it is increasing employed in SSc. Skin thickness increased in SSc patients compared with
healthy controls , and was significant different between edematous, fibrotic, and atrophic
]. Echographic images of SSc patients skin differed from healthy controls . The
degree of skin echogenicity correlated with the amount of sclerosis on histologic examination
]. During the oedematous phase, skin echogenicity was low and skin thickness was high.
When the oedematous phase was replaced by the indurative phase, skin echogenicity increased
and skin thickness decreased [
]. Skin stiffness of SSc patients is more recent and less
investigated [9±11]. The principle of this technique is the reduced skin elasticity caused by excessive
dermal deposition of collagenous and non-collagenous extracellular matrix mediated fibrosis
]. Increased skin stiffness, shown by specific color or higher ARFI quantification, was
reported in SSc patients compared with healthy controls [9±11]. To our knowledge, the
correlations between ultrasound measured skin thickness, echogenicty, and stiffness have not
been fully conducted. The purpose of this study was therefore to investigate the correlations
between them, and explore the usefulness of ultrasound, with the main focus on skin
echogenicity and stiffness, in SSc patients.
Patients and methods
28 patients with dcSSc and 15 age gender matched controls were prospectively recruited from
the rheumatology department of Peking union medical college hospital. The patients, who all
met the American College of Rheumatology 1980 criteria [
] or American College of
Rheumatology/European League Against Rheumatism 2013 criteria [
] for the classification of
scleroderma and dcSSc [
], underwent clinical and serological assessment at entry. The
disease duration was calculated from the onset of Raynaud's phenomenon. An experienced
physician assigned each patient mRSS on 0±3 ordinal scale over 17 anatomical sites according to
Moore et al seventeen point dermal ultrasound scoring system [
]. The physician was trained
at the European League Against Rheumatism Scleroderma Trials and Research group course
and blinded to the result of the ultrasound assessment. The 17 sites were bilateral middle
finger, hand dorsum, forearm, upper arm, thigh, lower leg, foot dorsum, forehead, anterior
chest, and anterior abdomen. The ethics committee of Peking Union Medical College Hospital
approved the study (No. S-191), and all participants signed informed consent.
Ultrasound examination and image analysis
Ultrasound and ARFI quantification were performed over the 17 sites corresponding to mRSS
by an experienced ultrasound physician, who was engaged in superficial organ examination
for more than 18 years and unaware of the patients' clinical data. A Siemens S2000 ultrasound
system (S2000; Siemens Medical Solutions, Inc. Siemens Healthcare, Erlangen, Germany)
fitted with a 9L4 MHz linear probe was used. To increase the accuracy of the measurements, the
probe was placed perpendicularly to the skin, and a layer of gel was applied to minimize the
compression from the transducer to the skin. The ultrasound image was adopted when the
epidermis, dermis, and subcutis were clearly visualized and the interfaces between them were
parallel and distinct. The skin stiffness was measured by ARFI quantification. With ARFI
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technique in the form of Virtual Touch Quantification (VTQ), transducers are used to
mechanically excite tissue with short-duration acoustic radiation forces, leading to shear waves
propagation away from the region of excitation [
]. The stiffer the tissue, the faster the
shear waves propagate. Thus, the shear wave velocity measured by ARFI quantification gives
tissue stiffness information of the region of interest (ROI). The ROI box had a preset size of
6mm (width) × 5mm (depth). Five trials of ARFI quantification was performed at each site.
When ªXº displayed on the screen, the measurements were interpreted as invalid. The five
consecutive ARFI quantification measurements with no ªXº were taken and the results were
averaged. All static ultrasound images were stored and later analyzed by the other three
independent outside ultrasound physicians with more than 20 years experience in superficial
organs examination. Two ultrasound physicians evaluated all images independently and
blinded to the patients' clinical information. In cases in which there was a discrepancy between
the two reviewers, a third ultrasound physician served as a blinded expert. They discussed to
reach a consensus for classifying the patient's skin echogenicity. The patient's skin
echogenicity of each site was compared with site matched normal skin in healthy controls (Fig 1A), and
classified into isoechogenic (Fig 1B), hypoechogenic (Fig 1C), and hyperechogenic (Fig 1D).
The skin thickness, the combined epidermis and dermis, was determined (Fig 2).
Fig 1. Ultrasound findings of the dcSSc patients and the control's right forearm skin. The echogenicity was determined as compared with
sitematched, normal skin in healthy controls (Fig 1A), and was classified into isoechogenic (Fig 1B), hypoechogenic (Fig 1C), and hyperechogenic (Fig 1D).
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Fig 2. Ultrasound measured skin thickness of the dcSSc patients and the control's right forearm. The skin thickness was 0.6mm (between arrows) for
controls (Fig 2A), and 1.0mm (between arrows) for patients (Fig 2B).
SPSS software version 14.0 was used for statistical analysis, with p<0.05 considered statistically
significant. Data were expressed as median (lower quartile, upper quartile). The intraclass
correlation coefficient (ICC) was calculated to examine the inter-observer reliability of skin
echogenicity classification. Differences in skin thickness, ARFI quantification and mRSS between
isoechogenic, hypoechogenic, hyperechogenic and controls were assessed by Kruskal-Wallis
test with Bonferroni multiple testing correction.
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2.55 (1.92, 2.88) m/s for isoechoic, hypoechoic and hyperechoic respectively. The
quantification was significantly higher in hyperechoic than isoechoic (p<0.001), no significant difference
was found between hyperechoic and hypoechoic, or between hypoechoic and isoechoic
(p = 0.117) (Fig 4). The local mRSS was expressed as median (lower quartile, upper quartile)
for the three groups (isoechoic, hypoechoic and hyperechoic) respectively, and it was 0 (0, 1), 1
(0, 1), 1(0, 2) for isoechoic, hypoechoic and hyperechoic respectively. The mRSS was
significantly higher in hyperechoic and/or hypoechoic than isoechoic (p<0.001), no significant
difference was found between hyperechoic and hypoechoic (p = 0.600).
Between isoechoic patients and healthy controls, the skin thickness was no significant
different (1.0 (0.8, 1.2) mm v.s. 0.7(0.5, 0.9) mm, p = 0.142), however, the ARFI quantification
was significantly higher in isoechoic than controls (1.83(1.48, 2.48) m/s v.s. 1.1(0.8, 1.49) m/s,
Fig 3. The skin thickness of dcSSc patients and controls. Box plots represent the 25 and 75th percentile
of measures, the median (line in box) and the minimum and maximum values (whiskers). The thickness
increased as the echogenicity changed on the order of isoechoic, hypoechoic and hyperechoic (p<0.001). No
significant difference was found between isoechoic patients and healthy controls (p = 0.142).
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Fig 4. The ARFI quantification of dcSSc patients and controls. Box plots represent the 25 and 75th
percentile of measures, the median (line in box) and the minimum and maximum values (whiskers). The ARFI
quantification was significantly higher in hyperechoic than isoechoic (p<0.001), no significant difference was
found between hyperechoic and hypoechoic, or between hypoechoic and isoechoic (p = 0.117). The ARFI
quantification was significantly higher in isoechoic than controls (p<0.001).
Our study showed that skin echogenicity correlated with skin thickness and local mRSS. The
thickness increased as the echogenicity changed on the order of isoechoic, hypoechoic and
hyperechoic. The mRSS was significantly higher in hyperechoic and/or hypoechoic than
isoechoic. We hypothesized that isoechogenicity in our study may be associated with very early
disease or atrophy, while hypoechogenicity and hyperechogenicity may correlate with edema
and sclerosis. Our results indicate that ultrasound measured skin thickness is more sensitive
than mRSS to detect skin changes, which is in accordance with previous studies [
2, 18, 19
Ultrasound role is becoming more and more relevant in systemic sclerosis. The majority of
articles reported the use of thickness for skin involvement assessment, only a few studied skin
3, 4, 7, 8, 12
]. Hesselstrand et al [
] reported the inverse relationship between
skin echogenicity and thickness in SSc patients with short disease duration (<2 years). Over
the five examined sites (finger, hand dorsum, forearm, leg, and chest), Hesselstrand et al found
a mild-to-moderate positive correlation between local skin thickness and the local/total mRSS
(spearman correlation coefficient +0.36 ~ +0.72), while a mild negative correlation between
local skin echogenicity and the local/total mRSS (spearman correlation coefficient -0.18 ~
-0.47). Hesselstrand et al [
] used an arbitrary score of 0±255 to measure the mean
echogenicity of a selected region. A low value represents high water content and a high value represents
low water content. It's difficult to obtain site-matched, unaffected skin for comparison in
patients with dcSSc. Therefore, we determined echogenicity compared to site-matched normal
skin in healthy controls. The theoretical basis for this is the previous findings that skin echo
structure of SSc patients differed from healthy controls [
], and skin thickness and
echogenicity was no significant different in healthy controls with regards to gender (male and female)
and age (15±70 years old), except anatomical sites [
Imaging of the elastic properties of skin using ARFI quantification has become the subject
of increasing research in patients with SSc [
]. Our pilot article showed increased ARFI
quantification in dcSSc patients compared with healthy controls, and ARFI quantification was
more sensitive than mRSS. In this study ARFI quantification was significantly higher in
hyperechoic than isoechoic, suggesting higher grades of fibrosis in hyperechoic lesions. Moreover,
ARFI quantification, instead of skin echogenicity or thickness, was significant different
between isoechoic and controls, indicating ARFI quantification may be more sensitive than
skin echogenicity and thickness to detect subtle skin changes. The results are similar to Kissin
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et al  and our previous study that demonstrated higher skin stiffness in so-called
uninvolved skin as compared with healthy control skin, due to the abnormal endothelial activation
and procollagen production [
Our study is limited by the relatively small number of patients and controls included, single
centre design and lack of information about ultrasound validity to detect change in patients'
follow up and clinical trial. These preliminary findings need to be confirmed in large studies.
In conclusion, skin ultrasound is feasible for assessing the skin involvement in dcSSc. Skin
echogenicity correlates with skin thickness, stiffness, and mRSS. ARFI quantification may be
more sensitive to detect skin changes, compared with skin echogenicity and thickness.
S1 File. The Institutional Review Board 1 approval.
S2 File. The Institutional Review Board 2 approval.
S3 File. STROBE checklist.
S4 File. Patients and controls data.
We thank Dr. Haiyu Pang for the assistance in data analysis.
Conceptualization: HL YH YJ XZ.
Data curation: HL YH QZ LW YJ JL.
Formal analysis: DX QW ML FZ XZ.
Funding acquisition: YH.
Investigation: HL YH QZ DX LW.
Methodology: HL YH QZ YJ XZ.
Project administration: YH YJ XZ.
Resources: DX QW ML FZ XZ.
Supervision: YJ XZ.
Visualization: HL YH QZ.
Writing ± original draft: HL YH QZ.
Writing ± review & editing: HL YH QZ LW.
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