The Updated Role of Ultrasound in Assessing Dermatological Manifestations in Systemic Sclerosis

Figures & data

Figure 1 High-frequency ultrasound, 18-MHz, B-mode, at the upper arm (A), abdomen (B), foot (C) in a patient with systemic sclerosis.

Note: Figure courtesy of Tânia Santiago.

Table 1 Recent Milestones in the Study of Skin Ultrasound, Analysed by Skin High-Frequency Ultrasound in Systemic Sclerosis

First Author	Study Type	SSc Patients (n)	Control Population	Summary of Results
Sulli et al (2014)^Citation20	CC	43 lcSSc 14 dcSSc	37 HC	A positive correlation was observed between nailfold microvascular damage severity and both ultrasound-DT (p-value=0.028) and mRSS values (p-value<0.0001). This study demonstrates a relationship between nailfold microangiopathy severity, DT and blood perfusion, in SSc patients
Sulli et al (2017)^Citation30	CC	50 lcSSc	50 mHC	This study strongly supports that subclinical dermal involvement may be detectable by US, even in skin areas with a normal mRSS, in patients classified as having lcSSc.
Ruaro et al (2018)^Citation31	CC	45 lcSSc 17 dcSSc	62 mHC	This study demonstrates, for the first time, a significant inverse relationship between skin BP, measured by LASCA and DT, evaluated by both US and mRSS, in SSc patients. All measurements were taken at the level of dorsum of the middle phalanx of the third fingers.
Ruaro et al (2019)^Citation32	CC	40 lcSSc 23 dcSSc	63 mHC	This study demonstrates a correlation between two of the most important aspects in the classification and monitoring of SSc patients. That is microvascular damage progression (evaluated by NVC) and skin damage (assessed by mRSS, US and PST)
Ruaro et al (2019)^Citation33	CC	48 lcSSc	48 mHC	The 22 MHz US probe is more sensitive in detecting subclinical DT changes than is an 18 MHz probe Subclinical dermal involvement is detectable by skin high frequency US, also in the clinically unaffected skin areas of lcSSc patients
Li et al (2018)^Citation42	CS	31 SSc	31 mHC	These authors also demonstrated a positive correlation between skin damage, evaluated in five different sites, ie the dorsal of the forearm, hand, finger, leg and manubrium, and disease activity
Naredo et al (2020)^Citation43	CC	40 lcSSc 23 dcSSc	6 HC	A 50 MHz probe provides better resolution and visualization of the derma, allowing for a more accurate DT determination and a correct assessment of the different skin layers. DT was significantly higher in SSc patients than in the control group (p-value <0.05). Moreover, a texture computed analysis of the dermis and hypodermis discriminated SSc from healthy subjects.
Chen et al (2020)^Citation44	CC	44 SSc	22 HC	There was good agreement between the ultrasound-measured skin thickness and the histological skin thickness, in 9 dcSSc and4 lcSSc patients.^Citation44

Abbreviations: CC, case-control study; CS, cross-sectional study; mHC, age- and gender-matched healthy controls; LASCA, laser speckle contrast analysis; PST, plicometer skin test; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; SSc, systemic sclerosis.

Table 2 The Main Characteristics of the Studies Using Ultrasound for the Study of Localized Scleroderma

First Author	Study Type	SSc Patients Number/Total Skin Lesions	Control Population Number	Main Findings
Perez et al (2020)^Citation50	CS	13 patients (median age: 10 y) Total skin lesions: 13	Control was represented by corresponding healthy skin of enrolled patients	- A significantly lower dermal thickness and hypodermis in LS lesions compared to healthy skin - Only one patient (active LS) had skin thickening - 7/13 subjects had echogenic changes
Ranosz-Janicka (2019)^Citation51	CC	40 adult patients. Total skin lesions: 92	Site-matched unaffected skin	- An increase in the dermal thickness in all erythematous and sclerotic lesions - A decrease in the dermal thickness in 94.3% of atrophic lesions. - Dermal hyperechogenicity in 96% of sclerotic lesions and 91.4% of atrophic lesions
Porta et al (2014)^Citation34	CC	10 juvenile LS patients	Normal skin in the contralateral area	- An increase in dermal thickness of involved areas compared to normal contralateral areas - The data from this study suggest that treatment response may be monitored by skin ultrasound
Weibel et al (2020)^Citation52	CC	24 patients (age at start of treatment 9.6 y)	The unaffected contralateral side	-Baseline (start of treatment):a slight decrease in the median dermal thickness and increase in dermal echogenicity in LS area compared to the contralateral healthy side - Weak positive correlation of dermal thickness and negative correlation of dermal echogenicity with clinical score
Arisi et al (2019)^Citation45	CC	17 adult patients	Healthy skin contiguous to morphea lesions	- An increase in dermal thickness and a decrease in echogenicity of affected skin - “Yoyo” figures were detected in 47% of affected skin areas and only in 5.9% of the healthy skin (p-value = 0.02) - The data from this study support the utility of US in patient follow-up to monitor treatment response
Murray et al (2016)^Citation48	CS	32 adult patients	Unaffected skin sites in the same enrolled patients	- An increase in epidermal thickness in the affected site compared to the unaffected site (in active morphea plaques,(-value=0.03))

Abbreviations: CC, case-control study; CS, cross-sectional study; LS, localized scleroderma.

Table 3 The Main Characteristics of the Studies Using Ultrasound Elastography

First Author	Study Type	SSc Patients (n)	Control Population (n)	Main Findings
Iagnocco (2010)^Citation38	CC	18 (10dcSSc;8llcSSc)	15 mHC	- Blue areas in subjects; never detected in controls in forearm; not in fingers. -Changes independent of clinical evidence of skin involvement.
Di Geso (2011)^Citation39	CS	22 (14lcSSc/18dcSSc)	-	- Elastography can improve the reliability of the US dermal thickness at finger in SSc patients.
Cannao (2014)^Citation54	CC	6	6	- Stiffer tissue (from a semi-quantitative scale in which lower levels corresponded to harder tissues) compared with controls: total median score 6 (4-6) vs 11 (9-11) p-value <0.001
Hou (2015)^Citation56	CC	15dcSSc	15mHC	-SWV values were higher in dcSSc than in controls at the hands, forearms and feet (p-value < 0.05) - SWV values of uninvolved skin were higher than those of controls (p < 0.001) - SWV values increased with increasing skin scores except for skin score 3 (p < 0.05)
Santiago (2016)^Citation57	CC, P	26 (13dcSSc, 13lcSSc)	17mHC	- SWV values were significantly higher in SSc than in controls in 11/16 mRSS sites - SWV values were strongly correlated with the local mRSS in the forearm, hand, phalanx and thigh - In SSc, clinically unaffected skin could also be differentiated from healthy skin from controls
Liu (2017)^Citation58	CC	28dcSSc	15mHC	- ARFI quantification was significantly higher in hyperechoic than isoechoic (p<0.001). The mRSS were significantly higher in hyperechoic and/or hypoechoic than isoechoic
Çildağ (2017)^Citation55	CS	40dcSSc	-	- No patients had a red pattern (group 1); 14 had a green pattern (group 2) and 26 had a blue pattern (group 3). -The color-scale groups had a statistically significant difference in duration of disease (p-value = 0.013).
Yang (2018)^Citation59	CC	37 (14lcSSc,23dcSSc)	37	- Skin elastic modulus values (E-score) were significantly higher in SSc patients than controls, at all measured sites (p-value<0.001). - mRSS correlated more closely with skin stiffness (r=0.889, p-value<0.001) than with ST (r=0.465, p-value=0.002).
Sobolewski (2020)^Citation60	CC	40 (29lcSSc; 11dcSSc)	28	- The elastographic strain was significantly higher than in controls, in SSc patients with normal mRSS values - SWE in the fingers is highly accurate to distinguish SSc patients - SWE values were more reproducible than those of the mRSS clinical examination (ICC 0.987 vs 0.941)
Santiago (2020)^Citation62	CC	21(12lcSSc; 9dcSSc)	15	- There was a significant decrease over time. in the skin stiffness at all Rodnan sites (p-value ≤ 0.001) (except in the fingers), in SSc patients - The % of the reduction in skin stiffness varied in the different Rodnan sites and in different phases of the disease. - There was a statistically significant change in the local Rodnan score only in the upper arm (p-value = 0.046) and forearm (p-value= 0.026)
Chen (2020)^Citation44	CC	44 (22dcSSc, 22lcSSc)	22	- Both Ultrasound-ST and skin stiffness were significantly higher in SSc patients (p-value < 0.001) and even higher in those with dcSSc, than in controls. - No clear correlation could be established between ultrasound-determined skin thickness and stiffness at the same site. - Ultrasound-skin thickness correlated well with histological skin thickness (r= 0.6926, p-value = 0.009) in the forearm (n=13SSc)
Flower (2020)^Citation61	CC	53 (45lcSSc, 8dcSSc)	15	- ST (hand/forearm) and SWE (finger/hand) correlated with local mRSS at some sites. - Subclinical abnormalities in ST, echogenicity and SWE were present in clinically uninvolved SSc skin. - Changes in SWE were sometimes apparent, despite objectively normal ST. - ST, SWE and local mRSS correlated strongly with collagen quantification (rho 0.697, 0.709, 0.649 respectively).

Abbreviations: CC, case-control study; CS, cross-sectional study; mHC, age- and gender-matched healthy controls; SWV, shear wave velocity; ARFI, acoustic radiation force impulse; SWE, shear wave elastography; ST, skin thickness P, prospective study; mRSS, modified Rodnan skin score; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; SSc, systemic sclerosis.

Figure 2 Shear-wave elastography, 8-MHz, (A and B) and high-frequency ultrasound, 18-MHz (C and D) at the abdomen in a healthy control (A and C) and a patient with systemic sclerosis (B and D). Mean of three shear-wave velocity values was 1.7m/s (A) and mean dermal thickness was 1.55 mm in the control (C), and 2.2 m/s (B) and 1.76 mm (D) in the patient. The shear-wave velocities’ values are displayed in a quantitative data box, at the left side of the image. Higher shear-wave velocity values indicate higher tissue stiffness. The colour scale indicate the stiffness of all tissues within the region of interest. (red=hard tissue; blue=soft tissue).

Note: Figure courtesy of Tânia Santiago.

Table 4 Recent Milestones in the Study of Cutaneous Ulcers Analysed by Ultrasound in Systemic Sclerosis

First Author	Study Type	SSc Patients (n)	Control Population	Summary of Results
Suliman et al (2018)^Citation41	CS	11 patients with ulcerated and non-ulcerated lesions	None	A 5–18 MHz ultrasound probe was used Ulcerated lesions had a greater surface area than non-ulcerated lesions (55.5 vs 12 mm2), depth (median 2 mm vs 0 mm),and power Doppler signal (3 vs 0 patients)
Hughes et al (2017)^Citation63	CS	11 patients with SSc and 15 with DU	None	DU HUS (35 MHz) was feasible and well tolerated by patients. Most of them were “classifiable” allowing for the measurement of the DU width and depth. The mean (SD) DU depth and width was 0.99 (0.45) and 5.74 (2.16) mm, respectively

Abbreviations: CC, case-control study; CS, cross-sectional study; DU, digital ulcers; HUS, high-frequency ultrasound; SSc, systemic sclerosis.

Figure 3 Digital ulcer ultrasound. Fingertip DU (A) and extensor aspect (D) (with the DU indicated by a red arrow). DU using high-frequency ultrasound images of the “long” (B) and “short” axis. Measurements (B and C and E and F) can be obtained of the ulcer width (red bars) and depth (yellow bars).

Notes: Adapted with permission from Hughes M, Moore T, Manning J, Dinsdale G, Herrick AL, Murray A. A pilot study using high-frequency ultrasound to measure digital ulcers: a possible outcome measure in systemic sclerosis clinical trials? Clin Exp Rheumatol. 2017;35 Suppl 106(4):218–219. © Clinical and Experimental Rheumatology.⁶³

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