RESEARCH ARTICLE Open Access
How much o skin imp o emen o e ime
in sys emic scle osis is due o no mal
ageing? A p ospec i e s udy wi h shea -
wa e elas og aphy
T. San iago
1,2*
, M. San iago
1,2
, M. Cou inho
1,2
, M. J. Sal ado
1,2
and J. A. P. Da Sil a
1,2,3
Abs ac
Backg ound: Measu emen o skin in ol emen is essen ial o he diagnosis and assessmen o p ognosis and
disease p og ession in sys emic scle osis (SSc). The modi ied Rodnan skin sco e (mRSS) is he gold s anda d
measu e o skin hickness, bu i has been c i icised o he lack o objec i i y, poo in e -obse e ep oducibili y
and lack o sensi i i y o change. Recen ly, shea -wa e elas og aphy (SWE) eme ged as a p omising ool o he
objec i e and quan i a i e assessmen o he skin in SSc pa ien s. Howe e , no s udies ha e e alua ed i s sensi i i y
o change o e ime.
Objec i e: To assess changes in skin s i ness in SSc pa ien s using SWE du ing a 5-yea ollow-up.
Me hods: Skin s i ness [i.e. shea -wa e eloci y alues (SWV) in me es pe second] was assessed by SWE ul asound
(using i ual ouch image quan i ica ion) a he 17 si es o he mRSS, in each pa icipan , a baseline and ollow-up.
mRSS was pe o med a bo h ime poin s. Di e ences be ween g oups we e analysed using he ela ed-samples
Wilcoxon signed- ank es and he Mann–Whi ney U es .
Resul s: We included 21 pa ien s [85.7% emales; mean age 56.3 (10.4) yea s a baseline, 57.1% wi h limi ed SSc] and
15 heal hy con ols [73.3% emales; mean age 53.6 (14.1) yea s)]. The median ollow-up was 4.9 (0.4) yea s.
Skin s i ness dec eased signi ican ly a all Rodnan si es (p≤0.001) (excep in he inge s), in SSc pa ien s, o e ime. The
same phenomenon occu ed in con ols, bu o a lesse deg ee, in e ms o pe cen age change.
The pe cen age educ ion in skin s i ness a ied in he di e en Rodnan si es and in di e en phases o he disease. In
addi ion, SWV alues also dec eased signi ican ly in 15/16 skin si es wi h local no mal Rodnan a baseline, whe eas local
Rodnan skin sco e only changed signi ican ly in he uppe a m (p= 0.046) and o ea m (p=0.026).
Conclusion: This s udy p o ides i s - ime e idence sugges ing ha skin SWV alues a e mo e sensi i e o change o e
ime han mRSS and educe signi ican ly o e ime in SSc and no mal con ols.
Keywo ds: Skin, S i ness, Shea -wa e elas og aphy, Sys emic scle osis, Ul asound
© The Au ho (s). 2020 Open Access This a icle is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License,
which pe mi s use, sha ing, adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e
app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons licence, and indica e i
changes we e made. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle's C ea i e Commons
licence, unless indica ed o he wise in a c edi line o he ma e ial. I ma e ial is no included in he a icle's C ea i e Commons
licence and you in ended use is no pe mi ed by s a u o y egula ion o exceeds he pe mi ed use, you will need o ob ain
pe mission di ec ly om he copy igh holde . To iew a copy o his licence, isi h p://c ea i ecommons.o g/licenses/by/4.0/.
The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he
da a made a ailable in his a icle, unless o he wise s a ed in a c edi line o he da a.
* Co espondence: [email p o ec ed]
1
Rheuma ology Depa men , Cen o Hospi ala e Uni e si á io de Coimb a,
Coimb a, Po ugal
2
Facul y o Medicine, Uni e si y o Coimb a, Coimb a, Po ugal
Full lis o au ho in o ma ion is a ailable a he end o he a icle
San iago e al. A h i is Resea ch & The apy (2020) 22:50
h ps://doi.o g/10.1186/s13075-020-02150-x
In oduc ion
Skin in ol emen is a majo ea u e o sys emic scle osis
(SSc) [1]. The ex en and a e o p og ession o skin i-
b osis is o pa amoun impo ance as i co ela es wi h
unc ional limi a ions, in e nal o gan in ol emen and
su i al [1]. The e o e, measu emen o skin in ol e-
men is no only essen ial o he diagnosis and assess-
men o p ognosis in SSc, bu also c ucial o suppo he
de elopmen o new he apies. The modi ied Rodnan
skin sco e (mRSS), a semi-quan i a i e me hod based on
palpa ion, is cu en ly he gold s anda d measu e o skin
changes in SSc and is o en he p ima y o seconda y
ou come measu e in clinical ials. Howe e , i has been
c i icised o i s lack o objec i i y, poo in e -obse e
ep oducibili y and lack o sensi i i y o change in skin
hickness o e ime [2,3].
Di e en ul asound me hods a e being in es iga ed as
means o imp o e he assessmen o skin in ol emen in
SSc. High- equency ul asound o e s a po en ial o ob-
jec i e, sensi i e and eliable assessmen o de mal hick-
ness in SSc [4–6]. Howe e , i does no assess he issue
elas ic p ope ies.
In ecen yea s, shea -wa e elas og aphy (SWE) has
been in es iga ed as a quan i a i e and ope a o -
independen ool o e alua e skin s i ness [7–9]. Shea -
wa e eloci y (SWV) alues e lec issue s i ness: he
s i e he issue, he as e he shea -wa es p opaga e.
SWE may, he e o e, p o ide a no el oppo uni y o ob-
jec i ely assess ib osis—a c ucial ea u e in he complex
p ocess o skin in ol emen in SSc [10,11].
C oss-sec ional s udies ha e shown ha SWV alues a e
signi ican ly highe in SSc pa ien s han in con ols, in al-
mos all o he Rodnan si es [7–9]. In e es ingly, clinically
una ec ed skin o pa ien s wi h SSc could also be di e en-
ia ed om he skin o heal hy compa a o s [7,8]. Two
p e ious s udies ha e shown excellen ep oducibili y o
SWV measu emen s, wi h in e - a e in aclass co ela ion
coe icien s (ICCs) anging om 0.48 (phalanx) o 0.91
(uppe a m). The co esponding alues o in a- a e
compa isons we e 0.48 (ches ) o 0.98 (phalanx) [7,8].
This is he i s s udy o e alua e he p og ession o
skin s i ness o e ime wi h SWE in pa ien s wi h SSc
and in no mal con ols.
Me hods
Pa icipan s
All pa icipan s we e ec ui ed om a c oss-sec ional
e alua ion p e iously desc ibed elsewhe e [9]. In his
longi udinal s udy, we included 21 o he o iginal 26 pa-
ien s (3 died and 2 we e los o ollow-up) and 15 o he
17 ini ial heal hy con ols (1 died and 1 was los o
ollow-up). The heal hy con ols we e ec ui ed among
hospi al s a and pa ien ’s amily membe s, using as ex-
clusion c i e ia, any diagnosis o o he skin diso de s
(e.g. pso iasis), connec i e issue disease o heuma ic in-
lamma o y disease. No signi ican di e ences we e
ound be ween pa ien s and con ols, ega ding age and
gende .
All pa icipan s we e submi ed o a clinical and ul a-
sound e alua ion a baseline and a ollow-up, a median
o 4.9 (0.4) yea s la e .
All SSc pa ien s ul illed he 2013 ACR/EULAR c i e ia
o he classi ica ion o SSc [12]. The disease was classi ied
as di use cu aneous o limi ed cu aneous SSc, acco ding
o he ex en o skin in ol emen [13].
E hics
E hical app o al was ob ained om he E hics Commi -
ee o Cen o Hospi ala e Uni e si á io de Coimb a
(CHUC –118-17). All pa ien s and con ols p o ided
signed in o med consen p io o any s udy p ocedu es.
Clinical skin hickness sco ing (mRSS)
Skin hickness was clinically assessed using he mRSS,
sco ing he palpa ion a each o he 17 skin si es on a 0–
3 scale [14]. The same expe ienced heuma ologis
(MJS) pe o med he mRSS a baseline and ollow-up,
on he same day o he skin ul asound.
Clinical phase o skin in ol emen
Skin in ol emen phase was clinically assessed and clas-
si ied as oedema ous, ib o ic o a ophic by he same
heuma ologis (MJS) a baseline and ollow-up, on he
same day o he skin ul asound, ollowing cu en ly ac-
cep ed desc ip ions [15–18].
Skin ul asound e alua ion
Skin s i ness was measu ed a baseline and ollow-up,
h ough shea -wa e elas og aphy, using i ual ouch
image quan i ica ion (VTIQ), a he same 17 si es o he
mRSS. SWE was pe o med wi h an ACUSON Ul asound
Sys em (Siemens Heal hca e), using a linea 4–9-MHz
ansduce . The ul asound p o ocol has been desc ibed
elsewhe e [7]. In b ie , accep ance o an ul asound image
o analysis was based on clea isualisa ion o an in e ace
be ween he epide mis, de mis and subcu aneous issues
and on an au oma ed image quali y indica o p o ided by
he ul asound sys em. The sonog aphe placed sampling
ga es wi h he minimum possible size (2 × 2 mm) o e he
de mis. The VTIQ ou pu simul aneously displays a
colou -coded issue s i ness map and absolu e shea -wa e
eloci y alues (in me es pe second, up o 10 m/s) in one
single image. Highe shea -wa e eloci ies indica e g ea e
issue s i ness. The SWV o each si e scanned was es ab-
lished as he mean o h ee consecu i e measu emen s.
The same heuma ologis (TS) pe o med all ul a-
sound measu emen s, blinded o he a ibu ed Rodnan
skin sco e. The in a-obse e ep oducibili y o SWE in
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 2 o 7
his examine ’s hands is e lec ed by in aclass co el-
a ion coe icien s anging om 0.70 ( oo ) o 0.98 ( in-
ge ) in SSc and 0.81 ( high) o 0.97 ( inge ) in heal hy
con ols (Table S1).
S a is ical me hods
Con inuous a iables we e epo ed as means (s anda d
de ia ion), i no mally dis ibu ed o median (in e qua ile
ange), i no no mally dis ibu ed. Ca ego ical a iables
we e p esen ed as equencies. Di e ences be ween
g oups we e analysed using he ela ed-samples Wilcoxon
signed- ank es and he Mann–Whi ney U es .
Resul s
Clinical ea u es
Baseline clinical ea u es o he pa ien s wi h SSc and
heal hy con ols a e p esen ed in Table 1. All pa ien s in
an oedema ous phase a baseline p og essed o a ib o ic
(n= 3) o a ophic phase (n= 2). O he 16 pa ien s in a
ib o ic phase a baseline, 11 main ained he ib o ic
phase and 5 p og essed o an a ophic phase.
Changes in skin s i ness du ing ollow-up
Signi ican dec eases in SWV alues we e obse ed in all
Rodnan skin si es o e he ollow-up pe iod (p≤0.001),
excep in he inge s (Table S2). mRSS only iden i ied
signi ican changes in he uppe a m (p= 0.046) and
o ea m (p= 0.024) (Table S2).
Simila signi ican dec eases in SWV alues we e ob-
se ed in heal hy con ols in all skin si es (p= 0.001), ex-
cep he leg.
A he second examina ion, SWVs in SSc pa ien s be-
came simila o ha o con ols in all si es, excep he
hands and inge s (p= 0.001) (Table S2).
The median pe cen age change in skin s i ness (i.e. pe -
cen age change o SWV om baseline) was mo e p o-
nounced in SSc han in con ols. This di e ence eached
s a is ical signi icance in he uppe a m (median pe cen age
change −53.2% in SSc s −41.5% in con ols, p=0.007)
(Fig. 1and Table 2). In addi ion, he pe cen age change o
SWV was a iable in di e en skin si es (Table 2).
Taking all cases in o accoun , and based in simple
a i hme ic, he e ec s o ageing seem o explain om
40% (leg) o 90% (ches ) o he skin s i ness educ ion
obse ed in SSc pa ien s. The only excep ion is he skin
o he inge s, whe e he disease is associa ed wi h a
smalle dec ease in skin s i ness han obse ed in
heal hy con ols (da a no shown).
Skin s i ness and i s p og ession acco ding o he clinical
phase o he disease
Pa ien s in an oedema ous phase had highe SWV com-
pa ed o pa ien s in a ib o ic phase. These di e ences
we e s a is ically signi ican a he abdomen, uppe a m,
o ea m, hand and oo (p< 0.05).
The pe cen age change di e ed acco ding o he phase o
he disease a baseline (Table S3 and Supplemen a y Fig. S1).
Namely, pa ien s in an oedema ous phase a baseline had a
highe pe cen age educ ion in skin s i ness, in he majo i y
o skin Rodnan si es, han pa ien s in a ib o ic phase.
Changes in skin s i ness acco ding o he o m o he
disease
A baseline and ollow-up, pa ien s wi h a di use o m had
highe SWV alues han pa ien s wi h a limi ed o m (Table
S6). These di e ences we e s a is ically signi ican a he
uppe a m, hand and inge (p< 0.05). Howe e , he e we e
no s a is ically signi ican di e ences in pe cen age change
educ ion in skin s i ness be ween pa ien s wi h he limi ed
and di use o ms o SSc.
Table 1 Clinical and demog aphic cha ac e is ics o he
pa icipan s a baseline
SSc pa ien s
(N= 21)
Con ols
(N= 15)
Female, n(%) 18 (85.7) 11 (73.3)
Age (yea s) 58.0 (48.5–63.0) 55.0 (45.0–
63.0)
Smoking habi s, n(%)
Ne e 17 (80.9) 11 (73.3)
Ex-smoke 4 (19.1) 4 (26.6)
Disease du a ion since diagnosis,
yea s
10.0 (5.5–14.0) –
Disease du a ion since RP, yea s 14.0 (6.5–16.5) –
Limi ed o m, n(%) 12 (57.1) –
mRSS o al 8.0 (4.0–15.0) –
Phase, n(%) –
Oedema ous 5 (23.8)
Fib o ic 16 (76.2)
ANA posi i e, n(%) 20 (95.2) –
ACA posi i e, n(%) 9 (42.9) –
An i-Scl 70 posi i e, n(%) 7 (33.3) –
Immunosupp essi e ea men
a
(yes), n(%)
6/21 –
Vasodila o s ea men
b
(yes), n
(%)
9/21 –
Values a e in median (Q1–Q3), unless s a ed o he wise
RP Raynaud phenomenon, ANA an i-nuclea an ibody, ACA an i-cen ome e
an ibody, mRSS modi ied Rodnan skin sco e
a
Me ho exa e (a e age dose 15 mg/week, N= 2); p ednisolone o equi alen
(a e age dose 5 mg/day (N=4)
b
Ni edipine (a e age dose 30 mg/day, N= 7) and/o pen oxi ylline (a e age
dose 800 mg/day, N=5)
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 3 o 7
Changes in skin s i ness in si es wi h no mal mRSS
The obse a ion o highe SWV alues compa ed wi h con-
ols in si es wi h clinically una ec ed skin (mRSS = 0) a
baseline made in ou o iginal s udy was con i med in his
subg oup [7](TableS4 and Table S5).
The longi udinal analyses demons a ed ha SWV alues
also dec eased signi ican ly o e he 5 yea s ollow-up in all
skin si es wi h Rodnan = 0 a baseline (excep in he inge s).
The e we e no s a is ically signi ican di e ences be ween pa-
ien s and con ols a he end o ollow-up in any o hese
si es (Table S4). Na u ally, he Rodnan skin sco e could no
iden i y any changes in such si es.
Discussion
This is he i s s udy e alua ing changes o skin s i -
ness o e ime in pa ien s wi h SSc, using shea -wa e
elas og aphy. This s udy p o ides e idence sugges ing
ha skin s i ness (i.e. SWV alues) dec eased signi i-
can ly in almos all Rodnan skin si es in SSc pa ien s,
Fig. 1 Shea -wa e eloci y alues (me es pe second), measu ed by shea -wa e elas og aphy, a he Rodnan skin si es, a baseline and ollow-up,
in SSc and con ols. Pe cen age change alues a e p esen ed as median (Q1–Q3). Pa ien s 2 and 3 p og essed om oedema ous o a ophic
phase. Red do ed lines ep esen oedema ous pa ien s a baseline, and he g ey lines ep esen pa ien s in ib o ic phase a baseline
Table 2 Compa ison o pe cen age changes in shea -wa e eloci y alues, in each Rodnan si e o analysis, obse ed in SSc pa ien s
and con ols
Rodnan si es SSc pa ien s (n= 21)
#
Con ols (n= 15)
#
SSc s con ols (p alue)
†
Ches −51.5% (−55.2 o −41.7) −46.9% (−50.0 o −32.0) NS
Abdomen −38.9% (−58.1 o −28.7) −32.6% (−43.9 o −8.2) NS
Uppe a m −53.2% (−60.2 o −40.7) −41.5% (−48.7 o −38.8) 0.007
Fo ea m −44.3% (−57.5 o −40.7) −37.1% (−52.0 o −23.3) NS
Hand −33.5% (−52.6 o −19.9) −26.2% (−38.6 o −8.5) NS
Finge −5.3% (−36.9 o 34.7) −24.6% (−29.8 o −12.4) NS
Thigh −37.1% (−45.3 o −31.2) −31.6% (−37.3 o −24.0) NS
Leg −25.8% (−37.8 o −3.2) −10.3% (−27.3 o −6.9) NS
Foo −36.4% (−56.6 o −29.7) −27.1% (−45.2 o −14.3) NS
S a is ically signi ican esul s a e in bold
NS non-signi ican
#
Values a e in medians (Q1–Q3)
†
Mann–Whi ney U es
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 4 o 7
as well as in heal hy con ols, o e 5 yea s o ollow-
up. Shea -wa e elas og aphy was ema kably mo e
sensi i e o change o e ime han mRSS.
The obse ed dec ease in s i ness ollows he classical
clinical expec a ion ha skin in SSc e ol es om an
ea ly oedema ous s a us owa ds a ib o ic and inally an
a ophic phase a e eaching a maximal indu a ion [15,
16]. In ac , a baseline, he i e pa ien s in he
oedema ous phase had highe SWV alues han pa ien s
in a ib o ic phase in he co esponding skin si es. Du -
ing ollow-up, SWV alues dec eased in almos all skin
si es, which pa allels he decline o oedema, he onse o
ib osis and, inally, a ophy.
Su p isingly, howe e , ou obse a ions in heal hy con-
ols sugges ha a subs an ial pa o he dec ease in
skin s i ness obse ed in pa ien s wi h SSc is p obably
explained by no mal skin ageing. Collagen ib e ne wo k
o he de mis laye is known o change wi h ageing and
his is expec ed o a ec he elas ici y o his laye [18].
In ac , Shus e e al. measu ed he skin collagen and
de mal hickness in skin biopsies ob ained om he o e-
a m o ~ 150 heal hy con ols [18]. They demons a ed
ha skin collagen dec eased wi h age, namely a e he
age o 20 in males and 50 in emales [18]. Ano he s udy
by Le eque e al. ound ha skin hickness s a s o de-
c ease om he age o 45 yea s bo h in male and emale,
wi h he emale’s skin becoming hinne han ha o
males [19]. In e es ingly, hese indings we e ecen ly
co obo a ed by a s udy using SWE o de e mine age-
ela ed changes o he skin in heal hy con ols [20].
These au ho s demons a ed ha SWV alues dec ease
signi ican ly in heal hy con ols olde han 50 yea s com-
pa ed wi h he 20- o 50-yea g oup, a he inge and
o ea m [20]. As he p e iously men ioned s udies we e
c oss-sec ional, we canno in e skin changes o e ime
om hem [18–20]. O no e, in he p esen s udy, 72.2%
o he pa icipan s we e olde han 50 a baseline [60.3
(7.7) yea s]. O he ac o s, besides age i sel , such as skin
si e, gende , ho monal phase and con ex ual ac o s, may
ha e also con ibu ed o he obse ed changes and de-
se e conside a ion in u u e s udies.
Ou esul s sugges ha elas og aphy may be use ul as
an aid in dis inguishing be ween changes in he skin due
o oedema and indu a ion o scle osis, a ecognised limi-
a ion o mRSS [15]. This may be pa icula ly impo an
in he assessmen o he ea ly phases o disease and e-
sponse o ea men . Simila obse a ions ha e been
made in wo longi udinal s udies o ul asound de mal
hickness: hickness dec eased and pa ien s became
mo e simila o he con ol popula ion, be ween he 1s
and he 4 h yea s o ollow-up [4,21]. Kaloudi e al.
ound ha de mal hickness dec eased as he clinical
phase p og essed om he oedema ous o he a ophic
phase [6].
A ele an key message om ou indings p o ides he
e idence ha skin SWV e alua ion is a mo e sensi i e
ins umen o measu e skin change o e ime han
mRSS. In ac , SWE iden i ied signi ican changes o e
ime a all skin si es (excep inge s), whe e mRSS only
showed signi ica i e di e ences in he uppe a m and
o ea m.
Ano he key message is he ac ha SWE cap u ed
signi ican changes o e ime in skin si es wi h local no -
mal mRSS a baseline. This is ein o ced by he ob ious
ac ha mRSS would, by de ini ion, be unable o iden-
i y age- ela ed skin changes in no mal skin and, hus,
he impac o ageing in SSc.
These compa isons should, howe e , be in e p e ed in
ligh o e idence ha he mRSS and SWE measu e
di e en skin p ope ies: mRSS measu es no only hick-
ness, bu also ex u e and ixa ion [15], while elas og a-
phy measu es only skin s i ness. In u u e s udies, i
would be o in e es no only o alida e SWE agains
de mal hickness ul asound o op ical cohe ence om-
og aphy, bu also agains his ologic indings.
We also obse ed ha pe cen age SWV educ ion was
mo e p onounced in ce ain si es (ches , uppe a m, and
o ea ms) han in o he s. This is in line wi h s udies ha
ha e iden i ied he ches and o ea ms as he si es wi h
mo e p onounced skin changes o e ime, as opposed o
he lowe ex emi ies, abdomen, inge s, and ace, which
end o be mo e s able [22]. These indings aise he hy-
po hesis ha excluding ela i ely s a ic skin si es may
imp o e he sensi i i y o change o o al skin sco es.
This is he i s s udy add essing he sensi i i y o e
ime o SWE in SSc and con ols. The same obse e s
pe o med ul asound e alua ions and mRSS a baseline
and ollow-up. Al hough ou da a u he suppo s he
use o SWE as a po en ial ou come measu e o skin in-
ol emen in SSc, i s in e p e a ion is limi ed by he
small sample size, o cing a mo e desc ip i e han s a is-
ical subg oup analysis. Fu u e skin ul asound s udies
would bene i om a coho o ea ly di use pa ien s
wi h a sho e e alua ion in e al o u he cla i y
whe he changes a e age- o disease- ela ed, compa ed
o la e disease and heal hy con ols. I should also be
conside ed ha abou hal o he pa ien s ecei ed im-
munosupp essi e ea men be ween he wo clinical
and ul asound e alua ions: i canno be uled ou ha
some o he changes obse ed we e in luenced by hese
medica ions.
Conclusions
In conclusion, indings epo ed he ein highligh ha a
subs an ial pa o he imp o emen o he skin in SSc
may be explained by no mal ageing. They suppo he
highe disc iminan abili y o shea -wa e elas og aphy in
de ec ing sub le skin changes no iden i ied by mRSS.
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 5 o 7

Fu he longi udinal s udies wi h a highe numbe o pa-
ien s in di e en phases o skin in ol emen a e needed
o ully cla i y i s po en ial. Es ablishing no mal e e -
ence da a o hese ul asound measu emen s may also
os e ea lie diagnosis.
Supplemen a y in o ma ion
Supplemen a y in o ma ion accompanies his pape a h ps://doi.o g/10.
1186/s13075-020-02150-x.
Addi ional ile 1: Table S1. ICCs o in a-obse e ep oducibili y o skin
s i ness ul asound measu emen s pe o med by he US examine e-
sponsible o his s udy. Table S2. Shea -wa e eloci y alues and mRSS,
pe si e o analysis, a baseline and ollow-up, in SSc pa ien s and con-
ols. Table S3. Shea -wa e eloci y alues, a Rodnan skin si es, be ween
baseline and ollow-up, in he pa ien s wi h SSc acco ding o clinical skin
phase o he disease. Table S4. Shea -wa e eloci y alues a Rodnan
si es wi h clinically una ec ed skin (i.e. mRSS=0) and in con ols, a base-
line and ollow-up. Table S5. Pe cen age changes in shea -wa e eloci y
alues a Rodnan si es wi h una ec ed skin a baseline (i.e. mRSS=0) and
in con ols, be ween baseline and end o ollow-up. Table S6. Shea -
wa e eloci y alues, a Rodnan skin si es, a baseline and ollow-up, in
pa ien s wi h limi ed s di use SSc. Figu e S1. Shea -wa e eloci y
alues in he skin Rodnan si es a baseline and ollow-up, in SSc pa ien s,
acco ding he p og ession o he skin phase o he disease. Pa ien s in an
oedema ous phase p og essed o a ib o ic (n=3) o a ophic phase (n=2);
11 main ained he ib o ic phase; and 5 p og essed om a ib o ic o an
a ophic phase. Pe cen age change alues a e in medians (Q1-Q3).
Abb e ia ions
CHUC: Cen o Hospi ala e Uni e si á io de Coimb a; mRSS: Modi ied Rodnan
skin sco e; SSc: Sys emic scle osis; SWE: Shea -wa e elas og aphy; SWV: Shea -
wa e eloci y; VTIQ: Vi ual ouch imaging and quan i ica ion
Acknowledgemen s
The au ho s would like o hank all he pa icipan s who con ibu ed hei
ime o his s udy.
Pa ien and public in ol emen s a emen
No equi ed.
Au ho s’con ibu ions
TS, MJS, and JAPS con ibu ed o he concep ion, design o he s udy, and
d a ing o he manusc ip . TS and MS con ibu ed o he acquisi ion and
analysis o he da a. All au ho s con ibu ed o e ising he manusc ip
c i ically o impo an in ellec ual con en . The au ho s ead and app o ed
he inal manusc ip .
Funding
The au ho s ha e no decla ed a speci ic g an o his esea ch om any
unding agency in he public, comme cial, o no - o -p o i sec o s.
A ailabili y o da a and ma e ials
All da a ele an o he s udy a e included in he a icle o uploaded as
supplemen a y in o ma ion.
E hics app o al and consen o pa icipa e
Cen o Hospi ala e Uni e si á io de Coimb a (CHUC –118-17).
Consen o publica ion
No equi ed.
Compe ing in e es s
The au ho s decla e ha hey ha e no compe ing in e es s.
Au ho de ails
1
Rheuma ology Depa men , Cen o Hospi ala e Uni e si á io de Coimb a,
Coimb a, Po ugal.
2
Facul y o Medicine, Uni e si y o Coimb a, Coimb a,
Po ugal.
3
Coimb a Ins i u e o Clinical and Biomedical Resea ch (iCBR),
Facul y o Medicine, Uni e si y o Coimb a, Coimb a, Po ugal.
Recei ed: 9 Decembe 2019 Accep ed: 9 Ma ch 2020
Re e ences
1. Den on CP, Khanna D. Sys emic scle osis. Lance . 2017;390:1685–99.
2. Pope JE, Ba on M, Bellamy N, Campbell J, e al. Va iabili y o skin sco es and
clinical measu emen s in scle ode ma. J Rheuma ol. 1995;22:1271–6.
3. Kaldas M, Khanna PP, Fu s DE, Clemen s PJ, e al. Sensi i i y o change o
he modi ied Rodnan skin sco e in di use sys emic scle osis--assessmen o
indi idual body si es in wo la ge andomized con olled ials.
Rheuma ology (Ox o d). 2009;48:1143–6.
4. Hessels and R, Ca les am J, Wild M, Sandq is G, And éasson K. High
equency ul asound o skin in ol emen in sys emic scle osis - a ollow-up
s udy. A h i is Res The . 2015;17:329.
5. Moo e TL, Lun M, McManus B, Ande son ME, He ick AL. Se en een-poin
de mal ul asound sco ing sys em--a eliable measu e o skin hickness in
pa ien s wi h sys emic scle osis. Rheuma ology (Ox o d). 2003;42:1559–63.
6. Kaloudi O, Bandinelli F, Filippucci E, Con o i ML, Minia i I, Guiducci S, Po a
F, Candelie i A, Con o i D, G assi i G, G assi W, Ma ucci-Ce inic M. High
equency ul asound measu emen o digi al de mal hickness in sys emic
scle osis. Ann Rheum Dis. 2010;69:1140–3.
7. San iago T, Alcace -Pi a ch B, Sal ado MJ, Del Galdo F, Redmond AC, da
Sil a JA. A p elimina y s udy using i ual ouch imaging and quan i ica ion
o he assessmen o skin s i ness in sys emic scle osis. Clin Exp Rheuma ol.
2016;100:137–41.
8. Hou Y, Zhu QL, Liu H, Jiang YX, Wang L, Xu D, Li MT, Zeng XF, Zhang FC. A
p elimina y s udy o acous ic adia ion o ce impulse quan i ica ion o he
assessmen o skin in di use cu aneous sys emic scle osis. J Rheuma ol.
2015;42:449–55.
9. Liu H, Hou Y, Zhu QL, Xu D, Wang L, Li JC, Jiang YX, Wang Q, Li MT, Zhang FC,
Zeng XF. A p elimina y s udy o skin ul asound in di use cu aneous sys emic
scle osis: does skin echogenici y ma e ? PLoS One. 2017;12:e0174481.
10. Iagnocco A, Kaloudi O, Pe ella C, Bandinelli F, Riccie i V, Vasile M, Po a F,
Valesini G, Ma ucci-Ce inic M. Ul asound elas og aphy assessmen o skin
in ol emen in sys emic scle osis: ligh s and shadows. J Rheuma ol. 2010;37:
1688–91.
11. Taljano ic MS, Gimbe LH, Becke GW, La LD, Klause AS, Mel ille DM, Gao
L, Wi e RS. Shea -wa e elas og aphy: basic physics and musculoskele al
applica ions. Radiog aphics. 2017;37:855–70.
12. an den Hoogen F, Khanna D, F ansen J, e al. 2013 classi ica ion c i e ia o
sys emic scle osis: an Ame ican College o Rheuma ology/Eu opean League
agains Rheuma ism collabo a i e ini ia i e. Ann Rheum Dis. 2013;72:1747–55.
13. LEROY EC, BLACK C, FLEISCHMAJER R, e al. Scle ode ma (sys emic scle osis):
classi ica ion, subse s and pa hogenesis. J Rheuma ol. 1988;15:202–5.
14. Rodnan GP, Lipinski E, Luksick J. Skin hickness and collagen con en in
p og essi e sys emic scle osis and localized scle ode ma. A h i is Rheum.
1979;22:130–40.
15. Czi ják L, Foeld a i I, Mülle -Ladne U. Skin in ol emen in sys emic scle osis.
Rheuma ology (Ox o d). 2008;47(Suppl 5): 44–5.
16. Shah AA, Wigley FM. My app oach o he ea men o scle ode ma. Mayo
Clin P oc. 2013;88:377–93.
17. Khanna D, Fu s DE, Clemen s PJ, Allano e Y, e al. S anda diza ion o he
modi ied Rodnan skin sco e o use in clinical ials o sys emic scle osis. J
Scle ode ma Rela Diso d. 2017;2:11–8.
18. Shus e S, Black MM, McVi ie E. The in luence o age and sex on skin
hickness, skin collagen and densi y. B J De ma ol. 1975;93:639–43.
19. Le eque JL, Co cu P, de Rigal J, Agache P. In i o s udies o he e olu ion
o physical p ope ies o he human skin wi h age. In J De ma ol. 1984;23:
322–9.
20. Yang Y, Wang L, Yan F, Xiang X, Tang Y, Zhang L, Liu J, Qiu L.
De e mina ion o no mal skin elas ici y by using eal- ime shea wa e
elas og aphy. J Ul asound Med. 2018;37:2507–16.
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 6 o 7
21. Akesson A, Hessels and R, Scheja A, Wild M. Longi udinal de elopmen o
skin in ol emen and eliabili y o high equency ul asound in sys emic
scle osis. Ann Rheum Dis. 2004;63:791–6.
22. Silman A, Ha ison M, B ennan P. Is i possible o educe obse e a iabili y
in skin sco e assessmen o scle ode ma? The ad hoc in e na ional g oup on
he assessmen o disease ou come in scle ode ma. J Rheuma ol. 1995;22:
1277–80.
Publishe ’sNo e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a ilia ions.
San iago e al. A h i is Resea ch & The apy (2020) 22:50 Page 7 o 7