How much of skin improvement over time in systemic sclerosis is due to normal ageing? A prospective study with shear-wave elastography

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. 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