This is the first study evaluating changes of skin stiffness over-time in patients with SSc, using shear-wave elastography. This study provides evidence suggesting that skin stiffness (i.e. SWV values) decreased significantly in almost all Rodnan skin sites in SSc patients, as well as in healthy controls, over 5 years of follow-up. Shear-wave elastography was remarkably more sensitive to change over time than mRSS.
The observed decrease in stiffness follows the classical clinical expectation that skin in SSc evolves from an early oedematous status towards a fibrotic and finally an atrophic phase after reaching a maximal induration.15,16 In fact, at baseline, the five patients in oedematous phase had higher SWV values than patients in a fibrotic phase in the corresponding skin sites. During follow-up, SWV values decreased in almost all skin sites, which parallels the decline of oedema, the onset of fibrosis and, finally, atrophy.
Surprisingly, however, our observations in healthy controls suggest that a substantial part of the decrease in skin stiffness observed in patients with SSc is probably explained by normal skin ageing. Collagen fiber network of the dermis layer is known to change with aging and this is expected to affect the elasticity of this layer.18 In fact, Shuster et al measured the skin collagen and dermal thickness in skin biopsies obtained from the forearm of ~150 healthy controls.18 They demonstrated that skin collagen decreased with age, namely after the age of 20 in males and 50 in females.18 Another study by Leveque et al, found that skin thickness starts to decrease from the age of 45 years both in male and female, with female´s skin becoming thinner that that of males.19 Interestingly, these findings were recently corroborated by a study using SWE to determine age-related changes of the skin in healthy controls.20 These authors demonstrated that SWV values decrease significantly in healthy controls older than 50 years compared with the 20- to 50-year group, at the finger and forearm.20 As the previous mentioned studies were cross-sectional, we cannot infer skin changes overtime from them.18-20 Of note, in the present study 72.2% of the participants were older than 50 at baseline [60.3 (7.7) years]. Other factors, besides age itself, such as skin site, gender, hormonal phase and contextual factors may have also contributed to the observed changes and deserve consideration in future studies.
Our results suggest that elastography may be useful as an aid in distinguishing between changes in skin due to oedema and induration or sclerosis, a recognized limitation of mRSS.15 This may be particularly important in the assessment of the early phases of disease and response to treatment. Similar observations have been made in two longitudinal studies of ultrasound dermal thickness: thickness decreased and patients became more similar to the control population, between the 1st and the 4th years of follow-up.,4,21 Kaloudi et al. found that dermal thickness decreased as the clinical phase progressed from the edematous to the atrophic phase.6
A relevant key message from our findings provide is the evidence that skin SWV evaluation is a more sensitive instrument to measure skin change over time than mRSS. In fact, SWE identified significant changes overtime at all skin sites (except fingers), where mRSS only showed significative differences in upper arm and forearm.
Another key message is the fact that SWE captured significant changes over time in skin sites with local normal mRSS at baseline. This is reinforced by the obvious fact that mRSS would, by definition, be unable to identify age-related skin changes in normal skin, and thus the impact of ageing in SSc.
These comparisons should, however, be interpreted in light of evidence that the mRSS and SWE measure different skin properties: mRSS measures not only thickness, but also texture and fixation,15 while elastography measures only skin stiffness. In future studies, it would be of interest not only to validate SWE against dermal thickness ultrasound or optical coherence tomography, but also against histologic findings.
We also observed that percentage SWV reduction was more pronounced in certain sites (chest, upper arm, and forearms) than in others. This is in line with studies that have identified the chest and forearms as the sites with more pronounced skin changes overtime, as opposed to the lower extremities, abdomen, fingers and face, which tend to be more stable.22 These findings raise the hypothesis that excluding relatively static skin sites may improve the sensitivity to change of total skin scores.
This is the first study addressing the sensitivity over time of SWE in SSc and controls. The same observers performed ultrasound evaluations and mRSS at baseline and follow-up. Although our data further supports the use of SWE as a potential outcome measure of skin involvement in SSc, its interpretation is limited by the small sample size, forcing a more descriptive than statistical subgroup analysis. Future skin ultrasound studies would benefit from a cohort of early diffuse patients with a shorter evaluation interval to further clarify whether changes are age- or disease-related, compared to later disease and healthy controls. It should also be considered that about half of the patients received immunosuppressive treatment between the two clinical and ultrasound evaluations: it cannot be ruled out that some of the changes observed were influenced by these medications.