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Clinical and epidemiological research
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High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis
  1. Olga Kaloudi1,
  2. Francesca Bandinelli1,
  3. Emilio Filippucci2,
  4. Maria Letizia Conforti1,
  5. Irene Miniati1,
  6. Serena Guiducci1,
  7. Francesco Porta1,
  8. Antonio Candelieri3,
  9. Domenico Conforti3,
  10. Genesio Grassiri4,
  11. Walter Grassi2,
  12. Marco Matucci-Cerinic1
  1. 1Department of Biomedicine, Division of Rheumatology AOUC, Centre Denothe, University of Florence, Florence, Italy
  2. 2Division of Rheumatology, University of Marche, Jesi, Ancona, Italy
  3. 3Laboratory of Decision Engineering for Health Care Delivery, Department of Electronics, Informatics and Systems, University of Calabria, Cosenza, Italy
  4. 4Esaote, Genoa, Italy
  1. Correspondence to Olga Kaloudi, Department of Biomedicine, Division of Rheumatology AOUC, Centre Denothe, University of Florence, Villa Monna Tessa, Viale Pieraccini 18, Florence 50139, Italy; olgakaloudi{at}hotmail.com

Abstract

Background Currently, assessment of dermal thickness in systemic sclerosis (SSc) is performed by palpation and assessment using the modified Rodnan skin score (mRSS).

Objective To verify whether high frequency ultrasound (US) may be a reliable and a reproducible method to measure digital dermal thickness.

Methods In 70 patients with SSc, skin thickness was evaluated with US by 2 observers at 2 different sites on the second digit of the dominant limb to determine the interobserver variability. Patients and controls were examined twice by the first observer for intraobserver variability. Patients were divided into three subgroups according to the phase of the disease (oedematous, fibrotic or atrophic).

Results At both examined areas, US showed a significant dermal thickening (p<0.001) in the whole group of patients with SSc. A low intraobserver and interobserver variability was found. A highly significant correlation between the global mRSS and the local dermal thickness at the two examined sites (p=0.032, p=0.021) was detected. Skin thickness was significantly higher in the oedematous than in the fibrotic group (p<0.001) and significantly higher in the fibrotic and the oedematous group (p<0.001) than in the atrophic group (p<0.002).

Conclusions US is a reliable tool giving reproducible results, and is able to detect digital dermal thickening in SSc.

https://doi.org/10.1136/ard.2009.114843

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    Introduction

    In systemic sclerosis (SSc), skin involvement is frequently the major clinical feature that can span from mild oedema to extensive skin fibrosis and eventually to atrophy. The degree of skin involvement is an important measure and a predictor of mortality.1 Rodnan pioneered the assessment of cutaneous involvement using a semiquantitative score to measure skin thickness by palpation, which correlated with weight of skin punch biopsy scores.2 This score has subsequently been simplified (modified Rodnan skin thickness score (mRSS)) and has been shown to be reliable and sensitive to change.3 Several studies, including retrospective cohort analyses and prospective clinical trials, have shown that the severity of skin sclerosis, as assessed by the mRSS, is predictive of disease outcome: patients who achieved improvement in the skin score of at least 25% between baseline and the 2 year follow-up assessment had a 5 year survival among ‘non-improvers’.4 Therefore, the mRSS represents a surrogate marker of disease severity in patients with SSc and has been validated as a useful clinical trial outcome measure. Limitations of mRSS are the intraobserver and interobserver variability (12% and 25%, respectively),5 and the need for standardisation among different centres when using skin scoring for clinical trials.6 Furthermore, although mRSS measures skin thickness it cannot differentiate between skin thickness and tightness. For this reason, the development of more objective, precise and sensitive measures of skin involvement is needed for use in clinical trials and in clinical practice.

    Previously, ultrasound (US) has been suggested for the measurement of dermal thickness in SSc as a reliable and change-sensitive methodology. Initial studies using dermal US in the assessment of SSc used 10 MHz7 and 15 MHz probes.8 For this purpose, a high frequency probe (18 MHz) offers considerably better resolution that allows dermis to be distinguished from subcutaneous fat and allows for measurement of skin thickness, regardless of the underlying tissue. In early SSc, high-frequency US has been shown to identify the oedematous phase that may precede palpable skin involvement.9

    The aim of this study was to evaluate if, in the oedematous, fibrotic and atrophic phases of SSc, high-frequency US might be a reliable and reproducible method to assess digital dermal thickness and its correlation with mRSS.

    Patients and methods

    A total of 70 Caucasian patients with SSc were consecutively recruited at the Department of Biomedicine, Division of Rheumatology, of the University of Florence, Florence, Italy (see supplementary methods 1).

    US evaluation

    Skin thickness was measured using a My Lab 25 US system (Esaote, Genoa, Italy) with a 6–18 MHz probe. Measurements were made at each of two skin sites (see supplementary methods 2).

    Statistical analysis

    For details of statistical analysis, see supplementary methods 3.

    Results

    The demographic and clinical features of patients with SSc are shown in table 1.

    View this table:
    Table 1

    Demographic, clinical and imaging features of patients with systemic sclerosis (SSc)

    Interobserver and intraobserver variability

    The intraobserver variability was significantly low for sites 1 (intraclass correlation coefficient (ICC) 0.960, 95% CI 0.937 to 0.975) and 2 (ICC 0.917, 95% CI 0.870 to 0.948). Over site 1, the ICC was 0.969, 95% CI 0.950 to 0.980 and over site 2 the ICC was 0.924, 95% CI 0.880 to 0.952.

    The statistical analysis showed that the measurements of the two observers (site 1: p=0.260, site 2: p=0.288) and the same observer at the same site (site 1: p=0.416, site 2: p=0.228) were statistically significant. (figure 1A,B for site 1).

    Figure 1
    Figure 1

    A. comparison of means of the two observers at site 1. B. Comparison of means of the same observer at site 1.

    Dermal thickness

    The dermal thickness was significantly higher in patients with SSc than in controls (site 1: 1.382 ± 0.5 mm vs 0.869 ± 0.73 mm, p<0.008; site 2: 1.4899 ± 0.46 mm vs 0.984 ± 0.69 mm, p=0.009) (figure 2). Thickness was higher in patients with diffuse SSc (dSSc) than limited SSc (lSSc) at site 1 (1.487 ± 0.58 mm vs 1.366 ± 0.49 mm, p=0.008) and lower at site 2 (1.36 ± 0.5 vs 1.5 ± 46 mm, p=0.009).

    Figure 2
    Figure 2

    Dermal thickness measurements obtained in mm in controls and patients with systemic sclerosis (SSc) by the two observers is shown at site 1.

    Correlation of dermal thickness with mRSS and Health Assessment Questionnaire (HAQ)

    There was a highly significant correlation between the global mRSS and the US results obtained at sites 1 and 2 (p=0.032 for site 1 and p=0.021 for site 2). No correlation between dermal thickness and local mRSS and HAQ was found.

    Dermal thickness in different phases of the disease

    Dermal thickness was significantly different in the three phases of skin involvement. In the oedematous phase, thickness of the dorsal phalanx was significantly higher (site 1: 1.752 ± 0.52 mm, site 2: 1.87 ± 0.35 mm) than in the fibrotic phase (site 1: 1.389 ± site 2: 1.447 ± 0.33 mm; site 1: p<0.001, site 2: p<0.011). In the fibrotic phase, dermal thickness was significantly higher than in the atrophic phase (site 1: 1.003 ± 0.35 mm, site 2: 1.164 ± 0.38 mm; site 1 p<0.001, site 2 p<0.002).

    Discussion

    Recently, US has been proposed as a non-invasive method for measuring skin involvement in SSc. In a cross-sectional study on 41 patients with SSc, Akesson et al, using a 20 MHz probe, examined 3 skin areas and reported an interobserver variability of 1% for proximal phalanx, 4.2% for hand and 0.0016% for forearm.8 Moore et al10 developed a 17-point dermal US scoring system that resulted reliable with low interobserver and intraobserver variability. Our results are in agreement with these studies and confirm the low interobserver and intraobserver variability of US in measuring dermal thickness in patients with SSc. According to the data reported by Moore et al, only dermal measurement was considered for US assessment of SSc skin because of the high variability of epidermal measurement.10

    The clinical impact of our data was verified, defining the local mRSS and correlating it with US dermal thickness. In the fingers, our results did not demonstrate a correlation between mRSS and US. In mRSS, investigations have shown that interobserver variability can still be considerable even after repeated teaching and even if experienced experts are included in the study.5 This evidence may indicate that one of the two methods may not be sensitive enough to detect skin thickness, or that mRSS may not detect skin texture. However, the correlation between the local US findings and the total mRSS is in agreement with previous studies9 and may suggest that the severity of skin involvement of the digits corresponds to the total mRSS. This dichotomy of measurement is supported by the US differences detected between patients with lSSc and dSSc.

    In this study, a new finding is the correlation between dermal thickness and the clinical phase of skin involvement. This relationship implies that skin oedema may result also in an increase of skin thickness. Akesson et al showed a diminished skin thickness in most patients with SSc with repeated measurements at 2–4 years, suggesting a replacement of interstitial fluid by newly synthesised collagen.11 In contrast with Hesselstrand et al9 that studied a cohort of patients with disease duration <2 years and found oedema, we did not find any correlation between disease duration and skin thickness, indicating that oedema can be present at the onset of the disease. These results are in agreement with Akesson et al, who did not find any relationship between skin thickness of the phalanx and disease duration7 and with other studies where the correlation between skin thickness and echogenicity of the phalanx was weak.9 However, this discrepancy may be caused by the difficulty of obtaining a perpendicular picture of this area.

    It should be also pointed out that the reference values and the distribution of a control population have not yet been well defined. In this and also in other studies, patients with SSc showed a dermal thickness significantly higher than controls.

    There is a technical detail to be considered. During the measurement we did not consider the dorsal digital vein that may contribute to create overestimation of skin thickness. In fact, these veins are lying in the dermal surface and may be included in the measurement of skin thickness.

    We wish also to point out that this study is limited by the few patients with dSSc and by the observational and single centre study design. Two patients had flexion contractures that made measurements difficult. More serial measurements are needed to better define the progression of skin thickness and its relationship with mRSS changes.

    In conclusion, our results suggest that the US technique is a reliable tool that gives reproducible results to detect skin thickness in the digits of patients with SSc. US is a promising tool that may help the doctor to understand the phase of the disease, that is oedematous versus fibrotic versus atrophic, and the thickness of the dermis as an outcome measure. The limitation of our work is that our results, although significant, are limited to the fingers and therefore new studies are warranted to further evaluate US as a tool for studying the whole body surface. In the future, we require US probes that can measure the oedema that increases the thickness of the skin and the quantity of the collagen present in the skin as a result of the fibrotic process at the same time. In the future, the evolution of US probes might allow an objective evaluation of the skin thickness due to oedema and to fibrosis, thus this could become an outcome measurement of skin involvement in clinical trials and, hopefully, in clinical practice.

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    Supplementary materials

    Footnotes

    • Funding This study was supported by the technical equipment generously provided by Esaote.

    • Ethics approval This study was conducted with the approval of the Florence Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent Obtained.