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Research Letter |

14-MHz Ultrasonography as an Outcome Measure in Morphea (Localized Scleroderma) FREE

Kaveh A. Nezafati, MD; Rachael L. Cayce, MD; Joseph S. Susa, DO; Anthony T. Setiawan, MD; Temel Tirkes, MD; Sandra E. Bendeck, MD; Heidi T. Jacobe, MD
[+] Author Affiliations

Author Affiliations: Departments of Dermatology (Drs Nezafati, Cayce, Susa, Bendeck, and Jacobe) and Radiology (Drs Setiawan and Tirkes), University of Texas Southwestern Medical Center, Dallas. Dr Tirkes is now in private practice in Bloomington, Indiana; Dr Bendeck is now with Kaiser Permanente, Hayward/Fremont Medical Centers, Department of Dermatology, Union City, California.


Arch Dermatol. 2011;147(9):1112-1115. doi:10.1001/archdermatol.2011.243.
Text Size: A A A
Published online

The determination of therapeutic efficacy in morphea (aka, localized scleroderma) is difficult owing to a lack of validated outcome measures.1,2 Outside of the United States, 20- to 25-MHz ultrasonography has demonstrated its validity, reproducibility, and responsiveness to change.3 Preliminary studies on the lower-frequency ultrasonography available in the United States (10-15 MHz) demonstrate that it may have similar attributes.46 However, studies correlating ultrasonographic findings with lesion stage (inflammatory, sclerotic, or atrophic), clinical scoring systems, or histologic traits have not been conducted.

We identified 14 patients with 16 morphea lesions (Table) from the University of Texas Southwestern Medical Center Morphea Registry and DNA repository. Each patient and lesion was assessed for morphea subtype and clinical stage and was assigned a Modified Rodnan Skin Score (mRSS) by a single board-certified dermatologist (H.T.J.).

Table Graphic Jump LocationTable. Patient Demographic and Clinical Characteristics

A single site for ultrasonography and biopsy, as well as a control site, was chosen by the dermatologist and marked with a surgical pen. Ultrasonographic examination was performed by 2 radiologists blinded to the results of the clinical assessment of each patient. Each lesion had dermal thickness measured and echogenicity determined as compared with site-matched, unaffected skin (hypoechogenic, isoechogenic, and hyperechogenic) (Figure 1 and Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Morphea lesions and their controls were imaged using 14-MHz ultrasonography. The interface between the dermis and the subcutaneous fat, or hypodermis (H), is easily seen by this technique. Measurements of dermal depth (Dph) were obtained by 2 blinded observers. Lesions were compared with controls to determine dermal echogenicity. The echogenicity or brightness of a structure depends on the acoustic impedances at a tissue interface. Structures with greater acoustic impedances will be displayed as brighter and hyperechogenic. To increase the accuracy of the measurements, a thick layer of hypoechogenic ultrasonography gel (G) was applied to the skin to clearly depict the surface. The gel is invisible by ultrasonography (dark zone superficial to the surface). A and B, Morphea lesion in the atrophic phase in which the dermis demonstrates decreased echogenicity (A) compared with its control (B). C and D, By contrast a morphea lesion in the sclerotic phase shows substantial hyperechogenicity (C) compared with its control (D).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Morphea lesions were biopsied in the same location that ultrasonographic examination was performed. The specimens were graded by a single dermatopathologist who was blinded to the clinical and ultrasonographic data. Representative specimens of lesions from each of the 3 clinical stages of a morphea lesion are shown. A, Clinically atrophic lesions were found to be hypoechoic compared with their controls (Figure 1A and B) (P  =  .03). B, Clinically sclerotic lesions of morphea were found to be hyperechoic compared with their controls (Figure 1C and D) (P  =  .01). C, Clinically inflammatory lesions were found to have an echogenicity similar to controls (isoechogenic) (P  =  .04).

One board-certified dermatopathologist (J.S.S.), blinded to both clinical and sonographic data, graded each specimen for inflammation, edema, and sclerosis using a previously published scoring system7 and calculated dermal thickness.

To examine the correlation between ultrasonographic finding and clinical stage, mRSS, dermal thickness, and grade of fibrosis, the Fisher exact test was used. To examine the correlation between thickness on ultrasonography and histologic findings, the Spearman correlation coefficient was used. The intrarater correlation and interrater correlation of ultrasonographic measurements was analyzed using the intraclass correlation coefficient.

Prior studies identified assessment of disease stage as important features in the evaluation and treatment of morphea.8 Ultrasonography was able to reliably differentiate between the clinical stages of morphea. A significant number of inflammatory lesions were isoechogenic (5 of 6) (P  =  .04). Most sclerotic lesions were hyperechogenic (5 of 6) (P  =  .01). Atrophy appeared on ultrasonography as hypoechogenicity in 2 of 3 lesions that were deemed to be atrophic on the clinical examination (P  =  .03) (Figure 3A).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Ultrasonography is capable of differentiating between disease activity (inflammation and sclerosis) and damage (atrophy). A, In our study, early inflammatory lesions of morphea appeared isoechogenic (P  =  .04); sclerosis appeared hyperechogenic (P  =  .01), while atrophic lesions appeared hypoechogenic (P  =  .03). B, Hyperechogenicity seen on ultrasonogram correlates with the presence of histologic sclerosis. Sixteen lesions were examined by ultrasonography and histologic analysis. Hyperechogenicity was associated with moderate or severe grades of histologic sclerosis (P  =  .04).

No significant relationship was found between mRSS and ultrasonography findings of echogenicity or dermal depth measurement (P  =  .60 and P  =  .40, respectively).

Ultrasonography measurements of dermal thickness were reproducible by a single clinician and between clinicians (intrarater and interrater correlation, 0.99 and 0.97, respectively).

Ultrasonography findings were compared with the putative gold standard for evaluation of morphea, histologic analysis. Hyperechogenicity on ultrasonography was significantly associated (P  =  .04) with grades of moderate or extensive sclerosis on dermatopathologic examination (Figure 3B). There was not a significant relationship between the depth of sclerosis as measured by ultrasonography and histologic analysis (R  =  0.75; P  =  .33).

The high validity and reliability demonstrated by 14-MHz ultrasonography in this study indicates it might be a useful outcome measure. Fourteen-MHz ultrasonography could differentiate between all the clinical stages of disease. It could also differentiate active disease, which appeared hyperechoic (sclerosis) or isoechoic (inflammation), from atrophy or damage, which appeared hypoechoic. We also found that ultrasonography demonstrated a significant correlation between the amount of sclerosis on histologic examination and degree of echogenicity.

There was no significant association between mRSS and echogenicity or dermal depth on ultrasonography. This discrepancy highlights the inadequacy of the mRSS, which relies solely on the investigator's ability to pinch or move skin.

As in prior studies, the measurements obtained by 14-MHz ultrasonography demonstrated extremely high reliability. Both the intrarater and interrater reliability of ultrasonography exceeded the reliability of existing clinical sclerosis scores.9,10

The main limitation of this study was the small number of patients included and the smaller number of lesions with suitable, full-thickness biopsies. Depth of disease is important for selection of therapy. Biopsies, which are both invasive and unreliable in their ability to assess the depth of sclerosis, are not always helpful. Fourteen-MHz ultrasonography, which penetrates up to 40 mm, may be a useful, noninvasive tool to investigate the depth of involvement beyond the dermis. Fourteen-MHz ultrasonography is likely better suited than 20-MHz for this function owing to its deeper penetration.

The value of ultrasonography as an outcome measure will depend on its ability to demonstrate that it can detect changes in lesions over time. If ultrasonography assessment is found to distinguish longitudinal changes in plaque sclerosis and depth, it could be a very valuable tool in following up entire cohorts of patients in a clinical trial, or it could give the clinical dermatologist a follow-up tool for individual patients with morphea.

ARTICLE INFORMATION

Correspondence: Dr Jacobe, Department of Dermatology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Ste JA5.120H, Dallas, TX 75390-9069 (Heidi.Jacobe@utsouthwestern.edu).

Accepted for Publication: January 24, 2011.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Cayce, Tirkes, Bendeck, and Jacobe. Acquisition of data: Nezafati, Cayce, Susa, Setiawan, Tirkes, and Jacobe. Analysis and interpretation of data: Nezafati, Cayce, Susa, Setiawan, and Jacobe. Drafting of the manuscript: Nezafati and Cayce. Critical revision of the manuscript for important intellectual content: Nezafati, Susa, Setiawan, Tirkes, Bendeck, and Jacobe. Obtained funding: Setiawan and Jacobe. Administrative, technical, and material support: Susa, Tirkes, and Bendeck. Study supervision: Tirkes.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by the Dermatology Foundation Clinical Development Award in Medical Dermatology and National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases K23 Award (Dr Jacobe).

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

Laxer RM, Zulian F. Localized scleroderma.  Curr Opin Rheumatol. 2006;18(6):606-613
PubMed   |  Link to Article
Seibold JR, Furst DE, Clements PJ. Why everything (or nothing) seems to work in the treatment of scleroderma.  J Rheumatol. 1992;19(5):673-676
PubMed
Kreuter A, Gambichler T, Breuckmann F,  et al.  Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma.  Arch Dermatol. 2005;141(7):847-852
PubMed   |  Link to Article
Serup J. Localized scleroderma (morphoea): thickness of sclerotic plaques as measured by 15 MHz pulsed ultrasound.  Acta Derm Venereol. 1984;64(3):214-219
PubMed
Cosnes A, Anglade M-C, Revuz J, Radier C. Thirteen-megahertz ultrasound probe: its role in diagnosing localized scleroderma.  Br J Dermatol. 2003;148(4):724-729
PubMed   |  Link to Article
Li SC, Liebling MS, Haines KA. Ultrasonography is a sensitive tool for monitoring localized scleroderma.  Rheumatology (Oxford). 2007;46(8):1316-1319
PubMed   |  Link to Article
Verrecchia F, Laboureau J, Verola O,  et al.  Skin involvement in scleroderma —where histological and clinical scores meet.  Rheumatology (Oxford). 2007;46(5):833-841
PubMed   |  Link to Article
Arkachaisri T, Vilaiyuk S, Torok KS, Medsger TA Jr. Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study.  Rheumatology (Oxford). 2010;49(2):373-381
PubMed   |  Link to Article
Clements P, Lachenbruch P, Siebold J,  et al.  Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis.  J Rheumatol. 1995;22(7):1281-1285
PubMed
Pope JE, Baron M, Bellamy N,  et al.  Variability of skin scores and clinical measurements in scleroderma.  J Rheumatol. 1995;22(7):1271-1276
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Morphea lesions and their controls were imaged using 14-MHz ultrasonography. The interface between the dermis and the subcutaneous fat, or hypodermis (H), is easily seen by this technique. Measurements of dermal depth (Dph) were obtained by 2 blinded observers. Lesions were compared with controls to determine dermal echogenicity. The echogenicity or brightness of a structure depends on the acoustic impedances at a tissue interface. Structures with greater acoustic impedances will be displayed as brighter and hyperechogenic. To increase the accuracy of the measurements, a thick layer of hypoechogenic ultrasonography gel (G) was applied to the skin to clearly depict the surface. The gel is invisible by ultrasonography (dark zone superficial to the surface). A and B, Morphea lesion in the atrophic phase in which the dermis demonstrates decreased echogenicity (A) compared with its control (B). C and D, By contrast a morphea lesion in the sclerotic phase shows substantial hyperechogenicity (C) compared with its control (D).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Morphea lesions were biopsied in the same location that ultrasonographic examination was performed. The specimens were graded by a single dermatopathologist who was blinded to the clinical and ultrasonographic data. Representative specimens of lesions from each of the 3 clinical stages of a morphea lesion are shown. A, Clinically atrophic lesions were found to be hypoechoic compared with their controls (Figure 1A and B) (P  =  .03). B, Clinically sclerotic lesions of morphea were found to be hyperechoic compared with their controls (Figure 1C and D) (P  =  .01). C, Clinically inflammatory lesions were found to have an echogenicity similar to controls (isoechogenic) (P  =  .04).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Ultrasonography is capable of differentiating between disease activity (inflammation and sclerosis) and damage (atrophy). A, In our study, early inflammatory lesions of morphea appeared isoechogenic (P  =  .04); sclerosis appeared hyperechogenic (P  =  .01), while atrophic lesions appeared hypoechogenic (P  =  .03). B, Hyperechogenicity seen on ultrasonogram correlates with the presence of histologic sclerosis. Sixteen lesions were examined by ultrasonography and histologic analysis. Hyperechogenicity was associated with moderate or severe grades of histologic sclerosis (P  =  .04).

Tables

Table Graphic Jump LocationTable. Patient Demographic and Clinical Characteristics

References

Laxer RM, Zulian F. Localized scleroderma.  Curr Opin Rheumatol. 2006;18(6):606-613
PubMed   |  Link to Article
Seibold JR, Furst DE, Clements PJ. Why everything (or nothing) seems to work in the treatment of scleroderma.  J Rheumatol. 1992;19(5):673-676
PubMed
Kreuter A, Gambichler T, Breuckmann F,  et al.  Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma.  Arch Dermatol. 2005;141(7):847-852
PubMed   |  Link to Article
Serup J. Localized scleroderma (morphoea): thickness of sclerotic plaques as measured by 15 MHz pulsed ultrasound.  Acta Derm Venereol. 1984;64(3):214-219
PubMed
Cosnes A, Anglade M-C, Revuz J, Radier C. Thirteen-megahertz ultrasound probe: its role in diagnosing localized scleroderma.  Br J Dermatol. 2003;148(4):724-729
PubMed   |  Link to Article
Li SC, Liebling MS, Haines KA. Ultrasonography is a sensitive tool for monitoring localized scleroderma.  Rheumatology (Oxford). 2007;46(8):1316-1319
PubMed   |  Link to Article
Verrecchia F, Laboureau J, Verola O,  et al.  Skin involvement in scleroderma —where histological and clinical scores meet.  Rheumatology (Oxford). 2007;46(5):833-841
PubMed   |  Link to Article
Arkachaisri T, Vilaiyuk S, Torok KS, Medsger TA Jr. Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study.  Rheumatology (Oxford). 2010;49(2):373-381
PubMed   |  Link to Article
Clements P, Lachenbruch P, Siebold J,  et al.  Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis.  J Rheumatol. 1995;22(7):1281-1285
PubMed
Pope JE, Baron M, Bellamy N,  et al.  Variability of skin scores and clinical measurements in scleroderma.  J Rheumatol. 1995;22(7):1271-1276
PubMed

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