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Non-invasive measurement of sclerosis in cutaneous cGVHD patients with the handheld device Myoton: a cross-sectional study

A Correction to this article was published on 17 January 2020

This article has been updated

Chronic graft-versus-host disease (cGVHD) is the leading cause of long-term mortality and morbidity after stem cell transplantation (SCT). Skin is the most commonly affected organ [1]. Skin manifestations of cGVHD are broadly divided into two categories: erythema and sclerosis. Among patients being treated for cGVHD, 20% develop sclerosis within 3 years of transplant, leading to significant disability [2]. The current standard for monitoring cGVHD sclerosis is the NIH Skin Score [3]. However, this scoring system is subjective, coarse, and unreliable [4]. Sclerosis measurement by exam is difficult due to ill-defined borders and paucity of reliable visible changes. Sclerosis scores among multiple observers rarely exhibit substantial agreement, with a minimal reliable change detection of 17–26% BSA [5]. This has impeded assessment of disease progression and treatment response [4]. Developing a quantitative and reproducible measurement of sclerosis was deemed a top priority in the 2014 NIH Consensus on Response Criteria for cGVHD [6]. Serial skin biopsy is not practical to assess treatment response and histology is generally non-specific [7]. This motivated interest in imaging tools for sclerotic cGVHD. A magnetic resonance imaging study of 15 cGVHD patients was able to identify abnormalities in the dermis, subcutaneous tissue, and muscle [8]. Ultrasound has shown differences in normalized shear wave speed in a study of four healthy controls versus five cGVHD patients [9]. Neither technology has yet advanced to large studies or widespread clinical use.

In this study, we investigated the feasibility of using an affordable tool to rapidly and directly measure cutaneous sclerosis in cGVHD patients. We employed the Myoton, a commercially available, non-invasive handheld device developed to measure muscle biomechanical properties. It has been applied in diverse fields [10], but has not yet been used in dermal disorders. It delivers a brief mechanical impulse to which tissue responds with a damped natural oscillation. Biomechanical properties are automatically extracted from the oscillatory response curve [11].

The durometer is another handheld device that appears similar to the Myoton at first inspection. However, the underlying principle and function are very different between the two devices. The durometer is designed for determining surface hardness by measuring the amount of force required to produce an indentation. Therefore, the durometer reading is highly dependent on the force applied by the individual conducting the measurement. By contrast, the Myoton applies a fixed mechanical impulse, and calculates biomechanical properties based on the tissue’s inherent response. The durometer has been used to measure skin hardness in patients with scleroderma, but no results have been published in cGVHD [12].

For our study, the Myoton was modified for enhanced selection of cutaneous tissue. First, a 12 mm diameter disk was attached, distributing the surface impulse over a 16-fold larger surface area than the standard 3 mm testing end (probe), which decreases surface power density to select for more superficial skin tissue and reduces the amount of residual strain imparted during the measurement. Second, impulse delivery time (tap time) was decreased from 15 ms to 7 ms, which proportionally decreases the total transferred mechanical energy and translates into a smaller effective mass of natural tissue oscillation (i.e., selection of more superficial tissue).

In this cross-sectional study, cGVHD patients (n = 10) with an NIH 2014 Skin Features Score of 3 (severe sclerosis) and healthy subjects (n = 14) were recruited. For each subject, the Myoton was used to measure skin stiffness bilaterally in 9 anatomic regions (shin, dorsal forearm, upper arm, shoulder, chest, abdomen, calf, upper back, and lower back), resulting in 18 total measurement sites. For patient comfort, only nine patients were measured on the chest and eight were measured on lower and upper back (Fig. 1a). Generally, cGVHD patients did not have skin involvement in all sites. Only four patients demonstrated chest sclerosis, while nine had shin involvement. Subjects were instructed to relax in a supine position during measurements. They felt a slight, painless pressure for 7 ms at a time during the mechanical impulse, with the probe resting perpendicular to the skin surface. Twenty measurements with 2 s intervals per site were conducted to minimize measurement variation. A single measurer, JC, operated the Myoton after 8 h of training by AV, the inventor of the device. Each measurement session lasted ~20 min. Two different, but essentially identical devices were employed in measuring total 24 patients. Stiffness measurements of cGVHD patients (n = 10) were compared to age-matched healthy controls (n = 14) by anatomic region (Fig. 1a). By a Wilcoxon rank-sum test (α = 0.05), in 7 of the 9 measured regions (14 of 18 measurement sites), cGVHD patients demonstrated significantly higher skin stiffness compared to healthy subjects (p < 0.05). The only sites without statistically significant differences were the abdomen and the lower back, likely because the participating patients were not affected at the periumbilical or lumbar measurement locations. When the average stiffness over all 9 anatomic regions (overall stiffness) was compared between patients and controls, cGVHD patients had significantly higher overall skin stiffness (645 ± 126 N/m vs. 411 ± 80 N/m, p = 0.001). Notably, three patients with severe sclerotic cGVHD were not measured at all anatomic sites due to wounds, and thus were excluded from the overall stiffness calculation. Therefore, this comparison underestimates the measurable effect size (difference between controls and cGVHD patients). The variation of skin stiffness measurements is generally higher in cGVHD patients compared to controls, as evidenced by the large interquartile range (Fig. 1a), which reflects the heterogeneous presentation of the disease. The supplemental table specifically highlights the sites which were or were not affected in each subject.

Fig. 1
figure1

a Box-and-whisker plot of skin stiffness of cGVHD patients and healthy controls, measured with the Myoton device in 9 anatomic regions. (Overall stiffness p = 0.001). ^Only 9 cGVHD patients were measured on chest and 8 on upper and lower back. b Box-and-whisker plot of skin stiffness in healthy controls, stratified by BMI. (Overall stiffness p = 0.662). c Box-and-whisker plot of healthy control skin stiffness measured with Myoton stratified by age. (Overall stiffness p = 0.004). *statistically significant differences

An additional analysis divided healthy subjects into normal (<25 kg/m2) or high (≥25 kg/m2) body mass index (BMI) groups. Controls with BMI ≥25 demonstrated higher stiffness measurements of the calf and lower back (Fig. 1b), likely because underlying muscle tissue still has some contribution to the Myoton signal despite the device modifications. However, overall skin stiffness, calculated by averaging the skin stiffness over all 9 anatomic sites, exhibited no statistically significant difference between controls with higher and lower BMI (p = 0.662). Further analysis compared subjects ≥50 years old to subjects <50. Older subjects showed higher skin stiffness on the shoulder, chest, abdomen, calf, and lower back (Fig. 1c), with significantly higher overall stiffness (468 ± 77 N/m vs. 355 ± 36 N/m, p = 0.004), but not as marked elevations as in cGVHD patients (645 ± 126 N/m).

Our results demonstrate that the Myoton can objectively distinguish between healthy subjects and cGVHD patients with severe sclerosis. Limitations of this preliminary study include small sample size and limitation to NIH Score three patients, which makes it difficult to assess generalizability of results. While our results indicate that skin stiffness measurements are significantly greater in patients with severe sclerotic cGVHD than healthy controls, further investigation is required to determine whether this translates to patients with mild-moderate disease. Further device development is also needed to assess the degree to which the Myoton is isolating skin and subcutaneous tissue. In this study, one observer performed all measurements, so the results do not speak to the interobserver reproducibility of the device.

We have taken the first step toward developing a new method to objectively measure sclerotic GVHD disease. Reproducibility, generalizability, and the relative contributions of different soft tissue layers to the Myoton signal remain to be determined. If prospective longitudinal studies can correlate stiffness value changes to clinical disease progression, the Myoton can become an important tool for monitoring patient course and treatment response in sclerotic cGVHD.

Change history

  • 17 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

Dr. E.R.T. is grateful for support from NIH K12 CA090625. J.S.G was supported by the Vanderbilt Medical Scholars Program. This study is also supported in part by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service and also by the Baltic-American Freedom Foundation.

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NIH K12 CA090625, Baltic-American Freedom Foundation, VA CSRD CDA IK2 CX001785

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Correspondence to Eric R. Tkaczyk.

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Chen, F., Dellalana, L.E., Gandelman, J.S. et al. Non-invasive measurement of sclerosis in cutaneous cGVHD patients with the handheld device Myoton: a cross-sectional study. Bone Marrow Transplant 54, 616–619 (2019). https://doi.org/10.1038/s41409-018-0346-7

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