Role of imaging in morphea assessment: A review of the literature

Abstract Background Localized scleroderma, known as morphea, is a connective tissue disorder characterized by inflammation and fibrosis of the skin and the soft tissue. There exist no universally accepted validated outcome measures in order to monitor the disease activity. Besides clinical scores to evaluate outcome measures, imaging modalities are increasingly utilized in assessing patients with morphea, such as high‐frequency ultrasonography (US), shear‐wave elastography (SWE), and magnetic resonance imaging (MRI). However, the accuracy of these imaging modalities in monitoring morphea activity is not yet clear. Aims To review the literature regarding the role of imaging modalities in assessing patients with morphea. Materials & Methods In this study, we searched the PubMed/Medline database for articles published from inception until February 2023. Results A total number of 23 original articles in three categories of US, elastography, and MRI were included. Discussion Regarding US, criteria, including increased dermal thickness, increased echogenicity of the subcutaneous tissue, and decreased dermal echogenicity, were indicators of active morphea lesions when using high frequencies probe (18–20 MHz) color Doppler sonography. Moreover, studies evaluating SWE, a novel method to quantitatively assess tissue stiffness, demonstrated increased dermal stiffness in active lesions. Conclusion Studies showed that MRI can help to determine the depth of disease, particularly as a first‐line and follow‐up diagnostic tool, especially in generalized and deep morphea. In addition, brain MRI may be useful for patients with localized craniofacial scleroderma experiencing new or worsening neurological symptoms.


INTRODUCTION
Localized scleroderma (LoS), also known as morphea, is a rare connective tissue disorder characterized by inflammation and fibrosis of the skin as well as the soft tissue that causes the imbalance of collagen production and destruction. [1][2][3][4] Although the exact pathogenesis of morphea remains unclear, it is believed that genetic predisposition, immune system dysregulation, trauma, and iatrogenic factors might be responsible for causing the disease. 1,2 Morphea, which is seen in all age ranges, is divided into four major subtypes: plaque type (circumscribed), linear, generalized, and mixed.
Notably, plaque type and linear morphea are the most common types and main focus of most studies. 2 The clinical presentation of morphea differs according to its subtype, degree of involvement, and stage In addition, computerized surface area measurement is insensitive to improvement. Moreover, durometer has poor correlation with clinical skin scores, and its sensitivity to change is unknown. Cutometer has not been validated in morphea, and thermography is incapable of distinguishing between active and inactive phases. 4 Some imaging modalities are utilized in assessing patients with morphea, such as high-frequency ultrasonography (US), shear-wave elastography (SWE), and magnetic resonance imaging (MRI). These imaging modalities are promising tools in the diagnosis and monitoring of morphea lesions. Furthermore, they seem to be more reliable and quantitative than other currently applied methods. However, there is no consensus on the definite monitoring criteria for morphea yet. 3,4 The aim of this study was to review the literature on the role of imaging modalities in assessing patients with morphea in terms of disease activity, discriminating between different phases, and response to the treatment.

METHODS AND MATERIALS
In this study, we searched the PubMed/Medline database for articles published from inception until February 2023 using the related keywords. Our search terms were "LoS," "morphea," "imaging," "US," "Elastography," and "MRI." Out of the 439 retrieved articles, 23 original studies were included in our study.

RESULTS
A total number of 23 original articles were enrolled in our study. In this study, we categorized our findings into three sections, and we reviewed the role of US, elastography, and MRI in morphea assessment. The characteristics of the included studies are described in Table 1.

Ultrasonography
Ultrasound imaging is a noninvasive and objective method for evaluating morphea. The combination of US and Doppler imaging allows for the evaluation of both superficial and deep soft tissue thicknesses, echogenicity as well as subcutaneous vascularity of skin lesions in LoS.
By using high-frequency ultrasound, quantitative assessments with higher resolutions can be performed. [5][6][7] The study done by Serup   sample sizes, lack of sufficient follow-up study by US and using A-mode (amplitude mode) scan in some studies which give one dimension plotted images in compared to 2D images in the B-mode (brightness mode) scan which have higher resolution and simple to interpreted (Table 1).
In our institution as a referral dermatologic center, we use both gray scale and color Doppler B-mode ultrasound performed with Aixplorer

Elastography
Elastography is a novel method to quantitatively assess tissue stiffness and is performed in two ways: strain elastography (SE) and did not analyze different stages of the disease and also did not explore the association between skin stiffness and pathologic findings. 21 All of the abovementioned studies are cross-sectional and did not follow skin stiffness by SWE ultrasound after treatment. We conducted a cohort study of morphea patients and experimentally use shear-wave elastography performed with Aixplorer (SuperSonic Imagine) using 20 MHz probe and calculate dermal and hypodermal elasticity by using copious amount of gel and minimal hand pressure and report tissue stiffness average of three measurements express in kPa for normal and abnormal dermis and hypodermis at baseline and then follow them in 3 and 6 months interval after treatment ( Figure 2). Data will be published soon.

Magnetic resonance imaging (MRI)
MRI has been shown to be a valuable diagnostic tool for detecting and monitoring musculoskeletal involvement in morphea patients given its excellent soft-tissue contrast and lack of ionizing radiation. The results of a previous study on MRI findings of 43 patients with LoS excluded the superficial subtype which is confined to the epidermis and dermis detected musculoskeletal involvement in 74% of patients.
MRI detected musculoskeletal involvements in 96% of the clinically suspected patients and in 38% of not clinically suspected patients.
They found "fascial thickening" as the most common musculoskeletal MRI finding (60%). Moreover, increased fascial enhancement, articular synovitis, tenosynovitis, and subcutaneous septal thickening were the most prevalent findings. Moreover, they found that all pansclerotic morphea patients had articular synovitis. 25 In a recent study, MRIs of the extremities in 14 children with juvenile localized scleroderma were evaluated. Deep tissue involvement was detected in 65% of them. Fascial thickening and fascial enhancement were the most common findings of deep tissue involvement.
Besides, infiltration and atrophy of the subcutaneous fat were the most prevalent subcutaneous finding. Moreover, muscle and bone marrow edema were seen in 40% and 20% of the images, respectively. In six patients, subsequent imaging after treatment was done in 2-5 years of follow-up, showed improvement but not necessarily resolution of the superficial and deep involvement. They concluded that axial T1, axial fluid-sensitive, and axial T1-FS contrast-enhanced sequences should be included in the imaging protocol, and the findings that were detected in contrast-enhanced sequences were also seen in fluid-sensitive sequences, meaning that intravenous contrast is not necessary for these examinations. 26 In this regard, in a study performed by Schanz  indicating that the pathology extends beyond clinical margins. 28 In Shahidi et al. study, 33 patients with morphea were given methotrexate and pulses of methylprednisolone. They mentioned that cutaneous fat enhancement was the most prevalent finding in MRI.
Then, the effectiveness of the treatment was examined by MRI. They concluded that the clinical markers of mLoSSI and LoSDI except for skin thickness and new lesion extension were in association with MRI scores before and after the therapy. However, they did not explain other MRI findings or MRI scoring in detail. 29 Liu et al. evaluated 23 patients with morphea mainly linear type and revealed positive findings in half of the patients. They reported leg length discrepancy, muscle atrophy, bone remodeling deformity, abnormal bone marrow signals, and joint contracture as the main peripheral findings. They also reported intracranial calcifications and white matter abnormalities. They also found central nervous system abnormalities in 3 patients with "en coup de sabre" deformity that were neurologically asymptomatic. 30 Furthermore, neuroimaging manifestations of localized craniofa-

CONCLUSION
One of the most challenging issues in treating morphea patients is the lack of globally accepted assessment tools for monitoring the results of treatment and disease activity. [33][34][35][36] In this regard, ultrasound is a potential and reliable imaging modality in the quantitative morphea assessment. However, ultrasound has limitations such as being operator dependent and lack of consistent intra or interoperator measurement of tissue thickness. It should be considered that there are discrepancies in available literature because of different cross-sectional study designs, using A-mode scan and various probe frequencies, and small sample sizes. To establish a quantitative, valid, and reproducible outcome measure, larger prospective cohort studies using higher probe frequencies should be conducted. In addition, shear-wave elastography can be used for disease monitoring and assessing therapeutic effects. SWE is a novel tool that is not universally available and it is not FDA approved for skin so far. To determine the role of SWE in detecting lesion progression and changes overtime, future studies are needed.
MRI provides complementary information about the depth of the disease especially in deep or generalized morphea (GM) as well as neurologic manifestations of localized craniofacial scleroderma. MRI has also limitations, including being expensive, time-consuming, infeasible in routine clinical settings, and a low signal-to-noise ratio for superficial layers intrinsically.
In conclusion, we recommend color Doppler ultrasound with high frequencies probe (18-20 MHz) and if available, SWE for assessing and monitoring superficial soft tissue involvement. In GM or DM, MRI helps to determine the depth of disease, particularly as a first-line and followup diagnostic tool. In addition, brain MRI may be useful for patients