Morphea, localized scleroderma (LS), is an inflammatory connective tissue disease that may lead to skin thickening and hardening due to fibrosis. The course of LS includes an early inflammatory stage. It starts with hyperaemia of the skin and is followed by fibrosis, sclerosis, and, finally, atrophy [
Morphea affects the underlying structures [
Although numerous therapeutic modalities including methotrexate (MTX) in combination with systemic corticosteroid have been discussed for these debilitating forms of morphea, optimal treatment is unknown maybe due to a lack of consensus as to the methods of evaluation and monitoring of treatment response [
Although several clinical and paraclinical diagnostic and assessment tools including the modified LS skin severity index (mLoSSI), the localized scleroderma cutaneous assessment tool (LoSCAT), ultrasonography (US), elastography, and skin biopsy have been documented, all of them have some limitations; for example, only a limited subset of the clinical parameters is evaluated by each mLoSSI and LoSCAT, or elastography is so hard to perform, US is usually not so helpful on the scalp/face due to a thin tissue, and finally no one really wants to biopsy the face. Magnetic Resonance Imaging (MRI) has recently been shown to be a useful diagnostic tool for identifying the musculoskeletal involvement in patients with morphea [
The aim of this study was to document the MRI changes in patients with morphea who were treated with MTX and high-dose corticosteroid.
The study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences. Informed consent was sought from the patients in accordance with legal requirements.
This study was conducted on 33 patients from the outpatient’s dermatology clinic, who fulfilled the inclusion criteria. The inclusion criteria were immunocompetent patients 10 years old or older with confirmed morphea (generalized or linear forms), normal bone mineral density, and being negative for latent infections, endocrinopathies, and cardiovascular, renal, and pulmonary disorders. The patients were excluded if they had systemic sclerosis, major concomitant medical conditions, leukopenia <3.0 × 109/l, thrombocytopenia <100 × 109/l, liver transaminase levels more than twice the upper limit of normal, or renal impairment defined as creatinine clearance <90 ml/min/1.73 m2, osteopenia, and osteoporosis, or if the patient was unwilling or unable to adhere to the protocol.
Morphea diagnosis was confirmed by histological examination. Owing to the activation of latent infections during immunosuppressive treatment regimens, the patients were also examined for tuberculosis, viral hepatitis, and HIV infections.
Treatment protocol and duration encompassed six months and, in this period, the patients received MTX, methylprednisolone, and folic acid. MTX was started with a weekly oral dosage of 15 mg, and 1 mg of daily folic acid was prescribed to diminish its toxicity. At the beginning of each month, patients were hospitalized for three days to administer 20–30 mg/kg (500–1000 mg/m2) per pulse, up to a maximum dose of 1 g intravenous methylprednisolone (or 2 mg/kg/day of prednisolone with a maximum dose of 60 mg and 1 mg/kg/week of MTX with a maximum dose of 15 mg/week in pediatrics). On the other hand, all patients were followed up to 18 months and methotrexate (15 mg/wk) was continued in this period.
The localized scleroderma assessment tool (LoSCAT) assesses 18 cutaneous anatomic sites, capturing both disease activity and damage parameters. Scores for each site are based on the most severe score for each parameter. To minimize intersubject variability, all skin changes are compared with the contralateral or ipsilateral skin area.
The modified LS skin severity index (mLoSSI) includes the total of three separate activity scores as follows: (A) erythema (ER), (B) skin thickness (ST), and (C) new lesion/lesion extension (N/E). Three cutaneous damage domains are summated to obtain the localized scleroderma damage index (LoSDI) as follows: (A) dermal atrophy (DAT), (B) subcutaneous atrophy (SAT), and (C) dyspigmentation (DP) [
Patients were visited monthly with complete laboratory data to check for probable adverse side-effects. Efficacy of the treatment was assessed clinically by mLoSSI and LoSDI before starting the medication. MRI was also performed before and after 6 months of the treatment by 1.5T closed-bore MRI body scanner which elucidates the depth and thickness of the soft-tissue structures and the degree of inflammation and edema. MRI scans were performed for all patients using high-performance gradients (maximum amplitude, 45 mT/m; minimum rise time, 200
The variables were checked for having normal distribution by using Shapiro-Wilk test. According to nonparametric clinical variables (LoSDI, mLoSSI, and MRI), the Wilcoxon signed-rank test was used instead of paired-samples
In present study, the female to male ratio was 5.6:1 (28 women and five men). The median age was 29.00 with
As mentioned previously, the efficacy of the treatment was evaluated by mLoSSI, LoSDI, and MRI, which is shown in Table
Efficacy of the treatment regimen.
| | | | | |
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| Erythema | <0.001 | 2.00 (2.00-2.00) | 1.00 (1.00-1.50) | <0.001 |
Skin thickness | <0.001 | 1.00 (1.00-2.00) | 1.00 (1.00-1.50) | 0.002 | |
New lesion/lesion extension | <0.001 | 1.00 (1.00-1.50) | 0.00 (0.00-0.00) | <0.001 | |
| |||||
| Dermal atrophy | <0.001 | 2.00 (2.00-2.00) | 1.00 (1.00-1.00) | <0.001 |
Subcutaneous atrophy | <0.001 | 1.00 (0.00-2.00) | 1.00 (0.00-2.00) | 0.014 | |
Dyspigmentation | <0.001 | 2.00 (2.00-3.00) | 1.00 (1.00-2.00) | <0.001 | |
| |||||
| 0.004 | 4.00 (3.00-6.00) | 2.00 (1.00-3.00) | <0.001 |
LoSDI: localized scleroderma damage index; mLoSSI: modified localized skin severity index;
According to mLoSSI, erythema, skin thickness, and new lesion/lesion extension were significantly improved after the treatment. Furthermore, all parameters of LoSDI including dermal atrophy, subcutaneous atrophy, and dyspigmentation were also noticeably improved after treatment. The treatment regimen was evaluated to be an effective method according to MRI by a P-value <0.001 (Figure
The association between MRI and mLoSSI and LoSDI.
| | | | |
---|---|---|---|---|
| 0.479 | 0.008 | 0.467 | 0.008 |
| ||||
| 0.345 | 0.053 | 0.466 | 0.008 |
| ||||
| 0.451 | 0.009 | 0.322 | 0.068 |
| ||||
| 0.528 | 0.004 | 0.558 | 0.002 |
| ||||
| 0.642 | <0.001 | 0.585 | <0.001 |
| ||||
| 0.536 | 0.002 | 0.596 | <0.001 |
A patient with linear morphea before (a) and after (b) treatment. MRI results before (c) and after (d) treatment.
Among the 33 patients who received treatment, all of them experienced some adverse side-effects. According to the precise inclusion criteria, which excluded patients with latent infection, none of them experienced any severe adverse effect of immunosuppression.
Weight gain and acne vulgaris were the most prevalent side-effects, detected in 26 and 23 patients, respectively. These were primarily due to high dosages of glucocorticoid. Constitutional side-effects such as fatigue (n=13), nausea (n=11), and headache (n=5) were also reported in less than half of the patients, which could probably be due to MTX. Striae rubrae and alopecia were two cosmetically important adverse effects, respectively, observed in seven and six patients. Secondary Cushing syndrome was observed in approximately 10% of the patients (three individuals) as the most important adverse effect in this study. Finally, hypokalemia (n=8), leukopenia (n=2), and anorexia (n=1) were other reported side-effects.
It is worth noting that this study demonstrated the effectiveness and sensitivity of MRI to treatment and its association with LoSCAT that would definitely be more novel and unique in the treatment of these patients.
Over the years, a variety of therapeutic options has been reported for morphea, topical and systemic corticosteroids, topical and systemic calcipotriol, topical tacrolimus, phototherapy, and MTX [
In the study conducted by Kreuter et al., fourteen LS patients were treated with 15 mg/week of MTX and monthly methylprednisolone pulse (1000 mg for three days) for six months. The effectiveness of the treatment was evaluated by ultrasound (US) and histological findings. Almost all of the patients had achieved clinical improvement, which was confirmed by paraclinical criteria [
Several clinical and laboratory methods have been reported to measure morphea disease activity. One of these criteria is LoSCAT. Arkachaisri et al. [
In 2010, a new standard was designed for the measurement of damage that was composed of DT, SAT, and DP. The reliability of this score with mLoSSL and PGA was acceptable. In our study, mLoSSI and LoSDI were significantly improved after treatment. Similar to earlier studies [
An important issue is the lack of a universal agreement on the optimal tools to be used for assessment of disease activity and damage severity or monitoring of the treatment response. Skin scores and recently more sensitive tools including laser Doppler flowmetry, Doppler US, and MRI have been used for evaluation and monitoring of the lesions [
Ultrasonography has been utilized for assessment of the superficial linear and circumscribed lesions because of its availability and excellent soft-tissue resolution, but evaluation of deep tissues may be impossible by US [
The data clearly show that MRI plays a key role and is able to document both dermal and musculoskeletal involvement at the initial presentation, as well as the changes occurring during these therapies. A valuable follow-up instrument should be able to differentiate between therapy responders, patients with stable disease, and those who are unresponsive to treatment. In our series, we found treatment success, which is in line with previous studies. Schanz et al. [
Schanz et al. [
This study is subject to a number of important limitations: the lack of correlative laboratory disease activity markers and clearly defined criteria to judge the MRI changes; lack of a control group can be mentioned as another limitation, but it should be noted that it is inconsistent with ethical principles for patients not treated for several months.
We demonstrate the ability of MRI to capture disease improvement in patients with linear morphea responding to a methotrexate and corticosteroid regimen as defined by a significant change in the mLoSSI and LoSDI scores. Larger and comparative studies are needed to elucidate the diagnostic and monitoring applications of MRI in different types of morphea.
Localized scleroderma
Methotrexate
Magnetic resonance imaging
Modified LS skin severity index
Localized scleroderma damage index.
There are no linked research data sets for this article. Data will be made available on request
This study was reviewed and approved by the ethics committee of Shahid Beheshti University of Medical Sciences, approval code number IR.SBMU.SRC.REC.1393.3.
The authors declare that they have no conflicts of interest.
The study was supported by the Skin Research Center of Shahid Beheshti University of Medical Sciences, and the authors wish to add that this article is the result of a dermatology specialty thesis of Dr. Razieh Jahangard in Shahid Beheshti University of Medical Sciences, Tehran, Iran.