Generalized early inflammatory morphea mimicking interstitial T-cell lymphoma: A diagnostic pitfall.

Early generalized morphea can clinically mimic mycosis fungoides. The microscopic features of early inflammatory morphea may show variable degrees of infiltration and do not have the characteristic dermal collagen sclerosis. We report the case of a 63-year-old female patient who presented with a 2-month history of an asymptomatic skin rash. Physical examination revealed multiple erythematous to dusky patches on the trunk and thighs, resembling the patch stage of mycosis fungoides. Two skin biopsies were performed, both of which showed prominent interstitial lymphoid infiltration in the reticular dermis without dermal sclerosis. Small lymphocyte exocytosis and lining along the dermal-epidermal junction were observed focally in the epidermis. Small clusters of plasma cells and eosinophils were observed in perivascular areas. Although no predominant clonality was found for CD4 and CD8 stains, 50% loss of CD5 antigen and 90% loss of CD7 antigen expression were apparent in immunohistochemical studies. Subsequent blood tests showed a normal blood cell count and positive human T-lymphotropic virus Type 1 antibodies. The overall findings suggested interstitial mycosis fungoides or early adult T-cell lymphoma-leukemia. The patient refused aggressive treatment, and 3 months later, she presented with indurated plaques from the previous rash. A repeat biopsy revealed the typical features of morphea. This report discussed the pitfalls in the clinical and histopathological diagnosis of early generalized inflammatory morphea that both clinicians and pathologists should consider.

The Free Sign in morphea and other sclerosing disorders: A clue to the presence of early sclerosis?

BACKGROUND: The Floating Sign is a histopathologic clue to the diagnosis of autoimmune sclerosing skin disorders such as morphea and interstitial granulomatous dermatitis (IGD). On the other hand, the "free-floating" sign has been associated with neoplasms, for example, dermatofibroma and interstitial mycosis fungoides. Herein, we report the Free Sign in sclerosing skin disorders. METHODS: In a case-control study, we applied detailed histopathologic definitions of Floating Sign and Free Sign to assess their presence in morphea, IGD, and other sclerosing disorders. RESULTS: Free Sign was present in most cases of morphea (46/55, 84%) and IGD (7/13, 54%) but not necrobiosis lipoidica (NL) (6/14, 42.8%) or sclerodermoid graft versus host disease (SGVHD) (2/7, 28.5%). The sensitivity and specificity of Free Sign for morphea versus other disorders was 84% and 56%, respectively. Floating Sign was not identified in most cases: NL (3/14, 21.4%), SGVHD (1/7, 14.2%), morphea (5/55, 9%), IGD (1/13, 7.7%). The diagnostic sensitivity of Floating Sign in morphea was 9%. CONCLUSIONS: The Free Sign was present in most cases of morphea in our series and may represent a clue to the presence of evolving sclerosis. Free Sign may be seen in other sclerosing disorders. Technical artifact is a potential cause of a false-positive Free Sign.

High-frequency ultrasound evaluation of morphea: Retrospective analytical study.

BACKGROUND: To date, there are no accepted outcome measures to monitor morphea, and consensus on specific monitoring criteria for morphea remains elusive. A few studies have assessed the criterion validity of skin ultrasound in morphea. So, in this study, we approach ultrasound findings in morphea lesions. MATERIAL AND METHODS: This was a retrospective-analytical study conducted between December 2021 and May 2023. Patients were clinically evaluated at a dermatology outpatient clinic and then referred for high-frequency ultrasound (HF-US) evaluation and were selected to be included in this study. The lesions were confirmed by histopathology as well. Sonographic evaluations were performed on the lesion site and the symmetrical uninvolved other side. Dermal thickness and dermal echogenicities were recorded. Statistical analysis of group differences was performed by using the 2-tailed Student t-test. A p-value of less than 0.05 was considered statistically significant. RESULTS: Forty-one morphea lesions in the inflammatory phase of 27 patients were included in the study. The mean dermal thickness of morphea lesions was 1107.97 ± 414.3 and the mean dermal thickness of the control side was 1094.65 ± 331.06, The difference between these two variables was not statistically significant. The mean dermal density of lesions was 49.13 ± 18.97 and the mean dermal density of the control side was 52.22 ± 25.33. The difference between these two variables was not statistically significant. CONCLUSION: This study shows that HF-US indicated increasing dermal thickness and reducing the dermal density of the morphea lesions in the inflammatory phase confirmed with the histopathology.

Anti-synthetase and myelodysplastic syndromes with deep morphea: an example of shared immunopathogenesis? A case-based review.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient.

Novel multispectral imaging to predict disease progression in pediatric morphea.

BACKGROUND: Morphea, or localized scleroderma, is an inflammatory, fibrosing skin disorder that can be progressive and debilitating. Infrared thermography frequently has false positive results. The aim of this study was to assess the ability of multispectral imaging to predict disease progression in children with morphea. METHODS: Children with morphea were recruited between 2016 and 2022. Multispectral images of affected and matched contralateral unaffected sites were obtained using the Antera™ 3D camera. Clinical assessment was performed using the Localized Scleroderma Assessment Tool (LoSCAT). Children were followed up every 3 months for imaging and clinical review. The main outcome measurement was correlation of hemoglobin gradient between affected and matched contralateral unaffected tissue and progression. RESULTS: Of 17 children, the average age was 12 years (range 6-18 years); most were female (76.5%) and white (94.1%). Nearly two-thirds (64.7%) had linear morphea, 35.2% had plaque morphea; 58.8% had been treated with systemic agents. The average LoSCAT score was 20.6 (range 5-73). The average hemoglobin gradient between affected and matched contralateral unaffected skin was four times higher in those who had progression (average differential 0.3, range 0.1-0.4) compared to those who did not (average differential 0.08, range 0.02-0.15). Using a cut off of a 0.18 hemoglobin gradient between affected and unaffected skin, the sensitivity of multispectral imaging for detecting progression in pediatric morphea is 90% with specificity of 100%. CONCLUSIONS: Multispectral imaging is a novel assessment tool with promising accuracy in predicting progression as an adjunct to clinical assessment in pediatric morphea. Further research should examine its performance against thermography.

Morphea as an isotopic response to pigmented purpuric dermatosis and lichen striatus.

Morphea is an uncommon inflammatory and fibrosing disorder that has a polymorphous clinical presentation. We report two cases of morphea developing as an isotopic response after a preceding benign skin disease, accompanied by a review of the literature. This case series highlights the importance of return to care recommendations for benign skin conditions such lichen striatus and pigmented purpuric dermatoses due to the rare possibility of subsequent morphea development.

Spatial Transcriptomics Identifies Cellular and Molecular Characteristics of Scleroderma Skin Lesions: Pilot Study in Juvenile Scleroderma.

Juvenile localized and systemic scleroderma are rare autoimmune diseases which cause significant disability and morbidity in children. The mechanisms driving juvenile scleroderma remain unclear, necessitating further cellular and molecular level studies. The Visium CytAssist spatial transcriptomics (ST) platform, which preserves the spatial location of cells and simultaneously sequences the whole transcriptome, was employed to profile the histopathological slides from skin lesions of juvenile scleroderma patients. (1) Spatial domains were identified from ST data and exhibited strong concordance with the pathologist's annotations of anatomical structures. (2) The integration of paired ST data and single-cell RNA sequencing (scRNA-seq) from the same patients validated the comparable accuracy of the two platforms and facilitated the estimation of cell type composition in ST data. (3) The pathologist-annotated immune infiltrates, such as perivascular immune infiltrates, were clearly delineated by the ST analysis, underscoring the biological relevance of the findings. This is the first study utilizing spatial transcriptomics to investigate skin lesions in juvenile scleroderma patients. The validity of the ST data was corroborated by gene expression analyses and the pathologist's assessments. Integration with scRNA-seq data facilitated the cell type-level analysis and validation. Analyses of immune infiltrates through combined ST data and pathological review enhances our understanding of the pathogenesis of juvenile scleroderma.

Interferon-Gamma-Inducible Protein-10 (IP-10) and Tumor Necrosis Factor-α (TNF-α) as Serological Predictors of Active Disease Status in Localized Scleroderma.

We investigated the ability of a panel of immune-related cytokines and chemokines to predict the disease activity state in localized scleroderma (LS) subjects followed longitudinally. A total of 194 sera samples were obtained from 45 LS subjects with diverse types of LS (40% linear, 20% mixed, 16% craniofacial, 13% generalized, and 11% circumscribed) in our cohort. Cytokines/chemokines that were significantly elevated at the baseline active disease visit compared to the inactive disease state at follow-up were Interferon-Gamma-Inducible Protein (IP)-10 (p < 0.021) and Tumor Necrosis Factor (TNF)-α (p < 0.033). Mixed effect logit modeling identified IP-10 (Odds Ratio (OR) [95% confidence interval] = 2.1 [1.4, 3.2], p < 0.001), TNF-α (OR = 1.8 [1.1, 3.0], p = 0.016), and Monocyte Chemoattractant Protein (MCP)-1 (OR = 2.0 [1.1, 3.9], p = 0.034) as significant predictors of active disease status. These findings support earlier correlations between IP-10 and TNF-α with disease activity parameters in a cross-sectional Luminex™ serological study and may enhance clinical decision-making when disease activity is challenging to assess by clinical examination alone.

S2k guideline: Diagnosis and therapy of localized scleroderma.

The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoS can be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.

Measuring asymmetry in facial morphea via 3-dimensional stereophotogrammetry.

BACKGROUND: Objectively determining tissue loss in craniofacial morphea is challenging. However, 3-dimensional (3D) stereophotogrammetry is a noninvasive modality that may be a useful adjunct. OBJECTIVE: To prospectively evaluate 3D stereophotogrammetry in the assessment of craniofacial linear morphea. METHODS: Participants underwent clinical, quality-of-life, and 3D-stereophotogrammetry assessments. Traditional photographs and 3D-stereophotogrammetry images were rated as mild, moderate, or severe by 2 experts and 2 nonexperts. In addition, interrater and intrarater reliability (on delayed rescoring) were calculated. RESULTS: Of 23 patients with craniofacial morphea, 3D stereophotogrammetry detected pathologic asymmetry in 14 (20.6%) patients. Providers rated patients as more severely affected when using 3D stereophotogrammetry versus when using traditional photographs (19% severe on 3D stereophotogrammetry vs 0% severe on traditional photographs, P = .004). Qualitative ratings of both traditional and 3D images showed high inter- and intrarater reliability between experts and nonexperts alike. Physicians' Global Assessment of Damage scores correlated with mouth asymmetry (P = .0021), cheek asymmetry (P = .04), and 3D-stereophotogrammetry ratings (median, mild: 27.5 vs moderate: 46.5 vs severe: 64, P = .0152). Lower face asymmetry correlated with worse quality-of-life scores (P = .013). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSION: 3D stereophotogrammetry can reliably detect and quantify asymmetry in craniofacial morphea with greater sensitivity than that observed with traditional assessment alone. 3D stereophotogrammetry may be a useful adjunct to clinical examination.

Efficacy of ultraviolet A1 phototherapy for inflammatory, sclerotic and neoplastic dermatological diseases: A 10-year tertiary referral center experience.

BACKGROUND: Ultraviolet (UV) A1 phototherapy is considered a beneficial treatment for various inflammatory, sclerotic, malignant, and other skin conditions. However, the available data regarding its efficacy for different indications, the potential side effects, and the recommended treatment protocols are sparse. OBJECTIVES: To assess the efficacy of UVA1 phototherapy and identify correlation between different indications and treatment protocols to response rates. METHODS: We performed a retrospective study of a cohort of 335 patients treated with UVA1 phototherapy at the Department of Dermatology at Hadassah Medical Center, Jerusalem, Israel, between 2008 and 2018. RESULTS: The study population included 163 patients with inflammatory diseases (mainly atopic dermatitis and other types of eczema), 67 patients with sclerotic diseases (morphea and graft versus host disease), nine patients with neoplastic diseases (cutaneous T cell lymphoma), and 188 patients with other cutaneous disorders. Response rates ranged between 85% and 89% across indications, without differences in response rates among the indication groups (p = .941). In a multivariant logistic regression model, increased number of treatments and higher maximal dosages were associated with response to treatment (p < .001). Using ROC analysis, a cut-off of 8 UVA1 phototherapy treatments was chosen as predictive for beneficial response (86.4% sensitivity, 78% specificity). A cut-off of 40 J/cm2 was chosen as an optimal maximal dosage for differentiating between responders and non-responders (51.1% sensitivity, 83.1% specificity). CONCLUSIONS: UVA1 phototherapy is an effective treatment for a variety of skin conditions. In most patients, at least eight treatments of a medium-high dosage are required for clinical response.

Study about evaluation of efficacy of methotrexate in localized scleroderma using ultrasonography.

BACKGROUND: The treatment and curative effect evaluation of localized scleroderma (LS) still perplexes many clinical workers. PURPOSE: To investigate the efficiacy of methotrexate in the treatment of LS by the evaluation of ultrasonography. METHODS: A prospective study enrolled 10 patients treated with MTX for at least 6 months was conducted. Treatment outcome was evaluated by a clinical score and 15-MHz ultrasonography. Safety assessment included the monitoring of adverse drug reactions and clinical laboratory examinations. RESULTS: Eight of the 10 patients achieved clinical remission only with MTX. One patient was relieved after MTX combined with corticosteroids, while another one does not improve after the treatment of mycophenolate mofetil and corticosteroids. The effective rate of MTX is 80%. Nine patients were significantly improved with a decrease of the Localized Scleroderma Cutaneous Assessment Tool (the mean score of the LoSCAT cutaneous activity dropped from 5.2 to 1.0, p < 0.001, the mean score of the LS cutaneous damage dropped from 4.3 to 2.3, p = 0.002). The average difference of thickness between skin lesions and normal skin evaluated by ultrasonography decreased from 0.13 cm to 0.04 cm (p = 0.009) in eight patients. No serious adverse reactions occurred. CONCLUSION: Methotrexate is a safe and effective treatment for patients with LS. Ultrasonography can be considered as an efficient assessment tool for evaluation LS.

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

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.

Ultrasound Morphea Activity Scoring (US-MAS): Modified US-MAS.

Morphea, an autoimmune connective tissue disease that affects the skin, can be supported by color Doppler ultrasound in its diagnosis and assessment of activity. To date, there are no reliable laboratory parameters to track activity, and ultrasound presents a higher axial spatial resolution than magnetic resonance imaging and computed tomography, which is critical for studying the superficial layers. The quality of the ultrasonographic assessment of activity in morphea depends on the standardization and features of the acquisition of the anatomical data. We propose a detailed ultrasound morphea activity scoring called modified US-MAS (mUS-MAS) that could allow us to systematically register the cutaneous abnormalities in the corporal regions and their subregions. The selection of the scanning sites will depend on the corporal regions of involvement and their adjacent segments. Through systematic and sequential ultrasound data analysis, we propose that this scoring system can better support description and activity tracking accuracy.

Top Advances in Dermatologic Ultrasound.

The advances in dermatologic ultrasound have been significantly influenced by the development of high- and ultrahigh-frequency probes, the provision of guidelines for performing the examinations, and a growing number of publications in the field. This review analyzes the most significant contributions that have impacted the daily practice of dermatologists in recent years. This includes the advances in anatomical detection and the patterns of benign and malignant cutaneous tumors, inflammatory dermatologic conditions, vascular anomalies, nail abnormalities, and aesthetic procedures. The knowledge of these advances is a primer for the operators of these examinations.

Presenting characteristics and progression of pediatric-onset morphea: Interim analysis of a prospective registry.

Morphea is a rare fibrosing disorder with a highly variable disease course, which can complicate management. Here, we present a prospective cohort study describing the current treatments used in the management of pediatric-onset morphea and assessing responses to systemic and topical therapies. Most patients demonstrated inactive disease by 1 year, regardless of treatment, though recurrences were common in our cohort overall (39%). Our results support the need for continuous monitoring of all children with morphea following the completion of treatment, including topical treatment, due to high rates of disease relapse.

Bilateral en coup de sabre morphea in a male child: A rare presentation.

En coup de sabre is a rare subtype of morphea. Only a few bilateral cases have been reported to date. We report a case of a 12-year-old male child with two linear brownish depressed asymptomatic lesions over the forehead with hair loss on the scalp. After thorough clinical, ultrasonography and brain imaging, a diagnosis of bilateral en coup de sabre morphea was made and the patient was treated with oral steroids and weekly methotrexate.

Linear morphea with overlying lichen sclerosus and calcinosis cutis associated with juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is associated with many distinguishing features including cutaneous calcinosis, vasculitis, and ulcerated lesions. In this case, we describe an unusual presentation in a 12-year-old girl who had muscle weakness along with linear morphea over the right upper and lower extremities with overlying lichen sclerosus and calcinosis cutis. Of interest, these initial cutaneous manifestations occurred years before onset of myositis.

Color Doppler Ultrasound Assessment of Subclinical Activity With Scoring of Morphea.

BACKGROUND: Detection of activity in morphea is paramount for adequately managing the disease. Subclinical ultrasound involvement on inactive lesions or healthy skin areas adjacent to morphea has not been described to date. OBJECTIVES: The study aimed to detect morphea's subclinical activity by Color Doppler ultrasound not identified with the clinical scorings. MATERIALS & METHODS: This cross-sectional retrospective study was done from January 2014 to July 2019 in patients with a clinicopathological diagnosis of morphea. The modified Localized Scleroderma Skin Severity Index (mLoSSI) and The Ultrasound Morphea Activity Score (US-MAS) were used to correlate clinical and subclinical activity. RESULTS: A total of 36 patients met the inclusion criteria. 54% of cases presented subclinical activity in areas adjacent to the clinically active lesion, 23% in nonadjacent regions, and 23% demonstrated activity at a clinically inactive lesion site.100% of patients with morphea "en coup de sabre" involving the frontal region of the face concomitantly presented both subclinical activities of morphea on the frontal facial region and the scalp following the same axis.A positive relationship was observed between the degree of clinical activity measured by mLoSSI and US-MAS scoring.The main limitations of our study were the low number of patients and the inability to detect alterations < 0.1 mm. CONCLUSIONS: Subclinical activity is frequent in morphea, can extend beyond the lesional areas, including apparently noninvolved adjacent and distant corporal regions, and can be detected by color Doppler ultrasound.

Single-Cell Transcriptome Analysis Identifies Subclusters with Inflammatory Fibroblast Responses in Localized Scleroderma.

Localized scleroderma (LS) is an autoimmune disease with both inflammatory and fibrotic components causing an abnormal deposition of collagen in the skin and underlying tissue, often leading to disfigurement and disability. Much of its pathophysiology is extrapolated from systemic sclerosis (SSc) since the histopathology findings in the skin are nearly identical. However, LS is critically understudied. Single-cell RNA sequencing (scRNA seq) technology provides a novel way to obtain detailed information at the individual cellular level, overcoming this barrier. Here, we analyzed the affected skin of 14 patients with LS (pediatric and adult) and 14 healthy controls. Fibroblast populations were the focus, since they are the main drivers of fibrosis in SSc. We identified 12 fibroblast subclusters in LS, which overall had an inflammatory gene expression (IFN and HLA-associated genes). A myofibroblast-like cluster (SFRP4/PRSS23) was more prevalent in LS subjects and shared many upregulated genes expressed in SSc-associated myofibroblasts, though it also had strong expression of CXCL9/10/11, known CXCR3 ligands. A CXCL2/IRF1 cluster identified was unique to LS, with a robust inflammatory gene signature, including IL-6, and according to cell communication analysis are influenced by macrophages. In summary, potential disease-propagating fibroblasts and associated gene signatures were identified in LS skin via scRNA seq.