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.

Questions raised by a case of adult-onset linear nodular scleroderma.

Morphea presenting clinically with nodular or keloidal skin changes is extremely rare. Nodular scleroderma or keloidal morphea presenting in a linear distribution is even more uncommon. We present an otherwise healthy young woman with unilateral, linear, nodular scleroderma and review the somewhat confounding earlier literature in this area. To date, this young woman's skin changes have proven refractory to oral hydroxychloroquine and ultraviolet A1 phototherapy. Several aspects of this case including the patient's family history of Raynaud disease, her nodular sclerodermatous skin lesions, and the presence of U1RNP autoantibodies raised concern about her management with respect to future risk of developing systemic sclerosis.

Phototherapy in sclerosing and pseudo-sclerosing skin diseases Fototerapia en enfermedades cutáneas esclerosantes y pseudoesclerosantes.

Sclerosing and pseudo-sclerosing skin diseases are a therapeutic challenge. Ultraviolet radiation, depending on its wavelength, penetrates into different layers of the skin and acts on cells that promote tissue remodeling and differentiation, such as keratinocytes and fibroblasts. Furthermore, it modulates the inflammatory processes in dendritic cells, endothelial cells, and leukocytes by intervening in the production of cytokines and profibrotic molecules. For these reasons ultraviolet light is a useful option in the treatment of these conditions. Las enfermedades esclerosantes y pseudoesclerosantes de la piel son un grupo de dermatosis que suponen un reto terapéutico para el clínico. La radiación ultravioleta, de acuerdo con su longitud de onda, penetra en las diferentes capas de la piel y actúa sobre aquellas células que favorecen la diferenciación y remodelación tisular como queratinocitos y fibroblastos. Además, modula los procesos inflamatorios en células dendríticas, endoteliales y leucocitos al intervenir en la producción de citoquinas y moléculas profibróticas, volviéndose una alternativa útil en el tratamiento de estas condiciones.

Biological effects of a new ultraviolet A1 prototype based on light-emitting diodes on the treatment of localized scleroderma.

Ultraviolet A1 (UVA1 ) phototherapy (spectral range 340-400 nm) is a well-established treatment option for various skin diseases such as localized scleroderma. Recent improvements of conventional UVA1 light sources (metal-halide or fluorescent lamps) have brought attention to a new light-emitting diode (LED) technology with remarkable advantages in handling and clinical routine. This study provides a preclinical histological and molecular evaluation of an LED-based UVA1 prototype with a narrower spectral range (360-400 nm) for treating localized scleroderma. Scleroderma mouse models and fibroblasts in vitro were exposed to LED-based UVA1 phototherapy or to irradiation with a commercially available metal-halide lamp emitting low-dose (20, 40 J/cm2 ), medium-dose (60 J/cm2 ) and high-dose (80, 100 J/cm2 ) UVA1 light. Both UVA1 light sources affected inflammatory genes (IL-1α and IL-6) and growth factors (TGFß-1 and TGFß-2). Increased collagen type 1 was reduced after UVA1 phototherapy. Matrix metalloproteinase-1 was more enhanced after a medium dose of LED-based UVA1 phototherapy than after conventional treatment. In vivo, dermal thickness and the amount of collagen were reduced after both treatment methods. Remarkably, myofibroblasts were more effectively reduced by a medium dose of LED-based UVA1 phototherapy. The study indicates that LED-based UVA1 phototherapy yields similar or even better results than conventional treatment. In terms of biosafety and patient comfort, LED-based UVA1 phototherapy offers clear advantages over conventional treatment because of the use of a narrower and less harmful UVA1 spectrum, less heat generation and shorter treatment times at the same irradiation intensity. Clinical studies are required to confirm these results in patients with localized scleroderma.

Paediatric morphoea: a holistic review. Part 2: diagnosis, measures of disease activity, management and natural history.

Paediatric morphoea is a debilitating fibrosing disorder of uncertain aetiology, affecting the skin and subcutaneous tissues. Defining optimum management strategies in paediatric morphoea remains an ongoing challenge, owing to the varied presentations and a relative paucity of paediatric-specific studies. We performed a literature search on PubMed, MEDLINE and Google Scholar, using keywords such as 'pediatric morphea', 'juvenile localised scleroderma' and 'juvenile systemic sclerosis'. Relevant studies, including randomized trials, reviews of standard current guidelines and original research articles, were selected and results analysed before summarizing them. In Part 1 of this review, we described the epidemiology, aetiopathogenesis and clinical classification; in this part, we discuss the diagnosis, markers of disease activity, management and natural history in paediatric morphoea.

Long-standing morphea and the risk of squamous cell carcinoma of the skin.

Scleroderma is a heterogeneous group of fibrosing connective tissue disorders of unknown etiology. Morphea is a localized form of scleroderma that occasionally leads to chronic erosions and ulcerations of the skin. Fibrosis, inflammation and chronic ulcerations may eventually promote skin neoplasms; morphea is therefore a rare but established risk factor for cutaneous squamous cell carcinoma (cSCC). We present a review of 16 scleroderma patients: 15 case reports from the literature (identified by a PubMed search) and one case from our clinic of a patient who had developed cSCC, and we discuss potential underlying mechanisms. Statistical analysis revealed that the lower extremities were the body site most commonly affected by cSCC in these scleroderma patients. The mean time interval between the onset of scleroderma and the development of cSCC was ten to twenty years. In patients with morphea, we recommend checking for skin tumors during follow-up examinations as well as a careful risk-benefit analysis when considering the application of immunosuppressants or phototherapy in view of their potential carcinogenic side effects.

Patch-type granuloma annulare: An institution-based study of 23 cases.

BACKGROUND: Granuloma annulare (GA) is a skin disorder of uncertain etiology. Patch (type) GA is an uncommon variant of GA with a paucity of data characterizing it. We describe the features of 23 cases of patch GA. METHODS: The archives of dermatopathology were searched for cases of patch GA. The clinical history and morphology for each patient were reviewed. Only cases with patch clinical morphology were included. The clinical and histopathologic features were assessed including the pattern of granulomatous inflammation and presence of other inflammatory cell types. RESULTS: Most patients were female (19/23) with erythematous patches on the trunk and proximal extremities. The most common clinical differential diagnosis included mycosis fungoides (MF), morphea and contact dermatitis. Dyslipidemia was the most common comorbidity (30%), followed by diabetes (15%) and hypertension (15%). Histopathologic features included interstitial lymphocytes and histiocytes with dermal mucin. Two cases showed focal palisaded granulomas. Eosinophils and plasma cells were present in 1/3 of cases. CONCLUSION: Patch GA is an uncommon GA variant with an interstitial granulomatous histopathologic pattern that predominantly affects women over 50. It can mimic interstitial MF and early morphea both clinically and histopathologically. Awareness of this GA variant can help prevent misdiagnosis and inappropriate treatment for these patients.

Challenges in the diagnosis and treatment of disabling pansclerotic morphea of childhood: case-based review.

Disabling pansclerotic morphea of childhood (DPMC) is a rare subtype of juvenile localized scleroderma (JLS) characterized by pansclerosis mainly affecting children under the age of 14. This aggressive disease has a poor prognosis due to the rapid progression of deep musculoskeletal atrophy resulting in cutaneous ulceration and severe joint contractures. We describe the challenges in treating a previously well 5-year-old male who has refractory symptoms of DPMC. Over the 29 months, since his initial presentation, we trialed over ten therapies. There was subjective improvement with prednisolone and mycophenolate mofetil (MMF). However, other therapies including biologics and tyrosine kinase inhibitors (TKI) were ineffective. The patient has been referred for hematopoietic stem cell transplant given ongoing disease progression. We conducted a literature search focusing on English articles with keywords including DPMC. Publications with limited information or describing cases aged 20 and above were excluded. Thirty-seven case reports were identified and the reported treatments were evaluated. Methotrexate and corticosteroids have been the most commonly utilized. MMF has been anecdotally effective. Biologics, TKI, and Janus kinase inhibitors lack evidence in DPMC, but have had demonstrated efficacy in similar pathologies including systemic sclerosis, and, thus, have been used for DPMC. Phototherapy has been documented to be reducing skin thickness and stiffness of plaques. Eventually, most children require multi-modal and high-dose immunosuppressive therapies to reduce the inflammation inflicted by the disease. Long-term antibiotics and nutritional support are important in the ongoing care of these patients.

Clinical, histological and high-frequency ultrasonographic evaluation (50 MHz) of morphoea treated with ultraviolet A1 phototherapy.

BACKGROUND: There are few studies in the literature correlating the ultrasonographic findings, clinical scoring systems or histological findings in morphoea after ultraviolet (UV)A1 phototherapy. AIMS: To evaluate the quantitative and morphological aspects of high-frequency ultrasonography in the treatment of plaque morphoea in response to UVA1 phototherapy, and to correlate these with clinical and histological scores. METHODS: In total, 17 patients with morphoea were studied. Initially and at study end, high-frequency ultrasonography (50 MHz) was performed on the edge of a morphoea lesion treated with UVA1 phototherapy. A quantitative and qualitative analysis of dermal features was performed and compared with the features of healthy skin. Skin biopsy specimens were obtained from lesions analysed at the beginning and end of the study, assessing dermal sclerosis and dermal inflammatory infiltrate and their distribution. RESULTS: All affected skin showed a statistically significant increase in dermal thickness and hypoechogenicity, corresponding to a reduction in dermal density by ultrasonography compared with healthy skin. Morphological evaluation identified undulations of the dermis in 11 of 17 lesions (64.7%) and in 5 healthy skin areas (29.4%) (P = 0.08), while 'yoyo' figures were identified in 8 lesions (47%) but only 1 healthy skin area (5.9%) (P = 0.02). Ultrasonographic morphological analysis highlighted an improvement in dermal hyperechogenic bands and disappearance of yoyo figures after UVA1 treatment. Histology revealed a reduction in dermal sclerosis and inflammation, although this was not statistically significant. CONCLUSIONS: Ultrasonographic pattern analysis of morphoea is a suitable technique for monitoring UVA1 phototherapy response.

Bee venom acupuncture for circumscribed morphea in a patient with systemic sclerosis: A case report.

RATIONALE: Bee venom has been reported to demonstrate antinociceptive and anti-inflammatory effects in experimental studies, but there remain questions regarding the clinical use of bee venom, especially for scleroderma. This case report shows the successful outcome of bee venom acupuncture for circumscribed morphea in a patient with systemic sclerosis, which is considered to be a rare condition. PATIENT CONCERNS: A 64-year-old Korean woman had circular white areas (3 and 1 cm diameter) with severe itch in the right lateral iliac crest. Based on an initial diagnosis of systemic sclerosis (1 year prior to presentation at our clinic), she had been treated with painkillers, steroids, antitussive expectorants, and aspirin, with minimal effect on her recent skin symptoms. DIAGNOSES: In this study, the diagnosis of circumscribed morphea was based on localized skin symptoms of the patient with systemic sclerosis. INTERVENTIONS: The patient visited Gachon University Korean Medical Hospital for treatment of topical skin symptoms. After being evaluated for bee venom compatibility, she was administered subcutaneous bee venom acupuncture along the margins of the patches (superficial circumscribed lesions) using the shallow surround needling method twice per week for 1 week and then once per week for the following 3 weeks. OUTCOMES: Itch levels were evaluated before each treatment session: by her second visit, her itch had decreased from 8 to 3 on a 10-point numerical rating scale; by her sixth visit, her itch had decreased from 3 to 0. She did not experience adverse effects, and these improvements were maintained until the 2-month follow-up evaluation. LESSONS: Bee venom treatment demonstrates the potential to serve as an effective localized therapy for circumscribed morphea.

A Case of Bullous Morphea Resistant to Methotrexate and Phototherapy Successfully Treated With Mycophenolate Mofetil.

Bullous morphea is rare clinical variant of localized scleroderma characterized by the formation of bullae on sclerotic morphea plaques. Severe disease may be highly disabling and greatly impair quality of life. Current treatment strategies are based on anecdotal reports of clinical experience and include topical corticosteroids, methotrexate and phototherapy. Herein, we describe the case of a 56-year-old woman with progressive bullous sclerotic lesions who was successfully treated with mycophenolate mofetil after treatment failure with psoralen plus ultraviolet A therapy, ultraviolet A1 phototherapy, and methotrexate. Treatment with mycophenolate mofetil halted disease progression after 8 weeks. No major adverse effects were recorded in a 3-year follow-up with continuous treatment. This case suggests mycophenolate mofetil may be considered as an alternative for the treatment of resistant bullous morphea lesions. J Drugs Dermatol. 2018;17(10):1123-1125.

Localized morphea after breast implant for breast cancer: A case report.

PURPOSE: Early breast cancer follow-up guidelines for patients who underwent surgery suggest a regular and accurate clinical examination of the breast area, for an early identification of cutaneous or subcutaneous breast cancer relapse. Nonetheless, breast skin lesions arising in patients treated with mastectomy for breast cancer can be caused by several diseases. A series of diagnostic hypotheses should be considered, not only focusing on cutaneous metastasis, but also on dermatologic and systemic diseases. CASE REPORT: In February 2015, a 37-year-old patient underwent a right subcutaneous mastectomy for stage IIA breast cancer. Five months after beginning adjuvant chemotherapy, she noted hyperpigmentation and thickening of the skin on the right breast. Differential diagnosis included local relapse, skin infection, lymphoma, or primary cutaneous disease, and a skin biopsy was performed. The histopathologic specimen showed full-thickness sclerosis, with features of localized morphea. Therapy with clobetasol was prescribed, with progressive resolution of the thickness. The collaboration between many professionals in a multidisciplinary team (oncologist, dermatologist, plastic surgeon, and pathologist) was crucial to achieving the diagnosis. CONCLUSION: In the literature, some articles describe correlation between connective tissue diseases and silicone breast implants, but the pathogenetic mechanisms are unknown. We report a rare case of breast morphea after positioning a silicone implant in a patient who had undergone mastectomy. This clinical report represents an interesting model of multidisciplinary management of a patient with breast cancer who developed an uncommon dermatologic disease. Further studies are needed to clarify the association between silicone implants and breast morphea.

Morfea en la infancia: actualización / Morphea in Childhood: An Update

La morfea es una enfermedad de la piel que se manifiesta en forma de inflamación y fibrosis. En niños y jóvenes, también se conoce como esclerodermia juvenil localizada. En edad infantil, afecta con mayor frecuencia al sexo femenino y la edad de comienzo se ha establecido en torno a los 5-7 años. Una clasificación reciente divide la morfea en: circunscrita (en placas), lineal, generalizada, panesclerótica y mixta. Alrededor de un 40% de los pacientes presentan manifestaciones extracutáneas. Los tratamientos empleados en morfea infantil son: fototerapia, calcitriol oral, calcipotriol tópico, tacrolimus 0,1% tópico, metotrexato, glucocorticoides tópicos y sistémicos, mofetil micofenolato, bosentán e imiquimod 5% tópico. Diversas medidas de resultado pueden ayudar a monitorizar el tratamiento. Los estudios pronósticos son escasos, pero apuntan hacia una enfermedad con tendencia a un curso crónico o intermitente-recurrente y una frecuencia considerable de secuelas

Morphea is an inflammatory, fibrosing skin disorder. When it occurs in childhood, it is also known as localized juvenile scleroderma. It is more common in girls and typically appears around the age of 5 to 7 years. According to a recent classification system, morphea is divided into 5 types: circumscribed (plaque), linear, generalized, pansclerotic, and mixed. Approximately 40% of patients present extracutaneous manifestations. Childhood morphea is treated with phototherapy, oral or topical calcitriol, topical tacrolimus 0.1%, methotrexate, topical or systemic corticosteroids, mycophenolate mofetil, bosentán, and topical imiquimod 5%. A variety of measuring tools are used to monitor response to treatment. Few prognostic studies have been conducted, but findings to date suggest that the disease tends to run a chronic or intermittent-recurrent course and frequently causes sequelae

Diagnostic criteria, severity classification and guidelines of localized scleroderma.

We established diagnostic criteria and severity classification of localized scleroderma because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for localized scleroderma, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of localized scleroderma.

The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice.

PURPOSE: To define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. MATERIALS AND METHODS: 42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365±5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. RESULTS: Skin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9±113.2µm and 394±125.9µm, respectively) in comparison to the dermal thickness of non-treated animals (599±55.7µm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11±1.7 and 13±2.2, respectively, as compared to that in non-treated mice (23±3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. CONCLUSIONS: The results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment.

Morphea in Childhood: An Update. / Morfea en la infancia: actualización.

Morphea is an inflammatory, fibrosing skin disorder. When it occurs in childhood, it is also known as localized juvenile scleroderma. It is more common in girls and typically appears around the age of 5 to 7 years. According to a recent classification system, morphea is divided into 5 types: circumscribed (plaque), linear, generalized, pansclerotic, and mixed. Approximately 40% of patients present extracutaneous manifestations. Childhood morphea is treated with phototherapy, oral or topical calcitriol, topical tacrolimus 0.1%, methotrexate, topical or systemic corticosteroids, mycophenolate mofetil, bosentán, and topical imiquimod 5%. A variety of measuring tools are used to monitor response to treatment. Few prognostic studies have been conducted, but findings to date suggest that the disease tends to run a chronic or intermittent-recurrent course and frequently causes sequelae.

Effects of UVA1 Phototherapy on Expression of Human Endogenous Retroviral Sequence (HERV)-K10 gag in Morphea: A Preliminary Study.

BACKGROUND Morphea, also known as localized scleroderma, is a rare autoimmune connective tissue disease characterized by skin fibrosis. UVA1 phototherapy is an important asset in the reduction of clinical manifestations in morphea. There are studies claiming that UV light modulates the expression of some human endogenous retroviral sequences. The aim of this study was to determine if the expression of HERV-K10 gag element is lowered by UVA1 phototherapy in morphea, a disease in which such irradiation has a soothing effect. MATERIAL AND METHODS The expression levels of the HERV-K10 gag were assessed by real-time PCR (polymerase chain reaction) in peripheral blood mononuclear cells (PBMC) and skin-punch biopsies of healthy volunteers and 9 morphea patients before and after phototherapy. Additionally, correlations between the HERV-K10 gag expression and age, disease duration, the Localized Scleroderma Skin Severity Index (LoSSI), and antinuclear antibody (ANA) titers were assessed. RESULTS In PBMC, HERV-K10 gag mRNA was significantly elevated after UVA1 phototherapy compared to healthy controls. Most of the patients responded with an increased expression level of this sequence. However, we found no statistical evidence at this point that phototherapy indeed has an effect on the HERV-K10 gag expression (there were no statistical differences in PBMC of morphea patients before and after phototherapy). Similarly, there was no statistically relevant effect of the UVA1 on the expression of HERV-K10 gag in skin. CONCLUSIONS At this point, the effect of UVA1 phototherapy on the expression of HERV-K10 gag cannot be statistically confirmed.

Fractional carbon dioxide laser versus low-dose UVA-1 phototherapy for treatment of localized scleroderma: a clinical and immunohistochemical randomized controlled study.

Morphea is a rare fibrosing skin disorder that occurs as a result of abnormal homogenized collagen synthesis. Fractional ablative laser resurfacing has been used effectively in scar treatment via abnormal collagen degradation and induction of healthy collagen synthesis. Therefore, fractional ablative laser can provide an effective modality in treatment of morphea. The study aimed at evaluating the efficacy of fractional carbon dioxide laser as a new modality for the treatment of localized scleroderma and to compare its results with the well-established method of UVA-1 phototherapy. Seventeen patients with plaque and linear morphea were included in this parallel intra-individual comparative randomized controlled clinical trial. Each with two comparable morphea lesions that were randomly assigned to either 30 sessions of low-dose (30 J/cm2) UVA-1 phototherapy (340-400 nm) or 3 sessions of fractional CO2 laser (10,600 nm-power 25 W). The response to therapy was then evaluated clinically and histopathologically via validated scoring systems. Immunohistochemical analysis of TGF-ß1 and MMP1 was done. Patient satisfaction was also assessed. Wilcoxon signed rank test for paired (matched) samples and Spearman rank correlation equation were used as indicated. Comparing the two groups, there was an obvious improvement with fractional CO2 laser that was superior to that of low-dose UVA-1 phototherapy. Statistically, there was a significant difference in the clinical scores (p = 0.001), collagen homogenization scores (p = 0.012), and patient satisfaction scores (p = 0.001). In conclusion, fractional carbon dioxide laser is a promising treatment modality for cases of localized morphea, with proved efficacy of this treatment on clinical and histopathological levels.