Iontophoresis of treprostinil promotes wound healing in a murine model of scleroderma-related ulcers.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing. METHODS: We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization. RESULTS: uPAR-/- mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR-/- mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution. CONCLUSION: This study suggests that excisional wounds in uPAR-/- mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans.

Morfea superficial / Superficial morphea

La morfea superficial es una variante rara de morfea que se distingue de la clásica tanto en la clínica como en la histopatología. Se caracteriza por máculas hipopigmentadas o hiperpigmentadas, con mínima o ninguna induración, sin síntomas asociados, contractura ni atrofia. En la histopatología, se observa un compromiso limitado a las fibras colágenas en la dermis reticular superficial. Se comunica el caso de una paciente con diagnóstico de morfea superficial tratada con fototerapia ultravioleta B y metotrexato.

Superficial morphea is a rare variant of morphea that is distinguished from the classic variant both clinically and histopathologically. It is characterized by hypo or hyperpigmented patches with minimal to no induration, without associated symptoms, without contracture or atrophy. At the histopathological level, a limited involvement of collagen fibers is observed at the level of the uperficial reticular dermis. The case of a patient with superficial morphea treated with ultraviolet B phototherapy and methotrexate is presented.

Evaluation of the Effectiveness and Tolerability of Mycophenolate Mofetil and Mycophenolic Acid for the Treatment of Morphea.

Importance: First-line systemic therapy for morphea includes methotrexate with or without systemic corticosteroids. When this regimen is ineffective, not tolerated, or contraindicated, a trial of mycophenolate mofetil (MMF) or mycophenolic acid (MPA)-referred to herein as mycophenolate-is recommended; however, evidence to support this recommendation remains weak. Objective: To evaluate the effectiveness and tolerability of mycophenolate for the treatment of morphea. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 1999, to December 31, 2018, among 77 patients with morphea from 8 institutions who were treated with mycophenolate. Main Outcomes and Measures: The primary outcome was morphea disease activity, severity, and response at 0, 3 to 6, and 9 to 12 months of mycophenolate treatment. A secondary outcome was whether mycophenolate was a well-tolerated treatment of morphea. Results: There were 61 female patients (79%) and 16 male patients (21%) in the study, with a median age at disease onset of 36 years (interquartile range, 16-53 years) and median diagnostic delay of 8 months (interquartile range, 4-14 months). Generalized morphea (37 [48%]), pansclerotic morphea (12 [16%]), and linear morphea of the trunk and/or extremities (9 [12%]) were the most common subtypes of morphea identified. Forty-one patients (53%) had an associated functional impairment, and 49 patients (64%) had severe disease. Twelve patients received initial treatment with mycophenolate as monotherapy or combination therapy and 65 patients received mycophenolate after prior treatment was ineffective (50 of 65 [77%]) or poorly tolerated (21 of 65 [32%]). Treatments prior to mycophenolate included methotrexate (48 of 65 [74%]), systemic corticosteroids (42 of 65 [65%]), hydroxychloroquine (20 of 65 [31%]), and/or phototherapy (14 of 65 [22%]). After 3 to 6 months of mycophenolate treatment, 66 of 73 patients had stable (n = 22) or improved (n = 44) disease. After 9 to 12 months of treatment, 47 of 54 patients had stable (n = 14) or improved (n = 33) disease. Twenty-seven patients (35%) achieved disease remission at completion of the study. Treatments received in conjunction with mycophenolate were frequent. Mycophenolate was well tolerated. Gastrointestinal adverse effects were the most common (24 [31%]); cytopenia (3 [4%]) and infection (2 [3%]) occurred less frequently. Conclusions and Relevance: This study suggests that mycophenolate is a well-tolerated and beneficial treatment of recalcitrant, severe morphea.

Update on the Systemic Treatment of Pediatric Localized Scleroderma.

Juvenile localized scleroderma (jLS) is an orphan disease that can lead to cosmetic disfiguration and orthopedic problems. Two recent publications review the current recommendations regarding diagnosis, assessment, follow up and treatment of pediatric localized scleroderma cases, both of which suggest the Localized Scleroderma Cutaneous Assessment Tool as an important instrument to assess activity and damage. This review focuses on the systemic treatment of jLS. Systemic treatment includes synthetic and biologic disease-modifying antirheumatic drugs. Systemic therapy is indicated if the lesion crosses any joint, or leads to potential cosmetic disfiguration or orthopedic problems. The only controlled trial of systemic treatment has shown the efficacy of methotrexate, which is the first choice of treatment. It appears superior to phototherapy according to a recently published meta-analysis. In case of methotrexate intolerance, mycophenolate mofetil is an option. In case of methotrexate nonresponse, addition of mycophenolate mofetil, tocilizumab or abatacept seems to be effective. Future treatment options derived and extrapolated from adult trials regarding treatment of skin involvement of systemic scleroderma or fibrosis are promising, as the final pathway in the skin seems to be similar in both diseases.

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.

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

Comparing ultraviolet light A photo(chemo)therapy with Methotrexate protocol in childhood localized scleroderma: Evidence from systematic review and meta-analysis approach.

OBJECTIVE: Localized scleroderma is a skin fibrosing disorder that, if untreated, may result in severe disability. The purpose of this systematic review is to compare the present evidence concerning the effectiveness of Methotrexate versus phototherapy, alone or associated with Psoralen, in childhood localized scleroderma. METHOD: A systematic search between January 1996 and May 2017 was performed to identify studies investigating the efficacy of Methotrexate (MTX) or phototherapy (UVA) for treating localized scleroderma with onset ≤18 years. Due to a lack of validated clinical criteria, four clinical response criteria were used to assess the treatment efficacy as primary outcome. We determined a combined estimate of the proportion of children responding to MTX and UVA. RESULTS: A total of 19 studies was included (8 MTX; 11 UVA). In the methotrexate group, 193 children were included in the analysis; in the phototherapy group, a total of 48 treated children. For both groups age, disease subtype, glucocorticoids (GCs) use, and side effects of treatment were also analyzed. The meta-analysis suggested that UVA and MTX protocols have both a favorable effect in active lesions of childhood localized scleroderma. However, MTX resulted significantly superior to UVA, with or without Psoralen. CONCLUSION: Our study supports the combination of MTX and GCs in patients with a high risk of complication. Phototherapy with UVA1 could represent a therapeutic option in patients with limited scleroderma, where lesions do not cross joints and they do not lead to potential cosmetic changes.

Concentraciones sanguíneas infraterapéuticas de everólimus asociado al consumo de caramelos con extracto de hipérico (Hypericum perforatum o hierba de San Juan) / Decreased everolimus blood concentration associated with consumption of St. John’s wort (Hypericum perforatum) extract sweets

No disponible

Morphea and Eosinophilic Fasciitis: An Update.

Morphea, also known as localized scleroderma, encompasses a group of idiopathic sclerotic skin diseases. The spectrum ranges from relatively mild phenotypes, which generally cause few problems besides local discomfort and visible disfigurement, to subtypes with severe complications such as joint contractures and limb length discrepancies. Eosinophilic fasciitis (EF, Shulman syndrome) is often regarded as belonging to the severe end of the morphea spectrum. The exact driving mechanisms behind morphea and EF pathogenesis remain to be elucidated. However, extensive extracellular matrix formation and autoimmune dysfunction are thought to be key pathogenic processes. Likewise, these processes are considered essential in systemic sclerosis (SSc) pathogenesis. In addition, similarities in clinical presentation between morphea and SSc have led to many theories about their relatedness. Importantly, morphea may be differentiated from SSc based on absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes. The diagnosis of morphea is often based on characteristic clinical findings. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases. However, full-thickness skin biopsies, containing fascia and muscle tissue, are required for the diagnosis of EF. Monitoring of disease activity and damage, especially of subcutaneous involvement, is one of the most challenging aspects of morphea care. Therefore, data harmonization is crucial for optimizing standard care and for comparability of study results. Recently, the localized scleroderma cutaneous assessment tool (LoSCAT) has been developed and validated for morphea. The LoSCAT is currently the most widely reported outcome measure for morphea. Care providers should take disease subtype, degree of activity, depth of involvement, and quality-of-life impairments into account when initiating treatment. In most patients with circumscribed superficial subtypes, treatment with topical therapies suffices. In more widespread disease, UVA1 phototherapy or systemic treatment with methotrexate (MTX), with or without a systemic corticosteroid combination, should be initiated. Disappointingly, few alternatives for MTX have been described and additional research is still needed to optimize treatment for these debilitating conditions. In this review, we present a state-of-the-art flow chart that guides care providers in the treatment of morphea and EF.

Phototherapy for sclerosing skin conditions.

Phototherapy is an effective treatment strategy for a variety of sclerosing skin conditions. There are a number of phototherapeutic modalities used for the treatment of sclerosing skin conditions, including ultraviolet (UV)A1, broadband UVA, psoralen plus UVA, and narrowband UVB phototherapy. As controlled trials with validated outcome measures are lacking for these therapies, existing evidence is largely level II for morphea and is even more minimal for scleroderma and other sclerosing disorders (scleroderma, lichen sclerosus, and chronic graft-versus-host disease, among others). Studies do suggest that phototherapy may be effective for many of these disorders, including those that have been unresponsive to other therapies. Phototherapy remains an attractive therapeutic option for patients due to its efficacy and favorable risk-versus-benefit profile. Phototherapy also offers a therapeutic alternative to systemic immunosuppressives for patients who cannot tolerate these medications.

A Pediatric Case of Sclerodermatous Graft-Versus-Host Disease Responsive to Ultraviolet A1 Phototherapy.

Graft-versus-host disease (GVHD) is one of the major complications after hematopoietic stem cell transplantation and is responsible for post-therapeutic morbidity, mortality, and poor quality of life of recipients. Sclerodermatous graft-versus-host disease (sGVHD) is a rare variant of chronic GVHD characterized by deposition of collagen in the skin and other soft tissues and resulting in loss of range of motion and functional capabilities. Treatment of sGVHD is challenging and largely limited by systemic side effects. Ultraviolet A1 phototherapy has been reported to be effective in connective tissue disorders, including sGVHD. We report a case of sGVHD in a 15-year-old girl that was resistant to traditional therapy but showed improvement in cutaneous symptoms with ultraviolet A1 phototherapy three times a week for 6 weeks (10 J/cm(2) single dose, 180 J/cm(2) cumulative dose).

Atypical presentations of eosinophilic fasciitis.

Eosinophilic fasciitis is an uncommon connective tissue disease that may mimic and overlap with other sclerosing disorders such as morphea and lichen sclerosus. Herein, we report four patients (two men and two women, aged 16-64 yeas) with eosinophilic fasciitis. There was overlap with both morphea and lichen sclerosus in 2 patients and with morphoea alone in 1 patient. Magnetic resonance imaging (MRI) was used for diagnosis in three patients and for assessing treatment response in one patient. Eosinophilic fasciitis may co-exist with morhoea and lichen sclerosus. In view of the overlapping clinical and histopathological features of these disorders, MRI may be helful in delineating the conditions by detecting involvement of fascia.

[Interferon in combined therapy of human papillomavirus infections associated with sexually transmitted infections. linical observation].

To investigate the effectiveness of Ingaron (interferon-) in the treatment of HPV infection associated with sexually transmitted infections, the authors analyzed the scientific literature on the association of human papillomavirus infection with other viral and microbial pathogens. A clinical case of the association of human papillomavirus infection, urogenital infections (urogenital chlamydia and genital herpes) and localized scleroderma penis is described. The results of integrated therapy of diseases with the help of Interferon-gamma have been presented. According to the literature, up to 70-80% of HPV infections are associated with microbial (opportunistic, obligate pathogens) and viral infectious agents. Chronic inflammation caused by bacterial and viral associations destroys the immune system and it leads to the ineffectiveness of the therapy. Pathogenic therapy of sexually transmitted infections in combination with interferon-gamma (Ingaron) contributes to the eradication of bacterial pathogens, prevention of viral STI recurrence and elimination of high oncogenic risk types of HPV. Thus, we can reasonably infer that Ingaron (interferon-) alleviates the initial immune disturbances, improves the effectiveness of the treatment and may be recommended for treating HPV infection associated with sexually transmitted infections.

The role of capsaicin in dermatology.

Neurogenic pain and pruritus are the common chief complaints at dermatology office visits. Unfortunately, they are also notoriously difficult conditions to treat. Topical capsaicin used as a single therapy or as an adjuvant offers a low-risk option for patients who do not achieve control on other therapies. This chapter presents the evidence behind topical capsaicin use in dermatologic conditions characterized by neurogenic pain or pruritus, including postherpetic neuralgia, notalgia paresthetica, brachioradial pruritus, lichen simplex chronicus, prurigo nodularis, pruritus ani, pruritus of hemodialysis, aquagenic pruritus, apocrine chromhidrosis, lipodermatosclerosis, alopecia areata, and psoriasis. It presents the most common capsaicin formulations, dosages, and durations of treatment for each condition. Additionally, the chapter addresses various adverse effects and limitations in the use of topical capsaicin in dermatology.

Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies.

Scleroderma refers to a heterogeneous group of autoimmune fibrosing disorders. The nomenclature of scleroderma has changed dramatically in recent years, with morphea (localized scleroderma), limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma encompassing the currently accepted disease subtypes. Major advances have been made in the molecular studies of morphea and systemic sclerosis; however, their etiologies and pathogenesis remain incompletely understood. Although morphea and systemic sclerosis demonstrate activation of similar inflammatory and fibrotic pathways, important differences in signaling pathways and gene signatures indicate they are likely biologically distinct processes. Morphea can cause significant morbidity but does not affect mortality, whereas systemic sclerosis has the highest disease-specific mortality of all autoimmune connective tissue diseases. Treatment recommendations for morphea and systemic sclerosis are based on limited data and largely expert opinions. Current collaborative efforts in morphea and systemic sclerosis research will hopefully lead to better understanding of the etiology and pathogenesis of these rare and varied diseases and improved treatment options.