Case of localized scleroderma successfully treated with bath psoralen and ultraviolet A therapy

The patient was a 12-year-old girl with linear scleroderma distributed on the right abdomen, dorsal aspect of the right thigh, lower leg and foot. The initial regimen of oral prednisolone and methotrexate, or i.v. methylprednisolone failed in the treatment of the scleroderma. Then bath psoralen and ultraviolet A therapy (bath-PUVA) therapy of 0.2 J–4.0 J/cm² daily to total doses 62.8 J/cm² combined with oral prednisolone was started. After bath-PUVA therapy, regression of the skin sclerosis was observed, the possible mobile range of the right ankle was increased and histological examination confirmed improvement of the sclerosis. The successful results of bath-PUVA therapy in this case suggest its utility for localized scleroderma.     

Measurement of transepidermal water loss in localized scleroderma

Localized scleroderma (LS) is a disease characterized by fibrotic changes in the dermis. Connective tissue growth factor and transforming growth factor β2 are the main mediators of fibrogenesis; this, along with excessive connective tissue production, affects epidermal keratinocytes, and thereby contributes to the changed quality of skin barrier. The objective of this article was to study the objective measurement of the skin barrier quality in LS with transepidermal water loss (TEWL) meter. The measurements of TEWL were performed on LS plaques in all three stages of various body locations. Control measurements were made on the contralateral side of healthy skin. The difference between TEWL in LS area and the contralateral side of the healthy skin was evaluated. A higher average TEWL 7.86 g/m²/h (SD 5.29) was observed on LS plaques compared with the control measurements on healthy skin 6.39 g/m²/h (SD 2.77). TEWL average values decreased from the inflammatory stage, through the sclerotic and to the atrophic stage. The mean difference 1.301 g/m²/h (SD 5.16) was found between TEWL on LS plaques and on the contralateral healthy skin in 82 measurements, i.e., a higher TEWL was observed in LS. The difference was statistically significant with p = 0.0250. Although fibrogenesis in scleroderma is localized in dermis, the skin barrier changes can be detected.     

Antinucleosome antibody is a major autoantibody in localized scleroderma

BACKGROUND: Localized scleroderma (LSc) exhibits autoimmunity, and antihistone antibody is frequently detected. The major antigens recognized by antihistone antibody are histones H1, H2A and H2B, which are located on the outer side of the nucleosome and are relatively more accessible for antibody binding. Therefore, it has been hypothesized that antihistone antibody is induced by nucleosome or native chromatin as immunogens in LSc. OBJECTIVES: To determine whether antinucleosome antibody is present in patients with LSc. METHODS: Antinucleosome antibody, antihistone antibody and antidouble-stranded DNA (dsDNA) antibody were determined by enzyme-linked immunosorbent assay. Results IgG or IgM antinucleosome antibody was detected more frequently in patients with LSc than was antihistone antibody: in 40 of 49 (82%) vs. 26 of 49 (53%), respectively. No patients had anti-dsDNA antibody. The prevalence of antinucleosome antibody positivity was comparable in the three subgroups of LSc (generalized morphoea, 89%; linear scleroderma, 71%; morphoea, 90%). Patients with systemic lupus erythematosus (SLE) exhibited a similar frequency of antinucleosome antibody positivity (13 of 15, 87%), but their IgG levels of this autoantibody were much higher than those found in patients with LSc. By contrast, IgM antinucleosome antibody levels were normal in patients with SLE, while they were significantly increased in patients with LSc compared with normal controls. Antinucleosome antibody was also detected at lower frequency in patients with systemic sclerosis (five of 20, 25%) or dermatomyositis (five of 15, 33%). Nucleosome-restricted antibodies, i.e. antibodies that react with the whole nucleosome particle but not with its individual components (histones and dsDNA) were also present in 35% of patients with LSc. CONCLUSIONS: Although antinucleosome antibody was not specific to LSc, its high prevalence in LSc indicates that antinucleosome antibody is a major autoantibody in this disease.     

Localized linear scleroderma with cutaneous calcinosis

A 38-year-old woman developed sclerotic and atrophic changes of the left femur in the winter of 1976. In 1980, she was referred to our dermatology clinic and was diagnosed with localized linear scleroderma from the results of the physical examinations and the histological findings. Although several local and systemic treatments were employed over the following 10 years, the sclerotic lesion did not show any remarkable improvement. In 1991, several hard and white papules appeared in the lesion, and a biopsy specimen of these white papules revealed calcinosis.     

Radiation-induced localized scleroderma in breast cancer patients

Radiation-induced scleroderma in breast cancer patients appears to occur in approximately one out of every 500 patients. We report four cases that developed within 3 months of conservative breast surgery and postoperative radiation treatment. The reaction was contained entirely within the treatment field and demonstrated the typical features of this condition where the breast becomes erythematous, violaceous, indurated, retracted, and progressively pigmented. The breast tends to soften and become more comfortable over 1–4 years; however, significant induration, retraction and pigmentary changes remain. There appears to be no predictive factors. Radiation-induced scleroderma must be differentiated from cellulitis and recurrent breast cancer.     

Thirteen-megahertz ultrasound probe: its role in diagnosing localized scleroderma

BACKGROUND: Ultrasound imaging has been shown to be useful for the evaluation of systemic and localized scleroderma (LS). However, its specificity and sensitivity have not been studied. OBJECTIVES: To define morphological ultrasound diagnostic criteria in LS and to test their sensitivity and specificity with a 13-MHz ultrasound probe. METHODS: Forty plaques in 26 consecutive patients with LS were examined and compared blindly with 17 control plaques in 16 patients with skin diseases where LS was in the differential diagnosis. Data were also compared with a normal control group. Five patients were re-evaluated 12-18 months after the first examination. RESULTS: Ultrasound examination disclosed a characteristic dense image resembling a flattened 'yo-yo'. Undulations of the dermis, disorganization, loss of thickness and thickened hyperechoic bands in the hypodermis, and the 'yo-yo' image had a high sensitivity and a high specificity for LS. A 92% sensitivity and a 100% specificity for LS were found when at least four of these five signs were present. CONCLUSIONS: Thirteen-megahertz ultrasound is a valuable tool for diagnosing LS. Morphological ultrasound diagnostic criteria had a high specificity and a high sensitivity.     

Ultraviolet A1 phototherapy for the treatment of localized scleroderma

Ultraviolet (UV)A1 phototherapy is effective for T-cell-mediated skin diseases such as atopic dermatitis and mast cell-mediated skin diseases such as mastocytoma. UVA1 phototherapy is also effective against the sclerotic lesions of systemic sclerosis and morphea. Currently, in Japan, access to UVA1 phototherapy is limited because the UVA1 phototherapy device has not yet been approved. On the basis of our experience, we report three patients with localized scleroderma who responded successfully to UVA1 phototherapy. Efficacy was assessed by histological analysis and elastography. UVA1 successfully ameliorated sclerotic lesions, including morphea, linear scleroderma and morphea lesions in a patient with limited cutaneous systemic sclerosis. No side-effects were observed during UVA1 phototherapy.     

A case of linear scleroderma with muscle calcification

We report a 21-year-old man with linear scleroderma with muscle calcification revealed by a computed tomographic (CT) scan. Levels of serum calcium and phosphorus were normal. This is the first report of localized scleroderma with muscle calcification. Muscle involvement may cause contracture or functional abnormalities of the extremities. Therefore, CT scans may be useful in evaluating muscle involvement in patients with localized scleroderma.     

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.     

Chronic venous insufficiency – a potential trigger for localized scleroderma

Localized scleroderma is a cutaneous disease that is characterized by an initial inflammatory response, followed by sclerosis of the skin. The cause of localized scleroderma has not yet been determined. Seifarth et al. reported two cases of localized scleroderma at sites of chronic venous insufficiency. We document here three more patients in whom localized scleroderma was located at insufficient veins. Treatment of underlying chronic venous insufficiency (CVI) leads to a substantial clinical improvement of scleroderma at the site of insufficient veins, but not elsewhere. Experimental data support the concept of chronic venous insufficiency creating a microenvironment, which may lead to localized scleroderma. Local hypoxaemia, which is present in CVI, induces the release of endothelium-derived cytokines, such as IL-1. Subsequently, expression of endothelial adhesion molecules and consequently leucocyte extravasation are induced. Infiltrating leucocytes secrete a number of inflammatory mediators, including transforming growth factor beta, which is a potent stimulus for collagen synthesis. Therefore, it may well be that CVI is a potential trigger factor for localized scleroderma. In addition, localized scleroderma may only develop if a certain amount of trigger factors are present - and resolves if one or more of the contributing factors (i.e. CVI) can be treated.     

Topical tacrolimus 0.1% ointment in the treatment of localized scleroderma. An open label clinical and histological study

Localized scleroderma or morphea, although a self‐limited and benign disease, may leave substantial physical and cosmetic deformity necessitating treatment but treatment remains to date unsatisfactory. The aim of our study was to evaluate the efficacy of topical tacrolimus ointment in the treatment of morphea. Thirteen patients with morphea used tacrolimus 0.1% cream b.i.d. without occlusion for 4 months. Patients were followed up for up to a year. A 4‐mm biopsy was taken before starting treatment in seven patients and 4 months after continuous use of tacrolimus 0.1% ointment, next to the previous biopsy site. Masson trichrome and elastica stains were performed to evaluate the distribution of elastic fibers as well as the streptavidin‐biotin horseradish peroxide immunohistochemical method for the detection of CD20/L‐26, CD3, CD8, CD4, CD1a, human leukocyte antigen‐DR and CD25. Four patients had a less than 25% improvement, two patients responded by 50–70% and the remaining seven by more than 70%. Patients with thick, well‐established lesions responded poorly in comparison to others with less thick and more erythematous ones. Patients with mild‐to‐moderate fibrosis histologically were more likely to improve after treatment, while the lymphocytic infiltrate decreased regardless of initial degree before treatment. It was concluded that topical tacrolimus 0.1% cream may be used in patients with morphea, particularly with early inflammatory lesions, even as a first‐line treatment.     

Elevated soluble CD23 levels in the sera from patients with localized scleroderma

Soluble CD23 (sCD23) is closely related to B-cell activation and elevated serum levels of sCD23 have been reported in several autoimmune disorders. This study investigated the serum levels of sCD23 and determined the correlation of sCD23 with other immunologic abnormalities and clinical features in localized scleroderma. We examined 49 serum samples by an enzyme-linked immunosorbent assay in the following three subgroups: 15 patients with generalized morphoea, 22 with linear scleroderma, and 12 with morphoea. The serum levels of sCD23 were significantly elevated in patients with localized scleroderma, compared with those in healthy individuals. Of the three subgroups of localized scleroderma, patients with generalized morphoea had the highest levels of serum sCD23. The frequency of IgM antihistone antibody (AHA) and IgM rheumatoid factor (RF), the number of linear lesions, and the frequency of muscle involvement were significantly higher in patients with elevated sCD23 levels than in those with normal levels of sCD23. A significant correlation between the serum sCD23 level and the number of involved areas of the body was observed. Our data suggest that the activation of virgin B cells, which is reflected by elevated sCD23 levels, is closely associated with the production of IgM autoantibodies in localized scleroderma and furthermore that the serum levels of sCD23 are a new serological indicator of the severity of localized scleroderma.     

Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases

Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma.     

Impact of a new simplified disability scoring system for adult patients with localized scleroderma

Localized scleroderma (LoS) involves dermal but not internal inflammation and fibrosis. Cosmetic changes often impact quality of life (QOL), however, impairment of activities of daily living (ADL) in LoS patients has not been investigated. To determine what factor(s) are associated with ADL in adult patients with LoS, we performed a retrospective observational study in 177 Japanese adult LoS patients using a novel LoS disability score based on Barthel's indices of ADL: feeding, bathing, grooming, dressing, bowels, bladder, toilet use, transfers, mobility and stairs. LoS disability scores increased in proportion to the number of affected body parts but were not correlated to age and duration of illness. The presence of leg lesions significantly impaired ADL of LoS patients compared with lesions on other body parts. Patients treated with systemic medications, who tended to have multiple lesions, presented higher LoS disability scores than those without systemic treatments. Our study proposes that physicians evaluate ADL, not only QOL, in LoS patients. Our findings using LoS disability scoring indicate that multiple affected body parts and leg lesions are risk factors for ADL impairment.     

Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children

BACKGROUND: Localized scleroderma (LS) or morphoea is often considered to be a benign self-limiting condition confined to the skin and subcutaneous tissue. However, the course of the disease is unpredictable and severe functional and cosmetic disability may result. Drug treatment with systemic corticosteroids in combination with methotrexate has been reported to be beneficial in LS, but data in children is limited. OBJECTIVES: To evaluate the efficacy and tolerability of systemic corticosteroids in combination with methotrexate in children with LS. METHODS: Treatment and outcome of 34 patients with LS were retrospectively analysed. Pulsed intravenous methylprednisolone was given, followed by oral prednisolone on a reducing regimen and maintenance treatment with methotrexate. We assessed treatment outcome clinically and by thermography and monitored adverse events. RESULTS: From the onset of treatment, the disease stopped progressing in 94% of the patients. All patients demonstrated significant clinical improvement within a mean time of 5.7 +/- 3.9 months. Mean duration of follow-up over the treatment period and beyond was 2.9 +/- 2.0 years. In 16 (47%) patients therapy was discontinued when the disease was considered to be inactive clinically; however, seven (44%) of the 16 developed a relapse, necessitating repeat treatment. At last follow-up (range 0.2-7.0 years), 24 (71%) of the 34 patients had completely inactive disease. Observed adverse events were moderate and transient and no patient had to stop therapy. CONCLUSIONS: These data suggest that systemic corticosteroids and methotrexate in combination are beneficial and well tolerated in the treatment of children with LS. Because of the risk of relapse after discontinuing therapy, long-term monitoring is mandatory.     

Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma

Abstract:  Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor β. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.