[Localized scleroderma (localized morphea)].
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Child↗
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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.
Adult↗
Clinical significance of serum levels of soluble interleukin-2 receptor in patients with localized scleroderma.
Localized scleroderma has been reported to be accompanied by abnormal immune reactions, including autoantibody production and lymphocyte activation. Lymphocyte activation can be quantitatively detected by measuring soluble interleukin-2 receptor (sIL-2R) in serum samples. In this study, serum sIL-2R levels were assayed by a sensitive enzyme-linked immunosorbent assay, in 48 patients with localized scleroderma, in 20 with systemic sclerosis (SSc) and in 20 healthy controls. Serum levels of sIL-2R were significantly higher in patients with localized scleroderma than in healthy controls. The serum levels of sIL-2R were correlated with the number of sclerotic lesions, the number of involved areas, the levels of anti-ssDNA, and the levels of antihistone antibody immunoglobulin M. Moreover, sIL-2R levels in sera from patients with SSc were also significantly higher than in healthy controls. Elevated serum levels of sIL-2R in localized scleroderma suggest that lymphocyte activation is one of the early processes in the development of this disease.
Adolescent↗
Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma.
Localized scleroderma has been reported to be accompanied by immunological abnormalities related to B cells, but little is known about T-cell activation in this disease. In this study, serum levels of interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-6 (IL-6), which are known to be released by activated T cells, were determined using a sensitive enzyme-linked immunosorbent assay in 48 patients with localized scleroderma and 20 with systemic sclerosis, and in 20 healthy control subjects. IL-2, IL-4 and IL-6 were detected in serum from patients with localized scleroderma but not in that from healthy controls. The presence of antihistone antibodies correlated significantly with elevated IL-4 and IL-6 levels. Decreased serum levels of IL-2, IL-4 and IL-6 paralleled improvement in cutaneous sclerosis. Frequent detection of these lymphokines in serum from patients with localized scleroderma reflects T-cell activation in this disorder.
Autoantibodies↗
D-penicillamine in the treatment of localized scleroderma.
Localized scleroderma has no recognized internal organ involvement but may be disfiguring and disabling when the cutaneous lesions are extensive or affect children. There is no accepted or proven treatment for localized scleroderma. Case reports of 11 patients with severe, extensive localized scleroderma who were treated with D-penicillamine are summarized in this article. This drug was judged to have a favorable effect on the disease course in 7 (64%) of 11 patients. Improvement began within 3 to 6 months and consisted of cessation of active cutaneous lesions in all 7 patients, skin softening in 5, and more normal growth of the affected limb in 2 of 3 children. Joint stiffness and contractures also improved. The dose of D-penicillamine associated with a favorable response was as low as 2 to 5 mg/kg per day given over a period ranging from 15 to 53 months. D-Penicillamine caused nephrotic syndrome in 1 patient and milder reversible proteinuria in 3 other patients; none developed renal insufficiency. These data suggest that D-penicillamine may be effective in severe cases of localized scleroderma.
Dose-Response Relationship, Drug↗
Rheumatoid factor isotypes in localized scleroderma.
Localized scleroderma is a connective tissue disorder that is sometimes accompanied by various immunological abnormalities. In this study, we analysed serum levels of rheumatoid factor (RF) isotypes in patients with localized scleroderma and in normal controls to determine if any of these isotypes reflect the severity of the disease. IgM RF, IgG RF and IgA RF were positive in 30%, 21%, and 7% of the patients, respectively. The levels of IgM RF were significantly higher in the patients with generalized morphea (GM), the most severe form of localized scleroderma, than those with linear scleroderma (LS) (P < 0.005) or normal controls (P < 0.0005). The levels of IgG RF were significantly higher in patients with GM than normal controls (P < 0.05). The levels of IgA RF were significantly higher in patients with GM or LS than normal controls (P < 0.001 and P < 0.01, respectively). The count of sclerotic lesions was significantly higher in patients with IgM RF than those without (P < 0.05). These results suggest that the presence of RF isotypes is one of the immunological abnormalities of localized scleroderma. IgM RF seemed to be most useful of these three factors to determine the severity of disease.
Adolescent↗
Soluble CD4 and CD8 in serum from patients with localized scleroderma.
Localized scleroderma has been shown to be accompanied by various immunologic abnormalities. To obtain functional information on activated CD4+ or CD8+ T cells, we studied the levels of soluble CD4 (sCD4) and soluble CD8 (sCD8) in serum from patients with localized scleroderma. Serum samples were examined by enzyme-linked immunosorbent assay. The samples were obtained from 49 patients in the following three subgroups: 15 patients with generalized morphea, 22 with linear scleroderma, and 12 with morphea. The levels of sCD4 and sCD8 were significantly elevated in patients with generalized morphea. Furthermore, these patients showed significantly higher levels of sCD4 than those with systemic sclerosis (SSc). The frequency of positivity for IgG anti-single-stranded DNA (ssDNA) antibody was significantly higher in localized scleroderma patients with elevated sCD4 levels than in patients with normal sCD4 levels. The frequency of positivity for antinuclear antibodies, IgM antihistone antibodies, IgG anti-ssDNA antibody and rheumatoid factor, and elevated sCD23 levels were significantly higher in localized scleroderma patients with elevated sCD8 levels than in patients with normal sCD8 levels. Our findings suggest that both CD4+ and CD8+ T cells are activated in vivo in generalized morphea and that the immunologic events in generalized morphea are different from those in SSc.
Adult↗
Management of localized scleroderma.
Localized scleroderma denotes a spectrum of conditions characterized by circumscribed fibrotic areas involving different levels of the dermis, subcutis, and sometimes underlying soft tissue and bone. Although the clinical course of the disease is often benign, widespread lesions and disabling joint contractures may lead to significant complications. The pathogenesis of the different types of localized scleroderma is still unknown. Numerous therapeutic agents have been reported to be effective in this disease spectrum, but controlled studies are rare. The purpose of this review is to summarize previous experience and to discuss recent advances in the management of localized scleroderma.
Clinical Trials as Topic↗
Localized scleroderma.
Localized scleroderma has no recognized internal organ involvement. It may rarely coexist with a systemic connective tissue disease, but is not thought to progress to systemic sclerosis. Although never fatal, localized scleroderma may cause considerable disability from joint contractures and subcutaneous atrophy. Facial lesions are particularly disfiguring and may be accompanied by hemiatrophy. Serum auto-antibodies are common but do not imply systemic disease. The presence of ANAs or antibodies to ssDNA correlates directly with more extensive and prolonged disease. Blood eosinophilia may be striking, and its presence correlates with active disease. Patients with elevated serum IgG appear to be at a greater risk for the subsequent development of contractures. These laboratory abnormalities are useful in determining prognosis and during follow-up. No accepted and effective treatment exists. Physical therapy should be instituted immediately in all patients at risk for contractures. Systemic corticosteroids, used early in patients with active and widespread involvement, can be expected to improve the inflammatory phase. A variety of systemic agents have been reported to be helpful, but no controlled studies exist on their effectiveness.
Diagnosis, Differential↗
Treatment options for localized scleroderma.
Localized scleroderma, or morphea, is a chronic disease that causes a thickening and induration of the skin. For plaque type morphea, the treatments of choice include super-potent corticosteroids and calcipotriol. For the more generalized forms, as well as the linear forms, UVA is currently the best therapeutic modality. Patients with localized scleroderma are managed by both rheumatologists and dermatologists. There is still much therapeutic uncertainty in this disease.
Dermatologic Agents↗
Ultraviolet A1 phototherapy decreases inhibitory SMAD7 gene expression in localized scleroderma.
Localized scleroderma (LS) is a connective skin disease with marked sclerosis of the skin as the most prominent feature. Transforming growth factor beta (TGF-beta) plays a central role in the pathogenesis of sclerotic skin diseases. Recently, special attention was contributed to a family of transcription factor proteins involved in TGF-beta signal transduction from cell surface to the nucleus, the so-called SMADs. Ultraviolet (UV) irradiation has been reported to alter TGF-beta/SMAD pathway in human skin. We sought to investigate the effects of UVA1 on the gene and protein expressions of the TGF-beta/SMAD pathway in LS. UVA1 phototherapy was performed in eight LS patients five times weekly for 8 weeks resulting in a total of 40 treatment sessions (single dose 50 J/cm(2), cumulative dose 2,000 J/cm(2)). TGF-beta1, SMAD3, SMAD4, and SMAD7 mRNA expressions were determined by semiquantitative real-time reverse transcription polymerase chain reaction in lesional and unaffected skin of patients with LS. Additionally, immunohistochemical staining was performed in lesional skin before and after irradiation. Skin status markedly improved in all patients, resulting in a significant reduction of the clinical score from baseline to the end of treatment. Inhibitory SMAD7 mRNA was significantly higher in lesional skin as compared to unaffected skin, and significantly decreased after UVA1 phototherapy. In contrast, SMAD7 mRNA levels remained unchanged in irradiated, healthy skin after UVA1. Both TGF-beta and SMAD3 mRNA levels decreased after UVA1, whereas SMAD4 mRNA increased. However, changes in TGF-beta, SMAD3, and SMAD4 mRNA after UVA1 did not reach statistical significance. Immunohistochemical investigation did not reveal significant changes in the protein expression of SMADs after UVA1. Similar to scleroderma, SMAD7-mediated negative regulation seems to be impaired in LS. UVA1 phototherapy demonstrated the alteration of SMAD7 gene expression in LS, as SMAD7 mRNA levels normalized after UVA1. The pathogenetic relevance of SMAD7 levels with respect to clinical improvement needs further investigation.
Adult↗
Localized scleroderma.
Localized scleroderma can be divided into three main subtypes: morphea, linear scleroderma, and generalized morphea. Plaque morphea usually has a good prognosis. Variants of morphea, including guttate morphea and atrophoderma of Pasini and Pierini, are seen. Linear scleroderma, whether involving an extremity or the face, is often associated with serological abnormalities. Cosmetic and functional prognosis may be poor. Therapy is usually ineffective. Generalized morphea may be difficult to differentiate from systemic scleroderma. However, progression to systemic scleroderma is uncommon.
Adult↗
Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized scleroderma.
Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin alphavbeta5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alphavbeta5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alphavbeta5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-alphavbeta5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA-Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-beta1, exogenous latent TGF-beta1 stimulation increased expression of type I procollagen in an alphavbeta5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of alphavbeta5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.
Antibodies↗
Unilateral generalized morphea is a rare variant of localized scleroderma.
Localized scleroderma (LS) is a rare connective tissue disorder generally involving the entire dermis and usually limited to the subcutaneous tissue. However, it may progress to large indurated plaques, growth retardation, muscle atrophy, and even to flexion deformities or poorly healing ulcerations. LS has been classified as plaque, generalized, bullous, linear, and deep forms exhibiting different clinical subtypes. Recently, an unusual case of unilateral generalized morphea (UGM) in childhood extending from the middle dermis to the subcutaneous fat tissue has been reported. We here describe four young patients exhibiting a similar subtype of LS. All patients demonstrated a prominent unilateral skin involvement starting in childhood or adolescence. Histology revealed prominent accentuation of intradermal involvement. Except for positive anti-nuclear antibodies, no specific antibody pattern could be observed. In presenting these clinically homogenous cases we hereby introduce UGM as an extreme variant of the linear form of LS in childhood. As the onset of UGM usually occurs in pediatric patients, pediatricians should be cognizant of the presentation of this uncommon condition. Treatment with combined low-dose methotrexate and pulsed high-dose corticosteroid therapy might represent a promising treatment option for UGM.
Adolescent↗
Immunophenotyping of chimeric cells in localized scleroderma.
OBJECTIVE: Localized scleroderma causes thickening of the skin due to excessive collagen deposition. This condition has clinical and histopathological similarities to chronic graft-vs-host disease. We wanted to identify whether chimeric cells are present in the affected tissue in localized scleroderma and to further investigate the role of chimerism by immunophenotyping the chimeric cells. We hypothesize that the presence of chimerism and immunotypic chimeric cells will lend to an understanding of the pathogenesis of localized scleroderma and possible mechanisms by which chimeric cells participate in autoimmunity. METHODS: We studied skin biopsies from 18 localized scleroderma patients and compared them with concurrent biopsies from unaffected skin in a subset of patients. Skin biopsies from morphoea and linear scleroderma patients were analysed for the presence of chimeric cells using male-female (X, Y) differences. Cell surface markers (CD4, CD8, CD19/20, CD68, S100, CD14 and CD56) were determined for cell phenotyping of chimeric cells. RESULTS: Overall, the affected tissue contained a greater number of lymphocytic inflammatory cells. In the affected tissue, 38% of the total chimeric cells were CD68+ (dendritic cell, monocyte and macrophage marker), 29% Langerin/S100+ (dendritic cell marker), 26% CD8+ (cytotoxic T-lymphocyte marker), 20% CD19/20+ (B-lymphocyte marker), 14% CD4+ (T-helper lymphocyte) and 0% CD56+ (natural killer cell marker). CONCLUSIONS: We report that not only are chimeric cells present in affected localized scleroderma lesions but they also are more likely to be dendritic cells and B lymphocytes suggesting a role in the pathogenesis of localized scleroderma.
Adolescent↗
Double-blind, placebo-controlled study of intralesional interferon gamma for the treatment of localized scleroderma.
BACKGROUND: Localized scleroderma is characterized by circumscribed fibrotic plaques and may progress to widespread skin involvement and fibrosis. Interferon gamma (IFN-gamma) has been shown to be a potent inhibitor of collagen synthesis and of the migration and proliferation of dermal fibroblasts. OBJECTIVE: Our purpose was to determine whether IFN-gamma is effective in the treatment of localized scleroderma. METHODS: A double-blind, randomized, placebo-controlled, multicenter study was conducted. Twenty-four patients with progressive lesions received 100 micrograms of IFN-gamma or placebo subcutaneously on 5 consecutive days for 2 weeks followed by 100 micrograms of IFN-gamma or placebo once weekly for 4 weeks. Thereafter patients were observed for 18 weeks. To determine whether improvement could be related to an altered level of collagen messenger RNA (mRNA), biopsy specimens were taken from uninvolved and involved skin before and after therapy. RESULTS: The patients treated with IFN-gamma or placebo showed no significant difference in size or fibrosis of lesions or collagen type I mRNA synthesis. However, a reduction in the number of new lesions was observed in the IFN-gamma-treated group. The biopsy specimens obtained from involved skin showed a moderate increase of type I collagen and a significant decrease in the small proteoglycan decorin mRNA levels. CONCLUSIONS: The results indicate that IFN-gamma is ineffective in the treatment of localized scleroderma, but may inhibit the development of new lesions.
Collagen↗
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.
Adult↗
Methotrexate and corticosteroid therapy for pediatric localized scleroderma.
INTRODUCTION: Localized scleroderma (LS) can cause permanent disability, and there is no universally accepted effective treatment. Methotrexate (MTX) has been shown to be effective in the treatment of systemic sclerosis. OBJECTIVES: To determine the efficacy and tolerability of MTX and corticosteroid therapy in patients with LS. METHODS: MTX, 0.3 to 0.6 mg/kg per week, was given to 10 patients (6 girls, 4 boys; mean age, 6.8 years; mean disease duration before starting treatment, 4 years) with active LS. In addition, pulse intravenous methylprednisolone, 30 mg/kg for 3 days monthly for 3 months, was given to 9 patients at the initiation of therapy. RESULTS: One patient discontinued taking MTX after a month; the remaining 9 patients responded. The median time to response was 3 months (95% CI, 1.15-4.85). One responder discontinued taking MTX after a year because of leukopenia; the LS worsened within 2 months. In another patient LS flared up after 10 months and responded to an increased dose of MTX and intravenous methylprednisolone. At the last follow-up visit, all patients who continued to receive MTX therapy had inactive skin lesions. CONCLUSION: Treatment with MTX and corticosteroids appears to be effective in the treatment of LS and is generally well tolerated. A placebo-controlled study is necessary to confirm the efficacy of MTX therapy in LS.
Administration, Oral↗