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Two cases of systemic scleroderma in girls are reported. One patient, aged 11 years, has systemic scleroderma with Raynaud's phenomenon, and pulmonary involvement. The other, aged 8 years, has systemic scleroderma with lung involvement. The specific features of pediatric systemic scleroderma are reviewed briefly.
Peripheral blood mononuclear cells from 63 patients with systemic scleroderma, including incipient or prodromal acrosclerosis, and from 20 healthy individuals were tested for natural killer (NK) cell activity and antibody-dependent cell cytotoxicity in a 4 h 51Cr release assay using K562 and L1210 cell lines respectively. In patients with systemic scleroderma natural killer cell activity was significantly decreased compared with the controls. NK cell activity was markedly lowered in patients with diffuse scleroderma and in transitional form acrosclerosis-diffuse scleroderma, and was normal in cases of acrosclerosis and/or CREST syndrome and in cases of prodromal or incipient scleroderma. Antibody-dependent cell cytotoxicity of mononuclear cells from the systemic scleroderma patients was within the normal range. The lowered natural killer cell activity correlated with the severity of systemic scleroderma, in terms of the extent of skin and organ involvement.
Progressive systemic scleroderma (PSS) is caused by generalized connective tissue disorder. The most frequent visceral manifestations are pulmonary and oesophageal involvement. Early detection of such visceral manifestations, which are sometimes life-limiting, is of paramount importance in any diagnostic procedures. The sensitivity of the methods differs and depends on the stage of the disease. Modified high-resolution computed tomographic scans (HRCT) were obtained in 28 patients with early forms of PSS and showed pulmonary involvement in 79% and signs of oesophageal involvement in 54%. HRCT is much more sensitive than chest radiography, lung scintigraphy and lung function tests even at an early stage of the disease. Classification of PSS should take account of the clinical type of sclerosis and of immunological and other parameters of prognostic importance.
The German Network for Systemic Scleroderma (Deutsches Netzwerk Für Systemische Sklerodermie [DNSS]) has as its aim to improve and standardize the diagnosis and treatment of this rare disease. 14.6 % of patients in the DNSS register have been shown to have pulmonary hypertension (PHT). Comparable international data range from 12 % to 26.7 %. The DNSS recommends annual echocardiography for patients with scleroderma and right-heart catheterization if the systolic pulmonary arterial pressure is higher than 35 mmHg. Aggressive immunosuppressive treatment--in the first instance with cyclophosphamide--should be given only if there is also progressive fibrosis. Drugs that lower the level of PHT also have a favourable effect on other signs of scleroderma.
Thirty-three patients with systemic scleroderma were examined using a complex of enzymatic tests to detect pancreatic involvement. The diagnostic informative value of these tests was found to be not inferior to that of acknowledged instrumental methods of examination: pancreatic involvement was detected in 25 of the 33 patients with systemic scleroderma.
The major pathological processes of systemic scleroderma (SSc) comprise inflammation and microvascular damage in the early or acute progressive stage as well as tissue fibrosis and hypoxia in the chronic end stage. Fibrosis seems to be a general phenomenon characterized by an increase of hydroxylysine aldehyde derived collagen cross-links which has been shown in vitro for systemic scleroderma fibroblasts. In the present study, we analyzed the cross-link pattern and the gene expression of lysyl hydroxylase 2 (LH2) in the skin of SSc. Furthermore, we determined the modulatory impact of inflammatory cytokines (interleukin 4, TNF- alphaand interleukin 1alpha/beta) and prolonged hypoxia on the cross-link profile and the gene expression of LH2, respectively. The concentration of hydroxylysine aldehyde derived cross-links was significantly increased in SSc, while the level of lysine aldehyde derived cross-links was not changed. Accordingly, a marked increase of the transcriptional level of LH2 was found. In long term dermal fibroblast cultures, only interleukin 4 induced an increase of hydroxylysine aldehyde derived cross-links accompanied by a higher gene expression of LH2. Furthermore, prolonged hypoxia induced a marked increase of the mRNA level of LH2 in relation to collagen I. The skin of SSc is characterized by an increase of the transcriptional activity of LH2 leading to an altered cross-link pattern. The changes in the quality of the collagenous matrix can also be obtained in cell culture by the exposure of fibroblasts to interleukin 4 or prolonged hypoxia emphasizing the role of this mediator in the acute and the low oxygen tension in the chronic phase of the disease.
A group of 191 patients with systemic scleroderma and 12 patients with silicosis-associated scleroderma were investigated for connective tissue turnover. The serum levels of type III collagen aminopropeptide (P-III-P), the laminin PI (Lam PI) fragment and the acid lysosomal beta-galactosidase (beta-Gal) were determined by specific radioimmunoassays and spectrofluorometry, respectively. Increased levels of type III collagen aminopropeptide strongly correlated with enhanced activity of beta-galactosidase. Both parameters correlated with the clinical course in idiopathic systemic scleroderma and in silicosis-associated scleroderma. Serum levels of Lam PI were also found to be elevated in both groups, although there was no correlation with the severity of the disease. Autoantibodies directed against the DNA topoisomerase Scl-70 and against centromeric proteins were found in a similar range in patients with idiopathic systemic and silicosis-associated scleroderma. These results suggest that P-III-P, Lam PI and beta-Gal are useful serological markers of fibrotic activity and demonstrate similarities between idiopathic systemic scleroderma and scleroderma associated with silica-dust exposure.
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Scleroderma encompasses a wide variety of diseases, including localized scleroderma, overlap syndromes, sclerodermoid conditions, and systemic scleroderma. This article emphasizes the systemic scleroderma.
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BACKGROUND: Anti-Fc gamma receptor (anti-Fc gamma R) autoantibodies occur in patients with systemic scleroderma. Their clinical significance is unknown. OBJECTIVE: Our purpose was to determine the incidence of anti-Fc gamma R autoantibodies in patients with localized and systemic scleroderma and to examine the relation between these autoantibodies, the severity of the disease, and the presence of other autoantibodies. METHODS: Patients were placed into three clinical groups: three had diffuse systemic scleroderma, 47 had limited systemic scleroderma, and nine had localized systemic scleroderma. Antinuclear antibody titer and pattern were measured by indirect immunofluorescence with human epithelial (HEp)-2 cells and tissue sections, whereas anti-Scl-70 antibodies were measured by gel diffusion technique. Anti-Fc gamma R autoantibodies were measured in serum from patients and from 25 healthy persons by enzyme-linked immunosorbent assay with human recombinant Fc gamma RII (CD32) and Fc gamma RIII (CD16). RESULTS: Anti-Fc gamma R autoantibodies were detected in 54% of patients and in none of the healthy control subjects. Autoantibodies were present in all three clinical groups and were most frequently directed against Fc gamma RIII. Correlation between patients' clinical and laboratory data and anti-Fc gamma R autoantibodies could not be demonstrated. CONCLUSION: The presence of anti-Fc gamma R autoantibodies in the serum of patients with either systemic or localized scleroderma and the lack of these autoantibodies in healthy persons suggest that they may play a role in the pathogenesis of these diseases.
Although morphoea (localized scleroderma) and systemic sclerosis are distinct disease entities, the skin lesions show identical histological characteristics and both diseases respond favourably to low-dose treatment with methotrexate (MTX). The aim of this study was to find out whether MTX treatment induces different histological response patterns in these two diseases. In seven patients with morphoea and eight with systemic sclerosis, skin biopsies were taken before and after 24 weeks of treatment with low-dose MTX. In the centre and active margin of morphoea lesions, a significant reduction in tenascin staining was seen after 24 weeks of treatment, in contrast to systemic sclerosis. The numbers of mast cells decreased in the active margin of morphoea lesions, whereas in systemic sclerosis no significant change was seen after MTX therapy. Epidermal proliferation and staining of heparan sulphate proteoglycans showed no changes. Although skin lesions from both diseases respond clinically to treatment with MTX, systemic sclerosis shows no change in the immunohistochemical parameters investigated, whereas morphoea does. This difference in dynamic pattern suggests that the apparently similar lesions in localized and systemic sclerosis are not identical.
Four patients with systemic scleroderma and 1 patient with localized scleroderma were treated with ciclosporin (CS), given in daily doses between 2.2 and 5.6 mg/kg body weight for 3-26 months. Under this medication clinical improvement was observed in 4 patients with partial regression of cutaneous sclerosis and inflammation, healing of fingertip ulcerations or leg ulcers and improvement of articular mobility. However, in 1 patient with rapidly advancing systemic scleroderma a short-term therapy with CS in low doses (2-3 mg/kg body weight) resulted in arterial hypertension and renal dysfunction. Therefore careful selection of patients and close-meshed controls are indicated when CS is considered as anti-inflammatory treatment in scleroderma.
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Echocardiographic investigation of 65 patients with systemic scleroderma showed that the left ventricular sizes and indices of central hemodynamics were frequently lowered in them; an increase in sizes was observed mainly in the patients with stage II-III of disease. In 3/4 of the same patients pericarditis was revealed; on the whole, it was detected in 26 (40%) examinees. One patient had changes which were typical of asymmetric obstructive cardiopathy. In location of the valvular apparatus signs of mitral stenosis were found in one patient, those of mitral insufficiency in one patient and those of aortic insufficiency in one patient. Signs of mitral prolapse were noted in 7 (10.9%) patients, i.e. twice more frequently than in the entire population. Echocardiography made it possible to specify the nature of cardiac pathology and brought to light some additional features of the involvement of different heart membranes in systemic scleroderma.
The diagnostic and prognostic value of anti-Scl-70 autoantibodies in systemic scleroderma and other connective tissue diseases was investigated. A clinical and immunological study consisting of a search for anti-Scl-70 autoantibodies by immunodiffusion and immunoblot and a search for anti-centromere autoantibodies and antinuclear factors by indirect immunofluorescence was conducted in 57 cases of systemic scleroderma, 45 cases of CREST syndrome, 41 patients with suspected systemic scleroderma but who did not respond to the American rheumatism association (ARA) criteria, 35 cases of systemic lupus erythematosus, 8 cases of polymyositis, 40 cases of Raynaud's phenomenon and 48 controls. Anti-Scl-70 autoantibodies were found by immunodiffusion in 40 and by immunoblot in 45 cases of scleroderma with lesions proximal to the metacarpo-phalangeal joint (a major ARA criterion) and in 3 patients with suspected scleroderma but only one minor criterion: sclerodactyly. In systemic scleroderma with proximal lesions, the anti-Scl-70 autoantibody has a sensitivity of 0.85 and a specificity of 0.99. Anti-centromere autoantibodies were present in 39 cases of complete or incomplete CREST syndrome, 3 cases of Raynaud's phenomenon probably evolving towards a connective tissue disease and 1 case of systemic scleroderma with proximal lesions. The anti-Scl-70 and anti-centromere autoantibodies seem unable to coexist in the same patient and appear to be markers of two forms of scleroderma with different courses and prognoses. The Scl-70 antigen, which is the target of the anti-Scl-70 antibody, has been identified as topoisomerase 1, and a functional abnormality of this enzyme might contribute to some of the chromosomal abnormalities described in scleroderma.