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PubMed1993

Antibody specificities of Thai and Australian scleroderma sera with topoisomerase I recombinant fusion proteins.

Autoantibodies that react with the nuclear enzyme topoisomerase I (Topo I) are used as a diagnostic marker of diffuse scleroderma. To better define immune reactivity to Topo I, antibody epitopes in two patient populations were analyzed using recombinant Topo I proteins. Two overlapping partial cDNA clones encoding the complete amino acid sequence of Topo I were isolated from human placenta. Using the polymerase chain reaction, specific regions of Topo I were amplified and cloned into the pGEX expression vectors. To map Topo I epitopes, recombinant fusion proteins were analyzed by immunoblotting with 66 anti-Topo I sera from Thai and Australian patients with diffuse scleroderma. Six distinct epitope regions were identified along the length of the 765 amino acid enzyme. Almost all sera contained antibodies that recognized the midregion of Topo I (amino acids 453-560), as well as antibodies to one of more of the other epitope regions. Sixty percent of the sera contained antibodies that recognized a COOH-terminal epitope region (amino acids 658-765) encompassing the active site of the enzyme. This subset of Topo I antibodies could be responsible for the inhibition of enzymatic activity previously reported in vitro. Heterogeneous patterns of reactivity with the six Topo I epitope regions were observed, although over half the sera could be assigned to one of six distinct patterns. In general, antibodies in the Thai sera reacted more strongly with the six epitope regions. Furthermore, two of the epitope regions reacted exclusively with Thai sera, suggesting a degree of racial or geographical specificity in the autoantibody response to Topo I. The identification of multiple epitopes in Topo I conforms with the polyclonal autoantibody response to intracellular Ag found in other multisystem autoimmune diseases and is presumed to be driven by the presentation of multiple peptides from Topo I itself.

Amino Acid Sequence↗
PubMed1990

Direct quantitation of skin elasticity in systemic sclerosis.

A simple instrument, the "skin elastometer," was used to evaluate the elastic and plastic properties of volar forearm skin in 24 patients with systemic sclerosis and 24 healthy individuals matched for age, race and sex. Skin elastance in 17 patients with diffuse scleroderma was found to be significantly different from matched controls (p less than 0.001), and was associated with clinical skin scores independently determined by examination (r = 0.89, p less than 0.001). Seven patients with limited scleroderma (the CREST variant) had values for skin elastance which were intermediate between those of the patients with diffuse scleroderma and healthy persons. Plastic deformation of the stretched skin was similar in patients and controls. Quantitative measurement of skin elastance is a simple technique which may prove to be of value in the assessment of patients with systemic sclerosis.

Adult↗
PubMedDate not supplied

C4A and C4B null alleles are genetic markers of different types of systemic sclerosis in Japanese patients.

OBJECTIVE: The contribution of the polymorphism of complement C4A and C4B alleles to the pathogenesis of systemic sclerosis (SSc) was studied in Japanese patients. METHODS: C4A and C4B typing was carried out in 44 SSc patients and in 83 normal subjects using electrophoresis followed by immunofixation and immunoblotting. HLA-DR typing and HLA DRB1*15 and *08 genotyping were carried out by the PCR method and the PCR-SSCP method, respectively. RESULTS: In SSc with diffuse scleroderma, the frequency of C4BQ0 was significantly increased (44.4%, p < 0.001, pc < 0.01). In SSc with antitopoisomerase I antibody (a-Scl-70) C4BQ0 was also increased (50.0%, p < 0.001, pc < 0.01). Association analysis indicated that the increase in C4BQ0 was not primary but reflected an increase in HLA-DRB1*1502. In contrast, C4A/Q0 was significantly increased in limited scleroderma (53.8%, p < 0.005, pc < 0.05) and SSc without a-SCL-70 (53.8%, p < 0.005, pc < 0.05). CONCLUSION: Diffuse scleroderma with SSC with a-Scl-70 have different genetical backgrounds from limited scleroderma and SSc without a-Scl-70, respectively, in Japanese patients. C4AQ0 were independent genetic markers for each clinical subgroup and for a a-Scl-70 positivity.

Adult↗
PubMed1987

[Uric acid levels of the serum of healthy persons and patients with various rheumatic diseases].

Serum uric acid levels were investigated in a series of 1715 subjects. Of them 596 were patients with inflammatory rheumatic disorders, 162 gout patients, 236 with osteoarthrosis, 79 with systemic lupus erythematosus or diffuse scleroderma and 642 healthy subjects. On analyzing the results, very high uricemia values were found in the gout patients. Increased uricemia values were observed is patients with psoriatic arthritis and diffuse connective tissue disorders (systemic lupus erythematosus and diffuse scleroderma). Hyperuricemia was found in psoriatic arthritis, rheumatoid arthritis and in nosological entities classified under diffuse connective tissue disorders in 5.6 to 10.1% of patients. In the healthy examinees hyperuricemia was recorded in 3.8% of the cases.

Adolescent↗
PubMed2000

The frequency and significance of anticardiolipin antibodies in scleroderma.

OBJECTIVE: To determine the frequency and significance of anticardiolipin antibodies (aCL) in scleroderma. METHODS: We serially tested for aCL in a standardized fashion in patients with scleroderma who were outpatients and gave consent to enter this study. RESULTS: Sixty-three patients participated in this study. Thirty-six had diffuse scleroderma and 27 had limited scleroderma. Three (4.8%) were positive for aCL, of whom 2 had limited scleroderma. In only one patient aCL may have been clinically significant. This woman had limited scleroderma for years and had medium vessel occlusive disease with gangrene eventually requiring midfoot amputations and chronic warfarin treatment. She did not have features of systemic lupus erythematosus or other overlap conditions. The other 2 patients had no manifestations of the antiphospholipid antibody syndrome. CONCLUSION: aCL in scleroderma rarely manifest clinically. The range of frequency of positive aCL in the literature is from 0 to 63%. From our study and the literature, we cannot ascertain if the prevalence is different in limited and diffuse scleroderma.

Adult↗
PubMedDate not supplied

[Serum uric acid levels in disorders of the rheumatic type].

Serum uric acid levels were investigated in a series of 1715 subjects. Of these 596 were patients suffering from inflammatory rheumatic disorders, 162 patients with gout, 236 with osteoarthrosis and 79 with systemic lupus erythematosus or diffuse scleroderma. 642 healthy subjects completed the series. On analyzing the results, very high uricemia values were found in patients with gout. Increased average uricemia values were observed in patients with psoriatic arthritis and diffuse connective tissue disorders (systemic lupus erythematosus and diffuse scleroderma). Hyperuricemia was found in psoriatic arthritis, rheumatoid arthritis, and in nosologic units classified under diffuse connective tissue disorders in 5.6 to 10.1% of patients. In the healthy subjects examined, hyperuricemia was recorded in 3.8% of cases.

Adolescent↗
PubMed2000

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

Adolescent↗
PubMed1991

Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin".

We studied the immunohistochemistry of the skin of scleroderma patients to determine the differences (if any) between clinically "affected" and "nonaffected" areas. We examined paired skin biopsy samples from clinically involved forearm skin ("affected") and clinically uninvolved proximal skin ("nonaffected") taken from 19 patients with diffuse scleroderma and from 15 normal control subjects. We stained the sections with antibodies to endothelial leukocyte-adherence molecule type 1 (ELAM-1; to detect endothelial activation) and to procollagen-1 (PC-1; to detect newly formed, unprocessed collagen). There was increased expression of ELAM-1 and PC-1 in sclerodermatous skin as compared with the controls, but there was no difference between clinically affected and nonaffected skin samples. In 10 of 11 patients whose condition was getting worse, endothelial and fibroblast activation preceded fibrosis. Endothelial and fibroblast activation are more widespread in the skin of scleroderma patients than is evident by inspection on physical examination. What appears to be "normal" skin in diffuse scleroderma is already pathologic, as shown by abnormal endothelial activation and procollagen production.

Adult↗
PubMed1989

Increased mast cell numbers in the sclerotic skin of porphyria cutanea tarda.

We quantitated numbers of mast cells in the sclerotic skin noted on the dorsa of the hands of 10 patients with porphyria cutanea tarda (PCT), and compared them with those of diffuse scleroderma and healthy controls. Mast cell counts in sclerodermoid skin of PCT patients were significantly greater than those in involved skin of 9 patients with diffuse scleroderma in its late stage and also greater than those in normal skin of 8 controls. When mast cell density was analyzed according to the depth of the dermis, an 84% increase was noted in the uppermost layer (0-0.2 mm in depth) and a 150% increase in the second uppermost layer (0.2-0.4 mm in depth) in the patients with PCT when compared with those in the corresponding sites of the controls. These results suggest a possible role of mast cells in the pathogenesis of sclerodermoid skin of PCT.

Adult↗
PubMed1997

Predictors of survival in 171 patients with systemic sclerosis (scleroderma).

Predictors of survival were determined in 171 patients with systemic sclerosis by univariate analysis, and the Cox proportional hazards model using both cross sectional data at entry into the follow-up and time-dependent follow-up data. Clinical and laboratory data were evaluated from 1982 to the end of 1993. The presence of diffuse scleroderma, kidney and cardiac involvements were unfavourable prognostic signs in both the univariate analysis, and the Cox proportional hazards models. The Cox model, using the variables detected at study entry, indicated that pericarditis, and anaemia were bad prognostic signs. Analysis with time dependent data has not been reported in systemic sclerosis. The appearance of pigmentation disturbances, anaemia, and respiratory failure during the follow-up also caused a poor prognosis of the disease by the Cox model. In the stepwise selection models, diffuse scleroderma, internal organ manifestations including renal, and cardiac involvements were predominantly selected as the most unfavourable factors for survival. As to the extent of skin involvement and internal organ manifestations, the general behaviour of the disease seems to be similar throughout the world. The early appearance of pericarditis and pigmentation disturbances at study entry are bad prognostic signs.

Adult↗
PubMed1994

[Pulmonary involvement in sclerodermia].

Progressive systemic sclerosis (PSS) is a connective tissue disease characterized by fibrosis and thickness of cutis and subcutis (scleroderma) and deterioration of small arteries and capillary vessels, with changeable visceral renal, cardiac, intestinal and pulmonary involvements. The disease is characterized by cutaneous sclerosis, that is to say by the increase of consistence and thickness of cutis that lose her usual elasticity. The sclerosis can be limited to the fingers (sclerodactyly) or can involve otherwise (acrosclerosis); many other time is diffuse also to upper limbs and to thorax (diffuse scleroderma). The disease is rare and its incidence is variable from 2 to 10 x 10(6); more frequently hits women than men in the ratio of 3 to 1 or 8 to 1 (according to certain Authors). In the elderly is more frequently represented by the CREST syndrome (calcinosis, Raynaud's phenomenon, oesophageal dismotility, sclerodactyly, teleangiectasia). The authors have considered nine patients with pulmonary involvement of progressive systemic sclerosis: five with CREST syndrome and four with diffuse scleroderma. In addition to the common routine examinations, we performed chest radiography (CXR), pulmonary function tests, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL), Gallium 67 scanning and high resolution computed tomography (HRCT) with the purpose to consider the role of these medical examinations in diagnosis and the follow-up of pulmonary involvement in scleroderma. From the results we have observed that: 1) in early disease chest radiography may be silent even if the patient shows a restrictive syndrome and reduction of diffusion capacity of carbon monoxide (DLCO); 2) chest radiography, pulmonary function tests and Gallium 67 scanning have traditionally been used to measure the degree of lung involvement in SSP but unfortunately, none of these reliably predicts disease activity or future course; 3) bronchoalveolar lavage shows the degree of lung inflammation (alveolitis) characterized by the increase of total BAL cell counts and by higher neutrophil cells in the initial stage of the disease; 4) even HRCT shows in this stage, the typical aspect of higher endoalveolar cellularity with ground glass appearance. With the progression of anatomical damage, there can be found even appearance of complete destruction of pulmonary architecture with the typical alteration of honeycomb. These findings support the hypothesis that a ground glass appearance on HRCT is the radiographic equivalent of alveolitis found in BAL. Furthermore HRCT shows itself useful in the follow-up the disease and in detecting of its activity condition.(ABSTRACT TRUNCATED AT 400 WORDS)

Bronchoalveolar Lavage Fluid↗
PubMed1994

[Initial visceral involvement with diffuse systemic scleroderma].

Progressive systemic sclerosis (PSS) is characterized in most patients by initially unspecific symptoms like acrocyanosis. Raynaud's phenomenon, general malaise or acral paresthesia. Clinical manifestations appear with an edematous-inflammatory stage of disease leading to a chronic-progressive phase with increasing fibrosclerosis of the skin and internal organs. Dermal involvement and the demonstration of immunopathological abnormalities in the peripheral blood precede visceral fibrosis in most cases. We report on an unusual case of diffuse PSS with preceding involvement of internal organs. Early visceral fibrosis is demonstrated by histomorphological results and is correlated with laboratory findings. Serum antinuclear antibodies could not be obtained until 4 months ante finem and the liver was also involved in the fibrotic process.

Antibodies, Antinuclear↗
PubMed1992

Reactivity of anti-mitochondrial antibodies in primary biliary cirrhosis and systemic sclerosis.

Anti-mitochondrial antibodies (AMA) were detected by indirect immunofluorescence in the sera of 16 out of 17 (94%) patients with primary biliary cirrhosis (PBC). Immunoblotting experiments with mitochondrial polypeptides from the porcine liver as antigens revealed that three antigens were recognized by the sera from AMA-positive patients. These were a 70-kD protein recognized by nine out of 16 AMA-positive sera, a 50-kD protein recognized by 13 out of 16 AMA-positive sera and a 39-kD protein recognized by four out of 16 AMA-positive sera. The reactivity of these polypeptides was destroyed by brief exposure to trypsin. None of these antigens were recognized by any of the 30 control sera. These results show that the 70-kD, 50-kD and 39-kD proteins are the major mitochondrial autoantigens recognized by sera from patients with PBC. In addition, of 30 sera samples from patients with diffuse scleroderma, 13 reacted to the 70-kD and/or 50-kD antigens. Anti-centromere antibodies (ACA) were also detected in the sera of five of the 17 (29%) patients with PBC. The high prevalence of ACA in patients with PBC and the presence of anti-70- and 50-kD antibodies in patients with diffuse scleroderma provide evidence of an association between these two disorders.

Adult↗
PubMedDate not supplied

Clinical subsets of scleroderma: relevance of fluorescent and precipitating antinuclear antibodies.

Sera from 7 patients with localized and 35 with systemic scleroderma were studied for the presence of fluorescent antinuclear antibodies (FANA) (by indirect immunofluorescence on HEp-2 cells) and antibodies to extractable nuclear antigens (anti-ENA) (by immunodiffusion - ID - and counterimmunoelectrophoresis - CIE). In localized disease, antinuclear autoimmunity was limited to 1 FANA positive serum (14%); in systemic disease, the prevalence of FANA was 94% and that of anti-ENA ranged from 29% to 49% (by ID and CIE, respectively). The commonest ENA system, Scl-70, could be easily detected by CIE, in spite of the reported basic nature of the antigen. The anticentromere antibody occurred only in patients with acrosclerosis (7/26-27%), whereas the association of nucleolar + homogeneous FANA, as well as the anti-Scl-70, were found more frequently in diffuse scleroderma (9/9-100% and 6/9-67%, respectively). The presence of the anticentromere antibody excluded that of any anti-ENA, while a close association was found between nucleolar + homogeneous FANA and the anti-Scl-70. Pulmonary involvement was significantly more frequent in nucleolar + homogeneous FANA positive patients; moreover, in two cases the same pattern proved to predict the development of diffuse scleroderma.

Antibodies, Antinuclear↗
PubMed1988

The diagnosis and classification of scleroderma (systemic sclerosis).

Difficulty in the diagnosis of the disease scleroderma may occur at the early stage prior to the development of obvious skin sclerosis. A presumptive diagnosis may be made if Raynaud's phenomenon is accompanied by a positive 'neck test', 'scleroderma' capillary changes in the nailfolds or antinuclear antibodies. Definitive diagnosis may have to be delayed for several years from the onset of Raynaud's phenomenon until definite characteristic skin changes are seen. Ten cases in which an earlier diagnosis of scleroderma was not substantiated are listed. The earlier incorrect diagnosis would have been avoided by use of the methods described in this paper. Various terms have been used to denote subdivisions of scleroderma. These include acrosclerosis, diffuse scleroderma and CREST. We have used the terms Type 1, Type 2 and Type 3 based on the early extent of the skin sclerosis where Type 1 (limited extent) indicates sclerodactyly only, Type 2 (moderate extent) indicates sclerosis proximal to the metacarpophalangeal joints but excluding the trunk and Type 3 (extensive) indicates diffuse skin sclerosis including the trunk. The clinical value of this simple classification is reviewed and contrasted to other classifications which appear to be poorly defined and of limited use.

Adult↗