[ON A CASE OF PERIARTERITIS NODOSA WITH INTERSTITIAL DIFFUSE PULMONARY FIBROSIS AND PARIETAL FIBROUS ENDOCARDITIS].
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Endocardial Fibroelastosis↗
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[The mouth and diffuse diseases of the connective tissue].
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Connective Tissue↗
[Diffuse fasciite with eosinophilia : a new syndrome (author's transl)].
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Adult↗
Use of monoclonal antibodies for the characterization of novel DNA-binding proteins recognized by human autoimmune sera.
Autoantibodies to a DNA-binding heterodimer consisting of 70,000 and 80,000 dalton subunits were identified in 30-50% of human autoimmune sera from patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and scleroderma. Three murine monoclonal antibodies (mAb) against the heterodimer were produced in BALB/c mice by immunizing with isolated human B cell nuclei. By immunofluorescence, the mAb and autoimmune sera demonstrated both speckled nucleoplasmic staining and diffuse nucleolar staining in all human cell types examined. The nucleoplasmic staining was sensitive to DNase but not RNase pretreatment, while the nucleolar staining was sensitive to RNase but not DNase pretreatment. Biochemical characterization of the 70,000 and 80,000 dalton proteins using the mAb indicated that two forms of the antigen, with different mobilities on sucrose gradients, are present in human B cells. A 10 S form consists of the physically associated 70,000 and 80,000 dalton proteins, while a larger, 10-20 S form probably represents the same two proteins bound to DNA. Binding of the proteins to nucleolar RNA could not be confirmed in biochemical studies. These studies indicate that non-histone, DNA-binding proteins may be more frequently recognized by autoantibodies in SLE, MCTD, and scleroderma than has been previously recognized. Along with previous studies on RNA-binding proteins such as Sm, RNP, Ro, and La, the present findings suggest that nucleic acid-binding proteins, as a class, may be particularly frequent targets of autoimmunity in SLE and related disorders.
Animals↗
Serum xylosyltransferase: a new biochemical marker of the sclerotic process in systemic sclerosis.
UDP-D-xylose:proteoglycan core protein beta-D-xylosyltransferase (EC2.4.2.26) is the initial enzyme in the biosynthesis of chondroitin sulfate and dermatan sulfate proteoglycans in fibroblasts and chondrocytes. Secretion of xylosyltransferase into the extracellular space was determined in cultured human dermal fibroblasts. A more than 6-fold accumulation of xylosyltransferase activity in cell culture supernatant was observed (day 1, 0.6 microU per 106 cells; day 9, 4.1 microU per 106 cells); however, intracellular xylosyltransferase activity remained at a constant level (0.4 microU per 106 cells). Exposure of human chondrocytes to colchicine led to a 3-fold decreased level of xylosyltransferase and chondroitin-6-sulfate concentration in cell culture. Specific xylosyltransferase activity and chondroitin-6-sulfate concentration decreased in a concentration-dependent manner and in parallel in culture medium and accumulated 5-fold in cell lysates indicating that xylosyltransferase is secreted simultaneously into the extracellular space with chondroitin sulfate proteoglycans. Xylosyltransferase activities were determined in serum samples of 30 patients with systemic sclerosis. Xylosyltransferase activities in female (mean value 1.28 mU per liter, 90% range 1.10-1.55 mU per liter) and male patients (mean 1.39 mU per liter, 90% range 1.16-1. 57 mU per liter) with systemic sclerosis were significantly increased in comparison with blood donors of a corresponding age. Furthermore, xylosyltransferase activity was correlated with the clinical classification of systemic sclerosis. Female patients with diffuse cutaneous systemic sclerosis showed higher serum xylosyltransferase activities than patients with limited systemic sclerosis. These results confirm that the increase of proteoglycan biosynthesis in sclerotic processes of scleroderma is closely related to an elevated xylosyltransferase activity in blood and demonstrate the validity of xylosyltransferase as an additional diagnostic marker for determination of sclerotic activity in systemic sclerosis.
Adult↗
CT of interstitial lung disease: a diagnostic approach.
Weibel divided the pulmonary interstitium into three compartments: axial, parenchymal, and peripheral. Heitzman and others have shown that certain interstitial diseases selectively involve these compartments. A model is proposed of the CT appearances in interstitial lung disease based on Weibel's divisions. To assess the validity of this model, the distribution of disease was studied in 44 patients with proven interstitial lung disease. Lymphangitic carcinomatosis (n = 5), lymphoma (n = 2), and sarcoid in two of three patients typically involved the axial compartment. The middle (or parenchymal) compartment was abnormal in advanced stages of many interstitial diseases, particularly granulomatous diseases and drug toxicity (n = 2) in this series, but diffuse changes were seen early in extrinsic allergic alveolitis (n = 4). The peripheral compartment was predominantly affected in idiopathic pulmonary fibrosis (n = 9), rheumatoid lung (n = 3), and scleroderma (n = 1). Prominent nodularity was a feature of lymphangitic carcinomatosis and of the granulomatous diseases, silicosis and sarcoid. The presence or absence of nodules coupled with CT demonstration of differential involvement of the three interstitial compartments is useful in limiting diagnostic possibilities in interstitial disease. By more accurately showing disease distribution, a more reasonable approach to lung biopsy options may be developed.
Humans↗
[Anatomic and nosologic analysis of 100 cases of diffuse angiitis seen in rheumatology].
Diffuse inflammatory angiitis is seen in extremely varied aetiological and nosological situations. In some cases, the vascular disease represents the only sign of systemic disease. In other cases, it mays be associated with or complicated by diffuse systemic inflammatory conditions. This study analysed 100 cases of inflammatory angiitis with systemic manifestations seen over a period of 7 years in a rheumatology department. Patients with scleroderma, erythema nodosa, Behçet's syndrome and angiitis associated with microbial infectious diseases were excluded from this study. 24 cases in which the angiitis was clinically certain, but in which the vascular lesion was not confirmed histologically were also excluded. The type of histological lesion and the nosological distribution of these 100 cases are described in detail. The results of this analysis confirm the very great variety of the clinical and histological presentations. A number of rare syndromes were observed. Classical periarteritis nodosa only represented 14 per cent of the whole series and only 3 of the 14 cases had a demonstrable aetiology (2 HBs, 1: desensitisation to Candidin). The authors stress the histological diversity of inflammatory angiitis associated with rheumatoid arthritis and systemic lupus erythematosus. All sizes of vessels may be involved and all types of lesions can be observed in these two diseases. The authors also emphasise the lesser known clinical and histological features (stenosing endarteritis of the great vessels in systemic lupus erythematosus) and previously unreported cases (valvular lesions in 2 cases of Mac Duffie's syndrome, progression of 2 cases of delayed urticaria to pressure towards a clinical lupus with unusual laboratory findings).(ABSTRACT TRUNCATED AT 250 WORDS)
Arthritis, Rheumatoid↗
The association: scleroderma-silicosis or Erasmus' syndrome (author's transl).
Classically more common in women, scleroderma nevertheless affects with predilection men exposed to the inhalation of silica particles. The association scleroderma-silicosis is essentially a statistical finding. It has no particular clinical, radiological nor histological distinguishing characteristics, other than the syndromic juxtaposition of the stigmata of each of the two disorders. This serious pathological combination is not due merely to chance. It is the result of depressed cellular immunity, related to the cytotoxicity of silica and responsible for auto-immune reactions and the formation of circulating immune-complexes. In the presence of an underlying predisposition, the polyvisceral diffusion of inhaled toxic mineral particles could also facilitate the sclerodermic process by stimulating fibroblastic proliferation.
Female↗
Lymphocyte phenotyping in systemic sclerosis: a flow cytometry analysis of lymphocytes in bronchoalveolar lavage fluid.
OBJECTIVE: Patients with scleroderma (systemic sclerosis [SSc]) frequently develop interstitial lung disease. The purpose of this work was to evaluate the cell profile in the bronchoalveolar lavage fluid (BALF) in patients suffering from a diffuse form of systemic sclerosis as compared with healthy controls. STUDY DESIGN: Bronchoalveolar lavage was carried out in the right middle lobe of 25 untreated, nonsmoking patients with SSc and 12 healthy, nonsmoking volunteers. For the analysis of lymphocyte subsets, the following monoclonal antibodies were used: anti-CD3, anti-CD4, anti-CD8, anti-CD14, anti-CD16, anti-CD19, anti-CD25, anti-CD45, anti-CD56. Also, anti-HLA-DR and flow cytometry were used. RESULTS: We found an increase in the total number of cells with an increase in the percentage of lymphocytes and neutrophils in BALF from patients when compared with controls (P < .05). The proportion of lymphocytes, cytotoxic/suppressor CD8+ and activated lymphocytes T CD25+ were higher in patients' BALF (P < .05). The CD4+/CD8+ ratio in BALF from subjects was significantly lower than in controls. These findings were characteristic of patients with early-stage disease. CONCLUSION: Analysis of the BALF lymphocyte phenotype may be useful in the early detection of lung involvement in patients with SSc.
Adult↗
Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapy.
Although there is no cure for systemic sclerosis, the disease is certainly treatable. And the more that is understood of its pathogenesis, the better the prospects for treatment. Excessive collagen deposition in the skin and viscera is responsible for the morbidity and mortality. The immune system plays a critical role in setting up the fibrotic process, but impaired regulation of collagen gene expression probably underlies the persistence of fibrosis. The development of effective antifibrotic drugs, in particular agents that inhibit transcription factors involved in the activation of type I collagen genes, is likely to be the way forward for treatment of the later stages of diffuse systemic sclerosis, with immunomodulatory therapy for the earlier stages.
Collagen↗
Diffuse cutaneous systemic sclerosis associated with pan-serositis, disseminated intravascular coagulation, and diffuse alveolar haemorrhage.
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Adult↗
[Changes in esophageal peristalsis in diverse clinical forms and antibody specificity in scleroderma: a scintigraphic study in 100 cases].
OBJECTIVE: To define the prevalence and severity of esophageal involvement in systemic sclerosis (SSc) and its relationship with the different clinical forms and ANA specificities of the disease. METHODS: A hundred consecutive patients with SSc, 48 with cutaneous limited, 26 with intermediate and 26 with diffuse form of disease, 49 with anti-centromere and 37 with anti-Scl70 ANA pattern, were submitted to scintigraphy using a semisolid orally ingested bolus to detect esophageal hypomotility. RESULTS: An impairment of esophageal function has been observed in 68% of SSc patients. Esophageal dysmotility was significantly more frequent and severe in patients with cutaneous diffuse and intermediate forms of SSc and with anti-Scl70 ANA pattern. CONCLUSIONS: Esophageal involvement is very common in SSc. The scintigraphy confirms to be a useful and non invasive diagnostic method; moreover it permits to quantify the severity of the esophageal dysmotility by analyzing both global and segmental function.
Adult↗
Duration of Raynaud's phenomenon is negatively correlated with serum levels of interleukin 10 (IL-10), soluble receptor of interleukin 2 (sIL2R), and sFas in systemic sclerosis patients.
BACKGROUND: Dysfunction of blood vessels and endothelial cells is regarded as a primary triggering factor of the development of autoimmunological processes in systemic sclerosis (scleroderma, SSc). Literature data suggest that the duration of Raynaud's phenomenon may correlate with disease severity. MATERIAL/METHODS: The study comprised 34 patients with SSc, 19 with limited SSc (lSSc) and 15 with diffuse SSc (dSSc). The duration of Raynaud's phenomenon (before skin fibrosis development) was correlated with the serum levels of selected markers, measured by ELISA, reflecting disturbances in autoimmunological processes, angiogenesis, apoptosis, and fibrosis. RESULTS: A shorter duration of Raynaud's phenomenon was shown to correlate with higher serum levels of interleukin-10 (IL-10) in the whole SSc group and of aminoterminal propeptide of collagen III (PIIINP) in the lSSc subgroup (p<0.05). It also correlated with higher serum levels of soluble interleukin 2 receptor (sIL2R) and the soluble protein sFas in the whole SSc group and the lSSc subgroup (p<0.05). CONCLUSIONS: The results obtained confirm the importance of vasomotor disturbance duration in triggering fibrosis in the course of systemic sclerosis.
Cell Division↗
Esophageal motility disorders.
Esophageal motility disorders consist of a complex array of disturbances in normal esophageal function associated with dysphagia, gastroesophageal reflux, and noncardiac chest pain. A thorough knowledge of normal esophageal anatomy and physiology is important to a full understanding of these motility derangements. Through a complicated interaction of neuromuscular and hormonal influences, the voluntary act of swallowing transforms into an automated sequence of peristaltic waves propelling food and liquids into the stomach in concert with coordinated relaxation of the sphincters. Anatomic and physiologic barriers exist within the esophagus protecting against gastroesophageal reflux and aspiration. With improvements in diagnostic tools such as barium contrast radiography, scintigraphy, pH measurements, and esophageal manometrics with provocative testing, motility disorders have become better defined and understood. Primary motility disorders consist of achalasia, diffuse esophageal spasm (DES), "nutcracker esophagus," hypertensive lower esophageal sphincter, and nonspecific esophageal motility dysfunction (NEMD). A host of secondary and miscellaneous motility disorders also affect the esophagus, including scleroderma and other connective tissue diseases, diabetes mellitus, Chagas' disease, chronic idiopathic intestinal pseudo-obstruction, and neuromuscular disorders of striated muscle. Gastroesophageal reflux disease (GERD) may also be promoted by associated motility disturbances. Treatment modalities include surgical myotomy; dilatation; and pharmacologic manipulations, including use of nitrates, calcium-channel blockers, H2-blockers, and psychotropic drugs where appropriate.
Deglutition↗
Serological assessment of type I collagen burden in scleroderma spectrum disorders: a systematic review.
RATIONALE: The aim of the study was to evaluate the validity of collagen type I metabolites as markers of disease activity in scleroderma (SSc), through a systematic review of the literature and by validating the results by measuring collagen type I metabolites in well characterized patients with scleroderma spectrum disorders and in Raynaud's phenomenon. METHODS: A systematic review was performed of studies of collagen type I metabolites in scleroderma spectrum disorders published from 1980 to 2003. The collected results from the literature were compared with our own measurements of collagen type I metabolites (PINP and ICTP) in a small number of well characterized patients within the scleroderma spectrum and in patients with primary and "autoimmune" Raynaud's phenomenon. Peptide concentrations from all sources, including the present study, were compared. Reported correlations between peptide concentrations and clinical variables were also analysed. RESULTS: Of 19 papers identified by an extensive Medline search, 12 were eligible for systematic analysis. There was a considerable heterogeneity in the results with a wide range of metabolite concentrations. Values from disease groups and healthy controls overlapped. These findings were confirmed by our study where, similarly, there was a large range of values in all groups, but particularly in the diffuse SSc subset. When the correlation between peptide levels and clinical variables was assessed, large discordance between the studies was observed. CONCLUSIONS: We have not found sufficient evidence to support the use of serum markers of collagen turnover in the assessment of scleroderma activity and severity, in view of their low specificity and the heterogeneity of the results of various studies. Lack of standardized routine evaluation of SSc patients in clinical studies might have accounted for the variability of the findings. However, due to the small sizes of most published studies, demonstration of no effect should come from large-scale randomised trials. Longitudinal serial analysis of these molecules in individual patients may play a future role in the evaluation of the response to fibroblast-targeting therapeutic strategies in scleroderma patients.
Biomarkers↗
Outcome measurement in scleroderma clinical trials.
Clinical trials in scleroderma were reviewed to assess the clinimetric properties of frequently used outcome measures. Twenty-seven controlled intervention studies were found in the English literature; nine demonstrated effective therapy. The outcome measures used included skin involvement, functional status, physical performance (grip strength, oral aperture), and internal organ involvement (pulmonary, gastrointestinal, renal, and cardiac). Very few outcome measures detected between- or within-group differences even when an active drug was compared with a placebo. Skin measures were found to yield statistical differences in seven studies, patient global assessment in three, and physician global assessments in four. Internal organ measures detected differences between groups only rarely; the pulmonary diffusing capacity was statistically different twice. Physical performance measures (eg, grip strength and oral aperture) never yielded statistical differences, and in only one of five trials did a functional assessment detect statistical differences. To show drug efficacy in future trials in scleroderma, better outcome measures need to be developed and a consensus obtained on which outcomes to use so that potentially effective therapies can be tested in a standardized fashion against a placebo or current therapy. Currently, because of a lack of clinimetric data on outcome measures, therapeutic inefficacy cannot be differentiated from a lack of sensitivity in the outcome measures used. In the future, outcome measures should be chosen on the basis of the adequacy of their reliability, construct, and content validity and be sensitive to change. Ideally, outcome measures also should have criterion validity, ie, show a strong association between the measure (such as a skin score) and an irrefutable gold standard (such as skin pathology).
Clinical Trials as Topic↗
Prediction of five-year survival following presentation with scleroderma: development of a simple model using three disease factors at first visit.
OBJECTIVE: To identify combinations of easily acquired clinical variables, at first presentation with scleroderma, that would predict subsequent mortality. METHODS: In this prospective study of all new patients at one major scleroderma center, 280 patients with definite scleroderma (according to the American College of Rheumatology criteria) whose disease onset occurred from 1982 to 1991 and who were followed up to the end of 1996 were identified. Standardized data collection was performed at entry to obtain data on major clinical and laboratory variables. Vital status was determined by linkage to the National Death Index. RESULTS: At 5 years, 55 (26%) of 215 women and 21 (32%) of 65 men had died. Univariate analysis showed that older age, diffuse skin disease, higher skin score, low carbon monoxide diffusing capacity, abnormal electrocardiogram findings, proteinuria, hematuria, low hemoglobin level, elevated erythrocyte sedimentation rate (ESR), and presence of antitopoisomerase antibody were all associated with increased mortality. A logistic regression model, validated by Monte Carlo simulation, identified 3 factors, proteinuria, elevated ESR, and low carbon monoxide diffusing capacity, that in combination, had an accuracy of >80% in predicting mortality. The absence of these 3 factors was associated with 93% survival. CONCLUSION: A simple model has been developed that appears to accurately predict mortality over 5 years in a cohort of patients newly presenting with scleroderma.
Adult↗
Increased expression of type VI collagen genes in systemic sclerosis.
The expression of type VI collagen genes in affected skin from patients with systemic sclerosis (SSc) was examined by in situ hybridizations with a human alpha 2(VI) collagen sequence-specific complementary DNA. Five patients with diffuse, rapidly progressive SSc of recent onset (less than 12 months) were studied. The results showed increased expression of alpha 2(VI) collagen messenger RNA transcripts in the skin of scleroderma patients compared with that in the skin of normal subjects. These findings indicate that alterations in the expression of type VI collagen genes, similar to those previously described for types I and III collagen, are present in the affected skin of SSc patients. These alterations may result in excessive tissue accumulation of type VI collagen and may play a role in the progressive skin induration and sclerosis that are prominent features of SSc.
Adult↗