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PubMed2005

[Systemic sclerosis--clinical course and treatment possibilities].

Systemic sclerosis is an autoimmune disease, characterized by fibrosis of the skin and internal organs, such as esophagus, heart, lungs, and kidneys. Three main forms of systemic sclerosis are conspicuous: diffuse systemic sclerosis, limited systemic sclerosis and scleroderma sine sclerosis. Respective variants differ in skin sclerosis exacerbation, progress and prognosis; whereas organ involvement, osseous and articular alterations are comparable in all forms of the disease. Due to the fact that etiology of systemic sclerosis is not known, no specific therapy has been developed. The therapy is based on influencing main pathogenetic factors, such as peripheral circulation disturbances, abnormal immune activation and increase in collagen accumulation. An overview of clinical course of systemic sclerosis and new therapeutic modalities is provided.

Connective Tissue↗
PubMed2006

Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis.

OBJECTIVE: To determine serum levels and clinical correlation of 8-isoprostane, which is produced in vivo through free radical-catalysed peroxidation of arachidonic acid and reflects oxidative stress, in patients with systemic sclerosis (SSc). METHODS: Serum 8-isoprostane levels from 32 patients with diffuse cutaneous SSc (dSSc) and 25 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay. RESULTS: Serum 8-isoprostane levels were elevated in dSSc and lSSc patients by 75-fold compared with normal controls (n=32). Serum 8-isoprostane levels correlated negatively with pulmonary function, such as percentage vital capacity and diffusion capacity for carbon monoxide, and correlated positively with renal vascular damage determined by colour flow Doppler ultrasonography. Serum 8-isoprostane levels also correlated positively with serum levels of IgG and anti-agalactosyl IgG autoantibody. CONCLUSION: Increased 8-isoprostane levels correlated with the severity of pulmonary fibrosis, the extent of renal vascular damage and immunological abnormalities in SSc, suggesting that enhanced oxidative stress is related to the development of SSc.

Adult↗
PubMed2006

A case of early onset normotensive scleroderma renal crisis in a patient with diffuse cutaneous systemic sclerosis.

Scleroderma renal crisis (SRC) has classically been defined as a new onset of accelerated arterial hypertension associated with a rapid increase in serum creatinine concentration and/or microangiopathic hemolytic anemia. SRC occurs in approximately 20% of patients with systemic sclerosis who have diffuse cutaneous manifestations. In addition, 10% of reported cases of SRC with diffuse cutaneous involvement have normal blood pressures; in the majority of these cases, SRC occurs after treatment with corticosteroids. We describe a patient who presented with an early onset SRC in the setting of diffuse cutaneous systemic sclerosis in evolution without prior accelerated arterial hypertension or corticosteroid use.

Biopsy↗
PubMed2005

Relationship between occupational risk factors and severity markers of systemic sclerosis.

OBJECTIVE: To investigate a potential association between occupational risk factors and severity markers of systemic sclerosis (SSc) defined by diffuse cutaneous extent, pulmonary involvement, and immunologic profile, i.e., presence of antitopoisomerase I antibody (anti-topo I). METHODS: Occupational exposures were assessed in 105 patients with SSc from 1998 to 2002. Exposures to silica dust, welding fumes, solvents, and epoxy resins were investigated. A group of 39 exposed SSc patients and a group of 66 unexposed ones were identified and compared according to severity markers of SSc. The stage of cutaneous extent was defined according to the classification of Leroy, as limited scleroderma (lSSc) or diffuse scleroderma (dSSc). Respiratory status was defined by pulmonary function tests and high resolution computed tomography. Immunological profile was determined by the presence of anti-topo I or anticentromere antibodies (ACA). Statistical relationships between occupational exposures and severity markers of SSc were evaluated using a multiple correspondence analysis and Fisher's exact test. RESULTS: Diffuse scleroderma affected mainly patients exposed during their occupational life to toxic agents. There were significant or close to significant associations between toxic exposure and dSSc (p = 0.06), pulmonary involvement (p = 0.10), and negative ACA (p = 0.03). The most incriminated products seemed to be epoxy resins (p = 0.06), white spirit (p = 0.07), aromatic solvents (p = 0.07), and silica coupled to welding fumes (p = 0.10). CONCLUSION: Our results indicate that occupational toxic factors have an influence on the severity of SSc.

Adult↗
PubMed2006

Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma.

OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.

Animals↗
PubMed1998

Scleroderma fibroblasts promote migration of mononuclear leucocytes across endothelial cell monolayers.

Perivascular infiltrates of inflammatory cells are a hallmark of lesional skin in scleroderma. We have explored the potential for scleroderma fibroblasts to modulate mononuclear leucocyte migration across endothelial cell monolayers in tissue culture, and to regulate expression of endothelial cell adhesion molecules. Fibroblasts were grown from skin biopsies of eight patients with active diffuse cutaneous scleroderma and from four healthy controls. Co-culture and conditioned medium transfer experiments examined the effect of soluble fibroblast products on mononuclear leucocyte (U937) cell migration across endothelial cell (1E-7) monolayers grown on tissue culture inserts. Co-culture of scleroderma, but not control fibroblasts, promoted transendothelial migration of U937 cells. Scleroderma fibroblast-conditioned medium had qualitatively similar effects and equivalent results were obtained using Jurkat-6 (T lymphocyte) cells, and with peripheral blood mononuclear cells from a patient with diffuse cutaneous scleroderma. Promotion of leucocyte migration does not appear to result from increased endothelial adhesion molecule expression, since fibroblast-conditioned medium did not up-regulate endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) or E-selectin. Moreover, leucocyte migration across cytokine-activated endothelial cell layers in co-culture with fibroblasts was less than across resting cells, although the selective effect of scleroderma fibroblast co-culture persisted. Recombinant monocyte chemoattractant protein-1 (MCP-1) or IL-8 increased passage of mononuclear leucocytes across endothelial cell monolayers, whilst anti-MCP-1, but not anti-IL-8 antibodies, significantly reduced the effect of fibroblast conditioned medium. These data suggest that systemic sclerosis (SSc) fibroblasts promote leucocyte migration across endothelial cell monolayers in tissue culture via an MCP-1-dependent mechanism. These findings may be relevant to the perivascular mononuclear leucocyte infiltrates characteristic of early SSc lesions.

Cell Line, Transformed↗
PubMed2006

Ascending aortic aneurysm in a man with scleroderma.

Macrovascular involvement in scleroderma has received relatively little attention. We hereby describe a 5.6-cm ascending aortic aneurysm in a 56-year-old man presenting with increased dyspnea, diagnosed with antibody-negative, rapidly progressive diffuse cutaneous scleroderma. The patient had sclerosis and induration of all extremities, face, thorax and abdomen. Other features included Raynaud's phenomenon, arthralgia, dysphagia, dyspnea attributed to pulmonary fibrosis, pericardial effusion, and cardiomyopathy. To the best of our knowledge, there is only one other report to date in the English language of a thoracic aortic aneurysm associated with scleroderma.

Aortic Aneurysm↗
PubMed1996

Optimal evaluation of patients with nonobstructive esophageal dysphagia. Manometry, scintigraphy, or videoesophagography?

The aims of this study were to compare diagnostic accuracy, cost, and patient tolerance of videoesophagography and esophageal transit scintigraphy to esophageal manometry in the evaluation of nonobstructive esophageal dysphagia. Eighty-nine consecutive patients underwent videoesophagography, scintigraphy, and manometry. The sensitivities for diagnosing specific esophageal motility disorders, using esophageal manometry as the standard, were 75% and 68% for videoesophagography and scintigraphy, respectively, with positive predictive accuracies of 96% and 95% for achalasia, 100% and 67% for diffuse esophageal spasm, 100% and 75% for scleroderma, 50% and 67% for isolated LES dysfunction, 57% and 48% for nonspecific esophageal motility disorders, and 70% and 68% for normal esophageal motility. The cost for videoesophagography is less than that for either manometry or scintigraphy. Both videoesophagography and scintigraphy were better tolerated than manometry. It is concluded that videoesophagography and scintigraphy accurately diagnose primary esophageal motility disorders, achalasia, scleroderma, and diffuse esophageal spasm, but are less accurate in distinguishing nonspecific esophageal motility disorders from normal. When considering accuracy, cost, and patient acceptance, these findings suggest that videoesophagography is a useful initial diagnostic study for the evaluation of nonobstructive esophageal dysphagia.

Adult↗
PubMed2003

[Plasmapheresis therapy in systemic sclerosis].

BACKGROUND: Systemic sclerosis (SSc) is a polysystemic autoimmune disorder characterized by excessive production of extracellular matrix and vascular abnormalities, involving the skin and internal organs. There is currently no real disease-modifying therapy of SSc and there are only few reports on the use of plasmapheresis in SSc. OBJECTIVES: Authors present 4 cases of SSc treated with plasmapheresis within one year from disease onset. All patients had diffuse cutaneous form of SSc with rapid progression and with different internal organ manifestations. METHODS: The patients were treated with plasmapheresis performed every 3 months besides symptomatic drug treatment. Clinical symptoms, Rodnan skin score, immunolaboratory markers (serum immunoglobulin, complement, several autoantibodies, leukocyte CD markers) and soluble adhesion molecules (E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule, which were showed as the markers of disease activity in previous works) were determined before and after the plasmapheresis. RESULTS: The progression of the disease slowed down significantly in all patients, no more new clinical manifestation appeared, Rodnan skin score significantly decreased. There was a reduction in CD4/CD8 ratio (approaching normal ratio), in expression of CD69, as early activation marker. There was a significant suppression of soluble adhesion molecules also in all patients. CONCLUSION: In patients with diffuse cutaneous form of SSc, plasmapheresis may be effective with decreasing progression of the disease and improving clinical symptoms (especially skin manifestation) in the early phase of the disease.

Adult↗
PubMed2005

Clonal T cells in the blood of patients with systemic sclerosis.

BACKGROUND: It has been suggested that clonal T cells may play a critical role in the pathogenesis of systemic sclerosis. OBSERVATIONS: A monoclonal population of T cells was found in blood samples from 13 (34%) of 38 consecutive patients with a definite diagnosis of systemic sclerosis who were prospectively examined by T-cell receptor gamma gene rearrangement using polymerase chain reaction analysis and denaturating gradient gel electrophoresis. In the healthy control group, the same type of examination revealed a monoclonal population of T cells in the blood samples from only 3 healthy subjects (4%)(odds ratio, 12.28; 95% confidence interval, 2.76-54.64; P = .001). Patients who had a circulating clonal population of T cells were older than those who did not (67 years vs 48 years; P = .04). There was a marked relationship between systemic sclerosis subtypes and the presence of a circulating clonal population of T cells. Twelve (43%) of 28 patients with limited cutaneous sclerosis exhibited a circulating clonal population of T cells, whereas only 1 (10%) of the 10 patients with diffuse cutanous sclerosis had evidence of T-cell clonality (P<.01). CONCLUSIONS: Clonally expanded T cells were more commonly detected in patients with limited cutaneous sclerosis than in those with diffuse cutaneous sclerosis, which is also in accordance with a possible role of clonal T cells in patients with limited cutaneous sclerosis.

Adult↗
PubMed2006

[Antinuclear antibodies].

Antinuclear antibodies react with various nuclear autoantigens. Testing for them is critical for diagnosing connective tissue diseases, but they may be also found in other inflammatory diseases and in the elderly. They constitute a group of heterogeneous autoantibodies, and their specificity helps to discriminate between various connective tissue diseases. Screening for total antinuclear antibodies is generally performed by indirect immunofluorescence on HEp2 cells. In the presence of antinuclear antibodies, anti-dsDNA antibodies and anti-ENA (extractable nuclear antigens) antibodies must be sought. Positivity for IgG anti-dsDNA antibodies is highly characteristic of systemic lupus. A rapid increase in their titer suggests visceral, particularly renal, involvement. Anti-Sm antibodies are also characteristic of systemic lupus, while anti-JO1 and anti-Scl70 antibodies suggest, respectively, myositis and diffuse systemic sclerosis. Antibody titers do not provide information about disease course. The presence of anti-Ro/SSA antibodies during pregnancy requires a workup for cardiac conduction disturbances in the fetus.

Aged↗
PubMed2005

Distinct expression of adhesion molecules on skin fibroblasts from patients with diffuse and limited systemic sclerosis. A pilot study.

OBJECTIVE: . Systemic sclerosis (SSc) is characterized by excessive production of collagen and other components of the extracellular matrix (ECM) by fibroblasts. The ECM receptors, integrins and CD44 (hyaluronan receptor), play a key role in the homeostasis of connective tissue and may also have a role in the pathogenesis of fibrosis. We investigated the expression of integrins and CD44 on skin fibroblasts from patients with limited and diffuse SSc. METHODS: We studied 13 patients with SSc, 8 with limited SSc, and 5 with diffuse SSc, and 8 control subjects. Fibroblasts were isolated and cultured from biopsies taken from the lesional skin of the second finger of the left hand. Cell-surface expression of beta1, beta3, alpha1-alpha6, alphav integrins, and CD44 was evaluated by immunofluorescence and flow cytometry analysis. RESULTS: Fibroblasts from limited SSc showed significantly decreased expression of alpha2, alpha3, alpha4 integrins, while diffuse SSc fibroblasts had significantly reduced expression of alpha5, alphav integrins, and CD44. Diffuse SSc also had significantly increased expression of alpha6 integrin on fibroblasts. In controls, the expression of alpha4 and alpha5 correlated positively, while in limited and diffuse SSc it did not. CONCLUSION: This is the first study evaluating separately the expression of adhesion molecules on skin fibroblasts from limited and diffuse subsets of SSc. We detected a distinct pattern of expression with decrease of collagen and fibronectin receptors in limited SSc, and downregulation of fibronectin and hyaluronan receptors in diffuse SSc. These results suggest that changes of fibroblasts/ECM interactions and mechanisms underlying the pathogenesis of fibrosis in SSc may differ in the single subset of the disease.

Cells, Cultured↗
PubMed2005

Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase III antibody: analytical accuracy and clinical associations in systemic sclerosis.

OBJECTIVE: We have recently developed an enzyme-linked immunosorbent assay (ELISA) for detection of anti-RNA polymerase III (anti-RNAP III) antibody, using a recombinant fragment containing the immunodominant epitope as the antigen source. This study was conducted to assess the analytical accuracy and clinical associations of the anti-RNAP III ELISA in patients with systemic sclerosis (SSc). METHODS: To evaluate analytical sensitivity and specificity of the ELISA, both immunoprecipitation tests and ELISA were used to detect anti-RNAP III antibody in 534 SSc sera from patients at 3 medical centers. Sera from 522 SSc patients and 516 controls, including patients with other connective tissue diseases and blood bank donors, were also evaluated to assess the clinical sensitivity and specificity of the ELISA. Clinical findings in anti-RNAP III antibody-positive SSc patients were compared between patient groups stratified according to anti-RNAP III antibody levels determined by the ELISA. RESULTS: In SSc patients, our ELISA showed analytical sensitivity of 91% and analytical specificity of 99% compared with the immunoprecipitation assay (a gold standard for detection of anti-RNAP III antibody). The additional analysis using a large series of SSc and control sera showed that clinical sensitivity and specificity of the ELISA with respect to the diagnosis of SSc were 17% and 98%, respectively. A high level of anti-RNAP III antibody was associated with diffuse cutaneous SSc, higher maximum total skin score, and increased frequency of tendon friction rubs. CONCLUSION: The anti-RNAP III ELISA is analytically accurate and clinically specific. With this assay, testing for anti-RNAP III antibody can be made routinely available.

Antibodies, Antinuclear↗
PubMed1998

A study of the frequency of pericardial and pleural effusions in scleroderma.

OBJECTIVE: To determine the frequency of pericardial and pleural effusions in scleroderma. METHODS: Using a case-control format, patients with scleroderma and no known cardiac disease were recruited. Echocardiograms and chest radiographs were performed. Age- and gender-matched controls had echocardiograms performed which were read by a cardiologist, blinded to the diagnosis. The medical records of 60 other scleroderma patients were also reviewed. RESULTS: Thirty-seven scleroderma subjects were recruited, of whom 18 had diffuse disease. Only eight subjects with diffuse disease and five with limited scleroderma had normal echocardiograms compared to 20 of 37 controls (P < 0.1). Two had pericardial effusions, both with diffuse scleroderma, and none of the controls had effusions present. Pulmonary hypertension occurred in three with diffuse disease and no controls. A chart review of a further 60 patients with scleroderma was performed. Pleural effusions were identified in 7% (4/58) of the cohort of scleroderma patients and were more frequent in diffuse disease (10%). A total of 17% (4/23) of diffuse and 4% (1/23) of limited scleroderma patients had evidence of pericardial effusions. CONCLUSIONS: Pericardial effusions do occur in scleroderma without evidence of clinical cardiac dysfunction and are more common in diffuse scleroderma. Pleural effusions in scleroderma occur less frequently, in 70%.

Adult↗
PubMed2005

Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis.

OBJECTIVE: Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease. METHODS: Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM). RESULTS: At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations. CONCLUSIONS: In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Adult↗
PubMed2004

HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women.

OBJECTIVE: We investigated HLA class II alleles in women with systemic sclerosis (SSc), a rare disease that preferentially affects women. METHODS: Specific alleles of DRB1, DQA1 and DQB1 were determined by DNA-based HLA typing for women with SSc (n = 102) and healthy women (n = 533). All study subjects were Caucasian. DRB1, DQA1 and DQB1 allele frequencies of women with SSc were compared with those of healthy women. RESULTS: Among women with SSc, 29.4% (30/102) and among healthy women 10.7% (57/533) had DRB1*11. Allele frequencies were compared for women with SSc and healthy women (each woman has two alleles). The allele frequency of DRB1*11 was 15.7% (32/204 alleles) in SSc women and 5.8% (62/1066 alleles) in healthy women (P = 0.000002). The increase of DRB1*11 was found both in diffuse (P = 0.0001) and limited SSc (P = 0.002) (allele frequencies 15.0 and 17.2%, respectively). Among women with diffuse SSc, there was a disproportionate increase of the DRB1*1104 allele (P = 0.0004) with no increase of DRB1*1101 (P = 1.00). In contrast, in limited SSc the strongest association was with DRB1*1101 (P = 0.008), with a less significant increase of DRB1*1104 (P = 0.04). CONCLUSIONS: An increase of DRB1*11 in SSc is consistent with other reports. Although present in both diffuse and limited SSc disease subsets, the increase was predominantly due to over-representation of DRB1*1104 in women with diffuse SSc. Women with limited SSc had a preponderance of DRB1*1101, the most common allele in healthy women. DRB1*1104 and DRB1*1101 differ by a single amino acid at position 86, where the former has valine and the latter glycine.

Adolescent↗