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PubMed1983

Serological markers in progressive systemic sclerosis: clinical correlations.

The relation between clinical and serological findings was studied in 75 patients with definite progressive systemic sclerosis (PSS). Antinuclear antibodies were detected by indirect immunofluorescence in 95% of the patients by means of HEp-2 cells. The centromere pattern was observed in 50% of the patients with calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia (CREST) and only 7% of the group with diffuse disease. Precipitating antibodies to nuclear and cytoplasmic antigens were detected by immunodiffusion in 53% of the patients and identified as anti Scl-70 in 16 (21%). We confirmed that autoantibodies are very frequent in PSS but varied in specificity. A combination of immunodiffusion and indirect immunofluorescence was useful in detecting antibodies characteristic of PSS (i.e., anti-Scl-70 and anticentromere) in 51% of these patients. Anticentromere antibody has a high specificity for CREST and identifies patients with less severe disease (i.e., more prolonged course and less involvement of internal organs). Anti-Scl-70 was associated with a high frequency of lung involvement.

Adult↗
PubMed1994

Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemic sclerosis. A possible mechanism of vascular damage.

BACKGROUND: One of the main features of systemic sclerosis (SSc) is vascular damage, the mechanism of which is not understood. The aim of this study was to investigate if complement (C) regulatory molecules, membrane cofactor protein (MCP), decay-accelerating factor (DAF), and CD59, which normally protect endothelial cells from damage by autologous C, are absent or down-regulated in vascular endothelium of patients with SSc. A deficiency or persistent down-regulation of the above molecules is likely to render vascular endothelium of these patients susceptible to damage by physiologically or pathologically activated C. From this point of view, expression of MCP, DAF, and CD59 was tested on endothelium of skin of normal subjects and patients with diffuse and limited forms of SSc. EXPERIMENTAL DESIGN: Punch biopsies of normal skin (N = 11) and lesional and non-lesional skin of patients with diffuse (N = 5) and limited (N = 5) forms of SSc were obtained and serial sections prepared. Immunoperoxidase staining of these sections was carried out using four monoclonal antibodies (MoAbs) directed to different epitopes of DAF, four to different epitopes of MCP, one to CD59 and one to von Willebrand factor. von Willebrand factor served as a marker of endothelial cells. Besides normal skin, lesional skin of systemic lupus erythematosus and several inflammatory and proliferative diseases, described below, served as controls. RESULTS: The endothelium of normal skin strongly expressed all the three proteins. However, the endothelium of lesional and nonlesional skin of all the 10 patients with diffuse or limited forms of the disease tested, expressed either decreased or undetectable amounts of MCP and DAF. CD59 expression was normal in some patients and lower than normal in others. Aberrant expression of MCP, DAF, or CD59 was not found in other control inflammatory, connective tissue and proliferative diseases studied. CONCLUSIONS: In view of the common function of MCP and DAF to protect self cells from autologous C, their decrease or virtual absence from the endothelium of patients with SSc strongly suggests that this deficiency may contribute to vascular damage, resulting in intima proliferation and, finally, fibrosis.

Antibodies, Monoclonal↗
PubMed1993

Circulating intercellular adhesion molecule-1 in patients with systemic sclerosis.

In view of recent data demonstrating increased expression of intercellular adhesion molecule-1 (ICAM-1) in the skin of patients with systemic sclerosis (SSc) we studied whether levels of soluble ICAM-1 (s-ICAM-1) shed into the circulation are increased in patients with this disorder. We also compared blood levels of s-ICAM-1 in SSc with those in systemic lupus erythematosus (SLE) and we investigated any possible association of s-ICAM-1 with soluble IL-2 receptor (s-IL 2R) levels, the latter being considered as a marker of lymphocyte activation. Patients with SSc had increased levels of sICAM-1 compared with healthy control subjects (mean +/- SEM, 587 +/- 34 versus 373 +/- 27 ng/ml, P < 0.0001). Patients with diffuse rapidly progressive disease had the highest s-ICAM-1 levels. No association was observed between the extent of skin or internal organ involvement and s-ICAM-1 levels. Patients with digital ulcers had significantly elevated s-ICAM-1, but not s-IL 2R, levels. No correlation was detected between individual s-ICAM-1 and S-IL 2R levels in SSc patients. These novel findings suggest that circulating s-ICAM-1 levels may be a useful marker of endothelial activation in SSc; however, further studies are needed to determine the role of ICAM-1 in the pathogenesis of this disorder.

Adolescent↗
PubMed1999

Distribution and antigen specificity of anti-U1RNP antibodies in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a generalized connective tissue disease which is characterized by the presence of several autoantibodies. To determine the prevalence and antigen specificity of anti-U1RNP antibodies (anti-U1RNP) in patients with SSc, serum samples from 223 patients with SSc, 117 patients with systemic lupus erythematosus (SLE), 18 patients with mixed connective tissue disease (MCTD) and 40 healthy control subjects were examined by indirect immunofluorescent analysis (IIF), double immunodiffusion, and immunoblotting using nuclear extract of HeLa cells. Eighteen of the 223 (8%) serum samples from patients with SSc were shown to be positive for anti-U1RNP. The frequency of anti-U1RNP positivity in limited cutaneous SSc (14%) was significantly higher than that in those with diffuse cutaneous SSc (3%). Anti-Sm antibodies were detected in patients with SLE positive for anti-U1RNP, but not in those with SSc positive for anti-U1RNP or those with MCTD. Immunoblotting demonstrated that anti-70-kD antibodies were detected more often in patients with SSc positive for anti-U1RNP and in those with MCTD than in those with SLE. Furthermore, anti-U1RNP was closely correlated with pulmonary fibrosis and joint involvement in patients with SSc. These results suggest that anti-70-kD antibodies are useful in the classification of patients with anti-U1RNP.

Antibodies, Antinuclear↗
PubMed1990

[Progressive systemic sclerosis and polymyositis overlap syndrome: a report of 40 cases].

We studied 40 patients who had clinical features of both typical progressive systemic sclerosis (PSS) and polymyositis (PM). The indurated skin extended over the metacarpophalangeal joints in all patients. The sclerotic changes, diffuse in type, involved the whole body, including the face, neck, extremities and trunk in most cases. All showed Raynaud's phenomenon. All patients had muscle weakness, elevated skeletal muscle enzymes and myogenic disorders in electromyograms, and biopsy of muscles showed myositic changes. The symptoms involved multiple systems, particularly the gastrointestinal and circulatory systems, presenting features of both PSS and PM. Serologic examinations often revealed auto-antibodies in these patients. Treatment with small doses of corticosteroid and traditional chinese medicines usually had good results. We found that either PSS or PM might appear first, or they might appear simultaneously. It is our opinion that as long as we keep alert and carefully observe the features and their development, we can easily diagnose the disease early.

Adolescent↗
PubMedDate not supplied

Anti-SSB/La antibodies in Sjögren's syndrome and related autoimmune diseases. Results of a quantitative immunoassay using a highly purified antigen.

A quantitative immunoassay using a highly purified antigen from HeLa cells has allowed us to detect antibodies to SSB/La in 11/20 patients with primary Sjögren's syndrome (SS), 15/33 with SLE, and 11/35 with progressive systemic sclerosis (PSS). However, positive results were found in only 2/12 patients with idiopathic Raynaud's disease and 2/20 with rheumatoid arthritis, including 4 with secondary SS. Anti-SSB/La were associated with extraglandular manifestations in primary SS, and with a diffuse sclerodermic pattern in PSS. In SS, SLE and PSS, a positive anti-SSB/La test was strongly associated with nodal or spleen enlargement and with an increased level of gamma-globulins. A direct association was also found with positive tests for rheumatoid factors, anti-SSA/Ro and anti-Scl 70. An inverse relationship was however found with anti-nRNP +/- Sm and anticentromere antibodies. Our data suggest that anti-SSB/La antibodies can be regarded as a marker of B-lymphocyte activation in patients with either primary SS, SLE or PSS.

Antibodies, Antinuclear↗
PubMed2003

The prevalence and clinical significance of anti-U1 RNA antibodies in patients with systemic sclerosis.

We studied the prevalence and clinical significance of anti-U1 RNA antibodies in patients with systemic sclerosis. The presence of anti-U1 RNA antibodies was determined using immunoprecipitation in systemic sclerosis patients with anti-U1 RNP antibodies (n=36), antitopoisomerase I antibodies (n=20), or anticentromere antibodies (n=20), mixed connective tissue disease patients (n=23), systemic lupus erythematosus patients with anti-U1 RNP antibodies (n=26), and normal controls (n=20). Moreover, antigen specificities for anti-U1 RNP antibodies were examined in patients with systemic sclerosis by immunoblotting and enzyme-linked immunosorbent assay. Anti-U1 RNA antibodies was detected in 22 of 36 systemic sclerosis patients (61%) with anti-U1 RNP antibodies, 14 of 23 patients (61%) with mixed connective tissue disease, and eight of 26 systemic lupus erythematosus patients (31%) with anti-U1 RNP antibodies. Anti-U1 RNA antibodies were not detected in other groups. As for systemic sclerosis patients, the frequencies of pulmonary fibrosis and reduced percentage diffusion capacity for carbon monoxide were significantly greater in patients with anti-U1 RNA antibodies than in those without (76%vs 18%, p<0.005; 82%vs 27%, p<0.005, respectively). Moreover, patients with anti-U1 RNA antibodies had significantly lower percentage diffusion capacity for carbon monoxide and percentage vital capacity values than those without (51.9+/-16.8 vs 79.4+/-16.4, p<0.01; 83.8+/-21.4 vs 101.4+/-12.9, p<0.05, respectively). Regarding the antigen specificities of anti-U1 RNP antibodies in systemic sclerosis patients, the frequency of anti-70 kDa antibodies determined by immunoblotting was significantly higher in patients with anti-U1 RNA antibodies than in those without (77%vs 43%, p<0.05). This finding was also confirmed by enzyme-linked immunosorbent assay for anti-70 kDa antibodies (86%vs 43%, p<0.05). These results indicate that anti-U1 RNA antibodies may be a serologic indicator for pulmonary fibrosis in systemic sclerosis patients with anti-U1 RNP antibodies.

Autoantibodies↗
PubMed2006

Serum levels of monocyte chemotactic protein-3/CCL7 are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis.

OBJECTIVE: To determine serum levels of monocyte chemotactic protein-3 (MCP-3) and its clinical associations in patients with systemic sclerosis (SSc). METHODS: Serum MCP-3 levels from 69 patients with SSc were examined by ELISA. RESULTS: Serum MCP-3 levels were raised in patients with SSc (n = 69) compared with healthy controls (n = 28). Patients with diffuse cutaneous SSc (n = 36) had higher levels of serum MCP-3 than those with limited cutaneous SSc (n = 33). Patients with raised MCP-3 levels had pulmonary fibrosis and decreased vital capacity (VC) more often than those with normal MCP-3 levels. MCP-3 levels correlated positively with the extent of skin fibrosis, and inversely with %VC and carbon monoxide transfer factor (Tlco) in patients with SSc. CONCLUSION: MCP-3 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that MCP-3 may have a role in the development of fibrosis in SSc.

Adolescent↗
PubMed1984

Steroid-responsive interstitial pulmonary disease in systemic sclerosis. Monitoring by bronchoalveolar lavage.

We describe a 38-year-old woman with systemic sclerosis of recent onset and progressive dyspnea. Studies of pulmonary function revealed a restrictive ventilatory disorder with decreased diffusing capacity. Interstitial fibrosis and infiltration with lymphocytes and plasma cells with formation of follicles were observed in the lung biopsy. Analysis of fluid from bronchoalveolar lavage showed an increase in the total number of cells, with a relative increase in neutrophils. Also, the relative amount of the immunoglobulins, IgG and IgM, was increased. During corticosteroid treatment, rapid improvement of pulmonary volumes occurred, together with disappearance of neutrophils and an increase in the percentage of lymphocytes in the lavage fluid. Later on, the total number of cells in the fluid from bronchoalveolar lavage and the percentage of lymphocytes reached normal values. Bronchoalveolar lavage may be of value in assessing and monitoring pulmonary disease in patients with systemic sclerosis.

Adult↗
PubMed1995

Autoantibodies to pyruvate dehydrogenase complex in patients with systemic sclerosis. Possible role of anti-E1 alpha antibody as a serologic indicator for development of primary biliary cirrhosis.

OBJECTIVE: To determine the prevalence and clinical significance of anti-pyruvate dehydrogenase complex (anti-PDC) antibodies in systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (n = 81) or diffuse cutaneous SSc (n = 63) were examined for anti-PDC antibodies by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. RESULTS: IgG- and/or IgM-isotype anti-PDC antibodies were demonstrated by ELISA in 26 of 144 patients with SSc (18%). By immunoblotting, 19 patients had IgG anti-PDC antibodies. Among these patients with IgG anti-PDC antibodies, antibody to the E1 alpha subunit was significantly associated with the presence of laboratory abnormalities typical of primary biliary cirrhosis (PBC). CONCLUSION: Antibody to the E1 alpha subunit of PDC may be a serologic indicator for the development of PBC in patients with SSc.

Adult↗
PubMed1997

Organizing diffuse alveolar damage associated with progressive systemic sclerosis.

Diffuse alveolar damage (DAD) is a relatively nonspecific pattern of acute lung injury that can be observed in a wide range of clinical circumstances. DAD has often been recognized in association with various connective tissue diseases; however, to our knowledge, it has not been previously reported in the setting of progressive systemic sclerosis. Herein we describe two patients with established diagnoses of progressive systemic sclerosis who had development of the acute respiratory distress syndrome. Open-lung biopsy specimens from both patients showed a histologic pattern of DAD with no identifiable cause other than their progressive systemic sclerosis. Our results suggest that DAD should be added to the list of pleuropulmonary complications of progressive systemic sclerosis.

Aged↗
PubMedDate not supplied

High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement.

OBJECTIVES: YKL-40, a growth factor of connective tissue cells, is elevated in sera from patients with diseases characterized by inflammation, tissue remodelling, or fibrosis. The aim of the study was to determine serum YKL-40 levels in patients with systemic sclerosis (SSc) and to explore any possible clinical and prognostic associations. METHODS: YKL-40 was measured in sera from 88 patients with SSc (26 with diffuse and 62 with limited skin involvement) and in sera from 88 matched healthy controls. Immunohistochemical staining for YKL-40 antigen was performed in a biopsy from a patient with pulmonary SSc. RESULTS: Serum YKL-40 levels of the SSc patients were significantly higher than those of the controls (p<0.00001). Patients with pulmonary fibrosis by chest X-ray, obstructive ventilatory pattern, reduced diffusing capacity (DLco), and digital joint deformity due to skin retraction had significantly higher serum YKL-40 compared with patients without these findings. Patients with elevated serum YKL-40 had shorter survival times than patients with normal serum YKL-40 (p = 0.0005), although this was not independent of age and pulmonary function. YKL-40 protein expression was found in inflammatory cells in fibrosing pulmonary tissue from a patient with SSc. CONCLUSIONS: Serum YKL-40 is elevated in patients with SSc with pulmonary involvement.

Adipokines↗
PubMed1998

A pilot study of intermittent intravenous cyclophosphamide for the treatment of systemic sclerosis associated lung disease.

OBJECTIVE: Pulmonary fibrosis, a frequent manifestation of systemic sclerosis (SSc), is considered incurable. Our aim was to assess the effect of therapy with intravenous (i.v.) cyclophosphamide on the course of pulmonary fibrosis in patients with SSc. METHODS: Five patients with SSc and clinical, laboratory, or radiographic findings of interstitial lung disease were treated with cyclophosphamide (1 g) administered i.v. monthly for 48 weeks. The dyspnea score, pulmonary function tests, arterial blood oxygen content, radiologic abnormalities, and bronchoalveolar lavage (BAL) fluid cellularity were determined before and after therapy. RESULTS: The dyspnea score decreased by 42% after 48 weeks of therapy. Forced vital capacity (FVC, percentage of predicted) increased by 7%, and carbon monoxide diffusing capacity (DLCO) decreased by 12%, but these changes were not statistically significant. Arterial blood oxygenation remained unchanged. At baseline, high resolution computed tomography of the lungs showed honeycombing, reticulonodular, or ground glass patterns in each patient examined. These radiologic abnormalities did not improve during treatment. A marked decrease in BAL fluid cell number, but not in the percentage of neutrophils, was observed after therapy. Nausea and leukopenia were frequent but mild side effects. One patient developed hemorrhagic cystitis. CONCLUSION: The results suggest that intermittent treatment with i.v. cyclophosphamide reduces the severity of dyspnea, but fails to improve FVC or DLCO, or cause resolution of radiologic abnormalities, in patients with SSc.

Adult↗
PubMed2003

Systemic sclerosis: patients' perceptions of their condition.

OBJECTIVE: To examine patients' beliefs about systemic sclerosis (SSc) and to investigate the relationship between these beliefs, symptom report, and clinical and demographic variables. METHODS: A total of 49 patients (7 male, 42 female) with SSc underwent clinical examination and completed the Revised Illness Perception Questionnaire. This measure assesses beliefs about symptoms, chronicity or recurrence of the condition, consequences, personal and treatment control, illness coherence, perceived causes of the condition, and patients' emotional response to their condition. RESULTS: The symptoms patients most frequently associated with their SSc were stiff joints (79%), pain (75%), and fatigue (75%). The most commonly reported causes of SSc were stress (53%), altered immunity (49%), and chance or bad luck (46%). More than 96% of patients believed that their condition would be chronic and 78% believed that the condition had serious consequences on their lives. Patients with diffuse cutaneous SSc reported more significant consequences of the condition and less personal control of their SSc compared with patients with limited cutaneous disease. There were no significant differences in illness beliefs between patients with nonsevere and severe ischemia. Multiple regression analyses indicated that illness beliefs, in particular perceived consequences associated with the condition, accounted for a significant proportion of the variance in emotional response to the condition. CONCLUSIONS: The beliefs held and symptoms experienced by patients with SSc are not ruled by disease subtype, skin score, functional ability, or severity of digital ischemia. This suggests patients' beliefs and emotional response are associated with the meaning they ascribe to their condition rather than its severity.

Adult↗
PubMed2001

Relationship between parity and clinical and biological features in patients with systemic sclerosis.

OBJECTIVE: To assess the influence of parity on the clinical and biological features of systemic sclerosis (SSc). METHODS: We recorded the following clinical and biological data of 100 consecutive women with SSc: age, disease duration before diagnosis, cutaneous extension of sclerosis according to LeRoy's classification, pulmonary involvement, and antinuclear antibodies. We compared these features to the number and sex of children who were born before SSc onset. Date of birth of the first children was systematically recorded. RESULTS: Patients with limited SSc had more children before SSc onset than patients with diffuse SSc (2.4 +/- 1.8 vs 1.7 +/- 1.5; p < 0.05). The interval between first birth and SSc onset was shorter for patients with limited SSc than for patients with diffuse SSc (11.0 +/- 9.9 vs 23.5 +/- 14.5 yrs; p < 0.01). Patients with pulmonary fibrosis had more children than patients without pulmonary fibrosis (2.5 +/- 1.9 vs 2.0 +/- 1.6; p < 0.05). Age at first birth was significantly higher when the child was a girl than a boy (26.8 +/- 7.5 vs 22.9 +/- 5.3 yrs; p < 0.05). The interval between the first birth and SSc onset was shorter when the child was a girl than a boy (16.2 +/- 9.6 vs 25.4 +/- 13.4 yrs; p < 0.05). CONCLUSION: Pregnancy related microchimerism could be preferentially associated with limited SSc and pulmonary fibrosis. Microchimerism may be facilitated in cases in which the fetus is female.

Adult↗
PubMed1998

The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis.

OBJECTIVE: To test the ability of the modified Rodnan skin score to reflect skin thickness in skin biopsies from 141 patients with systemic sclerosis (SSc) obtained at entry during a prospective, double blind study of ketanserin versus placebo in SSc. METHODS: Punch skin biopsies (4 mm) were obtained from the dorsal surface of the distal forearm of 141 patients. Biopsy specimens were trimmed and weighed (wet weight) and then desiccated and reweighed (dry weight). Skin score was recorded for 17 areas, graded 0-4+, while edema was graded 0-4+ in 10 of the same sites using finger pressure. RESULTS: Total skin score correlated with wet weight (r = 0.553) and dry weight (r = 0.517) of the skin biopsies. Local skin score from the biopsied forearm also correlated with wet and dry weight (r = 0.536 and 0.530, respectively). Dry weight as a percentage of wet weight was the same for diffuse cutaneous SSc (dSSc) and limited cutaneous SSc (lSSc) (30.7% for both, NS), despite increased wet weight in patients with dSSc versus lSSc (17.75 vs 13.03 g; p < 0.001). Edema scores correlated poorly both with wet weight (r = 0.069) and dry weight (r = 0.169). CONCLUSION: Total and forearm skin score correlates well with both wet and dry forearm skin biopsy weight from forearm biopsies, indicating that skin score reflects the underlying pathology of SSc. Further, the percentage of dry to wet weight is similar for lSSc and dSSc, supporting the usefulness of skin score in differentiating SSc disease subtypes.

Adolescent↗
PubMed1983

Lower esophageal rings as a cause of dysphagia in progressive systemic sclerosis--coincidence or consequence?

Lower esophageal rings were found in five of 40 consecutive patients seen with progressive systemic sclerosis. Three of these five patients had diffuse skin involvement and two had the CREST variant of progressive systemic sclerosis. All of the patients with lower esophageal rings had intermittent esophageal obstruction (initially attributed to esophageal dysmotility), but so did five of seven patients with esophageal strictures without lower esophageal rings. Esophageal bougienage relieved this symptom in four of the five patients with rings in which it was performed. Persistent relief of these obstructive symptoms (6-36 months) in the patients with rings was in contrast to the recurrent dilatations that have been needed in the group of patients with peptic strictures. In contrast to esophageal aperistalsis and/or stricture formation, the lower esophageal ring, perhaps as a consequence of chronic gastroesophageal reflux, may be a more treatable cause of dysphagia in patients with progressive systemic sclerosis.

Adult↗
PubMed2003

Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations.

Most studies have suggested that ethnic factors impact significantly on systemic sclerosis. Extensive epidemiologic studies have been carried out in white individuals, and limited data suggest that blacks are affected twice as frequently; Japanese patients have a lower prevalence than whites. This highest rate that has been described has been in Choctaw Native Americans. Blacks have a lower age at onset, as well as a higher frequency of diffuse skin involvement, pulmonary disease, and an overall worse prognosis than whites. Limited data in Hispanics and Native Americans suggest that they have more severe disease than whites. Whites have the highest frequency of anti-centromere antibodies (associated with limited skin involvement and less pulmonary fibrosis), whereas blacks have a higher frequency of anti-ribonucleoprotein and fibrillarin autoantibodies; the latter is a nucleolar antibody associated with a poorer prognosis. Ethnic differences are also seen for associations with non-major histocompatibility complex genes, such as FBN1 (fibrillin) genes, in Choctaws and Japanese and SPARC (osteonectin) in whites, Hispanics, and Choctaws. Although these facts do not entirely rule out socioeconomic factors associated with ethnicity, nevertheless ethnicity has an important impact on the pathogenesis of systemic sclerosis, perhaps because of genetic factors.

Autoantibodies↗