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PubMedDate not supplied

Calcium influx into red blood cells: the effect of sera from patients with systemic sclerosis.

The rheology of red blood cells in patients with systemic sclerosis is abnormal. To investigate this further we have examined the effect of sera from patients with systemic sclerosis on the handling of calcium ions by the erythrocyte membrane. Normal erythrocytes were filled with a photoprotein (aequorin) which emits light on contact with calcium. These photoprotein loaded normal erythrocytes were then incubated overnight with serum from: normal subjects (n = 20), from patients with systemic sclerosis (n = 27) or from patients with primary Raynaud's disease (n = 10). There was no significant difference in basal calcium leakage, as measured by the amount of light produced following the addition of triton X-100. Induced calcium influx, as measured by the amount of light produced following the addition of ionophore A23817, was significantly greater in the photoprotein loaded erythrocytes incubated overnight with serum from patients with systemic sclerosis compared to those incubated with serum from normal subjects (p less than 0.02) or patients with primary Raynaud's disease (p less than 0.01). This modulation of Ca2+ handling in erythrocytes by a serum factor from patients with systemic sclerosis could account for the alterations in erythrocyte function, such as red cell deformability, observed in systemic sclerosis.

Adult↗

PubMed1990

Penicillamine in systemic sclerosis: a reappraisal.

In a 36-month prospective trial 21 patients with systemic sclerosis (diffuse systemic sclerosis 16 patients and 5 subjects with limited cutaneous subtype) were treated with D-penicillamine. In all patients with diffuse systemic sclerosis there was objective improvement. The degree and extent of skin involvement decreased significantly (p less than 0.001), whereas no objective improvement was noted in patients with limited cutaneous subtype. Further, no systemic progression of the disease was observed during the study period. Our results suggest that a prolonged treatment with D-penicillamine in small doses is not only beneficial and effective but also free of side-effects, if used at an earlier stage.

Adult↗

PubMed1999

Lymphatic microangiopathy of the skin in systemic sclerosis.

METHODS: The cutaneous capillary lymphatic system in patients with systemic sclerosis was investigated using fluorescence microlymphography. The distal upper limbs of 16 healthy controls (mean age 62.3+/-13.1 yr) and 16 patients with systemic sclerosis (mean age 58.9+/-13.6 yr) were examined and the following parameters were evaluated: (a) single lymphatic capillaries; (b) lymphatic capillary network and cutaneous backflow; (c) extension of the stained lymphatics; (d) diameter of single lymphatic capillaries. RESULTS: At the finger level, lymphatic capillaries were lacking in five patients, while they were present in all controls (P < 0.05). Extension of the stained lymphatics was increased in 11 patients (8.1+/-6.0 mm) compared to the 16 healthy controls (2.0+/-1.2 mm) (P < 0.0001). Cutaneous backflow was observed in three patients (P < 0.05). At the hand level, lymphatic network extension was significantly different between patients (3.8+/-2.4 mm) and controls (1.2+/-0.8 mm) (P < 0.01); however, no significant differences were found at the forearm level. CONCLUSION: Lesional skin in patients with systemic sclerosis exhibits evidence of lymphatic microangiopathy.

Adult↗

PubMed2006

Postocclusive reactive hyperemia inversely correlates with urinary 15-F2t-isoprostane levels in systemic sclerosis.

Microvascular dysfunction and increased oxidative stress are major hallmarks of the systemic sclerosis disease process. The primary objective of this study was to test whether there is a link between peak postocclusive hyperemia and urinary levels of the F2-isoprostane 15-F2t-IsoP (8-iso-PGF2alpha) in patients suffering from systemic sclerosis. We enrolled 43 patients suffering from systemic sclerosis, 33 patients with primary Raynaud's phenomenon (RP), and 25 healthy volunteers. Microvascular function was assessed using the postocclusive hyperemia monitored by laser Doppler flowmetry. Endothelium-independent response was monitored after 0.4 mg sublingual nitroglycerin. Oxidative stress status was assessed by urinary levels of the F2-isoprostane 15-F2t-IsoP using GC-MS. The peak postocclusive vascular conductance was altered in subjects with systemic sclerosis and primary RP compared to controls (respectively 28 (7-48), 30 (13-48), and 39.9 (13-63) mV/mm Hg, p = 0.01). F2-isoprostanes were increased in the systemic sclerosis group compared to primary Raynaud's phenomenon and healthy controls (respectively 230 (155-387), 182 (101-284), and 207 (109-291) pg/mg, p = 0.006). In patients suffering from systemic sclerosis, there was a significant inverse correlation between F2-isoprostanes and postocclusive hyperemia, expressed as raw data (R = -0.45, p = 0.007) or as an increase over baseline (R = -0.28, p = 0.04). Conversely, no correlation was found with the nitroglycerin response. In conclusion, we provide evidence that there is an inverse correlation between postocclusive hyperemia and urinary F2-isoprostane levels in patients suffering from systemic sclerosis. Whether oxygen free radicals initiate the vascular dysfunction or whether there is an initial trigger that initiates both processes will need to be further clarified in future studies.

Dinoprost↗

PubMed2006

Pulmonary involvement in systemic sclerosis.

Scleroderma, also known as progressive systemic sclerosis (SSc), is a multisystem autoimmune disorder characterized by inflammation and fibrosis involving the skin as well as internal organs such as the vasculature, esophagus, and the respiratory tract. Pulmonary involvement consists most often of interstitial fibrosis and pulmonary vascular disease leading to pulmonary arterial hypertension (PAH). Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis. Pulmonary hemorrhage with acute renal failure and diffuse alveolar hemorrhage in the absence of a history of renal involvement or penicillamine intake have rarely been reported in patients with systemic sclerosis.On high resolution CT, evidence of interstitial disease is seen in approximately 90% of patients, the main findings being a fine reticular pattern involving the subpleural regions of the lower lobe. Other common findings include ground-glass opacities, honeycombing, and parenchymal micronodules. The most distinctive pulmonary histologic findings in patients with scleroderma are the vascular changes found in PAH in the absence of significant interstitial fibrosis.There is no strong evidence that any drug alters the course of the two main types of lung disease in systemic sclerosis. This apparent failure of therapy may reflect the fact that pulmonary involvement is usually identified at an established or late stage. It has been suggested that, for fibrosing alveolitis, corticosteroids are most effective if given in combination with cyclophosphamide. In some patients with SSc, PAH has been considered as a major cause of morbidity and mortality. Centrally infused prostacyclin (epoprostenol) and its subcutaneously infused analog treprostinil improve hemodynamics, as well as the quality of life and survival in these patients. Iloprost has also shown a positive effect on PAH in SSc patients. More recently, bosentan, an endothelin receptor antagonist, has proved effective in controlling PAH after 6 months' treatment. Sildenafil has been used as a selective pulmonary vasodilator in SSc patients with isolated PAH. This drug decreased mean pulmonary artery pressure and pulmonary vascular resistance, and increased cardiac output, with much improvement of the physical condition of the patients. Lung transplant can be considered as a last option.Clinicians must be aware of the possibility of lung disease in patients with SSc so that it can be treated as early as possible.

Endothelin Receptor Antagonists↗

PubMed1990

Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis.

Anticardiolipin antibody-positive patients with progressive systemic sclerosis were analyzed. Elevated anticardiolipin antibody titers were observed in 13 of 40 cases (33%). Anticardiolipin antibody titer was significantly higher in patients with progressive systemic sclerosis type 1 than in those with type 2 or type 3. Occurrence of anticardiolipin antibody was significantly more frequent in patients positive for anti-nRNP antibodies, rheumatoid factor, or thrombocytopenia. In contrast, patients with proximal scleroderma, scarring, or esophageal hypomotility were positive for anticardiolipin antibody less frequently. These results suggest that anticardiolipin antibody might be closely associated with lupuslike clinical manifestations in a subset of progressive systemic sclerosis or definite progressive systemic sclerosis with thrombocytopenia, rheumatoid factor, or anti-nRNP antibodies.

Autoantibodies↗

PubMed2005

Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach.

BACKGROUND: Systemic sclerosis is an autoimmune disease characterized by immunological abnormalities, vascular damage, and fibroblast proliferation. We have previously shown that a molecular mimicry mechanism links antibodies against the human-cytomegalovirus-derived protein UL94 to the pathogenesis of systemic sclerosis. The UL94 epitope shows homology with NAG-2, a surface molecule highly expressed on endothelial cells. Anti-UL94 peptide antibodies purified from patients' sera induce apoptosis of endothelial cells upon engagement of the NAG-2-integrin complex. METHODS AND FINDINGS: We show here that NAG-2 is expressed on dermal fibroblasts and that anti-UL94 antibodies bind to fibroblasts. We have used the gene array strategy (Affimetrix oligonucleotide microarrays) to analyze the transcriptional profile in response to a 4-h and an 8-h treatment with antibodies against the UL94 peptide in endothelial cells and dermal fibroblasts. Exposure of endothelial cells to anti-UL94 antibodies had a profound impact on gene expression, resulting in the upregulation of 1,645 transcripts. Several gene clusters were upregulated including genes encoding adhesion molecules, chemokines, colony-stimulating factors (CSFs), growth factors, and molecules involved in apoptosis. Following antibody stimulation, dermal fibroblasts showed an upregulation of 989 transcripts and acquired a "scleroderma-like" phenotype. Indeed, genes involved in extracellular matrix deposition, growth factors, chemokines, and cytokines were upregulated. We confirmed the microarray results by real-time quantitative polymerase chain reaction and by measuring some of the corresponding proteins with ELISA and Western blotting. CONCLUSION: Our results show that anti-human-cytomegalovirus antibodies may be linked to the pathogenesis of systemic sclerosis not only by inducing endothelial cell activation and apoptosis but also by causing activation of fibroblasts, one of the hallmarks of the disease.

Autoantibodies↗

PubMed1995

Incidence of cancer among patients with systemic sclerosis.

BACKGROUND: To determine cancer risk among patients with systemic sclerosis and localized scleroderma, a population-based retrospective cohort study was performed. Patients in Sweden with a discharge diagnosis of systemic sclerosis or localized scleroderma were obtained from the computerized database of hospital discharge diagnoses for the years 1965-1983. Nine hundred seventeen patients with systemic sclerosis and 102 with localized scleroderma were identified. METHODS: Using record linkage analysis with data from the Swedish National Cancer Registry, standardized incidence ratios (SIR)s (the ratio of observed to expected incidence) were calculated for specific cancer sites. RESULTS: The SIR for developing cancer in the cohort with systemic sclerosis was 1.5 (95% CI, 1.2-1.9). For specific cancer sites, risks were elevated for lung cancer (SIR, 4.9; 95% CI, 2.8-8.1), nonmelanoma skin cancers (SIR, 4.2; 95% CI, 1.4-9.8), and primary liver cancer (SIR, 3.3; 95% CI, 1.1-7.6). There was a suggestive increase in hematopoietic cancers (SIR, 2.3; 95% CI, 0.9-4.8). In contrast, cancer risks in the similarly ascertained cohort with localized scleroderma were no different from those of the general population. CONCLUSIONS: This study confirms earlier reports of an association between systemic sclerosis and an increased risk of cancer. Specific tumor sites correspond to the sites commonly affected by fibrosis such as the lung and skin.

Adult↗

PubMed2002

[Cardiovascular involvement in systemic sclerosis].

Heart involvement is frequent in systemic sclerosis. Cardiomyopathy is the main localization but its diagnosis is often late. Cardiac echography or radionuclide imaging show early involvement of the myocardium while showing alterations of diastolic function of the left ventricle or perfusion defects. The pathogenesis of this cardiomyopathy is supposed to be related to myocardial ischemia in relation with vasospasm, or with organic lesions of small arteries or coronary microcirculation. Pericarditis rarely is of clinical significance. Pulmonary hypertension concerns patients with proximal and advanced systemic sclerosis or limited forms such as CREST. It can be efficiently diagnosed by doppler echography but its therapy is difficult and its prognosis is poor. Epoprostenol in continuous venous infusion seems to be efficient but the accessibility to this therapy is difficult. While the involvement of middle-sized arteries of the hands is common, systemic sclerosis seems to be associated to an increased frequency of large-sized arteries disease.

CREST Syndrome↗

PubMed2002

Evolution of ambulatory measurement of blood pressure and parameters of arterial stiffness over a 1-year period in patients with systemic sclerosis: ERAMS study.

UNLABELLED: Patients with systemic sclerosis commonly exhibit increased arterial stiffness, which may be predictive of the overall severity of the disease. The aim of the present study was to check the stability of parameters of arterial stiffness after 1 year in this population. ERAMS is a French multicentric prospective study designed to identify a link between arterial distensibility and outcome in 100 patients with systemic sclerosis. Arterial distensibility was evaluated by 24-h ambulatory monitoring of QKD interval along with blood pressure (BP) and heart rate (HR) (four measurements/hour). The index QKD(100-60), which is linked to aortic distensibility, was calculated automatically. QKD(100-60) is the value of QKD (which depends on pulse wave velocity) for 100 mm Hg sBP and 60 bpm HR. The reproducibility of QKD(100-60) was assessed on the first patients to be followed up for a complete year. So far the 100 patients have been recruited from 14 participating centres and 48 were re-evaluated after 1 year. QKD(100-60) was highly reproducible: 201 +/- 6 vs202 +/- 18 msec, standard deviation of difference = 13 msec. IN CONCLUSION: determination of QKD(100-60) to assess arterial stiffness gives stable results over 1 year in patients with systemic sclerosis.

Adult↗

PubMed1999

Pregnancy in women with systemic sclerosis.

OBJECTIVE: To determine pregnancy outcomes in women with systemic sclerosis. METHODS: Women of childbearing age with systemic sclerosis seen at the University of Pittsburgh between 1987 and 1996 were observed prospectively. Pregnancy outcomes included abortion, miscarriage, preterm and term birth, and perinatal death. Complications of pregnancy and scleroderma were determined during and after pregnancy. RESULTS: Fifty-nine women with systemic sclerosis had 91 pregnancies during the 10-year period. No increase in the frequency of miscarriage was found, except in those with long-standing diffuse scleroderma. Preterm births occurred in 29% of pregnancies, and all but one of the infants survived. Symptoms related to scleroderma, particularly Raynaud phenomenon, improved during pregnancy, but esophageal reflux became worse. After pregnancy, some women with diffuse scleroderma had increased skin thickening. There were three cases of renal crisis during pregnancy, all in women with early diffuse scleroderma. Four women had five healthy infants while taking angiotensin-converting-enzyme inhibitors. CONCLUSION: Women with systemic sclerosis can safely have healthy pregnancies. Those with early diffuse scleroderma should wait until their disease stabilizes before becoming pregnant to decrease the risk of renal crisis. High-risk pregnancy management should be standard for all scleroderma pregnancies because of the high frequency of premature births.

Adult↗

PubMed2002

[Systemic sclerosis associated with microscopic polyangitis presenting with high myeloperoxidase (MPO) titer and necrotizing angitis: a case report].

We herein report a case of systemic sclerosis associated with microscopic polyangitis. The patient was a 54-year-old woman, who was diagnosed to have systemic sclerosis at a hospital in 1992, but she did not receive any medical treatment. She had been suffering from pyrexia, paresthesia and muscle weakness of both lower limbs since the beginning of 2001, and was introduced to our hospital. She showed hardened skin extending from her fingers to upper arms, weakness in both lower limbs and livedo reticularis. Her laboratory test showed WBC 11, 600/microliter, CRP 6.63 mg/dl, CH 50 24 U/ml, anti Scl-70 antibody 90.1 index, and MPO-ANCA 281 EU, but no impaired renal function was recognized. Chest computed tomography showed interstitial pneumonia while necrotising vasculitis of the right sural nerve was found in a biopsy specimen. Based on these findings, we diagnosed her to have systemic sclerosis accompanied with microscopic polyangitis (MPA). She received steroid treatment after the diagnosis was made, and her symptoms and the laboratory findings thereafter immediately improved. Many cases have been reported to have ANCA positive systemic sclerosis among patients with systemic sclerosis that are complicated MPO-ANCA-related vasculitis. However, since our patient demonstrated necrotising vasculitis in a sural nerve biopsy and no evidence of an impaired renal function, we diagnosed her to have systemic sclerosis complicated with MPA instead of ANCA positive systemic sclerosis. The pathological state of this patient thus seemed to be different from that of ANCA-positive systemic sclerosis. We concluded that this patient had both systemic sclerosis and MPA. It is therefore important to note that some patients who have been reported to have ANCA-positive systemic sclerosis may also have systemic sclerosis complicated with MPA.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1994

Analysis of the oral manifestations of systemic sclerosis.

The oral signs and symptoms in 32 patients with systemic sclerosis were evaluated. Oral mucosal telangiectasia was present in 18 cases (56.3%) and was not restricted to the limited form of systemic sclerosis. The interincisal distance was significantly decreased in the patients with systemic sclerosis compared with the 17 controls (p < 0.001). The distance between the vermillion borders was also significantly decreased when the 14 patients with salivary hypofunction were compared with the 18 cases without decreased salivary secretion (p < 0.05). Twenty-two (69%) of the patients exhibited keratoconjunctivitis sicca, salivary hypofunction, or both. Lip biopsy was performed in 16 cases. Two cases with inflammatory signs characteristic of Sjögren's syndrome were found, and six patients showed the histologic signs of labial gland fibrosis. Five of these cases belonged to the group of limited cutaneous systemic sclerosis that indicates the generalized nature of the fibrotic processes even in systemic sclerosis with less extensive skin involvement. Of the 10 cases investigated by electron microscopy, all but one showed a thickening of the capillary basal lamina, lamellar arrangement within the basement membrane, or capillary endothelial vacuolization. Three of these cases belonged to the patients with disease onset within 2 years, showing that capillary vascular lesion is present in the early cases and that vascular injury affects even those tissues that do not seem to be evidently involved by clinical examination.

Antibodies, Antinuclear↗

PubMed1995

Ultrasound measurement of skin thickness in systemic sclerosis.

Sclerotic skin change in systemic sclerosis (SSc) usually accompanies increased skin thickness. In order to quantify the cutaneous changes and to clarify the changes in the 'uninvolved' skin in systemic sclerosis (SSc), we measured the skin thickness on the chest, the forearms and the hands of 79 patients with SSc and 81 healthy controls with a B-mode ultrasound (30 MHz) apparatus. The thickness of the 'uninvolved', as well as the 'involved' skin in patients with SSc was significantly greater than that of healthy controls. Increased skin thickness on the forearms and/or the hands showed a 64.6% sensitivity and a 100% specificity for SSc. These results indicated that the skin which appears to be 'uninvolved' in patients with SSc is already pathologic, as shown by increased thickness. Moreover, measurement of skin thickness may be beneficial in the diagnosis of this disease at an early stage.

Adolescent↗

PubMed2003

Current status of outcome measure development for clinical trials in systemic sclerosis. Report from OMERACT 6.

Systemic sclerosis (SSc), also known as scleroderma, is a complex, multisystem disease that results in severe morbidity, disability, and life-threatening complications. The wide range of biological systems clinically involved, and the large spectrum of disease activity and damage that occurs in this disease have limited clinical investigation of SSc, especially therapeutic trials. The OMERACT 6 Workshop on Systemic Sclerosis was conceived as a starting point for the process of assessing the current state of the science in outcome assessment in SSc and then setting a realistic research agenda and priorities for future work in this area This article reviews the current status of assessment tools for research in SSc within the main fundamental domains of illness in SSc, including problems related to skin, pulmonary, cardiac, peripheral vascular (Raynaud's phenomenon and digital ulceration), renal, and musculoskeletal systems as well as health-related quality of life and physical functioning. The current level of validation of outcome measures in SSc is assessed according to the guidelines set forth by prior OMERACT meetings.

Clinical Trials as Topic↗

PubMed1995

Esophageal scintigraphy of systemic sclerosis.

UNLABELLED: Esophageal involvement is common in systemic sclerosis, and esophageal scintigraphy can be used to detect and follow esophageal dysfunction. This study assesses the value of visual and quantitative analysis of esophageal scintigraphy performed as a multiple swallow test in normals and patients with systemic sclerosis. METHODS: Forty patients with systemic sclerosis and 40 sex- and age-matched healthy subjects (controls) were studied. A multiple swallow technique was used and both quantitative and qualitative analyses were performed. Visual analysis of condensed images was performed independently by two physicians. Each swallow was assigned a score on a scale from 1 to 4. In the quantitative analysis, time-activity curves based on the mean condensed images were used to calculate the following 3 parameters: residual activity 12 or 25 sec after the beginning of the swallow, measured with or without baseline correction, respectively, and time from onset of swallow to 50% of peak activity. RESULTS: Both visual and quantitative analysis showed a highly significant (p < 0.001) difference between the patient group and the control group. Visual analysis was best reflected by the residual activity 25 sec after the beginning of the swallow without correction for background. Receiver operating characteristic curves were used to study the ability to separate the two groups using visual or quantitative analysis. A high rate of positive tests in the patient group was achieved only at the cost of a relatively high rate of positive tests in the control group. CONCLUSION: Our results indicate high variability in esophageal motility in controls. This variability impairs the possibilities of developing a screening test to identify asymptomatic patients early in the disease course.

Adult↗

PubMed1981

Impotence in progressively systemic sclerosis.

Five men with progressive systemic sclerosis presented with impotence as a significant initial feature of their disease. Endocrine, urologic, and psychiatric evaluations failed to reveal another cause for impotence. We suggest that male erectile dysfunction represents another manifestation of systemic sclerosis. Possible mechanisms for this phenomenon are discussed.

Adult↗

PubMed2002

Histometric data obtained by in vivo confocal laser scanning microscopy in patients with systemic sclerosis.

BACKGROUND: It would be a benefit if time-saving, non-invasive methods could give hints for diagnosing systemic sclerosis. To investigate the skin of patients with systemic sclerosis using confocal laser scanning microscopy in vivo and to develop histometric parameters to describe characteristic cutaneous changes of systemic sclerosis observed by this new technique, we conducted an exploratory study. MATERIALS AND METHODS: Fifteen patients with systemic sclerosis treated with extracorporal photopheresis were compared with 15 healthy volunteers and 10 patients with other disorders also treated with extracorporal photopheresis. All subjects were investigated using confocal laser scanning microscopy in vivo. RESULTS: Micromorphologic characteristics of skin of patients with systemic sclerosis and measuring parameters for melanisation, epidermal hypotrophy, and fibrosis for dislocation of capillaries by collagen deposits in the papillary dermis were evaluated. An interesting finding was an increased thickness of the tissue in the dermal papillae superior to the first dermal papilla vessel. It was also possible to reproduce characteristic histologic features by confocal laser scanning microscopy in vivo. Histometric parameters for fibrosis and vascular features developed in this study showed significant differences in patients with systemic sclerosis compared to controls. CONCLUSIONS: Although the predominant histopathological features in systemic sclerosis are findings of the reticular dermis and the subcutis, and in histopathological investigation the epidermis seems to remain unaffected by the disease, we have demonstrate some characteristic differences in the epidermis and papillary dermis by confocal laser scanning microscopy in vivo. Some of them have not been described so far. However, to use this technique as a tool for diagnosis and/or staging of systemic sclerosis, further studies are needed investigating the sensitivity and specificity of the histometric parameters developed in this study.

Adult↗