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PubMed2000

Exhaled nitric oxide in systemic sclerosis: relationships with lung involvement and pulmonary hypertension.

OBJECTIVE: To measure nitric oxide (NO) concentration in exhaled air of patients with systemic sclerosis (SSc) and to investigate its relationships with lung involvement, complicated or not by pulmonary hypertension (PH). METHODS: Exhaled NO was measured by chemiluminescence in 47 patients with SSc (16 with PH) and in 30 controls. All the patients underwent Doppler echocardiography to assess pulmonary artery pressure (PAP), lung function tests, and thin section computed tomographic scans of the lung to quantify the extent of fibrosing alveolitis. RESULTS: Exhaled NO levels were higher in patients with SSc (16.6 +/- 9.1 ppb), particularly those with interstitial lung disease (ILD) (18.3 +/- 10.4 ppb), compared to controls (9.9 +/- 2.9 ppb; p < 0.0001). In patients with PH, exhaled NO was less than in patients without PH (10.7 +/- 5.9 vs 19.6 +/- 9 ppb, respectively; p < 0.001), and patients with PH without ILD had even lower exhaled NO than patients with PH and ILD (6.6 +/- 1.1 vs 12.6 +/- 6.3 ppb; p = 0.004). There was an inverse correlation between PAP and exhaled NO (r = 04).53, p = 0.004). Exhaled NO was not correlated to age, disease duration, current therapy, or form of disease (limited or diffuse). CONCLUSION: The increased concentration of exhaled NO in patients with SSc may reflect respiratory tract inflammation. The relatively low value of exhaled NO in patients with PH and the negative correlation between PAP and exhaled NO suggest the important role of NO in regulating pulmonary vascular resistance in patients with SSc.

Adult↗
PubMed2001

[Interleukin-2 and interleukin-6 in serum as markers of disease progression in systemic sclerosis].

It is hypothesized that abnormalities of cell-mediated immunity participate in the pathogenesis of systemic sclerosis (SSc). However, the role of many cellular markers of immune activation remain still not well known, particularly as comparable with clinical status. The aim of this study was to examine the levels of some cytokines: IL-2, IL-6, TNF-alpha and to evaluate their role as parameters of disease activity and severity in systemic sclerosis. Fourty-seven patients with SSc we included in the study. Concentrations of cytokines were determined by an-enzyme-linked immunosorbent assay--ELISA. Controls were healthy age-and-sex marched volunteers. Interleukin-2 was identified in 45% of sera from patients with SSc, predominantly among patients with the rapidly progressive disease and with the diffuse SSc. The presence of IL-2 in SSc sera may also be indicative of disease activity. The frequency of positivity for IL-6 in examined SSc sera was similarly and was 50%. The prominently frequent incidence of the IL-6 in early stage of disease and in patients with severe systemic involvement indicated a potential role of this cytokine as a parameter of disease activity. TNF-alpha was not detected in the examined sera.

Adolescent↗
PubMed1994

Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon.

OBJECTIVE: To determine the presence of transforming growth factor beta 1 (TGF beta 1) and inflammatory cell markers (HLA-DR and Factor XIIIa) and to compare these with the presence of type I procollagen, in clinically uninvolved and involved skin from patients with different subsets of systemic sclerosis (SSc), and to analyze circulating levels of TGF beta 1 in SSc patients. METHODS: TGF beta 1, HLA-DR, Factor XIIIa, and type I procollagen were detected in skin biopsy sections using a biotin-streptavidin-peroxidase system. Levels of circulating TGF beta 1 were measured using a capture enzyme-linked immunosorbent assay technique. RESULTS: Patients with active diffuse cutaneous SSc (dcSSc) showed minimal TGF beta 1 but significant type I procollagen staining in involved skin, while the clinically uninvolved skin of these patients showed moderate extracellular and intra-epidermal TGF beta 1 immunoreactivity. Patients with limited cutaneous SSc (lcSSc) showed elevated TGF beta 1 staining in both involved and uninvolved skin, as well as procollagen staining. Significant TGF beta 1 reactivity, HLA-DR and Factor XIIIa immunoreactivity, numerous inflammatory cells, and procollagen staining were seen in specimens from patients with morphea. Sequential biopsies suggested the presence of cytokine activity at the earliest stages of disease, which was not maintained with progression of sclerosis. Among the disease groups studied, elevated levels of circulating TGF beta 1 were seen only in patients with morphea. CONCLUSION: The pattern of TGF beta 1 staining in dermal sections from patients with dcSSc, lcSSc, and morphea suggests that this cytokine is important in the pathogenesis of scleroderma. Furthermore, the presence of TGF beta 1 prior to the onset of fibrosis indicates an early involvement of this growth factor, possibly in the inflammatory stage of the disease.

Biomarkers↗
PubMed1985

Pulmonary manifestations of the rheumatic diseases.

The collagen vascular diseases represent a heterogeneous group of multisystem disorders with a wide range of clinicopathologic features. Although these diseases represent distinct clinical entities, a great deal of overlap exists between them. For example, the diffuse interstitial fibrosis of SLE, RA, DM-PM, PSS, and MCTD are indistinguishable clinically, radiographically, and histologically. Conversely, the pulmonary manifestations of the various vasculitides all differ significantly from each other in their clinicopathologic presentation, as well as in their response to therapy. For diagnostic purposes, histologic evidence will usually be required for the pulmonary manifestations of the rheumatic diseases. Therapy must then be individualized for each of these entities, as the protocol and response are variable.

Arthritis, Rheumatoid↗
PubMed2000

Isolated pulmonary hypertension in diffuse cutaneous systemic sclerosis successfully treated with long-term plasma exchange.

Isolated pulmonary hypertension (PHT) in patients with diffuse cutaneous systemic sclerosis (dSSc) is one of the most severe complication. Here we report the case of a 22 year-old white woman with anti-U3RNP antibody-positive dSSc complicated by severe, isolated PHT successfully treated with long-term plasma exchange. This beneficial effect persisted for two years, even after plasma exchange discontinuation. This is the first observation of isolated PHT in dSSc responsive to plasma exchange therapy.

Adult↗
PubMedDate not supplied

Endothelin-1 serum levels correlate with MCP-1 but not with homocysteine plasma concentration in patients with systemic sclerosis.

OBJECTIVES: To determine whether homocysteine (Hcy) plasma levels are correlated with molecules indicative of endothelial cell and fibroblast activation, including endothelin-1 (ET-1) and monocyte chemoattractant protein-1 and -3 (MCP-1, MCP-3), in patients with systemic sclerosis (SSc). METHODS: Eighty-two patients were enrolled in this study; the control group included 75 age- and sex-matched subjects. Plasma Hcy was determined by high-performance liquid chromatography; folic acid, and vitamin B(12) plasma levels were determined by a chemiluminescence method. ET-1, MCP-1, and MCP-3 were determined by enzyme-linked immunosorbent assay (ELISA). Analysis of the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was performed by polymerase chain reaction (PCR) and digestion with the enzyme HinfI. RESULTS: Hcy levels were lower in patients whereas ET-1 was significantly higher in patients and correlated with MCP-1. Stratification of the patients on the basis of Hcy levels was not associated with any statistical difference in the concentration of ET-1, MCP-1, and MCP-3. Patients with diffuse disease presented the highest levels of ET-1 and MCP-1. The distribution of the MTHFR genotypes was not different in patients and controls. CONCLUSIONS: In SSc, Hcy plasma concentration does not influence ET-1, MCP-1, or MCP-3 levels. On the contrary, ET-1, a marker of vascular activation, correlates with MCP-1, a chemokine involved in the fibrotic process of SSc.

Biomarkers↗
PubMed2002

Elevated levels of circulating CD44 in patients with systemic sclerosis: association with a milder subset.

OBJECTIVE: To determine serum levels of soluble CD44 (sCD44), one of the adhesion molecules that regulate the migration of leucocytes, and clinical associations of these levels in patients with systemic sclerosis (SSc). METHODS: Serum sCD44 levels were examined by enzyme-linked immunosorbent assay. RESULTS: Serum sCD44 levels were elevated in SSc patients compared with normal controls. Serum sCD44 levels were higher in patients with limited cutaneous SSc than in those with diffuse cutaneous SSc. Patients with elevated sCD44 levels had pulmonary fibrosis less frequently than those with normal sCD44 levels. Serum sCD44 levels remained elevated during the follow-up in almost all patients with elevated levels at their first visit, whereas they remained normal in all patients with normal levels. CONCLUSION: Elevated sCD44 levels were associated with a relatively mild subset of SSc. These results suggest that CD44 could be a potential therapeutic target in SSc.

Adolescent↗
PubMed2006

Myocardial damages in systemic sclerosis detected by gated myocardial perfusion SPECT and sympathetic imaging.

BACKGROUND: Cardiac involvement is an important factor for the appropriate management of systemic sclerosis (SSc). The possibility for detecting early myocardial damage was investigated using (99m)Tc methoxyisobutylisonitrile (MIBI) gated perfusion single photon emission computed tomography (SPECT) and (123)I metaiodobenzylguanidine (MIBG) sympathetic imaging. METHODS AND RESULTS: Twenty-three patients with SSc and 14 control subjects were studied. The severity of SSc was defined by disease type and semi-quantitative skin thickness scores. A myocardial perfusion study was performed using (99m)Tc MIBI exercise--rest study, and systolic and diastolic parameters were calculated from the volume curve of the gated SPECT. (123)I MIBG was evaluated by segmental defects, a heart-to-mediastinum ratio and washout rate (WR). No significant exercise-induced ischemia was observed and the left ventricular ejection fraction was within normal range in patients with SSc. However, diastolic function calculated by time to peak filling (TPF) in the early diastole was significantly prolonged in SSc compared with the control group (184+/-35 ms, 160+/-25 ms, p=0.030) and more rapid MIBG WR from the myocardium (18.2+/-7.0% vs 11.1+/-4.3%, p=0.0015). Compared with the control group, the severe group with either diffuse SSc or a skin thickness score >or=10 had more prolonged TPF/RR interval than the less severe group. Both diastolic and sympathetic abnormalities were observed in 7 (30%) patients, and 1 abnormality in 17 (74%) patients with SSc. CONCLUSIONS: In patients with SSc, either diastolic dysfunction or sympathetic derangement, or both were observed even without induced ischemia and normal ventricular contractility. Based on these subclinical early findings, further follow-up studies are recommended.

3-Iodobenzylguanidine↗
PubMedDate not supplied

Collagenopathic cardiopathies.

Collagenopathic cardiopathies are a subject of extreme etiologic, pathogenetic and clinical interest. These disorders are associated with congenital or acquired anomalies of the connective tissue and because of the diffusion and nearly total distribution of this tissue, have a higher frequency than what has been previously estimated. The collagenopathic cardiopathies, can be divided into two main groups: one deriving from hereditary connective tissue diseases, and the other from acquired connective tissue diseases. The first group has a Mendelian type of transmission whereas the other appears to be secondary to various kinds of stimuli (viral, immunologic etc.) although polygenic factors are present. Of the first group we considered Marfan's syndrome, the Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, cutis laxa and the diseases of the fundamental substance with particular reference to mucopolysaccharidosis type 1H (Hurler's syndrome). In all of these disorders a specific metabolic disturbance is responsible for the cardiovascular damage which is expressed, depending on the specific genetic component in a more or less serious form. Among the acquired diseases of the connective tissue, we examined rheumatoid arthritis, systemic lupus erythematosus, polydermatomyositis, scleroderma; of the reactive arthritis, rheumatic fever; of the seronegative forms, spondyloarthritis, ankylosing spondylitis and Reiter's syndrome, mixed connective tissue disease and Lyme's disease. It must be emphasized that all of these disorders share relatively common pathogenetic characteristics which point to the importance of the presence of various types of antigens, immune complexes and the significant role of some of the histocompatibility antigens, as well as possible disturbances of cell-mediated immunity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathies↗
PubMed1994

Antihistone antibodies in systemic sclerosis. Association with pulmonary fibrosis.

OBJECTIVE: To determine the prevalence and clinical significance of antihistone antibodies (AHA) in systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (n = 44), diffuse cutaneous SSc (dcSSc; n = 48), and other SSc-related disorders (n = 22) were examined by enzyme-linked immunosorbent assay and immunoblotting for AHA. RESULTS: AHA were demonstrated in 29% of the 92 SSc patients and in 44% of those with dcSSc. The presence of AHA correlated with severe pulmonary fibrosis in those with dcSSc. Immunoblotting revealed that the predominant antigen was histone H1. CONCLUSION: AHA might be a serologic indicator of the severity of pulmonary fibrosis in SSc.

Adult↗
PubMed1994

HLA-DQB1 associations with anti-topoisomerase-1 antibodies in patients with systemic sclerosis and their first degree relatives. United Kingdom Systemic Sclerosis Study Group.

The frequency and functional properties of anti-topoisomerase-1 antibodies (ATA) have been studied in 58 systemic sclerosis (SSc) probands, 218 first degree relatives and 22 spouses. The dependence of ATA on the presence of certain HLA-DRB1 and HLA-DQB1 alleles was examined. ATA were detected by immunodiffusion, by absorption or inhibition of topoisomerase-1 enzymic activity, by immunoblotting of a K562 cell extract and by immunoprecipitation of 35S radiolabelled cell lines. HLA class II typing for HLA-DRB1 and HLA-DQB1 was performed by oligonucleotide typing in 49 families. Six probands and two relatives had ATA. The relatives with ATA had SSc. All eight individuals with ATA directly inhibited topoisomerase-1 function. Four of the eight had limited skin disease and four had diffuse skin involvement. The seven who were genotyped had at least one HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Therefore, ATA are not widely dispersed within families, but rather are only present in those with SSc, and certain genetic requirements appear necessary for their generation.

Alleles↗
PubMed1978

[HLA antigen frequencies in patients with progressive systemic sclerosis and morphea (author's transl)].

Forty three patients with progressive systemic sclerosis and 24 patients with morphea are typed for 30 antigens of the HLA-A and B series. There is an increase of the frequency of HLA-B8 in patients with progressive systemic sclerosis (37% vs. 20% in controls: P less than 0.001, Pcorr. = n.s.). The increase of the HLA-B8 frequency seems to be most pronounced in patients with a diffuse form of progressive systemic sclerosis. 4 out of 5 patients are HLA-B8 positive (P = 0.00672). In patients with acrosclerosis is HLA-B8 only slightly increased (32%), but the increase is greater in male patients (44%) and in patients with an early onset of the disease (36%). With the exception of HLA-A1 there is no deviation of the frequencies of any other HLA antigen tested, especially not of HLA-Aw24. The number of patients with morphea is to small for statistical evaluation.

Adult↗
PubMedDate not supplied

Factor VIII complex in progressive systemic sclerosis.

Factor VIII complex and its related activities (Coagulant, Antigen and Ristocetin Cofactor) have been investigated in 23 patients with Progressive Systemic Sclerosis (PSS) divided into two groups: acrosclerosis and diffuse sclerosis. All Factor VIII-related activities were higher in PSS patients than in normal subjects. No difference in F. VIII-related Antigen (F. VIIIR:Ag), F. VIII-related Ristocetin Cofactor (F. VIIIR:Co) and F. VIII Coagulant activity (F. VIII:C) was found comparing the patient groups. F. VIII:C was increased significantly less than F. VIIIR:Ag and F. VIIIR:Co in both patient groups. Some hypotheses about the pathogenesis of this increase are discussed.

Adult↗
PubMed2000

Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid peroxidation in systemic sclerosis: evidence of free radical-mediated injury.

OBJECTIVE: To elucidate whether oxidative injury occurs in systemic sclerosis (SSc) and whether it affects the erythrocyte membrane (EM) properties. METHODS: EM fluidity and lipid composition (cholesterol:phospholipid molar ratio [C:PL], fatty acid composition) were studied in 52 patients with SSc and in 53 subjects without SSc (32 with primary Raynaud's phenomenon [RP] and 21 healthy subjects [controls]). Fluidity was measured as the fluorescence anisotropy of the hydrophobic fluorescent probe DPH (1,6-diphenyl-1,3,5-hexatriene). Lipid peroxidation products were determined as thiobarbituric acid-reactive substances (TBARS). RESULTS: EM fluidity was significantly lower in SSc patients than in primary RP patients and controls (P < 0.001). The EM C:PL molar ratio was significantly higher in SSc patients than in primary RP patients and controls (P < 0.05). Levels of EM polyunsaturated n6 fatty acids (PUFA n6) were significantly lower in SSc patients than in primary RP patients and controls (P < 0.001). TBARS were significantly increased in SSc patients compared with primary RP patients and controls (P < 0.001). Multiple regression analyses indicated that the reduced EM fluidity was partly due to its greater C:PL molar ratio, lower PUFA n6 content, and higher TBARS levels. EM fluidity was lower among patients with nailfold capillary loss (P < 0.001) and digital ischemic ulcers (P < 0.05). EM lipid peroxidation products were higher among patients with pulmonary involvement (bibasal pulmonary fibrosis [P < 0.05] and reduced levels of diffusing capacity for carbon monoxide [P < 0.001]) and among patients who were positive for anti-topoisomerase I antibodies (P < 0.05) or negative for anticentromere antibodies (P < 0.001). CONCLUSION: Our findings support the idea that oxidative injury occurs in SSc and that, through lipid peroxidation, it induces structural and functional changes of the EM that may contribute to the development of the microvascular abnormalities that are seen in the disease.

Erythrocyte Membrane↗
PubMed2006

Evaluation of interleukin 13 polymorphisms in systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. It is characterized by excessive cutaneous and visceral fibrosis, damage to small blood vessels, and production of autoantibodies. Interleukin-13 (IL-13) has been shown to be involved in abnormal fibrosis in other diseases. Therefore, we have evaluated its possible involvement in SSc. We analyzed four IL13 gene polymorphisms, rs1800925 (IL13-1055), rs20541 (Arg130Gln), rs847, and rs2243204 in 107 unrelated SSc patients (40 patients having diffuse cutaneous form and 67 patients having limited cutaneous form) and in 170 controls. All subjects were Caucasians. In the total patient population and in the diffuse cutaneous subset, we observed an association between two IL13 polymorphisms, IL13 rs1800925 (IL13-1055), and IL13 rs2243204, and disease (p=0.03-0.04). The IL13 rs2243204T allele was more common in SSc patients (p=0.01, OR=2.3 CI 1.21-4.38) and in the diffuse cutaneous form (p=0.01, OR=2.95, CI 1.35-6.49) than in control subjects. Our result supports the suggestion that polymorphisms in IL13 are associated to SSc and skin fibrosis process. However, further studies on larger and independent population and functional analyses are needed to confirm these findings.

Aged↗
PubMed2001

Evidence for increased pyridinoline concentration in fibrotic tissues in diffuse systemic sclerosis.

Systemic sclerosis is a generalized disease characterized mainly by the accumulation of collagen in the skin and internal organs. The aim of our study was to determine the amount of collagen cross-link pyridinoline (Pyd) in a variety of fibrotic tissues (skin, fascia, endocardium, bladder) from an autopsy patient with diffuse systemic sclerosis, and to compare these with normal tissues from the same patient. Mean concentrations of Pyd in the fibrotic skin samples (66 mmol/mol collagen) were more than two-times greater than those in the uninvolved normal samples (27 mmol/mol collagen). The increase of Pyd in the endocardium, fascia, and bladder was also markedly higher (1.41 x, 1.26 x and 2.64 x higher than normal samples). The increased deposition of collagen in systemic sclerosis is accompanied by a significantly increased amount of Pyd in the collagen of fibrotic tissues.

Amino Acids↗
PubMed1993

Carboxyterminal type I procollagen peptide concentrations in systemic sclerosis: higher levels in early diffuse disease.

Systemic sclerosis (SSc) is characterized by increased collagen deposition in skin and internal organs, and increased serum concentrations of different connective tissue metabolites have been reported. In this study serum concentrations of carboxyterminal type I (PICP) and aminoterminal type III procollagen peptide (PIIINP) were higher in 24 patients with diffuse cutaneous systemic sclerosis (dSSc), than in 30 patients with limited cutaneous systemic sclerosis (lSSc). Thirty patients with advanced and progressing disease had higher serum concentrations of both peptides than 24 patients with milder disease. In patients with advanced disease, both peptides showed a negative correlation to disease duration. Despite being relatively higher both in early, widespread and advanced disease, serum PICP concentrations varied only within the normal range for healthy controls. Thus PICP is of limited value as a marker of disease activity in SSc.

Adult↗
PubMed2005

Clinical significance of serum levels of matrix metalloproteinase-13 in patients with systemic sclerosis.

OBJECTIVES: To investigate the clinical significance of serum matrix metalloproteinase-13 (MMP-13) levels in patients with systemic sclerosis (SSc). METHODS: Serum MMP-13 levels were determined by using a peptide substrate cleavage assay in 20 patients with diffuse cutaneous SSc (dcSSc), 20 with limited cutaneous SSc (lcSSc) and 10 normal controls. RESULTS: The serum MMP-13 levels in patients with dcSSc or lcSSc were significantly lower than those in normal controls (53.4 +/- 14.1 vs 73.2 +/- 11.5 ng/ml, P < 0.0005; 59.4 +/- 14.8 vs 73.2 +/- 11.5 ng/ml, P < 0.005, respectively), but there was no significant difference in the serum MMP-13 levels between patients with dcSSc and those with lcSSc. Disease duration prior to the diagnosis was significantly shorter in SSc patients with decreased serum MMP-13 levels than in those with normal levels (3.0 +/- 2.2 vs 8.6 +/- 7.6 yr, P < 0.0005). In addition, serum MMP-13 levels were moderately correlated with the duration of the disease (r = 0.451, P < 0.05). Though there was no significant difference in the frequencies of pulmonary fibrosis or reduced %DLco (diffusing capacity of lung for carbon monoxide), the frequency of reduced %VC (vital capacity) was significantly greater in patients with decreased serum MMP-13 levels than in those with normal levels (73 vs 24%, P < 0.05). CONCLUSIONS: Matrix metalloproteinase-13 may be involved in the fibrotic process of SSc, especially in the initiation of fibrosis. The serum MMP-13 levels may serve as a useful marker for the severity of pulmonary fibrosis in patients with SSc.

Adult↗