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PubMed1985

Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease.

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.

Adolescent↗
PubMed2006

Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis.

OBJECTIVE: To investigate the correlation between the degree of dermal fibrosis and myofibroblast infiltration using clinical assessments of skin thickness and hardness in systemic sclerosis (SSc). METHODS: Eleven patients with diffuse SSc and 10 healthy controls were evaluated using the modified Rodnan skin thickness score and durometry (hardness measurement). Biopsy samples were obtained from the dorsal mid-forearm in all subjects at the baseline visit and again 6-12 months later in patients with SSc. Five of the patients with SSc received treatment with cyclophosphamide (CYC) in the interval between skin biopsies. Biopsy sections were assessed for myofibroblast and hyalinized collagen content by 2 blinded observers. RESULTS: Myofibroblast and hyalinized collagen scores each correlated with the forearm skin score (r = 0.83, P < 0.0001 and r = 0.78, P < 0.0001, respectively) and with the forearm durometry score (r = 0.72, P < 0.0004 and r = 0.69, P < 0.0008, respectively). The change in the dermal hyalinized collagen score correlated with the change in the forearm durometry score (r = 0.74, P < 0.0213). The myofibroblast score decreased in all 5 patients who received CYC and increased in those receiving non-CYC treatments (P < 0.01 for the difference). CONCLUSION: Myofibroblasts play an important role in the pathogenesis of fibrosis, and our data imply that quantification of myofibroblasts and hyalinized collagen in skin may be a useful outcome measure in clinical studies of SSc.

Adult↗
PubMed2003

Serum concentrations of the CXC chemokines interleukin 8 and growth-regulated oncogene-alpha are elevated in patients with systemic sclerosis.

OBJECTIVE: To determine whether serum concentrations of 2 CXC chemokines, interleukin 8 (IL-8) and growth-regulated oncogene-alpha (GRO-alpha), which are potent chemoattractants and activators for neutrophils, are elevated and whether they correlate with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 36), limited cutaneous SSc (lSSc; n = 42), systemic lupus erythematosus (SLE; n = 15), dermatomyositis (DM; n = 15), and healthy controls (n = 35) were examined by ELISA. RESULTS: Serum IL-8 was detected significantly more frequently in patients with dSSc (61%) and lSSc (55%) relative to healthy controls (6%), patients with SLE (7%), and those with DM (13%). Similarly, serum GRO-alpha concentrations in SSc patients were significantly increased compared with controls, patients with SLE, or those with DM. Elevated IL-8 concentrations significantly correlated with decreased % DLCO and rheumatoid factor positivity, while increased GRO-alpha levels were significantly associated with decreased % DLCO and % vital capacity, involvement of kidney and muscle, the presence of anti-topoisomerase I antibody, and increased serum IgG levels. CONCLUSION: Our results suggest that the elevation of serum levels of the CXC chemokines IL-8 and GRO-alpha is specific to SSc and that the elevation of CXC chemokines, particularly GRO-alpha, correlates with the involvement of internal organs, especially pulmonary damage.

Adolescent↗
PubMed1996

Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis.

OBJECTIVE: To determine whether measurement of different markers of endothelial damage, activation of coagulation, and platelet activation might differentiate between patients with primary Raynaud's phenomenon (PRP), limited cutaneous and diffuse systemic sclerosis (lcSSc and dSSc), and healthy control subjects. METHODS: Under carefully controlled conditions, fasting blood was drawn from 19 healthy control subjects, 10 patients with PRP, 17 with lcSSc and nine with dSSc for measurement of the following: von Willebrand factor (VWF) and soluble thrombomodulin as markers of endothelial damage/activation, thromboxane (as thromboxane B2) and beta-thromboglobulin as markers of platelet activation, and tissue plasminogen activator antigen, tissue plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) as markers of fibrinolysis. RESULTS: VWF was increased significantly in patients with SSc, and there was also a linear trend for thromboxane and tissue plasminogen activator antigen (in addition to VWF) to differentiate between different subgroups of patients with Raynaud's phenomenon. Patients with dSSc had the highest values. A combined index of VWF and thromboxane showed a highly significant trend across the four groups studied. CONCLUSION: VWF, and to a lesser extent thromboxane and tissue plasminogen activator antigen, are associated with disease severity in patients with Raynaud's phenomenon. Prospective studies are now required to establish if these parameters can be used as markers of disease progression.

Adult↗
PubMed2005

Inhibition of collagen gene expression in systemic sclerosis dermal fibroblasts by mithramycin.

BACKGROUND: The anti-tumour antibiotic mithramycin is also a potent inhibitor of fibrosis after glaucoma surgery. This drug displays high affinity binding to GC-rich sequences in DNA, including those present in the promoter of the gene encoding the alpha1 chain of type I collagen (COL1A1). OBJECTIVE: To evaluate the effects of mithramycin on COL1A1 expression in systemic sclerosis fibroblasts. METHODS: Confluent cultures of dermal fibroblasts from patients with recent onset diffuse systemic sclerosis were treated with mithramycin in vitro. Cell viability and protein expression were examined by fluorescence and confocal imaging. Type I collagen production was analysed by confocal imaging and metabolic labelling. COL1A1 messenger RNA levels and stability were assessed by northern hybridisation, and COL1A1 transcription was examined by transient transfections. RESULTS: Treatment of systemic sclerosis fibroblasts with mithramycin (10-100 nmol/l) did not cause significant cytotoxicity. Type I collagen biosynthesis decreased by 33-40% and 50-70% in cells cultured with mithramycin at 10 nmol/l and 100 nmol/l, respectively. Mithramycin at 50 nmol/l decreased COL1A1 mRNA levels by 40-60%. The effects of mithramycin on collagen gene expression were mediated by transcriptional and post-transcriptional mechanisms as shown by the reduction of COL1A1 promoter activity and by a decrease in the stability of these transcripts, respectively. CONCLUSIONS: Mithramycin causes potent inhibition of collagen production and gene expression in systemic sclerosis dermal fibroblasts in vitro in the absence of cytotoxic effects. These results suggest that this drug may be an effective treatment for the fibrotic process which is the hallmark of systemic sclerosis.

Blotting, Northern↗
PubMed2004

Health-related quality of life in systemic sclerosis as measured by the Short Form 36: relationship with clinical and biologic markers.

OBJECTIVE: To evaluate health-related quality of life (HRQOL) in patients with systemic sclerosis (SSc) using the Short Form 36 (SF-36) and to correlate SF-36 scores with clinical and biologic markers. METHODS: The SF-36 was administered to 24 controls and 24 SSc patients. SSc patients also were evaluated for subset (limited SSc [lSSc] and diffuse SSc [dSSc]), age, disease duration, angiotensin-converting enzyme (ACE) levels, autoantibodies, and skin and internal organ involvement. RESULTS: The physical summary score (PSS) was lower in SSc patients than in controls (P < 0.05), whereas the mental summary score (MSS) was higher in dSSc than in lSSc patients (P < 0.05). Five of 8 single SF-36 domain scores were lower in SSc patients than in controls (P < 0.05). Vitality was higher in dSSc than in controls (P < 0.001). In SSc, elder age correlated with lower PSS; low ACE levels and high skin score correlated with higher general mental health and role limitations due to physical problems, respectively (P < 0.05). Patients with heart involvement had higher scores in general health perceptions (P < 0.05). CONCLUSION: The SF-36 shows that HRQOL is impaired in patients with SSc. Higher scores in MSS and vitality in patients with dSSc and correlations of high SF-36 scores with specific organ involvement suggest that SSc patients with severe disease are more able to cope with HRQOL modification.

Adaptation, Psychological↗
PubMed1999

Circulating P- and L-selectin and T-lymphocyte activation and patients with autoimmune rheumatic diseases.

Circulating levels of P- and L-selectins and the degree of T-lymphocyte activation were assessed by enzyme-linked immunosorbent assays in 75 selected patients with rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) at various clinical stages, and in 40 healthy blood donors matched for age and gender. Mean levels of P-selectin were significantly higher than normal in RA (lower in patients with clinical remission) and SSc (higher in patients with early-onset diffuse disease), but not in SLE. In contrast, mean L-selectin levels were significantly higher than normal in SLE (no correlation to the degree of disease activity), but not in RA or SSc. Mean levels of soluble interleukin-2 receptors (sIL-2R), reflecting mainly T-lymphocyte activation, in patients with active RA, SSc and SLE were almost double the normal level; however, correlations between individual levels of circulating P- or L-selectins and sIL-2R within groups revealed a strong positive correlation only between L-selectin and sIL-2R (r = 0.66, p<0.001), and only in patients with SLE. Given the different expression of P- and L-selectins, these findings indicate a distinct pattern of immune cell activation in chronic diseases that share an overactivation of T-lymphocytes. The possible clinical value of quantitation of circulating P-selectin in patients with RA and SSc on the one hand, and L-selectin in patients with SLE on the other, should be investigated by prospective studies.

Adult↗
PubMed1994

Pulmonary function and gastroesophageal reflux in systemic sclerosis.

OBJECTIVE: To determine the relations among esophageal dysfunction, gastroesophageal reflux, and lung involvement in patients with systemic sclerosis. DESIGN: Retrospective review of esophageal motility, esophageal pH, and pulmonary function data. SETTING: University hospital outpatient clinic and community. PATIENTS: 39 consecutively referred patients who were grouped according to the presence or absence of abnormal distal (pH < 4.0 for > 5% of the 24-hour monitoring period) or proximal (pH < 4.0 for > 1% of the 24-hour period) gastroesophageal acid reflux. Patients were also grouped according to the presence or absence of distal esophageal peristalsis. MEASUREMENTS: Esophageal manometry, dual-probe (distal and proximal) esophageal 24-hour pH measurements, and pulmonary function studies (forced vital capacity, forced expiratory volume at 1 second, total lung capacity, and single-breath carbon monoxide diffusing capacity [DLco]). RESULTS: The mean total lung capacity (values as percentage predicted) was 87.1% +/- 11.2% (SD) for patients with abnormal proximal reflux and 77.8% +/- 21.6% for patients with normal proximal reflux (difference, 9.3%; 95% CI, -1.4% to 20.0%). The mean forced vital capacity for these patients was 91.1% +/- 12.4% and 85.4% +/- 25.6%, respectively (difference, 5.7%; CI, -6.9% to 18.1%). The mean total lung capacity was 83.8% +/- 15.4% for patients with abnormal distal reflux and 77.9% +/- 22.7% for patients with normal distal reflux (difference, 5.9%; CI, -7.6% to 19.4%). Among potential confounders of pulmonary measures, only smoking was related to decreased pulmonary function (smoking related to decreased DLco P < 0.01). Smoking was more common in patients with abnormal distal reflux than in those with normal distal reflux (65% compared with 25%, P = 0.03). After adjusting for smoking, the difference in mean DLco between patients with abnormal compared with normal distal reflux was 7.19% (Cl, -8.5% to 22.9%). CONCLUSION: Important measures of lung volume indicative of interstitial lung disease (total lung capacity, forced vital capacity) do not appear to be related to abnormal gastroesophageal acid reflux in patients with systemic sclerosis.

Esophagus↗
PubMed2005

Anti-lipoprotein lipase antibody in systemic sclerosis: association with elevated serum triglyceride concentrations.

OBJECTIVE: The vascular damage systemic sclerosis (SSc) consists mainly of microvascular changes, but recently macrovascular changes with dyslipidemia were recognized. In systemic lupus erythematosus (SLE), autoantibody to lipoprotein lipase (LPL), a key enzyme that hydrolyzes triglycerides, suggested a role of autoimmunity for elevated serum triglyceride levels and atherosclerosis. We investigated the prevalence and levels of anti-LPL antibodies, their clinical correlation, and their functional significance in patients with SSc. METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 55), limited cutaneous SSc (lSSc; n = 75), SLE (n = 21), and dermatomyositis (DM; n = 21) and healthy controls (n = 41) were examined by ELISA. The presence of anti-LPL antibody was evaluated by immunoblotting analysis using purified LPL. To determine the functional relevance of anti-LPL antibody in vivo, we assessed whether anti-LPL autoantibody was able to inhibit LPL activity using the LPL activity kit. RESULTS: ELISA revealed that IgG or IgM anti-LPL antibodies were detected in 35% of SSc patients, while they were also positive in 67% of SLE patients and 43% of DM patients. The presence of IgG anti-LPL antibody was associated with elevated serum triglyceride levels, greater extent of skin fibrosis, and more frequent presence of lung fibrosis, heart involvement, and anti-topoisomerase I antibodies. The presence of anti-LPL autoantibody was confirmed by immunoblotting analysis. LPL activity was inhibited by IgG anti-LPL antibodies in sera from SSc patients with elevated serum triglyceride levels. CONCLUSION: Our results suggest that anti-LPL autoantibody contributes to elevated serum triglyceride levels by inhibiting LPL enzyme activity in patients with SSc.

Autoantibodies↗
PubMed1992

[A case of progressive systemic sclerosis complicated by crescentic glomerulonephritis and diffuse pulmonary hemorrhage].

A 38-year-old man was hospitalized for proteinuria, and pitting edema. He had noticed Raynaud's phenomenon at about age fifteen. One month prior to admission, his urine contained protein and the serum creatinine was 3.0 mg/dl. On admission, sclerodactylia, digital pitting scar of fingertips, digital bone absorption and pulmonary fibrosis were observed and a diagnosis of progressive systemic sclerosis (PSS) was made. Laboratory investigations revealed: 24-hour urine protein excretion 3 g; serum creatinine 5.6 mg/dl; creatinine clearance 13.5 ml/min; antinuclear factor strongly positive in a speckled pattern; antibodies to nRNP positive with a titer of 1: 20, 480; antibodies to DNA, Sm, SS-A, SS-B, Scl-70, centromere and Jo-1 negative; serum complement normal. A renal biopsy revealed focal and segmental necrotizing glomerulonephritis with 70% crescents but no vascular changes. Circulating antiglomerular basement membrane antibodies were negative. Immunofluorescence disclosed granular deposits of IgM and C3 in the mesangium and along the capillary walls. Treatment was begun with methylprednisolone pulse therapy. After 5 month, serum creatine and creatinine clearance were 1.9 mg/dl and 35 ml/min, respectively. A year after the discharge, he was readmitted for hemoptysis and worsening of proteinuria and microhematuria. A chest radiograph demonstrated bilateral alveolar consolidation. Serum creatinine was elevated to 3.5 mg/dl. The continuous hemoptysis resulted in a severe dyspnea associated with a rapid fall in the hemoglobin. On the fourth hospital day, the PaO2 was 41 Torr on oxygen by mask that necessitated mechanical ventilation and pulse therapy was started. However, the patient died on the ninth hospital day of respiratory failure due to pulmonary hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation.

OBJECTIVE: To investigate expression of the chemokine receptor CCR2 on key cell types involved in the pathogenesis of systemic sclerosis (SSc) and to assess the potential for autocrine activation of SSc dermal fibroblasts via CCL2/CCR2. METHODS: Chemokine receptor expression in skin biopsy tissues and explanted dermal fibroblasts from a well-characterized cohort of SSc patients was examined using immunohistochemistry and flow cytometry techniques. Autocrine regulation of the expression of fibrotic markers in CCR2+ SSc fibroblast cell lines was assessed using specific ligand or receptor antagonists. RESULTS: We identified strong CCR2 expression in skin biopsy samples of early-stage diffuse cutaneous SSc (dcSSc), but not late-stage dcSSc or limited cutaneous SSc. Double labeling confirmed up-regulation of CCL2/CCR2 on myofibroblasts, pericytes, lymphocytes, macrophages, and endothelial cells. Explanted dermal fibroblasts from early dcSSc tissues expressed CCR2 and CXCR2 in 55% and 66% of cell strains, respectively. There was no expression in control fibroblasts. CCR2+ fibroblasts demonstrated a profibrotic phenotype, with overexpression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), and CCL2. Flow cytometric analysis identified a subset of CCR2+ SSc fibroblasts expressing the myofibroblast marker alpha-SMA. In these cultures, specific inhibition of CCL2 or CCR2 attenuated the overexpression of alpha-SMA, but not CTGF or plasminogen activator inhibitor 1. CONCLUSION: Our results show that CCR2 is up-regulated in early dcSSc on cell types known to be activated in the disease, which is consistent with a key role in SSc pathogenesis. CCR2 expression on SSc fibroblasts appears to regulate the expression of CCL2 and alpha-SMA. Our findings suggest potential autocrine regulation of key profibrotic properties via a CCL2/CCR2 loop in early-stage dcSSc.

Actins↗
PubMed2002

Abnormal expression of intracellular cytokines and chemokine receptors in peripheral blood T lymphocytes from patients with systemic sclerosis.

In patients with systemic sclerosis (SSc), there are conflicting findings regarding which is predominant between type 1 and type 2 immune responses. To determine the balance between type 1 and type 2 T lymphocytes in peripheral blood from SSc patients, we investigated the expression of intracellular cytokines, such as interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-13, and chemokine receptors such as CXCR3 and CCR4 by flow cytometry. The frequency of IFN-gamma-producing cells among CD8+ cells was significantly increased in patients with diffuse cutaneous SSc (n = 11, P < 0.0001) and limited cutaneous SSc (lSSc; n= 16, P < 0.0001) compared with normal controls (n = 17) while there was no significant difference in the frequency of IL-4- or IL-13-producing cells. In contrast, the frequency of IFN-gamma- or IL-4-producing cells among CD4+ cells was similar between the three groups. Similar results were obtained when absolute numbers were assessed. The frequency of IFN-gamma-producing cells among CD8+ cells inversely correlated with percentage DLco in SSc patients (r = - 0.650, P < 0.005). CXCR3+ CD8+ cells selectively produced IFN-gamma, and the frequency of CXCR3+ CD45RO+ cells among CD8+ cells was higher in lSSc patients (n = 14, P < 0.01) than in normal controls (n = 22). In contrast, there was no significant difference in the frequencies of CXCR3- or CCR4-expressing CD45RO+ cells among CD4+ cells. These results demonstrate the predominance of type 1 cytokine-producing cells (Tc1 cells) in peripheral blood CD8+ T cells from SSc patients, but no definite Th1/Th2 imbalance in CD4+ T cells. Tc1 cells may be associated with pulmonary vascular damage in SSc.

Adult↗
PubMedDate not supplied

Capillary density in patients with systemic sclerosis, as determined by microscopy counts and compared with computer-based analysis.

OBJECTIVE: To develop a method enabling capillary density to be determined rapidly and accurately in patients with systemic sclerosis. METHOD: Capillary density was determined in 11 controls and 22 patients: 5 with diffuse cutaneous systemic sclerosis (dSSc), 12 with limited cutaneous systemic sclerosis (lSSc), two with suspected systemic sclerosis (suspSSc), 2 with sclerodermatomyositis, and one with undifferentiated connective tissue disease. Using a microscope equipped with a graticule, nailfold capillaries were counted within a 3 mm length of the nailfold; these counts were made by 4 different observers. The results were compared with the corresponding values obtained by the computerbased analysis of photographs. RESULTS: The median capillary density according to the direct counts was 8.0 loops/mm (6.7-10.0) in the controls, 6.0 loops/mm (range 4.8-8.8) in the dSSc subgroup, 5.6 loops/mm (4.2-6.5) in the lSSc subgroup, and 7.2 loops/mm (6.2-8.2) in the suspSSc subgroup. In the series as a whole, there was no significant difference between the median values for the left hands and those for the right hands, nor between the median value for all digit IVs and the median value for all four digits analysed (II, III, IV, and V). Interobserver variation was small between the 4 different observers. Direct microscopy counts were slightly higher than the corresponding values obtained by computer-based analysis. CONCLUSION: Direct microscopy counting is a rapid, simple, and reliable means of determining capillary density for screening purposes.

Adult↗
PubMed2006

Variations of neuronal nitric oxide synthase in systemic sclerosis skin.

OBJECTIVE: In systemic sclerosis (SSc), derangement of the peripheral nervous system is linked to vascular tone dysfunction. Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS, NOS-I) might play a dynamic role in the control of vascular tone. This study was performed to verify, by immunohistochemical and biochemical analyses, the presence and expression of nNOS and protein gene product 9.5 (PGP 9.5) in SSc skin, in different subsets and various phases of the disease. METHODS: Biopsy samples of clinically involved skin from 32 SSc patients (12 with limited cutaneous SSc [lcSSc] and 20 with the diffuse form [dcSSc]) and skin samples from 6 healthy controls were either immunostained with anti-PGP 9.5 and anti-nNOS antibodies or analyzed by semiquantitative reverse transcription-polymerase chain reaction and Western blotting. RESULTS: Immunohistochemical and biochemical data showed a decrease in PGP 9.5 and nNOS innervation and in their messenger RNA (mRNA) levels in lcSSc and dcSSc skin. In the edematous phase of SSc, a light alteration in cutaneous innervation was initiated and slowly progressed into the sclerotic phase, becoming most evident in the atrophic phase. Levels of nNOS mRNA were significantly lower between the edematous phase and the sclerotic phase in both dcSSc and lcSSc skin, which was attributable to the earlier occurrence of more severe pathologic alterations. CONCLUSION: Total cutaneous innervation and nNOS innervation slowly disappear in the skin of SSc patients. Expression of nNOS depends on the severity of tissue damage in SSc, and increased synthesis of NO also contributes to this process. It remains to be determined whether the changes in cutaneous innervation are due to the disease itself or whether these changes contribute to the pathogenesis and evolution of SSc.

Female↗
PubMed2005

Carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis.

Oxygen-derived free radicals produced by phagocytes have been postulated to contribute to lung tissue damage occurring during diffuse lung diseases (DLD). The two-dimensional electrophoretic (2-DE) analysis of bronchoalveolar lavage (BAL) protein composition revealed different protein profiles in sarcoidosis (S), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) with a significant increase of low molecular weight proteins in IPF. Some of these proteins are involved in antioxidant processes. The aims of this report were to analyse the oxidative stress occurring in patients with DLD through determination of BAL protein carbonyl content and to identify target proteins of oxidation by a proteomic approach (2-DE combined with immunoblotting with specific antibodies for carbonyl groups). Carbonylated proteins detected by enzyme-linked immunosorbent assay (ELISA) were increased in BAL of patients with S, IPF and SSc compared to healthy controls with a significant difference for S and IPF. The proteomic approach to the analysis of BAL revealed that protein carbonylation was a process involving specific carbonylation-sensitive proteins and that in IPF a greater number of proteins target of oxidation were present. In conclusion, to our knowledge, this is the first report providing a database of proteins target of oxidation in BAL of patients with sarcoidosis, idiopathic pulmonary fibrosis and systemic sclerosis.

Blotting, Western↗
PubMed2004

Association between systemic sclerosis and breast cancer: eight new cases and review of the literature.

Several studies have demonstrated an increased frequency of cancer in patients with systemic sclerosis (SSc), specially lung and breast cancers. The pathogenesis of the association between SSc and cancer is not fully established. The aim of this study was to describe new cases of the association between SSc and breast cancer and to perform a review of the literature. We retrospectively studied the medical files of eight patients followed in our institution for SSc and breast cancer. We analyzed them with data available in the literature for a total of 46 patients. Cutaneous extension of SSc was clearly mentioned in 17 cases: the SSc was limited in 10 cases and diffuse in 7 cases The median age at the diagnosis of cancer was 54 years (range: 40-71). The median duration between SSc onset and breast cancer diagnosis was 11.5 months (range: 0-288). The duration between SSc onset and breast cancer diagnosis was < or = 12 months in 27 of 44 patients (61.4%), and in 11 (25%) of them the diagnosis of both diseases was made simultaneously. It was clearly mentioned for 35 patients whether the diagnosis of breast cancer was made before or after the onset of SSc. The diagnosis of breast cancer was made before SSc onset in 17 of 35 patients (48.6%) and after SSc onset in 18 of 35 patients (51.4%). For 33 patients, the follow-up was available: 18 (54.5%) died, 11 (33.3%) of them within the 1st year after the diagnosis of the cancer. For none of the patients did the anticancer treatment improve the SSc. The close temporal relationship between SSc onset and breast cancer diagnosis is highly suggestive of a pathophysiological link. SSc is probably not a paraneoplastic disease since the anticancer treatment has no influence on the evolution of SSc. However, it can be suggested that SSc could be a disease facilitating breast cancer and/or metastases development.

Adult↗
PubMed2006

[Bosentan for treatment of active digital ulcers in patients with systemic sclerosis].

OBJECTIVES: To describe the effect of bosentan and its dual inhibition of endothelin-1 ETA and ETB receptors on digital ulcers in patients with systemic sclerosis (SSc). METHODS: Patients receiving bosentan for SSc-related digital ulcers were identified in eight centers, and their characteristics and follow-up were recorded. RESULTS: Nine (six with diffuse and three with limited cutaneous forms of SSc) patients (median age: 54 years) had received bosentan for digital ulcers. Complete healing occurred in seven (median time to improvement: 4 weeks). Another experienced a significant decrease in the number of ulcers (from 22 to 5) in 8 weeks, while one had no improvement. After a median follow-up of 24.3 months, only one recurrence was observed. Raynaud phenomenon improved in all but one patient. DISCUSSION: These data suggest that some patients may benefit from bosentan to treat digital ulcers. The short time to healing in these patients with rather chronic ulcers argues strongly in favor of its use. These results also strengthen the evidence that endothelin-1 plays an important role in the vascular manifestations of SSc. CONCLUSION: Bosentan can be effective in the treatment of digital ulcers in some SSc patients with SSc, probably especially those involving substantial ischemia. Bosentan is not a first-line drug in this indication yet and must be carefully used by specialists in SSc. Forthcoming results from the international RAPIDS-2 study should clarify the indications for bosentan in the treatment of SSc-related digital ulcers.

Adult↗
PubMed2002

Protease nexin-1 messenger RNA levels are not affected by serum or interferon beta in cultured systemic sclerosis fibroblasts.

The aim of the present study was to analyze the effect of serum and human recombinant beta interferon (rIFNbeta) treatment on PN-1 mRNA levels in cultured dermal fibroblasts obtained from the skin of healthy donors and from lesional skin of systemic sclerosis (SSc) patients with the limited (CREST syndrome) or the diffuse form of SSc. Total RNA was isolated from fibroblasts derived from the skin of healthy individuals and from lesional skin of patients with CREST syndrome and the diffuse form of SSc cultured under different conditions (1% or 10% serum-supplemented medium) and treated with 500 IU/ml of rIFNbeta. PN-1 gene expression was assessed by Northern blot analysis. We detected variable PN-1 mRNA levels in normal control fibroblasts as well as in SSc fibroblasts under the different culture conditions (1% or 10% serum-supplemented medium). Accumulated PN-1 mRNA levels found in normal cultured fibroblasts were similar to or even higher than in SSc fibroblasts. PN-1 messenger levels were not significantly altered by IFNbeta treatment in normal or SSc cultured fibroblasts despite the presence of an IFN-stimulated responsive element (ISRE) in the promoter of the PN-1 gene. Our findings suggest that PN-1 expression in SSc fibroblasts at the mRNA level requires further investigation in a large number of SSc patients to better characterize the role of this serpin in the pathogenesis of SSc. We conclude that the transcriptional regulation of PN-1 is not associated with IFNbeta, an antifibrotic cytokine naturally produced by fibroblasts.

Adolescent↗