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Systemic Sclerosis (systemic + sclerosis)
Kinds of Systemic Sclerosis Terms modified by Systemic Sclerosis Selected AbstractsIS SCLERODERMA RENAL CRISIS WITH ANTI-CENTROMERE ANTIBODY-POSITIVE LIMITED CUTANEOUS SYSTEMIC SCLEROSIS OVERLOOKED IN PATIENTS WITH HYPERTENSION AND/OR RENAL DYSFUNCTION?NEPHROLOGY, Issue 2 2008TOSHIRO SUGIMOTO [source] Detection of Subclinical Cardiac Involvement in Systemic Sclerosis by Echocardiographic Strain ImagingECHOCARDIOGRAPHY, Issue 2 2008Alper Kepez M.D. Background: Cardiac involvement is one of the major problems in systemic sclerosis (SSc). Subclinical cardiac involvement has a higher frequency than thought previously. In this study we investigated whether subclinical cardiac involvement can be detected by using echocardiographic strain imaging in SSc patients without pulmonary hypertension. Methods: Echocardiographic examinations were performed to 27 SSc patients and 26 healthy controls. Left ventricular strain parameters were obtained from apical views and average strain value was calculated from these measurements. Results: There were no significant differences between patients and controls regarding two-dimensional (2D), conventional Doppler and tissue Doppler velocity measurements. Strain was reduced in 6 of 12 segments of the left ventricle (LV) and in 1 of 2 segments of the right ventricle (RV). Strain rate (SR) was reduced in 2 of 12 segments of the LV and 1 of 2 segments of the RV in SSc patients as compared to controls (P < 0.05 for all). These involvements did not match any particular coronary artery distribution. More important differences were detected by average strain and SR values of the LV between patients and controls (19.78 ± 3.00% vs 23.41 ± 2.73%, P < 0.001; 2.01 ± 0.41 vs 2.23 ± 0.27/sec, P = 0.026, respectively). Furthermore, carbon monoxide diffusion capacity (DLCO) in scleroderma patients significantly correlated with LV average strain (r = 0.59; P = 0.001). Conclusion: Evaluation of ventricular function by using echocardiographic strain imaging appears to be useful to detect subclinical cardiac involvement in SSc patients with normal standard echocardiographic and tissue Doppler velocity findings. [source] Heart Rate Turbulence Impairment and Ventricular Arrhythmias in Patients with Systemic SclerosisPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2010PIOTR BIENIAS M.D., Ph.D. Background:,Arrhythmias, conduction disturbances, and cardiac autonomic nervous system dysfunction are the most frequent cardiovascular complications in systemic sclerosis (scleroderma). The aim of the study was to assess heart rate turbulence (HRT) in systemic sclerosis patients and to identify the relationship between HRT and occurrence of arrhythmias. Methods:,Forty-five patients with scleroderma (aged 54.6 ± 14.7 years) and 30 healthy sex- and age-matched subjects were examined. In addition to routine studies, 24-hour Holter monitoring with assessment of HRT was performed. Results:,As compared to controls, HRT was significantly impaired in systemic sclerosis patients. Abnormal HRT defined as turbulence onset (TO) ,0.0% and/or turbulence slope (TS) ,2.5 ms/RR (ms/RR interval) was found in 19 (42%) scleroderma patients and in no members of the control group. Serious ventricular arrhythmias Lown class IV (VA-LownIV), for example, couplets and/or nonsustained ventricular tachycardias, were observed in 16 (36%) scleroderma patients. The median value of TS was significantly lower in systemic sclerosis patients with VA-LownIV than in patients without VA-LownIV (3.68 vs 7.00 ms/RR, P = 0.02). The area under curve of ROC analysis for prediction of VA-LownIV was 0.72 (95% confidence interval [CI] 0.56,0.87) and revealed that TS <9.0 ms/RR was associated with VA-Lown IV occurrence, with sensitivity of 93.7% and specificity of 44.8%. Univariate and multivariate analyses confirmed that lower values of TS were associated with VA-LownIV occurrence (odds ratio 1.52, 95% CI 1.09,2.12, P = 0.01). Conclusions:,Patients with systemic sclerosis are characterized by significant HRT impairment. Assessment of HRT and especially TS is useful in the identification of patients at risk for ventricular arrhythmias. (PACE 2010; 920,928) [source] Transdermal Fentanyl: Little Absorption in Two Patients with Systemic Sclerosis?PAIN MEDICINE, Issue 3 2001Matthias Karst MD Two patients suffering from systemic sclerosis (SSc) were treated with the 25 ,/hr transdermal fentanyl patch for pain from either deltoid muscle tendinitis of the left arm or from ischemia of the left-hand thumb. When the medication was changed to either oral morphine or oral methadone, the effects did not correspond to the drug conversion table. These findings suggest that patients with SSc and other systemic skin diseases may be at risk for limited absorption of transdermal fentanyl. In contrast, no restriction of the absorption of transdermal testosterone was observed. [source] Ichthyotic-Appearing Skin Changes Associated with Childhood Morphea, Systemic Sclerosis, and Systemic Lupus Erythematosus/Scleroderma OverlapPEDIATRIC DERMATOLOGY, Issue 2 2010Christy M. Williams M.D. We report three children with ichthyotic-appearing skin changes that may be an early feature reflecting underlying dermal sclerosis. Detection of these subtle skin changes may be predictive of more widespread cutaneous involvement, ultimately prompting earlier treatment. [source] Systemic Sclerosis Up To Date (Special Issue)THE JOURNAL OF DERMATOLOGY, Issue 1 2010Kazuhiko TAKEHARA M.D., Ph.D. No abstract is available for this article. [source] Esophageal manometry in 28 systemic sclerosis Brazilian patients: findings and correlationsDISEASES OF THE ESOPHAGUS, Issue 8 2009D. C. Calderaro SUMMARY Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. Esophageal involvement affects 50,90% of patients and is characterized by abnormal motility and hypotonic lower esophageal sphincter. Data on the association of esophageal abnormalities and age, gender, SSc subset or duration, autoantibody profile, esophageal symptoms, and medication are lacking or conflicting. The aim of this study was the evaluation of these associations in Brazilian sclerodermic patients from the Rheumatology Division, Clinics Hospital, Federal University, Minas Gerais. They underwent medical records review, clinical interview, and esophageal manometry. The normal cutoff level for lower esophageal sphincter pressure was 14 mmHg. Abnormal peristalsis occurred when less than 80% of peristaltic waves were propagated. P -values less than 0.05 were considered significant. Twenty-eight patients were included: 71% were women. The population presented medium age and disease duration of 46 years and 12 years, respectively. Cutaneous diffuse SSc occurred in 39% and its limited form in 61%. Dysphagia, pyrosis, and regurgitation occurred, respectively, in 71%, 43%, and 61% of patients. Lower esophageal sphincter pressure and number of peristaltic waves-propagated medias were, respectively, 17.2 mmHg and 2.3. SSc-related manometric abnormalities were present in 86% of patients. Manometry revealed distal esophageal body hypomotility, hypotonic lower esophageal sphincter, or both, respectively, in 82%, 39%, and 36% of patients. One patient presented the manometric pattern of esophageal achalasia. Male patients more frequently presented hypotonic inferior esophageal sphincter. Manometric findings have had no relationship with the other variables. Nifedipine use did not influence manometric findings. [source] Elevated exhalation of hydrogen peroxide in patients with systemic sclerosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2003uczyńska Abstract Background Systemic sclerosis is accompanied by an influx of activated phagocytes into distal airways. These cells release H2O2, which may evaporate from the airways surface and be detected in expired breath condensate. We tested whether patients with systemic sclerosis exhale more H2O2 than healthy subjects and whether breath condensate H2O2 levels correlate with some clinical parameters. Material and methods H2O2 was measured fluorimetrically in the expired breath condensate of 27 patients (22 women, five men, mean age 49 ± 13·1 years) with systemic sclerosis and 27 age- and sex- matched healthy controls. Results Exhaled H2O2 levels were 3·5-fold higher (0·88 ± 0·62 µM vs. 0·25 ± 0·17 µM, P < 0·001) in the patients with systemic sclerosis than in the controls. Treatment with cyclophosphamide and/or prednisone (29 ± 50 months, range 3,168 months) did not significantly decrease H2O2 exhalation (0·78 ± 0·50 µM, n= 10 vs. 0·94 ± 0·67 µM, n= 17, P > 0·05). No significant difference was found between patients with limited and diffuse scleroderma (1·03 ± 0·69 µM, n= 17 vs. 0·63 ± 0·41 µM, n= 10, P > 0·05). H2O2 levels correlated with disease duration (r = 0·38, P < 0·05) and time from the first Raynaud's episode (r = 0·44, P < 0·05). Conclusions Patients with systemic sclerosis exhale more H2O2 than healthy controls, suggesting involvement of reactive oxygen species in disease processes. Lack of significant intergroups differences in H2O2 levels may have resulted from the small number of patients analyzed. [source] Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivoJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 10 2009Paulius Venalis Abstract Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc. [source] Inducible costimulator ligand regulates bleomycin-induced lung and skin fibrosis in a mouse model independently of the inducible costimulator/inducible costimulator ligand pathwayARTHRITIS & RHEUMATISM, Issue 6 2010Chihiro Tanaka Objective Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin and internal organs, including the lungs. Inducible costimulator (ICOS), which is expressed on activated T cells, and its ligand ICOSL, which is expressed on antigen-presenting cells, have been considered a single receptor,ligand pair. Although the ICOS/ICOSL pathway is known to play various roles in adaptive immunity, its roles in innate immunity and tissue fibrosis remain unknown. Methods We assessed the roles of ICOS and ICOSL in tissue fibrosis by administering bleomycin intratracheally or intradermally into mice deficient in ICOS and/or ICOSL. Tissue fibrosis was evaluated by histologic or biochemical examination. Results ICOS deficiency attenuated the lung and skin fibrosis, whereas ICOSL deficiency aggravated it. Mice deficient in both ICOS and ICOSL exhibited accelerated fibrosis, reflecting a dominant role of ICOSL over ICOS in this model. Interestingly, ICOSL expression on macrophages and B cells derived from bronchoalveolar lavage fluid was significantly elevated in ICOS-deficient mice as compared with wild-type mice during this process. Thus, the levels of ICOSL expression on B cells and macrophages were inversely associated with the severity of tissue fibrosis. Conclusion Our results indicate that ICOSL expression on antigen-presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue fibrosis that is independent of the ICOS/ICOSL pathway. Further studies will be needed to clarify the roles of ICOS and ICOSL in the development of systemic sclerosis. [source] Decreased lymphatic vessel counts in patients with systemic sclerosis: Association with fingertip ulcersARTHRITIS & RHEUMATISM, Issue 5 2010Alfiya Akhmetshina Objective Systemic sclerosis (SSc) is a connective tissue disease that is characterized by microvascular disease and tissue fibrosis. Progressive loss and irregular architecture of the small blood vessels are well characterized, but the potential involvement of the lymphatic vessel system has not been analyzed directly in SSc. This study was undertaken to assess whether the lymphatic vascular system is affected in SSc, and whether changes to the lymphatic vessels are associated with dystrophic changes and tissue damage in patients with SSc. Methods Lymphatic endothelial cells in skin biopsy samples from patients with SSc and age- and sex-matched healthy volunteers were identified by staining for podoplanin and prox-1, both of which are specifically expressed in lymphatic endothelial cells but not in blood vascular endothelial cells. CD31 was used as a pan,endothelial cell marker. Statistical analyses were performed using Kruskal-Wallis, Mann-Whitney U, and Spearman's rank correlation tests. Results The numbers of podoplanin- and prox-1,positive lymphatic vessels were significantly reduced in patients with SSc as compared with healthy individuals. The number of podoplanin-positive lymphatic precollector vessels was significantly lower in SSc patients with fingertip ulcers than in SSc patients without ulcers. Moreover, the number of lymphatic vessels correlated inversely with the number of fingertip ulcers at the time of biopsy and with the number of fingertip ulcers per year. The inverse correlation between lymphatic precollector vessel counts and fingertip ulcers remained significant after statistical adjustment for the blood vessel count, age, and modified Rodnan skin thickness score. Conclusion These results demonstrate a severe reduction in the number of lymphatic capillaries and lymphatic precollector vessels in patients with SSc. Patients with decreased lymphatic vessel counts may be at particularly high risk of developing fingertip ulcers. [source] Systemic sclerosis and lupus: Points in an interferon-mediated continuumARTHRITIS & RHEUMATISM, Issue 2 2010Shervin Assassi Objective To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE). Methods We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN),inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes. Results Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti,U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score. Conclusion SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a "lupus-like" high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti,U1 RNP antibodies. [source] Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: Evidence of possible gene,gene interaction and alterations in Th1/Th2 cytokinesARTHRITIS & RHEUMATISM, Issue 12 2009Pravitt Gourh Objective Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. Methods We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene,gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. Results Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr = 1.4 × 10,15, odds ratio 3.37, 95% confidence interval 2.4,4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr = 2.4 × 10,5, odds ratio 1.29, 95% confidence interval 1.2,1.5). Furthermore, we identified gene,gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor , levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. Conclusion The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation. [source] STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosisARTHRITIS & RHEUMATISM, Issue 8 2009P. Dieudé Objective Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. Methods Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. Results STAT4 rs7574865 was shown to be associated with SSc (P = 0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11,1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiplicatively increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86,3.99) for combinations of genotypes with ,3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P = 2.2 × 10,4, OR 1.97, 95% CI 1.28,3.04). Conclusion Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis. [source] Independent association of anti,,2 -glycoprotein I antibodies with macrovascular disease and mortality in scleroderma patientsARTHRITIS & RHEUMATISM, Issue 8 2009Francesco Boin Objective Systemic sclerosis (SSc; scleroderma) is characterized by a unique widespread vascular involvement that can lead to severe digital ischemia, pulmonary arterial hypertension (PAH), or other organ dysfunction. Microthrombotic events and procoagulation factors such as anti,,2-glycoprotein I (anti-,2GPI) or anticardiolipin antibodies (aCL) may be implicated in the development of these manifestations. This study was undertaken to investigate whether anti-,2GPI and aCL are correlated with macrovascular disease, including ischemic digital loss and PAH, in SSc patients. Methods Seventy-five SSc patients with a history of ischemic digital loss and 75 matched SSc controls were evaluated. Anticentromere antibodies (ACAs), anti-,2GPI, and aCL were measured, and clinical associations were determined using conditional and simple logistic regression models. Results Positivity for anti-,2GPI was significantly more frequent in SSc patients with digital loss than in patients without digital loss (P = 0.017), with the IgA isotype of anti-,2GPI showing the strongest association (odds ratio [OR] 4.0). There was no significant difference in aCL frequency between patients with digital loss and control patients. After adjustment for demographic characteristics, disease type, smoking, and ACA, anti-,2GPI positivity was significantly associated with active digital ischemia (OR 9.4), echocardiographically evident PAH (OR 4.8), and mortality (OR 2.9). ACA positivity was associated with history of digital loss (OR 3.28), but not with PAH or mortality. History of digital loss was strongly associated with increased mortality (OR 12.5). Conclusion Anti-,2GPI is significantly associated with macrovascular disease in SSc and independently predicts mortality. It is unclear whether it has a pathogenetic role or simply reveals the presence of underlying endothelial injury. The use of anti-,2GPI as a biomarker of vascular disease in SSc should be further explored. [source] Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 4 2009Jean-François Classen Objective Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc. Methods Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center. Results Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFR, or PDGFR, in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal. Conclusion The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc. [source] Molecular framework for response to imatinib mesylate in systemic sclerosis,ARTHRITIS & RHEUMATISM, Issue 2 2009Lorinda Chung Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFR, and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10,8). The response of these patients and the findings of the analyses suggest that PDGFR, and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc. [source] Antiangiogenic plasma activity in patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 10 2007Mary Jo Mulligan-Kehoe Objective Systemic sclerosis (SSc; scleroderma) is a systemic connective tissue disease with an extensive vascular component that includes aberrant microvasculature and impaired wound healing. The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc. Methods Plasma samples were obtained from 30 patients with SSc and from 10 control patients without SSc. The samples were analyzed for the ability of plasma to affect endothelial cell migration and vascular structure formation and for the presence of antiangiogenic activity. Results Exposure of normal human microvascular dermal endothelial cells to plasma from patients with SSc resulted in decreased cell migration (mean ± SEM 52 ± 5%) and tube formation (34 ± 6%) compared with that in plasma from control patients (P < 0.001 for both). SSc plasma contained 2.9-fold more plasminogen kringle 1,3 fragments (angiostatin) than that in control plasma. The addition of angiostatin to control plasma resulted in inhibition of endothelial cell migration and proliferation similar to that observed in SSc plasma. In vitro studies demonstrated that granzyme B and other proteases contained in T cell granule content cleave plasminogen and plasmin into angiostatin fragments. Conclusion Plasminogen conformation in patients with SSc enables granzyme B and granule content protease to limit the proangiogenic effects of plasmin and increase the levels of antiangiogenic angiostatin. This increase in angiostatin production may account for some of the vascular defects observed in patients with SSc. [source] Impairment of endothelial cell differentiation from bone marrow,derived mesenchymal stem cells: New insight into the pathogenesis of systemic sclerosisARTHRITIS & RHEUMATISM, Issue 6 2007P. Cipriani Objective Systemic sclerosis (SSc) is a disorder characterized by vascular damage and fibrosis of the skin and internal organs. Despite marked tissue hypoxia, there is no evidence of compensatory angiogenesis. The ability of mesenchymal stem cells (MSCs) to differentiate into endothelial cells was recently demonstrated. The aim of this study was to determine whether impaired differentiation of MSCs into endothelial cells in SSc might contribute to disease pathogenesis by decreasing endothelial repair. Methods MSCs obtained from 7 SSc patients and 15 healthy controls were characterized. The number of colony-forming unit,fibroblastoid colonies was determined. After culture in endothelial-specific medium, the endothelial-like MSC (EL-MSC) phenotype was assessed according to the surface expression of vascular endothelial growth factor receptors (VEGFRs). Senescence, chemoinvasion, and capillary morphogenesis studies were also performed. Results MSCs from SSc patients displayed the same phenotype and clonogenic activity as those from controls. In SSc MSCs, a decreased percentage of VEGFR-2+, CXCR4+, VEGFR-2+/CXCR4+ cells and early senescence was detected. After culturing, SSc EL-MSCs showed increased expression of VEGFR-1, VEGFR-2, and CXCR4, did not express CD31 or annexin V, and showed significantly decreased migration after specific stimuli. Moreover, the addition of VEGF and stromal cell,derived factor 1 to cultured SSc EL-MSCs increased their angiogenic potential less than that in controls. Conclusion Our data strongly suggest that endothelial repair may be affected in SSc. The possibility that endothelial progenitor cells could be used to increase vessel growth in chronic ischemic tissues may open up new avenues in the treatment of vascular damage caused by SSc. [source] Differential expression of stromal cell,derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implicationsARTHRITIS & RHEUMATISM, Issue 9 2006Paola Cipriani Objective Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell,derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. Methods We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription,polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. Results SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. Conclusion Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc. [source] The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosisBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2008Y. Hamaguchi Summary Background, Systemic sclerosis (SSc) is a connective tissue disorder with excessive fibrosis of the skin and various internal organs. Although SSc is a heterogeneous disease, it has been reported that the particular antinuclear antibodies (ANA) are often indicative of clinical features, disease course and overall severity. Objective, To clarify the association of clinical and prognostic features with serum ANA in Japanese patients with SSc. Methods, We studied 203 Japanese patients diagnosed with SSc, who visited our hospital during the period 1983,2005. Six SSc-related ANA were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation assays. Results, Patients with SSc were classified into six ANA-based subgroups and a group without ANA. As expected, antitopoisomerase I antibody (Ab, n = 64), anti-RNA polymerases (RNAP) Ab (n = 12) and anti-U3 RNP Ab (n = 5) were associated with diffuse cutaneous SSc, whereas anticentromere Ab (ACA, n = 75), anti-Th/To Ab (n = 7) and anti-U1 RNP Ab (n = 10) were frequently detected in patients with limited cutaneous SSc. Clinical features of the ANA-negative group (n = 10) were heterogeneous. Consistent with previous findings in Caucasian and/or black African patients, antitopoisomerase I Ab was associated with the involvement of vascular and pulmonary fibrosis, leading to decreased survival rate. However, no patients with anti-RNAP Ab developed renal crisis and the frequency of isolated pulmonary hypertension in patients with ACA, anti-Th/To Ab or anti-U3 RNP Ab was similar to that in other ANA-based subgroups. Conclusion, These results indicate that the clinical relevance of SSc-related ANA in Japanese patients differs in some aspects from that in Caucasian and/or black African patients. [source] Treatment of severe scleroderma skin ulcers with recombinant human erythropoietinCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2007C. Ferri Summary Systemic sclerosis (SSc) is frequently complicated by skin ulcers, often unresponsive to traditional treatments. A preliminary evaluation of the effects of recombinant human erythropoietin (rHuEPO) was carried out in 14 patients with SSc with nonhealing, severe cutaneous ulcers. Patients received rHuEPO subcutaneously at a dosage of 150 IU/kg 3 times weekly for 2 weeks, twice weekly for the next 2 weeks, and then once weekly for 1 month. At follow-up 3,6 months from the beginning of the treatment, six patients showed complete resolution of the skin ulcers, while a significant reduction (> 60%) in lesional areas was obtained in the other eight patients (mean ± SD ulcer area reduced from 27.6 ± 28 to 5.3 ± 7.8 cm2; P < 0.005). Moreover, patients' quality of life significantly improved (pain, as measured on visual analogue scale reduced from 96 ± 5 to 46 ± 17 points; P = 0.0001; disability as measured by the Health Assessment Questionnaire,Disability Index reduced from 1.6 ± 0.5 to 0.9 ± 0.4 points; P = 0.0001). The rHuEPO may represent a novel treatment of nonhealing scleroderma skin ulcers, suggesting some important aetiopathological implications. [source] Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2004C. NISHIJIMA SUMMARY Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence, or, levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover. [source] Circulating ,/, T lymphocytes from systemic sclerosis (SSc) patients display a T helper (Th) 1 polarizationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2001R. Giacomelli Systemic sclerosis (SSc) is a connective tissue disease in which immune system activation is evidenced by high levels of different cytokines in the sera and/or in the supernatants of cultured peripheral blood mononuclear cells (PBMC) and by the presence of specific autoantibodies. ,/, T cells accumulate in the lung and the skin of SSc patients suggesting their potential role in the development and maintenance of the disease. The aim of this study was to assess cytokine production and cytotoxic activity of circulating ,/, T lymphocytes obtained from SSc patients and to evaluate their potential role during this disorder. Our results showed that both the proportion and the absolute number of IFN- ,,/, -producing cells (i.e. displaying a Th1 polarization) in SSc was significantly higher than either the proportion and the absolute number of IL-4 ,/, -producing cells in SSc or the proportion and the absolute number of IFN- ,,/, -producing cells in healthy controls (P < 0·05 for both groups). Furthermore, the cytotoxic activity of enriched ,/, T cells was significantly increased in SSc patients compared with controls. The results concerning the V,1+ T cell subset paralleled those of total ,/, T lymphocytes. In contrast, ,/, T cells from SSc and control subjects displayed Th2 cytokine production. All these findings were independent of both disease subset and clinical status. Our data demonstrate that, although SSc is generally considered a Th2 autoimmune disease, Th1 polarization of ,/, T cells and an increase in their cytotoxic activity is observed in SSc, suggesting that ,/, T cells could have a relatively autonomous role in the pathogenesis in this disease. [source] Detection of Subclinical Cardiac Involvement in Systemic Sclerosis by Echocardiographic Strain ImagingECHOCARDIOGRAPHY, Issue 2 2008Alper Kepez M.D. Background: Cardiac involvement is one of the major problems in systemic sclerosis (SSc). Subclinical cardiac involvement has a higher frequency than thought previously. In this study we investigated whether subclinical cardiac involvement can be detected by using echocardiographic strain imaging in SSc patients without pulmonary hypertension. Methods: Echocardiographic examinations were performed to 27 SSc patients and 26 healthy controls. Left ventricular strain parameters were obtained from apical views and average strain value was calculated from these measurements. Results: There were no significant differences between patients and controls regarding two-dimensional (2D), conventional Doppler and tissue Doppler velocity measurements. Strain was reduced in 6 of 12 segments of the left ventricle (LV) and in 1 of 2 segments of the right ventricle (RV). Strain rate (SR) was reduced in 2 of 12 segments of the LV and 1 of 2 segments of the RV in SSc patients as compared to controls (P < 0.05 for all). These involvements did not match any particular coronary artery distribution. More important differences were detected by average strain and SR values of the LV between patients and controls (19.78 ± 3.00% vs 23.41 ± 2.73%, P < 0.001; 2.01 ± 0.41 vs 2.23 ± 0.27/sec, P = 0.026, respectively). Furthermore, carbon monoxide diffusion capacity (DLCO) in scleroderma patients significantly correlated with LV average strain (r = 0.59; P = 0.001). Conclusion: Evaluation of ventricular function by using echocardiographic strain imaging appears to be useful to detect subclinical cardiac involvement in SSc patients with normal standard echocardiographic and tissue Doppler velocity findings. [source] Elevated exhalation of hydrogen peroxide in patients with systemic sclerosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2003uczyńska Abstract Background Systemic sclerosis is accompanied by an influx of activated phagocytes into distal airways. These cells release H2O2, which may evaporate from the airways surface and be detected in expired breath condensate. We tested whether patients with systemic sclerosis exhale more H2O2 than healthy subjects and whether breath condensate H2O2 levels correlate with some clinical parameters. Material and methods H2O2 was measured fluorimetrically in the expired breath condensate of 27 patients (22 women, five men, mean age 49 ± 13·1 years) with systemic sclerosis and 27 age- and sex- matched healthy controls. Results Exhaled H2O2 levels were 3·5-fold higher (0·88 ± 0·62 µM vs. 0·25 ± 0·17 µM, P < 0·001) in the patients with systemic sclerosis than in the controls. Treatment with cyclophosphamide and/or prednisone (29 ± 50 months, range 3,168 months) did not significantly decrease H2O2 exhalation (0·78 ± 0·50 µM, n= 10 vs. 0·94 ± 0·67 µM, n= 17, P > 0·05). No significant difference was found between patients with limited and diffuse scleroderma (1·03 ± 0·69 µM, n= 17 vs. 0·63 ± 0·41 µM, n= 10, P > 0·05). H2O2 levels correlated with disease duration (r = 0·38, P < 0·05) and time from the first Raynaud's episode (r = 0·44, P < 0·05). Conclusions Patients with systemic sclerosis exhale more H2O2 than healthy controls, suggesting involvement of reactive oxygen species in disease processes. Lack of significant intergroups differences in H2O2 levels may have resulted from the small number of patients analyzed. [source] Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized sclerodermaEXPERIMENTAL DERMATOLOGY, Issue 8 2009Nobuyo Higashi-Kuwata Abstract:, Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor ,. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma. [source] Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseasesEXPERIMENTAL DERMATOLOGY, Issue 2 2007Takashi Matsushita Abstract:, Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma. [source] Role of X chromosome defects in primary biliary cirrhosisHEPATOLOGY RESEARCH, Issue 2007Pietro Invernizzi Similar to the majority of autoimmune conditions, primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by a striking female predominance; it is characterized by high titer serum autoantibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. Familiarity and high concordance rates for the disease among monozygotic twins strongly support the role of genetics in the disease. Experimental efforts have been dedicated by our and other research groups to investigate the role of X chromosome abnormalities (i.e. monosomyrates and inactivation patterns) in autoimmunity. Our recent work has demonstrated enhanced X monosomy in women with PBC as well as two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease. We will review herein the most recent evidence on the role of the X chromosome in PBC onset and discuss the potential implications. Future developments of these findings will be discussed. [source] Scleroderma: it has been a long hard journeyINTERNAL MEDICINE JOURNAL, Issue 8 2006P. J. Roberts-Thomson Abstract Progress in the understanding of the aetiopathogenesis of scleroderma (systemic sclerosis) has been painfully slow and this has greatly impeded the application of specific disease modifying treatments. This article provides a brief historical overview of scleroderma (including the important Australian contribution of Dr Alfred Barnett and colleagues , see accompanying article in this issue on pages 513,18), highlights some recent pathogenic developments and summarises some exciting new therapies. Cautious optimism can now be offered to scleroderma sufferers. [source] | ||||||||||||||||||||||||||||