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SSc Patients (ssc + patient)
Selected AbstractsDetection 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] Right Heart Function and Scleroderma: Insights from Tricuspid Annular Plane Systolic ExcursionECHOCARDIOGRAPHY, Issue 2 2007Chiu-Yen Lee M.D. Objective: The purpose of this study was to evaluate the use of echocardiographic parameters as predictors of rehospitalization in scleroderma patients. Methods: Echocardiographic studies were conducted in 38 patients with systolic scleroderma (SSc) to assess cardiopulmonary function. Forty-five age-matched volunteers without any sign of heart failure served as the control group. Transmitral flow pattern, tricuspid annular plane systolic excursion (TAPSE), left ventricular ejection fraction (LVEF), and right ventricular ejection fraction (RVEF) were evaluated. All patients were subsequently followed for one year. Results: Peak transmitral early-diastolic velocity (mitral E) and TAPSE measurements were significantly different between SSc and control patients (mitral E: 74.1 ± 16.3 vs. 83.5 ± 17.0 cm/s with P = 0.012; TAPSE: 2.4 ± 0.43 vs. 1.9 ± 0.39 cm with P < 0.0001). LVEF was similar, but RVEF was lower in the SSc group (LVEF: 61.7 ± 9.7 vs. 61.7 ± 5.8% with P = 0.962; RVEF: 49.6 ± 6.8 vs. 39.2 ± 6.7% with P < 0.0001). A strong correlation was found between TAPSE and RVEF. A TAPSE less than 1.96 cm indicted a RVEF less than 40% with a sensitivity of 81% and specificity of 78%. Contrary to expectation, pulmonary artery systolic pressure (PASP) did not correlate well with RV function (r = 0.261, r2= 0.068, P = 0.016). Finally, the frequency of rehospitalization was inversely correlated with RVEF and TAPSE in SSc patients. Conclusions: We can predict the rehospitalization rate of SSc patients by TAPSE and RVEF, suggesting the involvement of heart, skin, lung, and other organs in scleroderma patients. [source] Methods to detect antifibrillarin antibodies in patients with systemic sclerosis (SSc): A comparisonJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 1 2004Josefina Huerta García Abstract Autoantibodies against nucleolar antigens are common in systemic sclerosis (SSc). They include autoantibodies against fibrillarin (Fb), which are serological markers for SSc. Fb is associated with the evolutionally-conserved box C/D of small nucleolar RNAs (snoRNAs). We compared indirect immunofluorescence (IIF), Western blot (WB), and immunoprecipitation (IPP) of total small RNAs assays to determine which of these techniques is most specific for the detection of snoRNPs. We also examined the frequency and specificity of autoantibodies from SSc patients to snoRNAs, snRNAs, and scRNAs, and concluded that 1) IIF can not determine autoantibody specificity against Fb, 2) 36% of SSc sera were false-negative by WB, and 3) by IPP, anti-Fb autoantibodies from SSc patients can bind U3, U8, U13, U15, and U22 snoRNAs. J. Clin. Lab. Anal. 18:19,26, 2004. © 2004 Wiley-Liss, Inc. [source] Electrocardiographic Evaluation in Patients with Systemic Scleroderma and without Clinically Evident Heart DiseaseANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2009Anna Bie, Ph.D., ous-Wilk M.D. Background: In patients with systemic scleroderma (SSc), clinically evident cardiac involvement is recognized to be a poor prognostic factor. The aim of the study was to evaluate electrocardiographic changes, parameters of heart rate variability (HRV), and heart rate turbulence (HRT) in patients with SSc without evident symptoms of heart disease. Methods: A group of 27 patients with SSc were subjected to standard electrocardiography (ECG) examination and 24-hour Holter monitoring. Analysis of HRV in time and frequency domains, HRT, and echocardiography were also performed. Results: Holter monitoring revealed a larger number of premature supraventricular contractions (PSVCs), as well as premature ventricular contractions (PVCs) in the patients with systemic scleroderma, as compared with the control group. Moreover, the SSc patients showed decreased parameters of time and frequency domains, as referred to the controls, especially during night hours. In four patients, abnormal HRT values were present. On echocardiography, only slight changes were found, however in five patients left ventricle diastolic dysfunction was diagnosed. Conclusions: The noninvasive electrocardiographic methods seems to be useful for detecting early heart involvement in course of SSc and could be recommended for routine used in clinical practice. Significance of HRT analysis in patients with SSc needs further elucidation. [source] Association of a KCNA5 gene polymorphism with systemic sclerosis,associated pulmonary arterial hypertension in the European Caucasian populationARTHRITIS & RHEUMATISM, Issue 10 2010J. Wipff Objective Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor , receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. Methods Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. Results The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48,0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13,0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21,0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. Conclusion Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc. [source] Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosisARTHRITIS & RHEUMATISM, Issue 8 2010Ayumi Yoshizaki Objective Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice. Methods Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts. Results Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor ,1, was attenuated by rapamycin. Hypergammaglobulinemia and anti,topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner. Conclusion This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients. [source] Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: A population-based studyARTHRITIS & RHEUMATISM, Issue 7 2010Tracy Frech Objective To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). Methods A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. Results A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was ,8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99,3.41], P = 2.42 × 10,15) and second-degree relatives (1.48 [95% CI 1.34,2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44,11.83], P = 4.04 × 10,9) and second-degree relatives (2.39 [95% CI 1.21,4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04,2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18,1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06,1.35], P = 0.004). Conclusion These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives. [source] MicroRNA-29, a key regulator of collagen expression in systemic sclerosisARTHRITIS & RHEUMATISM, Issue 6 2010Britta Maurer Objective To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc). Methods MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA-29 (miR-29) was determined by TaqMan real-time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin-induced skin fibrosis. Cells were transfected with precursor miRNA (pre-miRNA)/anti-miRNA of miR-29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor , (TGF,), platelet-derived growth factor B (PDGF-B), or interleukin-4 (IL-4) was used. The effects of inhibiting PDGF-B and TGF, signaling on the levels of miR-29 were studied in vitro and in the bleomycin model. Results We found that miR-29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre-miR-29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR-29a. TGF,, PDGF-B, or IL-4 reduced the levels of miR-29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR-29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF-B and TGF, pathways by treatment with imatinib restored the levels of miR-29a in vitro and in the bleomycin model in vivo. Conclusion These data add the posttranscriptional regulation of collagens by miR-29a as a novel aspect to the fibrogenesis of SSc and suggest miR-29a as a potential therapeutic target. [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] Fox-2 protein regulates the alternative splicing of scleroderma-associated lysyl hydroxylase 2 messenger RNA,ARTHRITIS & RHEUMATISM, Issue 4 2010Puneet Seth Objective Scleroderma (systemic sclerosis [SSc]) is a complex connective tissue disorder characterized by hardening and thickening of the skin. One hallmark of scleroderma is excessive accumulation of collagen accompanied by increased levels of pyridinoline collagen crosslinks derived from hydroxylysine residues in the collagen telopeptide domains. Lysyl hydroxylase 2 (LH2), an important alternatively spliced enzyme in collagen biosynthesis, acts as a collagen telopeptide hydroxylase. Changes in the pattern of LH2 alternative splicing, favoring increased inclusion of the alternatively spliced LH2 exon 13A, thereby increasing the levels of the long transcript of LH2 (LH2[long]), are linked to scleroderma disease. This study was undertaken to examine the role played by RNA binding protein Fox-2 in regulating exon 13A inclusion, which leads to the generation of scleroderma-associated LH2(long) messenger RNA (mRNA). Methods Phylogenetic sequence analysis of introns flanking exon 13A was performed. A tetracycline-inducible system in T-Rex 293 cells was used to induce Fox-2 protein, and endogenous LH2(long) mRNA was determined by reverse transcriptase,polymerase chain reaction. An LH2 minigene was designed, validated, and used in Fox-2 overexpression and mutagenesis experiments. Knockdown of Fox-2 was performed in mouse embryonic fibroblasts and in fibroblasts from SSc patients. Results Overexpression of Fox-2 enhanced the inclusion of exon 13A and increased the generation of LH2(long) mRNA, whereas knockdown of Fox-2 decreased LH2(long) transcripts. Mutational analysis of an LH2 minigene demonstrated that 2 of the 4 Fox binding motifs flanking LH2 exon 13A are required for inclusion of exon 13A. In early passage fibroblasts derived from patients with scleroderma, the knockdown of Fox-2 protein significantly decreased the endogenous levels of LH2(long) mRNA. Conclusion Our findings indicate that Fox-2 plays an integral role in the regulation of LH2 splicing. Knockdown of Fox-2 and other methods to decrease the levels of fibrosis-associated LH2(long) mRNA in primary scleroderma cells may suggest a novel approach to strategies directed against scleroderma. [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] The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosisARTHRITIS & RHEUMATISM, Issue 1 2010Nicole Reich Objective Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis. Methods Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2,transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor , (TGF,), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors. Results Fra-2,transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGF, and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGF, and PDGF and decreased the release of collagen from SSc fibroblasts. Conclusion We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGF, and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc. [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] HLA,DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome-wide association study in Koreans with replication in North AmericansARTHRITIS & RHEUMATISM, Issue 12 2009Xiaodong Zhou Objective To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. Methods A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. Results The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA,DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P = 8.16 × 10,13). Subtyping analysis of HLA,DPB1 showed that DPB1*1301 (P = 7.61 × 10,8) and DPB1*0901 (P = 2.55 × 10,5) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti,DNA topoisomerase I (P = 7.58 × 10,17/4.84 × 10,16) or anticentromere autoantibodies (P = 1.12 × 10,3/3.2 × 10,5), respectively. Conclusion The results of our genome-wide association study in Korean subjects indicate that the region of HLA,DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA,DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti,DNA topoisomerase I or anticentromere autoantibodies. [source] The FAS ,670A>G polymorphism influences susceptibility to systemic sclerosis phenotypesARTHRITIS & RHEUMATISM, Issue 12 2009J. Broen Objective To investigate the possible role of the FAS ,670A>G functional polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. Methods A total of 2,900 SSc patients and 3,186 healthy controls were included in this study. We analyzed the genotype and allele frequencies of the FAS ,670A>G polymorphism in 9 distinct ethnic cohorts, including 6 cohorts of European ancestry (a Spanish cohort of 228 SSc patients and 265 controls, a Dutch cohort of 203 SSc patients and 277 controls, a German cohort of 313 SSc patients and 247 controls, an Italian cohort of 323 SSc cases and 89 controls, a British cohort of 269 SSc patients, and a Swedish cohort of 182 patients) and 3 distinct ethnic cohorts from the US (a cohort of 1,047 white patients and 692 controls, a cohort of 159 Hispanic patients and 137 controls, and a cohort of 176 black SSc patients and 194 controls). Genotyping was performed using a TaqMan 5, allelic discrimination assay. Results In the British, Italian, and American white cohorts we observed an association of the FAS ,670G allele with limited cutaneous SSc (lcSSc) (odds ratios [ORs] 1.25, 1.43, and 1.18, respectively). A meta-analysis comprising all 9 cohorts revealed an association of both the FAS ,670G allele (OR 1.10) and the FAS ,670GG genotype (OR 1.13) with the lcSSc phenotype. In a meta-analysis including only white subjects, both the FAS ,670G allele and the FAS ,670GG genotype remained associated with lcSSc (allele OR 1.12; genotype OR 1.16). In addition, a recessive model of the ,670GG genotype exhibited a strong association with SSc, lcSSc, and anticentromere antibody,positive lcSSc (OR 1.23, OR 1.33, and OR 1.45, respectively). Conclusion Our data show that the FAS ,670A>G polymorphism plays a role in lcSSc susceptibility. A similar trend has been observed in other autoimmune diseases. [source] BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4ARTHRITIS & RHEUMATISM, Issue 11 2009P. Dieudé Objective To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene,gene interactions between BANK1 and IRF5 as well as STAT4. Methods BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. Results The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64,0.93) and an OR of 0.73 (95% CI 0.61,0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57,0.86], P = 3.39 × 10,4) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06,1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. Conclusion Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects. [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] Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 6 2009Carmine Cardillo Objective Impaired endothelium-dependent vasodilator function may contribute to vascular damage in patients with systemic sclerosis (SSc). This study was undertaken to investigate whether increased activity of the endothelin 1 (ET-1) system plays a role in the occurrence of endothelial dysfunction in patients with SSc. Methods In 12 patients with SSc (6 with diffuse cutaneous SSc [dcSSc] and 6 with limited cutaneous SSc [lcSSc]), forearm blood flow responses to graded doses of acetylcholine (ACh) and sodium nitroprusside (SNP) given intraarterially were assessed by plethysmography, during infusion of saline and following selective blockade of ETA receptors with BQ-123 (10 nmoles/minute). Results During saline infusion, the vasodilator response to ACh was blunted in patients with SSc as compared with that in healthy controls (P < 0.001), whereas the response to SNP was not different between groups (P = 0.27). The vasodilator effect of ETA receptor antagonism was higher in patients than in controls (P < 0.001), indicating enhanced ET-1,mediated vasoconstriction in SSc. In patients, ETA receptor blockade resulted in a potentiation of the vasodilator response to ACh (P < 0.001 versus saline), but did not affect the response to SNP (P = 0.31). Notably, both the vasodilator effect of ETA receptor antagonism and the improvement in the responsiveness to ACh following BQ-123 infusion were higher in patients with dcSSc than in those with lcSSc (P < 0.01). Conclusion ET-1,dependent vasoconstrictor tone is increased predominantly in the subgroup of SSc patients with dcSSc, in whom acute blockade of ETA receptors was able to improve impaired endothelium-dependent vasodilator function. Our results suggest novel vasculoprotective effects of ETA receptor antagonism and support further exploration of strategies that target the ET-1 pathway in SSc. [source] Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese populationARTHRITIS & RHEUMATISM, Issue 6 2009Ikue Ito Objective Interferon regulatory factor 5, an established susceptibility factor for systemic lupus erythematosus (SLE), plays a role in type I interferon and proinflammatory cytokine induction. A recent study showed association of a functional single-nucleotide polymorphism (SNP) in intron 1 of IRF5, rs2004640, with systemic sclerosis (SSc) in a European French population. We undertook the present study to determine whether IRF5 polymorphisms are also associated with a predisposition to SSc in Japanese. Methods A case,control association study was performed for rs2004640 as well as for rs10954213 and rs2280714, all of which were previously reported to be associated with SLE, in 281 SSc patients and 477 healthy controls. Patients with SSc complicated by SLE or Sjögren's syndrome were excluded. Association of the rs2280714 genotype with messenger RNA (mRNA) levels of IRF5 and adjacently located transportin 3 (TNPO3) was examined using the GENEVAR database. Results All 3 SNPs were significantly associated with SSc, with the rs2280714 A allele having the strongest association (allele frequency P = 0.0012, odds ratio 1.42 [95% confidence interval 1.15,1.75]). Association was preferentially observed in subsets of patients with diffuse cutaneous SSc (dcSSc) and anti,topoisomerase I antibody positivity. Conditional analysis revealed that rs2280714 could account for most of the association of these SNPs, while an additional contribution of rs2004640 was also suggested for dcSSc. The genotype of rs2280714 was strongly associated with IRF5 mRNA expression, while only marginal association was detected with TNPO3 mRNA expression. Conclusion Association of IRF5 with SSc was replicated in a Japanese population. Whether the causal SNP is different among populations requires further investigation. [source] Anti,U3 RNP autoantibodies in systemic sclerosisARTHRITIS & RHEUMATISM, Issue 4 2009Rohit Aggarwal Objective To describe the classification, demographic and clinical features, and survival in anti,U3 RNP autoantibody,positive patients with systemic sclerosis (SSc). Methods Medical records of 108 anti,U3 RNP,positive and 2,471 anti,U3 RNP,negative SSc patients first evaluated during 1985,2003 were reviewed. Anti,U3 RNP antibody was detected by protein and RNA immunoprecipitation. Disease classification, demographic and clinical features, organ system involvement, and survival were compared between the 2 patient groups, by Student's t -test, chi-square analysis, and Mantel-Haenszel test. Results The anti,U3 RNP,positive group had a higher proportion of African American patients (27% versus 5%; P < 0.001) and male patients (29% versus 19%; P = 0.021), and was younger at the time of first physician diagnosis (mean age 42.8 years versus 47.4 years; P = 0.001). The 2 groups had similar proportions of patients with diffuse cutaneous involvement (47% and 45% in those with and those without anti,U3 RNP, respectively). However, among patients with diffuse cutaneous involvement, the mean maximum modified Rodnan skin score was significantly lower in the anti,U3 RNP group (22.3 versus 27.9; P < 0.001). Skeletal muscle involvement was more frequent in anti,U3 RNP,positive patients (25% versus 14%; P = 0.002), as was "intrinsic" pulmonary arterial hypertension (PAH) (31% versus 13%; P < 0.001). The frequency of gastrointestinal involvement, cardiac involvement, pulmonary fibrosis, and "renal crisis" did not differ significantly between the 2 groups. Survival was worse in the anti,U3 RNP,positive group (hazard ratio 1.38 [95% confidence interval 1.05,1.82]). PAH was the most common known cause of death in patients with anti,U3 RNP (30%, versus 10% in the anti,U3 RNP,negative group; P < 0.001). Conclusion The present findings demonstrate that the frequencies of African American race and male sex are greater among SSc patients with anti,U3 RNP antibody than those without, and the former group is younger at SSc diagnosis. Anti,U3 RNP,positive patients have more frequent skeletal muscle involvement and PAH, the latter being the most common cause of death. [source] Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin-13 associated with increased skin fibrosisARTHRITIS & RHEUMATISM, Issue 4 2009Patrizia Fuschiotti Objective T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell,derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc. Methods To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4+ and CD8+ T cell subsets to produce cytokines following in vitro activation. Results High levels of the profibrotic type 2 cytokine interleukin-13 (IL-13) were produced following activation of peripheral blood effector CD8+ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4+ T cells showed a lower and more variable level of IL-13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients. Conclusion Dysregulated IL-13 production by effector CD8+ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target. [source] Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor , in a subset of normal and systemic sclerosis patient seraARTHRITIS & RHEUMATISM, Issue 4 2009Nick Loizos Objective To investigate whether agonist anti,platelet-derived growth factor receptor , (anti-PDGFR,) antibodies are present in the serum of patients with systemic sclerosis (SSc; scleroderma). Methods Sera were obtained from healthy subjects and scleroderma patients. An electrochemiluminescence binding assay was performed for detection of serum autoantibodies to PDGFR,, PDGFR,, epidermal growth factor receptor (EGFR), and colony-stimulating factor receptor 1 (CSFR1). Serum immunoglobulin was purified by protein A/G chromatography. To assess Ig agonist activity, PDGFR,-expressing cells were incubated with pure Ig and the level of receptor phosphorylation determined in an enzyme-linked immunoassay, as well as by Western blotting. Ig agonist activity was also assessed in a mitogenic assay and by MAP kinase activation in a PDGFR,-expressing cell line. Results Sera from 34.3% of the healthy subjects and 32.7% of the SSc patients contained detectable autoantibodies to PDGFR, and PDGFR,, but not EGFR or CSFR1. Purified Ig from these sera was shown to retain PDGFR binding activity and, at 200-1,000 ,g/ml, exhibited no agonist activity in a cell-based PDGFR, phosphorylation assay and did not stimulate a mitogenic response or MAP kinase activation in a PDGFR,-expressing cell line. Two purified Ig samples that were unable to bind PDGFR, did exhibit binding activity to a nonglycosylated form of PDGFR,. Conclusion Although approximately one-third of sera from scleroderma patients contained detectable autoantibodies to PDGFR, these antibodies were not specific to scleroderma, since they were also detected in a similar percentage of samples from normal subjects. PDGFR, agonist activity was not demonstrated when purified Ig from these sera was tested in cell-based assays. [source] Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: Impact of interstitial lung diseaseARTHRITIS & RHEUMATISM, Issue 2 2009Stephen C. Mathai Objective Pulmonary hypertension (PH) is an important cause of mortality in systemic sclerosis (SSc), where it can be isolated (pulmonary arterial hypertension [PAH]) or associated with interstitial lung disease (ILD). This study was undertaken to characterize determinants of survival among SSc patients with either type of PH who received PAH-specific therapy. Methods Consecutive SSc patients with PAH or ILD-associated PH confirmed by right heart catheterization were included in the study. Kaplan-Meier and Cox proportional hazards models were used to compare survival between SSc patients with PAH and those with ILD-associated PH and to identify predictors of survival. Results Fifty-nine patients (39 with PAH and 20 with ILD-associated PH) were identified. The majority (15 of 20 with ILD-associated PH and 27 of 39 with PAH) received an endothelin receptor antagonist as initial therapy. Median followup time was 4.4 years (range 2.7,7.4 years). Survival was significantly worse in SSc patients with ILD-associated PH than in those with PAH (1-, 2-, and 3-year survival rates 82%, 46%, and 39% versus 87%, 79%, and 64%, respectively; P < 0.01 by log rank test). In a multivariable analysis, ILD-associated PH was associated with a 5-fold increase in risk of death compared with PAH. Pulmonary vascular resistance index was also an independent predictor of mortality in the overall cohort (hazard ratio 1.05, P < 0.01) and was a significant univariable risk factor in each group separately. Type of initial PAH therapy and the use of warfarin were not related to survival. Conclusion Survival in SSc complicated by PH remains poor despite currently available treatment options. While therapy may be associated with improved survival in PAH compared with historical controls, the prognosis for patients with ILD-associated PH is particularly grim. Early diagnosis and treatment may improve outcomes since worsening hemodynamic factors were associated with reduced survival. [source] High N-terminal pro,brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 1 2008Y. Allanore Objective To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc). Methods Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N-terminal pro,brain natriuretic peptide (NT-proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36-month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea. Results Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan-Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P < 0.01 for each comparison), elevated plasma NT-proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P = 0.08), and erythrocyte sedimentation rate >28 mm/hour (P = 0.015). In multivariate analyses, an elevated baseline NT-proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69,62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45,387.6]) were predictors of the occurrence of PAH during followup. An increased NT-proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90,450.33]). Conclusion This prospective study identified a decreased DLCO/VA ratio and an increased NT-proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy. [source] Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 10 2007Yann Parel Objective Fibrotic skin changes in systemic sclerosis (SSc) are preceded by the appearance of an inflammatory infiltrate rich in T cells. Since no direct comparison with T cells in normal skin has been performed previously, this study was undertaken to functionally characterize T cells in the skin of patients with early active SSc and in normal skin. Methods We characterized coreceptor expression, T cell receptor (TCR) usage, cytokine production, and helper and cytolytic activity of T cell lines and clones established from skin biopsy specimens from 6 SSc patients and 4 healthy individuals. Immunofluorescence analysis of skin biopsy and peripheral blood samples was performed to confirm the presence of specific subsets in vivo. Results A distinct subset expressing both CD4 and CD8,/, coreceptors at high levels (double-positive [DP]) was present in T cell lines from SSc and normal skin. DP T cells actively transcribed both accessory molecules, exerted clonally distributed cytolytic and helper activity, and expressed TCR clonotypes distinct from those in CD4+ or CD8+ single-positive (SP) T cells. In SSc skin, DP T cells produced very high levels of interleukin-4 (IL-4) compared with CD4+ SP T cells. Furthermore, DP T cells were directly identified in SSc skin, thus providing evidence that they are a distinct subset in vivo. Conclusion The present findings show that T cells with the unusual CD4+CD8+ DP phenotype are present in the skin. Their very high level of IL-4 production in early active SSc may contribute to enhanced extracellular matrix deposition by fibroblasts. [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] Hemorheologic profile in systemic sclerosis: Role of NOS3 ,786T>C and 894G>T polymorphisms in modulating both the hemorheologic parameters and the susceptibility to the diseaseARTHRITIS & RHEUMATISM, Issue 7 2006Cinzia Fatini Objective Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients. Methods We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds,1), plasma viscosity (PLV; at a shear rate of 94.5 seconds,1), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis. Results A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds,1, odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4,19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2,6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4,10.8, P = 0.007), and NOS3 ,786C and 894T alleles significantly affected the DI (for ,786C allele, OR 2.3, 95% CI 1.01,5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01,4.8, P = 0.04). The simultaneous presence of the ,786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4,5.7, P = 0.004). Conclusion Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease. [source] Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 6 2006Masataka Kuwana Objective To evaluate whether atorvastatin can increase bone marrow,derived circulating endothelial precursors (CEPs) and improve the vascular symptoms in patients with systemic sclerosis (SSc; scleroderma). Methods The study was designed as an open-label, prospective study involving 14 patients with SSc who received 10 mg/day of atorvastatin for 12 weeks and were followed up for the subsequent 4 weeks. CEPs were quantified at weeks 0 (pretreatment), 4, 8, 12 (during treatment), and 16 (posttreatment) by cell sorting followed by 3-color flow cytometry. Raynaud's phenomenon variables, global measures, and psychological scales as well as circulating angiogenic factors and endothelial activation/injury markers were serially assessed. The potential of CEPs to differentiate into mature endothelial cells was examined in cultures with angiogenic stimuli. Results None of the patients experienced an adverse event, but 1 dropped out because of an excessive decrease in serum total cholesterol. Atorvastatin treatment resulted in a 1.7- to 8.0-fold increase in CEPs from baseline levels (P < 0.0001), but the numbers returned to within baseline levels at posttreatment. However, 8 patients (62%) experienced a gradual decrease in the number of CEPs, even while taking atorvastatin. Variables indicating the extent of Raynaud's phenomenon improved significantly, and up-regulated levels of angiogenic factors and vascular endothelial activation/injury markers decreased significantly during atorvastatin treatment. These variables returned to within baseline levels after discontinuation of the drug. In contrast, atorvastatin failed to improve the in vitro maturation potential of CEPs. Conclusion The results of this pilot study suggest that atorvastatin treatment can increase CEPs and may be effective in improving Raynaud's phenomenon, even in SSc patients who have CEP dysfunction intrinsically. [source] N-terminal pro,brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockersARTHRITIS & RHEUMATISM, Issue 12 2003Y. Allanore Objective To evaluate N-terminal pro,brain natriuretic peptide (NT-proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine-type calcium-channel blocker (DTCCB) in patients with systemic sclerosis (SSc). Methods We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean ± SD age 56 ± 11 years and mean ± SD duration of cutaneous disease 9 ± 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT-proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6,9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline). Results At baseline, 13 patients had high NT-proBNP values for their ages. High NT-proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT-proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT-proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06). Conclusion NT-proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT-proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH. [source] | |||||||||||||||||||