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Find video protocols related to scientific articles indexed in Pubmed.
The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
Hum. Mol. Genet.
PUBLISHED: 09-08-2014
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Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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Association of the HLA-DRB1 with scleroderma in Chinese population.
PLoS ONE
PUBLISHED: 09-03-2014
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Multiple alleles of the Human leukocyte antigen (HLA) DRB1 have been strongly associated with systemic sclerosis (SSc) and its clinical or serological subsets. However, the associations vary in different ethnic populations. To define SSc-risk and/or -protective alleles of HLA-DRB1 in Chinese population, we studied a Han Chinese cohort containing 585 patients with SSc and 458 gender-matched, unrelated controls. The HLA-DRB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher's test) from 2×2 tables of allele frequency and disease status. The major SSc-risk allele subtypes of HLA-DRB1 are the DRB1*15?02 and *16?02 in this Chinese cohort. Particularly, DRB1*15?02 was most significantly associated with anti-centromere autoantibodies (ACA) positive, and DRB1*16?02 with anti-topoisomerase I autoantibodies (ATA) positive patients. On the other hand, DRB1*01?01 and *04?06 were strong SSc-protective alleles in Chinese, especially in patients who were ACA positive and had diffuse cutaneous SSc (dcSSc), respectively. In addition, DRB1*11 and *07?01 also showed significant association with SSc as a risk for and protection from SSc, respectively, and which is consistent with the studies of Spanish, US Caucasian and Hispanic populations. DRB1*15 was associated with ATA positive Chinese SSc that is consistent with Black South African and Korean SSc. These findings of HLA-DRB1 alleles in association with Chinese SSc provide the growing knowledge of genetics of SSc, and indicate that the genetic heterogeneity among ethnicities may significantly impact the complex trait of SSc.
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Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis.
PUBLISHED: 04-24-2014
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Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis.
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Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria.
J Clin Epidemiol
PUBLISHED: 04-08-2014
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Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc.
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Correlates and responsiveness to change of measures of skin and musculoskeletal disease in early diffuse systemic sclerosis.
Arthritis Care Res (Hoboken)
PUBLISHED: 03-25-2014
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Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study.
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International consensus criteria for the diagnosis of Raynaud's phenomenon.
J. Autoimmun.
PUBLISHED: 02-01-2014
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Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP.
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A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility.
Arthritis Res. Ther.
PUBLISHED: 01-09-2014
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A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.
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Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.
Am. J. Hum. Genet.
PUBLISHED: 01-07-2014
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In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
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Lack of Association of the CD247 SNP rs2056626 with Systemic Sclerosis in Han Chinese.
Open Rheumatol J
PUBLISHED: 01-01-2014
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Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. A recent genome-wide association study (GWAS) indicated that CD247 was strongly associated with SSc, which was subsequently confirmed in a SSc cohort of European population. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc. The studies herein aimed to examine whether the SSc-associated SNP rs2056626 of CD247 identified in Caucasian is also associated with Han Chinese SSc. A Han Chinese cohort consisting of 387 SSc patients and 523 healthy controls were examined in the studies. TaqMan assays were performed to examine the SNP. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts and disease status. The results showed that there was no association between rs2056626 of CD247 and SSc or any SSc subtypes of Han Chinese. The negative results are important in understanding genetics of SSc in different ethnic populations, which further suggest complex nature of genetics of SSc.
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Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population.
PLoS ONE
PUBLISHED: 01-01-2014
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Human leukocyte antigen DPB1 was reported to contain singly nucleotide polymorphisms conferring the strongest susceptibility to systemic sclerosis in Korean population. However, associations of specific DPB1 alleles with SSc vary in different ethnic populations. The aim of this study was to profile DPB1 alleles in Chinese population and to identify specific DPB1 alleles in association with SSc and clinical and serological features of SSc in Han Chinese. A cohort containing 338 patients with SSc and 480 gender-matched and unrelated controls were examined in the study. The HLA-DPB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher's test) from 2×2 tables of allele counts or allele carriers and disease status. Thirty eight DPB1 alleles were found in the cohort. DPB1*05:01 was the most common allele in this cohort. DPB1*03:01 and *13:01 were significantly increased in SSc. DPB1*13:01 association had already been described in other ethnic populations, whereas DPB1*03:01 was specific to Han Chinese patients with SSc. In addition, comparisons between SSc subsets indicated that patients carrying DPB1*03:01 were more likely to develop pulmonary fibrosis, DPB1*04 carriers were increased in SSc patients with anti-centromere autoantibodies and in contrast, SSc patients with homozygous DPB1*05:01 showed an opposite association with marginal significance.
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Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis.
N. Engl. J. Med.
PUBLISHED: 12-18-2013
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Background Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. Methods We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. Results Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. Conclusions Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).
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What does global gene expression profiling tell us about the pathogenesis of systemic sclerosis?
Curr Opin Rheumatol
PUBLISHED: 09-25-2013
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The purpose of this study is to review recent hypothesis-driven studies that utilize global gene expression data for elucidating the molecular basis of systemic sclerosis (SSc) and its various clinical manifestations.
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Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis.
Clin. Rheumatol.
PUBLISHED: 08-27-2013
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The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area.
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The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context.
BMJ Open
PUBLISHED: 08-10-2013
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Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN.
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Morphea in adults and children cohort III: nested case-control study--the clinical significance of autoantibodies in morphea.
JAMA Dermatol
PUBLISHED: 08-09-2013
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Small studies have implicated the association of specific autoantibodies with morphea subtype or severity, but no large-scale studies have been conducted. This prospective case-control study confirmed the presence of antinuclear antibodies (ANAs) and other autoantibodies in morphea but found they are of limited significance.
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Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 07-18-2013
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We undertook this hypothesis-generating study to identify skin transcripts correlating with severity of interstitial lung disease (ILD) in systemic sclerosis (SSc).
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Use of the Patient-generated Index in systemic sclerosis to assess patient-centered outcomes.
J. Rheumatol.
PUBLISHED: 06-15-2013
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To evaluate the content and construct validity of an individualized patient-reported instrument, the Patient-generated Index (PGI), in patients with systemic sclerosis (SSc), and to compare its performance to that of other instruments and to the Patient-reported Outcomes Measurement Information System (PROMIS) framework.
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A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.
Hum. Mol. Genet.
PUBLISHED: 06-04-2013
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Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
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Measuring illness behavior in patients with systemic sclerosis.
Arthritis Care Res (Hoboken)
PUBLISHED: 05-23-2013
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Illness behaviors (cognitive, affective, and behavioral reactions) among individuals with systemic sclerosis (SSc; scleroderma) are of clinical concern due to relationships between these behaviors and physical and mental quality of life, such as pain and symptoms of depression. Self-report measures with good psychometric properties can aid in the accurate assessment of illness behavior. The Illness Behavior Questionnaire (IBQ) was designed to measure abnormal illness behaviors; however, despite its longstanding use, there is disagreement regarding its subscales. The goal of the present study was to evaluate the validity of the IBQ in a cohort of patients with SSc.
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Can serum surfactant protein D or CC-chemokine ligand 18 predict outcome of interstitial lung disease in patients with early systemic sclerosis?
J. Rheumatol.
PUBLISHED: 04-15-2013
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To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease.
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Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 03-19-2013
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To measure interferon (IFN)-inducible chemokines in the plasma of patients with systemic sclerosis (SSc) and investigate whether the chemokine levels are correlated with disease severity.
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New insight on the Xq28 association with systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 02-26-2013
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To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).
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Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis?
Arthritis Care Res (Hoboken)
PUBLISHED: 01-18-2013
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There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort.
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Genetics of scleroderma: implications for personalized medicine?
BMC Med
PUBLISHED: 01-11-2013
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Significant advances have been made in understanding the genetic basis of systemic sclerosis (scleroderma) in recent years. Can these discoveries lead to individualized monitoring and treatment? Besides robustly replicated genetic susceptibility loci, several genes have been recently linked to various systemic sclerosis disease manifestations. Furthermore, inclusion of genetic studies in design and analysis of drug trials could lead to development of genetic biomarkers that predict treatment response. Future genetic studies in well-characterized systemic sclerosis cohorts paired with advanced analytic approaches can lead to development of genetic biomarkers for targeted diagnostic and therapeutic interventions in systemic sclerosis.
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Right bundle branch block: a predictor of mortality in early systemic sclerosis.
PLoS ONE
PUBLISHED: 01-01-2013
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To evaluate the prognostic significance of baseline electrocardiogram (ECG) abnormalities in a multiethnic cohort of patients with early systemic sclerosis (SSc) and to determine the serological, clinical, and echocardiogram correlates of ECG findings.
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A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.
Hum. Mol. Genet.
PUBLISHED: 11-10-2011
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A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(?2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
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Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-16-2011
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Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.
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A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease.
Arthritis Rheum.
PUBLISHED: 07-20-2011
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Transforming growth factor ? (TGF?) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGF? and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy.
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Minimally important differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.
J. Rheumatol.
PUBLISHED: 07-01-2011
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To provide minimally important difference (MID) estimates for the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) in a longitudinal observational cohort.
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Cigarette smoking is not a risk factor for systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 06-08-2011
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To investigate the association of cigarette smoking with susceptibility to systemic sclerosis (SSc) in a large, well-defined patient population.
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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
PLoS Genet.
PUBLISHED: 05-25-2011
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The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P?=?2.32×10(-12), OR?=?0.75). Also, rs12540874 in GRB10 gene (P?=?1.27 × 10(-6), OR?=?1.15) and rs11047102 in SOX5 gene (P?=?1.39×10(-7), OR?=?1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P?=?1.79×10(-61), OR?=?2.48), in the HLA-DPA1/B1 loci with ATA (P?=?4.57×10(-76), OR?=?8.84), and in NOTCH4 with ACA P?=?8.84×10(-21), OR?=?0.55) and ATA (P?=?1.14×10(-8), OR?=?0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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Anti-fibrillarin antibody in African American patients with systemic sclerosis: immunogenetics, clinical features, and survival analysis.
J. Rheumatol.
PUBLISHED: 05-15-2011
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Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
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Predictors of fatigue severity in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.
PLoS ONE
PUBLISHED: 04-13-2011
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Longitudinal studies examining the baseline predictors of fatigue in SSc have not been reported. Our objectives were to examine the course of fatigue severity over time and to identify baseline clinical, demographic, and psychosocial predictors of sequentially obtained fatigue scores in early SSc. We also examined baseline predictors of change in fatigue severity over time.
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Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic sclerosis: results from 2 large European Caucasian cohorts.
J. Rheumatol.
PUBLISHED: 03-01-2011
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Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.
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HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis.
Arthritis Rheum.
PUBLISHED: 02-01-2011
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To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc).
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Quality indicator set for systemic sclerosis.
Clin. Exp. Rheumatol.
PUBLISHED: 01-26-2011
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Systemic sclerosis (SSc) is associated with a marked economic burden, high treatment costs and decreased productivity. Although treatment strategies for SSc can have a substantial effect on patients outcomes, it is not known whether patients with SSc consistently receive such care. Evaluation of process-of-care quality requires specification of quality indicators (QIs), clinically detailed statements of the eligible patients and the care they should receive to achieve a minimal level of quality of care. Our objective was to develop QIs for patients with SSc.
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Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts.
Arthritis Res. Ther.
PUBLISHED: 01-11-2011
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Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN.
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Determinants of work disability in patients with systemic sclerosis: a longitudinal study of the GENISOS cohort.
Semin. Arthritis Rheum.
PUBLISHED: 01-01-2011
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To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors.
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Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5.
J. Rheumatol.
PUBLISHED: 10-15-2010
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to identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.
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Gender and ethnicity differences in patients with diffuse systemic sclerosis--analysis from three large randomized clinical trials.
Rheumatology (Oxford)
PUBLISHED: 10-01-2010
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Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs).
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Association of gastrointestinal involvement and depressive symptoms in patients with systemic sclerosis.
Rheumatology (Oxford)
PUBLISHED: 09-30-2010
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SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc.
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Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial.
Ann. Rheum. Dis.
PUBLISHED: 08-30-2010
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Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis) was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.
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Course of dermal ulcers and musculoskeletal involvement in systemic sclerosis patients in the scleroderma lung study.
Arthritis Care Res (Hoboken)
PUBLISHED: 08-27-2010
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To evaluate changes in vascular and musculoskeletal involvement in subjects in the Scleroderma Lung Study, a multicenter, double-blind, randomized, controlled trial comparing placebo treatment with oral cyclophosphamide (CYC) for 1 year in systemic sclerosis patients with interstitial lung disease. Subjects were then followed off the study agent for an additional 12 months.
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The symptom burden index: development and initial findings from use with patients with systemic sclerosis.
J. Rheumatol.
PUBLISHED: 06-01-2010
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Our study had 3 aims: (1) to evaluate the functioning of the Symptom Burden Index (SBI) in patients with systemic sclerosis (SSc); (2) to determine the amount of burden per problem experienced by patients as well as the number of patients experiencing each measured problem area, and the number of SSc problems per patient; and (3) to characterize the burden profiles of problem area-specific subgroups of patients.
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Plasma endogenous enkephalin levels in early systemic sclerosis: clinical and laboratory associations.
Clin. Exp. Rheumatol.
PUBLISHED: 05-14-2010
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Met- and leu-enkephalins are endogenous opioid neuropeptides with potent analgesic, vasoactive, immunomodulatory and anti-apoptotic properties. We hypothesised that clinical or immunological variables of early systemic sclerosis (SSc) might be correlated to plasma enkephalin levels.
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Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.
Arthritis Res. Ther.
PUBLISHED: 05-07-2010
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The objective of the present study was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC), expressed as a percentage of the predicted value, and to identify predictors of the decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS).
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Separate influences of birth order and gravidity/parity on the development of systemic sclerosis.
Arthritis Care Res (Hoboken)
PUBLISHED: 04-15-2010
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Birth order has been valuable in revealing the role of environmental influences on the risk of developing certain diseases such as allergy and atopy. In addition, pregnancy has profound effects on the immune system such as short-term effects that permit fetal survival as well as longer-term effects that could influence late-onset diseases. In order to better evaluate these influences, we studied the association of birth order and gravidity/parity as risk factors for systemic sclerosis (SSc; scleroderma).
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Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-04-2010
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Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft-versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc.
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Systemic sclerosis and lupus: points in an interferon-mediated continuum.
Arthritis Rheum.
PUBLISHED: 01-30-2010
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To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).
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Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis.
J. Autoimmun.
PUBLISHED: 01-25-2010
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To determine aggregation of autoimmune diseases in the first degree relatives (FDR) of patients with systemic sclerosis (SSc) and to investigate frequencies of antinuclear antibodies (ANA) and other autoantibodies in the FDRs and spouses of patients with SSc.
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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
Nat. Genet.
PUBLISHED: 01-04-2010
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.
Arthritis Rheum.
PUBLISHED: 12-02-2009
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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.
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Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis.
Hum. Mol. Genet.
PUBLISHED: 11-18-2009
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We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.
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Perceived functioning has ethnic-specific associations in systemic sclerosis: another dimension of personalized medicine.
J. Rheumatol.
PUBLISHED: 11-16-2009
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To measure self-reported physical and mental functioning and associated clinical features at study entry in 3 ethnic groups with systemic sclerosis (SSc).
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Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.
J. Rheumatol.
PUBLISHED: 11-16-2009
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IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Measures of response in clinical trials of systemic sclerosis: the Combined Response Index for Systemic Sclerosis (CRISS) and Outcome Measures in Pulmonary Arterial Hypertension related to Systemic Sclerosis (EPOSS).
J. Rheumatol.
PUBLISHED: 10-13-2009
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There have been steady efforts to develop a combined response index for systemic sclerosis (CRISS). A parallel and equally successful effort has been made by an Expert Panel on Outcome Measures in PAH related to Systemic Sclerosis (EPOSS) to measure effect in treatment of pulmonary arterial hypertension of systemic sclerosis (PAH-SSc). CRISS conducted a Delphi process combined with expert review to identify 11 candidate domains for inclusion in a core set of outcomes for SSc clinical trials: soluble biomarkers, cardiac, digital ulcers, gastrointestinal, global health, health related quality of life (HRQOL) and function, musculoskeletal, pulmonary, Raynauds, renal, and skin. Tools within domains were also agreed upon. Concentrating on one aspect of disease, PAH, EPOSS also conducted a Delphi process and judged the following domains as the most appropriate for randomized controlled trials in PAH-SSc: lung vascular/pulmonary arterial pressure, cardiac function, exercise testing; severity of dyspnea, discontinuation of treatment; quality of life/activities of daily living; global state; and survival. Possible useful tools within each domain were also agreed on. Patient derived, physician derived, and objective measures of response will be included and combined with the idea that each reflects different aspects of PAH (EPOSS) and overall disease (CRISS) although this assumption may not prove true and can be separated if statistically and clinically valid to do so. In either case, prospective studies will require measurement of all domains, and tools are required and will be developed to define appropriate combined measures of response. CRISS and EPOSS are being developed through the OMERACT process. Through Delphi process and literature review significant progress has been made for both indices, and prospective data are being collected.
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Clinical and genetic factors predictive of mortality in early systemic sclerosis.
Arthritis Rheum.
PUBLISHED: 10-01-2009
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To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort.
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Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-23-2009
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It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients.
J. Rheumatol.
PUBLISHED: 09-01-2009
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To investigate the diagnostic accuracy of antimitochondrial antibodies (AMA), sp100, and gp210 antibodies for primary biliary cirrhosis (PBC) in a large population of patients with systemic sclerosis (SSc); to examine concordance of these antibodies with subsets of SSc. Further, to assess the association of SSc-related antibodies with hepatic parameter abnormalities.
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Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.
Arthritis Rheum.
PUBLISHED: 08-29-2009
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To refine the previously developed scleroderma (systemic sclerosis [SSc]) gastrointestinal tract (GIT) instrument (SSC-GIT 1.0).
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Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls.
Ann. Rheum. Dis.
PUBLISHED: 07-12-2009
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To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study.
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Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.
J. Autoimmun.
PUBLISHED: 07-07-2009
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Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.
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Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations.
Arthritis Res. Ther.
PUBLISHED: 06-08-2009
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Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.
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Lack of evidence for bacterial infections in skin in patients with systemic sclerosis.
Am. J. Med. Sci.
PUBLISHED: 04-30-2009
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In some patients with systemic sclerosis (SSc), persistent bacterial infection involving dermal microvascular endothelial cells may result in endothelial injury, leading to the obliterative microvasculopathy typical of the disease. Alternatively, in some patients with SSc persistent bacterial infection involving activated dermal fibroblasts or other cells found in scleroderma skin might result in the fibrosing features of this disease. In this study, we investigated bacterial infection in skin in patients with SSc.
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