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1.
J Exp Med ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757866

RESUMO

Systemic sclerosis (SSc; scleroderma) is a multisystem fibrotic disease. The mammalian cleavage factor I 25-kD subunit (CFIm25; encoded by NUDT21) is a key regulator of alternative polyadenylation, and its depletion causes predominantly 3'UTR shortening through loss of stimulation of distal polyadenylation sites. A shortened 3'UTR will often lack microRNA target sites, resulting in increased mRNA translation due to evasion of microRNA-mediated repression. Herein, we report that CFlm25 is downregulated in SSc skin, primary dermal fibroblasts, and two murine models of dermal fibrosis. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3'UTR shortening of key TGFß-regulated fibrotic genes and enhance their protein expression. Moreover, several of these fibrotic transcripts show 3'UTR shortening in SSc skin. Finally, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Overall, our data link this novel RNA-processing mechanism to dermal fibrosis and SSc pathogenesis.

2.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

3.
Ann Rheum Dis ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767698

RESUMO

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

4.
Ann Rheum Dis ; 78(10): 1371-1378, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31391177

RESUMO

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.

5.
Ann Rheum Dis ; 78(11): 1583-1591, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31439591

RESUMO

OBJECTIVES: There is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis. METHODS: SSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed. RESULTS: IRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-ß signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression. CONCLUSIONS: IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-ß-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

6.
Arthritis Rheumatol ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342624

RESUMO

OBJECTIVES: T cells play a key role in the pathogenesis of early systemic sclerosis. This study assessed the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A 12-month, randomized, double-blind, placebo-controlled trial with participants randomized in a 1:1 ratio to either abatacept 125 mg subcutaneous or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at six months for worsening disease. The co-primary end points were change in modified Rodnan skin score (mRSS) and safety over 12 months. Treatment differences in longitudinal outcomes were assessed using linear mixed models, with outcomes censored after initiation of escape therapy. Baseline skin tissue was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in mRSS at 12 months was -6.24 units in the abatacept and -4.49 units in the placebo, with adjusted mean treatment difference of -1.75 units (p=0.28). Two secondary outcome measures (HAQ-DI and a composite measure) were clinically and statistically significant favoring abatacept. A larger proportion of placebo subjects required escape therapy relative to abatacept (36% vs. 16%). Decline in mRSS over 12 months was clinically and significantly higher in abatacept vs. placebo for the Inflammatory (p<0.001) and Normal-like skin gene expression subsets (p=0.03). 35 participants in the abatacept versus 40 in the placebo had adverse events (AEs), including two and one deaths, respectively. CONCLUSIONS: In this Phase 2 trial, abatacept was well tolerated, but change in mRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed some evidence in favor of abatacept. These data should be confirmed in a Phase 3 trial. This article is protected by copyright. All rights reserved.

7.
Hum Mol Genet ; 28(20): 3498-3513, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211845

RESUMO

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn's disease via altered methylation and expression of EPHB4-a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10-4), Crohn's disease (rg = 0.097 ± 0.06, P = 3.27 × 10-3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10-3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10-3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10-3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10-3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

9.
N Engl J Med ; 380(26): 2518-2528, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31112379

RESUMO

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).


Assuntos
Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Escleroderma Sistêmico/complicações , Administração Oral , Adulto , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Capacidade Vital
10.
J Rheumatol ; 46(12): 1597-1604, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30709959

RESUMO

OBJECTIVE: To identify baseline features that predict progression of hand contractures and to assess the effect of contractures on functional status in the prospective GENISOS cohort. METHODS: Rate of decline in hand extension, as an indicator of hand contracture, was the primary outcome. We assessed longitudinal hand extension measurements, modified Health Assessment Questionnaire (MHAQ) score, Medical Outcomes Study Short Form-36 (SF-36) physical function score, and demographic, clinical, and serological variables. Subjects with ≥ 2 hand measurements at least 6 months apart were included. RESULTS: A total of 1087 hand measurements for 219 patients were available over an average of 8.1 ± 4.8 years. Hand extension decreased on average by 0.11 cm/year. Antitopoisomerase I antibody (ATA) positivity and higher modified Rodnan Skin Score (mRSS) were predictive of faster decline in hand extension (p = 0.009 and p = 0.046, respectively). In a subgroup analysis of 62 patients with ≤ 2 years from SSc onset, ATA and diffuse disease type were associated with faster decline in hand extension; anticentromere positivity was associated with slower rate of decline. Although the rate of decline in patients with disease duration ≤ 2 years was numerically higher, the difference was not statistically significant. Hand extension continued to decline in a linear fashion over time and was inversely related to overall functional status. CONCLUSION: ATA was predictive of contracture development in both early disease (≤ 2 yrs) and in the overall cohort. Hand extension declined linearly over time and was inversely associated with MHAQ and SF-36 scores. ATA positivity and higher baseline mRSS were predictive of faster decline in hand extension.

11.
Ann Rheum Dis ; 78(3): 311-319, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30573655

RESUMO

OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.


Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Miosite/genética , Locos de Características Quantitativas/genética , Doenças Reumáticas/genética , Escleroderma Sistêmico/genética , Adulto , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Quinases Lim/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/imunologia , Miosite/imunologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/imunologia , Proteínas Repressoras/imunologia , Doenças Reumáticas/imunologia , Escleroderma Sistêmico/imunologia , alfa Carioferinas/imunologia
12.
Genome Med ; 10(1): 97, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572963

RESUMO

BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. RESULTS: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. CONCLUSIONS: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/genética , Doença Celíaca/genética , Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Escleroderma Sistêmico/genética
13.
J Rheumatol ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442821

RESUMO

OBJECTIVE: Findings from previous genome-wide association studies indicated an association of the NOTCH4 gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of NOTCH4 in SSc. METHODS: All exons of NOTCH4 were sequenced and analyzed in a total of 1006 patients with SSc and 1004 controls of US white ancestry with the Ion Torrent system. Identified SSc-associated variants were confirmed with Sanger sequencing, and then examined in a Chinese Han cohort consisting of 576 patients with SSc and 574 controls. The NOTCH4 variants were analyzed for association with SSc as a whole and with SSc clinical and autoantibody subtypes with and without the influence of specific HLA-class II alleles that had been previously identified as major genetic factors in SSc. RESULTS: A total of 12 SSc-associated and SSc subtype-associated exonic variants of NOTCH4 were identified in the US cohort. Three of them are nonsynonymous single-nucleotide polymorphisms and 1 is a CTG tandem repeat that encodes for a poly-leucine, all of which are located in the NOTCH4 extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA-class II alleles indicated an independent association of the NOTCH4 variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of NOTCH4 to SSc and its subtypes. CONCLUSION: Multiple NOTCH4 exonic variants were associated with SSc and/or SSc subtypes. Several of these variants encode nonsynonymous sequence changes occurring in the NECD, which implicates a potentially functional effect of NOTCH4.

14.
J Rheumatol ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275260

RESUMO

OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc). METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration. RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations. CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

15.
J Rheumatol ; 45(8): 1153-1158, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29961690

RESUMO

OBJECTIVE: The 2 pneumoproteins, KL-6 and CCL-18, are promising biomarkers in systemic sclerosis (SSc)-related interstitial lung disease (ILD). Our goal was to determine their predictive significance for forced vital capacity % (FVC%) decline within the first year of followup in patients with early SSc-ILD. METHODS: Early SSc patients with imaging-verified ILD enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort were included. Annualized rate of change in FVC% based on the baseline and followup measurement within 12-18 months was used as the surrogate outcomes for ILD progression. RESULTS: Eighty-two early SSc-ILD patients with mean disease duration of 2.3 years were investigated. FVC% change ranged from -23% to 38%. Baseline KL-6 levels were higher in patients than healthy controls (p < 0.0001). Higher KL-6 levels were predictive of faster FVC% decline at the 1-year followup (r = -0.23, p = 0.037). Upon categorizing KL-6 using a previously published cutoff of 1273 U/ml, its predictive significance remained in the univariable model (b = -0.07, p = 0.01), indicating that patients with positive KL-6 had on average 7% more decline in annualized percent change of FVC%. Moreover, KL-6 remained an independent predictor after adjustment for sex, disease type, anti-Scl-70, and immunosuppressive treatment status in multivariable models. Although CCL-18 was higher in patients than controls (p < 0.001), its levels did not predict FVC decline rate (p = 0.458). CONCLUSION: KL-6 but not CCL-18 is predictive of early SSc-ILD progression. KL-6 is a promising pneumoprotein that can contribute to SSc-ILD clinical trial enrichment.

16.
Rheumatology (Oxford) ; 57(9): 1623-1631, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868924

RESUMO

Objectives: The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts. Methods: Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts. Results: Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN. Conclusion: Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.


Assuntos
Medidas de Resultados Relatados pelo Paciente , Satisfação do Paciente , Assistência Centrada no Paciente , Escleroderma Sistêmico/epidemiologia , Canadá/epidemiologia , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , Índice de Gravidade de Doença , Inquéritos e Questionários , Estados Unidos/epidemiologia
17.
Arthritis Rheumatol ; 70(10): 1654-1660, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29732714

RESUMO

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

18.
BMJ Open ; 8(3): e018641, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29511009

RESUMO

OBJECTIVE: Valid measures of appearance concern are needed in systemic sclerosis (SSc), a rare, disfiguring autoimmune disease. The Derriford Appearance Scale-24 (DAS-24) assesses appearance-related distress related to visible differences. There is uncertainty regarding its factor structure, possibly due to its scoring method. DESIGN: Cross-sectional survey. SETTING: Participants with SSc were recruited from 27 centres in Canada, the USA and the UK. Participants who self-identified as having visible differences were recruited from community and clinical settings in the UK. PARTICIPANTS: Two samples were analysed (n=950 participants with SSc; n=1265 participants with visible differences). PRIMARY AND SECONDARY OUTCOME MEASURES: The DAS-24 factor structure was evaluated using two scoring methods. Convergent validity was evaluated with measures of social interaction anxiety, depression, fear of negative evaluation, social discomfort and dissatisfaction with appearance. RESULTS: When items marked by respondents as 'not applicable' were scored as 0, per standard DAS-24 scoring, a one-factor model fit poorly; when treated as missing data, the one-factor model fit well. Convergent validity analyses revealed strong correlations that were similar across scoring methods. CONCLUSIONS: Treating 'not applicable' responses as missing improved the measurement model, but did not substantively influence practical inferences that can be drawn from DAS-24 scores. Indications of item redundancy and poorly performing items suggest that the DAS-24 could be improved and potentially shortened.


Assuntos
Imagem Corporal , Aparência Física , Projetos de Pesquisa/normas , Escleroderma Sistêmico/psicologia , Estresse Psicológico/etiologia , Inquéritos e Questionários/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Reino Unido , Estados Unidos , Adulto Jovem
19.
Arthritis Care Res (Hoboken) ; 70(11): 1646-1652, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29409146

RESUMO

OBJECTIVE: Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently 3 versions of the BFNE with strong demonstrated measurement properties: two 8-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients. METHODS: Participants were 1,010 patients with SSc enrolled in the Scleroderma Patient-Centered Intervention Network cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson's product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively. RESULTS: Confirmatory factor analysis demonstrated that 1-factor models fit acceptably well for the 12-item BFNE-II, the 8-item BFNE-S, and the 8-item BFNE-8. Additionally, all Cronbach's alphas demonstrated excellent internal consistency reliability (BFNE-II = 0.98, BFNE-S = 0.97, BFNE-8 = 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education. CONCLUSION: Psychometric support was found for all 3 versions of the BFNE, although the longer 12-item BFNE-II did not improve measurement compared to the shorter 8-item versions (BFNE-S and BFNE-8). Of these 2, the BFNE-S has been more widely studied, with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc.

20.
N Engl J Med ; 378(1): 35-47, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29298160

RESUMO

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).


Assuntos
Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/terapia , Adolescente , Adulto , Idoso , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressores/efeitos adversos , Infecção/etiologia , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/mortalidade , Condicionamento Pré-Transplante , Transplante Autólogo , Adulto Jovem
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