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1.
Lancet Respir Med ; 9(1): 96-106, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33412120

RESUMO

BACKGROUND: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. METHODS: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. FINDINGS: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. INTERPRETATION: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. FUNDING: Boehringer Ingelheim.


Assuntos
Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Escleroderma Sistêmico/complicações , Resultado do Tratamento
2.
Arthritis Rheumatol ; 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33350170

RESUMO

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc) related interstitial lung disease (ILD). We hypothesized that a composite serum Interferon Inducible Serum Protein Score would exhibit predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate versus cyclophosphamide, were examined. Results were validated in an independent observational cohort on active treatment. A composite score of 6 interferon inducible proteins (IP-10, MIG, MCP-2, B2M, TNFR2, and MIP-3 beta) was calculated and its predictive significance for longitudinal forced vital capacity % predicted measurements was examined. RESULTS: Higher baseline Interferon Inducible Protein Score predicted better response over 3 to 12-month visits in the mycophenolate (b=0.41, p=0.001) and cyclophosphamide (b=0.91, p=0.009) arms. In contrast, higher baseline c-reactive protein (CRP) levels predicted worse ILD course in both treatment arms. The predictive significance of Interferon Inducible Protein Score and CRP remained after adjustment for baseline demographic/clinical predictors. During the second-year placebo treatment period of the cyclophosphamide arm, higher Interferon Inducible Protein Score at 12 months showed a trend for predicting worse ILD course (b=-0.61, p=0.068) while it continued predicting better response to active immunosuppression in the mycophenolate arm (b=0.28, p=0.029). The predictive significance of baseline Interferon Inducible Protein Score was replicated in the independent cohort (rs =0.43; p=0.028). CONCLUSIONS: Higher Interferon Inducible Protein Score in SSc-ILD predicts better response to immunosuppression and could be potentially used for identifying patients who may derive the most benefit from these two treatments.

3.
Arthritis Rheumatol ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131208

RESUMO

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulations in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: Baseline serum protein profile of 66 participants with dcSSc enrolled in the Scleroderma: Cyclophosphamide Or Transplant trial and 66 healthy, age- and gender-matched controls was investigated. A panel of 230 proteins, including several cytokines and chemokines was determined. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Mean disease duration was 2.3 years, all had interstitial lung disease (ILD), and none were treated with immunosuppressive agents at baseline visit. Ninety proteins were differentially expressed compared to controls. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion and diapedesis were the top over-represented pathways. Eighteen proteins correlated with modified Rodnan Skin Score (mRSS). Soluble EGFR was significantly down-regulated in dcSSc and showed the strongest negative correlation with mRSS and predicted its course, whereas Alpha 1 Antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with mRSS. Furthermore, higher CA15.3 correlated with more severe ILD, based on lower forced vital capacity and higher high-resolution CT scores. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSIONS: dcSSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.

4.
Arthritis Rheumatol ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33142016

RESUMO

OBJECTIVE: In the SENSCIS trial in subjects with systemic sclerosis-associated ILD (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. We investigated the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. METHODS: In post-hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC ≥5% predicted or death and absolute decline in FVC ≥10% predicted or death. RESULTS: A total of 288 subjects received nintedanib and 288 received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had an FVC decline >5%-≤10% predicted, and 3.5% and 5.2% had an FVC decline >10%-≤15% predicted; 34.5% and 43.8% had a decrease in FVC ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio for an absolute decline in FVC ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% CI: 0.66, 1.06) (P=0.14) and the hazard ratio for an absolute decline in FVC ≥10% predicted was 0.64 (95% CI: 0.43, 0.95); P=0.029. CONCLUSION: These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.

5.
Ann Rheum Dis ; 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004331

RESUMO

OBJECTIVES: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time. METHODS: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model. RESULTS: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693. CONCLUSIONS: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc.

6.
J Invest Dermatol ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069728

RESUMO

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 × 10-12) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 × 10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 × 10-8) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

7.
Ann Rheum Dis ; 79(12): 1608-1615, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32933919

RESUMO

OBJECTIVE: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. METHODS: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). RESULTS: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. CONCLUSIONS: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.

8.
ACR Open Rheumatol ; 2(8): 496-502, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32720753

RESUMO

OBJECTIVE: The modified Rodnan skin score (mRSS) is often used as a primary outcome measure in systemic sclerosis (SSc) randomized clinical trials (RCTs). Previous cohort studies with predominantly European Caucasian patients showed that setting an upper limit of mRSS as a selection criterion for RCTs leads effectively to enrichment with progressive patients. This study aimed to demonstrate this effect in an ethnically diverse cohort, rich in patients positive for anti-RNA polymerase III antibodies (Pol3). METHODS: We selected from the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) cohort patients with diffuse cutaneous SSc (dcSSc), who had mRSS of 7 or more at inclusion and a documented mRSS after 12 ± 2 months. Progression of skin fibrosis was defined as an increase in mRSS greater than 5 points and 25% or more from baseline. To identify the optimal cutoff for the baseline mRSS yielding the highest sensitivity for progressive skin fibrosis, we developed ROC curves and logistic regression models with "progression" as the outcome variable and a binary variable of baseline mRSS cutoff point as predictor. RESULTS: We included 152 patients (age and disease duration [mean ± SD, years]: 48.7 ± 13.0 and 2.4 ± 1.5 respectively, 22.4% males, 34.2% Pol3-positive). Seventeen patients (11.2%) had skin fibrosis progression after 12 ± 2 months. An mRSS cutoff of 27 or less had the highest probability of progression (odds ratio, 9.12; 95% confidence interval: 1.173-70.851; P = 0.035; area under the curve, 0.652; sensitivity, 94%). CONCLUSION: We demonstrated in an ethnically diverse cohort of patients with early dcSSc and with a high proportion of patients who are Pol3-positive that setting an upper limit of the mRSS as a selection criterion leads effectively to cohort enrichment with progressors.

9.
JMIR Res Protoc ; 9(4): e16799, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32329747

RESUMO

BACKGROUND: Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc. OBJECTIVE: The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program. METHODS: The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program. RESULTS: Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020. CONCLUSIONS: The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16799.

10.
J Rheumatol ; 47(11): 1668-1677, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32173657

RESUMO

OBJECTIVE: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC. METHODS: ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. RESULTS: Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10-5), CTNND2 (rs1859082; P = 5.58 × 10-5), HECW2 (rs16849716; P = 1.2 × 10-4), and GPATCH2L (rs935332; P = 4.92 × 10-5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP. CONCLUSION: Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.

11.
Sci Rep ; 10(1): 1862, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024964

RESUMO

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn's disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.


Assuntos
Doença de Crohn/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Arthritis Rheumatol ; 72(1): 125-136, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31342624

RESUMO

OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.


Assuntos
Abatacepte/uso terapêutico , Esclerodermia Difusa/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Esclerodermia Difusa/genética , Esclerodermia Difusa/fisiopatologia , Análise de Sequência de RNA , Índice de Gravidade de Doença , Pele/metabolismo , Resultado do Tratamento , Escala Visual Analógica , Capacidade Vital
13.
J Exp Med ; 217(2)2020 02 03.
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.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Regulação para Baixo/genética , Poliadenilação/genética , Escleroderma Sistêmico/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Bleomicina/farmacologia , Células Cultivadas , Fator de Especificidade de Clivagem e Poliadenilação/genética , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibrose , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia , Pele/patologia , Transfecção
14.
Ann Rheum Dis ; 79(3): 379-386, 2020 03.
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.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Esclerodermia Difusa/genética , Esclerodermia Difusa/imunologia , Adulto , Biomarcadores/análise , Biópsia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Sistema de Registros , Análise de Regressão , Esclerodermia Difusa/patologia , Análise de Sequência de RNA , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Transcriptoma
15.
Proc Natl Acad Sci U S A ; 117(1): 552-562, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871193

RESUMO

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/genética , Antígenos HLA/genética , Mimetismo Molecular/imunologia , Escleroderma Sistêmico/genética , Afro-Americanos/genética , Alelos , Sequência de Aminoácidos/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Autoantígenos/imunologia , Biologia Computacional , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Antígenos HLA/imunologia , Humanos , Masculino , Mimiviridae/imunologia , Phycodnaviridae/imunologia , Estrutura Secundária de Proteína/genética , Medição de Risco , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Homologia de Sequência de Aminoácidos
16.
Nat Commun ; 10(1): 4955, 2019 10 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.


Assuntos
Fibrose/genética , Escleroderma Sistêmico/genética , Doenças Vasculares/genética , Teorema de Bayes , Imunoprecipitação da Cromatina , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
17.
Ann Rheum Dis ; 78(10): 1371-1378, 2019 10.
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.


Assuntos
Interferons/sangue , Neutrófilos/metabolismo , Escleroderma Sistêmico/genética , Transcriptoma , Condicionamento Pré-Transplante/métodos , Adulto , Ciclofosfamida/uso terapêutico , Regulação para Baixo , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multinível , Agonistas Mieloablativos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/terapia , Transplante Autólogo , Resultado do Tratamento , Regulação para Cima
18.
Ann Rheum Dis ; 78(11): 1583-1591, 2019 11.
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.


Assuntos
Inflamação/genética , Fator Regulador 7 de Interferon/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/patologia , Animais , Bleomicina , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Humanos , Camundongos , Camundongos Knockout , Escleroderma Sistêmico/induzido quimicamente , Transdução de Sinais/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
20.
Hum Mol Genet ; 28(20): 3498-3513, 2019 10 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.


Assuntos
Predisposição Genética para Doença/genética , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/genética , Esquizofrenia/etiologia , Esquizofrenia/genética , Estudo de Associação Genômica Ampla , Humanos , Doenças do Sistema Imunitário/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/epidemiologia
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