Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Arthritis Rheumatol ; 72(1): 125-136, 2020 Jan.
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.

2.
Arthritis Res Ther ; 21(1): 49, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728065

RESUMO

BACKGROUND: Infectious agents have long been postulated to be disease triggers for systemic sclerosis (SSc), but a definitive link has not been found. Metagenomic analyses of high-throughput data allows for the unbiased identification of potential microbiome pathogens in skin biopsies of SSc patients and allows insight into the relationship with host gene expression. METHODS: We examined skin biopsies from a diverse cohort of 23 SSc patients (including lesional forearm and non-lesional back samples) by RNA-seq. Metagenomic filtering and annotation was performed using the Integrated Metagenomic Sequencing Analysis (IMSA). Associations between microbiome composition and gene expression were analyzed using single-sample gene set enrichment analysis (ssGSEA). RESULTS: We find the skin of SSc patients exhibits substantial changes in microbial composition relative to controls, characterized by sharp decreases in lipophilic taxa, such as Propionibacterium, combined with increases in a wide range of gram-negative taxa, including Burkholderia, Citrobacter, and Vibrio. CONCLUSIONS: Microbiome dysbiosis is associated with disease duration and increased inflammatory gene expression. These data provide a comprehensive portrait of the SSc skin microbiome and its association with local gene expression, which mirrors the molecular changes in lesional skin.

3.
Clin Exp Rheumatol ; 36 Suppl 113(4): 146-149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30277862

RESUMO

OBJECTIVES: This clinical trial was designed to study the safety and efficacy of blocking IL-1 in skin fibrosis of patients with diffuse cutaneous systemic sclerosis (dcSSc), and to test the hypothesis that inhibition of IL-1 by rilonacept will downregulate expression of the 2G SSc gene biomarker as a surrogate for the modified Rodnan skin score (MRSS). METHODS: 19 dcSSc patients were randomised 2:1 active treatment:placebo in this double blinded trial. Study patients received weekly treatments with either subcutaneous rilanocept 320 mg loading dose at day 0 and then 160 mg for each of the 5 subsequent weekly doses, or placebo. Skin biopsies were taken to test 2G SSc biomarker gene expression at day 0 before treatment and one week after the final study drug dose, comparing gene expression changes between rilonacept- and placebo-treated patients, as well as the change in gene expression at week 6 compared to baseline in rilonacept-treated patients. Safety assessments extended to 6 weeks after the final dose of study drug or placebo. Other secondary outcome measures included global and IL-1-regulated gene expression, serum biomarkers and the MRSS. RESULTS: Rilonacept compared to placebo-treated patients did not show any treatment-related effect on the 2G SSc biomarker. Rilonacept treatment also failed to alter IL-6 expression in skin, serum IL-6, C-reactive protein, or CCL18, a marker of IL-6 activity in SSc. CONCLUSIONS: In this small trial we did not observe any effect of blocking IL-1 on clinical skin disease or biomarkers of IL-1 activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Esclerodermia Difusa/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Adulto , Animais , Anti-Inflamatórios/efeitos adversos , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Esclerodermia Difusa/sangue , Esclerodermia Difusa/genética , Esclerodermia Difusa/imunologia , Dermatopatias/diagnóstico , Dermatopatias/imunologia , Dermatopatias/metabolismo , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
4.
Arthritis Res Ther ; 20(1): 185, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115106

RESUMO

BACKGROUND: Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in SSc. Identification of a serum-based proteomic diagnostic biomarker for SSc-PAH would allow for rapid non-invasive screening and could positively impact patient survival. Identification and validation of novel proteins could potentially facilitate the identification of SSc-PAH, and might also point to important protein mediators in pathogenesis. METHODS: Thirteen treatment-naïve SSc-PAH patients had serum collected at time of diagnosis and were used as the discovery cohort for the protein-expression biomarker. Two proteins, Midkine and Follistatin-like 3 (FSTL3) were then validated by enzyme-linked immunosorbent assays. Midkine and FSTL3 were tested in combination to identify SSc-PAH and were validated in two independent cohorts of SSc-PAH (n = 23, n = 11). RESULTS: Eighty-two proteins were found to be differentially regulated in SSc-PAH sera. Two proteins (Midkine and FSTL3) were also shown to be elevated in publicly available data and their expression was evaluated in independent cohorts. In the validation cohorts, the combination of Midkine and FSTL3 had an area under the receiver operating characteristic curve (AUC) of 0.85 and 0.92 with respective corresponding measures of sensitivity of 76% and 91%, and specificity measures of 76% and 80%. CONCLUSIONS: These findings indicate that there is a clear delineation between overall protein expression in sera from SSc patients and those with SSc-PAH. The combination of Midkine and FSTL3 can serve as an SSc-PAH biomarker and are potential drug targets for this rare disease population.


Assuntos
Biomarcadores/sangue , Proteínas Relacionadas à Folistatina/sangue , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Midkina/sangue , Escleroderma Sistêmico/complicações , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Precoce , Feminino , Humanos , Hipertensão Pulmonar/sangue , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Sensibilidade e Especificidade
5.
PLoS One ; 13(1): e0189498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293537

RESUMO

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Humanos , Polimorfismo de Nucleotídeo Único
6.
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 , 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
7.
J Invest Dermatol ; 138(4): 826-835, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29179949

RESUMO

Systemic sclerosis is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. We studied differentially expressed coding and non-coding genes in relation to systemic sclerosis pathogenesis with a specific focus on antisense non-coding RNAs. Skin biopsy-derived RNAs from 14 early systemic sclerosis patients and six healthy individuals were sequenced with ion-torrent and analyzed using DEseq2. Overall, 4,901 genes with a fold change >1.5 and a false discovery rate <5% were detected in patients versus controls. Upregulated genes clustered in immunologic, cell adhesion, and keratin-related processes. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. Sense genes expressed opposite of these antisense genes were also deregulated in 42% of the observed sense-antisense gene pairs. The majority of the antisense genes had a similar effect sizes in an independent North American dataset with three genes (CTBP1-AS2, OTUD6B-AS1, and AGAP2-AS1) exceeding the study-wide Bonferroni-corrected P-value (PBonf < 0.0023, Pcombined = 1.1 × 10-9, 1.4 × 10-8, 1.7 × 10-6, respectively). In this study, we highlight that together with coding genes, (antisense) long non-coding RNAs are deregulated in skin tissue of systemic sclerosis patients suggesting a novel class of genes involved in pathogenesis of systemic sclerosis.


Assuntos
RNA Longo não Codificante/genética , Escleroderma Sistêmico/genética , Pele/metabolismo , Regulação para Cima , Células Cultivadas , Humanos , RNA Longo não Codificante/biossíntese , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/patologia , Fatores de Transcrição , Ativação Transcricional
8.
Arthritis Rheumatol ; 70(4): 566-577, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29245183

RESUMO

OBJECTIVE: Immune dysfunction is an important component of the disease process underlying systemic sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. This study was undertaken to measure the expression and function of the coinhibitory receptors (co-IRs) programmed cell death 1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) in lymphocyte subsets from the peripheral blood of patients with SSc. METHODS: Co-IR expression levels on subsets of immune cells were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of SSc and healthy control peripheral blood mononuclear cells (PBMCs) in the presence of co-IR-blocking antibodies. Supernatants from cultures of stimulated PBMCs were added to SSc fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls. RESULTS: Levels of the co-IRs PD-1 and TIGIT were increased, and each was coexpressed, in distinct T cell subsets from SSc patients compared to healthy controls. Levels of TIM-3 were increased in SSc natural killer cells. PD-1, TIGIT, and TIM-3 antibody blockade revealed patient-specific roles of each of these co-IRs in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT and TIM-3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating that enhanced T cell exhaustion is present in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed the gene expression profile in SSc fibroblasts. CONCLUSION: The altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated cross-talk of immune cells and fibroblasts at sites of inflammation and/or fibrosis.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/sangue , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Receptores Imunológicos/sangue , Escleroderma Sistêmico/sangue , Adulto , Idoso , Anticorpos Bloqueadores/metabolismo , Feminino , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/imunologia , Escleroderma Sistêmico/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
J Invest Dermatol ; 137(12): 2473-2483, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28807667

RESUMO

Several studies have suggested that Wnts might contribute to skin fibrosis in systemic sclerosis (SSc) by affecting the differentiation of pluripotent dermal cells. We tested C-82, a therapeutic that inhibits canonical Wnt signaling by blocking the interaction of the protein CBP with ß-Catenin and inhibiting Wnt-activated genes. We used a trial design formulating C-82 for topical application and conducting a placebo-controlled, double-blinded clinical trial in which patients with diffuse cutaneous SSc were treated with C-82 or placebo on opposite forearms. C-82- compared with placebo-treated forearms did not show any clinical effect. Skin biopsies performed before and after treatment showed a very weak trend toward improvement in the C-82-treated skin of biomarkers of local skin disease, THBS1 and COMP. However, on microarray analysis C-82 treatment strongly up-regulated two clusters of genes that correlate negatively with the severity of SSc skin disease. These clusters are highly associated with metabolism and one gene, PLIN2, expressed only by sebocytes and subcutaneous fat cells. These changes in gene expression strongly support a role for Wnts in differentiation of pluripotent cells into profibrotic fibroblasts and the potential for C-82 with longer treatment to promote fat regeneration in SSc skin.


Assuntos
Adipogenia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Piperazinas/farmacologia , Esclerodermia Difusa/tratamento farmacológico , Pele/metabolismo , beta Catenina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Diferenciação Celular , Análise por Conglomerados , Método Duplo-Cego , Epiderme/metabolismo , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Esclerodermia Difusa/metabolismo , Pele/efeitos dos fármacos , Fatores de Tempo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/antagonistas & inibidores
10.
Ann Rheum Dis ; 76(8): 1374-1380, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28213563

RESUMO

OBJECTIVES: We developed a patient-reported outcome (PRO) instrument to assess the skin-related quality of life in patients with systemic sclerosis (SSc). METHODS: Participants with SSc provided input on skin-related health effects through focus groups. We developed items for scleroderma skin PRO (SSPRO) to encompass these effects. Further consideration from cognitive interviews and an expert panel led to reduction and modification of items. A 22-item SSPRO was field tested. Psychometric analysis included test-retest reliability, internal consistency and exploratory factor analysis (EFA). Construct validity was assessed through correlation with other participant and physician-assessed measures. RESULTS: 140 participants completed the SSPRO: mean age was 53.4 years, median disease duration was 5 years, 82.1% were female and 32.9% had diffuse cutaneous SSc. EFA supported four factors in SSPRO corresponding to hypothesised constructs: physical effects, physical limitations, emotional effects and social effects. Removal of 4/22 items resulted in acceptable goodness-of-fit statistics. Test-retest reliability (intraclass correlation coefficient=0.61-0.83) was moderate to high and internal consistency (Cronbach's α=0.89-0.96) was high. SSPRO correlated strongly with other participant-reported measures (r=0.59-0.88) suggesting construct validity, and less well with physician-assessed measures (r=0.31-0.40). SSPRO scores were significantly different for each level of participant-reported skin severity, and for limited versus diffuse cutaneous SSc. CONCLUSIONS: SSPRO has been developed with extensive patient input and demonstrates evidence for reliability and validity. It is complementary to existing measures of SSc skin involvement with emphasis on the patient's experience. Further research is needed to assess its sensitivity to change.


Assuntos
Medidas de Resultados Relatados pelo Paciente , Escleroderma Sistêmico/fisiopatologia , Dermatopatias/fisiopatologia , Adulto , Idoso , Análise Fatorial , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Pesquisa Qualitativa , Qualidade de Vida , Reprodutibilidade dos Testes , Escleroderma Sistêmico/complicações , Índice de Gravidade de Doença , Dermatopatias/etiologia , Inquéritos e Questionários
11.
J Invest Dermatol ; 137(1): 62-70, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27640094

RESUMO

In this study we systematically investigated alterations in the serum proteome of patients with diffuse cutaneous systemic sclerosis and identified differentially expressed proteins that correlated with disease severity. Our goal was to identify a combination of serum proteins that would provide a biological measure for the extent of skin disease and that could be combined into a longitudinal pharmacodynamic biomarker. We found that 16% of the sera proteins analyzed by SOMAscan aptamer technology, from two cohorts of patients with diffuse cutaneous systemic sclerosis, were identified as differentially regulated between diffuse cutaneous systemic sclerosis and controls and correlated with modified Rodnan skin score. This dataset showed tumor necrosis factor-α, IFN-γ, transforming growth factor-ß, and IL-13 as potential upstream regulators of the serum protein patterns in the sera of patients with diffuse cutaneous systemic sclerosis. By ELISA, two analytes (ST2 and Spondin-1) best described longitudinal change in modified Rodnan skin score, using linear mixed models. This model was then validated in three independent cohorts. In this study we discovered a large array of proteins not previously associated with systemic sclerosis that provide insight into pathogenesis and potential targets for therapeutic intervention. Furthermore, we show that two of these proteins can be combined to form a robust longitudinal biomarker that might be used in clinical trials to assess changes in diffuse cutaneous systemic sclerosis skin disease over time.


Assuntos
Citocinas/metabolismo , Proteoma/metabolismo , Esclerodermia Difusa/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Reprodutibilidade dos Testes , Esclerodermia Difusa/tratamento farmacológico , Esclerodermia Difusa/fisiopatologia , Índice de Gravidade de Doença
12.
Arthritis Res Ther ; 18(1): 155, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27377409

RESUMO

BACKGROUND: MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used. METHODS: RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. RESULTS: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. CONCLUSIONS: miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD.


Assuntos
Doenças Pulmonares Intersticiais/etiologia , MicroRNAs/metabolismo , Fibrose Pulmonar/etiologia , Escleroderma Sistêmico/complicações , Animais , Modelos Animais de Doenças , Progressão da Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Reação em Cadeia da Polimerase em Tempo Real
13.
Rheumatology (Oxford) ; 55(5): 911-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26880832

RESUMO

OBJECTIVE: To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. METHODS: SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. RESULTS: Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. CONCLUSION: Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease.


Assuntos
Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Adulto , Idoso , Biópsia , Movimento Celular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miofibroblastos/patologia , Qualidade de Vida , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/patologia , Esclerodermia Difusa/reabilitação , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/patologia , Esclerodermia Localizada/reabilitação , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/reabilitação , Pele/patologia , Inquéritos e Questionários
14.
Arthritis Res Ther ; 18: 20, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26792595

RESUMO

BACKGROUND: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc. METHODS: A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc. RESULTS: We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (ß = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (ß = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (ß = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort. CONCLUSIONS: Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Pneumonias Intersticiais Idiopáticas/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Escleroderma Sistêmico/diagnóstico
15.
Arthritis Care Res (Hoboken) ; 68(2): 167-78, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26806474

RESUMO

OBJECTIVE: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). METHODS: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. RESULTS: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02). CONCLUSION: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.


Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto , Reumatologia/métodos , Esclerodermia Difusa , Índice de Gravidade de Doença , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria
16.
Arthritis Rheumatol ; 68(2): 299-311, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26808827

RESUMO

OBJECTIVE: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). METHODS: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. RESULTS: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02). CONCLUSION: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.


Assuntos
Antirreumáticos/uso terapêutico , Metotrexato/uso terapêutico , Esclerodermia Difusa/tratamento farmacológico , Adulto , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Reumatologia , Sociedades Médicas
17.
Arthritis Rheumatol ; 67(11): 3004-15, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26240058

RESUMO

OBJECTIVE: To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally. METHODS: Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes. RESULTS: Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic/transforming growth factor ß-regulated, interferon-regulated/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross-sectional THBS1 and longitudinal THBS1 and MS4A4A. The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: CTGF, CD163, CCL2, and WIF1. In an independent validation data set, biomarker levels calculated using both models correlated highly with the MRSS. CONCLUSION: Skin gene expression can be used effectively to monitor changes in SSc skin disease over time. We implemented 2 relatively simple models on a NanoString platform permitting highly reproducible assays that can be applied directly to samples from patients or collected as part of clinical trials.


Assuntos
Esclerodermia Difusa/patologia , Pele/patologia , Trombospondina 1 , Antígenos/genética , Biomarcadores , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteínas do Citoesqueleto/genética , Expressão Gênica , Humanos , Modelos Teóricos , Esclerodermia Difusa/genética , Índice de Gravidade de Doença , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Trombospondina 1/genética
18.
J Clin Invest ; 125(7): 2795-807, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26098215

RESUMO

BACKGROUND: TGF-ß has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-ß-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-ß may benefit these patients. METHODS: Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-ß isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-ß-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS: In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-ß-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION: The rapid inhibition of TGF-ß-regulated gene expression in response to fresolimumab strongly implicates TGF-ß in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01284322.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Escleroderma Sistêmico/terapia , Adulto , Anticorpos Monoclonais Humanizados , Proteína de Matriz Oligomérica de Cartilagem/genética , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Miofibroblastos/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Trombospondina 1/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Resultado do Tratamento
19.
Rheumatology (Oxford) ; 54(8): 1464-71, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25784774

RESUMO

OBJECTIVE: An accelerated rate of decline in forced vital capacity (FVC) affects >50% of patients with SSc but data on the variability and determinants of this change are scarce. We sought to identify trajectories of FVC and their associated variables in SSc patients over a 12-year period. METHODS: Clinical and pulmonary function data were retrospectively collected. SSc patients with three or more FVC values were included. Group-based modelling was used to cluster similar FVC patterns into trajectories. Baseline variables were associated with the trajectories using multinomial logistic regression. The effect of CYC on FVC was examined with each trajectory as a time-varying covariate. RESULTS: In 254 SSc patients we identified seven distinct FVC trajectories: very low slow decline (5.5%), very low improve (13.8%), low fast decline (9.5%), low stable (19.7%), low-normal improve (31.1%), normal improve (16.1%) and normal stable (4.3%). Younger age and the presence of pulmonary hypertension, Interstitial lung disease and shortness of breath at baseline significantly increased the odds of declining trajectories vs the reference trajectory (low-normal improve). CYC was associated with FVC improvement in the low fast decline trajectory. CONCLUSION: The course of FVC in SSc was highly variable, with improvement and stability experienced even by those with low baseline FVC. Trajectory modelling was able to identify SSc patients who were most likely to experience FVC decline and thus could be a useful tool for patient management as well as clinical trial design.


Assuntos
Progressão da Doença , Pulmão/fisiopatologia , Modelos Biológicos , Escleroderma Sistêmico/fisiopatologia , Capacidade Vital/fisiologia , Adulto , Estudos de Coortes , Gerenciamento Clínico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
20.
Semin Arthritis Rheum ; 44(6): 680-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25578738

RESUMO

OBJECTIVE: To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS: SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS: This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS: In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.


Assuntos
Anticorpos Antinucleares/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Nefropatias/etiologia , Pulmão/fisiopatologia , Síndromes de Malabsorção/etiologia , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar , Fibrose Pulmonar/etiologia , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Fatores Sexuais , Úlcera Cutânea/etiologia , Telangiectasia/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA