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1.
Rheumatology (Oxford) ; 60(9): 3986-4000, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34117886

RESUMO

Adult-onset Still's disease (AOSD) is a rare, but characteristic non-familial, multi-genic systemic auto-inflammatory disorder, characterized by high spiking fever, salmon-like evanescent skin rash, polyarthritis, sore throat, hyperferritinemia and leucocytosis. The hallmark of AOSD is a cytokine storm triggered by dysregulation of inflammation. Nowadays, with advances in anti-cytokine biologic agents, the treatment of AOSD is no longer limited to NSAIDs, glucocorticoids or conventional synthetic DMARDs. In this review, we focussed on the roles of these cytokines in the pathogenesis of AOSD and summarized the current and emerging biological therapy.


Assuntos
Terapia Biológica/métodos , Doença de Still de Início Tardio/terapia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Humanos , Doença de Still de Início Tardio/imunologia
2.
Rheumatology (Oxford) ; 60(10): 4520-4529, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33493278

RESUMO

OBJECTIVES: To describe the detailed characteristics and explore the potential risk factors of relapses in patients with adult-onset Still's disease (AOSD). METHODS: We enrolled patients with AOSD admitted to the Department of Rheumatology and Immunology, Ruijin Hospital from August 2016 to September 2019. Kaplan-Meier curves and the log rank test were used to estimate the cumulative relapse probability and persistent remission rate before the first occurrence of relapse. The multivariate Cox proportional hazard method was utilized to identify risk factors associated with relapses of AOSD. RESULTS: A total of 122 patients with AOSD were enrolled with a median follow-up of 12.6 months. Among them, 26 (21.3%) patients had at least one relapse. The cumulative relapse rates of AOSD patients were 14.42%, 21.79%, 24.81% and 28.57% at 6, 12, 18 and 36 months, respectively. According to the multivariate analysis, intensive treatment (odds ratio: 6.848; 95% CI: 2.441, 19.211) and macrophage activation syndrome (odds ratio: 4.020, 95% CI: 1.564, 10.322) were associated with increased risk of relapse. CONCLUSION: Our study indicated that relapses occurred in at least one-fifth of patients with AOSD, and patients with high disease severity at initial attack may have an increased risk of relapse, which needs more intensive therapy and close follow-up.

3.
Arthritis Rheumatol ; 73(6): 1033-1043, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33381895

RESUMO

OBJECTIVE: Adult-onset Still's disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin-like receptor A3 (LIR-A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD. METHODS: The LILRA3 deletion polymorphism and its tagging single-nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of LILRA3 on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR-A3 were detected using enzyme-linked immunosorbent assay (ELISA), and the correlation between LIR-A3 plasma levels and disease activity and levels of circulating NET-DNA was investigated. LIR-A3-induced NETs were determined using PicoGreen double-stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil-like differentiated NB4 cell line transfected with LIR-B2 small interfering RNA. RESULTS: The findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030-4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027). Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3+/+ patients. Plasma levels of LIR-A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET-DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR-A3. Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression. CONCLUSION: Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR-A3 may play a pathogenic role by inducing formation of NETs.


Assuntos
Armadilhas Extracelulares/genética , Ativação de Neutrófilo/genética , Receptores Imunológicos/genética , Doença de Still de Início Tardio/genética , Adulto , Estudos de Casos e Controles , Armadilhas Extracelulares/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Leucocitose , Masculino , Neutrófilos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Receptores Imunológicos/metabolismo , Doença de Still de Início Tardio/metabolismo
4.
Front Immunol ; 11: 563335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240258

RESUMO

Adult-onset Still's disease (AOSD) is an autoinflammatory disease with multisystem involvement. Early identification of patients with severe complications and those refractory to glucocorticoid is crucial to improve therapeutic strategy in AOSD. Exaggerated neutrophil activation and enhanced formation of neutrophil extracellular traps (NETs) in patients with AOSD were found to be closely associated with etiopathogenesis. In this study, we aim to investigate, to our knowledge for the first time, the clinical value of circulating NETs by machine learning to distinguish AOSD patients with organ involvement and refractory to glucocorticoid. Plasma samples were used to measure cell-free DNA, NE-DNA, MPO-DNA, and citH3-DNA complexes from training and validation sets. The training set included 40 AOSD patients and 24 healthy controls (HCs), and the validation set included 26 AOSD patients and 16 HCs. Support vector machines (SVM) were used for modeling and validation of circulating NETs signature for the diagnosis of AOSD and identifying patients refractory to low-dose glucocorticoid treatment. The training set was used to build a model, and the validation set was used to test the predictive capacity of the model. A total of four circulating NETs showed similar trends in different individuals and could distinguish patients with AOSD from HCs by SVM (AUC value: 0.88). Circulating NETs in plasma were closely correlated with systemic score, laboratory tests, and cytokines. Moreover, circulating NETs had the potential to distinguish patients with liver and cardiopulmonary system involvement. Furthermore, the AUC value of combined NETs to identify patients who were refractory to low-dose glucocorticoid was 0.917. In conclusion, circulating NETs signature provide added clinical value in monitoring AOSD patients. It may provide evidence to predict who is prone to be refractory to low-dose glucocorticoid and help to make efficient therapeutic strategy.


Assuntos
Armadilhas Extracelulares/metabolismo , Glucocorticoides/administração & dosagem , Doença de Still de Início Tardio/diagnóstico , Doença de Still de Início Tardio/tratamento farmacológico , Máquina de Vetores de Suporte , Adulto , Estudos de Casos e Controles , Ácidos Nucleicos Livres , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença de Still de Início Tardio/sangue , Doença de Still de Início Tardio/imunologia , Resultado do Tratamento , Adulto Jovem
6.
Lupus ; 29(10): 1287-1291, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32605525

RESUMO

Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening form of antiphospholipid syndrome (APS), which could be triggered by malignancy. Chronic myelomonocytic leukaemia (CMML) is an uncommon hematologic malignancy. We report a case of a 49-year-old male patient who presented multiple thromboses with a high titre of anti-ß2-glycoprotein-I antibody. Unexpectedly, there was persistent monocytosis combined with <20% blasts in his bone marrow. Thus, a diagnosis of probable CAPS and CMML was made. After treatment with prednisone, hydroxychloroquine and warfarin, the thromboses dissolved, and an improved presentation of peripheral blood and bone marrow was observed. Here, we also provide a mini review of cases of APS complicated with CMML identified from searches of MEDLINE, EMBASE and Web of Science databases. The review describes the clinical characteristics, laboratory data, treatments and outcomes.


Assuntos
Síndrome Antifosfolipídica/etiologia , Leucemia Mielomonocítica Crônica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Medula Óssea/patologia , Angiografia por Tomografia Computadorizada , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Trombose/etiologia , Varfarina/uso terapêutico
7.
Front Immunol ; 11: 603389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33552062

RESUMO

The catastrophic outbreak of coronavirus disease 2019 (COVID-19) is currently a public emergency. Adult-onset Still's disease (AOSD) is an autoinflammatory disease characterized by life-threatening complications. Systemic hyperinflammation and cytokine storm play a critical role in the pathogenesis of both COVID-19 and AOSD. We aimed to compare the similarities and differences focusing on ferritin and cytokine levels between severe COVID-19 and active AOSD. A literature search was performed using the databases PubMed, EMBASE, and Web of Science to collect the levels of cytokine including IL-1ß, IL-6, IL-18, TNF-α, IL-10, and ferritin in severe COVID-19 patients. After extracting available data of indicators of interest, we acquired these statistics with a single-arm meta-analysis. Furthermore, a comparison was conducted between 52 patients with active AOSD in our center and severe COVID-19 patients from databases. The levels of IL-6 and IL-10 were higher in severe COVID-19 compared with those in active AOSD. There were no significant differences on the cytokine of IL-1ß and TNF-α. Fold changes of IL-18 were defined as the mean expression level ratio of severe COVID-19 to healthy controls in the COVID-19 study and active AOSD to healthy controls in our study, individually. Although the fold change of IL-18 in patients with AOSD was significantly higher than patients with severe COVID-19 (fold change: 594.00 vs 2.17), there was no statistical comparability. In addition, the level of ferritin was higher in active AOSD in comparison with severe COVID-19. Our findings suggest that severe COVID-19 and active AOSD have differences in cytokine panel and ferritin level, indicating the pathogenic role of ferritin in overwhelming inflammation. And it paves the way to make efficacy therapeutic strategy targeting the hyperinflammatory process in COVID-19 according to AOSD management, especially in severe COVID-19.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Inflamação/imunologia , Doença de Still de Início Tardio/imunologia , Adulto , Idoso , COVID-19/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Citocinas/sangue , Feminino , Ferritinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Still de Início Tardio/epidemiologia
8.
Front Med (Lausanne) ; 7: 621005, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425966

RESUMO

Objective: Adult-onset Still's disease (AOSD) is a systemic disorder commonly accompanied by liver involvement. This study aims to illustrate the detailed information of liver abnormalities in patients with AOSD and evaluate the impact on the prognosis. Methods: A total number of 128 hospitalized patients, who met the Yamaguchi criteria of AOSD in the Department of Rheumatology and Immunology, Ruijin Hospital from July 2016 to August 2019 were consecutively enrolled and followed up. The demographic characteristics, clinical features, laboratory tests, treatments and prognosis were recorded. Correlations of liver function tests (LFTs) with disease activity and laboratory parameters were analyzed by the Spearman test. Risk factors of the refractory AOSD were evaluated by multivariate logistic regression analysis. Results: Liver involvement was presented in 104 (81.3%) patients with AOSD. We observed that 34 (32.7%) patients were with mild elevation, 32 (30.8%) patients were with moderate elevation, and 38 (36.5%) patients were with severe elevation. The majority of elevated ALT, AST and ALP decreased to normal within the range of 2 months, except for GGT. Furthermore, the LFTs were found significantly correlated with disease activity. Besides, we found patients with higher levels of LFTs tended to require more intensive treatments and suffered from poorer prognosis. Multivariate logistic regression analysis showed ALP ≥ 141 IU/L and GGT ≥ 132 IU/L are independent risk factors of refractory AOSD. Conclusion: Liver involvement is common in patients with AOSD, the levels of LFTs are associated with disease activity and related to the treatment strategies and prognosis.

9.
Lipids Health Dis ; 14: 33, 2015 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-25928384

RESUMO

BACKGROUND: To investigate the association of a coronary artery disease (CAD) risk SNP rs6903956 with asymptomatic hyperuricemia (aHU) susceptibility in Han Chinese. METHODS: Two hundred and twenty one patients with aHU and 447 healthy controls were recruited for this study. SNP rs6903956 were genotyped using TaqMan probe. RESULTS: The overall genotype and allele frequency distribution of the rs6903956 showed significant difference between aHU cases and controls (p<0.001 for genotype and allele, respectively). AA genotype of rs6903956 was significantly associated with aHU (OR=8.672, 95% CI 2.811-26.753, p<0.001) in our Han Chinese aHU cohort. Multivariate logistic regression analysis indicated that rs6903956 might be an independent risk factor for aHU susceptibility (OR=10.642 [2.671-42.400], p=0.001 for codominant model and OR=9.205 [2.336-36.280], p=0.002 for recessive model) after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus, abnormal glycometabolism, lipid abnormality and alcohol intake. No significant genotype-specific difference in uric acid levels was observed in aHU patients and controls. CONCLUSIONS: Our findings are the first to establish a genetic link of a CAD-associated rs6903956 with aHU in a Han Chinese population, providing the genetic evidence to support the close relationship between hyperuricemia and CAD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Hiperuricemia/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Doenças Assintomáticas/epidemiologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Úrico/sangue
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