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1.
Rheumatol Int ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499196

RESUMO

In view of the possible involvement of vascular endothelial growth factor-C (VEGF-C) in pathogenesis of adult-onset Still's disease (AOSD) based on our previous genome-wide association study (GWAS) results, the primary objective of this study, therefore, was to investigate the correlations between the content of VEGF-C in serum and clinical and biochemical markers of AOSD. Blood samples were collected from 80 patients with AOSD, 26 with rheumatoid arthritis (RA), 30 with systemic lupus erythematosus (SLE) and 31 healthy control subjects. The serum VEGF-C levels were determined using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis and comparisons were conducted. A significantly higher serum VEGF-C level was observed in patients with AOSD than in HC. Serum VEGF-C levels had high AUC value of 0.8145 for distinguishing AOSD group from healthy group with sensitivity of 0.7097 and specificity of 0.8250. It also showed good diagnostic value to differentiate AOSD from other autoinflammatory diseases with sensitivity of 0.7500 and specificity of 0.5500. AOSD patients with fever, arthralgia, skin rash, sore throat, lymphadenopathy, splenomegaly hepatomegaly and pleuritis, had a higher level than those who did not have these symptoms (p = 0.0012, p = 0.0092, p = 0.0056, p = 0.0123, p = 0.0068, p = 0.0030, p = 0.0020, and p = 0.0018, respectively). The serum VEGF-C levels were also positively correlated with laboratory features and several cytokines related to AOSD disease activity. In conclusion, our study unveiled a close association between serum VEGF-C levels and AOSD including disease activity and clinical hematological manifestations, suggesting the potential utility of VEGF-C as a candidate biomarker to assess disease activity in AOSD.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34508561

RESUMO

OBJECTIVES: To explore the efficacy of plasma exchange (PE) therapy in refractory idiopathic inflammatory myopathy (IIM) patients with positive anti-signal recognition particle (SRP) antibody. METHODS: Nine refractory IIM patients with positive anti-SRP antibody were enrolled, who received PE therapy at Ruijin Hospital from Octobor 2017 to December 2020. The clinical manifestations, laboratory tests, chest CT and lower extremity MRI images before and after PE therapy were compared. The treatment response was evaluated by the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. RESULTS: 88.9% (8/9) subjects had achieved improvement by 3 weeks after PE therapy, with 55.6% (5/9) minimal improvement and 33.3% (3/9) moderate improvement. There were statistically significant improvements between baseline and after PE therapy at 3 weeks on the core set measures: physician global activity, patient global activity, Health Assessment Questionnaire (HAQ), manual muscle testing (MMT), extramuscular disease activity, and muscle enzymes activity including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), except for alanine transaminase (ALT). Moreover, the chest CT showed regression of ground glass opacities and irregular linear opacities after PE therapy in four patients with interstitial lung disease. The MRI images of lower extremity in four patients showed reduction of muscle oedema after the therapy. CONCLUSION: PE therapy is effective for refractory IIM patients with positive anti-SRP antibody. It should be considered as an alternative treatment for those patients who are resistant to the combined therapy of glucocorticoids and immunosuppressive agents.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34559215

RESUMO

OBJECTIVES: Thrombosis occurring in the central nerve system is common in antiphospholipid syndrome (APS) patients, leading to neuropsychiatric symptoms. We investigated the prevalence of silent brain abnormalities on magnetic resonance imaging (MRI) in primary antiphospholipid syndrome (PAPS) patients and antiphospholipid antibodies (aPL) carriers and assessed the association between the vascular risk factors, aPL profile, clinical manifestations, and MRI abnormalities. METHODS: We consecutively included 44 PAPS patients, 24 aPL carriers and 23 healthy controls with comparable age and gender in a single-center, observational cross-sectional study. None of the patients had a history of stroke, TIA, migraine, dementia, epilepsy and bipolar disorders. On cerebral MRI, we assessed the imaging features and location of abnormality. Multivariate analysis was performed to identify the risk factors contributing to the MRI abnormalities. RESULTS: 38 (55.88%) patients persisted abnormal MRI findings, while only one healthy control showed some abnormalities in the MR findings. Lacunes were the most frequent MRI abnormality in aPL (+) group (31/68, 45.59%), which were followed by white matter hyperintensities (20/68, 29.41%). In all study population, age (OR = 1.086, p= 0.016) and LA positivity (OR = 5.191, p= 0.002) were the independent associated factors with the brain MRI abnormalities. When analyzed only in the aPL (+) group, age (OR = 1.116, p= 0.007), female gender (OR = 7.519, p= 0.025) and thrombocytopenia (OR = 8.336, p= 0.047) were the significant independent risk factors with abnormal MRI. CONCLUSIONS: PAPS patients and aPL carriers showed a high prevalence of brain MRI abnormalities, indicating an increased cerebrovascular risk, which emphasized attention to silent cerebral lesions in persistently aPL positive patients.

4.
Front Immunol ; 12: 702425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489952

RESUMO

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by thrombosis and/or recurrent fetal loss. This clinical phenotype heterogeneity may result in differences in response to treatment and prognosis. In this study, we aimed to identify primary thrombotic APS (TAPS) from primary obstetric APS (OAPS) using urine proteomics as a non-invasive method. Only patients with primary APS were enrolled in this study from 2016 to 2018 at a single clinical center in Shanghai. Urine samples from 15 patients with TAPS, 9 patients with OAPS, and 15 healthy controls (HCs) were collected and analyzed using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis to identify differentially expressed proteins. Cluster analysis of urine proteomics identified differentiated proteins among the TAPS, OAPS, and HC groups. Urinary proteins were enriched in cytokine and cytokine receptor pathways. Representative secreted cytokines screened out (fold change >1.20, or <0.83, p<0.05) in these differentiated proteins were measured by enzyme-linked immunosorbent assay in a validation cohort. The results showed that the levels of C-X-C motif chemokine ligand 12 (CXCL12) were higher in the urine of patients with TAPS than in those with OAPS (p=0.035), while the levels of platelet-derived growth factor subunit B (PDGFB) were lower in patients with TAPS than in those with OAPS (p=0.041). In addition, correlation analysis showed that CXCL12 levels were positively correlated with immunoglobulin G anti-ß2-glycoprotein I antibody (r=0.617, p=0.016). Our results demonstrated that urinary CXCL12 and PDGFB might serve as potential non-invasive markers to differentiate primary TAPS from primary OAPS.

7.
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.

8.
J Autoimmun ; 116: 102562, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33168359

RESUMO

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

9.
Front Med (Lausanne) ; 7: 566738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33364243

RESUMO

Objective: Adult-onset Still's disease (AOSD) is an autoinflammatory disease with a higher prevalence rate in young females. The purpose of this study is to investigate whether AOSD has an adverse impact on pregnancy outcomes, or conversely exacerbated by pregnancy. Methods: The outcomes of 191 pregnancies were evaluated in 86 female patients with AOSD. The generalized linear mixed model and propensity score matching method were conducted to evaluate the influence of AOSD on pregnancy outcomes. A dependent sample sign test was applied to assess the impact of pregnancy on the relapse of AOSD. Results: The results showed that the post-AOSD group had a lower proportion of normal delivery (25.0 vs. 52.4%, p = 0.036) and a higher proportion of spontaneous abortion (STA) (18.8 vs. 0.6%, p = 0.002) compared with the pre-AOSD group. Moreover, pregnancy after being diagnosed with AOSD was a significant high risk factor of STA (adjusted OR = 4.577, 95% CI: 4.166-845.119; p = 0.003). Disease flare upon conception was observed in one of 16 post-AOSD pregnancies (p = 1.000). There were 11 patients with new-onset AOSD during gestation or postpartum, among which five (45.4%) evolved into the polycyclic course. Conclusions: AOSD patients might suffer from a higher risk of STA, however, pregnancy might not be related with the exacerbation of diagnosed AOSD. New-onset AOSD during gestation or postpartum tend to evolve into the polycyclic course.

10.
J Immunol Res ; 2020: 2180708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224991

RESUMO

Background: Systemic lupus erythematosus (SLE) is a disease characterized by the production of a large number of autoantibodies. Defected phagocytosis of macrophage plays an important role in innate immunity in the pathogenesis of SLE. Tyro3 is a receptor responsible for the recognition of apoptotic cells during efferocytosis by macrophages. To investigate the role of Tyro3 receptor in macrophages' efferocytosis of apoptotic cells in SLE, we aimed to reveal the clinical relevance and impact of Tyro3 autoantibody on SLE. Methods: The serum levels of IgG-type autoantibody against Tyro3 receptor were detected in new-onset, treatment-naïve SLE patients (n = 70), rheumatoid arthritis (RA) (n = 24), primary Sjögren's Syndrome (pSS) (n = 21), and healthy controls (HCs) (n = 70) using enzyme-linked immunosorbent assay (ELISA). The effects of purified Tyro3 autoantibody from SLE patients on the efferocytosis of human monocyte-derived macrophages were measured by flow cytometry and immunofluorescence. Results: The serum levels of IgG-type autoantibody against Tyro3 receptor were significantly elevated in patients with SLE compared to RA, pSS, and HCs (all p < 0.0001). The levels of anti-Tyro3 IgG were positively associated with the SLE disease activity index (SLEDAI) score (r = 0.254, p = 0.034), erythrocyte sedimentation rate (ESR) (r = 0.430, p < 0.001), C-reactive protein (CRP) (r = 0.246, p = 0.049), and immunoglobulin G (IgG) (r = 0.408, p = 0.001) and negatively associated with haemoglobin (Hb) (r = -0.294, p = 0.014). ROC curves illustrated that the anti-Tyro3 antibody could differentiate patients with SLE from HCs. Furthermore, flow cytometry and immunofluorescence demonstrated that purified anti-Tyro3 IgG inhibited the efferocytosis of macrophages (p = 0.004 and 0.044, respectively) compared with unconjugated human IgG. Conclusions: These observations indicated that autoantibody against Tyro3 was associated with disease activity and could impair efferocytosis of macrophages. It might be a potential novel disease biomarker and might be involved in the pathogenesis of SLE.


Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Fagocitose/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Adulto , Apoptose/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de Doença , Síndrome de Sjogren/imunologia
11.
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
12.
Front Immunol ; 11: 2112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013889

RESUMO

Adult-onset Still's disease (AOSD) is a systemic, multigenic autoinflammatory disease, and the diagnosis of AOSD must rule out neoplasms, infections, and other autoimmune diseases. Development of a rapid and efficient but non-invasive diagnosis method is urgently needed for improving AOSD therapy. In this study, we first performed a urinary proteomic study using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis in patients with AOSD and healthy control (HC) subjects. The urinary proteins were enriched in pathways of the innate immune system and neutrophil degranulation, and we identified that the α-1-acid glycoprotein 1 (LRG1), orosomucoid 1 (ORM1), and ORM2 proteins were highly expressed in patients with AOSD. The elevated urine levels of LRG1, ORM1, and ORM2 were further validated by enzyme-linked immunosorbent assay in active patients with AOSD, disease controls, and HC subjects. Receiver operating characteristic curves showed that the areas under the curve of LRG1, ORM1, and ORM2 were 0.700, 0.837, and 0.736, respectively (all p < 0.05). Furthermore, we found that the urine levels of LRG1, ORM1, and ORM2 were positively correlated with the systemic score and erythrocyte sedimentation rate and that the urine levels of LRG1 were positively correlated with interleukin 1ß (IL-1ß), IL-6, and IL-18 levels, whereas the urine levels of ORM1 were positively correlated with the IL-1ß level. Together, our study identified novel urinary markers for non-invasive and simple screening of AOSD.


Assuntos
Imunidade Inata , Proteômica , Doença de Still de Início Tardio/urina , Adulto , Idoso , Biomarcadores/urina , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Still de Início Tardio/imunologia , Espectrometria de Massas em Tandem
14.
Exp Ther Med ; 20(5): 91, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32973940

RESUMO

Gilbert syndrome (GS) is a hereditary unconjugated hyperbilirubinemia that results from mutations in the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene. To the best of our knowledge, there are currently no reports that focus on patients with systemic lupus erythematosus (SLE) coexisting with GS. The present study aimed to evaluate the clinical characteristics and genotype of UGT1A1 in a Chinese patient with SLE and GS. Complete medical records and laboratory data were reviewed for a patient with SLE referred to Ruijin Hospital (Shanghai, China) for treatment between March 2016 and January 2020. Genetic analysis of the UGT1A1 gene was performed by PCR amplification and Sanger sequencing. The serum total bilirubin and unconjugated bilirubin concentrations on admission were 96.2 and 86.8 µmol/l, respectively. The homozygous mutation c.1456T>G (p.Y486D) in exon 5 was detected in this patient. The patient had a good response to phenobarbital orally at a dose of 30 mg/day and a decrease in serum bilirubin was observed. Elevated unconjugated hyperbilirubinemia in SLE needs to be differentiated from other diseases, such as GS, which can be diagnosed by UGT1A1 genetic sequencing.

16.
Clin Rheumatol ; 39(12): 3723-3732, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32447600

RESUMO

OBJECTIVE: Adult-onset Still's disease (AOSD) is an autoinflammatory disorder leading to multiorgan involvements. We sought to investigate mood status and the health-related quality of life (HRQoL) in these patients. METHODS: In this study, 82 AOSD patients and 82 age- and sex-matched healthy controls were included. Demographic and clinical data of recruited patients were collected. The Hospital Anxiety and Depression Scale (HADS) and Medical Outcomes Survey Short Form-36 (SF-36) were used to evaluate the mood status and quality of life, respectively. Spearman correlation and multivariable linear regression analyses were used to assess the disease-related risk factors associated with anxiety and depression. RESULTS: Forty-four active and thirty-eight relieved patients were enrolled. We found that scores of both HADS anxiety (HADS-A) and depression (HADS-D) subscales in active AOSD were significantly higher than inactive patients, which were significantly higher than controls. Moreover, the HADS-A was positively correlated to the patient's global assessment (PGA), pain, and dosage of prednisone, and the HADS-D was positively correlated to systemic score, PGA, and pain. Female, high dosage of corticosteroids, and PGA more than 50 had a significant association with HADS-A score, while the sore throat and PGA more than 50 had a significant association with HADS-D score. Furthermore, AOSD patients' anxiety and depression had a negative impact on HRQoL. CONCLUSION: Active AOSD patients tended to be anxious and depressed, suffering from poorer HRQoL compared to patients in remission. Therefore, the evaluation of mental health and HRQoL should be included in AOSD patients' long-term management. Key Points • Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder leading to multiorgan involvement. This study was so far the first published research focuses on AOSD patients' mental involvement and health-related quality of life (HRQoL). • Active AOSD patients were more tended to be anxious and depressive and suffered from poorer HRQoL compared to inactive patients. • Patients' anxiety and depression were associated with impaired HRQoL.


Assuntos
Qualidade de Vida , Adulto , Ansiedade/epidemiologia , Transtornos de Ansiedade , Depressão/complicações , Depressão/epidemiologia , Feminino , Humanos , Doença de Still de Início Tardio/complicações
17.
Rheumatology (Oxford) ; 59(11): 3293-3302, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32276274

RESUMO

OBJECTIVES: Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of inflammatory signals. Recently, a soluble form of TREM-1 (sTREM-1) was described. This study aimed to investigate the role of serum sTREM-1 in patients with adult-onset Still's disease (AOSD). METHODS: Serum sTREM-1 levels were detected in 108 AOSD patients, 88 RA patients and 112 healthy controls (HC). The correlations of sTREM-1 with disease activity, clinical characteristics and laboratory parameters in AOSD patients were analysed by the Spearman correlation test. Risk factors for the chronic course of AOSD were evaluated by multivariate logistic regression analysis. RESULTS: AOSD patients had significantly higher serum sTREM-1 levels than RA patients and HC, and serum sTREM-1 levels were correlated with the systemic score, ferritin, leucocyte count, CRP, IL-1ß and IL-6. The elevation in the initial sTREM-1 level by itself could discriminate patients developing the chronic course from patients developing the nonchronic course. Moreover, an elevated sTREM-1 level (> 526.4475 pg/ml) was an independent risk factor for the chronic course in active AOSD patients. Furthermore, interfering with TREM-1 engagement led to reductions in the secretion of pro-inflammatory cytokines, such as IL-1ß, IL-6 and TNF-α, in neutrophils and monocytes from active AOSD patients. CONCLUSION: Serum sTREM-1 levels are correlated with disease activity, and an elevation in the initial serum sTREM-1 level is a potential predictor of the chronic course in AOSD patients, which currently provides the best predictive model for identifying patients prone to developing the chronic course of AOSD.


Assuntos
Artrite Reumatoide/sangue , Doença de Still de Início Tardio/sangue , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Doença Crônica , Síndrome da Liberação de Citocina/complicações , Ferritinas/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Análise de Regressão , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue
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