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Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.
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BACKGROUND: There are large differences in clinical manifestations and biological markers between elderly patients with rheumatoid arthritis (EPRA, age >60) and younger patients with RA (YPRA, age ≤60), partly owing to variations in the immune system of different age groups. Here, we focused on the changes of immune cell infiltration in YPRA and EPRA. METHODS: The R packages "ssGSEA" and "GSEA" were used to identify the changes in immune cell infiltration and immune-related pathways between the two groups. The R packages "WGCNA" and "DEseq2" were used to screen and verify age-related differentially expressed genes (DEGs). Hub genes were identified using Cytoscape and cytoHubba. Spearman correlation coefficient was conducted to evaluate correlations between hub age-related genes and immune cells. RESULTS: Compared with 54 established YPRA, several immune cells and immune-related pathways were markedly decreased in 29 EPRA synovial tissues. Moreover, 78 age-related DEGs related to amino acid and glycosphingolipid synthesis and metabolism were identified. USP2 and ARG2 were verified to be upregulated in EPRA, signifying that these two genes could effectively distinguish YPRA and EPRA and have potential as biomarkers. In addition, we found that USP2 was significantly negatively correlated with B cells and monocytes, while there was a significant negative association between ARG2 and T cells. CONCLUSIONS: In conclusion, this study is the first to systematically analyze changes in immune cell infiltration between YPRA and EPRA patients and obtain hub age-related genes, which may provide the basis for illuminating the pathogenesis of EPRA and informing treatment strategies.
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Artritis Reumatoide , Anciano , Humanos , Aminoácidos , Artritis Reumatoide/genética , Linfocitos B , Biología Computacional , Membrana Sinovial , Ubiquitina TiolesterasaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary fibrosis disease that is fatal. Mesenchymal stem cells (MSCs)-secreted exosomes (exos) have been linked to improving PF. Moreover, exosomal microRNAs (miRs) can control the growth of numerous diseases, including lung disorders. Our bioinformatics analysis showed that miR-30b was downregulated in tissue samples from surgical remnants of biopsies or lungs explanted from patients with IPF who underwent pulmonary transplantation. This suggests that miR-30b plays an important role in both the pathogenesis and treatment of IPF. Herein, this research was designed to ascertain the mechanism of MSCs-exos-packaged miR-30b in alleviating PF. The serum was harvested from idiopathic PF (IPF) patients with interstitial pneumonia caused by dermatomyositis and the MLE12 lung epithelial cell fibrosis model was built with TGF-ß1 (10 ng/mL), followed by miR-30b expression determination. TGF-ß1-stimulated MLE12 cells were co-incubated with exos from MSCs with or without Spred2 or Runx1 overexpression, followed by measurement of cell viability and apoptosis. After establishing the IPF mouse model with bleomycin and injecting exos and/or silencing and overexpressing adenovirus vectors, fibrosis evaluation was conducted. In mice and cells, the expression of TGF-ß1, TNF-α, and IL-1ß was tested via ELISA, and the levels of E-cad, ZO-1, α-SMA, and collagen type I via western blot analysis. The promoters of miR-30b, Runx1, and Spred2 were investigated. miR-30b was downregulated in the serum of IPF patients and TGF-ß1-stimulated MLE12 cells. Mechanistically, miR-30b inhibited Spred2 transcription by negatively targeting Runx1. MSCs-exos or MSCs-exo-miR-30b decreased the apoptosis, inflammation, and fibrosis while increasing their viability in TGF-ß1-stimulated MLE12 cells, which was annulled by overexpressing Runx1 or Spred2. Exo-miR-30b decreased Runx1 expression to downregulate Spred2, reducing fibrosis and inflammation in IPF mice. Our results indicated that MSCs-exos-encapsulated miR-30b had a potential function to inhibit PF and part of its function may be achieved by targeting RUNX1 to reduce the Spred2 transcription level. Moreover, this work offered evidence and therapeutic targets for therapeutic strategies for managing clinical PF in patients.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , Fibrosis Pulmonar , Humanos , Ratones , Animales , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Exosomas/genética , Exosomas/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fibrosis , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteínas Represoras/metabolismoRESUMEN
OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.
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OBJECTIVE: To investigate the efficacy and safety of rituximab (RTX) maintenance therapy compared with traditional immunosuppressive agent (ISA) maintenance therapy in patients with relapsing or refractory SLE. METHODS: It is a prospective observational non-randomized cohort study. The study enrolled SLE patients in four centres who had received at least one course of RTX induction treatment. Patients with a clinical response to RTX were divided into two groups based on their maintenance therapy in the first 12 months: the RTX group and the ISA group. The relapse-free survival times were compared between the two groups. Univariate and multivariate analyses were conducted to identify predictive factors for disease relapse. RESULTS: Among the 82 patients included in the cohort, 67 (81.7%) patients had a clinical response at 6 months. RTX maintenance therapy was applied in 34 (50.7%) patients and ISA maintenance therapy was applied in the remaining 33 (49.3%) patients. After a median follow-up of 24 months, a total of 13 (19.4%) patients had experienced disease relapse, comprising three in the RTX group and 10 in the ISA group. Patients in the RTX group had a higher relapse-free survival rate than patients in the ISA group. Multivariate analysis identified hydroxychloroquine use, RTX maintenance therapy and haematological system involvement as independent predictors for sustained remission. CONCLUSION: This multicentre prospective cohort study demonstrated that long-term RTX maintenance therapy has high efficacy and acceptable safety in relapsing or refractory SLE patients who had a clinical response to RTX induction therapy.
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Inmunosupresores , Lupus Eritematoso Sistémico , Humanos , Rituximab/uso terapéutico , Estudios de Cohortes , Estudios Prospectivos , Resultado del Tratamiento , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Inducción de RemisiónRESUMEN
OBJECTIVE: To investigate the role and mechanism of microRNAs (miRNAs) in fibrotic processes involved in the pathology of systemic sclerosis (SSc). METHODS: R language and bioinformatics methods were used to identify differential miRNAs and mRNAs and analyze their biological functions. Transfection experiments were performed to evaluate the function and regulatory mechanism of miR-27a-3p in vitro. Levels of fibrosis-related genes, SPP1 and cell proliferation were assessed. RESULTS: MiR-27a-3p is reduced both in SSc lung and skin tissues. Overexpression of miR-27a-3p significantly inhibited fibrosis-related genes expression and protein abundance and cell proliferation, whereas inhibition of miR-27a-3p significantly enhanced these phenomena. Moreover, miR-27a-3p exerts its anti-fibrosis effect by negatively regulating SPP1 and ERK signal, more prominent in fibroblasts. CONCLUSIONS: Our findings show that miR-27a-3p regulates a common mechanism in the process of SSc skin and lung fibrosis. MiR-27a-3p/SPP1/ERK1/2 axis may be an important target for delaying the progression of SSc fibrosis.
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MicroARNs , Osteopontina , Esclerodermia Sistémica , Fibrosis , Humanos , Pulmón/metabolismo , MicroARNs/genética , Osteopontina/genética , ARN Mensajero/genética , Esclerodermia Sistémica/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is a remarkable heterogeneous autoimmune disease that is sometimes hard to diagnose at the early stage and can lead to premature mortality. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNAs greater than 200 nucleotides in length that can regulate gene expression in various human diseases, including SLE. Peripheral blood samples and renal tissue samples from SLE patients were used for study. Abnormally expressed lncRNAs in SLE have been shown to influence several signalling pathways, including the IFN-I, MAPK and WNT pathways. This can affect cellular phenotypes like cell activation, differentiation skewing, cytokine production and cell apoptosis. Many of the reported lncRNAs may be useful for diagnosing, evaluating progression and predicting potential organ damage in SLE patients. While numerous lncRNAs play important roles in SLE, more basic and clinical studies are warranted to clarify the function of these regulatory molecules and determine their diagnostic value.
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Lupus Eritematoso Sistémico , ARN Largo no Codificante , Apoptosis/genética , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , ARN Largo no Codificante/genética , Transducción de SeñalRESUMEN
BACKGROUND: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by abnormal immune cell activation. This study aimed to investigate differentially expressed long non-coding RNA (lncRNA) in peripheral blood mononuclear cells (PBMCs) in patients with pSS to identify lncRNAs that affect pSS pathogenesis. METHODS: Total RNA was extrated from PBMCs of 30 patients with pSS and 15 healthy persons. Transcriptome sequencing was used to screen differentially expressed lncRNAs and mRNAs in 8 RNA samples from the discovery cohort. The differentially expressed mRNAs underwent functional enrichment analysis. A protein interaction relationship (PPI) and competitive endogenous RNA (ceRNA) network was constructed. Real-time PCR was used to validate screened lncRNAs in all 45 RNA samples.. RESULTS: 1180 lncRNAs and 640 mRNAs were differentially expressed in pSS patients (fold change > 2 in healthy persons). The PPI network was constructed with 640 mRNAs and a ceRNA network with four key lncRNAs (GABPB1-AS1, PSMA3-AS1, LINC00847 and SNHG1). Real-time PCR revealed that GABPB1-AS1 and PSMA3-AS1 were significantly up-regulated 3.0- and 1.4-fold in the pSS group, respectively. The GABPB1-AS1 expression level was positively correlated with the percentage of B cells and IgG levels. CONCLUSIONS: GABPB1-AS1 was significently up-regulated in pSS patients, and its expression level is positively correlated with the percentage of B cells and IgG levels. GABPB1-AS1 may be involved in the pathogenesis of pSS and may be a promising biological marker.
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Subgrupos de Linfocitos B/inmunología , Leucocitos Mononucleares/inmunología , ARN Largo no Codificante/genética , Síndrome de Sjögren/genética , Adulto , Biomarcadores , Femenino , Factor de Transcripción de la Proteína de Unión a GA/genética , Redes Reguladoras de Genes , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , ARN sin Sentido/genética , TranscriptomaRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is the most common chronic autoimmune connective tissue disease. However, early RA is difficult to diagnose due to the lack of effective biomarkers. This study aimed to identify new biomarkers and mechanisms for RA disease progression at the transcriptome level through a combination of microarray and bioinformatics analyses. METHODS: Microarray datasets for synovial tissue in RA or osteoarthritis (OA) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by R software. Tissue/organ-specific genes were recognized by BioGPS. Enrichment analyses were performed and protein-protein interaction (PPI) networks were constructed to understand the functions and enriched pathways of DEGs and to identify hub genes. Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks. Biomarkers with high diagnostic value for the early diagnosis of RA were validated by GEO datasets. The ggpubr package was used to perform statistical analyses with Student's t-test. RESULTS: A total of 275 DEGs were identified between 16 RA samples and 10 OA samples from the datasets GSE77298 and GSE82107. Among these DEGs, 71 tissue/organ-specific expressed genes were recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEGs are mostly enriched in immune response, immune-related biological process, immune system, and cytokine signal pathways. Fifteen hub genes and gene cluster modules were identified by Cytoscape. Eight haematologic/immune system-specific expressed hub genes were verified by GEO datasets. GZMA, PRC1, and TTK may be potential biomarkers for diagnosis of early RA. NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158- miR-212-3p/miR-132-3p/miR-129-5p-TTK might be potential RNA regulatory pathways to regulate the disease progression of early RA. CONCLUSIONS: This work identified three haematologic/immune system-specific expressed genes, namely, GZMA, PRC1, and TTK, as potential biomarkers for the early diagnosis and treatment of RA and provided insight into the mechanisms of disease development in RA at the transcriptome level. In addition, we proposed that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158-miR-212-3p/miR-132-3p/miR-129-5p-TTK are potential RNA regulatory pathways that control disease progression in early RA.
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Artritis Reumatoide , MicroARNs , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/genética , Biomarcadores , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Sistema Inmunológico/metabolismo , MicroARNs/metabolismo , Mapas de Interacción de Proteínas/genéticaRESUMEN
OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) positive DM is a life-threatening disease often complicated with rapidly progressive interstitial lung disease (ILD). This study aimed to establish and validate a clinical prediction model for 6-month all-cause mortality in Chinese patients with anti-MDA5 positive DM-ILD. METHODS: We conducted a retrospective observational study using a single-centre derivation cohort and a multicentre validation cohort. Hospitalized DM patients with positive anti-MDA5 antibody and ILD course ≤3 months on admission were included. Patients' baseline characteristics were described and compared between the deceased and survivors by univariable Cox regression. Optimal cut-off values were defined by the 'survminer' R package for significant continuous variables. Independent prognostic factors were determined by the final multivariable Cox regression model chosen by backward stepwise algorithm, which could be reproduced in both cohorts. The Kaplan-Meier survival analyses based on the derived predictor were conducted. RESULTS: A total of 184 and 81 eligible patients were included with a cumulative 40.8 and 40.7% 6-month mortality in the derivation and validation cohorts, respectively. Based on multivariable Cox regression, the prognostic factor at baseline was identified and validated as three-category forced vital capacity (FVC)%: FVC% ≥50%, FVC% <50%, unable to perform. This significantly distinguishes three risk stages with mortalities of 15.3, 46.8, 97.4% in the derivation cohort, and 14.9, 58.3, 86.4 in the validation cohort, respectively (all P <0.05). CONCLUSION: The validated FVC%-based categorical predictor in anti-MDA5 positive DM-ILD is helpful for risk stratification in clinical practice and might facilitate cohort enrichment for future trials.
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Dermatomiositis/mortalidad , Dermatomiositis/fisiopatología , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/fisiopatología , Capacidad Vital , Adulto , Estudios de Cohortes , Dermatomiositis/genética , Progresión de la Enfermedad , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1/genética , Enfermedades Pulmonares Intersticiales/genética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Although great progress has been made in the treatment of RA with antagonists of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1, the disease remains refractory in some patients. Previous studies have found that small-molecule inflammatory mediators, such as prostaglandins, leukotrienes, reactive oxygen species, nitric oxide, lipoxins and platelet-activating factor, play a significant role in the development of RA. Such compounds help to induce, maintain or reduce inflammation and could therefore be potential therapeutic targets. In this review, we describe the roles of various classes of small-molecule inflammatory mediators in RA and discuss the effects of some drugs that modulate their activity. Many drugs targeting these mediators have demonstrated good efficacy in mouse models of RA but not in patients. However, it is clear that many small-molecule inflammatory mediators play key roles in the pathogenesis of RA, and a better understanding of the underlying molecular pathways may assist in the development of targeted therapies that are efficacious in RA patients.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Mediadores de Inflamación/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Leucotrienos/metabolismo , Lipoxinas/metabolismo , Óxido Nítrico/metabolismo , Factor de Activación Plaquetaria/metabolismo , Prostaglandinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). We identified 2672 LN patients, and about half of them were from east China. Our results based on the entire data set showed that PM2.5 and NO2 were risk factors for LN within one month after exposure, with odds ratio of 1.16 (95% confidence interval (CI), 1.08-1.19) at lag 18 day and 1.19 (95% CI, 1.12-1.26) at lag 16 day relative to an interquartile range (IQR) increase in PM2.5 and NO2, respectively. This positive association between LN and NO2 was also observed for south, west, and east China. In addition, we found that the short term exposure to CO and O3 was not generally associated with LN. Finally, the negative associations of LN with SO2 were found for the entire region and east China. Our results implied that SLE patients may gain the health benefits of air quality improvement in China. Our work also provided evidence that short-term variations in air pollution may trigger LN, and further studies are needed to confirm these findings and the potential pathogenic mechanisms should be explored.
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Contaminantes Atmosféricos , Contaminación del Aire , Lupus Eritematoso Sistémico , Nefritis Lúpica , Ozono , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , China/epidemiología , Exposición a Riesgos Ambientales/análisis , Humanos , Lupus Eritematoso Sistémico/epidemiología , Nefritis Lúpica/inducido químicamente , Nefritis Lúpica/epidemiología , Dióxido de Nitrógeno/análisis , Dióxido de Nitrógeno/toxicidad , Ozono/análisis , Material Particulado/análisis , Material Particulado/toxicidad , Dióxido de Azufre/análisisRESUMEN
BACKGROUND AND AIMS: To investigate the effects of serum uric acid (SUA) level and its fluctuation on renal dysfunction in gout patients. METHODS AND RESULTS: Data on gout patients was collected from Huzhou city electronic medical record system data sharing platform, and information about relevant diagnoses, prescriptions, biochemical indexes and imaging characteristics was extracted. The gout patients with baseline normal renal function were enrolled in this analysis, and the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was defined as renal dysfunction. The generalized estimating equation and Cox regression analysis were used. A total of 1009 patients with gout were enrolled. Compared with the reference group (normal baseline SUA with endpoint SUA to be < 6 mg/dL), endpoint SUA ≥ 10 mg/dL was associated with an increased risk of renal dysfunction (baseline normal SUA group: HR [95% CI] = 3.28 [1.21, 8.91]; baseline high SUA group: HR [95% CI] = 3.01 [1.43, 6.35]). Subgroup analysis of 771 SUA stable gout patients demonstrated that SUA levels at 8-10 (excluding 10), and ≥10 mg/dL were significantly associated with an increased risk for renal dysfunction, with HR [95%CI] to be 1.99 [1.05, 3.77], and 2.98 [1.38, 6.43], respectively. CONCLUSION: Regardless of the baseline SUA level, SUA >10 mg/dL was a significant risk factor for renal dysfunction. SUA between 6 and 10 mg/dL was a potential risk factor for renal dysfunction. No significant correlation of SUA fluctuation and renal function was found.
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Tasa de Filtración Glomerular , Gota/sangre , Hiperuricemia/sangre , Riñón/fisiopatología , Ácido Úrico/sangre , Adulto , Anciano , Biomarcadores/sangre , Registros Electrónicos de Salud , Femenino , Gota/diagnóstico , Gota/fisiopatología , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/fisiopatología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Long-standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL-1ß. However, how IL-1ß, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL-1ß could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK-2 cells by real-time PCR and Western-blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL-1ß also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF-κB pathway partly dampened the inhibitory effect of IL-1ß on ABCG2, indicating that IL-1ß reduced the ABCG2 expression partially through the NF-ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL-1ß, which is dependent on the NF-κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL-1ß, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas Portadoras/metabolismo , Interleucina-1beta/farmacología , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Secuencia de Bases , Transporte Biológico/efectos de los fármacos , Línea Celular , Humanos , Proteínas de la Membrana , Proteínas de Neoplasias/genética , Nitrilos/farmacología , Polimorfismo de Nucleótido Simple/genética , Prolina/análogos & derivados , Prolina/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfonas/farmacología , Tiocarbamatos/farmacología , Factores de Tiempo , Ácido Úrico/metabolismoRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.
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Antirreumáticos , Artritis Reumatoide , Certolizumab Pegol/uso terapéutico , Metotrexato/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , China , Método Doble Ciego , Quimioterapia Combinada , Humanos , Inducción de Remisión , Resultado del TratamientoRESUMEN
Background Previous reviews of the diagnosis for rheumatoid arthritis (RA) have not compared anti-mutated citrullinated vimentin (MCV) with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) in respect of sensitivity, specificity and the area under the curve (AUC) against disease controls for differential diagnosis. This meta-analysis aims to evaluate the value of anti-MCV in the diagnosis for RA, the combined sensitivity of anti-MCV and anti-CCP, and certain clinical characteristics related to the performance of anti-MCV. Methods Medline, Embase, Cochrane Library and Web of Science were searched for articles published up to 25 August 2018. A total of 33 studies including 6044 RA patients and 5094 healthy or disease controls achieved inclusive criteria. QUADAS-2 was applied to evaluate the quality of the included studies. The bivariate random effects model was employed in primary data synthesis to evaluate the diagnostic performance. Results The sensitivity of anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group was 0.71, 0.71, 0.77, with the specificity of 0.89, 0.95, 0.73, and the AUC of the SROC of 0.89, 0.95, 0.82, respectively. The predesign of the primary study and diagnostic criteria were statistically significant as sources of heterogeneity. Anti-MCV and anti-CCP tests demonstrated a sensitivity of 0.77 when performed in parallel, with a sensitivity of 0.60 when performed in series; whereas, the combination of anti-MCV and RF presented a sensitivity of 0.64 when used in series. Conclusions Anti-MCV demonstrates comparable diagnostic value to anti-CCP and RF, thus it can be an effective diagnostic marker for RA and may be written into the next authoritative criteria.
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Anticuerpos Antiproteína Citrulinada/metabolismo , Artritis Reumatoide/diagnóstico , Pruebas Inmunológicas/métodos , Péptidos Cíclicos/inmunología , Factor Reumatoide/inmunología , Vimentina/inmunología , Artritis Reumatoide/sangre , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: To investigate the expression of leukocyte immunoglobulin-like receptor A3 (LILRA3) in CD14+ monocytes of patients with rheumatoid arthritis (RA). METHODS: Fifty three RA patients admitted in the Second Affiliated Hospital of Zhejiang University School of Medicine from February 2017 to August 2017, and 21 healthy subjects were enrolled in the study. The expression of LILRA3 in CD14+ monocyte subset was determined by flow cytometry, and its correlations with clinical features, laboratory examination results, antibodies and disease activity were analyzed. RESULTS: LILRA3 percentage in the CD14+ monocyte subset of RA patients was higher than that in the healthy controls (P<0.01). The percentage of LILRA3 was positively correlated with number of tenderness joints, number of swollen joints and erythrocyte sedimentation rate (r=0.280, 0.371, 0.341, P <0.05 or <0.01), but was not correlated with the age, course of disease, Sharp score, C reactive protein, blood routine index and immunoglobulin (all P>0.05). In addition, the percentages of LILRA3 in the monocytes of rheumatoid factor (RF)-positive or anti-cyclic citrullinated peptide (CCP) antibody-positive patients were significantly higher than those of the RF-or anti-CCP antibody-negative patients (all P < 0.05); and the percentage of LILRA3 in patients with DAS28>5.1 was higher than that in patients with DAS28 ≤ 5.1 (P<0.05). CONCLUSIONS: The expression of LILRA3 is up-regulated in CD14+ monocyte subset isolated from RA patients, and it is correlated with disease activity.
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Artritis Reumatoide , Monocitos , Receptores Inmunológicos , Regulación hacia Arriba , Artritis Reumatoide/sangre , Artritis Reumatoide/fisiopatología , Autoanticuerpos/sangre , Biomarcadores/sangre , Citometría de Flujo , Humanos , Monocitos/metabolismo , Receptores Inmunológicos/genéticaRESUMEN
OBJECTIVES: To compare the sensitivities of individual and combined sonography of hyperechoic aggregates and the double-contour sign in detecting monosodium urate (MSU) crystal deposits in gouty joints. METHODS: Monosodium urate crystal deposits in symptomatic and contralateral asymptomatic joints of 70 patients with acute gout were evaluated by sonography of hyperechoic aggregates and the double-contour sign individually and in combination. All patients with acute gout in this study had at least 1 symptomatic joint with MSU deposits determined by dual-energy computed tomography. RESULTS: Of 195 symptomatic joints (92 in the upper limbs and 103 in the lower limbs) and an equal number of asymptomatic joints: (1) 97.14% (68 of 70) of patients had hyperechoic aggregate/double-contour sign-positive joints versus 74.29% (52 of 70) with double-contour sign-positive and 63.89% (46 of 70) with hyperechoic aggregate-positive joints; (2) 86.96% (80 of 92) of the symptomatic upper limb joints were double-contour sign/hyperechoic aggregate positive versus 46.74% (43 of 92) that were double-contour sign positive and 70.65% (65 of 92) that were hyperechoic aggregate positive; and (3) 98.06% (101 of 103) of the symptomatic lower limb joints were double-contour sign/hyperechoic aggregate positive versus 92.23% (95 of 103) that were double-contour sign positive and 41.75% (43 of 103) that were hyperechoic aggregate positive. CONCLUSIONS: Hyperechoic aggregates and the double-contour sign in combination improve the investigative sensitivity of sonography than either hyperechoic aggregates or the double-contour sign individually for detecting MSU crystal deposits in gouty joints.