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1.
Methods Mol Biol ; 2259: 143-151, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33687712

RESUMO

The versatility of protein microarrays provides researchers with a wide variety of possibilities to address proteomic studies. Therefore, protein microarrays are becoming very useful tools to identify candidate biomarkers in human body fluids for disease states such as rheumatoid arthritis (RA). In RA serum, there is a high prevalence of rheumatoid factor (RF), which is an antibody with high specificity against Fc portion of IgG. The presence of RF, in particular RF-IgM, has the great potential to interfere with antibody-based immunoassays by nonspecifically binding capture antibodies. Because of this concern, we describe a procedure to reduce the interference of RF-IgM on RA serum protein profiling approaches based on multiplexed antibody suspension bead arrays.


Assuntos
Artrite Reumatoide/sangue , Proteômica/métodos , Anticorpos Imobilizados/química , Artrite Reumatoide/diagnóstico , Biomarcadores/análise , Biomarcadores/sangue , Humanos , Imunoglobulina M/análise , Imunoglobulina M/sangue , Fator Reumatoide/análise , Fator Reumatoide/sangue
2.
Medicine (Baltimore) ; 100(13): e25019, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787585

RESUMO

BACKGROUND: We aimed to assess the efficacy of resistance exercise in rheumatoid arthritis (RA) in randomized controlled trials (RCTs). METHOD: PubMed, the Cochrane Library, and Embase were searched according to the index words to identify eligible RCTs, and relevant literature sources were also searched. The latest search was done in August 2019. Odds ratios (OR), mean difference (MD), and 95% confidence interval (95% CI) were used to analyze the main outcomes. RESULT: Seventeen RCTs were included in the meta-analysis with 512 patients in the resistance exercise group and 498 patients in the control group. The results showed that compared with the control group, resistance exercise significantly decreased disease activity score in 28 joints (DAS-28) scores (standard mean difference [SMD]: -0.69, 95% CI: -1.26 to -0.11), reduced erythrocyte sedimentation rate (ESR) (SMD: -0.86, 95% CI: -1.65 to -0.07), and shortened the time of 50 ft. walking (SMD: -0.64, 95% CI: -0.99 to -0.28). No significant difference was observed in visual analog scale (VAS) scores (SMD: -0.61, 95% CI: -1.49-0.27) and health assessment questionnaire (HAQ) scores (weighted mean difference: -0.10, 95% CI: -0.26-0.06). CONCLUSION: Resistance exercise showed reducing DAS-28 score, ESR score, and the time of 50 ft. walking in RA patients compared with the control group. However, high quality multicenter RCTs with larger sample sizes to confirm the conclusion.


Assuntos
Artrite Reumatoide/terapia , Terapia por Exercício/métodos , Treinamento de Resistência/métodos , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Sedimentação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento , Velocidade de Caminhada
3.
J Pharm Biomed Anal ; 197: 113971, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33639525

RESUMO

In this pilot study, we carried out metabolic profiling of patients with rheumatoid arthritis (RA) starting therapy with biological disease-modifying antirheumatic drugs (bDMARDs). The main aim of the study was to assess the occurring metabolic changes associated with therapy success and metabolic pathways involved. In particular, the potential of the metabolomics profiles was evaluated as therapeutically valuable prognostic indicators of the effectiveness of bDMARD treatment to identify responders versus non-responders prior to implementing treatment. Plasma metabolomic profiles of twenty-five patients with RA prior bDMARD treatment and after three months of therapy were obtained by 1H NMR, liquid chromatography - mass spectrometry, and gas chromatography - mass spectrometry and evaluated by statistical and multivariate analyses. In the group of responders, significant differences in their metabolic patterns were seen after three months of the bDMARD therapy compared with profiles prior to treatment. We identified 24 metabolites that differed significantly between these two-time points mainly belonging to amino acid metabolism, peptides, lipids, cofactors, and vitamins and xenobiotics. Eleven metabolites differentiated responders versus non-responders before treatment. Additionally, N-acetylglucosamine and N-acetylgalactosamine (GlycA) and N-acetylneuraminic acid (GlycB) persisted significant in comparison responders to non-responders after three months of therapy. Moreover, those two metabolites indicated prediction of response potential by results of receiver-operating characteristic (ROC) curve analysis. The applied analysis provides novel insights into the metabolic pathways involved in RA patient's response to bDMARD and therapy effectiveness. GlycA and GlycB are promising biomarkers to identify responding patients prior onset of bDMARD therapy.


Assuntos
Acetilgalactosamina/sangue , Artrite Reumatoide/sangue , Biomarcadores/sangue , Metabolômica , Ácido N-Acetilneuramínico/sangue , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Resultado do Tratamento
4.
Medicine (Baltimore) ; 100(3): e24186, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546034

RESUMO

ABSTRACT: Myostatin is a cytokine produced and released by myocytes that might have an outstanding role not only in muscle wasting during cachexia but also in inflammation. Herein we explore the association between myostatin levels and inflammatory parameters in rheumatoid arthritis (RA).One hundred twenty-seven women without rheumatic diseases and 84 women with a diagnosis of RA were assessed in a cross-sectional study. Outcomes reflecting the activity of the arthritis including Disease Activity Score (DAS28-ESR) and impairment in functioning by the Health Assessment Questionnaire-Disability Index were assessed in RA. We obtained Skeletal muscle mass index (SMI), fat-free mass index (FFMI), and fat mass index using dual-energy x-ray absorptiometry. Serum myostatin was determined by enzyme-linked immunosorbent assay. Myostatin levels were correlated with disease activity and parameters of muscle mass.The SMI was lower and concentration of myostatin was higher in RA patients than in controls (P = .008 and P < .001, respectively). Myostatin significantly positively correlated with C-reactive protein (rho = 0.48, P < .001), erythrocyte sedimentation rate (rho  = 0.28, P = .009), and DAS28-ESR (rho = 0.22, P  = .04), and negatively correlated with SMI (rho = -0.29, P = .008), (FFMI) (rho = -0.24, P = .027). In the multivariate logistic regression analysis, levels of myostatin remained associated with disease activity in RA (P = .027).In our study, myostatin was associated with disease activity in RA patients, suggesting a mechanistic link between myostatin, muscle wasting and inflammation in RA.


Assuntos
Artrite Reumatoide/sangue , Inflamação/sangue , Miostatina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
5.
Medicine (Baltimore) ; 100(5): e24562, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592912

RESUMO

ABSTRACT: We previously identified E26 transformation specific sequence 1 (ETS1) rs73013527 single nucleotide polymorphism associated with RA susceptibility and disease activity. In the present study, we aims to further investigate the association between ETS1 rs73013527 and receptor activator of nuclear factor kappa B ligand (RANKL), an index related to bone destruction and was reported to elevate in RA.We determined genotypes of ETS1 rs73013527, serum RANKL concentration, clinical characteristics (disease duration, disease activity score for 28 painful/swollen joints), and laboratory markers (rheumatoid factor, anti-citrullinated protein antibody, anti-keratin antibody, c-reactive protein, erythrocyte sedimentation rate) of 254 RA cases. Univariate and multivariate analysis were employed to explore the association between ETS1 rs73013527 and serum RANKL levels in RA patients.Univariate and multivariate analysis indicated no association of serum RANKL levels with patient age, gender, clinical characteristics, and laboratory markers. Univariate analysis, not multivariate analysis indicated genotype CT/TT of ETS1 rs73013527 was significantly associated with elevated RANKL levels in RA patients.ETS1 rs73013527 is in relation to serum RANKL levels among patients with RA. ETS1 probably might be an indirect factors involved in RANKL regulation in RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/fisiopatologia , Proteína Proto-Oncogênica c-ets-1/genética , Ligante RANK/sangue , Adulto , Idoso , Artrite Reumatoide/sangue , Biomarcadores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
6.
Mol Med Rep ; 23(1): 1, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33169172

RESUMO

Circular RNAs (circRNAs) have gained attention due to their performance in disease diagnosis. However, the characteristics of circRNAs in peripheral blood from patients with systemic lupus erythematosus (SLE) remain unknown. Therefore, the aim of the present study was to determine the expression profile and diagnostic potential of circRNAs in peripheral blood from patients with SLE. The global circRNA expression in the peripheral blood of patients with SLE and healthy controls (HCs) was detected using a circRNA microarray. Then, the expression levels of three upregulated circRNAs were selected for further validation by reverse transcription­quantitative PCR (RT­qPCR) in a training set. Moreover, the diagnostic value of these circRNAs was assessed by constructing a receiver operating characteristic curve, and then verified in a blind testing set. In total, 1,566 circRNAs were identified to be dysregulated between patients with SLE and HCs (≥2 fold change, P<0.05). Furthermore, the RT­qPCR results were consistent with the microarray data, in that all three selected circRNAs, hsa_circ_0082688, hsa_circ_0082689 and hsa_circ_0008675, were significantly upregulated in patients with SLE (P<0.05). Results from the training set demonstrated that the combination of hsa_circ_0082688­hsa_circ_0082689 may provide the most beneficial diagnostic potential. Moreover, the blind test results indicated that the combination model of hsa_circ_0082688­hsa_circ_0082689 could effectively discriminate between patients with SLE from patients with rheumatoid arthritis and HCs, with a sensitivity of 91.30%, a specificity of 78.57% and an accuracy of 82.28%. Moreover, the combination model of hsa_circ_0082688­hsa_circ_0082689 + anti­dsDNA could more effectively discriminated the SLE group from the control groups, with a sensitivity of 95.65%, a specificity of 100.00% and an accuracy of 98.73%. In addition, correlation analysis results suggested that all three circRNAs in patients with SLE did not correlate with the SLE disease activity index. In conclusion, the expression levels of hsa_circ_0082688­hsa_circ_0082689 may serve as potential biomarkers for SLE diagnosis.


Assuntos
Biomarcadores/sangue , Leucócitos Mononucleares/química , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , RNA Circular/sangue , Adolescente , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Correlação de Dados , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Circular/genética , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
7.
Cytokine ; 138: 155399, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33338916

RESUMO

BACKGROUND: The overall clinical outcome of inflammatory conditions is the result of the balance between pro-inflammatory and anti-inflammatory mediators. Because nuclear factor kappa B (NF-ĸB) is at the bottom of many inflammatory conditions, methods to evaluate the net effect of inflammation modulators on this master regulator have been conceptualized for years. METHODS: Using an ex vivo NF-ĸB reporter cell line-based assay, plasma samples of patients with rheumatoid arthritis (n = 27), psoriasis (n = 15), or severe coronavirus disease-19 (COVID-19) (n = 21) were investigated for NF-ĸB activation compared to plasma samples from 9 healthy volunteers. RESULTS: When separated by C-reactive protein (CRP) threshold levels, samples of patients exhibiting increased CRP levels (≥5 mg/l) activated NF-ĸB more efficiently than samples from patients with levels below 5 mg/l (P = 0.0001) or healthy controls (P = 0.04). Overall, there was a moderate association of CRP levels with NF-ĸB activation (Spearman r = 0.66; p < 0.0001). Plasma from COVID-19 patients activated NF-ĸB more efficiently (mean 2.4-fold compared to untreated reporter cells) than samples from any other condition (healthy controls, 1.8-fold, P = 0.0025; rheumatoid arthritis, 1.7-fold, P < 0.0001; psoriasis, 1.7-fold, P < 0.0001). In contrast, effects of rheumatoid arthritis, psoriasis, or healthy volunteer samples did not differ. CONCLUSION: This study shows that a NF-ĸB reporter cell line can be used to evaluate the net inflammatory effect of clinical plasma samples. Patients with chronic but stable rheumatoid arthritis or psoriasis do not exhibit increased plasma levels of NF-ĸB-activating compounds as opposed to COVID-19 patients with high inflammatory burden.


Assuntos
Artrite Reumatoide/patologia , NF-kappa B/sangue , NF-kappa B/metabolismo , Psoríase/patologia , Artrite Reumatoide/sangue , Proteína C-Reativa/análise , Linhagem Celular , Ativação Enzimática/fisiologia , Feminino , Células HEK293 , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , /imunologia
8.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327502

RESUMO

While the most common manifestations associated with rheumatoid arthritis (RA) are synovial damage and inflammation, the systemic effects of this autoimmune disorder are life-threatening, and are prevalent in 0.5-1% of the population, mainly associated with cardiovascular disorders (CVDs). Such effects have been instigated by an altered lipid profile in RA patients, which has been reported to correlate with CV risks. Altered lipid paradox is related to inflammatory burden in RA patients. The review highlights general lipid pathways (exogenous and endogenous), along with the changes in different forms of lipids and lipoproteins in RA conditions, which further contribute to elevated risks of CVDs like ischemic heart disease, atherosclerosis, myocardial infarction etc. The authors provide a deep insight on altered levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) in RA patients and their consequence on the cardiovascular health of the patient. This is followed by a detailed description of the impact of anti-rheumatoid therapy on the lipid profile in RA patients, comprising DMARDs, corticosteroids, anti-TNF agents, anti-IL-6 agents, JAK inhibitors and statins. Furthermore, this review elaborates on the prospects to be considered to optimize future investigation on management of RA and treatment therapies targeting altered lipid paradigms in patients.


Assuntos
Artrite Reumatoide/metabolismo , Doenças Cardiovasculares/metabolismo , Animais , Artrite Reumatoide/sangue , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Fatores de Risco , Triglicerídeos/sangue
9.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348817

RESUMO

Most rheumatic diseases, including rheumatoid arthritis (RA), are characterized by immune disorders that affect antibody activity. In the present study, using Dot blot and ELISA assay, we showed that patients with rheumatic disease produced significantly more antibodies against lipopolysaccharide (LPS) P. mirabilis O3 compared to healthy donors (p < 0.05), and affinity purified antibodies against LPS O3 may cross-react with collagen type I. It was demonstrated that purified of antibodies isolated from RA patients sera, reacted stronger with the collagen than healthy donors (p = 0.015), and cross-reaction was correlated with level of anti-citrullinated peptide antibodies (r = 0.7, p = 0.003). Moreover, using six different lipopolysaccharides were demonstrated the significant correlations in sera reactivity among lysine-containing lipopolysaccharides observed in patients' sera (p < 0.05). Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR) it was shown that unique wavenumbers of sera spectra correlate with reactivity with lipopolysaccharides allowing distinguish patients from healthy blood donors. Antibodies adsorption by synthetic antigens shows that in patients' group anti-LPS O3 antibodies can be adsorbed by both amides of galacturonic acid and lysine or threonine, which suggests less specificity of antibodies binding with non-carbohydrate LPS component. The observed correlations suggest that non-carbohydrate components of LPS may be an important epitope for less specific anti-LPS antibodies, which might lead to cross-reactions and affect disease development.


Assuntos
Anticorpos Antibacterianos/sangue , Artrite Reumatoide/imunologia , Colágeno Tipo I/metabolismo , Lipopolissacarídeos/imunologia , Lisina/imunologia , Proteus mirabilis/imunologia , Anticorpos Antibacterianos/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/microbiologia , Estudos de Casos e Controles , Colágeno Tipo I/imunologia , Reações Cruzadas , Epitopos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Intern Med ; 59(22): 2927-2930, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32999229

RESUMO

Tocilizumab (TCZ; Actemra/RoActemra) is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases and cytokine storms. The present case is a 63-year-old female well-controlled RA patient, who presented with a progressive cognitive impairment after 34 months of TCZ administration. Brain magnetic resonance imaging (MRI) showed leukencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). The discontinuation of TCZ improved her cognitive function and brain MRI findings at 3 months after drug cessation. The present case suggests that TCZ may sometimes cause leukoencephalopathy after long-term administration, and thus the early discontinuation of TCZ is recommended to achieve a good prognosis.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Leucoencefalopatias/induzido quimicamente , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Citocinas/sangue , Feminino , Humanos , Leucoencefalopatias/diagnóstico , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos
11.
N Engl J Med ; 383(16): 1511-1521, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33053283

RESUMO

BACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear. METHODS: In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6. RESULTS: A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels. CONCLUSIONS: In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Proteína Coestimuladora de Linfócitos T Induzíveis/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Abatacepte/efeitos adversos , Administração Oral , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Proteína C-Reativa/análise , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Infusões Intravenosas , Análise de Intenção de Tratamento , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Indução de Remissão
12.
Medicine (Baltimore) ; 99(41): e22504, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031288

RESUMO

In clinical trials of tofacitinib for rheumatoid arthritis (RA), Japanese and Korean patients had higher incidence of herpes zoster (HZ) than subjects from elsewhere; however, post-market data from Asia are lacking. Hence, we investigated the incidence of HZ and its risk factors in Taiwanese RA patients receiving tofacitinib. At a medical center in Taichung, Taiwan, we enrolled patients with active RA treated with tofacitinib between January 4, 2015 and December 9, 2017, following unsuccessful methotrexate therapy and no tofacitinib exposure RA patients as a control group. Demographic characteristics, interferon-gamma levels, and lymphocyte counts were compared. Among 125 tofacitinib-treated RA patients, 7 developed HZ, an incidence rate of 3.6/100 person-years. Patients with HZ had shorter disease duration than those without, but higher frequency of prior HZ. Baseline interferon-gamma levels and HLA-DR activated T cell counts were positively correlated and significantly lower in patients with HZ than without. Strikingly, 5/7 HZ cases occurred within 4 months of starting tofacitinib therapy. Incidence of HZ in tofacitinib-treated Taiwanese RA patients is lower than rates in Japan or Korea, and commensurate with the global average. HZ may occur soon after commencing tofacitinib therapy. The role of interferon-gamma and activated T cells in tofacitinib-related HZ deserves further investigation.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Linfócitos T , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Interferon gama/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia
13.
Medicine (Baltimore) ; 99(44): e22892, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126340

RESUMO

T cell immunoglobulin and mucin domain-3 (TIM-3) is a surface molecule expressed on immune cells which play a role in immune regulation. The aims of the present study were to determine whether circulating soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) are elevated in rheumatoid arthritis (RA) patients, and investigate the relationships between sTIM-3 and clinical features of RA.The study included 116 patients with established RA and 27 healthy control subjects. Serum levels of sTIM-3 were measured via the enzyme-linked immunosorbent assays (ELISA). Correlations between serum sTIM-3 and a range of parameters including anti-citrullinated peptide antibody (ACPA) titer, erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3) were assessed.Serum sTIM-3 was significantly elevated in RA patients compared with those in healthy subjects, and it was positively correlated with ACPA titer (r = 0.27 P = .005), ESR (r = 0.27, P = .004) and MMP-3 (r = 0.35, P < .001). In RA patients with high ACPA titers (≥200 U/mL), sTIM-3 was not correlated with ESR or MMP-3. Whereas, sTIM-3 was significantly correlated with ESR and MMP-3 in RA patients with low ACPA titers (<200 U/mL).Serum sTIM-3 was increased in RA patients, and it was associated with proinflammatory markers and disease activity in RA patients under a particular ACPA status. Our data suggest that circulating sTIM-3 may be a useful biomarker for the determination of disease activity in RA patients.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide , Receptor Celular 2 do Vírus da Hepatite A/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Sedimentação Sanguínea , Correlação de Dados , Progressão da Doença , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Metaloproteinase 3 da Matriz/sangue , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Gravidade do Paciente
14.
Nat Commun ; 11(1): 5420, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110080

RESUMO

Biomarkers are needed for predicting the effectiveness of disease modifying antirheumatic drugs (DMARDs). Here, using functional lipid mediator profiling and deeply phenotyped patients with early rheumatoid arthritis (RA), we observe that peripheral blood  specialized pro-resolving mediator (SPM) concentrations are linked with both DMARD responsiveness and disease pathotype. Machine learning analysis demonstrates that baseline plasma concentrations of resolvin D4, 10S, 17S-dihydroxy-docosapentaenoic acid, 15R-Lipoxin (LX)A4 and n-3 docosapentaenoic-derived Maresin 1 are predictive of DMARD responsiveness at 6 months. Assessment of circulating SPM concentrations 6-months after treatment initiation establishes that differences between responders and non-responders are maintained, with a decrease in SPM concentrations in patients resistant to DMARD therapy. These findings elucidate the potential utility of  plasma SPM concentrations as biomarkers of DMARD responsiveness in RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Líquido Sinovial/efeitos dos fármacos , Antirreumáticos/sangue , Artrite Reumatoide/patologia , Estudos de Coortes , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Graxos Insaturados/sangue , Humanos , Lipoxinas/sangue , Resultado do Tratamento
15.
Medicine (Baltimore) ; 99(35): e21827, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871905

RESUMO

To retrospectively evaluate initial tumor necrosis factor inhibitor (TNFi) failure patients for clinical predictors of response to a 2nd TNFi in our 4282 rheumatoid arthritis (RA) patient database.A cross-sectional retrospective manual chart review of the electronic health record (EHR) was performed on 322 "real world" RA patients who were prescribed 2 TNFis. Response to TNFi was determined by the treating provider who had real time Clinical Disease Activity Index (CDAI) scores to inform treatment decisions. Age, gender, body mass index (BMI), insurance provider, duration of disease, cyclic citrullinated peptide antibody (CCP) and rheumatoid factor (RF) positivity, concomitant disease modifying anti-rheumatic drug therapy, length of time between diagnosis and start of 1st and 2nd TNFi, transient efficacy of 1st TNFi (defined as response to TNFi at 3 months but later lost response), and reason for discontinuation of 1st TNFi were analyzed. A multivariable logistic regression model was used to model response to a 2nd TNFi.Response proportions to the 2nd TNFi were greater in females (161/223, 72.2% response female vs 41/75, 54.7% male, P < .01), those who began their 1st TNFi within 3 months of their RA diagnosis, and in RF+ patients (123/170, 72.4% response seropositive vs 66/110, 60.0% seronegative, P < .03). The higher female response rate was independent of age, BMI, and seropositivity.In RA patients who failed an initial TNFi, female patients and patients with RF+ were more likely to have a clinical response to a 2nd TNFi. In the absence of these predictors, stronger consideration for choosing a biologic with an alternative mechanism of action might be given when the 1st TNFi fails.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator Reumatoide/sangue , Fatores Sexuais , Tempo para o Tratamento
16.
Mol Immunol ; 127: 1-11, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32866740

RESUMO

T regulatory (Treg)/T-helper (Th) 17 imbalance has been shown to integrate with epigenetics to result in the development of autoimmune diseases. We aim to investigate the influence of disease staging on Treg/Th17 cells and whether the aberrant DNA methylation is implicated in the development of rheumatoid arthritis (RA). By recruiting 65 patients with multi-staging RA and 20 healthy controls (HC), we found that patients with active RA exhibited relative lymphopenia and higher WBC, neutrophils, and PLT. Circulating Treg/Th17 in patients with early active RA was significantly decreased. The expression of IL-6 and IL-17A was significantly increased in early active RA, whereas that of IL-10 and TGF-ß was on the contrary. Furthermore, the frequency of Treg cells and Treg/Th17 were negatively correlated with DAS28, and the frequency of Th17 cells was on the contrary. Levels of DNA methylation related enzymes had significant difference between early active RA and HC. Relative hypermethylation was observed at the gene level for Treg-specific demethylated region (TSDR) and hypomethylation for retinoic acid-related orphan receptor (ROR)-C in early active RA. Thus, manifestations of RA and Treg/Th17 imbalance vary with disease staging, and the aberrant DNA methylation pattern may contribute to RA disease pathogenesis. Our results highlight the importance of disease staging in clinical research.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Metilação de DNA/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Artrite Reumatoide/sangue , Contagem de Células Sanguíneas , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade
17.
Medicine (Baltimore) ; 99(30): e21151, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791688

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ≥24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines. DISCUSSION: The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will explore whether parameters at baseline can predict a nonclinical relapse after switching from originator IFX to CT-P13 by integrating multilateral assessments, i.e., clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on October 11, 2019 as jRCTs071190030.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Quimiocinas/sangue , Infliximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Substituição de Medicamentos , Estudos de Equivalência como Asunto , Humanos , Japão , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Índice de Gravidade de Doença , Ultrassonografia , Adulto Jovem
18.
J Clin Neurosci ; 78: 97-101, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32620475

RESUMO

BACKGROUND: The aim of this nationwide age- and sex matched longitudinal follow up study is to determine the risk of acute myocardial infarction (AMI) associated with the seropositive rheumatoid arthritis (RA) population in Korea. METHODS: Patient data were collected from the National Health Insurance Service Health Screening cohort. RA was identified using the International Classification of Diseases code M05 (seropositive RA), with a prescription of any disease-modifying anti-rheumatic drug (DMARD). A total of 2,765 patients were enrolled in the seropositive RA group from January 1, 2004 to December 31, 2015 from the NHIS. The control group consisted of 13,825 subjects. The 12-years AMI incidence rate for each group was calculated using the Kaplan-Meier method. A Cox proportional-hazards regression analysis was used to estimate the hazard ratio of AMI. RESULTS: During the follow-up period, 39 patients (1.41%) in the seropositive RA group and 111 (0.80%) in the control group experienced AMI (P = 0.003). The hazard ratio of AMI in the seropositive RA group was 3.879 (95% confidence interval (CI): 2.64-5.68) after adjusting for age and sex. The adjusted hazard ratio of AMI in the seropositive RA group was 4.212 (95% CI: 2.86-6.19) after adjusting for demographics and comorbid medical disorders. According to subgroup analysis, in male and female and the non-diabetes and non-hypertension and hypertension and dyslipidemia and non-dyslipidemia subgroups, AMI incidence rates were significantly higher in the seropositive RA group than in the control group. CONCLUSION: Our nationwide longitudinal study suggests an increased risk of AMI in seropositive RA patients.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/epidemiologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , República da Coreia/epidemiologia
19.
Medicine (Baltimore) ; 99(28): e21222, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664175

RESUMO

Cervus and cucumis peptides (Lugua polypeptides, LG) are traditional Chinese medicine, which are active components of polypeptide extracted from Sika deer bone and melon seed, and they contain bone induced polypeptide biological factors. Umbilical cord mesenchymal stem cell, (UC-MSC) have tissue repair multiple effects, anti-inflammatory, and immune regulation function, which become a very promising start in rheumatoid arthritis (RA) treatment. Hence, LG combined UC-MSC can significantly enhance the UC-MSC treatment of rheumatoid arthritis (RA).To explore the clinical curative effect and therapeutic mechanism of LG combined UC-MSC for treating RA.119 patients were divided into control and treatment groups, and both groups were treated with methotrexate tablets, leflunomide, and UC-MSC. But, LG were added to the treatment group. In vitro, the effects of LG on UC-MSC cell secretion of anti-inflammatory factors were also performed.The Health Assessment Questionnaire; the 28 joint disease activity score; C reactive protein; the erythrocyte sedimentation rate; rheumatoid factor; and anti-cyclic citrullinated peptide antibody were significantly reduced in treatment group 1 year after treatment (P < .05). In vitro, compared with the control group, the number of hepatocyte growth factor (HGF), the secretion of prostaglandin E2 (PGE2) and tumor necrosis factor-inducible gene 6 protein (TSG6) increased significantly (P < .05).LG combined UC-MSCs can significantly improve the curative effect of RA patients, while LG may reduce inflammatory cytokines, regulate immunity, improve microcirculation, and are conducive to UC-MSCs migration and the repair of damaged tissue.


Assuntos
Artrite Reumatoide/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/química , Adulto , Animais , Artrite Reumatoide/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Cucumis , Cervos , Feminino , Fator de Crescimento de Hepatócito/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Resultado do Tratamento , Cordão Umbilical/citologia
20.
Mol Immunol ; 125: 1-8, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610164

RESUMO

BACKGROUND: Follicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. METHODS: We recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-ß (Transforming growth factor-ß) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-ß mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. RESULTS: RA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-ß (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-ß mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-ß was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. CONCLUSIONS: The decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfh cells may be responsible for the immunopathogenesis of RA.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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