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1.
Gene ; 722: 144098, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494241

RESUMO

This study evaluated the possible association between SNPs in cytokines coding genes, namely IL10, IL6 and IFNG, cytokines serum levels and clinical assessment' scores in patients with Rheumatoid Arthritis(RA). SNPs genotyping was performed in 126 RA patients and 177 healthy individuals with Taqman probes specific for IL10 -1082 (T>C, rs1800896);INFG -1616 (A>G, rs2069705) and IL6 -174 (G>C, rs1800795) variants,positioned in regulatory regions. Cytokine Bead Array (CBA) was used to measure cytokine levels. We found association between INFG -1616 G allele(p = 0.0210; OR = 1.605) and INFG -1616 GG genotype (p = 0.0268; OR =2.609) and RA susceptibility. We also observed association between IL10 -1082 TT genotype and high clinical disease activity index (CDAI) values (p = 0.026; OR = 1.906; 95% CI = 1.082 - 3.359), IL10 -1082 CC genotype and low CDAI values (p = 0.016; OR = 0.256) and INFG -1616 AA and high CDAI values (p = 0.025; OR = 2.919). IL10 -1082 CC also exhibited the lowest IL-10 levels than IL10 -1082 TT (p = 0.020) and IL10 -1082 TC (p = 0.032). Finally, we verified higher IL-6 value in the RA patients than healthy control group (p = 0.007) and an association between high IL-6 levels and increased CDAI (r = 0.4648, p = 0.0015); DAS 28 (r = 0.3933, p= 0.0091), presence of bone erosions (r = 0.3170, p = 0.0361), ESR levels(r = 0.3041, p = 0.0448) and IFN-γ levels (r = 0.3049, p = 0.0468).Altogether, we suggest that IL10 -1082 (T>C, rs1800896) and INFG -1616(A>G, rs2069705) polymorphisms as well as IL-6 levels alterations may play a role for prognostic and disease follow-up.


Assuntos
Artrite Reumatoide/genética , Interferon gama/genética , Interleucina-10/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade
2.
Dentomaxillofac Radiol ; 49(1): 20190186, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31530023

RESUMO

OBJECTIVES: This study was undertaken as an attempt to assess radiographic temporomandibular joint (TMJ) changes in relation to rheumatoid factor (RF), anticitrullinated protein (ACCP) antibodies and disease activity score 28 (DAS28) in rheumatoid arthritis (RA) patients to find the best predictor of rheumatoid affection of the TMJ with the ultimate goal of maintaining TMJ function and preventing joint damage. METHODS: 20 Rheumatoid Arthritis patients as well as 20 volunteers were included in this study. RA group were assessed for RF, ACCP, DAS28. Both groups were assessed by CBCT for TMJ dimensions and radiographic osteoarthritic changes. All data were statistically analyzed. RESULTS: Rheumatoid Arthritis group showed significantly less condylar height and more radiographic osteoarthritic changes than the control group. RF showed no significant correlation with either TMJ measurements or TMJ radiographic osteoarthritic changes. ACCP showed significant inverse correlation with condylar height and anteroposterior (AP) dimensions, but non-significant relation with mediolateral dimension and radiographic osteoarthritic changes. DAS28 showed significant inverse correlation with condylar AP and mediolateral dimensions. It also showed significant correlation with flattening of the TMJ condylar head and flattening of the articular fossa. Patients with high and moderate disease activity showed significantly smaller AP TMJ dimension than patients with low disease activity. Disease activity showed statistically significant direct correlation with all osteoarthritic changes except for erosions of the glenoid fossa and condyle. CONCLUSION: Disease Activity Score28 score and disease activity are strong indicators of TMJ affection in RA patients when compared to RF and ACCP. ACCP is a better indicator of changes in condylar measurements than TMJ osteoarthritic changes. While RF is the least efficient indicator of TMJ involvement in RA patients.


Assuntos
Artrite Reumatoide , Côndilo Mandibular , Articulação Temporomandibular , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Humanos , Côndilo Mandibular/diagnóstico por imagem , Articulação Temporomandibular/diagnóstico por imagem
3.
Pain Res Manag ; 2019: 4705247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885755

RESUMO

Background: Moxibustion has a therapeutic effect of reducing swelling and relieving pain in patients with rheumatoid arthritis (RA) but its mechanism is uncertain. Objective: To evaluate the effect of moxibustion on serum levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in patients with RA and to explore the possible mechanism of moxibustion. Methods: This study involved 46 RA patients who had fulfilled the inclusion criteria and were randomly assigned to a treatment group and a control group in an equal ratio. The control group was treated with methotrexate or leflunomide, while the treatment group received methotrexate or leflunomide and moxibustion at ST 36 (Zusanli), BL 23 (Shenshu), and Ashi points. Patients' clinical symptoms, RA-associated serum markers, and serum levels of TNF-α, IL-1ß, HIF-1α, and VEGF were compared in the two groups before and after intervention. Statistical analysis was performed using SPSS 21.0 statistical software. Results: 37 of 46 RA patients eventually completed the whole treatment course. Compared with the control group, the treatment group significantly improved the clinical symptoms (P < 0.05) but with no significant differences in RA-associated serum markers (P > 0.05). There were significant differences in TNF-α and IL-1ß among the groups after 8 weeks of treatment (P < 0.05). HIF-1α and VEGF were decreased in the treatment group after therapy (P < 0.05). VEGF was reduced in the control group (P < 0.05), while HIF-1α was not significantly improved (P > 0.05). The reductions of HIF-1α and VEGF in the treatment group were superior to the control group (P < 0.05). Conclusions: Moxibustion enhanced the anti-inflammatory and analgesic effects of conventional medicine and can enhance the effect of conventional medicine, downregulating HIF-1α/VEGF contents to inhibit angiogenesis.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/terapia , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Moxibustão/métodos , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Anti-Inflamatórios/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Klin Lab Diagn ; 64(11): 673-676, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31747496

RESUMO

The aim was to study the level of some cytokines (IL-2, IL-6, IL-8 TNFα) and calcium regulating hormones (calcitonin, parathyroid hormone, 25 (OH) D) in the blood of patients with rheumatoid arthritis (RA) depending on rheumatoid factor (RF) and the assessment of the role of the revealed violations in the pathogenesis of bone loss in this pathology. For this purpose, 74 patients with RA (59 women, 15 men) aged from 27 to 71 were examined. On the basis of RF in the blood serum, the patients were divided into 2 groups: seronegative and seropositive RA. The control group included 16 healthy individuals (13 women, 3 men). The results obtained that the serological variant of RA affects the serum levels of proinflammatory cytokines and calcium-regulating hormones: more pronounced changes were found in seropositive RA. The high production of IL-2, IL-6, IL-8, TNF-α and parathyroid hormone detected in both groups of patients undoubtedly contributes to the mechanisms of bone loss in RA. In both groups we detected hypovitaminosis D. This results recommended to use this vitamin in the complex treatment of RA.


Assuntos
Artrite Reumatoide/sangue , Calcitonina/sangue , Citocinas/sangue , Hormônio Paratireóideo/sangue , Vitamina D/análogos & derivados , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide , Vitamina D/sangue
5.
Clin Biochem ; 74: 31-35, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31672652

RESUMO

BACKGROUND: In the chronic inflammation process in the course of rheumatoid arthritis (RA), many alterations in the expression of plasma proteins, as well as their posttranslational modifications (including glycosylation) can occur. Taking into account the disturbances in protein glycosylation and the emerging new treatment regimens, the aim of this study was to assess the serum profile of transferrin isoforms in RA patients treated with biological drugs. METHODS: The study included 20 patients (16 females and 4 males; mean age: 53.4 years; range: 24-67) with rheumatoid arthritis treated with rituximab. Serum samples were taken 3 times: before and 3 and 6 months during treatment. The isoforms of transferrin were separated by capillary electrophoresis (MINICAP electrophoretic system, Sebia, France) into five major fractions: asialo-, disialo-, trisialo-, tetrasialo- and pentasialotransferrin. The results were calculated as relative concentrations of each fraction. RESULTS: The median trisialotransferrin relative concentrations after 3 and 6 months treatment (4.40% and 4.10%, respectively) were significantly higher (p = 0.013, p = 0.009, respectively) than before treatment (3.50%). The levels of serum pentasialotransferrin were also increased 3 and 6 months following treatment (16.5% and 17.7%, p = 0.005 and p = 0.006, respectively) as compared to those before therapy (14.5%), while tetrasialotransferrin concentrations were lower (80.3% and 78.4%, p = 0.009 and p = 0.008, respectively) than before treatment (81.5%). Trisialotransferrin relative concentration correlated with Hb (p = 0.019), whereas pentasialotransferrin with PLT (p = 0.036) after treatment. CONCLUSIONS: This study indicates that treatment with rituximab of RA patients alters the serum profile of transferrin isoforms. Tri-, tetra- and pentasialotransferrin relative concentrations measurements can be a useful tool to monitor therapy.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/terapia , Produtos Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Transferrina/análise , Adulto , Idoso , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Eletroforese Capilar , Feminino , Seguimentos , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/sangue , Índice de Gravidade de Doença , Transferrina/química , Resultado do Tratamento , Adulto Jovem
6.
Mayo Clin Proc ; 94(11): 2241-2248, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31619364

RESUMO

OBJECTIVES: To compare the time from first joint swelling to fulfillment of the American College of Rheumatology/European League Against Rheumatism classification criteria between patients with seropositive and seronegative rheumatoid arthritis (RA) and to assess the impact of seronegative status on the time from first joint swelling to initiation of disease-modifying antirheumatic drug (DMARD) therapy and achievement of remission. PATIENTS AND METHODS: Times from first provider-documented joint swelling to fulfillment of the 1987 and 2010 American College of Rheumatology/European League Against Rheumatism criteria and to the clinical diagnosis of RA were measured in a population-based cohort of adults with incident RA between January 1, 2009, and December 31, 2014. Disease characteristics and achievement of remission were compared between seropositive (rheumatoid factor positive and/or anti-citrullinated peptide antibody positive) and seronegative (rheumatoid factor negative/anti-citrullinated peptide antibody negative) patients. RESULTS: The median time from first joint swelling to fulfillment of the 1987 (48 [interquartile range (IQR), 0-300] days vs 2 [IQR, 0-45] days; P=.001) and 2010 (14 [IQR, 0-196] days vs 0 [IQR, 0-29] days; P=.004) classification criteria and the median time from first joint swelling to the clinical diagnosis of RA (187 [IQR, 13-503] days vs 11 [IQR, 0-76] days; P<.001) were significantly longer in seronegative patients than in seropositive patients. The median time from first joint swelling to first prescribed DMARD therapy was significantly longer in seronegative patients (40 [IQR, 5-199] days vs 14 [IQR, 0-73] days; P=.01). Patients with seronegative RA were less likely to achieve remission (28% vs 50% at 5 years after fulfillment of the 2010 criteria; P=.007), but there was no difference when the patient global score was removed from the remission definition. CONCLUSION: Patients with seronegative RA experienced a delay in diagnosis, according to both the 1987 and 2010 classification criteria, as well as a delay in the initiation of DMARD therapy. Patients with seronegative RA were also less likely to attain remission, suggesting that the window of opportunity for intervention may be more frequently missed in this group.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Índice de Gravidade de Doença , Tempo para o Tratamento , Adulto , Artrite Reumatoide/sangue , Feminino , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Resultado do Tratamento
8.
Nat Commun ; 10(1): 4579, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594926

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Imunossupressores/farmacologia , Leflunomida/farmacologia , Acriflavina/farmacologia , Acriflavina/uso terapêutico , Adulto , Animais , Artrite Experimental/sangue , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Células Cultivadas , Colágeno/imunologia , Feminino , Hepatócitos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Ratos , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento
9.
PLoS Med ; 16(9): e1002901, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513665

RESUMO

BACKGROUND: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). METHODS AND FINDINGS: This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (ß: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (ß: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (ß: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (ß: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. CONCLUSIONS: In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. TRIAL REGISTRATION: The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , /uso terapêutico , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/imunologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Itália , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-1/imunologia , Fatores de Tempo , Resultado do Tratamento , /efeitos adversos
10.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540528

RESUMO

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon.


Assuntos
Adipocinas/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Lipídeos/sangue , Idoso , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-6/antagonistas & inibidores
11.
Medicina (Kaunas) ; 55(10)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554310

RESUMO

Background and objectives: Composition of the peripheral blood (PB) cell populations and their activation state reflect the immune status of a patient. Rheumatoid arthritis (RA) is characterized by abnormal B- and T-cell functions. The objective of this study was to assess the profiles of the PB mononuclear cell (PBMC) populations in patients with rheumatoid and osteoarthritis (OA) in comparison with healthy control (HC) subjects in order to evaluate the PBMC profiles as a potential diagnostic characteristic in RA. The second aim was to assess the CCR1 and CCR2 expression on PB lymphocytes and correlate it with the plasma levels of matrix metallopeptidase 9 (MMP-9), IL-17F, TNF-α, IL-6, and IL-10. Materials and Methods: The frequency and phenotype, including CCR1 and CCR2, of the PBMC populations (monocytes, CD19+B cells, and T/NK lymphocytes) in RA (n = 15) and OA (n = 10) patients and HC (n = 12) were analyzed by five-color flow cytometry. DNA of the viruses, HHV-6, HHV-7, and B19, in the whole blood and cell-free plasma, were assessed by nested-polymerase chain reaction (PCR). Results: Active persistent or acute infections, caused by HHV-6, HHV-7, or B19, were not detected in patients of this study. Both CCR1 and CCR2 were determined on the PB B and T/NK lymphocytes in several RA and OA patients and HCs. However, in patients, the frequency of the CCR1-positive T/NK lymphocytes showed a weak negative correlation with the IL-10 level, while the frequency of the CCR2-positive B cells correlated positively with the level of IL-6. Statistically significant differences in the proportions of the CD19-positive and CD19-negative lymphocyte and monocyte subsets within the PBMC set were determined between RA and OA patients and HC adults. Conclusions: We have shown in our pilot study with rather small cohorts of patients that the PBMC-population profiles were very consistent, and statistically significantly differed between RA and OA patients and HC subjects.


Assuntos
Antígenos CD19/análise , Artrite Reumatoide/imunologia , Leucócitos Mononucleares/imunologia , Osteoartrite/imunologia , Adulto , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Humanos , Contagem de Leucócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Osteoartrite/sangue , Projetos Piloto , Valores de Referência
12.
J Immunol Res ; 2019: 3575803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396542

RESUMO

Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n = 36, DAS28 ≥ 3.2), SLE (n = 28, SLEDAI > 6), and SSc (n = 22, revised EUSTAR index > 2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (P corr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (P corr < 0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.


Assuntos
Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Feminino , Humanos , Imunidade Inata/genética , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Transcriptoma
13.
Arthritis Rheumatol ; 71(9): 1450-1459, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385441

RESUMO

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib. METHODS: Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long-term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time-varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. RESULTS: Fifty-two MACE occurred in 4,076 patients over 12,873 patient-years of exposure (incidence rate 0.4 patients with events per 100 patient-years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. CONCLUSION: In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Sedimentação Sanguínea , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
14.
Clin Lab ; 65(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414744

RESUMO

BACKGROUND: Recently, long non-coding RNAs (lncRNAs) have attracted substantial attention owing to their unforeseen critical roles in a wide range of biological processes. The aim of our study was to provide an overview of lncRNA expression profiles in plasma of RA patients. METHODS: The Agilent LncRNA + mRNA Human Gene Expression Microarray V4.0 was employed to determine differentially expressed (DE) lncRNAs and mRNAs in plasma of four female newly diagnosed and DMARD-naïve RA patients and four female age-matched healthy controls. The KOBAS (KEGG Orthology Based Annotation System) software was applied to determine the gene ontology (GO) terms and pathway in which the DE mRNAs were enriched. Furthermore, a lncRNA-mRNA co-expression network was constructed according to the correlation between DE lncRNAs and mRNAs. RESULTS: Compared with healthy controls, a total of 289 DE lncRNAs (169 up-regulated and 120 down-regulated) and 468 DE mRNAs (280 up-regulated and 188 down-regulated) were found in the plasma of patients with RA. Bioinformatics analysis indicated that the DE mRNAs might be involved in the pathogenesis of RA mainly through platelets. In addition, a co-expression network composed of 229 network nodes and 340 connections between 116 lncRNAs and 113 mRNAs was constructed. CONCLUSIONS: We characterized the plasma lncRNA expression profiles in RA patients for the first time. Our results could shed new light on the pathogenesis of RA and help identify lncRNAs as novel diagnostic biomarkers and therapeutic targets for RA.


Assuntos
Artrite Reumatoide/genética , Biomarcadores/metabolismo , Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Longo não Codificante/genética , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Biologia Computacional , Feminino , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Pessoa de Meia-Idade , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , Transdução de Sinais/genética
15.
J Trace Elem Med Biol ; 56: 81-89, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442958

RESUMO

INTRODUCTION: Environmental risk factors regrading rheumatoid arthritis (RA) have not been explored extensively. Selenium (Se), zinc (Zn) and copper (Cu) nutrients were reported to associate with RA, but the results were inconsistent. Therefore, we conduct present study to meta-analyze the relationship between serum Se, Zn and Cu and RA and review the potential mechanisms. METHODS: PubMed, Web of Science and Cochrane Library were comprehensively searched till October 1, 2018 for pertinent studies. Standard mean differences (SMDs) and 95% confident intervals (CIs) were calculated according to random effects model. RESULTS: Finally 41 literatures were included. Meta-analysis of 16 studies involving 806 RA patients and 959 health controls showed that serum Se (SMD = -1.04, 95% CI = -1.58 to -0.50) was decreased in RA patients, and 23 literatures with 1398 patients and 1299 controls reported serum Zn (SMD = -1.20, 95% CI = -1.74 to -0.67) was decreased. But serum Cu (SMD = 1.26, 95% CI = 0.63 to -1.89) was increased with 26 studies including 1723 patients and 1451 controls. Meta-regression reported that steroid use was positively related to serum level of Se in RA (ß = 0.041, 95% CI = 0.002 to 0.079). Differences in serum Se, Zn and Cu between rheumatoid arthritis patients and controls were all related with the geographical distribution. CONCLUSIONS: Patients with RA have significant decreased serum Se and Zn and increased serum Cu than health controls, suggesting potential roles of Se, Zn and Cu in the pathogenesis of RA. Patients and rheumatologist should give enough attention to the monitor of these elements during follow up.


Assuntos
Artrite Reumatoide/sangue , Oligoelementos/sangue , Adulto , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão
16.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430907

RESUMO

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.


Assuntos
Artrite Reumatoide/patologia , Galectinas/imunologia , Granulócitos/patologia , /imunologia , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Células Cultivadas , Feminino , Galectinas/sangue , Granulócitos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fagocitose
17.
J Immunoassay Immunochem ; 40(5): 540-554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366272

RESUMO

Rheumatoid arthritis (RA) is an autoimmune and progressive disease. Evidence indicates that inflammatory mediators may contribute to the genesis and/or evolution of this clinical condition. Thus, the objective was to evaluate and compare the plasma levels of Interleukin-17 (IL-17), Tumor Necrosis Factor-Alpha (TNF-α) and Complement 3 (C3) in women with RA and healthy controls (HC), as well as to evaluate the association them with the disease activity. 25 women with RA and 15 HC were recruited. Plasma levels of biomarkers were measured by ELISA. All statistical analyzes were performed with a significance level set at α = 0.05. In the women with RA, the median age was 55 and, in the HC, was 50 years. The median value of DAS-28 was 3.79. The plasma levels of IL-17 (p = .03), TNF-α (p ≤ 0.01) and C3 (p ≤ 0.01) were higher in women with RA. The ROC curve showed that TNF- α has a higher discriminating ability than IL-17 and C3. DAS-28 score correlated significantly with C3 levels in women with RA (r = 0.91; p < .01). These findings reaffirm the participation of the immune system in pathophysiology of RA, suggest that TNF-α levels may be a good biomarker and that elevated C3 levels contribute to the worsening of the disease.


Assuntos
Artrite Reumatoide/sangue , Complemento C3/análise , Inflamação/sangue , Interleucina-17/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Artrite Reumatoide/patologia , Biomarcadores/sangue , Feminino , Humanos , Pessoa de Meia-Idade
18.
Nat Commun ; 10(1): 3417, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366909

RESUMO

High costs and technical limitations of cell sorting and single-cell techniques currently restrict the collection of large-scale, cell-type-specific DNA methylation data. This, in turn, impedes our ability to tackle key biological questions that pertain to variation within a population, such as identification of disease-associated genes at a cell-type-specific resolution. Here, we show mathematically and empirically that cell-type-specific methylation levels of an individual can be learned from its tissue-level bulk data, conceptually emulating the case where the individual has been profiled with a single-cell resolution and then signals were aggregated in each cell population separately. Provided with this unprecedented way to perform powerful large-scale epigenetic studies with cell-type-specific resolution, we revisit previous studies with tissue-level bulk methylation and reveal novel associations with leukocyte composition in blood and with rheumatoid arthritis. For the latter, we further show consistency with validation data collected from sorted leukocyte sub-types.


Assuntos
Separação Celular/métodos , Biologia Computacional/métodos , Metilação de DNA/genética , Epigênese Genética/genética , Análise de Célula Única/métodos , Artrite Reumatoide/sangue , Ilhas de CpG/genética , Humanos , Contagem de Leucócitos , Leucócitos/classificação , Leucócitos/citologia
19.
Med Sci Monit ; 25: 6474-6481, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31462627

RESUMO

BACKGROUND The objective of this study was to assess the diagnostic value of platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and neutrophil/lymphocyte ratio (NLR) as biomarkers in patients with rheumatoid arthritis (RA) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). MATERIAL AND METHODS Demographic and laboratory data were acquired for 198 RA and 103 RA-ILD patients and 290 healthy controls. The subjects were categorized into female and male groups and further subcategorized based on age into <60 years and ≥60 years subgroups. One-way analysis of variance (ANOVA), receiver operating characteristics (ROC), Pearson analysis, multiple linear regression analysis, and logistic regression analysis were performed to analyze the association of PLR, NLR, and LMR with RA and RA-ILD. RESULTS Mean PLR and NLR were lowest in the control group, followed by the RA and RA-ILD groups (p<0.05). Mean LMR was lowest in the RA-ILD group, followed by the RA and control groups (p<0.05). The area under the ROC (AUROC) values of the PLR to distinguish between RA and controls, RA-ILD and controls, and RA-ILD and RA were 0.676, 0.776, and 0.650, respectively (p<0.001). Multiple linear regression analysis suggested a significantly positive association between the level of PLR and the level of DAS28 (p<0.001). The odds ratio of PLR was 1.101 for RA (p=0.023) and 1.217 for RA-ILD (p<0.001) when compared to the controls. CONCLUSIONS PLR may be applied as a new biomarker for predicting and diagnosing RA and RA-ILD and for distinguishing RA-ILD patients from RA patients and healthy subjects.


Assuntos
Artrite Reumatoide/patologia , Biomarcadores/sangue , Plaquetas/patologia , Doenças Pulmonares Intersticiais/patologia , Linfócitos/patologia , Monócitos/patologia , Neutrófilos/patologia , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/complicações , Masculino , Pessoa de Meia-Idade , Curva ROC
20.
Rev Fac Cien Med Univ Nac Cordoba ; 76(3): 174-179, 2019 08 29.
Artigo em Espanhol | MEDLINE | ID: mdl-31465186

RESUMO

Background: Mortality from cardiovascular disease (CVD) is increased in rheumatoid arthritis, not explained by traditional cardiovascular risk factors (CVRF), suggesting a role of inflammation. This process would occur early. The common sonographic markers of subclinical atherosclerosis (SA), are increased carotid intima-media thickness (cIMT) or the presence of carotid atherosclerotic plaque and they are closely related to CVD. Aims: To evaluate sonographic markers and cardiovascular risk factors in early Arthritis (EA). Methods: A case control study of patients with EA, defined by 3 joints swollen with <1 year of evolution, served consecutively from January 2011 to may 2013, matched with healthy controls, by sex, age and cardiovascular risk factors (hypertension, diabetes mellitus, cardiovascular disease -IAM and ACV, dyslipidemia, family history of CVD) was conducted. We studied demographics data, cardiovascular risk factors, carotid ultrasound measuring increased cIMT or the presence of carotid atherosclerotic plaque in Common Carotid Artery (CCA) and Carotid Bulb (BC), laboratory test that included cholesterol, LDL, HDL, triglycerides in mg%, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR ), anti citrullinated peptide (ACCP), rheumatoid factor (RF), antinuclear antibodies (ANA). EA activity was measured by DAS 28, considering high disease activity (HDA) 5.1; moderate (MDA) from 5.1 to 3.2; and low (LDA) <3.2. Statistics: test Mann-Whitney and chi-square were used, p <0.05 was significant. Results: 25 women, 5 men, average age 43 years (DS 14.7) and 30 controls were included. The average DAS 28 was 4, 8 ± 1. 8; 47% had HDA, 33%MDA and 20%BDA. Both groups had similar values cIMT CCA (0, 57 ± 0.10 mm vs. 0.58 ± 0.15 mm, respectively, P = 0.82) and cIMT BC (0.18mm ± 0.67 vs 0.62 ± 0.15 mm respectively, P = 0.47). There were no carotid plaques. The median total cholesterol was 181,5 vs 183,5 (p = 0.35); triglycerides 99 vs 92,5 (p = 0.68); HDL 54,5 vs 52,5 (p = 0.921 and LDL 105 vs 110 (p = 0.27) in EA and controls respectively. The cIMT CCA and CB were not related to RF, ACCP, CRP, DAS 28 and smoking (NS). There was no difference in other cardiovascular risk factors Conclusions: Ultrasound evidence of atherosclerosis subclinical markers was not found in this study, suggesting that this process may occur after a year of diagnosis.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Biomarcadores/sangue , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Aterosclerose/sangue , Aterosclerose/complicações , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/etiologia , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/patologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ultrassonografia
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