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Background Studies have suggested that soluble factors in plasma from patients with active (aBD) and inactive (iBD) Behçet’s disease (BD) stimulate neutrophil function. Soluble CD40 ligand (sCD40L) is an important mediator of inflammation in BD. Its expression and effect on neutrophil oxidative burst and neutrophil extracellular trap (NET) release have not been characterized. In this study, we sought to investigate the role of plasma and the CD40L pathway on NET release and the oxidative burst profile in patients with aBD and iBD. Methods Neutrophils and peripheral blood mononuclear cells (PBMCs) were obtained from patients with aBD ( n  = 30), patients with iBD ( n  = 31), and healthy control subjects (HCs; n  = 30). sCD40L plasma concentration was determined in individual samples. A pool of plasma for each group was created. In some experiments, plasma pools were treated with recombinant CD40 (rhCD40-muIg) for sCD40L blockade. NET release and H 2 O 2 /O 2 − production were determined after stimulation with phorbol 12-myristate 13-acetate, sCD40L, or plasma pool. Flow cytometric analysis was performed to evaluate the expression of (1) CD40, Mac-1, and phosphorylated NF-κB p65 on neutrophils and monocytes and (2) CD40L on activated T cells and platelets. CD40L gene expression in PBMCs was determined by qRT-PCR. Results sCD40L plasma levels were significantly higher in patients with iBD (median 17,234, range 2346–19,279 pg/ml) and patients with aBD (median 18,289, range 413–19,883 pg/ml) than in HCs (median 47.5, range 33.7–26.7 pg/ml; p  < 0.001). NET release was constitutively increased in BD compared with HC. NET release and H 2 O 2 /O 2 − were higher after stimulation with sCD40L or BD plasma and decreased after sCD40L blockade. Mac-1 expression was constitutively increased in neutrophils of patients with aBD (88.7 ± 13.2% of cells) and patients with iBD (89.2 ± 20.1% of cells) compared with HC (27.1 ± 18.8% of cells; p  < 0.01). CD40 expression on phagocytes and CD40L expression on platelets were similar in the three groups. PBMCs as well as nonactivated and activated CD4 + T cells from patients with BD showed higher CD40L expression. Conclusions Plasma from patients with aBD exerts a stimulus on NET release and oxidative burst, probably induced by sCD40L.

Takayasu arteritis (TAK) is associated with high plasma homocysteine (Hcy) and elevated Hcy predicts ischemic events. Thus, this study aims to compare the frequency of single-nucleotide polymorphisms (SNPs) of genes involved in Hcy metabolism between TAK and controls and analyze associations with Hcy levels, TAK features, and acute ischemic arterial events (AIAEs). A cross-sectional study was performed with 73 TAK patients and 71 controls. SNPs of genes involved in the Hcy metabolism, plasma Hcy, and risk factors were analyzed for hyperhomocysteinemia (HHcy), cardiovascular disease (CVD), and AIAEs. Patients presented a higher frequency of risk factors for CVD and HHcy. At least one AIAE was observed in 27 (37.0%) patients and one control. The frequency of the SNPs was similar between both groups, and there was no association between SNP carriage and AIAEs. TAK patients presented higher Hcy levels than controls (13.9 ± 5.6 µmol/L vs. 8.6 ± 4.0 µmol/L; p < 0.001), and patients carrying MTHFR677TT presented higher Hcy levels than those carrying MTHFR677CT (20.4 ± 7.8 µmol/L vs. 13.7 ± 5.2 µmol/L; p = 0.02) or MTHFR677CC (20.4 ± 7.8 µmol/L vs. 13.1 ± 4.7 µmol/L; p = 0.009). TAK was an independent risk factor for HHcy [odds ratio (OR) = 10.20; 95% confidence interval (95% CI): 4.16–25.00; p < 0.001], and in TAK, thiazide diuretic use was a risk factor for HHcy (OR = 11.61; 95% CI: 1.63–82.63; p < 0.01). In conclusion, TAK was a risk factor for HHcy but not related to SNPs in genes encoding Hcy metabolism enzymes. The burden of chronic inflammation and thiazide diuretics contribute to HHcy in TAK.

Background Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotypes in biopsies from the airways of patients with active granulomatosis with polyangiitis (GPA) and to analyze their associations with T and B cells in those biopsies, and with nasal carriage of Staphylococcus aureus, disease parameters and therapy. Methods Consecutive GPA patients (n = 35) with active airway disease, who underwent respiratory tract biopsy were included. Immunohistochemical evaluation was performed to assess the distribution of macrophages and T and B cells using the markers CD68, CD3 and CD20, respectively. CD86 was used as the M1 marker and CD163 as the M2 marker while Tbet and GATA-3 were used as Th1 and Th2 markers, respectively. At the time of the biopsy patients were assessed for nasal carriage of Staphylococcus aureus and treatment. Results Percentages of macrophages and T cells were significantly higher than those of B cells in lesional tissue from the respiratory tract in GPA. M2 macrophages and Th2 cells were more frequent than M1 macrophages ( p  = 0.0007) and Th1 cells ( p  < 0.0001), respectively. Percentages of T cells were higher in nose biopsies than in biopsies from other sites ( p  = 0.021); macrophages and CD163 + macrophages were more predominant in biopsy sites other than the nose ( p  = 0.039 and p  = 0.012, respectively). Carriage of Staphylococcus aureus was associated with higher T cell scores ( p  = 0.014). The frequency of macrophages, especially M2 macrophages, was higher in GPA patients treated with immunosuppressive agents ( p  = 0.010); daily prednisolone dose was positively correlated with all macrophage markers. However, in multivariate analysis no independent associations were found between disease parameters and therapy with macrophage markers or T cells. Conclusion In GPA, M2 is the predominant macrophage phenotype in the respiratory tract. Although some associations were observed between macrophages and T cells with therapy and nasal carriage of Staphylococcus aureus , they were not independently significant in multivariate analysis.

BackgroundGiant cell arteritis (GCA) is the most common primary systemic vasculitis in people 50 years of age and over, and it is considered a medical emergency due to the potential risk of permanent visual loss. Color Doppler ultrasound (CDU) of the temporal arteries is a rapid, noninvasive method to diagnose GCA. This study aims to determine the diagnostic accuracy of the halo sign in temporal arteries by CDU in people with suspected GCA.MethodsThe systematic literature review included the search for publications in the following electronic databases: PubMed, Embase, CENTRAL, LILACS, WHO ICTRP, ClinicalTrials.gov, gray literature up to December 2022, and no date or language restrictions were applied. We analyzed studies including patients over 50 years of age with suspected GCA evaluating CDU of temporal arteries as a diagnostic tool against clinical diagnosis as a standard reference. Paper titles and abstracts were selected by two investigators independently for all available records. The quality of the studies was assessed using the Quality of Diagnostic Accuracy Studies tool (QUADAS-2) and the R software (version 4.2.1) was used for data analysis. The protocol of this review is registered with PROSPERO (CRD42016033079).ResultsTwenty-two studies including 2893 participants with suspected GCA who underwent temporal artery CDU were evaluated. The primary analysis results showed a sensitivity of 0.76 [95% confidence interval (95 CI) 0.69–0.81] and specificity of 0.93 (95 CI 0.89–0.95) when the halo sign was compared to clinical diagnosis. The sensitivity value of 0.84 (95 CI 0.72–0.92) and specificity of 0.95 (95 CI 0.88–0.98) were found in five studies involving 1037 participants that analyzed the halo sign and temporal artery compression sign. A sensitivity of 0.86 (95 CI 0.78–0.91) and specificity of 0.95 (95 CI 0.89–0.98) were found in four studies with 603 participants where the halo sign was evaluated CDU on temporal and axillary arteries.ConclusionThe detection of the halo sign by CDU of temporal arteries has good accuracy for the diagnosis of cranial GCA. The compression sign in temporal arteries and the addition of axillary arteries assessment improves the diagnostic performance of CDU for GCA.Trial registrationPROSPERO CRD42016046860.

Background Endothelial progenitor cells (EPCs) are responsible for endothelial damage repair. Takayasu’s arteritis (TA) is a chronic inflammatory disease that affects large vessels. The aim of the study was to evaluate the number of EPCs and the levels of vascular endothelial growth factor (VEGF) and the relationship of these variables in patients with TA. Methods Thirty women with TA and 30 healthy controls were included. EPCs were assessed by flow cytometry and cell culture and VEGF quantification was performed by commercial ELISA kits. Results Ages of patients and controls were similar. The number of EPCs in patients and controls (median (interquartile range) were 0.0073% (0.0081%) vs. 0.0062% (0.0089%), p = 0.779 by flow cytometry and 27.0 (42.3) colony forming units (CFUs) vs. 27.0 (20.5) CFUs, p = 0.473 by cells culture, respectively. VEGF levels in patients and controls was 274.5 (395.5) pg/ml vs. 243.5 (255.3) pg/ml, p = 0.460. There was no difference in the number of EPCs and VEGF level between patients with active and inactive disease. There was a tendency of the number of angioblast-like EPCs in patients taking anti-TNFs to be higher; and in patients using methotrexate to be lower. Conclusion No significant difference was found in the quantification of EPCs and VEGF levels in TA patients compared to controls, and no difference was observed between patients with active and inactive disease.

Background Modifiable cardiovascular risk factors (MCRFs), such as those related to aerobic capacity, muscle strength, physical activity, and body composition, have been poorly studied in Takayasu arteritis (TAK). Therefore, the aim of the study was to investigate MCRFs and their relationships with disease status and comorbidities among patients with TAK. Methods A multicenter cross-sectional study was conducted between 2019 and 2020, in which 20 adult women with TAK were compared with 16 healthy controls matched by gender, age, and body mass index. The following parameters were analyzed: aerobic capacity by cardiopulmonary test; muscle function by timed-stands test, timed up-and-go test, and handgrip test; muscle strength by one-repetition maximum test and handgrip test; body composition by densitometry; physical activity and metabolic equivalent by IPAQ, quality of life by HAQ and SF-36; disease activity by ITAS2010 and NIH score; and presence of comorbidities. Results Patients with TAK had a mean age of 41.5 (38.0–46.3) years, disease duration of 16.0 (9.5–20.0) years, and a mean BMI of 27.7±4.5 kg/m2. Three out of the 20 patients with TAK had active disease. Regarding comorbidities, 16 patients had systemic arterial hypertension, 11 had dyslipidemia, and two had type 2 diabetes mellitus, while the control group had no comorbidities. TAK had a significant reduction in aerobic capacity (absolute and relative VO2 peak), muscle strength in the lower limbs, increased visceral adipose tissue, waist-to-hip ratio, reduced walking capacity, decreased weekly metabolic equivalent, and quality of life (P< 0.05) as compared to controls. However, there were no correlations between these MCRFs parameters and disease activity. Conclusions TAK show impairment in MCRFs; therefore, strategies able to improve MCRF should be considered in this disease.

In this retrospective longitudinal cohort study we included 52 patients with Takayasu arteritis (TA) who were on regular follow-up at the Vasculitis Unit of Universidade Federal de São Paulo between 2003 and 2009. The mean age at study was 38 years and the mean age at diagnosis was 29 years. Patients were followed for a mean 74.3 months. A relapse-remitting course was observed in 41 patients (78.8%) whereas 9 (17.3%) had a monophasic course and only 2 (3.8%) patients were chronic-active. Disease remission was achieved in 50 patients (96.2%). Angiographic type V was observed in 42.3% of TA patients at diagnosis and in 61.5% during follow-up. The most affected arteries were the abdominal aorta (63.5%) and left subclavian (60.6%). Prednisone was used by 94% of TA patients and immunosuppressive agents were prescribed for 51 (98%) patients. Methotrexate was used by 82.7%, followed by cyclophosphamide (26.9%), azathioprine (25.0%), anti-TNFα agents (5.8%) and leflunomide (5.8%). Although, forty patients (76.9%) used prednisone and methotrexate as initial treatment, 75% of them developed new vascular lesions along follow-up. Eighteen TA patients (34.6%) needed to change immunosuppressive therapy due to failure or toxicity, among them 83.3% presented new lesions. Surgical treatment was performed in 34.6% of patients and restenosis was observed in 13.5% in a median time of 11 months after surgery. In conclusion besides prednisone and methotrexate is largely used in TA, the majority of patients still develop new arterial lesions along time.

The objective of this study was to evaluate traditional risk factors for cardiovascular disease (CVD) and endothelin-1 (ET-1) levels in Takayasu arteritis (TA) patients. Twenty-two TA patients and 37 controls were evaluated. TA patients had a higher prevalence of hypertension (63.6% vs. 21.6%, p = 0.001) and higher levels of triglycerides (129.5 mg/dL ± 70.8 vs. 88.4 mg/dL ± 60.8, p = 0.017) than controls. Mean number of CVD risk factors was 1.64 ± 1.22 in TA patients and 1.03 ± 1.44 among controls, p = 0.030. More TA patients presented at least one CVD risk factor when compared to controls (77.2% vs. 51.3%, p = 0.048). ET-1 levels were higher in patients than in controls (1.49 pg/mL ± 0.45 vs. 1.27 pg/mL ± 0.32, p = 0.034), however no significant difference was found between patients with active and inactive disease. In this study, TA patients presented a higher prevalence of hypertension, higher levels of triglycerides, and ET-1 than controls.

Type and frequency of systemic and neurologic manifestations of Behçet’s disease (BD) vary with ethnicity. In Brazil, BD occurs as sporadic cases. We describe clinical and radiological features of 36 Brazilian patients of mixed ethnicity with neuro-Behçet’s disease (NBD). Medical records of 178 BD patients were reviewed and 36 (20%) NBD patients were identified. Twenty-one NBD patients (58.3%) were female and 27 (75%) presented with parenchymal manifestations. Brainstem involvement was the most common neurologic syndrome (41.7%). Seizures (27.8%), isolated aseptic meningitis (16.7%), optic neuropathy (ON) (16.7%), cerebral venous thrombosis (CVT) (8.3%), peripheral neuropathy (2.8%), and spinal cord involvement (5.6%) were other neurologic manifestations observed among Brazilian NBD patients. Eighteen (50%) had at least one relapse, and isolated aseptic meningitis was the most common relapsing manifestation. No significant differences concerning the number of relapses between parenchymal and non-parenchymal groups were found. A multivariate model including disease duration, cell count in spinal fluid, cyclosporine use, immunosuppressive use at disease onset, age at NBD onset, and ON did not reveal any significant associations with NBD relapse. There was a low frequency of CVT and an unexpected higher number of isolated aseptic meningitis. Brazilian NBD patients present more parenchymal and atypical manifestations, and relapse more often than NBD patients from other populations.

This study aims to evaluate the influence of polymorphisms of the and genes on the outcomes of patients with Takayasu arteritis (TAK). A retrospective cohort study including 81 TAK patients was carried out. Polymorphisms of the genes (rs11119328), (rs1360780) and (N363S, Bcll, TthIIII1, ER22/23EK and 9ß) were genotyped by the Sanger technique. Associations between the gene variants and the haplotypes (HT) of the gene with variables related to the outcome of TAK and glucocorticoid (GC)-related adverse events (AEs) were analyzed. The polymorphism 9β of the gene, which leads to decreased GC sensitivity, was associated with a higher frequency of GC-related AEs [3.0 (2.0-3.8) vs. 2.0 (1.0-3.0); = 0.002] and weight gain (37.5% vs. 8.9%; = 0.012). Worsening glucose tolerance (i.e., a key GC-related AE) was an independent risk factor for acute ischemic events [odds ratio (OR) between 8.9 and 10.2] in all multivariate logistic regression models that included one of the polymorphisms in each model. Moreover, the carriage of 9β in the gene was also an independent risk factor for developing ischemic arterial events (OR: 4.4, 95% confidence interval: 1.1-18.3). None of the other polymorphisms of , and were associated with TAK features or outcomes, nor with GC-related AEs. Worsening glucose tolerance and the carriage of 9β of the gene were independent risk factors for acute ischemic events in TAK. The 9β polymorphism of the gene was associated with GC-related AEs in TAK in our patient population. None of the gene variants were predictors of sustained remission or arterial progression.