Objective. To describe the clinical, laboratory, and radiographic manifestations of Takayasu arteritis (TA) in a cohort from the US, evaluate the response to interventions, remission and relapse rates, and disease progression, and compare these observations with those from other cohorts in the US, Japan, India, Italy, and Mexico.Methods. Seventy-five patients were retrospectively studied using a uniform database that included clinical, laboratory, and imaging data. Vascular imaging studies were performed at least yearly to monitor disease progression.Results. Common manifestations at disease onset included loss or asymmetry of pulses (57%), limb blood pressure discrepancy (53%), and bruits (53%). Eleven percent of patients were asymptomatic prior to disease diagnosis. Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries.Ninety-three percent of longitudinally followed patients attained disease remission of any duration, but only 28% sustained remission of at least 6 months' duration after prednisone was tapered to <10 mg daily. Both angioplasty and vascular surgery were initially successful, but recurrent stenosis occurred in 78% of angioplasty and 36% of bypass/reconstruction procedures. More than two-thirds of patients had difficulty performing routine daily activities and approximately one-fourth of all patients were unable to work.Our cohort was similar to the National Institutes of Health, Italian, Japanese, and Mexican cohorts in terms of the predominance of female subjects and disease manifestations, but differed from the Indian cohort in that the latter group had a higher frequency of male subjects, abdominal aorta and renal artery involvement, and hypertension.Conclusion. Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction. Attempts to restore vascular patency are often initially successful, but restenosis occurs frequently. Chronic morbidity and disability occur in most patients with TA in the US.
Objectives To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu’s arteritis (TAK) and giant cell arteritis (GCA). Methods Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. Conclusions Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).
Objective To evaluate the frequency, timing, and clinical features of relapses in giant cell arteritis (GCA). Methods Patients with GCA enrolled in a prospective, multicenter, longitudinal study were included in the analysis. Relapse was defined as either new disease activity after a period of remission or worsening disease activity. Results The study included 128 subjects: 102 women (80%) and 26 men (20%). Mean ± SD age at diagnosis of GCA was 69.9 ± 8.6 years. Mean followup for the cohort was 21.4 ± 13.9 months. Median (interquartile range) duration of disease at study enrollment was 4.6 months (1.2, 16.8). During followup, 59 relapses were observed in 44 patients (34%). Ten patients (8%) experienced 2 or more relapses. The most common symptoms at relapse were headache (42%) and polymyalgia rheumatica (51%), but ischemic (some transient) manifestations (visual symptoms, tongue or jaw claudication, and/or limb claudication) occurred in 29% of relapses (12% cohort). Forty-three relapses (73%) occurred while patients were taking glucocorticoid therapy at a median (range) prednisone dose of 7.5 (0–35) mg. In 21% of relapses, both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were normal. Among 69 patients enrolled in the cohort with newly diagnosed disease, 24% experienced a first relapse within 12 months after diagnosis. Conclusion Among patients with GCA, relapses are common, often occurring during treatment. ESR and CRP are frequently normal at times of clinical relapse, highlighting the need for better biomarkers to assess disease activity in GCA. There remains a need for effective therapeutic alternatives to glucocorticoids in GCA.
Objective Systemic lupus erythematosus is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus, however, early T cell events triggering disease flares are incompletely understood. We studied DNA methylation in naïve CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. Methods A total of 74 lupus patients with disease activity ranging from 0–18 as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were included in this study. Naïve CD4+ T cells were isolated from peripheral blood samples and DNA extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcriptional activity using RNA sequencing and microRNA arrays. Results We demonstrate that naïve CD4+ T cells in lupus undergo an epigenetic pro-inflammatory shift implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without expression changes of corresponding genes, and poises naïve CD4+ T cells for Th2, Th17, and Tfh immune responses, and opposes inhibitory TGF-β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might be playing an important role in shifting the epigenetic landscape with increased disease activity in lupus naïve CD4+ T cells. Further, the expression of miR26a which is sensitive to glucose availability and which targets EZH2 was negatively correlated with disease activity in lupus patients. Conclusion An epigenetic landscape shift in naïve CD4+ T cells that favors T cell activation and non-Th1 immune responses predates transcriptional activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.
Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10−6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.
Objective Takayasu’s arteritis is a rare large vessel vasculitis with incompletely understood etiology. We performed the first unbiased genome-wide association study (GWAS) in Takayasu’s arteritis. Methods Two independent Takayasu’s arteritis cohorts from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 European-derived patients and 1,047 controls. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu’s arteritis. Results We identified genetic susceptibility loci for Takayasu’s arteritis with a genome-wide level of significance in IL6 (rs2069837, OR= 2.07, P= 6.70×10−9), RPS9/LILRB3 (rs11666543, OR= 1.65, P= 2.34×10−8), and an intergenic locus on chromosome 21q22 (rs2836878, OR= 1.79, P= 3.62×10−10). The genetic susceptibility locus in RPS9/LILRB3 is located within the leukocyte receptor complex (LRC) gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P= 2.29×10−8). In addition, we identified candidate susceptibility genes with suggestive levels of association (P <1×10−5) including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B in Takayasu’s arteritis. Conclusion This study identified novel genetic susceptibility loci for Takayasu’s arteritis and uncovered potentially important aspects in the pathophysiology of this form of vasculitis.
Objective. Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified Black race.Methods. EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52-week multicenter, double-blind, placebo-controlled trial in adults of self-identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the double-blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI-2K) (SRI-SLEDAI-2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose.Results. The modified intent-to-treat population comprised 448 patients, of whom 96.9% were women and the mean AE SD age was 38.8 AE 11.42 years. The primary end point (improvement in the SRI-SLEDAI-2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI-SLEDAI-2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double-blind phase withdrawals (belimumab 5.4%, placebo 6.7%).Conclusion. The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.ClinicalTrials.gov identifier: NCT01632241.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.