Search

Background: Vascular fibrosis directly causes vascular thickening in Takayasu arteritis (TAK), in which sustained transforming growth factor beta (TGF-β) activation is critical. Understanding TGF-β activation regulation and blocking it might yield a therapeutic effect in TAK. Proprotein convertase subtilisin/kexin type 5 (PCSK5) rs6560480 (T/C) is associated with TAK development. In this study, we assessed the association between the PCSK5 rs6560480 genotype and PCSK5 expression in TAK and explored its molecular role in TGF-β activation and vascular fibrosis development., Methods: In TAK patients, PCSK5 and TGF-β expression in plasma and aortic tissue was examined by ELISA and immunohistochemical staining, and PCSK5 rs6560480 was genotyped. The correlation between PCSK5 and extracellular matrix (ECM) expression was examined by Western blotting (WB) and immunohistochemistry staining. Detection by co-immunoprecipitation was performed to detect the interaction between PCSK5 and TGF-β in adventitial fibroblasts (AAFs). Downstream signaling pathways were detected by WB and validated with appropriate inhibitors. Potential immunosuppressive agents to inhibit the effects of PCSK5 were explored in cell culture and TAK patients., Results: Patients with PCSK5 rs6560480 TT patients had significantly higher PCSK5 levels and more thickened vascular lesions than patients with PCSK5 rs6560480 CT. PCSK5 expression was significantly increased in alpha smooth muscle actin (α-SMA)-positive myofibroblasts in TAK vascular lesions. Overexpressing PCSK5 facilitated TGF-β and downstream SMAD2/3 activation and ECM expression in AAFs and aorta in in-vitro culture. The mechanistic study supported that PCSK5 activated precursor TGF-β (pro-TGF-β) to the mature form by binding the pro-TGF-β cleavage site. Leflunomide inhibited PCSK5 and pro-TGF-β binding, decreasing TGF-β activation and ECM expression, which was also partially validated in leflunomide-treated patients., Conclusion: The findings revealed a novel pro-fibrotic mechanism of PCSK5 in TAK vascular fibrosis via TGF-β and downstream SMAD2/3 pathway activation. Leflunomide might be anti-fibrotic by disrupting PCSK5 and pro-TGF-β binding, presenting a new TAK treatment approach., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: To evaluate diagnostic accuracy for active Takayasu arteritis (TAK) for two novel 18 F-fluorodeoxyglucose PET-CT parameters, the inflammatory volume (MIV) and total inflammatory glycolysis (TIG), to quantitate volume of metabolically-active arterial tissue., Methods: From a cohort of TAK (n = 36, 35 immunosuppressive-naïve), images of PET-CTs were reviewed for mean and maximum standardized uptake value (SUV mean and SUV max ), target-to-blood pool ratio (TBR), target-to-liver ratio (TLR), and PET Vasculitis Activity Score (PETVAS). Regions of interest were drawn to semiautomatically calculate MIV in areas of 18 F-fluorodeoxyglucose uptake ≥ 1.5 SUV mean after excluding physiological tracer uptake. TIG was calculated by multiplying MIV with SUV mean . PET-CT parameters, ESR, CRP, and clinical disease activity scores were compared against the gold standard of physician global assessment of disease activity (PGA, active/inactive)., Results: Using dichotomized cut-offs for active TAK at SUV max (≥ 2.21), SUV mean (≥ 1.58), TBR (≥ 2.31), TLR (≥ 1.22), PETVAS (various cut-offs), ESR (≥ 40 mm/hour), and CRP (≥ 6 mg/L), the novel indices MIV (≥ 1.8) and TIG (≥ 2.7) performed similar [area under the receiver operating characteristics curve (AUC) 0.873 for both] to SUV max (AUC 0.841) and SUV mean (AUC 0.851), and better than TBR (AUC 0.773), TLR (AUC 0.773), PETVAS [≥ 5.5 (AUC 0.750), ≥ 10 (AUC 0.636), ≥ 15 (AUC 0.546)], ESR (AUC 0.748), or CRP (AUC 0.731). MIV and TIG had similar agreement with PGA or CRP as with SUV max or SUV mean , and better agreement than TBR, TLR, or PETVAS cut-offs., Conclusions: MIV and TIG performed similarly, therefore, are viable alternatives to existing PET-CT parameters to assess TAK disease activity in this preliminary report. Key Points • MIV and TIG performed similar to SUV max and SUV max for disease activity assessment in TAK. • MIV and TIG distinguished active TAK better than TBR, TLR, PETVAS cut-offs, ESR, or CRP. • MIV and TIG had better agreement with PGA or CRP than TBR, TLR, or PETVAS cut-offs., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Takayasu arteritis (TAK) is a chronic large vessel disease characterized by aortic fibrotic thickening, which was mainly mediated by activation of aorta adventitial fibroblasts (AAFs). Our previous genetic study demonstrated that TAK-associated locus IL6 rs2069837 regulated glycoprotein non-metastatic melanoma protein B (GPNMB) expression. Thus, this study aimed to investigate the pathogenic role of GPNMB in TAK. Through pathological staining, we find that GPNMB was mainly expressed in vascular adventitia and positively correlated with adventitial extracellular matrix (ECM) expression in TAK vascular lesion. Specifically, GPNMB was increased in adventitial CD68 + macrophages, which were closely located with CD90 + adventitial fibroblasts. In in-vitro cell culture, THP-1-derived macrophages with GPNMB overexpression promoted ECM expression in AAFs. This effect was also confirmed in aortic tissue or AAFs culture with GPNMB overexpression or active GPNMB protein stimulation. Mechanistically, Co-IP assay and siRNA or inhibitor intervention demonstrated that integrin αVβ1 receptor mediated GPNMB effect on AAFs, which also activated downstream Akt and Erk pathway in AAFs. Furthermore, we showed that leflunomide treatment inhibited GPNMB-mediated fibrosis in AAFs, as well as GPNMB expression in macrophages, which were also partially validated in leflunomide-treated patients. Taken together, these data indicated that macrophage-derived GPNMB promotes AAFs ECM expression via the integrin αVβ1 receptor and Akt/Erk signaling pathway and leflunomide might play an anti-fibrotic role in TAK by interfering with the macrophage-derived GPNMB/AAFs axis. This study provides evidence that targeting GPNMB is a potential therapeutic strategy for treating vascular fibrosis in TAK., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides., Competing Interests: Declaration of Competing Interest Dr. Michailidou received Advisory Board fees from ChemoCentryx. Dr. Khalidi received clinical trial support from BMS, Sanofi and Abbvie, travel support from Astra Zeneca, and Advisory Board fee from Roche. Dr. Koening served on the advisory board for Chemocentryx and Genentech. Dr. Specks reports receiving funds for the following activities: Consulting: AstraZeneca, ChemoCentryx. Research Support: AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Genentech/Roche, InflaRx. Dr. Sreih works at Bristol-Myers Squibb and owns Astra Zeneca and Alexion Stocks. Dr. Warrington received clinical trial support from Eli Lilly and Kiniksa. Dr. Monach received consulting fees from Kiniksa, Celgene/BMC, and ChemoCentryx. Dr. Merkel reports receiving funds for the following activities: Consulting and Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Takeda. Consulting only: CSL Behring, Dynacure, EMDSerono, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Sparrow, Talaris. Royalties: UpToDate. Dr. Lood received research funding from Pfizer, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, and Eli Lilly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: This study aims to investigate whether PD-1 expressions are abnormal in patients with TAK., Methods: PD-1 expression was analyzed by flow cytometry. Serum cytokines IL-10, IL-7, IL-2, IL-15, CCL2, CCL3, and CXCL10 were detected using a cytokine cytometric bead array. Immunohistochemistry staining analysis was used to test PD-1 and programmed death-ligand 1 (PD-L1) expression in the aorta of three patients with TAK and three patients with atherosclerosis as controls., Results: The mean fluorescence intensity of PD-1 in CD4 + PD-1 + cells was decreased in patients with TAK and the frequency of CD4 + Foxp3 - PD-1 + cells among CD4 + T cells was also decreased in peripheral blood relative to healthy controls ( P  < .05). The percentage of CD4 + CD25 + Foxp3 + PD-1 + cells in the CD4 + CD25 + T cell population was lower in patients with TAK than in healthy control and was lower in active TAK group ( P  < .05). Comparing PD-1 and PDL-1 expression in aorta tissue showed that patients with TAK tended to have lower levels than patients with atherosclerosis, but the difference was not significant ( P  > .05). Patients with TAK had higher serum levels of IL-10, IL-7, CCL2, and CCL3 ( P  < .05)., Conclusions: Abnormal expression of PD-1 in serum and aorta tissue of patients with TAK may contribute to TAK pathogenesis., Key Points: PD-1 expression in both peripheral blood and aorta tissue of TAK patients decreased relative to healthy controls, indicating that PD-1 might be involved in TAK pathogenesis.

Background and Aims: To establish reference intervals (RIs) for PTX-3 and to validate the performance of these RIs in a population including healthy volunteers and Takayasu's arteritis (TAK) patients., Materials and Methods: Plasma PTX-3 levels were determined in 166 healthy volunteers and 63 TAK patients. RIs were established in healthy volunteers according to guidelines from the Clinical and Laboratory Standards Institute (CLSI, C28-A3). Global assessment was used to quantitatively diagnose active/non-active TAK patients. Screening and monitoring performances were validated by identifying active TAK patients from the whole population or diagnosed TAK patients., Results: The PTX-3 RI was calculated to be 0.87-2.78 ng/mL. For screening purposes, 1.55 ng/mL had a high sensitivity of 90.32 % and the RI upper limit (2.78 ng/mL) had a high specificity of 97.94 %. For monitoring purposes, the sensitivity/specificity of the cut-off value (1.55 ng/mL) and RI median were 90.32 %/90.63 % and 80.85 %/90.63 %, respectively. These screening and monitoring performances of PTX-3 were superior to those of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)., Conclusion: The distribution of serum PTX-3 levels was stable and uniform across the population. The screening and monitoring performances of the cut-off value and RI-derived values of PTX-3 were higher than CRP and ESR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

It is now well established that Th17 lymphocytes associate with myriad immune-mediated inflammatory diseases. Over the past one and a half decades, a subset of Th17 lymphocytes viz. Th17.1 lymphocytes has been identified in pre-clinical and clinical models of inflammatory rheumatic diseases. These lymphocytes secrete IL-17A (signature cytokine of Th17 lymphocytes) as well as IFN-γ (the signature cytokine of Th1 lymphocytes). They express the chemokine markers for Th1 (CXCR3) as well as Th17 (CCR6) lymphocytes. Th17.1 lymphocytes also express the drug efflux protein p-glycoprotein, which associates with resistance to corticosteroids and other immunosuppressive drugs. This narrative review overviews the evidence regarding Th17.1 lymphocytes in different inflammatory rheumatic diseases. It is now recognized that Th17.1 lymphocytes are increased in the synovial fluid of affected joints in rheumatoid arthritis (RA) and associate with poor treatment response to abatacept. Th17.1 lymphocytes from synovial fluid of RA are less responsive to immunosuppression than those from the peripheral blood. In sarcoidosis, Th17.1 lymphocytes are concentrated in mediastinal lymph nodes and alveolar lining. Such Th17.1 lymphocytes in sarcoidosis are the predominant source of IFN-γ in the sarcoid lung. Th17.1 lymphocytes are elevated in lupus and Takayasu arteritis and associate with disease activity. Future studies should evaluate isolated Th17.1 lymphocytes from peripheral blood or sites of pathology such as synovial fluid and assess their modulation with immunosuppressive therapy in vitro. The analysis of gene expression signature of isolated Th17.1 lymphocytes might enable the identification of newer therapeutic strategies specifically targeting these cell populations in inflammatory rheumatic diseases. Key Points • Th17.1 lymphocytes are a subset of Th17 lymphocytes secreting both IFN-γ and IL-17 • Th17.1 lymphocytes drive neutrophilic inflammation, granuloma formation, and corticosteroid resistance • Th17.1 lymphocytes are elevated in rheumatoid arthritis and sarcoidosis at sites of inflammation • Increased circulating Th17.1 lymphocytes have been identified in lupus and Takayasu arteritis and associate with active disease., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: To identify the role of fatty acid binding protein 3 (FABP3) in vascular fibrosis in Takayasu's arteritis (TAK) and to explore the underlying molecular mechanism., Methods: The expression of FABP3 and extracellular matrix proteins (ECMs) were detected in aorta tissues from TAK patients (n = 12) and healthy controls (n = 8) by immunohistochemistry. The concentration of serum proteins was determined by ELISA. CCK8 and Ki67 staining were used to measure aorta adventitial fibroblast (AAF) proliferation. Widely targeted lipidomic profiling was used to screen for associated metabolic pathways. Changes in ECMs and fatty acid oxidation (FAO)-related enzymes were determined by RT-qPCR and Western blot. The interactions between FABP3 and these enzymes were explored with a co-immunoprecipitation (Co-IP) assay., Results: The expression of FABP3 was increased in the thickened adventitia of TAK patients and was positively correlated with the serum expression of ECMs. FABP3 knockdown inhibited AAF proliferation and ECM production, whereas FABP3 overexpression enhanced these processes. Further analysis revealed that FABP3 upregulation promoted carnitine palmitoyltransferase 1A and carnitine/acylcarnitine carrier protein (CACT) expression, two key enzymes in FAO, as well as adenosine triphosphate (ATP) levels. FABP3 and CACT were co-localized in the adventitia and bound to each other in AAFs. Etomoxir reversed the enhanced FAO, ATP production, AAF proliferation and ECM production mediated by FABP3 upregulation. Treatment with 60 g/day curcumin granules for 3 months reduced the level of serum FABP3. Curcumin also inhibited vascular fibrosis by reducing FABP3-enhanced FAO in AAFs., Conclusion: Elevated FABP3 expression accelerated vascular fibrosis in TAK, which was likely mediated by promoting FAO in AAFs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Takayasu arteritis (TA) is a major type of large vessel vasculitis characterized by progressive inflammation in vascular layers. In our recent study we identified a central role of mechanistic target of rapamycin (mTOR) hyperactivity in proinflammatory T cell differentiation in TA. This study was undertaken to explore potential mechanisms underpinning T cell-intrinsic mTOR hyperactivity and vascular inflammation in TA, with a focus on Notch-1., Methods: Notch-1 expression and activity was determined according to Notch-1, activated Notch-1, and HES-1 levels. We detected mTOR activity with intracellular expression of phosphorylated ribosomal protein S6. Differentiation of proinflammatory T cells was analyzed by detecting Th1 and Th17 lineage-determining transcription factors. The function of Notch-1 was evaluated using γ-secretase inhibitor DAPT and gene knockdown using a short hairpin RNA (shRNA) strategy. We performed our translational study using humanized NSG mouse chimeras in which human vasculitis was induced using immune cells from TA patients., Results: CD4+ T cells from TA patients exerted Notch-1 high , leading to mTOR hyperactivity and spontaneous maldifferentiation of Th1 cells and Th17 cells. Blockade of Notch-1 using DAPT and Notch-1 shRNA efficiently abrogated mTOR complex 1 (mTORC1) activation and proinflammatory T cell differentiation. Mechanistically, Notch-1 promoted mTOR expression, interacted with mTOR, and was associated with lysosomal localization of mTOR. Accordingly, systemic administration of DAPT and CD4+ T cell-specific gene knockdown of Notch-1 could alleviate vascular inflammation in humanized TA chimeras., Conclusion: Expression of Notch-1 is elevated in CD4+ T cells from TA patients, resulting in mTORC1 hyperactivity and proinflammatory T cell differentiation. Targeting Notch-1 is a promising therapeutic strategy for the clinical management of TA., (© 2022 American College of Rheumatology.)

Background: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response., Objectives: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK., Methods: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis., Results: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and α-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD., Conclusions: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation affects bone metabolism and accelerates bone loss. This study is aimed at analyzing the prevalence of low bone mineral density (LBMD) in patients with untreated Takayasu's arteritis (TA) and risk factors. Forty untreated TA patients were enrolled, including 38 premenopausal women and 2 men before 50 years old. The control group included 60 age- and gender-matched healthy persons. Bone mineral density (BMD) of lumbar vertebrae and hip in patients with TA and the control group was measured by the dual-energy X-ray method. Serum 25OHD and β -CTX were also measured. The lumbar BMD of TA patients (0.89 ± 0.11 g/cm 2 ) was significantly lower than that of the healthy control (0.97 ± 0.11 g/cm 2 ). The prevalence of LBMD at the lumbar spine (17.50%) was significantly higher than that of the control group (3.33%). However, there was no significant difference at the hip. The 25OHD of TA patients was lower than that of healthy controls, while the level of β -CTX was higher. The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in patients with LBMD were higher than those in patients with normal BMD. According to univariate correlation analysis, there was a significant negative correlation between LDL-C and lumbar BMD. Binary logistic regression analysis showed that LDL-C was an important factor affecting the occurrence of LBMD in patients with TA (OR = 25.269, P = 0.02). Our result reveals bone loss in TA patients, which hints the relationship among inflammation, lipid metabolism, and bone metabolism., Competing Interests: All authors declare that they have no competing interests, and all authors confirm its accuracy., (Copyright © 2021 Lingfei Mo et al.)

Recent studies have provided evidence of a close link between specific microbiota and inflammatory disorders. While the vessel wall microbiota has been recently described in large vessel vasculitis (LVV) and controls, the blood microbiome in these diseases has not been previously reported (LVV). We aimed to analyse the blood microbiome profile of LVV patients (Takayasu's arteritis [TAK], giant cell arteritis [GCA]) and healthy blood donors (HD). We studied the blood samples of 13 patients with TAK (20 samples), 9 patients with GCA (11 samples) and 15 HD patients. We assessed the blood microbiome profile by sequencing the 16S rDNA blood bacterial DNA. We used linear discriminant analysis (LDA) coupled with linear discriminant effect size measurement (LEfSe) to investigate the differences in the blood microbiome profile between TAK and GCA patients. An increase in the levels of Clostridia, Cytophagia and Deltaproteobacteria and a decrease in Bacilli at the class level were found in TAK patients compared with HD patients (LDA > 2, p < 0.05). Active TAK patients had significantly lower levels of Staphylococcus compared with inactive TAK patients. Samples of GCA patients had an increased abundance of Rhodococcus and an unidentified member of the Cytophagaceae family. Microbiota of TAK compared with GCA patients was found to show higher levels of Candidatus Aquiluna and Cloacibacterium (LDA > 2; p < 0.05). Differences highlighted in the blood microbiome were also associated with a shift of bacterial predicted metabolic functions in TAK in comparison with HD. Similar results were also found in patients with active versus inactive TAK. In conclusion, patients with TAK were found to present a specific blood microbiome profile in comparison with healthy donors and GCA subjects. Significant changes in the blood microbiome profiles of TAK patients were associated with specific metabolic functions.

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4 + T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Robinette, Rao and Monach.)

Serum homocysteine (HCY) levels have been associated with the occurrence of coronary stenosis and disease activity in large-vessel vasculitis. However, whether increases in serum HCY levels and traditional lipid indicators are associated with coronary artery involvement and disease activity in Chinese Han Takayasu arteritis (TA) patients is unknown. This study aims to investigate the clinical and laboratory features of TA by assessing their association with disease activity in TA patients, and to explore the risk factors associated with coronary artery involvement in these patients. Serum HCY levels and traditional lipid indicators were tested in one hundred ninety TA patients and one hundred fifty-four healthy controls. We analyzed the relationships of serum HCY levels and traditional lipid indicators with disease activity and analyzed the risk factors for coronary artery involvement. Twenty-one TA patients were found to have coronary artery stenosis (≥ 50%). TA patients had significantly higher levels of HCY than did healthy controls (p < 0.0001). Serum levels of HCY and low-density lipoprotein cholesterol (LDL-C); the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) to HDL-C, and triglycerides (TG) to HDL-C; and the values of atherogenic index of plasma (AIP) were significantly higher in patients with active TA than in patients with inactive TA and in TA patients with coronary artery involvement than in TA patients without coronary artery involvement. By contrast, the serum levels of HDL-C were significantly lower in patients with active TA than in patients with inactive TA and in TA patients with coronary artery involvement than in TA patients without coronary artery involvement (p < 0.05). In addition, the serum levels of TC and TG were significantly higher in TA patients with coronary artery involvement than those in TA patients without coronary artery involvement. Elevated serum HCY levels increased the risk of coronary artery involvement by 1.3-fold (p = 0.011, odds ratio [OR] = 1.275, 95% confidence interval [CI]: 1.056-1.539), and the cutoff value for serum HCY was 9.55 μmol/L. Elevated serum TG levels increased the risk of coronary artery involvement by 3.5-fold (p < 0.0001, OR = 3.534, 95% CI: 1.907-6.547), and the cutoff value for serum TG was 1.215 mmol/L. The risk of coronary artery involvement was 2.5-fold higher when an elevated TG/HDL-C ratio was present (p < 0.0001, OR = 2.513, 95% CI: 1.567-4.032). This study showed that serum HCY and TG levels and the TG/HDL-C ratio are independent risk factors for coronary artery involvement in TA patients.

Objectives: The effect and underlying mechanism of T-614 (iguratimod) on Takayasu's arteritis (TA) are unknown. Here, we report the effects of T-614 on cell proliferation and interleukin-8 (IL-8) production in human aortic adventitial fibroblasts (HAAFs) in vitro and explore its initial benefit in terms of vascular wall inflammation and remodeling for patients with TA., Methods: HAAFs were cultured with 0, 5, 50, 100, or 250 μg/ml T-614 in the absence or presence of tumor necrosis factor-α (TNF-α) in vitro. Cell viability was determined by a modified MTT assay. Supernatant IL-8 levels were measured by enzyme-linked immunosorbent assays., Results: In the presence of TNF-α, compared to that in the control group, cell viability of HAAFs significantly decreased in the 50, 100, and 250 μg/ml T-614 treatment groups (OD value: P  <   0.01, P  <   0.001, P  <   0.001, respectively; survival fraction (SF): P  <   0.05, P  <   0.001, P  <   0.001, respectively). However, there was no significant difference in cell viability between TNF-α-stimulated and unstimulated groups at the same concentration of T-614. In the absence or presence of TNF-α, T-614 suppressed HAAF cell viability dose-dependently (OD value: r  = -0.915, P  =   0.000; r  = -0.926, P  =   0.000, respectively; SF: r  = -0.897, P  =   0.000; r  = -0.885, P  =   0.000, respectively). Compared to that in the control group, in the absence of TNF-α, IL-8 levels in the 5 and 100 μg/ml T-614-treated groups were significantly higher ( P  <   0.05); in the presence of TNF-α, IL-8 levels in the 5, 50, and 100 μg/ml T-614-treated groups were significantly higher ( P  <   0.001, P  <   0.001, P  <   0.01, respectively). Further, there was a negative correlation between supernatant IL-8 levels and T-614 concentration in groups stimulated with TNF-α ( r  = -0.670, P  =   0.000), but there was no significant correlation between these parameters in groups that were not stimulated with TNF-α., Conclusions: In the absence or presence of TNF-α, T-614 can inhibit HAAF proliferation and promote IL-8 production in vitro; therefore, it could be used to prevent adventitial thickening of the aorta and improve vascular remodeling in inflammatory environments in vitro and might provide a new immunotherapeutic intervention for TA.

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

Giant cell arteritis and Takayasu arteritis are autoimmune vasculitides that cause aneurysm formation and tissue infarction. Extravascular inflammation consists of an intense acute phase response. Deeper understanding of pathogenic events in the vessel wall has highlighted the loss of tissue protective mechanisms, the intrusion of immune cells into "forbidden territory", and the autonomy of self-renewing vasculitic infiltrates. Adventitial vasa vasora critically control vessel wall access and drive differentiation of tissue-invasive T cells. Selected T cells establish tissue residency and build autonomous, self-sufficient inflammatory lesions. Pathogenic effector T cells intrude and survive due to failed immune checkpoint inhibition. Vasculitis-sustaining T cells and macrophages provide a broad portfolio of effector functions, involving heterogeneous populations of pro-inflammatory T cells and diverse macrophage subsets that ultimately induce wall capillarization and intimal hyperplasia. Redirecting diagnostic and therapeutic strategies from control of extravascular inflammatory markers to suppression of vascular inflammation will improve disease management., (Copyright © 2019. Published by Elsevier Inc.)

Aim: This study was designed to analyze microparticles (MPs) from endothelial cells (EMPs) and immune cells from healthy individuals and paitents with Takayasu arteritis (TA), and any possible relationships between MPs and TA acitivity., Methods: MPs derived from the plasma of 51 subjects were analyzed, including 32 patients with TA and 19 healthy individuals. Flow cytometry was performed with Annexin (Anx)-V and antibodies against surface markers of endothelial cells (CD144), T cells (CD3), B cells (CD19), and monocytes (CD14)., Results: The concentrations of total EMPs, AnxV＋ EMPs and AnxV- EMPs were significantly increased when comparing patients with TA and healthy controls (54×10 3 vs. 32×10 3 MPs /ml, P=0.0004; 22×10 3 vs. 12×10 3 MPs /ml, P=0.0006; and 31×10 3 vs. 19×10 3 MPs /ml, P=0.0005), and comparing active TA patients with remission ones (85×10 3 vs. 45×10 3 MPs /ml, P=0.016; 39×10 3 vs. 14×10 3 MPs /ml, P=0.0092; and 47×10 3 vs.29×10 3 MPs /ml, P=0.0371). In addition, the concentrations of total EMPs (odds ratio [OR]=1.024, 95% confidence interval [CI]: 1.001 to 1.048, P=0.037), AnxV＋(OR=1.089, 95%CI: 1.011 to 1.172, P=0.024), and AnxV- EMPs (OR=1.029, 95% CI: 1.002 to 1.056, P=0.034) were positively related to TA activity. With multiple linear regression analysis, platelet was associated with both total and AnxV- EMP concentrations independently, while erythrocyte sedimentation rate was independently correlated with AnxV＋EMPs., Conclusion: Concentrations of endothelial microparticles are correlated with inflammation in Takayasu arteritis and may be useful markers to assess disease activity.

Background: Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6., Methods: Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA., Results: The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway., Conclusions: IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

BACKGROUND This study aimed to evaluate the ratio of C-reactive protein (CRP) to albumin, inflammatory markers, and parameters from the complete blood count (CBC) in patients with Takayasu arteritis and the association with disease activity. MATERIAL AND METHODS A retrospective study included thirty-two patients with Takayasu arteritis and 32 healthy controls. Clinical and demographic characteristics of patients with Takayasu arteritis were recorded at baseline, before medication and on remission. Similar data were obtained for the controls at recruitment. Remission was defined as more than six months of stable disease without new vascular lesions in patients who previously had active disease. Kerr's criteria were used to define active Takayasu arteritis. RESULTS In patients with Takayasu arteritis, the erythrocyte sedimentation rate (ESR), CRP, CRP/albumin ratio, red cell distribution width (RDW), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) were significantly higher, and albumin and MPV were significantly lower compared with controls. The ESR, CRP, CRP/albumin ratio, NLR, PLR, and MLR were decreased in remission, whereas MPV was increased. CRP and the CRP/albumin ratio were positively correlated and albumin and MPV were negatively correlated with disease activity. The CRP/albumin ratio had the highest correlation with disease activity in Takayasu arteritis. The CRP/albumin ratio, RDW, NLR, PLR, and MLR were positively correlated with CRP and ESR. CONCLUSIONS The CRP/albumin ratio, RDW, NLR, PLR, MLR, and MPV were markers of remission of active disease, and the CRP/albumin ratio, total albumin, and MPV were markers of disease activity in Takayasu arteritis.

Background: Establishing the diagnosis and determining disease activity of Takayasu arteritis (TA) remains challenging. Novel biomarkers might help to solve this problem., Methods: In the screening phase, by using large-scale protein arrays detecting samples from 90 subjects (TA active, 29; TA inactive 31; and controls, 30). In the validation phase, by using enzyme-linked immunosorbent assay (ELISA), potential biomarkers for TA diagnosis, and activity classification were measured in independent cohorts, respectively., Results: In the screening phase, 18 cytokines significantly differentially enriched between TA patients and controls and another 15 cytokines significantly differentially enriched between TA patient in active and inactive status were identified (adjusted P<0.05). In the validation phase, TIMP (tissue inhibitor of metalloproteinases)-1 was identified as a specific biomarker for TA diagnosis that a cutoff value of 221.86 μg/L could provide a specificity of 89.58% and a positive predictive value of 0.92. Meanwhile, we found it unreliable to use a single biomarker for TA activity classification. Considering this, we further built a logistic regression model based on multiple cytokines, including CA (cancer antigen) 125, FLRG (follistatin-related protein), IGFBP (insulin-like growth factor-binding protein)-2, CA15-3, GROa (growth-regulated alpha protein), LYVE (lymphatic vessel endothelial hyaluronic acid receptor)-1, ULBP (UL16-binding protein)-2, and CD (cluster of differentiation) 99, with an area under the curve reaching 0.909 for discriminating TA activity status., Conclusions: This study suggested TIMP-1 as a specific biomarker for TA diagnosis with a cutoff value of 221.86 μg/L. Furthermore, we provided a logistic regression model based on 8 biomarkers for the precisive activity classification of TA with an area under the curve of 0.909.

Background: Takayasu arteritis (TA) is an idiopathic chronic inflammatory disease of the aorta and its branches, leading to stenosis, occlusion, and aneurysmal dilatation. Tumor necrosis factor-alpha (TNF-α) is a cytokine with pleomorphic actions and plays a pivotal role in inflammation; the serum level of TNF-α is genetically determined. However, the literature lacks adequate information on the association of TNF-α polymorphisms with TA. Hence, the present study investigates the contribution of TNF-α polymorphism toward the complex etiology of TA., Methods: A cross-sectional study was performed in 87 patients with TA and 90 controls. A promoter region polymorphism of TNF-α, rs1800629 G/A, or -308G/A was genotyped in all the study subjects followed by a case-control association study. Furthermore, to understand the biomarker profile, levels of specific markers such as erythrocyte sedimentation rate, serum high-sensitivity C-reactive protein, interleukin-18, interleukin-6, and TNF-α were measured in all the study subjects., Results: All the inflammatory markers were significantly higher in the TA patients than in the controls. The genetic study (available for 57 TA patients and 36 controls) revealed that the TNF-α -308A allele was overrepresented in the TA patients (12% vs 7%). The TNF-α -308A allele correlated with the increased TNF-α levels, but it could not attain significance because of a small sample size., Conclusion: The TNF-α -308G/A polymorphism is associated with TNF-α levels in Indian population, which might have implications for clinical risk stratification and treatment. The different TNF-α gene promoter polymorphism might contribute to the molecular pathogenesis of TA. However, further study of the underlying mechanism is warranted., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX., Methods: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses., Results: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK., Conclusions: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.

Introduction: The choice of metrics for defining active Takayasu arteritis (TAK) using fluorine-18-fluorodeoxyglucose (F-FDG)-PET remains controversial., Objective: The aim of this study was to compare in the same patients the diagnostic performance for the detection of active TAK of different metrics applied for the quantification of vascular F-FDG uptake with PET., Patients and Methods: Overall, 62 PET acquisitions were performed 90 min after F-FDG injection in 15 patients with TAK and analyzed retrospectively. The intensity of vascular F-FDG uptake was graded visually in comparison with the liver signal and with the numerical metrics, including maximum standard uptake value (SUV), maximum target to background ratio (TBR, ratio of SUVmax in the vessel wall and SUVmean of blood), most-diseased segment (MDS)-TBR (average of TBR from all active lesions), and global TBR (average TBR along the aorta and carotid arteries). The gold standard was disease activity identified using the National Institute of Health score for TAK., Results: Using visual analysis, the definition of F-FDG-PET as positive in presence of at least one vascular lesion with a signal more than liver provided the best diagnostic performance for detecting active TAK with a specificity of 98%, a sensitivity of 62% and an accuracy of 89%. Using numerical metrics, SUVmax [SUVmax >3.3; area under the curve (AUC)=0.84] and TBRmax (TBRmax >2.3; AUC=0.84) offered the best diagnostic performance for the detection of active TAK in comparison with MDS-TBR (MDS-TBR>1.7; AUC=0.70) and global TBR (global TBR >1.4; AUC=0.51)., Conclusion: In this study, we found that the analysis of the vascular region with the highest F-FDG uptake using either visual or numerical metrics provided the best diagnostic performance for the detection of active TAK with PET.

The objective of the study is to investigate the value of 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) for assessment of the activity of Takayasu's arteritis (TA) and the correlation between acute-phase reactive proteins (ARPs) and standard uptake value (SUV). Analyses of the clinical characteristics and 42 18 F-FDG-PET/CT scans in 39 TA patients were undertaken. The degree of FDG uptake in the blood vessel walls was assessed quantitatively by SUV. TA activity was analyzed by physician global assessment (PGA). Clinical and 18 F-FDG-PET/CT characteristics were compared between patients with clinically active and clinically inactive TA. Maximum SUV (SUV max ), mean SUV (SUV mean ), and SUV ratio (SUV ratio ) were significantly higher in the clinically active group than in the clinically inactive group (3.63 ± 1.96 vs. 1.82 ± 0.43, p = 0.007; 2.07 ± 0.71 vs. 1.43 ± 0.32, p = 0.009; 2.08 ± 1.17 vs. 0.95 ± 0.19, p = 0.000). Analyses of receiver operating characteristic (ROC) curves revealed a cutoff value of SUV max of 2.21, with sensitivity and specificity of 86.2 and 90.0%, respectively, for clinically active TA. The SUV ratio cutoff was 1.27 with a sensitivity and specificity of 79.3 and 100.0%, respectively. SUV ratio was slightly superior to SUV max and ARPs in the area under the curve (AUC) comparison. SUV max and SUV ratio showed a significant increasing trend with increasing US National Institutes of Health (NIH) score and levels of ARPs, interleukin-6, and serum amyloid-A protein. 18 F-FDG-PET/CT is a promising non-invasive, quantitative measurement with high sensitivity and specificity for determining TA activity.

Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis., Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation., Results: IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor., Conclusion: Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA.

A lack of absolute correlation between systemic inflammation parameters and ongoing vascular disease activity is an important problem in some patients with large vessel vasculitis, especially Takayasu arteritis (TAK). Systemic and vascular wall inflammation in TAK are obviously interrelated, but sometimes they may act independently. There are clear discrepancies between these two types of inflammation, including cytokine patterns and responses to treatment. Vascular and systemic inflammation may also be discordant in two subgroups of giant cell arteritis. The first subgroup is mainly characterized by severe systemic inflammation mostly associated with IL-6-driven immunity, while in the second subgroup there is less systemic inflammation but prominent neuro-ophthalmic ischaemic complications characterized mostly by IFN-γ-mediated effects. Although no definite boundaries exist, it may be suggested that the IL-6/Th17/IL-17 pathway primarily drives systemic inflammation while the IL-12/Th1/IFN-γ pathway dominates in vascular wall inflammation both in TAK and giant cell arteritis. Immunosuppressive treatment of TAK (especially corticosteroids) initially suppresses systemic inflammation, while longer treatment duration is required for the suppression of vascular inflammation. Therefore, evaluating only the systemic inflammation may be misleading. Vascular wall inflammation is currently evaluated using expensive imaging methods, which are not feasible for repetitive use. Although pentraxin-3 is superior to erythrocyte sedimentation rate and CRP, we need more reliable biomarkers to reflect vascular wall inflammation in patients with TAK.

Objectives: This study aimed to clarify potential mechanism of IL-6 involved in adventitial fibrosis via adventitial fibroblast in Takayasu arteritis (TAK)., Methods: Immunohistochemistry and double-labelled immunofluorescence were performed on vascular tissue from patients with TAK and controls. Human aorta adventitial fibroblast (AAF) was cultured and stimulated with interleukine 6 (IL-6)/IL-6 receptor (IL-6R). Real-time PCR, western blot, enzyme-linked immunosorbent assays, chromatin immunoprecipitation (ChIP) and reporter assay were conducted in vitro experiments to determine effect of IL-6/IL-6R on AAF., Results: The expression of IL-6, IL-6R, collagen I, collagen III, fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor (TGF-β) in TAK arteries was significantly higher than that in the normal arteries. Co-localisation of α-SMA and IL-6 and a positive correlation between their expression were observed in local lesions. In vitro experiments, collagen I, collagen III, fibronectin, α-SMA, and TGF-β expression increased significantly after stimulation and this fibrogenesis of AAFs was induced in TGF-β-dependent and -independent manners. Additionally, phosphorylation of JAK2, STAT3 and Akt was significantly enhanced both in IL-6/IL-6R-treated AAFs in vitro and in TAK adventitial α-SMA positive cells. When AAFs were pretreated with inhibitors against JAK2, STAT3, and Akt, fibrosis was significantly reduced. Furthermore, IL-6/IL-6R promoted mRNA expression of IL-6 and MCP-1 in AAFs. Finally, according to ChIP and reporter assay results, STAT3 was the main transcriptional factor in the fibrosis of AAFs induced by IL-6/IL-6R., Conclusions: IL-6/IL-6R induces fibrogenesis of AAFs via the JAK2/STAT3 and JAK2/Akt pathways, which provides theoretical evidence for IL-6 as a treatment target in TAK.

Purpose: The object of this study was to assess whether 18 F-fluorodeoxyglucose PET/CT (FDG PET/CT) provides novel information in patients with Takayasu's arteritis (TA) in addition to that provided by current activity assessment, to analyse the effects of possible confounders, such as arterial grafts, and to verify whether PET/CT could be informative in lesions <4 mm thick., Methods: We studied 30 patients with TA, evaluated from October 2010 to April 2014 by both PET/CT and magnetic resonance imaging (MRI). All arterial lesions were evaluated by PET both qualitatively (positive/negative) and semiquantitatively (maximum standardized uptake value, SUV max ), and the thickness of lesions in the MRI field of view was evaluated. In a per-patient analysis, the relationships between the PET data and acute-phase reactants and NIH criteria for active TA were evaluated. In a per-lesion analysis, the relationships between the PET features of each lesion and MRI morphological data were evaluated. The effects of the presence of arterial grafts were also evaluated., Results: Increased FDG uptake was seen in 16 of 30 patients (53%) and in 46 of 177 vascular lesions (26%). Significant periprosthetic FDG uptake was seen in 6 of 7 patients (86%) with previous vascular surgery and in 10 of 11 of grafts (91%). Graft-associated uptake influenced the PET results in three patients (10%) and the SUV max values in five patients (17%). Of 39 lesions with significant FDG uptake, 15 (38%) were <4 mm thick. Lesion thickness was correlated with lesion SUV max in FDG-avid lesions only. FDG arterial uptake was not associated with systemic inflammation or NIH criteria., Conclusions: PET/CT reveals unique and fundamental features of arterial involvement in TA. PET/CT may be useful in the assessment of local inflammatory and vascular remodelling events independent of systemic inflammation during follow-up, even in lesions in which the arterial wall is <4 mm. The presence of arterial grafts is a potential confounder. Prospective studies are required to correlate PET findings with relevant clinical outcomes.

Tumor necrosis factor (TNF) inhibitors have exhibited certain clinical efficacy in treating refractory Takayasu arteritis (TA), albeit with severe adverse effects. We aimed to explore the anti-TNF function of resveratrol, a natural compound, in the treatment of TA. A total of 271 patients diagnosed of acute TA were enrolled in this clinical trial, who were then randomized to be administered 250mg resveratrol or placebo on a daily basis for a period of 3 months, and revisited biweekly to assess treatment outcomes. Primary treatment outcome was defined as the disease activity, determined using the Birmingham Vascular Activity Score (BVAS). Secondary outcome was defined by laboratory parameters, including erythrocyte sedimentation rate (ESR), plasma levels of C-reactive protein (CRP) and TNF-α. BVAS score and laboratory parameters of patients receiving resveratrol treatment exhibited a steady decline throughout the study. In contrast, outcomes remained practically unchanged in placebo-treated patients. Strong linear correlations were also observed between TNF-α with BVAS scores, ESR and plasma levels of CRP. Resveratrol could greatly improve treatment outcome and laboratory parameters in acute TA patients, likely due to its anti-TNF property., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Objective: Takayasu's arteritis (TAK) is a chronic, large-vessel vasculitis. Vitamin D, as a steroidal hormone, has recently been shown to have immunoregulatory and immunosuppressive effects. Low vitamin D levels are demonstrated in various autoimmune disorders. The aim of this study is to investigate vitamin D levels in patients with TAK. A comprehensive review of vitamin D levels in systemic vasculitides (SVs) is also performed., Methods: The study included 36 patients with TAK, 28 patients with Behçet's disease (BD) as disease control and 30 sex-matched healthy controls. Plasma 25-hydroxy vitamin D (25(OH) vit D) levels were measured with high-performance liquid chromatography. "Deficiency" was defined as 25(OH) vit D levels below 25 nmol/l and "insufficiency" as below 50 nmol/l., Results: Plasma 25(OH) vit D levels were significantly lower in TAK patients (16.93 ± 10.62 nmol/l) than healthy controls (64.63 ± 21.82 nmol/l). Vitamin D level in BD patients (38.8 ± 20.9 nmol/l) is lower than healthy controls but higher than TAK patients. The frequency of vitamin D deficiency was 83.3% in patients with TAK compared to 3.3% in healthy controls. Plasma 25(OH) vit D levels were same between clinically active and inactive patients. In literature review, very few studies were found to investigate vitamin D in SVs., Conclusion: We observed a high prevalence of vitamin D deficiency in patients with TAK. As various immune effects of vitamin D on mononuclear cells and arterial endothelium is shown, vitamin D deficiency can be a predisposing factor for immune activation in SV. We therefore suggest monitorization and replacement of vitamin D status in all TAK and other SV patients., (© 2015 Wiley Periodicals, Inc.)

Objective: To evaluate (18)F-fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography-computed tomography (PET-CT) and serum levels of different cytokines and matrix metalloproteinases (MMPs) in patients with Takayasu arteritis (TA) and associations with disease activity., Methods: Serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 and MMP-9 were measured in 36 TA patients and 36 controls. Maximum standard uptake value (SUVmax) of (18)F-FDG in arterial walls was determined by PET-CT scans. TA patients were classified as active disease, inactive disease and possible active disease., Results: Serum IL-6 and MMP-3 levels were higher in TA patients than in controls (p<0.001). Serum IL-6 was higher in patients with active disease and in patients with possible active disease than in inactive disease (p<0.0001). Patients with active disease had higher serum TNFα levels than patients with inactive disease (p=0.049) while patients with possible active disease presented higher IL-18 levels than patients with inactive disease (p=0.046). Patients with active disease had higher SUVmax values than those with inactive disease (p=0.042). By receiver operating characteristic (ROC) curve SUVmax was predictive of active disease in TA and values ≥1.3 were associated with disease activity (p=0.039). Serum TNF-α levels were higher in patients with SUVmax≥1.3 than <1.3 (p=0.045) and controls (p=0.012). Serum IL-6 levels were higher in patients with SUVmax≥1.3 than in controls (p<0.001). No differences regarding other biomarkers were found between TA patients and controls., Conclusions: Higher serum IL-6 and TNFα levels as well as higher (18)F-FDG uptake in arterial wall are associated with active TA., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Objectives: Although not uniformly accepted, an increased uptake by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in large vessels is accepted to be a sign of active disease in Takayasu's arteritis (TAK). We aimed to investigate the value of 18F-FDG-PET/CT for clinical assessment in a subset of TAK patients having a persistent acute-phase response (APR) without any signs or symptoms of clinical disease activity., Method: We studied 14 patients (mean age: 38.6 ± 13.9 years, Female/Male: 11/3, and disease duration: 5.7 ± 5 years). Patients were clinically inactive (according to the definition of activity by Kerr et al.), while categorized as having "persistent" disease activity by physician's global assessment due only to APR. 18F-FDG uptake was graded using a four-point scale from grade 0 (no uptake present) to grade 3 (high grade: uptake higher than that of liver). Any uptake in major vessels with a grade ≥ 2 was accepted to be "active.", Results: Mean erythrocyte sedimentation rate was 50.8 ± 13.2 mm/hour and mean C-reactive protein level was 28.5 ± 22.1 mg/L. Active vasculitic lesions were observed by 18F-FDG-PET/CT in 9 of 14 (64.3%) patients. The median number of active vascular lesions was 2 (range: 1-5). A step-up treatment change was decided in 8 patients according to 18F-FDG-PET/CT results., Conclusion: We observed increased 18F-FDG uptake in the majority of TAK patients with an increased APR, but clinically silent disease. 18F-FDG-PET/CT showed the presence and localization of active inflammation in the aorta and its branches. Although specificity for observed lesions is not clear, 18F-FDG-PET/CT imaging may influence physician's assessment of clinical activity and treatment choices in TAK.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patient's response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

Objective: Large vessel vasculitides (LVV) are a group of autoimmune diseases characterized by injury to and anatomic modifications of large vessels, including the aorta and its branch vessels. Disease etiology is unknown. This study was undertaken to identify antigen targets within affected vessel walls in aortic root, ascending aorta, and aortic arch surgical specimens from patients with LVV, including giant cell arteritis, Takayasu arteritis, and isolated focal aortitis., Methods: Thoracic aortic aneurysm specimens and autologous blood were acquired from consenting patients who underwent aorta reconstruction procedures. Aorta proteins were extracted from both patients with LVV and age-, race-, and sex-matched disease controls with noninflammatory aneurysms. A total of 108 serum samples from patients with LVV, matched controls, and controls with antinuclear antibodies, different forms of vasculitis, or sepsis were tested., Results: Evaluation of 108 serum samples and 22 aortic tissue specimens showed that 78% of patients with LVV produced antibodies to 14-3-3 proteins in the aortic wall (93.7% specificity), whereas controls were less likely to do so (6.7% produced antibodies). LVV patient sera contained autoantibody sufficient to immunoprecipitate 14-3-3 protein(s) from aortic lysates. Three of 7 isoforms of 14-3-3 were found to be up-regulated in aorta specimens from patients with LVV, and 2 isoforms (ε and ζ) were found to be antigenic in LVV., Conclusion: This is the first study to use sterile, snap-frozen thoracic aorta biopsy specimens to identify autoantigens in LVV. Our findings indicate that 78% of patients with LVV have antibody reactivity to 14-3-3 protein(s). The precise role of these antibodies and 14-3-3 proteins in LVV pathogenesis deserves further study., (© 2015, American College of Rheumatology.)

Objectives: Assessment of disease activity is one of the major difficulties in patients with Takayasu arteritis (TAK) during follow-up. To date, no biomarker is universally accepted to be a surrogate for active disease in TAK. In this study, we aimed to investigate levels of various pro-and anti-inflammatory molecules including serum granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-8, IL-10, IL-18 and IL-23 in patients with TAK., Methods: The study included 51 patients (age: 40.6±12.2 years, F/M: 45/6) with TAK and 42 age- and sex-matched healthy controls (age: 38.1±7.4 years, F/M: 38/4). All patients fulfilled the criteria of the American College of Rheumatology (ACR). TAK patients were evaluated by physician's global assessment (PGA; active/inactive) and ITAS2010 (Indian Takayasu Arteritis Clinical Activity Score) in terms of clinical activity in baseline and follow-up visits. Commercial enzyme linked immuno-sorbent assay (ELISA) kits were used for measurements of serum cytokine levels., Results: At baseline, 21 (41.2%) patients were active according to PGA and 8 (15.7%) according to ITAS2010. Serum IL-6, IL-8 and IL-18 levels were significantly higher in patients with TAK, whereas GM-CSF, IL-10, IL-23 levels were similar to healthy controls. IL-8 significantly decreased in the follow-up, associated with a decrease of clinical activity, whereas IL-23 level significantly increased. When assessed by ITAS2010 active patients had significantly higher IL-18 levels., Conclusions: We found significantly increased IL-6, IL-8 and IL-18 levels in patients with TAK compared to healthy controls. Only IL-18 level was significantly higher in active patients assessed by ITAS2010. IL-18 was also the only cytokine in our study that correlated with CRP. These findings suggest that cytokines associated with neutrophilic, pro-inflammatory responses such as IL-6, IL-8 and IL-18 can be potential biomarkers for the assessment of disease activity in TAK and warrant further studies in larger series.

Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1β), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1β expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1β.

Background: Takayasu's arteritis (TA) is a chronic inflammatory disease affecting the large arteries and their branches; its etiology is still unknown. In individuals suffering from TA, arterial inflammation progresses to stenosis and/or occlusion, leading to organ damage and affecting survival. Relation of TA with Mycobacterium tuberculosis has been known, but there have been only a few systematic studies focusing on this association. The IS6110 sequence identifies the Mycobacterium tuberculosis complex and the HupB establishes the differences between M. tuberculosis and M. bovis. Our objective was to search the presence of IS6110 and HupB genes in aorta of patients with TA., Methods: We analyzed aorta tissues embedded in paraffin from 5760 autopsies obtained from our institution, we divided the selected samples as cases and controls;, Cases: aortic tissues of individuals with Takayasu's arteritis. Control positive: aortic tissues (with tuberculosis disease confirmed) and control negative with other disease aortic (atherosclerosis)., Results: Of 181 selected aorta tissues, 119 fulfilled the corresponding criteria for TA, TB or atherosclerosis. Thus 33 corresponded to TA, 33 to tuberculosis (TB) and 53 to atherosclerosis. The mean age was 22 ± 13, 41 ± 19, and 57 ± 10, respectively. IS6110 and HupB sequences were detected in 70% of TA tissues, 82% in tuberculosis, and in 32% with atherosclerosis. Important statistical differences between groups with TA, tuberculosis versus atherosclerosis (p = 0.004 and 0.0001, respectively) were found., Conclusion: We identified a higher frequency of IS6110 and HupB genes in aortic tissues of TA patients. This data suggests that arterial damage could occur due to previous infection with M. tuberculosis.

Takayasu's arteritis (TA) is an inflammatory fibrosing arteritis affecting predominately the aorta and its main branches. Pathogenesis of this disease remains enigmatic. Despite the numerous studies, the role of adventitia in vascular lesion formation in the setting of TA has been ignored. Virtually nothing is known about the mechanism regulating inflammation in the adventitia in the setting of TA. The present study included subjects with Takayasu's arteritis and normal healthy control subjects. Isolated T cells from peripheral blood mononuclear cells (PBMCs) using nylon wool and HUT-78 (human cutaneous T lymphoma cell line) were stimulated with PHA for 24 h. Stimulated cell were fixed with paraformaldehyde and fractionated into membrane, cytosolic and nuclear fractions. These cellular fractions were co-cultured with human fibrosarcoma cell line (HT-1080) and transcriptional expression of matrix metalloproteinases (MMP-1, 3, 9 and TIMP-1) was determined using semiquantitative RT-PCR. Stimulation of MMPs-TIMP synthesis by HT-1080 cells was mimicked by a membranous fraction derived from activated T-cell isolated from TA subjects and activated HUT-78 cells, whereas cytosolic and nuclear fractions were ineffective. In conclusion, for the first time we provide evidence for the presence of a cell surface-specific antigenic moiety on T-cells of TA subjects, which is responsible for activation of fibroblasts (cells predominantly present in adventitia) to enhance MMP production and, therefore, may lead to extracellular matrix degradation., (Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.)

Aims: Isolated aortitis (IA) is a newly recognized condition, but its differentiation from Takayasu arteritis (TA) is still a challenge. This study aims to explore the characteristics of IA., Methods: The clinical and pathological data of 965 cases with excised ascending aortas were obtained by chart and slide review. IA cases were compared with TA cases and examined for CD3, CD4, CD8, CD20, CD68, CD138 and IgG4 of the infiltrates using immunohistochemistry., Results: 24 cases of IA and eight cases of TA were identified. IA cases tended to be older than TA cases (mean 46.3 vs 33.9 years). Both groups had the same male/female ratio (1.0). IA cases tended to have a bigger aortic diameter (mean 59.7 vs 47.6 mm), statistically less intimal thickening (mean 678 vs 1101 μm), fewer lesions outside the ascending aorta (8% vs 100%), a lower erythrocyte sedimentation rate (mean 14.6 vs 27.0 mm/h) and more active aortitis (75.0% vs 62.5%) than TA cases. The number of CD3+ cells was equal to CD20+ cells in the media but fewer than CD20+ cells in the adventitia of IA cases. Their CD4/CD8+ ratio ranged from 1.0 to 1.8 while the number of CD68+ macrophages varied largely. IgG4+ cells ranged from 0 to 40 (mean 4) cells/HPF and the IgG4+/CD138+ ratio ranged from 0 to 0.36 (mean 0.06) in IA cases., Conclusions: Cases of IA tend to have more histologically active inflammation except for a relatively normal erythrocyte sedimentation rate, localised lesions and milder intimal fibrosis than cases of TA. IgG4 abnormality may not be the main cause of IA.

Background: Because pentraxin-3 (PTX3) is produced by immune and vascular cells in response to proinflammatory signals, it may be a useful biomarker for defining disease activity in patients with Takayasu arteritis., Objective: To compare PTX3 levels in patients who have Takayasu arteritis with those in healthy and infected controls, and to compare accuracy of PTX3 levels with that of C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) for distinguishing active and inactive disease., Design: Cross-sectional, noninterventional study conducted between September 2005 and October 2008., Setting: Immunology and rheumatology clinic at a university hospital in Italy., Patients: 57 consecutive patients with Takayasu arteritis and known disease activity, 57 healthy blood donor controls, and 15 patients with acute infection., Measurements: Disease activity by clinical criteria; plasma PTX3 and CRP levels and ESR., Results: 27 patients had active Takayasu arteritis; 30 had inactive disease. Levels of PTX3 were higher in patients with active disease (median, >2.14 ng/mL [range, 0.57 to 48.18 ng/mL]) than in those with inactive disease (median, 0.63 ng/mL [range, 0.00 to 1.64 ng/mL]) and were higher than in healthy patients (median, 0.11 ng/mL [range, 0 to 1.20 ng/mL]) or those with acute infection (median, 0.26 ng/mL [range, 0 to 0.75 ng/mL]). A plasma PTX3 level greater than 1 ng/mL was more accurate than normal thresholds of CRP or ESR for distinguishing active from inactive disease., Limitation: The study excluded patients with unknown or equivocal disease status., Conclusion: Plasma levels of PTX3 could help distinguish active from inactive Takayasu arteritis but should not be adopted for clinical use until the findings are confirmed in a broader spectrum of patients whose disease activity is unknown or equivocal before testing.

Background: Antilipoprotein lipase (anti-LPL) antibodies were described in rheumatic diseases. In systemic lupus erythematosus they were highly associated with inflammatory markers and dyslipidemia, and may ultimately contribute to vascular damage. The relevance of this association in Takayasu's arteritis, which is characterized by major inflammatory process affecting vessels, has not been determined., Objectives: To analyze the presence of anti-LPL antibodies in patients with Takayasu's arteritis and its association with inflammatory markers and lipoprotein risk levels. Methods. Thirty sera from patients with Takayasu's arteritis, according to ACR criteria, were consecutively included. IgG anti-LPL was detected by a standard ELISA. Lipoprotein risk levels were evaluated according to NCEP/ATPIII. Inflammatory markers included ESR and CRP values., Results: Takayasu's arteritis patients had a mean age of 34 years old and all were females. Half of the patients presented high ESR and 60% elevated CRP. Lipoprotein NCEP risk levels were observed in approximately half of the patients: 53% for total cholesterol, 43% for triglycerides, 16% for HDL-c and 47% for LDL-c. In spite of the high frequency of dyslipidemia and inflammatory markers in these patients no anti-LPL were detected., Conclusions: The lack of anti-LPL antibodies in Takayasu's disease implies distinct mechanisms underlying dyslipidemia compared to systemic lupus erythematosus.

Introduction: Takayasu's arteritis is a chronic granulomatous vasculitis affecting the medium and large blood vessels that can lead to vascular occlusion. Inflammatory stages occur during the course of the disease. Angiography remains the gold standard examination of choice but less invasive techniques are needed to assess the activity of the disease and to monitor response to treatment., Case Report: We present a case of an asymptomatic 21 year-old female patient with occlusion and stenosis of supra-aortic trunks discovered while performing an ultrasonography for the study of a recent goiter., Results: Angiography confirmed stenosis and vascular occlusions, Takayasu's arteritis being diagnosed. Metalloprotease 9 levels at diagnosis were higher than in control patients and increased when symptoms began. Positron emission tomography performed after starting treatment showed an increase in uptake., Conclusions: These non-invasive markers could be useful to assess the activity of the disease and even to avoid invasive angiographic examinations.

We studied T-cell receptor (TCR) repertoire of circulating gamma delta (gammadelta) T-cells in 20 patients with Takayasu's arteritis (TA), 20 healthy controls (HC), 7 follow up TA patients, and 10 patients with rheumatoid arthritis (RA) and 5 Wegener's granulomatosis (WG) patients as disease controls. Patients with TA (8.1 +/- 5.1%) compared to HC (3.7 +/- 2.1%, P = 0.014), RA (4.8 +/- 0.6%, P = 0.032), and WG (4.2 +/- 0.8%, P = 0.030) as well as active TA compared to inactive TA (13.9 +/- 4.1% vs. 4.9 +/- 1.5%; P < 0.001) had higher number of gammadelta T-cells. The numbers of Vdelta1+ cells were significantly higher in patients with TA (40.0 +/- 20.8%) than HC (13.1 +/- 8.0%; P = 0.001), RA (19.5 +/- 1.8%, P = 0.004), and WG (17.0 +/- 3.9%, P = 0.007). The numbers of gammadelta T-cells normalized in all the 7 patients after 180 days of follow up (13.9 +/- 4.1% vs. 6.9 +/- 2.5%; P = 0.001). We also observed higher number of activated and IFN-gamma producing gammadelta T-cells in active TA. Our data show that gammadelta T-cells particularly those bearing Vdelta1 TCR may have an important role in the immunopathogenesis of TA.

We have investigated intracellular production by T cells and plasma levels of TNF-alpha, IL-2 and IFN-gamma in 12 active and 10 inactive Takayasu's arteritis (TA) patients and 12 healthy controls. The active TA compared to inactive TA and controls had higher TNF-alpha (52.7 +/- 22.3% vs. 32.9 +/- 14.2% and 35.2 +/- 14.5%, respectively; P = 0. 020), lower IL-2 (19.6 +/- 13.2% vs. 36.1 +/- 10.1% and 31.2 +/- 10.3%, respectively; P = 0.010) and comparable IFN-gamma (38.6 +/- 13.9% vs. 34.2 +/- 12.4% and 34.9 +/- 11.1%, respectively; P = 0.581) producing CD3+ T cells. There was no difference in the plasma levels of the cytokines between active TA, inactive TA and controls (TNF-alpha: 79.1 +/- 94.5 vs. 72.9 +/- 120.0 and 9.5 +/- 6.7 pg/ml, P = 0.110; IL-2: 4.3 +/- 4.8 vs. 6.6 +/- 4.7 and 8.6 +/- 4.5 pg/ml, P = 0.094 and IFN-gamma: 10.1 +/- 11.3 vs. 8.8 +/- 8.7 and 8.2 +/- 6.5 pg/ml, P = 0.871, respectively). The data show an important role of these high TNF-alpha and low IL-2 producing T cells in TA.