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Background: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan's Intractable Disease Registry., Methods and results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations)., Conclusions: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

In paediatric primary Sjögren's syndrome (SS), the initial symptoms manifest systemically, such as fever, general fatigue, and lymphadenopathy, rather than sicca symptoms. Most children with primary SS have autoantibodies, such as antinuclear, anti-Ro/SS-A, and/or anti-La/SS-B antibodies; however, some patients are seronegative. Similar to paediatric patients with primary SS, those with Takayasu arteritis (TAK) initially only present constitutional symptoms, making it difficult to suspect, unless characteristic features are present. To our knowledge, there have been no reports of the coexistence of both diseases in children. We present a rare case of seronegative SS complicated by TAK in a 9-year-old girl who presented with a persistent low-grade fever, general fatigue, cervical lymphadenopathy, and multiple caries. Although blood examination revealed all autoantibodies to be negative, a lip biopsy revealed lymphocytic sialadenitis, and a sialoscintigraphy indicated hypofunctional salivary glands, leading to the diagnosis of seronegative SS. The patient was treated with low-dose glucocorticoid and immunosuppressant administration to inhibit persistent inflammation and the progression of salivary gland dysfunction; although the symptoms resolved, inflammatory markers remained elevated. When the patient was 14 years old, cervical bruits were incidentally found, and TAK was suspected based on cervical ultrasonography and magnetic resonance angiography findings. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography results demonstrated increased fluorodeoxyglucose accumulation from the ascending to descending aorta. Therefore, she was diagnosed with SS complicated by TAK, which is rare. Aortitis should be suspected when the cause of persistent inflammation cannot be ascertained in patients with SS., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Takayasu arteritis can affect the coronary ostia, leading to myocardial ischemia. Coronary ostial angioplasty effectively treats coronary artery ostial lesions associated with Takayasu arteritis. We present a case of juvenile Takayasu arteritis with bilateral subclavian artery occlusions treated with a novel coronary artery ostial angioplasty using the external iliac artery., (© 2022. The Author(s).)

Objectives: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK)., Methods: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients., Results: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography-computed tomography, and two on treatment intensification., Conclusions: We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown etiology. Although a number of investigators have attempted to determine biomarkers for diagnosing TAK, there exist no specific serological markers of this intractable disease. We undertook the exploration of novel serological markers which could be useful for an accurate diagnosis of TAK using an unbiased proteomics approach. The purified plasma samples from untreated patients with TAK and healthy individuals were separated by two-dimensional electrophoresis. The differentially expressed protein spots were detected by gel comparison and identified using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MS). Next, we validated plasma concentrations of identified proteins by enzyme-linked immunosorbent assay (ELISA). Two-dimensional electrophoresis and numerical analysis revealed 19 spots and 3 spot clusters whose sum of the sample averages was ≥ 0.01, and the average concentrations were ≥ 1.5 times in the patient group compared with the control group. Among them, 10 spots and spot clusters that met the condition of the average spot concentration being 2.5 times more than that in the control group were selected. After processing these spots using MS and conducting MS/MS ion search, we identified 10 proteins: apolipoprotein C-2 (ApoC-2), actin, apolipoprotein A-1, complement C3, kininogen-1, vitronectin, α2-macroglobulin, 14-3-3 protein ζ/δ, complement C4, and inter-α-trypsin inhibitor heavy chain H4 isoform 1 precursor. Finally, ELISA demonstrated that plasma ApoC-2 level was significantly elevated in patients with TAK compared with that in healthy individuals. Thus, ApoC-2 would be a promising candidate biomarker for TAK diagnosis., (© 2021. The Author(s).)

Background: Although high-dose glucocorticoids are effective in suppressing active inflammation of Takayasu arteritis (TAK), many patients experience relapse during tapering of glucocorticoids. Recently, the interleukin-6 receptor antibody, tocilizumab (TCZ), was reported to be effective for steroid-resistant TAK. However, there are no objective ways of diagnosing TAK recurrence because TCZ suppresses inflammatory biomarkers., Objectives: To investigate the efficacy of TCZ at 1-year follow-up and of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography for detection of recurrence of inflammation during TCZ treatment., Methods and Results: We treated 19 patients with refractory TAK with TCZ. TCZ was discontinued in 2 cases because of side effects. Abatement of arteritis symptoms along with reduction of glucocorticoid dosage was achieved in 12 patients, resulting in a remission induction rate of 70.6%. The dosage of glucocorticoid was reduced from 16.1 ± 10.2 mg to 3.8 ± 1.7 mg at 1 year (p<0.001) in these patients. In the remaining 5 patients, glucocorticoid tapering led to exacerbation of symptoms and glucocorticoid dose had to be increased. FDG-PET scan results closely matched clinical course in all 5 patients with recurrence even during TCZ treatment, while the scan was negative for the remaining 12 patients., Conclusions: TCZ injection provides robust steroid-sparing effect and improvement of inflammation without significant adverse effects. Recurrence of inflammation can be detected by FDG-PET even during TCZ treatment., Competing Interests: Declaration of Competing Interest The authors declare the following conflict of interest. Chugai Pharmaceutical Company, Daiichi-Sankyo, Pfizer, Otsuka Pharmaceutical Company (MI)., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK)., Methods: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety., Results: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported., Conclusion: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns., Trial Registration: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch&#95;e.jsp, JapicCTI-142616., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B , LILRA3 / LILRB2 , DUSP22 , and KLHL33 , respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6 / FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB , a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3 / LILRB2 is known to be a tagging SNP for the deletion of LILRA3 , a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 ( P = 1.2 × 10 -3 ). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells ( P = 8.8 × 10 -5 , enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK., Competing Interests: Conflict of interest statement: Editor Tasuku Honjo and several authors are affiliated with Kyoto University but do not have any active collaborations.

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.

Objective: To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK)., Methods: Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms., Results: The intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr's definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths., Conclusion: Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK., Trial Registration Number: JapicCTI-142616., Competing Interests: Competing interests: YN reports personal fees from Chugai as a consultant of the sponsor-initiated clinical trial (Chugai Pharmaceutical Co.) using tocilizumab for Takayasu arteritis; grants and personal fees from Chugai; grants and personal fees from Astellas, Pfizer, and MSD outside the submitted work; grants from Takeda, Otsuka, Bayer outside the submitted work; and personal fees from Daiichi Sankyo and Kowa Pharmaceutical Co. outside the submitted work. MI reports personal fees from Chugai during the conduct of the study; personal fees from Chugai; and grants and personal fees from Ono, Mitsubishi Tanabe, Daiichi Sankyo, Otsuka and Teijin Pharma outside the submitted work. ST reports grants and personal fees from Chugai during the conduct of the study; grants and personal fees from Eisai, Takeda, Bristol-Myers Squibb and Tanabe-Mitsubishi; and personal fees from Pfizer, Ayumi, Asahi Kasei Pharma, AbbVie, Santen, Nihon Pharmaceutical, Japan Blood Products Organization, Teijin and UCB Japan outside the submitted work. YT reports grants and personal fees from Chugai during the conduct of the study; grants and personal fees from Daiichi Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe and Bristol-Myers Squibb outside the submitted work; grants from MSD, Takeda, AbbVie, Kyowa-Kirin, Eisai and Ono outside the submitted work; and personal fees from YL Biologics, Eli Lilly, Sanofi, Janssen and UCB outside the submitted work. TI reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Ono, Pfizer, Mitsubishi-Tanabe and Astellas outside the submitted work. SY reports personal fees from Chugai during the conduct of the study and personal fees from Chugai outside the submitted work. AN reports personal fees from Chugai during the conduct of the study. SY reports personal fees from Chugai during the conduct of the study. NN reports personal fees from Chugai during the conduct of the study and grants and personal fees from Chugai outside the submitted work and has a patent for tocilizumab with royalties paid by Chugai. S Ooka reports personal fees from Chugai during the conduct of the study and a grant from Chugai outside the submitted work. H Yamada reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Teijin, Asahi Kasei, Astellas, Ono, Bristol-Myers Squibb, Pfizer, Eisai, Mitsubishi Tanabe, Janssen, AbbVie, Actelion, Nippon Shinyaku, GlaxoSmithKline and Bayer outside the submitted work. H Niiro reports personal fees from Chugai during the conduct of the study; grants and personal fees from Chugai, Mitsubishi Tanabe, Astellas, Bristol-Myers Squibb and Takeda outside the submitted work; and personal fees from Pfizer and Eisai outside the submitted work. H. Tsukamoto reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Astellas, Takeda, Pfizer, AbbVie, Eisai, Mitsubishi-Tanabe, Bristol-Myers Squibb, Ayumi, Mylan, Asahi Kasei Pharma, Actelion, Daiichi Sankyo, Nippon Kayaku, Thermo Fisher Diagnostics, Kissei and Eli Lilly outside the submitted work. S Banno reports personal fees from Chugai during the conduct of the study; personal fees from Kissei outside the submitted work; and grants from Chugai, Teijin, Kissei, Mitsubishi Tanabe, Takeda, Pfizer, Eisai, AbbVie, Bristol-Myers Squibb, Ono, Astellas, Janssen and UCB outside the submitted work. N Tamura reports personal fees from Chugai during the conduct of the study; grants and personal fees from Janssen, Astellas, Eisai, AbbVie, Pfizer and Daiichi Sankyo outside the submitted work; and personal fees from UCB, Bristol-Myers Squibb and Novartis outside the submitted work. Y Takasaki reports personal fees from Chugai during the conduct of the study and grants and personal fees from Santen, Daiichi Sankyo, Mitsubishi Tanabe, Bristol-Myers Squibb, AstraZeneca, Astellas, MSD, Chugai, Asahi Kasei, Eisai and Janssen outside the submitted work. H Yoshifuji reports personal fees from Chugai during the conduct of the study. A Kawakami reports personal fees from Chugai during the conduct of the study; grants and personal fees from Ono, Mitsubishi Tanabe, Takeda, Astellas, AbbVie, MSD, AstraZeneca, Actelion, Eisai, Kissei, Santen, Daiichi Sankyo, Pfizer, Sanofi, Asahi Kasei, Taisho Toyama, Teijin, Sumitomo Dainippon, Eli Lilly, Bristol-Myers Squibb and Janssen outside the submitted work; grants from Mochida, Boehringer Ingelheim, Otsuka and Kowa outside the submitted work; and personal fees from Novartis outside the submitted work. S Furuta reports personal fees from Chugai during the conduct of the study. T Atsumi reports personal fees from Chugai, Eli Lilly, GlaxoSmithKline, Pfizer and UCB Japan during the conduct of the study; grants and personal fees from Astellas, Takeda, Mitsubishi Tanabe, Chugai, Pfizer, Daiichi Sankyo, Eisai and AbbVie outside the submitted work; grants from Otsuka outside the submitted work; personal fees from Bristol-Myers Squibb outside the submitted work. K Suzuki reports personal fees from Chugai during the conduct of the study; grants and personal fees from Eisai, Bristol-Myers Squibb and Kissei outside the submitted work; grants from Daiichi Sankyo outside the submitted work; personal fees from AbbVie, Astellas, Chugai, Fuji Film, Janssen, Mitsubishi Tanabe, Pfizer, Shionogi, Takeda and UCB Japan outside the submitted work. R Hara reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Eisai and Toshiba Medical outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Takayasu arteritis (TA) is an autoimmune arteritis of unknown etiology. Currently, the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels are widely used to monitor disease activity of TA. However, sometimes it is difficult to reflect inflammatory symptoms in either CRP or ESR values, especially in TA patients with immunosuppressive therapies. Therefore, higher-accuracy biomarkers for evaluating disease activity need to be explored., Methods and Results: We examined 21 Japanese patients diagnosed with TA; 17 TA patients were treated with prednisone with or without additional immunosuppressive therapies and the remaining 4 patients were treated with infliximab, a human monoclonal anti-tumor necrosis factor (TNF)-α antibody. In active phase, the serum levels of both TNF-α and interleukin (IL)-6 were significantly higher than in healthy subjects, as is the case with both the levels of CRP and ESR. In contrast, the levels of both IL-12 and IL-23 remained in the normal range. Both TNF-α and IL-6 levels were markedly decreased in response to therapies, on equality with both CRP and ESR levels. Regarding the TA patients treated with infliximab, both CRP and IL-6 levels tended to be decreased after infliximab therapy. Conversely, TNF-α level after infliximab therapy was higher than before therapy., Conclusion: Both TNF-α and IL-6 levels, but not IL-12 or IL-23 levels, in the serum could be potent biomarkers that can reflect the activity of TA., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Takayasu arteritis (TA) is occasionally complicated with inflammatory bowel disease (IBD). This study assessed the endoscopic and genetic features of IBD complicated with TA (IBD-TA)., Methods: This study retrospectively reviewed the clinical charts of 142 TA patients (14 men and 128 women; median age 48.5 years [range, 18-97 years]). Human lymphocyte antigen (HLA) types and a single-nucleotide polymorphism rs6871626 in the IL12B gene were assessed in 101 and 81 patients with TA, respectively., Results: Inflammatory bowel disease was diagnosed in 13 (9.2%) of the 142 patients. The endoscopic features of IBD-TA at initial diagnosis (n = 8) showed discontinuous and focal mucosal inflammations (n = 7, 87.5%), and only one case was diagnosed as ulcerative colitis (UC) at the first colonoscopy. In the genetic comparison of HLA class I between TA patients with IBD and those without IBD, HLA-B*52:01 and C*12:02 were more frequent in the IBD-TA group (P = 0.001 and P = 0.009, respectively). Meanwhile, HLA-DRB-1*15:02, DQA-1*01:03, DQB-1*06:01, and DPB-1*09:01 as HLA class II were positively associated with IBD-TA (P = 0.004, P = 0.019, P = 0.019, and P = 0.002, respectively). IL12B rs6871626 did not show an association with IBD-TA compared with that with TA without IBD., Conclusions: The endoscopic findings of IBD-TA at initial diagnosis were atypical for UC or Crohn's disease. IBD-TA possessed the HLA haplotype, which had a susceptible effect on UC., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: We aimed to investigate the effects of immunosuppressive and biological agents on refractory Takayasu arteritis (TA) patients resistant to or dependent on glucocorticoids., Methods: Forty-four consecutive TA patients were enrolled, and the clinical characteristics and effectiveness of the immunosuppressive and biological agents in achieving and maintaining remission among glucocorticoid-resistant or glucocorticoid-dependent patients were investigated., Results: Fifteen patients showed favorable response to the initial glucocorticoid treatment, and 29 patients exhibited resistance to initial glucocorticoid treatment or relapsed with tapering glucocorticoid. Of the 29 patients, 5 responded to additional glucocorticoid treatment, and 22 of the remaining 24 glucocorticoid-resistant or glucocorticoid-dependent patients were prescribed immunosuppressive agents. Methotrexate was the most commonly used in these patients as the first-line treatment. In total, 10 patients maintained remission using immunosuppressive agents, with the effectiveness of each agent about 20%. The only significant difference between patients who were and were not able to achieve and maintain remission with immunosuppressive agents was the presence of the HLA-B52 allele (p<0.0001). Biological agents were administered to 6 patients refractory to immunosuppressive agents. All patients were administered tumor necrosis factor (TNF) inhibitors as the first-line treatment, and 3 patients maintained remission. Anti-interleukin-6 receptor antibody was administered to 2 patients who were resistant to the TNF inhibitors, and 1 patient achieved and maintained remission., Conclusion: In our cohort, 64% of the glucocorticoid-resistant or glucocorticoid-dependent patients maintained remission through a combined treatment with glucocorticoid, immunosuppressive agents, and/or biological agents. The combined use of immunosuppressive and biological agents appears to be a promising treatment option for achieving and maintaining remission in refractory TA patients., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Little is known about the obstetrical management of patients with Takayasu arteritis (TA) who have undergone extra-anatomic vascular bypass (EAVB). We describe two cases of EAVB. Case 1 underwent EAVB due to renovascular hypertension associated with stenosis of the abdominal aorta, and Case 2 due to amaurosis fugax episodes associated with stenosis of the brachiocephalic and left common carotid arteries. Pregnancy outcomes were favorable for both cases, though the original symptoms recurred during the third trimester in each case, possibly due to increased blood flow to the pregnant uterus. Neither bypass occlusion nor anastomotic aneurysm formation was observed. Pregnancy outcomes of patients with EAVB due to TA are favorable, although pregnancies of patients with TA who have cardiovascular complications are associated with an increased risk of maternal and fetal morbidity. The obstetrical management of these patients, however, should include monitoring for complications related to the EAVB., (© 2016 Japan Society of Obstetrics and Gynecology.)

Takayasu arteritis (TAK) is an acute and chronic vasculitis of unknown etiology. Recently, our group reported that SNP rs6871626 in the IL12B region had significant association with disease susceptibility to TAK. However, association of the SNP with clinical characteristics of TAK has yet to be determined. Therefore, we assessed whether this SNP was associated with TAK disease severity as represented by early onset and/or refractoriness to medical therapy. A total of 90 patients were genotyped for rs6871626 and their clinical charts were reviewed retrospectively. By examining the relationship between genotype and clinical profiles of patients, we found a strong association between the number of risk alleles and the frequency of severe cases as defined by (1) age at onset <20 years old, (2) steroid resistance, and/or (3) a relapse of disease [p = 0.03; odds ratio 3.75 (95 % confidence interval 1.13-13.5)]. Thus, our study points to potential diagnostic use of SNP rs6871626 for predicting disease severity of TAK, with the goal of genotyping-oriented therapy in the near future.

Aims: The assessment of the distribution and activity of vessel wall inflammation is clinically important in patients with Takayasu arteritis. Magnetic resonance imaging (MRI) is a useful tool, but the clinical utility of late gadolinium enhancement (LGE) in Takayasu arteritis has yet to be determined. The aim of the present study was to evaluate the utility of LGE in assessing vessel wall inflammation and disease activity in Takayasu arteritis., Methods and Results: We enrolled 49 patients with Takayasu arteritis who had undergone 1.5 T MRI. Patients were divided into Active (n = 19) and Inactive disease (n = 30) groups. The distribution of vessel wall inflammation using angiography and LGE was assessed by qualitative analysis. In 79% and 63% of patients in Active and Inactive groups, respectively, greater distribution of vessel wall inflammation was observed with LGE than with conventional angiography. MRI values of pre- and post-contrast signal-to-noise ratios (SNR), SNR increment (post-SNR minus pre-SNR), pre- and post-contrast contrast-to-noise ratios (CNR), and CNR increment (post-CNR minus pre-CNR) were evaluated at arterial wall sites with the highest signal intensity using quantitative analysis of post-contrast LGE images. No statistically significant differences in MRI parameters were observed between Active and Inactive groups. Contrast-enhanced MRI was unable to accurately detect active disease., Conclusion: Contrast-enhanced MRI has utility in detecting the distribution of vessel wall inflammation but has less utility in assessing disease activity in Takayasu arteritis.

Objective: Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases., Methods: We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases., Results: Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 × 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10(-10) )., Conclusion: UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence., (© 2015, American College of Rheumatology.)

Takayasu arteritis (TA) is a rare nonspecific inflammatory disease of unknown cause, predominantly affecting the aorta and its main branches, coronary arteries, and pulmonary arteries of young females. It induces a variety of nonspecific inflammatory symptoms and ischemic symptoms due to stenotic lesions. Further progression of TA causes destruction of the arterial wall media, leading to aortic regurgitation and aneurysms or rupture of the involved arteries. Although serological tests specific for TA are not available, new better biomarkers are emerging such as pentraxin3 and matrix metalloproteinases. Recent advances in imaging modalities including magnetic resonance angiography, computed tomography (CT), sonography, and fluorodeoxy glucose positron emission tomography/CT (FDG-PET/CT) allow earlier and accurate diagnosis of TA. Duration between onset of the disease and diagnosis has become much shorter during the last decade. Medical treatment for TA is also changing. In addition to the traditional glucocorticoids and immunosuppressants, many new biological agents are being applied to patients with TA refractory to conventional treatment with favorable results. As for treatment for vascular complications, efficacy of endovascular treatment is still a matter of controversy because of the high rate of restenosis at an early stage after the procedure. Based on these advances, the prognosis and quality of life of TA patients have improved to a great deal. However, there are many issues that remain to be solved in the management of TA., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Patients with Takayasu arteritis (TA) often show recurrence under steroid treatment without an elevation of C-reactive protein (CRP). There is a report that matrix metalloproteinase (MMP)-2, MMP-3, MMP-9 and pentraxin3 (PTX3) could be sensitive biomarkers, but the characteristics of these biomarkers have not been established., Methods and Results: We enrolled 45 consecutive patients; 28 were grouped in an active phase as evidenced by clinical recurrence within 2 years of blood sampling. Circulating levels of high-sensitivity (hs)CRP, MMPs, and PTX3 were determined. Patients in an active phase showed higher levels of hsCRP, MMP-9, and PTX3. Area under the receiving operating characteristics curves of hsCRP and PTX3 were significantly higher than that of MMP-9. Among the 28 patients with active TA, 71% was positive for hsCRP and 82% for PTX3. Patients without recurrence showed significantly higher plasma levels of MMP-9. There was a positive correlation between the plasma MMP-3 level and the prednisolone dose. However, PTX3 and MMP-9 levels did not have such a correlation., Conclusions: PTX3 and MMP-9, which are not affected by prednisolone, could be sensitive biomarkers for assessing TA activity. Evaluation of MMP-9 may suggest prior existence of TA.

Objectives: The aim of this study was to investigate whether the maximum standardized uptake value (max SUV) of (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) provides a quantitative indication of disease activity in Takayasu arteritis (TA) cases., Background: The clinical value of FDG-PET for assessing TA has been investigated. Clinical evaluation of disease activity is often difficult, because most patients develop recurrent inflammation while receiving corticosteroid treatment., Methods: Thirty-nine TA patients underwent FDG-PET/CT at Tokyo Medical and Dental University from 2006 to 2010 (35 women and 4 men; median age, 30 years). Disease activity was defined according to National Institutes of Health criteria. Biomarkers including C-reactive protein and erythrocyte sedimentation rate were measured. Forty subjects without vasculitis served as control subjects., Results: The max SUV was significantly higher in active than in inactive cases and control subjects (active [n = 27], median value, 2.7 vs. inactive [n = 12], 1.9; control [n = 40], 1.8; p < 0.001 each). Given a max SUV cutoff of 2.1, sensitivity for active-phase TA was 92.6%, specificity 91.7%, positive predictive value 96.2%, and negative predictive value 84.6%. In receiver-operating characteristic curves comparison, max SUV was superior to C-reactive protein (p < 0.05) and erythrocyte sedimentation rate (p < 0.05). Max SUV was significantly higher in relapsing on treatment cases (n = 17) than in stable on treatment cases (n = 12) (median value, 2.6 vs. 1.9; p < 0.001)., Conclusions: FDG-PET/CT is useful for detection of active inflammation not only in patients with active TA before treatment but also in relapsing patients receiving immunosuppressive agents. The max SUV is useful for assessing subtle activity of TA with high sensitivity., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The association of human leukocyte antigen (HLA) alleles and Takayasu arteritis (TA) is not fully understood. The aim of the present study was to investigate HLA alleles in Japanese patients with TA and the association of these alleles with clinical manifestations., Methods and Results: A total of 96 patients diagnosed with TA according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) and 371 healthy controls were enrolled in the present study. HLA genotyping showed a significant association of HLA-B67 (P=0.00024, odds ratio [OR]=4.94), a novel locus, and B52 (P<0.0001; OR=3.35), a conventional locus, with TA using both sequence-based typing and PCR-SSP assay. The frequency of HLA-B39, an allele reportedly associated with TA in Asian populations, was not higher than controls in the present study (P=0.86, OR=1.07). B52 had higher prevalence than B67 but the OR was higher for B67. We next studied the association of HLA-B67 and -B52 with clinical characteristics: age at disease onset, distribution of arteritis, pulmonary involvement, aortic regurgitation, systemic hypertension, steroid resistance and recurrence rate in TA. There was no significant difference in these clinical parameters between HLA-B67-positive or HLA-B52-positive patients and other patients., Conclusions: The HLA-B67 allele could be a new and important marker of TA because of its high OR compared to HLA-B52, although its prevalence in TA is lower.

Background: We aimed to describe the recent clinical characteristics of Takayasu arteritis (TA)., Methods and Results: We enrolled 106 consecutive TA patients and compared the clinical characteristics of patients with TA onset before 1999 and after 2000, patients with onset at age less than 39 years and more than 40 years, patients with monophasic and relapsing-remitting clinical course, and patients with and without human lymphocyte antigen (HLA)-B52 allele. Among the patients with TA onset after 2000, the time from onset to diagnosis had decreased; the frequency of occlusion in aortic arch branches and the complication of moderate or severe aortic regurgitation (AR) had decreased, and the maximum dose of prednisolone and the use of immunosuppressive agents had increased. In patients with onset at age more than 40 years, the complications of coronary artery lesions and hypertension had increased, and the incidence of moderate or severe AR had decreased. In the relapsing-remitting group, the maximum dose of prednisolone and the use of immunosuppressive agents had increased, and the mean dose reduction rate of prednisolone was significantly high. There was no significant difference between patients with and without HLA-B52 allele., Conclusions: The prognosis of TA patients has improved over the past decade, which may be related to early diagnosis because of the development of noninvasive diagnostic imaging tools and improved medical treatments.

Background: Inflammation and thrombosis are closely related processes, but the association between disease activity and thrombogenicity in Takayasu's arteritis (TA) is poorly understood. To investigate the link between platelet activation and disease activity, flow cytometric analyses of platelet P-selectin and activated GPIIb/IIIa expression were performed in patients with TA., Methods and Results: Twenty-two patients with TA, classified into active (Group A, n = 9) and inactive (Group I, n = 13) according to blood-derived inflammatory markers, and 14 healthy age- and gender-matched controls (Group C) were studied. Compared with Group C, the mean fluorescence intensity of P-selectin in response to 0.1-10 micromol/L of ADP was significantly upregulated in Group A, but not in Group I. No differences in platelet GPIIb/IIIa expression in stimulated platelets were seen among the 3 groups. Standard platelet aggregation studies revealed that disease activity did not influence platelet aggregation by ADP., Conclusions: P-selectin expression, but not activated GPIIb/IIIa, is enhanced in ADP-activated platelets from patients in the inflammatory stage of TA. P-selectin may play a significant role in the inflammatory and thrombotic responses associated with intractable TA, presumably by inducing platelet-leukocyte interactions.

A young female patient with Takayasu arteritis presented with unstable angina due to bilateral coronary artery involvement. Steroid pulse therapy and subsequent prednisolone administration were started, but early coronary artery bypass grafting was required because of the multiple angina attacks at rest, with a prednisolone dose of 22.5 mg (0.45 mg/kg/day). Since the left internal thoracic artery which was grafted to the left anterior descending artery resulted in graft failure a few days after the surgery, the immunosuppressive therapy was intensified with the addition of tocilizumab and methotrexate. After controlling the disease activity, coronary ostial angioplasty using external iliac artery grafts was successfully performed, with a prednisolone dose of 15 mg (0.3 mg/kg/day). Ten months after the operation, the patient has been free from chest pain. The present case demonstrated the importance of adequate preoperative immunosuppressive therapy, even when early surgical intervention is required. There are no established treatment regimens for immunosuppressive management in cases of Takayasu arteritis (TAK) requiring immediate surgical intervention. Even when early surgery is required, it is important to reduce disease activity with appropriate preoperative immunosuppressive therapy using steroids in addition to biological agents, such as tocilizumab. Coronary ostial angioplasty is the effective surgical revascularization technique for TAK with coronary artery involvement. [ABSTRACT FROM AUTHOR]

• Remission induction rate for intractable Takayasu arteritis by tocilizumab was 70.2%. • C-reactive protein stayed low in recurrent Takayasu arteritis under tocilizumab treatment. • Recurrence of inflammation can be detected by 18F-fluorodeoxyglucose positron emission tomography even during tocilizumab treatment. Although high-dose glucocorticoids are effective in suppressing active inflammation of Takayasu arteritis (TAK), many patients experience relapse during tapering of glucocorticoids. Recently, the interleukin-6 receptor antibody, tocilizumab (TCZ), was reported to be effective for steroid-resistant TAK. However, there are no objective ways of diagnosing TAK recurrence because TCZ suppresses inflammatory biomarkers. To investigate the efficacy of TCZ at 1-year follow-up and of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography for detection of recurrence of inflammation during TCZ treatment. We treated 19 patients with refractory TAK with TCZ. TCZ was discontinued in 2 cases because of side effects. Abatement of arteritis symptoms along with reduction of glucocorticoid dosage was achieved in 12 patients, resulting in a remission induction rate of 70.6%. The dosage of glucocorticoid was reduced from 16.1 ± 10.2 mg to 3.8 ± 1.7 mg at 1 year (p <0.001) in these patients. In the remaining 5 patients, glucocorticoid tapering led to exacerbation of symptoms and glucocorticoid dose had to be increased. FDG-PET scan results closely matched clinical course in all 5 patients with recurrence even during TCZ treatment, while the scan was negative for the remaining 12 patients. TCZ injection provides robust steroid-sparing effect and improvement of inflammation without significant adverse effects. Recurrence of inflammation can be detected by FDG-PET even during TCZ treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).Methods: Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms.Results: The intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr's definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths.Conclusion: Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK.Trial Registration Number: JapicCTI-142616. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. 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. [ABSTRACT FROM AUTHOR]