Search

Objective To develop a proposal for giant cell arteritis (GCA) remission criteria in order to implement a treat-to-target algorithm. Methods A task force consisting of 10 rheumatologists, three cardiologists, one nephrologist, and one cardiac surgeon was established in the Large-vessel Vasculitis Group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis to conduct a Delphi survey of remission criteria for GCA. The survey was circulated among the members over four reiterations with four face-to-face meetings. Items with a mean score of ≥4 were extracted as items for defining remission criteria. Results An initial literature review yielded a total of 117 candidate items for disease activity domains and treatment/comorbidity domains of remission criteria, of which 35 were extracted as disease activity domains (systematic symptoms, signs and symptoms of cranial and large-vessel area, inflammatory markers, and imaging findings). For the treatment/comorbidity domain, ≤5 mg/day of prednisolone one year after starting GCs was extracted. The definition of achievement of remission was the disappearance of active disease in the disease activity domain, normalization of inflammatory markers, and ≤5mg/day of prednisolone. Conclusions We developed proposals for remission criteria to guide the implementation of a treat-to-target algorithm for GCA.

ObjectiveWe conducted a nationwide epidemiological study to estimate the number of patients with Takayasu arteritis (TAK) and giant cell arteritis (GCA) in Japan and to describe the clinical characteristics of these patients.MethodsThe first survey was designed to estimate the number of patients with TAK and GCA who were treated at medical institutions in Japan in 2017. The second survey was designed to collect data on the clinical characteristics of the patients who were reported in the first survey.ResultsOf the 3495 institutions selected for the first survey, 1960 (56.1%) responded. The number of patients with clinically diagnosed TAK and GCA was estimated to be 5320 (95% confidence interval, 4810–5820) and 3200 (95% confidence interval, 2830–3570), respectively. Aortic regurgitation was reported in 35% of patients with TAK, and eye-related comorbidities were observed in 30.4% of patients with GCA. The common carotid and internal carotid arteries were the most frequently involved in patients with TAK (62.7%). Subclavian artery lesions and thoracic or abdominal aorta lesions were reported in 31% and 42.6% of patients with GCA, respectively.ConclusionsThe number of patients with TAK and GCA was estimated simultaneously, and significant differences in clinical characteristics were observed between the two diseases.

Objective: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes.Methods: We extracted data on 68 newly-diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with or without aortic lesions were identified based on findings from contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT. Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions. Primary outcome evaluation was failure to achieve clinical remission by week 24 and/or relapse within 104 weeks. Results: Aortic lesions were detected in 49 (72.1%) of the 68 patients with LV-GCA (defined as group 2). Patients without aortic lesions were classified as having LV-GCA with subclavian lesions (group 1, n=9) or LV-GCA without subclavian lesions (group 3, n=10). The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in LV-GCA with aortic lesions (group 2) was lower than in the other two groups, but these differences were not statistically significant. In group 2, 36 of the 49 patients had lesions in both the aorta and aortic branches. Stenosis of aortic branches at baseline was more frequently observed in group 1 (55.6%) than groups 2 and 3 (18.4% and 30.0%, respectively). Atypical lesions in group 3 included pulmonary, hepatic or mesenteric lesions. Mean time to achievement of low-dose GC treatment was not statistically significant among 3 groups. Methotrexate was administered at baseline to 0 %, 24.5%, and 20% in groups 1, 2, and 3, respectively. None of these patients received biologic agents. The cumulative rate of poor treatment outcomes over two years was 11.1%, 55.3%, and 88.0% in groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups. Conclusions: The patterns of large-vessel lesions were associated with the poor treatment outcomes and appear to be a pertinent factor for determining treatment strategies for LV-GCA.

Objectives We evaluated the real-world tolerability and effectiveness of tocilizumab in Japanese patients with Takayasu arteritis (TAK). Methods Patients with TAK who had not received tocilizumab in the previous 6 months were enrolled in ACTEMRA® (ACT)-Bridge, a phase 4, observational study, from 66 Japanese institutions (enrolment period, September 2017 to September 2020) and received weekly subcutaneous tocilizumab 162 mg (observation period, 52 weeks). Results Among 120 patients included (mean age, 38.4 years; mean disease duration, 7.7 years; treated for relapse, 50.8%; previous immunosuppressant use, 57.5%; glucocorticoid use at baseline, 97.5%), 49 (40.8%) reported adverse events. The most common adverse event of special interest was serious infection (7.5%). Relapse was observed in 24 (20.0%) patients (0.8%, 2.5%, and 16.7% reporting ≥3, 2, and 1 relapses, respectively). The reasons for diagnosing relapse included chest and back pain (45.8%), neck pain (25.0%), fatigue (16.7%), fever and headache (12.5% each), abnormal imaging findings (50.0%), and elevated inflammatory markers (16.7%). At the last observation, 83.0% of relapse-free patients recorded a concomitant glucocorticoid dose (prednisolone equivalent) Conclusions This study demonstrated the effectiveness of tocilizumab in patients with TAK, with no new safety concerns. Tocilizumab plus glucocorticoids may be considered a treatment option for TAK.

Numerous basic studies have shown a relationship between interleukin-6 (IL-6) and the development or severity of myocarditis. However, there has been no study in which the effect of IL-6 levels in patients with myocarditis was evaluated.We enrolled control patients (n = 12) and consecutive patients with acute myocarditis (n = 13), including lymphocytic, eosinophilic, and giant cell myocarditis, and investigated the pathological and clinical effects of IL-6 on human myocarditis.The serum IL-6 level in patients with myocarditis (16.7 [9.9, 103.8] pg/mL) was significantly higher than that in the control patients (1.4 [1.0, 1.9] pg/mL) (P0.001). Immunohistochemical analysis showed that IL-6 was expressed in infiltrating inflammatory cells of endomyocardial biopsy samples from all patients with myocarditis. Moreover, the log-transformed value of serum IL-6 level showed significant positive correlations with serum creatine kinase (CK) level, CK-MB level, peak CK level, peak CK-MB level and C-reactive protein level (all P ≤ 0.005) and a negative correlation with the left ventricular (LV) ejection fraction (p = 0.014). We divided the patients with myocarditis into a low IL-6 group (9.9 [4.5, 14.2] pg/dL, n = 7) and a high IL-6 group (108.9 [51.1, 130.9] pg/dL, n = 6). The degree of infiltration of IL-6-expressing inflammatory cells in myocardial samples obtained from patients in the high IL-6 group was significantly more severe than that in samples obtained from patients in the low IL-6 group. Furthermore, patients in the high IL-6 group significantly more frequently received catecholamine therapy (P = 0.005), venoarterial extracorporeal membrane oxygenation (P = 0.029), and artificial respirator support (P = 0.021) in the acute phase of myocarditis.The results suggest that there is a strong impact of IL-6 on cardiac injury and dysfunction in patients with myocarditis.

We describe the case of a young woman with Takayasu arteritis with severe stenosis in the main trunk of the left coronary artery. After administration of prednisolone and tocilizumab to control disease activity, coronary artery bypass grafting was performed. Here, we report the successful perioperative management of this cardiac surgery. (Level of Difficulty: Advanced.), Graphical abstract, We describe the case of a young woman with Takayasu arteritis with severe stenosis in the main trunk of the left coronary artery. After administration…

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 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_e.jsp, JapicCTI-142616.

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Hypothesis: We hypothesized that AHR has a role in PAH pathogenesis both in human and animal models. Methods: Wild type (WT) and Ahr -knockout ( Ahr -/- ) rats were either treated with AHR agonists or VEGFR2 inhibitors or fed a diet containing a Chinese herbal drug Qing-Dai, which may cause drug-induced PAH, in combination with hypoxia, and then subjected to hemodynamic analysis. Histological characteristics were analyzed in the lungs of these rats and patients with idiopathic PAH. RNA-seq and qRT-PCR were performed on specimens from SU5416/Hypoxia (SuHx) rats, including lungs and the peripheral blood mononuclear cells (PBMCs), and PBMCs of PAH patients. AHR agonistic activity in serum was judged by luciferase reporter assay. Results: WT rats treated with the potent endogenous AHR agonist (6-formylindolo[3,2-b]carbazole) in combination with hypoxia, developed severe pulmonary hypertension (PH) with plexiform-like lesions, whereas WT rats treated with the potent VEGFR2 inhibitors (KI8751 and TAK-593) did not. Ahr -/- rats did not develop PH in the SuHx rats. A diet containing Qing-Dai in combination with hypoxia led to development of PH in Ahr +/+ rats, but not in Ahr -/- rats. Several inflammatory signaling pathways were up-regulated in endothelial cells and PBMCs, which led to infiltration of CD4 + IL-21 + T cells and MRC1 + macrophages into vascular lesions in an AHR-dependent manner. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. The expression of several AHR-related genes were changed in PBMCs of PAH patients. Conclusions: AHR plays crucial roles in the development and progression of PAH, indicating that this receptor is a potential target for both diagnosis and treatment of PAH.

ObjectiveTo evaluate whether the distribution of large-vessel lesions (LVLs) in giant cell arteritis (GCA) is associated with poor treatment outcomes.MethodsIn a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014, 68 newly-diagnosed patients with LVLs were identified by imaging. Non-achievement of clinical remission by week 24 and/or relapse within 104 weeks were primarily evaluated. Factors influencing the poor treatment outcome were analyzed using Cox proportional hazard modeling. Cumulative rates and median time to the first event were analyzed by the Kaplan-Meier method and log-rank testing.ResultsAortic lesions were detected in 72.1% of the 68 GCA patients with LVLs (defined as group 2). Patients without aortic lesions were classified as having large-vessel GCA with subclavian lesions (group 1) or atypical large-vessel GCA without subclavian lesions (group 3). The mean age and proportions of PMR in group 3 were higher than those in the other two groups. Cranial lesions were observed in 66.7%, 55.1%, and 80.0% of patients in groups 1, 2 and 3, respectively. In group 2, 73.5% had lesions in both the aorta and aortic branches. Group 1 had axillary lesions in 33.3%, and carotid lesions in 44.4%. Atypical LVLs in group 3 included pulmonary, hepatic or mesenteric lesions in addition to carotid lesions. Baseline doses of GCs were not different across the groups. Mean time to achievement of low-dose GC treatment (prednisolone ≤5 mg/day) was also not significantly different between the groups. The cumulative rate of poor treatment outcome over the two years was 11.1%, 55.3% and 88.0% in the groups 1, 2 and 3, respectively; mean time to the events was significantly different among the groups. Multivariable analysis showed that the risk of poor treatment outcome was significantly higher in the group 3.ConclusionsThe distribution of LVLs was associated with treatment outcomes in large-vessel GCA. In addition to subclavian arteries, lesions in aorta and aortic branches other than subclavian arteries should be evaluated by imaging for large-vessel GCA. The pattern of LVLs determined by imaging should be considered when determining treatment strategies for GCA.

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.

Objectives Tocilizumab, an anti-IL-6 receptor antibody, was investigated in patients with refractory Takayasu arteritis (TAK) in a phase 3 randomized controlled trial. In this post hoc analysis, we investigated whether tocilizumab treatment inhibited the progression of vascular lesions caused by TAK in these patients. Methods Included patients received at least one dose of tocilizumab and underwent CT at baseline and at week 48 after tocilizumab initiation. Three radiologists not involved in the original trial independently evaluated the CT images. Twenty-two arteries from each patient were assessed for change from baseline in wall thickness (primary endpoint), dilatation/aneurysm, stenosis/occlusion or wall enhancement for at least 96 weeks after tocilizumab initiation. Patient-level assessments were also conducted. Results In 28 patients, 86.7% of 22 arteries had improved or stable wall thickness at week 96. Proportions of patients with improved or stable, partially progressed or newly progressed lesions were 57.1%, 10.7% and 28.6%, respectively, for wall thickness; proportions with improved or stable lesions were 92.9% for dilatation/aneurysm, and 85.7% for stenosis/occlusion. Patients with newly progressed lesions, reflecting more refractory disease, were prescribed glucocorticoids at dosages that could not be reduced below 0.1 mg/kg/day at week 96. Conclusions Approximately 60% of patients with TAK did not experience progression in wall thickness within 96 weeks after initiation of tocilizumab treatment. Few patients experienced progressed dilatation/aneurysm, or stenosis/occlusion. Wall thickness progression likely resulted from refractory TAK. Patients who experience this should be monitored regularly by imaging, and additional glucocorticoid or immunosuppressive treatment should be considered to avoid vascular progression. Trial registration Japan Pharmaceutical Information Centre number, JapicCTI-142616.

Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a well-known angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1sys−/−) and β-cell–specific Ang1 knockout (Ang1β-cell−/−) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1sys−/− and Ang1sys+/+ mice, serum insulin levels were lower in Ang1sys−/− mice, resulting in significant glucose intolerance. Similar results were observed in Ang1β-cell−/− mice, suggesting a critical role of β-cell–derived Ang1 in glucose homeostasis. There were no differences in β-cell area or vasculature density, but glucose-stimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1β-cell−/− compared with Ang1β-cell+/+ mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1β-cell−/− mice. In conclusion, β-cell–derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.

Significance Inflammatory signals are thought to be crucial for the pathogenesis of PAH; however, the underlying mechanism is still largely unknown. In this study, we demonstrate that AHR makes a causal contribution to the pathogenesis of PAH, activating a focal inflammatory response in the lungs and promoting infiltration of immune cells from the bone marrow. Furthermore, we found that PAH patients with higher AHR agonistic activity in sera are more susceptible to severe clinical events than those with lower activity. Because conventional therapy for pulmonary hypertension targeting pulmonary artery vasodilation has limited efficacy against severe PAH, the AHR-signaling pathway represents a promising therapeutic target for PAH. In addition, AHR agonistic activity in serum represents a biomarker for PAH., Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague–Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague–Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr−/−) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr−/− rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using 18F-FDG Positron emission tomography (PET) and magnetic resonance imaging (MRI). Endothelium-dependent and endothelium-independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared with the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function.NEW & NOTEWORTHY We demonstrated for the first time the impairment of vascular responses in the right coronary artery (RCA) of the dysfunctional right heart in pulmonary hypertensive rats in vivo. Treatment with an endothelin-1 receptor antagonist ameliorated vascular dysfunction in the RCA, enabled tissue remodeling of the right heart, and improved cardiac function. Our results suggest that impaired RCA function might also contribute to the early progression to heart failure in patients with severe pulmonary arterial hypertension (PAH). The endothelium of the coronary vasculature might be considered as a potential target in treatments to prevent heart failure in severe patients with PAH.

Background The epidemiology and clinical features of thromboangiitis obliterans (TAO) in Japan have not been updated extensively.Methods and Results:This retrospective study used the Japanese Ministry of Health, Labour and Welfare (JMHLW) medical support system database and associated health insurance data. The number of medical financial support recipients registered as TAO patients and estimated prevalence of TAO decreased from fiscal year (FY) 2000 (10,089 and 7.95 [95% confidence interval, CI: 7.79-8.10] per 100,000 population) to FY 2010 (7,147 and 5.58 [95% Cl: 5.45-5.71] per 100,000) and leveled off until 2014. The prevalence of TAO among patients with peripheral arterial occlusive diseases declined from 7.15% (95% Cl: 7.00-7.31) in FY 2008 to 6.12% (95% Cl: 5.98-6.26) in FY 2014. Clinicodemographic features were obtained from 89 new recipients in FY 2013 and 2014: 12 (13%) women, 36 (40%) aged ≥50 years, 26 (29%) had probable onset age ≥50 years, 7 (8%) were non-smokers, and 12 (13%) had arteriosclerosis-related comorbidities. The symptoms were similar regardless of registration age, smoking history, or sex. Although 40 (45%) had digit ulcers, only 12 (13%) fulfilled Shionoya's criteria. They rarely had infrapopliteal lesions combined with upper extremity involvement or phlebitis. Conclusions The prevalence of TAO has decreased in Japan. In the current diagnosis of TAO, various clinical characteristics including late onset, arteriosclerotic factors, non-smoking, or mild symptoms should be considered.

Background Pulmonary arterial hypertension (PAH), particularly connective tissue disease-associated PAH (CTD-PAH), is a progressive disease and novel therapeutic agents based on the specific molecular pathogenesis are desired. In the pathogenesis of CTD-PAH, inflammation, immune cell abnormality, and fibrosis play important roles. However, the existing mouse pulmonary hypertension (PH) models do not reflect these features enough. The relationship between inflammation and hypoxia is still unclear.Methods and Results:Intraperitoneal administration of pristane, a kind of mineral oil, and exposure to chronic hypoxia were combined, and this model is referred to as pristane/hypoxia (PriHx) mice. Hemodynamic and histological analyses showed that the PriHx mice showed a more severe phenotype of PH than pristane or hypoxia alone. Immunohistological and flow cytometric analyses revealed infiltration of immune cells, including hemosiderin-laden macrophages and activated CD4+helper T lymphocytes in the lungs of PriHx mice. Pristane administration exacerbated lung fibrosis and elevated the expression of fibrosis-related genes. Inflammation-related genes such asIl6andCxcl2were also upregulated in the lungs of PriHx mice, and interleukin (IL)-6 blockade by monoclonal anti-IL-6 receptor antibody MR16-1 ameliorated PH of PriHx mice. Conclusions A PriHx model, a novel mouse model of PH reflecting the pathological features of CTD-PAH, was developed through a combination of pristane administration and exposure to chronic hypoxia.

Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1–7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure., The enzyme ACE2 is involved in cardiac pathology and can counteract heart failure and other cardio-pulmonary diseases. Here the authors show that bacteria produce an ACE2-like enzyme that is effective in suppressing cardiac hypertrophy and fibrosis in mice.

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated afterload. Considerable clinical and experimental animal studies have shown that abnormalities of endothelial function represent a hallmark of heart failure. However, the relationships between right coronary endothelial dysfunction and the development of heart failure remain to be fully established especially in the right heart. Synchrotron radiation (SR) microangiography has provided the temporal and spatial resolution required to visualize microvessels of various organs in vivo [1]. Therefore, in this study, we aimed to validate a new approach for the in vivo assessment of endothelial coronary function of the rat right heart using SR microangiography.

Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in the pathogenesis of PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. We recently identified IL-21 as a novel downstream cytokine of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16–1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Together, the above data suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis might be a novel potential target for treating PAH.

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.

Summary: The four-chamber structure of the mammalian heart is established during embryonic development. While key regulators for ventricular development are well studied, regulatory mechanisms for atrial chamber morphogenesis remain poorly understood. Here, we found that angiopoietin-1 (Angpt1), a vascular maturation factor, is highly and specifically expressed in atrial myocardium during heart development. Loss of myocardial Angpt1 in mouse embryo led to severe impairment in atrial chamber morphogenesis. We revealed that Angpt1 deficiency results in excessive deposition of cardiac jelly, which disturbs regulation of myocardial growth, thereby impairing maturation of atrial chambers. Mechanistically, myocardial Angpt1 activates endocardial Tie2 and positively regulates expression of ADAMTS proteases, which is crucial for proper degradation of cardiac jelly. Accordingly, loss of Tie2 also impairs ADAMTS-mediated degradation of cardiac jelly in atrium. Collectively, myocardial Angpt1/endocardial Tie2 signaling in atrium promotes spatiotemporal degradation of cardiac jelly during early cardiac development and is therefore indispensable for atrial chamber morphogenesis. : Kim et al. demonstrate that myocardium-derived Angpt1 is indispensable for atrial chamber morphogenesis. Myocardial Angpt1 activates endocardial Tie2 signaling and positively regulates ADAMTS-dependent degradation of cardiac jelly. Proper distribution of cardiac jelly is critical for the regulation of myocardial growth and chamber morphogenesis in the atrium.

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.

Background:Giant cell arteritis (GCA) is characterized by cranial symptoms and large-vessel lesions (LVL) in the aorta or its branches. We retrospectively analyzed the Japanese patients newly diagnosed as GCA between 2007 and 2014, and subsequently treated with glucocorticoid (GC). The imaging studies revealed that LVLs were observed in approximately half of the GCA patients, and the LVLs were significantly associated with the increased probability of poor treatment outcomes (1).Objectives:The objective of this study is to evaluate whether the distribution of LVLs of GCA was associated with poor treatment response.Methods:In a retrospective, multi-centric, nationwide registry of GCA patients treated with GCs between 2007 and 2014, 68 newly-diagnosed GCA with LVLs by imaging were detected. All investigators were members of Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS). Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 104 weeks) were primarily evaluated. Cumulative rates and median time to the first event were analyzed by the Kaplan-Meier method and the log-rank test. Associated factors with the outcomes were analyzed by using the Cox proportional hazard model.Results:The mean age was 70.5 years, and 70.6% were women. Twenty-seven (39.7%) of the 68 patients were diagnosed as having GCA by both positive temporal artery biopsy and positive imaging, and 41 (60.3%) by positive imaging. Aortic lesions were detected in 72.1% (group 2, n=49) of the 68 GCA patients with LVLs. Patients without aortic lesions were categorized into two phenotypes: large-vessel GCA with subclavian lesions (group 1, n=9) and atypical large-vessel GCA without subclavian lesions (group 3, n=10). Cranial lesions were observed in 66.7%, 55.1%, and 80.0% in the group 1, 2, and 3, respectively. The initial mean dose (SD) of prednisolone was 0.74 (0.26) mg/kg/day, and 20.6 % received methotrexate for remission induction therapy. Baseline dose of GCs and mean time to achievement of low-dose GCs (prednisolone ≤ 5 mg/day) was not significantly different among the three groups.Overall, 35 (51.5%) of the 68 patients had the event of poor treatment outcomes. Eleven patients were not able to achieve clinical remission by week 24. Relapse after achievement of clinical remission was reported in total of 24 patients; 9 between week 0 and 24, 12 between week 24 and 52, 3 between week 52 and 104. The cumulative rate of events of poor treatment outcomes over the two years was 11.1% in patients with group 1, 55.3% in those with group 2, and 88.0% in those with group 3. Mean time to events was significantly different among the three groups. Multivariable analysis showed the risk of poor treatment outcomes was likely to decrease in the group 1 (hazard ratio 0.14 [95% CI 0.02-1.03], p=0.054), while it increased in the group 3 (hazard ratio 2.22 [95% CI 1.06-4.68], p=0.035).Conclusion:The distribution of LVLs were associated with poorer treatment outcomes. A half of the patients with aortic lesions had poor treatment outcomes while subclavian arteritis without aortic lesions had better clinical outcomes. Atypical large vessel-GCA without the aortic and subclavian artery involvement was the worst prognostic phenotype of LV-GCA. Extent of LVLs by imaging should be considered when determining the treatment strategy for GCA.References:[1]Sugihara T, et al. Arthritis Res Ther. 2020;22(1):72Acknowledgements:The authors would like to acknowledge Mitsuaki Isobe (Sakakibara Heart Institute), Yoshihiro Arimura (Kichijoji Asahi Hospital), and all the investigators in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS). In addition to the authors, the following investigators and institutions participated in this study: Department of Internal Medicine, Juntendo University Koshigaya Hospital (Shigeto Kobayashi); Niigata Rheumatic Center (Satoshi Ito); Niigata Prefectural Shibata Hospital (Noriyuki Homma).Disclosure of Interests:takahiko sugihara Speakers bureau: TS has received honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd., Grant/research support from: TS has received research grants from AsahiKASEI Co., Ltd., Daiichi Sankyo., and Ono Pharmaceutical., Haruhito A. Uchida Grant/research support from: HAU belongs to the Department of Chronic KidneyDisease and Cardiovascular Disease which is endowed by Chugai Pharmaceutical, MSD, Boehringer Ingelheim, and Kawanishi Holdings., Hajime Yoshifuji Speakers bureau: HY has received lecture fees from Chugai Pharmaceutical Co., Ltd. and Nihon Medi-Physics Co., Ltd., Yasuhiro Maejima Speakers bureau: YM have received honoraria from Chugai Pharmaceutical Co., Ltd.., Taio Naniwa Speakers bureau: TN has received lecture fees from Chugai Pharmaceutical Co., Ltd.., Grant/research support from: TN has received research grants from Chugai Pharmaceutical Co., Ltd.., Yasuhiro Katsumata Speakers bureau: YK has received honoraria from Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., Sanofi K.K., Pfizer Japan Inc., and Asahi Kasei Pharma Corp., Takahiro Okazaki Grant/research support from: TO has received research grants from Chugai Pharmaceutical Co., Ltd., Eisai Pharmaceutical., and Actelion, Jun Ishizaki: None declared, Yohko Murakawa Speakers bureau: YM has received honoraria from Abbvie, Astellas, Ayumi Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Kissei Pharmaceutical, Nippon Kayaku, Pfizer Pharmaceutical, Takeda Pharmaceutical, UCB Pharmaceutical, Grant/research support from: YM has received research grant support from Asahi Kasei Pharma, AbbVie Japan, Chugai Pharmaceutical, Daiichi Sankyo, Eisai Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Gilead Sciences Inc, Janssen Pharmaceutical, and Teijin Pharma., Noriyoshi Ogawa: None declared, Hiroaki Dobashi: None declared, Tetsuya Horita: None declared, Yoshiya Tanaka Speakers bureau: YT has received consulting fees, speaking fees, and/or honoraria from Daiichi-Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe, Bristol-Myers, Chugai, YL Biologics, Eli Lilly, Sanofi, Janssen, UCB, Grant/research support from: YT has received research grants from Mitsubishi-Tanabe, Takeda, Bristol-Myers, Chugai, Astellas, Abbvie, MSD, Daiichi-Sankyo, Pfizer, Kyowa- Kirin, Eisai, Ono., Shunsuke Furuta: None declared, Tsutomu Takeuchi Speakers bureau: TT has served on speakers’ fees for AbbVie, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe, Pfizer, Astellas, Daiichi Sankyo, Eisai, Sanofi, Teijin, Takeda, and Novartis., Consultant of: TT has received consulting fees from Astra Zeneca, Eli Lilly, Novartis, Mitsubishi Tanabe, AbbVie, Nippon Kayaku, Janssen, Astellas, Taiho, Chugai, Taisho Toyama, GlaxoSmithKline, and UCB., Grant/research support from: TT has received research grants from Astellas, Chugai, Daiichi Sankyo, Takeda, AbbVie, Asahi Kasei, Mitsubishi Tanabe, Pfizer, Eisai, AYUMI, Nippon Kayaku, and Novartis., Yoshinori Komagata Speakers bureau: YK has received speakers’ fees from Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Daiichi Sankyo, AbbVie, Nippon Shinyaku, Towa., Consultant of: YK has received consulting fees from Chugai, Kyowa Hakko Kirin, Asahi Kasei, UCB, Yoshikazu Nakaoka Speakers bureau: YN has received lecture fees from Astellas, Takeda, Daiichi Sankyo, Actelion, and Japan Blood Products Organization (JB)., Consultant of: YN has received consulting fees and/or lecture fees from AbbVie and Chugai, Grant/research support from: YN has received research grants from Chugai and Bayer Yakuhin, Ltd, masayoshi harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.

Background:In the TAKT study, a randomized controlled trial of tocilizumab (TCZ) in patients with refractory Takayasu arteritis (TAK) in Japan, the primary end point of time to relapse after induction of remission with glucocorticoid (GC) treatment showed a trend favoring TCZ over placebo (hazard ratio 0.41 [95.41% confidence interval, 0.15-1.10; p=0.0596]),1 but the double-blind period was too short for imaging evaluation.Objectives:To independently evaluate vascular imaging in a post hoc analysis of radiographs from the TAKT study.Methods:Computed tomography images from patients in the TAKT study were evaluated by three independent radiologists who were not involved in the original trial. Patients who received TCZ and had computed tomography images available (n=28) were included. Assessments were made in 22 arteries for the change from baseline in wall thickness (primary end point), dilatation/aneurysm, stenosis/occlusion, or wall enhancement for at least 96 weeks after the start of tocilizumab treatment. Patient-level assessments were also conducted.Results:Among 28 patients who received at least one dose of TCZ and for whom images were available, 86.7% of 22 arteries had improved/stable (no progression) wall thickness at week 96. The proportions of patients with no progressed, partially progressed, or newly progressed lesions were 57.1%, 10.7%, and 28.6% for wall thickness, and the proportions without progressed lesions were 92.9% for dilatation/aneurysm and 85.7% for stenosis/occlusion (Figure 1). Patients with newly progressed lesions, reflecting more refractory disease, were receiving glucocorticoid doses that could not be reduced below 0.1 mg/kg/day at week 96.Conclusion:Approximately 60% of patients with TAK treated with tocilizumab did not experience progression in wall thickness. Few patients experienced progressive dilatation/aneurysm or stenosis/occlusion. Wall thickness progression likely resulted from refractory TAK. Patients who experience this should be monitored regularly by imaging, and additional glucocorticoid or immunosuppressive treatment should be considered to avoid vascular progression.References:[1]Nakaoka Y et al. Ann Rheum Dis. 2018;77:348-354.Disclosure of Interests:Yoshikazu Nakaoka Consultant of: Roche/Genentech, Grant/research support from: Roche/Genentech, Masahiro Yanagawa Consultant of: Roche/Genentech, Akinori Hata Consultant of: Roche/Genentech, Katsuhisa Yamashita Employee of: Chugai Pharmaceutical Co., Ltd., Norihiro Okada Employee of: Chugai Pharmaceutical Co., Ltd., Shinji Yamakido Employee of: Chugai Pharmaceutical Co., Ltd., Hiromitsu Hayashi Consultant of: Roche/Genentech, David Jayne Consultant of: Roche/Genentech, Grant/research support from: Roche/Genentech

I thank Lee and Song1 for their thoughtful comments on our recent publication.2 The authors state that our study did not examine the steroid-sparing effect of tocilizumab because of mandatory glucocorticoid tapering. Given that the dose reduction rate of glucocorticoid significantly correlates with the relapse rate,3 this randomised, double-blind, placebo-controlled study was designed with mandatory glucocorticoid tapering to investigate whether tocilizumab treatment enables glucocorticoid tapering without relapse of Takayasu arteritis. Although the primary endpoint, …

Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 ( Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.

ObjectiveTo investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).MethodsPatients 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.ResultsThe 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.ConclusionAlthough 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 numberJapicCTI-142616.