BACKGROUND:In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version. METHODS AND RESULTS:Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS:Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Objective: Elevated levels of serum uric acid (SUA) increase the risk of gout and may be associated with the risk of cardiometabolic disorders and subsequent cardiovascular disease. Clinical evidence regarding the effects of xanthine oxidase (XO) inhibitors on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat, a non-purine selective inhibitor of XO, delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Design and method: This was an investigator-initiated, multicenter, randomized, controlled, open-label clinical trial undertaken at 48 Japanese sites. A total of 514 adults, who had both asymptomatic hyperuricemia with SUA >7.0 mg/dL and maximum IMT of the common carotid artery (CCA) 1.1 mm or greater at screening, were equally allocated to receive either dose-titrated febuxostat (10–60 mg daily) or non-pharmacological lifestyle modification for hyperuricemia as a control-arm. The primary endpoint was the percentage change from baseline in mean IMT of the CCA at 24 months. Key secondary outcomes included other carotid ultrasonographic parameters, SUA, and adverse events. Results: Compared with the control group, febuxostat had no significant effect on the primary endpoint (1.2% [95% CI, -0.6% to 3.0%] in the febuxostat group vs 1.4% [95% CI, -0.5% to 3.3%] in the control group; between-group difference [febuxostat-control], -0.2% [95% CI, -2.3% to 1.9%]; P = 0.83) and any other carotid ultrasonographic parameters. At 24 months, the between-group difference [febuxostat-control] in the SUA change from baseline was significant (-2.65 mg/dL [95% CI, -2.93 mg/dL to -2.37 mg/dL]; P < 0.001), and gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. Conclusions: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. However, febuxostat treatment was tolerable and did not increase the incidence of cardiovascular and all-cause mortality.

IgG4関連疾患(IgG4-related disease:IgG4-RD)は,Mikulicz病,自己免疫疾患,間質性腎炎,前立腺炎,後腹膜線維症等多彩な疾患を含む病態で,今世紀に本邦から発信された興味深い疾患である.厚生労働省のIgG4関連疾患研究班は,2011年に世界で初めての診断基準であるIgG4関連疾患包括診断基準を発表した.これにより,この新疾患は広く世界に受け入れられ,世界中から多くの報告がなされた.しかし,実臨床においては,生検組織が得られない組織があること,血清IgG4(immunoglobulin G4)値や組織中IgG4陽性細胞数のカットオフ値に対する感度・特異度等の問題が生じてきた.そのため,厚生労働省IgG4関連疾患研究班は,IgG4関連疾患包括診断基準2011を改訂した,2020年 改訂 IgG4関連疾患包括診断基準を提唱する.改訂基準は,1)臨床的・放射線学的診断,2)血清学的診断,3)病理学的診断の3項目からなる.さらに,改訂された病理学的診断基準は,従来の2項目に加え,花筵様線維化と閉塞性静脈炎を含めた3項目から構成される.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.

Editor's Note.- Articles in the RadioGraphics Update section provide current knowledge to supplement or update information found in full-length articles previously published in RadioGraphics. Authors of the previously published article provide a brief synopsis that emphasizes important new information such as technologic advances, revised imaging protocols, new clinical guidelines involving imaging, or updated classification schemes. Articles in this section are published solely online and are linked to the original article.

BACKGROUND:An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.METHODS AND FINDINGS:The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.CONCLUSIONS:In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.TRIAL REGISTRATION:University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Periaortitis and periarteritis are one of the clinical features of IgG4-related disease. Such vascular manifestations are reported to be present in 10-30% of overall IgG4-related disease, and they may also appear as an isolated lesion of IgG4-related disease. As other types of large vessel vasculitis, IgG4-related vasculitis may cause significant clinical consequences. On the other hand, the diagnosis of IgG4-related periaortitis/periarteritis seems to have been made on the basis of different diagnostic criteria in reported studies; thus far, difficulty seems to be present in assessing the true frequency of the disease as well as determining the optimal therapeutic strategy. In this review, in addition presenting the clinical and pathological features of IgG4-related periaortitis/periarteirtis, we would like to discuss on what kind of points should be resolved for the better understanding of vascular involvement of IgG4-related disease in terms of diagnosis and treatment.

The prevalence and extent of immunoglobulin G4 (IgG4)-positive cell infiltration were investigated in 282 surgical samples of aortic wall and aortic valve. Tissue infiltration of IgG4-positive cells was observed in 24 (17.3%) of 139 aortic valve samples and 46 (32%) of 143 aortic wall samples, and the condition of IgG4-positive cell infiltration > 30/hpf together with IgG4/CD138 ratio > 40% was observed in 2 (1.4%) of aortic valve samples and 14 (9.8%) of aortic wall samples. Among 275 patients, preoperative serum IgG4 level was available in 48 patients (50 samples), and it was > 135 mg/dL in only one patient. Of these 48 patients with serum IgG4 measurement, 29 patients had aortic valve stenosis and 12 had aortic aneurysm. Compared with 23 aortic stenosis patients without tissue infiltration of IgG4-positive cells in the aortic valve, six patients with IgG4-positive cell infiltration had a more prevalent smoking history (26% versus 83%) and borderline significantly higher serum IgG4 (median, 24.5 mg/dL versus 55.5 mg/dL), although either preoperative peak pressure gradient between left ventriculum and aorta or aortic valve area did not differ significantly between groups. Compared with six aortic aneurysm patients without tissue infiltration of IgG4-positive cells in the aortic wall, six patients with IgG4-positive cell infiltration had borderline significantly higher serum IgG4 (median, 28.9 mg/dL versus 68.2 mg/dL). The current study showed that tissue IgG4-positive infiltration is not a rare occurrence in the aortic stenosis and aortic aneurysm. Clinical significance of tissue IgG4-postive cell infiltration in these patients requires further investigation.

IgG4-related disease is a systemic disease, characterized by elevation of serum IgG4 and, histopathologically, massive infiltration of IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening. It may affect various organs simultaneously or metachronously. Here we analyzed the clinical and pathological characteristics of 99 patients diagnosed with IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. Of 99 patients (women/men, 15/84; mean age 67.3±9.5 years), 33 were diagnosed based on the histopathological findings of perivascular/retroperitoneal lesions, 50 were diagnosed based on the characteristic imaging findings of perivascular/retroperitoneal lesions and the presence of definitive IgG4-related disease in other organ(s), and the remaining 16 patients were diagnosed by experts based on the characteristic imaging findings of perivascular/retroperitoneal legions, serological findings, response to glucocorticoid treatment, and/or the presence of suspected IgG4-related disease in other organ(s). According to the new organ-specific criteria proposed by experts, 73 (73.7%) diagnoses were categorized to be definitive, and 6 (6.1%) and 17 (17.2%) diagnoses were categorized to be probable and possible, respectively. Further analyses are needed to clarify the optimal diagnostic and therapeutic strategy of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. (This is a translation of J Jpn Coll Angiol 2018; 58: 117-129.).

Clinical trials with autologous adipose-derived stem cell (AdSC) therapy for ischemic heart diseases (IHDs) are ongoing. However, little is known about combinational therapeutic effect of AdSCs and statin poly(lactic-co-glycolic) acid (PLGA) nanoparticles on the ischemic myocardium. We investigated the hypothesis that statins, which have pleiotropic effects, augment the therapeutic potential of AdSCs and that AdSCs also act as drug delivery tools. Simvastatin-conjugated nanoparticles (SimNPs) significantly promoted migration activity without changing proliferation activity and upregulated growth factor gene expression in vitro. A small number of intravenously administered SimNP-loaded AdSCs (10,000 cells per mouse) improved cardiac function following myocardial infarction, inducing endogenous cardiac regeneration in the infarcted myocardium. The de novo regenerated myocardium was thought to be derived from epicardial cells, which were positive for Wilms' tumor protein 1 expression. These findings were attributed to the sustained, local simvastatin release from the recruited SimNP-loaded AdSCs in the infarcted myocardium rather than to the direct contribution of recruited AdSCs to tissue regeneration. SimNP-loaded AdSCs may lead to a novel somatic stem cell therapy for IHDs. Stem Cells Translational Medicine 2019;8:1055-1067

Fluorine-18 fluorodeoxygluose (18F-FDG) positron emission tomography (PET) is a useful tool for evaluating disease activity in sarcoidosis including cardiac involvement. A 67-year-old patient who developed atrioventricular block requiring permanent pacemaker implantation was diagnosed with cardiac sarcoidosis. The patient did not undergo steroid or immunosuppressive therapy but underwent serial 18F-FDG PET examination, which showed spontaneous reduction in the myocardial FDG uptake, indicating the remission of immune-inflammatory activity. Although the global systolic function remained preserved, thinning of the septal wall emerged during the clinical course of follow-up, which is characteristic for cardiac sarcoidosis.

IgG4-related disease (IgG4-RD) is an inflammatory condition characterized by a high serum IgG4 concentration and the abundant infiltration of lymphocytes and IgG4-positive plasma cells in the tissue, as well as spatial (diverse clinical manifestations) and temporal (the possibility of recurrence) multiplicities. Since the initial documentation of IgG4-related disease in patients with autoimmune pancreatitis in 2001, a growing body of evidence has been accumulating to suggest that various-virtually all-organs can be affected by IgG4-RD. In general, steroid therapy is effective and is considered to be the first-line treatment for IgG4-RD. The precise mechanism underlying this systemic disorder has remained unknown. Considering that IgG4-RD was specified as being an intractable disease in 2015, further studies are needed to clarify whether IgG4-RD is indeed a distinct disease entity or a complex of disorders of different etiologies and clinical conditions.

Sakane, Kazushi; Hourai, Ryoto; Daimon, Masahiro; Sohmiya, Koichi; Kuwabara, Hiroko; Katsumata, Takahiro; Ozeki, Michishige; Hirose, Yoshinobu; Ishizaka, Nobukazu Author Information

Objective Although life-threatening cardiac complications in influenza infection are rare, subclinical influenza-associated cardiac abnormalities may occur more frequently. We investigated the prevalence of subclinical cardiac findings. Methods After obtaining their written informed consent, 102 subjects were enrolled in the present study. The study subjects underwent a first set of examinations, which included electrocardiography (ECG), echocardiography, and the measurement of their cardiac enzyme levels. Those with one or more abnormal findings among these examinations were encouraged to undergo a repeat examination 2 weeks later. Results Among the 102 subjects enrolled, 22 (21.6%) were judged to have cardiac findings, including ST-T abnormalities, pericardial effusion, diastolic dysfunction, and cardiac enzyme elevation. Eighteen of these 20 subjects underwent a second screening at a median of 14 days later, and it was found that 11 of the 18 subjects were free from cardiac findings on this second examination. This suggested that the abnormalities were only transient and they therefore might have been associated with influenza. Approximately 20% of the influenza patients enrolled had cardiac findings, including ST-T segment abnormalities, pericardial effusion, and cardiac enzyme elevation. Conclusion Among the 102 patients who were studied, the cardiac findings were only mild and transient; however, physicians should be aware of influenza infection-associated cardiac abnormalities because such abnormalities may not be rare.