Coronary (peri)-arteritis in patients with IgG4-related disease: A case series from the Central Anatolia Region of Turkey.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory disease which affects many systems, as well as the cardiovascular system. Identifying the coronary involvement like periaortitis, coronary periarteritis and pericarditis is important, as they often cause unfavorable outcomes. METHODS: Eighty-one patients with IgG4-RD were retrospectively evaluated for symptomatic coronary artery involvement from Hacettepe University Vasculitis Research Center (HUVAC) database. The demographic, laboratory, radiologic and clinical characteristics of the patients were assessed. RESULTS: Among 81 patients with IgG4-RD, 6 patients (M/F:5/1) had coronary artery involvement. The patients' median age was 57 and serum IgG4 levels were above normal except for one case. All patients with coronary arteritis revealed an increased coronary vessel wall thickening and stenotic lesions. The coronary aneurysm and pericarditis were observed in half of the patients. Immunosuppressive treatments were given to all the patients and most of them followed in stable condition. CONCLUSION: Coronary arteritis is a rare but notable manifestation of IgG4-RD. Although coronary periarteritis can cause significant morbidity and mortality, it seems better results can be achieved with early diagnosis and treatment.

Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease.

AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.

Lymphocytic thrombophilic arteritis and cutaneous polyarteritis nodosa: Clinicopathologic comparison with blinded histologic assessment.

BACKGROUND: Lymphocytic thrombophilic arteritis (LTA), or macular lymphocytic arteritis, is defined by a primary lymphocytic vasculitis. However, the nosology of LTA has been controversial, with speculation that it may represent an indolent non-nodule-forming variant of cutaneous polyarteritis nodosa (cPAN). OBJECTIVE: This study compares the clinicopathologic features of patients with LTA or cPAN to assess if these conditions should be considered distinct entities. METHODS: This is a cross-sectional study of all LTA and cPAN cases at a single tertiary center using prospectively collected clinical data and blinded histologic assessment. RESULTS: The study included 17 patients with LTA and 13 patients with cPAN. Clinically, cases of LTA were distinguished by a more widespread pattern of livedo racemosa, which was noninfiltrated and asymptomatic. In contrast, cPAN was associated with localized starburst livedo, purpura, and episodic features including nodules, pain, and large inflammatory ulcers. When patients were separated according to the presence (>5%) or paucity (≤5%) of neutrophils on blinded histology review, they had distinct clinical features and differences in disease course. LIMITATIONS: This was a single-center study. CONCLUSION: Our data support the classification of LTA and cPAN as separate entities rather than a spectrum of the same disorder and highlight the importance of clinicopathologic correlation in distinguishing these conditions.

A Randomized Placebo-Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate-to-Severe Plaque Psoriasis (VIP-S).

Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has reported high efficacy with a favorable safety profile in various psoriatic disease manifestations. Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, patients with moderate-to-severe psoriasis received secukinumab for 40 weeks. Vascular inflammation using 18F-2-fluorodeoxyglucose-positron emission tomography/computed tomography imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. The difference in change in aortic inflammation from baseline to week 12 for secukinumab (n = 46) versus placebo (n = 45) was -0.053 (95% confidence interval = -0.169 to 0.064; P= 0.37). Small increases in total cholesterol, low-density lipoprotein, and low-density lipoprotein particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At week 52, reductions in TNF-α (P= 0.0063) and ferritin (P= 0.0354), and an increase in fetuin-A (P= 0.0024), were observed with secukinumab treatment compared with baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared with baseline. Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment.

Arterial Wall Inflammation and Increased Hematopoietic Activity in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) confers an increased risk of cardiovascular disease (CVD), independent of blood pressure. Animal models have shown that aldosterone accelerates atherosclerosis through proinflammatory changes in innate immune cells; human data are scarce. OBJECTIVE: The objective of this article is to explore whether patients with PA have increased arterial wall inflammation, systemic inflammation, and reprogramming of monocytes. DESIGN: A cross-sectional cohort study compared vascular inflammation on 2'-deoxy-2'-(18F)fluoro-D-glucose; (18F-FDG) positron emission tomography-computed tomography, systemic inflammation, and monocyte phenotypes and transcriptome between PA patients and controls. SETTING: This study took place at Radboudumc and Rijnstate Hospital, the Netherlands. PATIENTS: Fifteen patients with PA and 15 age-, sex-, and blood pressure-matched controls with essential hypertension (EHT) participated. MAIN OUTCOME MEASURES AND RESULTS: PA patients displayed a higher arterial 18F-FDG uptake in the descending and abdominal aorta (P < .01, P < .05) and carotid and iliac arteries (both P < .01). In addition, bone marrow uptake was higher in PA patients (P < .05). Although PA patients had a higher monocyte-to-lymphocyte ratio (P < .05), systemic inflammatory markers, cytokine production capacity, and transcriptome of circulating monocytes did not differ. Monocyte-derived macrophages from PA patients expressed more TNFA; monocyte-derived macrophages of healthy donors cultured in PA serum displayed increased interleukin-6 and tumor necrosis factor-α production. CONCLUSIONS: Because increased arterial wall inflammation is associated with accelerated atherogenesis and unstable plaques, this might importantly contribute to the increased CVD risk in PA patients. We did not observe inflammatory reprogramming of circulating monocytes. However, subtle inflammatory changes are present in the peripheral blood cell composition and monocyte transcriptome of PA patients, and in their monocyte-derived macrophages. Most likely, arterial inflammation in PA requires interaction between various cell types.

Mitochondrial DNA: A new driver for sex differences in spontaneous hypertension.

The prevalence of arterial hypertension (AH) is higher in men than in premenopausal women of the same age. AH has been characterized as a chronic inflammatory disease and activation of Toll-like receptors (TLR) by damage-associated molecular patterns (DAMPs) is involved. Mitochondrial DNA (mtDNA) may be released by end-organ damage, which is recognized and activates TLR9. The serum level of mtDNA is increased in AH. The aim of this study was to compare the serum mtDNA levels between male and female spontaneously hypertensive rats (SHR) and to evaluate the sex differences in the effect of mtDNA on the function, inflammation and signaling pathway related to TLR9 in the vasculature. Male and female 15-week-old SHR and Wistar rats were used to evaluate the arterial blood pressure, serum mtDNA, contractile response, inflammatory markers and signaling pathway related to TLR9. Male SHR had higher arterial blood pressure values and serum mtDNA compared to female SHR and to male and female normotensive Wistar rats. In male SHR aorta, mtDNA incubation increased the contractile response to phenylephrine, which was blunted by inhibition of TLR9, and also increased pro-inflammatory molecules IL-6 and TNF-α. However, in female SHR aorta, mtDNA incubation did not change the contractile response, reduced pro-inflammatory molecules and prevented oxidative stress. mtDNA incubation did not change the expression of TLR9, MyD88 and eNOS neither in male nor in female SHR aorta, but it increased the phosphorylation of ERK1/2 in male and reduced in female SHR aorta. The mtDNA differential modulation of vascular response in male and female SHR might contribute to sex differences in AH. This study contributes to the understanding of a need for more personalized therapeutic strategies for men and women with hypertension. Keywords: Sex differences, Arterial hypertension, Mitochondrial DNA, Toll-Like receptor 9.

Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment.

AIMS: Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0-67.0] years, Lp(a) 200.0 [155.5-301.5] nmol/L [80.0 (62.5-121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8-55.5] and Lp(a) by 13.9% (95% CI 19.3-8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0-268.0) nmol/L [75.2 (56.0-107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (-8.3%) vs. placebo (-5.3%) [treatment difference -3.0% (95% CI -7.4% to 1.4%); P = 0.18]. CONCLUSION: Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.

The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of infiltrating leukocytes (i.e. neutrophils, eosinophils, lymphocytes, plasma cells, and macrophages) at lesion sites. The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.

Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans.

OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.

Stimulated Suicidal Erythrocyte Death in Arteritis.

BACKGROUND/AIMS: Arteritis is an inflammatory disease of the vascular wall leading to ischemia and vascular occlusion. Complications of arteritis include anemia, which could, at least in theory, result from suicidal erythrocyte death or eryptosis, which is characterized by erythrocyte shrinkage and phosphatidylserine (PS) exposure at the erythrocyte surface. Cellular mechanisms involved in the stimulation of eryptosis include increased cytosolic Ca2+-concentration ([Ca2+]i), oxidative stress and ceramide formation. The present study explored whether and how arteritis influences eryptosis. METHODS: Blood was drawn from patients suffering from arteritis (n=17) and from healthy volunteers (n=21). PS exposure was estimated from annexin V-binding, erythrocyte volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) from DCFDA fluorescence and ceramide abundance from FITC-conjugated antibody binding in flow cytometry. The patients suffered from anemia despite 2.8±0.4% reticulocytes. RESULTS: The percentage of PS-exposing erythrocytes was significantly higher in patients (1.1±0.1%) than in healthy volunteers (0.3±0.1%). The increase in PS exposure was paralleled by increase in oxidative stress and [Ca2+]i but not by significant changes of ceramide abundance. Erythrocyte PS exposure and ROS production were significantly enhanced in erythrocytes exposed to patient plasma as compared to exposure to plasma from healthy volunteers. CONCLUSION: Arteritis is associated with enhanced eryptosis due to increased [Ca2+]i and oxidative stress. The eryptosis contributes to or even accounts for the anemia in those patients. As eryptotic erythrocytes adhere to endothelial cells of the vascular wall, they could impede microcirculation and thus contribute to vascular occlusion.

iMAP™ imaging of tumorous lesions surrounding the coronary arteries in a patient with an elevated serum level of immunoglobulin G4.

A 76-year-old woman with multiple coronary risk factors was admitted to our hospital because of episodes of new-onset chest pain that had begun 3 days previously. She underwent percutaneous coronary intervention (PCI) for severe stenoses in the two high lateral (HL) branches. Intravascular ultrasound (IVUS) revealed massive stenotic lesions in the HL branches and tumorous nonstenotic lesions in the left anterior descending coronary artery (LAD) and the left circumflex coronary artery (LCx). iMAP™, optical coherence tomography (OCT), and coronary computed tomography angiography (CCTA) were performed. iMAP depicted fibrosis in the vessel (green areas) and nonfibrotic tissue change suggestive of inflammation outside the vessel (yellow/red areas). OCT revealed high-intensity homogenous intimal hyperplasia with superficial calcification, and CCTA showed massive periarterial soft lesions in the HL, LAD, and LCx. The serum IgG4 level was high at 252-427 mg/dL (8 measurements) (reference range, 4.8-105.0 mg/dL). We suspected IgG4-related coronary periarteritis on the basis of the comprehensive diagnostic criteria as a possible diagnosis. The clinical course was good after initial and subsequent PCIs for both the HL stenoses and the progressing LCx stenosis, and there was no recurrence of angina pectoris thereafter. Steroids were not administered because the massive lesions did not enlarge during the 16 months of follow-up. iMAP was able to evaluate the tissue characteristics of tumorous lesions in the stenosed HL branches and the nonstenotic LAD and LCx in a patient with an elevated level of IgG4.

Inflammation and congenital heart disease associated pulmonary hypertension.

BACKGROUND: Increased blood flow may trigger pulmonary arterial wall inflammation, which may influence progression of pulmonary artery hypertension in patients with congenital heart disease. In this study, we aimed to investigate the correlation between preoperative inflammation markers and pulmonary arterial hypertension. METHODS: A total of 201 patients with pulmonary hypertension were enrolled in this study retrospectively; they had undergone open heart surgery between January 2012 and December 2013. Patients' preoperative C-reactive protein (CRP), neutrophil to lymphocyte ratio, red blood cell distribution width, pulmonary pressures, and postoperative outcomes were evaluated. RESULTS: Patient age, neutrophil to lymphocyte ratio, red blood cell distribution width, and CRP were found to be significantly correlated with both preoperative peak and mean pulmonary artery pressures. These data were entered into a linear logistic regression analysis. Patient age, neutrophil to lymphocyte ratio, and CRP were found to be independently correlated with peak pulmonary pressure (P < .001, P < .001, and P = .004) and mean pulmonary artery pressure (P < .001, P < .001, and P = .001), whereas preoperative mean pulmonary artery pressure was found to be independently correlated with intensive care unit stay (P < .001). No parameter was found to be significantly correlated with extubation time and mortality. Eighteen patients had experienced pulmonary hypertensive crisis; in this subgroup, patients' mean pulmonary artery pressure and neutrophil to lymphocyte ratio were found to be significant (P = .047, P = .003). CONCLUSIONS: Preoperative inflammation markers may be correlated with the progression of pulmonary hypertensive disease, but further studies with larger sample size are needed to determine the predictive role of these markers for postoperative outcomes.

Interleukin-6, vascular endothelial growth factor and transforming growth factor beta 1 in canine steroid responsive meningitis-arteritis.

BACKGROUND: Steroid Responsive Meningitis-Arteritis (SRMA) is a common cause of inflammation of the canine central nervous system (CNS). To investigate if transforming growth factor beta 1 (TGF-ß1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) are involved in the production of excessive immunoglobulin A (IgA), the induction of acute phase proteins and in the development of a systemic necrotizing vasculitis, characteristic of SRMA, these three signalling proteins were evaluated. RESULTS: Cerebrospinal fluid (CSF) and serum samples of dogs during the acute phase of SRMA (SRMA) were tested for IL-6, VEGF and TGF- ß1. Results were compared to those of dogs affected with SRMA during treatment (SRMA Th) and during relapse (SRMA R), to dogs with other meningoencephalomyelitides (ME), with miscellaneous non-inflammatory diseases of the CNS (CNS-Mix), with idiopathic epilepsy (IE), with systemic inflammatory diseases (Syst. Infl.) and with healthy dogs (Healthy). Concentrations of IL-6 and VEGF in CSF were significantly elevated in the SRMA group compared to the other disease categories (p<0.05). The CSF concentrations of TGF-ß1 were increased in SRMA group, but statistically significant differences were found only in comparison with Healthy and CNS-Mix groups. No differences were detected in the serum concentrations of TGF-ß1 between the different groups. In untreated SRMA patients, a positive correlation (rSpear = 0.3549; P=0.0337) between concentrations of TGF-ß1 and IgA concentration was found in CSF, while concentrations of IL-6 and VEGF in CSF positively correlated with the degree of pleocytosis (rSpear=0.8323; P<0.0001 and rSpear=0.5711; P=0.0166, respectively). CONCLUSIONS: Our results suggest that these three signalling proteins are biomarkers of disease activity in SRMA. VEGF might play an important role in the development of a systemic arteritis. TGF-ß1 is considered to be involved in the excessive IgA production, while IL-6 in the pleocytosis. The combined intrathecal increase of TGF-ß1 and IL-6 detected in SRMA could possibly force CD4 progenitors to differentiate towards the newly described Th17 lymphocyte subset and enhance the autoimmune response.

A clinicopathologic study of immunoglobulin G4-related disease of the femoral and popliteal arteries in the spectrum of immunoglobulin G4-related periarteritis.

BACKGROUND: Immunoglobulin (Ig) G4-related disease has recently been recognized to occur in the cardiovascular system in the aorta and main branching arteries, often manifesting as aneurysms and arteritis/periarteritis. Peripheral arteries (the femoral and popliteal arteries) are frequent sites of arteriosclerosis obliterans (ASO) and occasionally show aneurysms or arteritis. This study re-examined peripheral arterial lesions from the standpoint of IgG4-related disease. METHODS: The study comprised 104 patients who underwent surgical treatment of peripheral arterial lesions, including 30 patients with peripheral arterial aneurysms (PAAs) and 74 with ASO. IgG4-related disease was identified on the basis of diffuse infiltration of numerous IgG4-positive plasmacytes as revealed by immunohistochemical examination. Clinicopathologic features were compared between IgG4-related and IgG4-unrelated lesions. RESULTS: IgG4-related disease was found in four of the 30 patients with PAAs (13.3%; two in the deep femoral artery, two in the popliteal artery) but not in any patients with ASO. IgG4-related PAA displayed clinicopathologic features resembling those of other IgG4-related diseases and a characteristic saccular appearance (P = .002). CONCLUSIONS: IgG4-related disease was detected in PAA patients but not in ASO patients. IgG4-related disease thus represents one potential etiology of aneurysm in the peripheral arteries.

Increased level of platelet P-selectin in nonarteritic anterior ischemic optic neuropathy.

PURPOSE: P-selectin receptor is expressed in platelets and endothelial cells in a cell-activation-dependent manner. Platelet P-selectin (CD62) levels may become elevated in a number of vasoocclusive diseases, including arteriosclerosis, atherothrombosis, and diabetes mellitus (DM). Nonarteritic anterior ischemic optic neuropathy (NAION) is associated with a sudden loss of vision due to the vascular insufficiency of ciliary arteries supplying the optic nerve. In this study, our aim was to investigate the presence of increased platelet reactivity in the development of NAION. METHODS: Twenty-one NAION patients, 39 healthy control subjects, and 44 patients suffering from diabetes mellitus (DM) were examined in our case-control, pilot study. Platelet activation was investigated by flow cytometric analysis of the mean fluorescence intensity (MFI) of CD62 on platelets. These results were compared among the different study groups. RESULTS: NAION patients showed considerably although not significantly (p = 0.2017) higher P-selectin MFI values (71.98 ± 40.30) versus healthy subjects (55.48 ± 20.95), insulin-dependent DM patients (50.02 ± 13.08), and non-insulin-dependent DM subjects (54.72 ± 24.74). However, logistic regression analysis resulted in a statistically significant adjusted effect on the odds of NAION when CD62 MFI values were logarithmically transformed (OR: 3.86, 95 % CI: 1.10 to 13.53, p = 0.0346). CONCLUSION: Elevated platelet CD62 positivity may be related to NAION, suggesting a possible role of enlarged platelet activity in the generation of this type of ischemic optic neuropathy.

[Evaluation of decreased glucose levels in the cerebrospinal fluid of dogs]. / Untersuchungen zu erniedrigten Glukosewertenim Liquor cerebrospinalis des Hundes.

OBJECTIVE: The aim of the study was to evaluate the glucose ratio (glucose level in the cerebrospinal fluid [CSF]/blood glucose level) as a quickly available marker for detecting bacterial meningoencephalomyelitis (BM). MATERIAL AND METHODS: Blood and CSF samples of 328 dogs were reviewed and evaluated retrospectively. Following the neurological diagnosis, the dogs were assigned to seven different groups: steroid-responsive meningitis-arteritis (SRMA), intervertebral disc disease (IVDD), neoplasia of the central nervous system (N), idiopathic epilepsy (IE), bacterial meningoencephalomyelitis (BM), meningoencephalomyelitis of other origin (ME) and healthy dogs. RESULTS: The median of the CSF-glucose level (mmol/l) and the median of the glucose ratio in the SRMA group displayed the lowest values and differed significantly from the CSF-glucose levels of dogs in the groups IVDD, N, IE and healthy dogs (CSF-glucose level: p<0.01; glucose ratio: p<0.05). In the BM group, both parameters did not differ significant- ly from other groups, but displayed similar low levels as in the SRMA group. There was a negative correlation between the CSF cell count and the CSF-glucose ratio (Spearman correlation coefficient -0.322, p=0.01, R²=0.108). CONCLUSION: The CSF-glucose concentration cannot be used as a distinct marker to differentiate BM from other inflammatory CNS-diseases, especially from SRMA usually accompanied by severe pleocytosis. Low CSF-glucose levels appear to be caused by elevated CSF cell counts rather than by bacterial metabolism. CLINICAL RELEVANCE: For a definitive diagnosis of bacterial meningoencephalomyelitis in dogs, the detection of microorganisms remains necessary.

Immunoglobulin G4-related coronary periarteritis in a patient presenting with myocardial ischemia.

Recent studies suggest that the cardiovascular system might be a possible target of immunoglobulin G4-related disease. Here we present a 66-year-old man who was admitted to our hospital because of chest symptoms suggestive of acute coronary syndrome. Besides luminal narrowing of the coronary arteries, marked periarterial thickening around the coronary artery was observed by computed tomography coronary angiography. Serum immunoglobulin G4 levels of this patient were elevated (564 mg/dL). The patient underwent coronary bypass surgery. After incision of the pericardium, a glittery white-yellowish, elastic-hard periarterial mass surrounding the left circumflex artery could be seen. Histologic analysis of the biopsy specimen showed the formation of lymphoid follicles and the presence of immunoglobulin G4-positive plasma cells; therefore, the diagnosis was immunoglobulin G4-related coronary periarteritis accompanied by physiologically significant myocardial ischemia.

Clinicopathologic analysis of acute vascular rejection cases after renal transplantation.

INTRODUCTION: Histopathologic change of acute vascular rejection (AVR) is characterized by intimal arteritis and transmural arteritis. In this report, we discuss the clinicopathologic analysis of AVR cases after renal transplantation. PATIENTS: AVR was diagnosed in 28 renal transplant recipients followed up in our institute between January 2003 and November 2010. RESULTS: Among 28 cases of AVR, 18 were mild (v1 in Banff 07 classification), 8 were moderate (v2), and 2 were severe (v3). Interstitial inflammation was present in 25 biopsy specimens. Moderate to severe tubulitis (t2-t3) was present in 10 biopsy specimens and transplant glomerulitis in 17; peritubular capillaritis was in 25 of the 28 biopsy specimens. C4d deposition in peritubular capillaries was observed in 11/28 cases. By using assays with plastic beads coated with human leukocyte antigen (HLA) in the 28 cases, we detected circulating anti-HLA alloantibody in 18 patients, among which 11/28 were donor-specific. Acute antibody-mediated rejection was diagnosed in 6 cases. Among AVR cases, 19/28 displayed steroid-resistant rejection (SRR) requiring greater anti-rejection therapy (ART), including muromonab CD3 injection, gusperimus injections, plasmapheresis, intravenous immune globulin, and/or rituximab injections. Twenty of 28 patients recovered renal allograft function after ART, and 26/28 grafts are functioning. Among the 2 cases of graft loss, only 1 patient lost his graft due to AVR. CONCLUSIONS: In some cases, AVR might be provoked by anti-donor antibodies. The prognosis of the graft exhibiting AVR was relatively good using available immunosuppression.

Extracellular hsp70 release in canine Steroid Responsive Meningitis-Arteritis.

The role of extracellular 70 kDa heat shock protein 70 (ehsp70) in central nervous system inflammation is vastly understudied, despite evidence supporting the ability to drive a pro-inflammatory state. We investigated the presence of ehsp70 in cerebrospinal fluid (CSF) and serum of dogs with Steroid Responsive Meningitis-Arteritis (SRMA), with the hypothesis that an ehsp70 response would occur, and might play a role in the pathogenesis of this disease. Samples from 30 dogs acutely affected with SRMA, and 30 dogs treated with corticosteroids and currently in clinical remission from SRMA were compared with normal dogs. Serum and CSF concentrations of ehsp70 were quantified using an enzyme-linked immunosorbent assay. An ehsp70 response occurred in the CSF of dogs with SRMA and this response was attenuated by corticosteroid treatment. There was no correlation between serum and CSF concentrations of ehsp70, supporting local production and release of ehsp70 and not simply leakage from serum. Dogs with SRMA thus represent a powerful spontaneous model by which to study the role of ehsp70 in CNS inflammation.