Heather L. Teague

Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study

Objective—To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography computed tomography. Approach—In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using 18F-fluorodeoxyglucose positron emission tomography computed tomography. Results—Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8–8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (&bgr;=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (&bgr;=0.53; P=0.02) and vascular inflammation (&bgr;=0.48; P=0.02). Conclusions—Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.

GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis

RATIONALE GlycA, an emerging inflammatory biomarker, predicted cardiovascular events in population-based studies. Psoriasis, an inflammatory disease associated with increased cardiovascular risk, provides a model to study inflammatory biomarkers in cardiovascular disease (CVD). Whether GlycA associates with psoriasis and how it predicts subclinical CVD beyond high-sensitivity C-reactive protein in psoriasis is unknown. OBJECTIVE To investigate the relationships between GlycA and psoriasis and between GlycA and subclinical CVD. METHODS AND RESULTS Patients with psoriasis and controls (n=412) participated in a 2-stage study. We measured GlycA by nuclear magnetic resonance spectroscopy. National Institutes of Health (NIH) participants underwent 18-F Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18-FDG PET/CT) scans to assess vascular inflammation (VI) and coronary computed tomographic angiography to quantify coronary artery disease burden. Psoriasis cohorts were young (mean age=47.9), with low cardiovascular risk and moderate skin disease. high-sensitivity C-reactive protein and GlycA were increased in psoriasis compared with controls (GlycA: [PENN: 408.8±75.4 versus 289.4±60.2, P<0.0001; NIH: 415.8±63.2 versus 346.2±46, P<0.0001]) and demonstrated a dose-response with psoriasis severity. In stage 2, VI (β=0.36, P<0.001) and coronary artery disease (β=0.29, P=0.004) associated with GlycA beyond CV risk factors in psoriasis. In receiver operating characteristic analysis, GlycA added value in predicting VI (P=0.01) and coronary artery disease (P<0.01). Finally, initiating anti-tumor necrosis factor therapy (n=16) reduced psoriasis severity (P<0.001), GlycA (463.7±92.5 versus 370.1±78.5, P<0.001) and VI (1.93±0.36 versus 1.76±0.19, P<0.001), whereas GlycA remained associated with VI (β=0.56, P<0.001) post treatment. CONCLUSIONS GlycA associated with psoriasis severity and subclinical CVD beyond traditional CV risk and high-sensitivity C-reactive protein. Moreover, psoriasis treatment reduced GlycA and VI. These findings support the potential use of GlycA in subclinical CVD risk assessment in psoriasis and potentially other inflammatory diseases.

Cholesterol efflux capacity in humans with psoriasis is inversely related to non-calcified burden of coronary atherosclerosis.

AIMS Cholesterol efflux capacity (CEC) was recently shown to predict future cardiovascular (CV) events. Psoriasis both increases CV risk and impairs CEC. However, whether having poor CEC is associated with coronary plaque burden is currently unknown. We aimed to assess the cross-sectional relationship between coronary plaque burden assessed by quantitative coronary computed tomography angiography (CCTA) with CEC in a well-phenotyped psoriasis cohort. METHODS AND RESULTS Total burden and non-calcified burden (NCB) plaque indices were assessed in 101 consecutive psoriasis patients using quantitative software. Cholesterol efflux capacity was quantified using a cell-based ex vivo assay measuring the ability of apoB-depleted plasma to mobilize cholesterol from lipid-loaded macrophages. Cholesterol efflux capacity was inversely correlated with NCB (unadjusted β-coefficient -0.33; P < 0.001), and this relationship persisted after adjustment for CV risk factors (β -0.24; P < 0.001), HDL-C levels (β -0.22; P < 0.001), and apoA1 levels (β -0.19; P < 0.001). Finally, we observed a significant gender interaction (P < 0.001) whereby women with low CEC had higher NCB compared to men with low CEC. CONCLUSIONS We show that CEC is inversely associated with prevalent coronary plaque burden measured by quantitative CCTA. Low CEC may therefore be an important biomarker for subclinical coronary atherosclerosis in psoriasis. CLINICALTRIALSGOV NCT01778569.

Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study.

Background: Psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction, provides an ideal human model to study inflammatory atherogenesis in vivo. We hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of noncalcified plaques with high-risk features. However, inadequate efforts have been made to directly measure coronary artery disease in this vulnerable population. As such, we sought to compare total coronary plaque burden and noncalcified coronary plaque burden (NCB) and high-risk plaque (HRP) prevalence between patients with psoriasis (n=105), patients with hyperlipidemia eligible for statin therapy under National Cholesterol Education Program-Adult Treatment Panel III guidelines (n=100) who were ≈10 years older, and healthy volunteers without psoriasis (n=25). Methods: Patients underwent coronary computed-tomography angiography for total coronary plaque burden and NCB quantification and HRP identification, defined as low attenuation (<30 hounsfield units), positive remodeling (>1.10), and spotty calcification. A consecutive sample of the first 50 patients with psoriasis was scanned again 1 year after therapy. Results: Despite being younger and at lower traditional risk than patients with hyperlipidemia, patients with psoriasis had increased NCB (mean±SD: 1.18±0.33 versus 1.11±0.32, P=0.02) and similar HRP prevalence (P=0.58). Furthermore, compared to healthy volunteers, patients with psoriasis had increased total coronary plaque burden (1.22±0.31 versus 1.04±0.22, P=0.001), NCB (1.18±0.33 versus 1.03±0.21, P=0.004), and HRP prevalence beyond traditional risk (odds ratio, 6.0; 95% confidence interval, 1.1–31.7; P=0.03). Last, among patients with psoriasis followed for 1 year, improvement in psoriasis severity was associated with improvement in total coronary plaque burden (&bgr;=0.45, 0.23–0.67; P<0.001) and NCB (&bgr;=0.53, 0.32–0.74; P<0.001) beyond traditional risk factors. Conclusions: Patients with psoriasis had greater NCB and increased HRP prevalence than healthy volunteers. In addition, patients with psoriasis had elevated NCB and equivalent HRP prevalence as older patients with hyperlipidemia. Last, modulation of target organ inflammation (eg, skin) was associated with an improvement in NCB at 1 year, suggesting that control of remote sites of inflammation may translate into reduced coronary artery disease risk.

Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography

Importance Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases. Objective To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti–tumor necrosis factor therapy on vascular inflammation. Design, Setting, and Participants In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016. Exposure Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score. Main Outcomes and Measures Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography. Results Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti–tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (&bgr; = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti–tumor necrosis factor therapy (&bgr; = 0.79; 95% CI, 0.269-1.311; P = .03). Conclusions and Relevance Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.

The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development

Inflammation is a critical component in the development of coronary heart disease (CHD), specifically in the process of atherogenesis. Human translational and preclinical studies have demonstrated that inflammation contributes to the development, sustainment, and progression of atherosclerosis, and epidemiological studies demonstrate that human diseases associated with increased systemic inflammation increase the risk of CHD-related events. Therefore, over the last decade, multiple clinical studies were designed to target the inflammatory cascade in order to reduce the risk of CHD and to identify which populations may benefit from these preventative treatment strategies. This review briefly summarizes inflammation as a risk factor in atherosclerosis, human disease states associated with accelerated atherosclerosis, and current treatment strategies for CHD targeting the inflammatory cascade.

IFN-γ and TNF-α synergism may provide a link between psoriasis and inflammatory atherogenesis

Chronic inflammation is a critical component of atherogenesis, however, reliable human translational models aimed at characterizing these mechanisms are lacking. Psoriasis, a chronic inflammatory skin disease associated with increased susceptibility to atherosclerosis, provides a clinical human model that can be utilized to investigate the links between chronic inflammation and atherosclerosis development. We sought to investigate key biological processes in psoriasis skin and human vascular tissue to identify biological components that may promote atherosclerosis in chronic inflammatory conditions. Using a bioinformatics approach of human skin and vascular tissue, we determined IFN-γ and TNF-α are the dominant pro-inflammatory signals linking atherosclerosis and psoriasis. We then stimulated primary aortic endothelial cells and ex-vivo atherosclerotic tissue with IFN-γ and TNF-α and found they synergistically increased monocyte and T-cell chemoattractants, expression of adhesion molecules on the endothelial cell surface, and decreased endothelial barrier integrity in vitro, therefore increasing permeability. Our data provide strong evidence of synergism between IFN-γ and TNF- α in inflammatory atherogenesis and provide rationale for dual cytokine antagonism in future studies.

Emerging Associations Between Neutrophils, Atherosclerosis, and Psoriasis

Purpose of ReviewAtherogenesis, once thought to be a passive process, is now recognized as a dynamic, immune-driven process. The critical innate immune cells, including neutrophils, normal-density granulocytes, and their newly identified subset low-density granulocytes, are moving to the forefront of interest in cardiovascular medicine due to their abundance in atherosclerotic plaques and chronic inflammatory diseases associating with early cardiovascular disease (CVD) such as psoriasis. In this review, we discuss the emerging roles of neutrophils in CVD and how they play a potential role in early CVD observed in psoriasis patients. This review aims to describe the roles of neutrophils in both early atherosclerosis and psoriasis.Recent FindingsRecent work has demonstrated mechanistic links between vascular inflammation and neutrophil frequency. Evolving mouse models and clinical trials targeting IL-17-associated pathways continue to elucidate contributions of neutrophils in both atherosclerosis and psoriasis.SummaryEarly animal, in vitro and human studies suggest an important emerging role of neutrophils in atherosclerosis and psoriasis.

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12-/+/Srb1-/-/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.

Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus

BACKGROUND Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque. METHODS SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation (18F-fluorodeoxyglucose-PET/CT [18F-FDG-PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein-exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype. RESULTS Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors. In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB. CONCLUSION Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis. TRIAL REGISTRATION Clinicaltrials.gov NCT00001372FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute.