Qimin Ng

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.

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.

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.

SMALL DENSE LOW-DENSITY LIPOPROTEIN (LDL) PARTICLE NUMBER PREDICTS VASCULAR INFLAMMATION INDEPENDENT OF TRADITIONAL LIPID CARDIOVASCULAR RISK FACTORS IN PSORIASIS

Small, dense low-density lipoproteins (sLDL-p) by nuclear magnetic resonance (NMR) were recently shown to be a strong predictor of CV events. If this relationship is true in inflammatory states, which modulate lipoprotein structure and function, is unclear. Psoriasis (PSO), a chronic inflammatory

18: IMPROVEMENT IN PSORIASIS SKIN DISEASE SEVERITY IS ASSOCIATED WITH REDUCTION OF CORONARY PLAQUE BURDEN

Purpose of Study Psoriasis (PSO), a chronic inflammatory disease associated with increased cardiovascular (CV) risk, provides a clinical human model to study inflammatory atherogenesis. While PSO severity is associated with both in vivo vascular disease and future CV risk, the longitudinal impact of PSO severity on coronary disease progression is unknown. We hypothesized that an improvement in PSO severity may lead to a reduction in coronary plaque burden by coronary CT angiography (CCTA). Methods Used Consecutively recruited PSO patients (N=50) underwent CCTA (320 detector row, Toshiba) and cardiometabolic profiling at baseline and 1-year follow-up. Total (TB) and non-calcified (NCB) coronary plaque burden were quantified using QAngio (Medis, Netherlands). PSO severity was measured as the psoriasis area severity index (PASI). The longitudinal change in coronary plaque burden was analyzed with unadjusted and adjusted regression. Summary of Results The cohort had a low Framingham Risk Score and mild to moderate PSO. Patients whose PSO severity improved (ΔPASI −27%; p<0.001) (N=33) had significant improvement in TB (β=0.40, p=0.003) and NCB (β=0.49, p<0.001) (table 1), beyond adjustment for traditional CV risk factors, BMI, statin use, & systemic/biologic PSO therapy. Conclusions Improvement in PSO severity was associated with improvement in coronary plaque burden by CCTA. Our study suggests that a reduction in skin inflammation may reduce the progression of early, non-calcified coronary plaque. Larger studies are needed to confirm these findings. Abstract 18 Figure 1 *P-value is calculated by comparing baseline and 1-year follow-up values for variables using paired t-test for continuous variables, and Pearsons chi-squared test for categorical variables. All values are expressed as Mean±SD, unless specified otherwise. PASI: Psoriasis Area Severity Index.

IMPROVEMENT IN PSORIASIS SKIN DISEASE SEVERITY IS ASSOCIATED WITH REDUCTION OF CORONARY PLAQUE BURDEN

18 Figure 1 *P-value is calculated by comparing baseline and 1-year follow-up values for variables using paired t-test for continuous variables, and Pearson’s chi-squared test for categorical variables. All values are expressed as Mean±SD, unless specified otherwise. PASI: Psoriasis Area Severity Index. 814 J Investig Med 2016;64:800–825 Abstracts group.bmj.com on December 16, 2016 Published by http://jim.bmj.com/ Downloaded from

23: VASCULAR INFLAMMATION AND AORTIC WALL CHARACTERISTICS MODULATE FOLLOWING LIFESTYLE CHANGES IN PSORIASIS PATIENTS AT 1 YEAR FOLLOW UP

Purpose of Study Psoriasis (PSO), a chronic inflammatory skin disease, is associated with increased CV risk and vascular inflammation (VI). However, the effect of therapeutic lifestyle changes (TLC) including exercise on VI over time is unknown. We hypothesized that TLC would lead to an improvement in VI at 1 year accompanied by improvements in aortic wall characteristics. Methods Used 65 PSO patients, recruited consecutively, underwent FDG PET/CT, phase contrast MRI scans and clinical visits for evaluation of VI, wall characteristics and exercise frequency, at baseline and 1 year follow-up. VI was measured as Target-to-background ratio (TBR), and aortic distensibility (AD) and wall thickness were assessed by commercial software on phase contrast MRI scans. Clinical parameters were ascertained by both survey and provider. Summary of Results VI decreased at 1 year (6.5% decrease in TBR; p<0.0001), and was inversely associated with exercise frequency beyond adjustment for CV risk factors (β=−0.27; p=0.001). Furthermore, this decrease in VI was associated with improvement in AD (40% increase; p<0.001) and aortic wall thickness (8.5% decrease; p<0.001). Conclusions Our findings suggest that VI improves with TLC. This 6.5% decrease in VI could lead to ∼30% reduction in future adverse events, based on a recent large prospective study. This VI reduction is also associated with improved aortic wall characteristics suggesting that targeting VI as a surrogate marker holds promise to understand the effects of TLC on CV disease. Abstract 23 Figure 1