Tsion M. Aberra

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.

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.

Association Between Aortic Vascular Inflammation and Coronary Artery Plaque Characteristics in Psoriasis

Importance Inflammation is critical to atherosclerosis. Psoriasis, a chronic inflammatory disease associated with early cardiovascular events and increased aortic vascular inflammation (VI), provides a model to study the process of early atherogenesis. Fludeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT) helps quantify aortic VI, and coronary computed tomography angiography provides coronary artery disease (CAD) assessment through evaluation of total plaque burden (TB) and noncalcified coronary plaque burden (NCB), luminal stenosis, and high-risk plaques (HRP). To our knowledge, association between aortic VI and broad CAD indices has not yet been assessed in a chronic inflammatory disease state. Such a study may provide information regarding the utility of aortic VI in capturing early CAD. Objective To assess the association between aortic VI and CAD indices, including TB, NCB, luminal stenosis, and HRP prevalence, in psoriasis. Design, Setting, and Participants In a cross-sectional cohort study at the National Institutes of Health, 215 consecutive patients with psoriasis were recruited from surrounding outpatient dermatology practices. All patients underwent 18F-FDG PET/CT for aortic VI assessment, and 190 of 215 patients underwent coronary computed tomography angiography to characterize CAD. The study was conducted between January 1, 2013, and May 31, 2017. Data were analyzed in March 2018. Exposures Aortic VI assessed by 18F-FDG PET/CT. Main Outcomes and Measures Primary outcome: TB and NCB. Secondary outcomes: luminal stenosis and HRP. Results Among 215 patients with psoriasis (mean [SD] age, 50.4 [12.6] years; 126 men [59%]), patients with increased aortic VI had increased TB (standardized &bgr; = 0.48; P < .001), and higher prevalence of luminal stenosis (OR, 3.63; 95% CI, 1.71-7.70; P = .001) and HRP (OR, 3.05; 95% CI, 1.42-6.47; P = .004). The aortic VI and TB association was primarily driven by NCB (&bgr; = 0.49; P < .001), whereas the aortic VI and HRP association was driven by low-attenuation plaque (OR, 5.63; 95% CI, 1.96-16.19; P = .001). All associations of aortic VI remained significant after adjustment for cardiovascular risk factors: aortic VI and TB (&bgr; = 0.23; P < .001), NCB (&bgr; = 0.24; P < .001), luminal stenosis (OR, 3.40; 95% CI, 1.40-8.24; P = .007), and HRP (OR, 2.72; 95% CI, 1.08-6.83; P = .03). No association was found between aortic VI and dense-calcified coronary plaque burden. Conclusions and Relevance Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.

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.

AORTIC VASCULAR INFLAMMATION BY 18-FDG PET/MRI IS RELATED TO CORONARY PLAQUE BURDEN BY QUANTITATIVE CORONARY CT ANGIOGRAPHY IN PSORIASIS

Psoriasis (PSO), a chronic inflammatory skin disease, is associated with vascular inflammation (VI) by 18-F FDG PET/MRI and an increased risk of MI. Coronary computed tomography angiography (CCTA) characterizes the composition of plaque in coronary heart disease (CHD). We hypothesized that VI in the

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

MP11: COMORBID DEPRESSION OR ANXIETY IS ASSOCIATED WITH AORTIC VASCULAR INFLAMMATION AND CORONARY HEART DISEASE BEYOND TRADITIONAL CARDIOVASCULAR RISK FACTORS IN PSORIASIS

Purpose of Study Psoriasis is a chronic inflammatory disorder associated with vascular inflammation (VI), measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT), and increased risk of MI. Patients with psoriasis are more likely to have comorbid depression and anxiety. Whether these comorbidities accelerate the development of CVD in psoriasis is unclear. We hypothesized that aortic VI and coronary plaque burden would be increased in patients with psoriasis who have depression and/or anxiety compared to those with psoriasis who do not. Methods Used Patients were prospectively enrolled. Those who reported a history of depression and/or anxiety (n=40) on survey and age- and gender-matched patients who reported no history of psychiatric illness (n=40) were selected. Target-to-Background ratio from 18FDG PET/CT was used to assess aortic VI, and coronary CT angiography scans were analyzed for coronary plaque composition. Summary of Results Both aortic VI and coronary plaque burden were higher in psoriasis patients with comorbid depression or anxiety compared to those without (table 1). After adjustment for Framingham Risk Score, body mass index, and statin use; VI (β=0.24, p=0.02), total plaque burden (β=0.13, p=0.04), and non-calcified burden (β=0.13, p=0.04) were associated with comorbid depression and/or anxiety. Conclusions Patients with psoriasis who have comorbid depression or anxiety have increased aortic VI and coronary plaque burden, suggesting that identification of psychiatric diagnoses in psoriasis may be warranted for future CV risk reduction in this high risk population. Abstract MP11 Figure 1

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