Joanna Silverman

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.

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.

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.

Identification of proresolving and inflammatory lipid mediators in human psoriasis

BACKGROUND Psoriasis (PSO) is an immune-mediated inflammatory disease associated with metabolic and cardiovascular comorbidities. It is now known that resolution of inflammation is an active process locally controlled by specialized proresolving mediators (SPMs), named resolvins (Rvs), protectins, and maresins. OBJECTIVE It is unknown whether these potent lipid mediators (LMs) are involved in PSO pathophysiology and if the skin and blood have disease-specific SPMs phenotype profiles. METHODS We used liquid chromatography-tandem mass spectrometry-based LM metabololipidomics to obtain skin and peripheral blood LM profiles from PSO compared to healthy subjects. Some LMs were tested in cell culture experiments with corresponding gene expression and protein concentration analyses. RESULTS The levels of several LM were significantly elevated in lesional PSO skin compared to nonlesional and skin from healthy subjects. Particularly, RvD5, protectins Dx, and aspirin-triggered forms of lipoxin were present only in lesional PSO skin, whereas protectin D1 was present in nonlesional PSO skin. To determine specific roles of SPMs on skin-related inflammatory cytokines, RvD1 and RvD5 were incubated with human keratinocytes. RvD1 and RvD5 reduced the expression levels of interleukin 24 and S100A12, whereas only RvD1 significantly abrogated interleukin-24 production by keratinocytes. CONCLUSIONS These findings suggest that an imbalance between locally produced proresolution and proinflammatory LMs identified in PSO skin and blood compartments might play a role in PSO pathophysiology. Moreover, some of the PSO-related cytokines can be modified by specific SPMs and involved mechanisms support investigation of targeting novel proresolving lipid mediators as a therapy for PSO.

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

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

21: DETERMINANTS OF VASCULAR INFLAMMATION BY 18-FLUORODEOXYGLUCOSE PET/MRI: FINDINGS FROM THE PSORIASIS, ATHEROSCLEROSIS AND CARDIOMETABOLIC DISEASE INITIATIVE

Purpose of Study Psoriasis (PSO), a chronic inflammatory disease associated with increased CV risk, provides a clinical human model to study inflammatory atherogenesis. We aimed to assess the major determinants of vascular inflammation (VI) measured by 18FDG PET-MRI in a well-phenotyped PSO cohort. Methods Used 124 consecutive patients with PSO underwent 18FDG PET-MRI scans. We used target-to-background ratio to quantify VI 120 minutes post FDG injection. Homeostatic model assessment of insulin resistance (HOMA-IR) was measured, along with cholesterol efflux capacity (CEC) and HDL particle concentration by NMR (Liposcience) fasting. Summary of Results Our cohort was middle aged (mean 49±13.3 years) with mild to moderate PSO, and low CV risk (median Framingham Risk Score (FRS) 2, IQR 2–6). PSO was associated with increased VI (β=0.27, p<0.005), compared to healthy controls. VI was associated with HOMA-IR (β=0.26, p<0.001), CEC (β=−0.12, p=0.04) and HDL particle concentration (β=−0.19, p=0.003) beyond traditional CV risk factors (age, gender, FRS and BMI). Among these, HOMA-IR provided maximum incremental value in predicting VI beyond traditional risk factors (χ2=39.36, p<0.001). Conclusions VI by FDG PET MRI is associated with traditional CV risk factors and cardiometabolic parameters. Insulin resistance and CEC were most strongly associated with VI by 18FDG PET-MRI beyond traditional CV risk factors and BMI in PSO suggesting that cardiometabolic disease increases CV risk in PSO. Abstract 21 Figure 1

DETERMINANTS OF VASCULAR INFLAMMATION BY 18-FLUORODEOXYGLUCOSE PET/MRI: FINDINGS FROM THE PSORIASIS, ATHEROSCLEROSIS AND CARDIOMETABOLIC DISEASE INITIATIVE

Psoriasis (PSO), a chronic inflammatory disease associated with increased CV risk, provides a clinical human model to study inflammatory atherogenesis. We aimed to assess the major determinants of vascular inflammation (VI) measured by 18FDG PET-MRI in a well-phenotyped PSO cohort. 124 consecutive