Comparison of the dietary omega-3 fatty acids impact on murine psoriasis-like skin inflammation and associated lipid dysfunction.

Persistent skin inflammation and impaired resolution are the main contributors to psoriasis and associated cardiometabolic complications. Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are known to exert beneficial effects on inflammatory response and lipid function. However, a specific role of omega-3 PUFAs in psoriasis and accompanied pathologies are still a matter of debate. Here, we carried out a direct comparison between EPA and DHA 12 weeks diet intervention treatment of psoriasis-like skin inflammation in the K14-Rac1V12 mouse model. By utilizing sensitive techniques, we targeted EPA- and DHA-derived specialized pro-resolving lipid mediators and identified tightly connected signaling pathways by RNA sequencing. Treatment with experimental diets significantly decreased circulating pro-inflammatory cytokines and bioactive lipid mediators, altered psoriasis macrophage phenotypes and genes of lipid oxidation. The superficial role of these changes was related to DHA treatment and included increased levels of resolvin D5, protectin DX and maresin 2 in the skin. EPA treated mice had less pronounced effects but demonstrated a decreased skin accumulation of prostaglandin E2 and thromboxane B2. These results indicate that modulating psoriasis skin inflammation with the omega-3 PUFAs may have clinical significance and DHA treatment might be considered over EPA in this specific disease.

Association of S100A8/A9 with Lipid-Rich Necrotic Core and Treatment with Biologic Therapy in Patients with Psoriasis: Results from an Observational Cohort Study.

Psoriasis is a systemic inflammatory disease with an increased risk of atherosclerotic events and premature cardiovascular disease. S100A7, A8/A9, and A12 are protein complexes that are produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. Lipid-rich necrotic core (LRNC) is a high-risk coronary plaque feature previously found to be associated with cardiovascular risk factors and psoriasis severity. LRNC can decrease with biologic therapy, but how this occurs remains unknown. We investigated the relationship between S100 proteins, LRNC, and biologic therapy in psoriasis. S100A8/A9 associated with LRNC in fully adjusted models (ß = 0.27, P = 0.009; n = 125 patients with psoriasis with available coronary computed tomography angiography scans; LRNC analyses; and serum S100A7, S100A8, S100A9, S100A12, and S100A8/A9 levels). At 1 year, in patients receiving biologic therapy (36 of 73 patients had 1-year coronary computed tomography angiography scans available), a 79% reduction in S100A8/A9 levels (‒172 [‒291.7 to 26.4] vs. ‒29.9 [‒137.9 to 50.5]; P = 0.04) and a 0.6 mm2 reduction in average LRNC area (0.04 [‒0.48 to 0.77] vs. ‒0.56 [‒1.8 to 0.13]; P = 0.02) were noted. These results highlight the potential role of S100A8/A9 in the development of high-risk coronary plaque in psoriasis.

Association of Biologic Therapy With Coronary Inflammation in Patients With Psoriasis as Assessed by Perivascular Fat Attenuation Index.

Importance: Psoriasis is a chronic inflammatory skin disease associated with increased coronary plaque burden and cardiovascular events. Biologic therapy for psoriasis has been found to be favorably associated with luminal coronary plaque, but it is unclear whether these associations are attributable to direct anti-inflammatory effects on the coronary arteries. Objective: To investigate the association of biologic therapy with coronary inflammation in patients with psoriasis using the perivascular fat attenuation index (FAI), a novel imaging biomarker that assesses coronary inflammation by mapping spatial changes of perivascular fat composition via coronary computed tomography angiography (CCTA). Design, Setting, and Participants: This prospective cohort study performed from January 1, 2013, through March 31, 2019, analyzed changes in FAI in patients with moderate to severe psoriasis who underwent CCTA at baseline and at 1 year and were not receiving biologic psoriasis therapy at baseline. Exposures: Biologic therapy for psoriasis. Main Outcomes and Measures: Perivascular FAI mapping was performed based on an established method by a reader blinded to patient demographics, visit, and treatment status. Results: Of the 134 patients (mean [SD] age, 51.1 [12.1] years; 84 [62.5%] male), most had low cardiovascular risk by traditional risk scores (median 10-year Framingham Risk Score, 3% [interquartile range, 1%-7%]) and moderate to severe skin disease. Of these patients, 82 received biologic psoriasis therapy (anti-tumor necrosis factor α, anti-interleukin [IL] 12/23, or anti-IL-17) for 1 year, and 52 did not receive any biologic therapy and were given topical or light therapy (control group). At baseline, 46 patients (27 in the treated group and 19 in the untreated group) had a focal coronary atherosclerotic plaque. Biologic therapy was associated with a significant decrease in FAI at 1 year (median FAI -71.22 HU [interquartile range (IQR), -75.85 to -68.11 HU] at baseline vs -76.09 HU [IQR, -80.08 to -70.37 HU] at 1 year; P < .001) concurrent with skin disease improvement (median PASI, 7.7 [IQR, 3.2-12.5] at baseline vs 3.2 [IQR, 1.8-5.7] at 1 year; P < .001), whereas no change in FAI was noted in those not receiving biologic therapy (median FAI, -71.98 [IQR, -77.36 to -65.64] at baseline vs -72.66 [IQR, -78.21 to -67.44] at 1 year; P = .39). The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents, including anti-tumor necrosis factor α (median FAI, -71.25 [IQR, -75.86 to -66.89] at baseline vs -75.49 [IQR, -79.12 to -68.58] at 1 year; P < .001) and anti-IL-12/23 or anti-IL-17 therapy (median FAI, -71.18 [IQR, -75.85 to -68.80] at baseline vs -76.92 [IQR, -81.16 to -71.67] at 1 year; P < .001). Conclusions and Relevance: In this study, biologic therapy for moderate to severe psoriasis was associated with reduced coronary inflammation assessed by perivascular FAI. This finding suggests that perivascular FAI measured by CCTA may be used to track response to interventions for coronary artery disease.

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 (ß = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (ß = 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.