Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease.

BACKGROUND: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. METHODS: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis; approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. RESULTS: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. CONCLUSIONS: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.

Biomarkers of subclinical atherosclerosis in patients with psoriasis.

Psoriasis is linked with increased risk of cardiovascular disease (CVD) that is underestimated by traditional risk stratification. We conducted a large-scale plasma proteomic analysis by use of a proximity extension assay in 85 patients with a history of moderate-to-severe psoriasis with or without established atherosclerotic CVD. Differentially expressed proteins associated with CVD were correlated with subclinical atherosclerotic markers including vascular inflammation determined by 18F-fluorodeoxyglucose positron emission tomography/computed tomography, carotid intima-media thickness (CIMT), carotid artery plaques, and coronary artery calcium score (CCS) in the patients without CVD and statin treatment. We also examined the association between the neutrophil-to-lymphocyte ratio (NLR) and subclinical atherosclerosis. In unadjusted analyses, growth differentiation factor-15 (GDF-15) levels and NLR were increased, while tumor necrosis factor (TNF)-related activation-inducing ligand (TRANCE) and TNF-related apoptosis-induced ligand (TRAIL) levels were decreased in patients with established CVD compared to those without CVD. Among patients with psoriasis without CVD and statin treatment, GDF-15 levels were negatively associated with vascular inflammation in the ascending aorta and entire aorta, and positively associated with CIMT and CCS. NLR was positively associated with vascular inflammation in the carotid arteries. Our data suggest that circulating GDF-15 levels and NLR might serve as biomarkers of subclinical atherosclerosis in patients with psoriasis.

Multiscale Biology of Cardiovascular Risk in Psoriasis: Protocol for a Case-Control Study.

BACKGROUND: Patients with psoriasis have increased risk of cardiovascular disease (CVD) independent of traditional risk factors. The molecular mechanisms underlying the psoriasis-CVD connection are not fully understood. Advances in high-throughput molecular profiling technologies and computational analysis techniques offer new opportunities to improve the understanding of disease connections. OBJECTIVE: We aim to characterize the complexity of cardiovascular risk in patients with psoriasis by integrating deep phenotypic data with systems biology techniques to perform comprehensive multiomic analyses and construct network models of the two interacting diseases. METHODS: The study aims to include 120 adult patients with psoriasis (60 with prior atherosclerotic CVD and 60 without CVD). Half of the patients are already receiving systemic antipsoriatic treatment. All patients complete a questionnaire, and a medical interview is conducted to collect medical history and information on, for example, socioeconomics, mental health, diet, and physical exercise. Participants are examined clinically with assessment of the Psoriasis Area and Severity Index and undergo imaging by transthoracic echocardiography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and carotid artery ultrasonography. Skin swabs are collected for analysis of microbiome metagenomics; skin biopsies and blood samples are collected for transcriptomic profiling by RNA sequencing; skin biopsies are collected for immunohistochemistry; plasma samples are collected for analyses of proteomics, lipidomics, and metabolomics; blood samples are collected for high-dimensional mass cytometry; and feces samples are collected for gut microbiome metagenomics. Bioinformatics and systems biology techniques are utilized to analyze the multiomic data and to integrate data into a network model of CVD in patients with psoriasis. RESULTS: Recruitment was completed in September 2020. Preliminary results of 18F-FDG-PET/CT data have recently been published, where vascular inflammation was reduced in the ascending aorta (P=.046) and aortic arch (P=.04) in patients treated with statins and was positively associated with inflammation in the visceral adipose tissue (P<.001), subcutaneous adipose tissue (P=.007), pericardial adipose tissue (P<.001), spleen (P=.001), and bone marrow (P<.001). CONCLUSIONS: This systems biology approach with integration of multiomics and clinical data in patients with psoriasis with or without CVD is likely to provide novel insights into the biological mechanisms underlying these diseases and their interplay that can impact future treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/28669.

Association between Vascular Inflammation and Inflammation in Adipose Tissue, Spleen, and Bone Marrow in Patients with Psoriasis.

Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with psoriasis (n = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (ß = 0.26; p < 0.001), SAT (ß = 0.28; p < 0.001), PAT (ß = 0.24; p < 0.001), spleen (ß = 1.35; p = 0.001), and bone marrow (ß = 1.14; p < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis.

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.

Surveillance With PET/CT and Liquid Biopsies of Stage I-III Lung Cancer Patients After Completion of Definitive Therapy: A Randomized Controlled Trial (SUPER).

Despite increased focus on prevention as well as improved treatment possibilities, lung cancer remains among the most frequent and deadliest cancer diagnoses worldwide. Even lung cancer patients treated with curative intent have a high risk of relapse, leading to a dismal prognosis. More knowledge on the efficacy of surveillance with both current and new technologies as well as on the impact on patient treatment, quality of life, and survival are urgently needed. We therefore designed a randomized phase 3 trial. In one arm, every other computed tomography (CT) scan is replaced by positron emission tomography/CT, the other arm is the standard follow-up scheme with CT. The standard arm is identical to the current national Danish follow-up program. The primary endpoint is to compare the number of relapses treatable with curative intent in the 2 arms. We aim to include 750 patients over a 3-year period. Additionally, we will test the feasibility of noninvasive lung cancer diagnostics and surveillance in the form of circulating tumor DNA analysis. For this purpose, blood samples are collected before treatment and at each following control. The blood samples are stored in a biobank for later analysis and will not be used for guiding patient treatment decisions.