V-domain Immunoglobulin Suppressor of T cell activation (VISTA) is an inhibitory B7 family immune-checkpoint molecule expressed on myeloid cells. VISTA-KO mice exhibit Psoriasis-like inflammation. Myeloid cells in psoriasis have multiple abnormalities, including aberrancies in monocytic myeloid-derived suppressor cells and adhesiveness. Whether VISTA signaling is related to Psoriasis myeloid dysfunction is unknown. Indeed, psoriasis monocytes contain a subset with dysregulated VISTA expression (MCF of 347±32 in psoriasis, n=10, vs MCF of 462±77 in controls , n=6), p< 0.05). To examine VISTA function in monocytes, we generated lentivirus-induced VISTA overexpressing human monocytes (THP-1), and stable VISTA overexpressing THP-1 cells (THP-1VISTA) were established. Flow cytometric analysis showed that stable THP-1VISTA transfectants induced VISTA expression when activated by LPS alone or in combination with Interferon-γ. Morphologically, activated THP-1VISTA transfectants, but not GFP transfectants, showed decreased aggregation. Next, we interrogated the inflammatory cytokine profile observed in activated THP-1VISTA cells using mRNA expression arrays. Relative to GFP-transfectants, VISTA-overexpressing monocytes showed upregulated disintegrin-like and metalloprotease domain with thrombospondin type 1 motif (ADAMTS1), yet downregulated TGF-β, tissue inhibitor of metalloproteinase (TIMP3), catenins (CTNNA1, CTNND1), matrix metalloproteinase (MMP14), and an extracellular cell adhesion protein (ANOS1). Add-back experiments using recombinant TGF-b to activated THP-1VISTA cells restored aggregation, likely via its restoration of integrin A6 (ITGA6) expression to the same level as control THP-1GFP. These findings uncover a previously unappreciated connectivity between VISTA, TGF-b, and monocyte adhesion, perhaps offering a new intervention point relevant to psoriasis and its monocyte-mediated associated comorbidities.

BACKGROUND.Candida auris has demonstrated the ability to colonize the skin of hospitalized patients, possibly contributing to nosocomial spread. OBJECTIVE. The objective was to determine whether two novel transdermal agents could clear skin colonization established by C. aurisMETHODS. A murine skin colonization model was first optimized and then used to test fungal burden reduction following treatment with 1% terbinafine or 1% clotrimazole in a proprietary Advanced Penetration Technology formulation (APT™). RESULTS. Both treatments significantly reduced fungal burden compared to control groups. CONCLUSION. These novel agents show promise as a topical means of preventing skin colonization by C. auris.

V-domain Immunoglobulin Suppressor of T cell activation (VISTA) is an inhibitory B7 family immune-checkpoint molecule. VISTA is highly expressed on myeloid, hematopoietic and cancer cells and participates in T cell-mediated autoimmunity and antitumor immunity, playing a broad role in regulation of myeloid- and T cell-mediated immunity. VISTA is upregulated on myeloid-derived suppressor cells (MDSCs) from AML patients. We previously reported MDSCs are increased but functionally impaired in psoriasis (Pso); VISTA knock-out (KO) mice exhibit Pso-like inflammation. VISTA-KO mice exhibit Pso-like inflammation. Whether VISTA signaling is related to Pso MDSC dysfunction is unknown. We analyzed VISTA expression on CD14+ Pso and healthy control (HC) monocytes (Mo) using flow cytometry. Mo-MDSC (CD14+HLA-DRneg) were elevated in Pso patients, and, as hypothesized, VISTA surface expression was elevated (1.6±0.9 % vs 13.2±4.0 % of Mo in HC vs Pso, n=4, 3, p<0.01). Innate signaling for human Mo activation via LPS attenuated VISTA gene expression in HC and Pso patients, suggesting VISTA expression is sensitive to inflammatory status. A novel VISTA ligand is V-Set and Immunoglobulin domain containing 3 (VSIG-3); consistent with a functional role for VISTA in human Mo, we found that VSIG-3 stimulation of CD14+ Mo attenuates IL-6 expression. In Pso patients, VSIG-3 was less effective in reducing IL-6 in Pso-Mo compared to HC (average IL-6 after VSIG-3 relative to LPS alone of 66±7.1% in HC versus a minimal effect on IL-6 of 89±7.0% in Pso, n=2, 3, p<0.05). Thus, in addition to T cell signals, VISTA expression/signaling is implicated in human Mo and dysregulated in Pso. VISTA pathway targeting may represent a novel immune rebalancing approach in Pso and related inflammatory diseases whose engagement inhibits T-cell proliferation as well as cytokine and chemokine production, demonstrated previously by VSIG-3 inhibition of anti-CD3-induced IL-17 secretion on PBMCs

Psoriasis is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aims to uncover shared molecular targets for psoriasis-ASCVD therapies and reduce diverse heterogeneous presentations into endotypes. We compared PAXgene RNA-seq of psoriasis patients with low (Agatston<100; n=21) versus moderate-to-high (Agatston≥100; n=7) coronary artery calcification scores (CACS), a surrogate for subclinical atherosclerosis. Differentially expressed genes (DEGs; α=0.05; |logFC|≥0.1; e. Bayes w/o adj.) were identified with a linear model controlling for age (56.8±13.8 yo), sex (38% F), and batch (n=3). Females were less likely to have moderate-to-high CACS than males (10% vs. 33%), although the odds ratio did not reach significance (OR=0.22; 95%CI:0.02,2.18; p=0.36). Pearson hierarchical clustering of the top 50 DEGs (|t|>3.3) revealed three distinct transcriptomic endotypes with median CACS values of 111 Agatston (IQR:0,189; 5 of 8 patients ≥100), 21 Agatston (IQR:0,83; 2 of 10 patients ≥100), and 0 Agatston (IQR:0,0; 0 of 10 patients ≥100), respectively (p=0.06, Kruskal-Wallis H test). Enriched pathways (α=0.01; e. Bayes w/o adj.) were identified using gene set variation analysis on MSigDB hallmark gene sets. The top three pathways by log-fold change were interferon-α (e.g., IFI44L), interferon-γ (e.g., IFIT1), and PI3K/AKT/mTOR signaling (e.g., E2F1). Thus, the psoriasis endotype most prone to calcifying ASCVD distinguishes itself by altered prominent inflammation pathways exhibiting interferon signatures. Identifying patients that express these signature pathways may advance personalized prediction and prevention of an ASCVD-prone psoriasis endotype.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory disease that affects approximately 20% of patients with plaque psoriasis (PsO). Neutrophil subsets are elevated in psoriatic disease, however their role in chronic inflammation and mechanisms driving synovio-entheseal inflammation has yet to be fully elucidated. We performed single cell RNASeq of peripheral blood neutrophils from age- and sex-matched patients to identify neutrophil specific pathways driving the development of PsA. Machine learning was performed for non-linear dimension reduction analysis and revealed significant heterogeneity within the neutrophil compartment, identified specific clusters enriched in PsA patients, and key molecular genes and networks (extracellular matrix remodeling, adhesome and inflammasome) that are differentially regulated in neutrophils from patients suffering psoriatic arthritis vs. plaque psoriasis. We also generated complex pseudotime trajectories to accurately reconstruct neutrophil biological transition states. We identified key regulatory genes and transcription factors such as MEF2C, shown to promote myeloid progenitor proliferation in a mouse model, and whose deletion suppresses progenitor expansion and corrects neutrophilia in miR-223-/- mice. We identified novel potential therapeutic targets for preventing or reversing neutrophil-mediated mechanisms driving psoriatic arthritis, and significantly expanded our understanding of the complicated disease pathophysiology that differentiates psoriatic arthritis from plaque psoriasis to guide therapeutic approaches.

We previously reported that individuals with psoriasis exhibit an increase in inflammatory monocytes which could be used as a predictor of psoriasis severity and which may act as immunologic sensors of systemic alterations in the inflammatory milieu. This current large cohort study confirms critical links between psoriasis-related transcript sensors and associated comorbidities. We present a multifaceted biological analysis incorporating whole blood RNA-seq data from individuals with psoriasis (n=68, 15 PsA; mean PASI=10.0 (range: 0-35.6)) and controls (n=15) along with phenotypic data and GSVA pathway enrichment (p<0.05). Using RNASeq performed on a NextSeq 550 (15M+ paired reads/sample, 75 bp), we identified significantly differentially expressed genes (DEGs; p<0.05) and pathways between psoriasis (including PsA) patients and controls as well as linear regression signatures of age and PASI. Linear regression with PASI revealed a unique set of biomarkers involved in interferon (IRF8), cytokine (CCR6), and T cell activity (IL17RC, CD40LG) in the most severe forms of psoriasis. Linear regression of age identified a signature in older individuals characterized by upregulation of genes associated with antigen-presenting cells (CD86, HLA-DRA) and downregulation of adhesion molecules (SIRPG, NRCAM, ITGA6) and metalloproteinases (ADAM12, MMP28). Application of a comprehensive systems biology approach revealed candidate gene targets within adhesion, interferon, TGF-β, and AKT/mTOR signaling pathways in psoriasis patients. We also identified interesting correlations between clinical outcomes (BMI, hsCRP, CBCs, and patient self-reported such as itch), surface markers via flow cytometry (intermediate monocyte %), and the transcriptome. Combining whole blood-derived RNA-seq data with phenotypic data may allow us to identify a patient-specific and multi-omic endotype that can point to specific biomarkers or targets within circulating immune cells and associated pathways.

Use of broad-spectrum antibiotics (e.g., doxycycline, minocycline) significantly alters the gut and skin microbiome leading to dysbiosis, resulting in microbial imbalance and has been associated with exacerbation of inflammation. Sarecycline was developed as the first narrow-spectrum tetracycline-class antibiotic to treat acne. Narrow-spectrum antibiotics are hypothesized to cause minimal interference with endogenous gastrointestinal (GI) tract microbiota, thereby maintaining innate microbial diversity. To examine the breadth of this effect, a panel of microorganisms that reflect the diversity of the gut microbiome were evaluated with sarecycline compared to the broad-spectrum minocycline using in vitro susceptibility testing and time-kill assays. Sarecycline had a lower minimum inhibitory concentration (MIC) against 3 out of 4 isolates from Actinobacteria phylum, 10 out of 12 isolates from Bacteroidetes, and 5 out of 7 isolates from the Firmicutes. Furthermore, sarecycline was less active against E. coli, and significantly less active against P. freudenreichii when compared to minocycline. Against fungi, sarecycline showed less activity against 4 representative Candida species. Time-kill curves for E. coli and C. tropicalis showed significantly less activity against E. coli for sarecycline compared to minocycline at all time-points (p-values <0.05). Similarly, sarecycline was significantly less effective in inhibiting C. tropicalis compared to minocycline at 20 and 22 hours exposure. Overall, sarecycline showed reduced antimicrobial activity against 79% of gut microflora tested compared to minocycline, suggesting that it has less potential to cause dysbiosis. Further in vivo testing is warranted.

The inability to over-express Aquaporin 6 (AQP6) in the plasma membrane of heterologous cells has hampered efforts to further characterize the function of this aquaglyceroporin membrane protein at atomic detail using crystallographic approaches. Using an Aquaporin 3-tGFP Reporter (AGR) system we have identified a region within loop C of AQP6 that is responsible for severely hampering plasma membrane expression. Serine substitution corroborated that amino acids present within AQP6 194–213 of AQP6 loop C contribute to intracellular endoplasmic reticulum (ER) retention. This intracellular retention signal may preclude proper plasma membrane trafficking and severely curtail expression of AQP6 in heterologous expression systems.

Skin is in direct interface with the environment, subjecting it to extrinsic damage and intrinsic metabolic processes that result in aging. Long noncoding RNAs (lncRNA) are regulatory molecules, impacting transcription, translation, and macromolecular organization. Unlike other classes of RNAs, lncRNAs are understudied in most fields, including aging. This study investigates the role for lncRNA and protein coding RNA in aging using NGS by comparing transcriptomes from paired neonatal and adult keratinocyte donors. The biological impact of the genes correlated with and differentially expressed during aging were identified using pathway analysis and GWAS. Age positively correlated (correlation coefficient ≥ 0.6) with expression of 925 protein coding and 181 lncRNA genes, and negatively correlated with 739 protein coding and 168 lncRNA genes. Both classes of genes have single nucleotide polymorphisms associated with inflammatory disorders, including psoriasis and IBD. The differentially expressed genes play roles in barrier function, adhesion, cytokine-receptor interactions, and cancer-associated pathways. Surprisingly, senescence associated lncRNAs showed variable regulation with age: NORAD and MIAT had weak negative correlations, yet PINT and PVT1, components of the p53/Myc pathway, are enriched with age. Comparison to publically available skin suction blister and dermal fibroblast aging datasets revealed a core set of age-associated protein coding genes, which may underlie skin aging regardless of the layer or embryonic origin on the cell. In contrast, lncRNAs were notably lineage specific and may represent a modality for cell-type specific targeting of the aging process. Given the finding of altered barrier function in aged human keratinocytes, these findings will be compared to psoriasis, atopic dermatitis, and ichthyosis, diseases in which barrier dysfunction contributes to pathogenesis.

With the hypothesis that new biomarker discovery will lead to better classification of individuals with psoriasis and aid in targeting of their primary disease and associated comorbidities, we are undertaking an endotype analysis of broadly-enrolled psoriasis and psoriatic arthritis (PsA) patients using a systems biology approach. Here we report our first findings using whole blood collected from psoriasis patients (n=33 including 7 with PsA; mean PASI=6.8 (range 0-29.6)) and 5 healthy controls. RNASeq was performed using Illumina TruSeq Total RNA kits and the NextSeq 550 sequencer (15M+ paired-end reads/sample, 75 cycles). Significant differentially expressed genes (DEGs; p<0.05 for all hits) were identified between psoriasis and PsA patients or their controls and pathway analysis was performed using gene set variation analysis. A general signature of psoriasis was found vs controls led by upregulated interferon signaling (e.g. MX1, ISG15) and inflammasome (e.g. LAMP2, NLRP2) genes that also tended to increase with age in linear regression analyses. Other endotypes were found using these proinflammatory biomarkers clustered by gender and ethnicity. Network analysis identified additional gene interactions with psoriasis in effector signaling, such as CD63, CALM2, and CASP1, as well as unique DEG in psoriasis patients with PSA, primarily in T/B cell and neutrophil activation. Cytometric analysis of the same samples revealed increased intermediate monocytes in psoriasis/PSA vs controls (p<0.01), confirming our prior results and the high inflammatory burden of psoriasis. Lastly, linear regression with PASI revealed a unique set of biomarkers involved in Treg (IL2RA) and B cell activity (CD72, CD19) in the most severe forms of psoriasis. Our ongoing strategy is to combine a multi-omic biomarker database with electronic health records to identify new therapeutic targets aimed at improving standard of care in psoriasis.

Mechanotransduction by hair cell stereocilia lies at the heart of sound detection in vertebrates. Considerable effort has been put forth to identify proteins that comprise the hair cell mechanotransduction apparatus. TMC1, a member of the transmembrane channel-like (TMC) family, was identified as a core protein of the mechanotransduction complex in hair cells. However, the inability of TMC1 to traffic through the endoplasmic reticulum in heterologous cellular systems has hindered efforts to characterize its function and fully identify its role in mechanotransduction. We developed a novel approach that allowed for the detection of uncharacterized protein regions, which preclude trafficking to the plasma membrane (PM) in heterologous cells. Tagging N-terminal fragments of TMC1 with Aquaporin 3 (AQP3) and GFP fusion reporter, which intrinsically label PM in HEK293 cells, indicated that residues at the edges of amino acid sequence 138–168 invoke intracellular localization and/or degradation. This signal is able to preclude surface localization of PM protein AQP3 in HEK293 cells. Substitutions of the residues by alanine or serine corroborated that the information determining the intracellular retention is present within amino acid sequence 138–168 of TMC1 N-terminus. This novel signal may preclude the proper trafficking of TMC1 to the PM in heterologous cells.

Independent associations have been reported between psoriasis (PsO), elevated serum resistin (also known as adipose tissue-specific secretory factor (ADSF)) levels, and cardiovascular disease (CVD). We sought to examine whether ASDF levels correlated with Psoriasis Area and Severity Index (PASI) score, and how this relationship may be modified in the presence of other variables including; sex, race, smoking and atherosclerosis status, age, BMI, LDL/HDL ratio, and systolic blood pressure (SBP; transformed from a continuous to a binary variable; normal: < 120 mmHg, high: > 120mmHg). We examined data derived from a cohort of PsO patients with quantified ASDF levels (n=100). Univariate analysis revealed a significant association between PASI score and sex (p= 0.0095), BMI (p=0.05), and SBP (p= 0.02). Statistically significant variables were selected forward into the multivariate model. ASDF and PASI were positively correlated and significant (p < 0.0001), after adjusting for sex, BMI, and SBP. To determine if SBP affected the relationship between PASI and ASDF, we assessed the following model: PASI = ß 0 + ß 1ASDF + ß 2Sex + ß 3BMI + ß 4SBP + ß 5ASDF*SBP. After addition of the interaction between ASDF and systolic blood pressure to the model, the interaction was significant at the a=0.10 level (p=0.068). Variables from above that remained statistically significant at the a=0.10 level were sex (p=0.026), BMI (p=0.055), and the interactive variable of ASDF and categorical SBP (p=0.014). Further analysis suggests that the correlation between ASDF and PASI increased for hypertensive PsO patients compared to normotensive patients. The correlation of ASDF with PASI and SBP suggests ASDF may be used as a serum marker for risk management. Further research is necessary to determine if ASDF and SBP could be combined to assess CVD risk among PsO patients.

Psoriasis (PsO) generates systemic inflammation which may be related to cardiovascular disease (CVD) events. Red cell distribution width (RDW) and mean platelet volume (MPV) appear to be systemic sensors that reflect disordered bone marrow response, and are markers for major adverse cardiac events. We asked whether elevated RDW and/or MPV were related to the risk of CVD events in PsO patients. We performed a retrospective study of psoriasis patients obtained from the Explorys electronic health record database. Psoriasis patients aged 18-65 with available RDW or MPV measurements were included. Patients with diabetes mellitus, Crohns disease, rheumatoid arthritis and generalized atherosclerosis were excluded. Chi-squared test was used for comparisons. Patients with psoriatic arthritis (PsA) were examined independently of PsO patients. A total of 39,510 patients had PsO; 1,920 patients exhibited elevated RDW plus MPV (5%), 7,060 had elevated RDW and normal MPV (18%), and 3,710 had normal RDW and elevated MPV (9%). The incidence of myocardial infarction (MI) was highest among patients with elevated RDW and MPV (OR 3.4, 95% CI 2.7-4.2, p<0.001), followed by patients with high RDW and normal MPV (OR 2.4, 95% CI 2.1-2.8, p<0.001), as compared to normal/low MPV and RDW patients. Atrial fibrillation, coronary artery disease, heart failure and peripheral vascular disease also had elevated OR ranging from 2-8.3, (p<0.001 each) in psoriasis patients with elevated RDW or elevated RDW plus MPV. Among patients with PSA, elevated RDW also increased the risk of an MI with an OR=1.8, p<0.001. In a cohort of 23 PsO patients followed longitudinally for 1 year, 4 patients had elevated RDW at baseline; among these, 3 patients had a PASI75 response, and RDW was normalized for these responders. Bone marrow sensing of psoriatic inflammation likely alters RDW and MPV responses that are also associated with increased CVD risk.

The well-characterized cell line Chinese hamster ovary (CHO) has been used to produce numerous biopharmaceuticals and is an important tool for basic research. However, introducing foreign DNA into specially modified CHO cells such as DG44 and Lec 3.2.8.1 can sometimes be an arduous process. Here we show that the Flp-intm plasmid can be modified to produce a fluorescent tracer protein tag (mCherrytm) as a fusion reporter, to allow for the rapid selection of single-cell sorted, isogenic Flp-intm-ready DG44 and Lec 3.2.8.1 cell lines. These two cell lines are stable and viable and may be useful for applications such as antibody production and crystallographic studies. Here we provide key details on how the modified pFRT/CherryZeo plasmid may be used to incorporate Flp-intm technology into virtually any desired target cell line in a fast, safe and reliable manner.

Psoriasis (Ps) is a chronic recurring hyperproliferative and inflammatory skin disease caused by the interaction among multigenetic and environmental factors.Recent studies revealed that DNA methylation (DNAm) could modulate gene expression in the pathogenesis of Ps.However, the relationship between whole-genome DNAm and gene expression in Ps has not been studied yet.In this study, we used our previous methylome and transcriptome dataset from the same 60 samples and reanalyzed differentially methylated sites (DMSs) and differentially expressed genes (DEGs) by comparing the involved psoriatic (PP), uninvolved psoriatic (PN) and normal (NN) skin tissue.Gene Ontology (GO) and KEGG pathway analysis were conducted then.We identified 1,460 unique genes that differed in expression and methylation levels in PP compared to NN and 2,194 genes in PP compared to PN.A total 656 genes with reverse correlation between expression and methylation overlapped in PP compared to NN and PP compared to PN.Further enriched GO categories included vascularture development, immuno-inflammatory responses to various stimuli and cytokine activity.KEGG analysis revealed superior Rap1 signaling pathway and cytokine-cytokine receptor interaction.Our results provided the most comprehensive correlation analysis of transcriptome and methylome in Ps.Further KEGG analysis suggested Rap1 signaling pathway may play a role in the development of psoriatic skin, which has not be reported previously.This integrated analysis provides additional insights into the pathogenic mechanisms involved in Ps.

Numerous cellular immune mediators are thought to initiate, as well as potentiate, the chronic inflammation characteristic of psoriasis. The progressive amplification of chronic inflammation also promotes co-morbidities such as atherogenesis, and thus patients with psoriasis have an increased risk of developing and dying of cardiovascular disease (CVD). Given that systemic treatments for psoriasis target shared inflammatory mechanisms observed in psoriasis as well as atherosclerotic cardiovascular disease (ASCVD), it is possible that effective suppression of skin inflammation could diminish distant pro-ASCVD effects. However, the parameters which best evaluate the potential for psoriasis treatments to reduce CVD event risk remains to be established. We performed a prospective longitudinal observational pilot study of the behavior of several biomarkers associated with an increased risk of CVD in psoriasis. Biomarkers including resistin, myeloperoxidase (MPO), and adiponectin were measured during and after one year of a continuous standard-of-care systemic therapies designed to achieve >75% psoriasis clearing based on validated measures of psoriasis severity in as many patients as possible. The average percent reduction in resistin from baseline to 1 year is 40.7% (n=26, 4.1 to 65.0%), and for MPO is 27.5% (n=15, -14.7 to 60.9%). The average percent increase for adiponectin from baseline to 1 year is 69.6% (n=15, -10.6 to 384%). To complement blood biomarkers, we quantified carotid artery inflammation using imaging via 18fluorodeoxyglucose (18FDG)-position emission tomography (PET) with magnetic resonance (MR) at baseline and 1 year of therapy. For this cohort (n=15), the difference between the most diseased segment (MDS) of carotid artery at baseline versus the same segment a year later is statistically significant (p=0.000163) at p ≤ 0.05. On average, vascular inflammation in the MDS was reduced by 29.1%. Patient improvement is reflected in the multiparameter biomarker observations as well as PET-MR measures.

Little is known about cimicosis, the resultant dermal reaction from feeding activity by the common bedbug, Cimex lectularius L. We fed C. lectularius on human study subjects four times over four weeks and measured serum cytokine and antibody levels, and subjects recorded any cimicosis. The average time for subjects to develop cimicosis decreased with each feeding from 8.4, to 2.1, 1.5 and 1.3 days, respectively. There were no significant changes in total IgG, IgG1, IgG2, IgG4 or IgE levels between the first and fourth bedbug feedings, but there was a significant decrease in total IgG3 levels (P <.001). IgG4 was not required for cimicosis. Higher IgG2 and IgG4 levels at study visit 4 were associated with an increased duration of cimicosis (P=.04) and lower pruritis (P=.03), respectively. There were no significant changes in serum TNF-alpha, IL-1 beta, IL-4, IL-5, IL-6, IL-10, IFN-gamma and IL-17A levels before and one hour after the C. lectularius feeding. Lower post-C. lectularius feeding IL-6 levels were associated with increased pruritis (P=.001) and the time to maximum pruritis ( P=.04), respectively. Higher post-C. lectularius feeding IL-5 levels were associated with a longer duration of pruritis (P=.05).

Background Psoriasis is a chronic inflammatory disease of the skin and joints that may also have systemic inflammatory effects, including the development of cardiovascular disease (CVD). Multiple epidemiologic studies have demonstrated increased rates of CVD in psoriasis patients, although a causal link has not been established. A growing body of evidence suggests that sub-clinical systemic inflammation may develop in psoriasis patients, even from a young age. We aimed to evaluate the prevalence of atherosclerosis and identify specific clinical risk factors associated with early vascular inflammation. Methods We conducted a cross-sectional study of a tertiary care cohort of psoriasis patients using coronary artery calcium (CAC) score and carotid intima-media thickness (CIMT) to detect atherosclerosis, along with high sensitivity C-reactive protein (hsCRP) to measure inflammation. Psoriasis patients and controls were recruited from our tertiary care dermatology clinic. Presence of atherosclerosis was defined using validated numeric values within CAC and CIMT imaging. Descriptive data comparing groups was analyzed using Welch’s t test and Pearson Chi square tests. Logistic regression was used to analyze clinical factors associated with atherosclerosis, and linear regression to evaluate the relationship between psoriasis and hsCRP. Results 296 patients were enrolled, with 283 (207 psoriatic and 76 controls) having all data for the hsCRP and atherosclerosis analysis. Atherosclerosis was found in 67.6 % of psoriasis subjects versus 52.6 % of controls; Psoriasis patients were found to have a 2.67-fold higher odds of having atherosclerosis compared to controls [95 % CI (1.2, 5.92); p = 0.016], after adjusting for age, gender, race, BMI, smoking, HDL and hsCRP. In addition, a non-significant trend was found between HsCRP and psoriasis severity, as measured by PASI, PGA, or BSA, again after adjusting for confounders. Conclusions A tertiary care cohort of psoriasis patients have a high prevalence of early atherosclerosis, increased hsCRP, and psoriasis remains a risk factor for the presence of atherosclerosis even after adjustment of key confounding clinical factors. Psoriasis may contribute to an accelerated systemic inflammatory cascade resulting in increased risk of CVD and CV events.

Psoriasis patients develop cardiovascular (CV) comorbidities that shorten their lifespan; why this occurs and whether treatment with current biologics improves these outcomes is unclear. KC-Tie2 mice develop psoriasiform skin inflammation with increases in IL-23/IL-17A and proinflammatory monocytes that precede the development of aortic vascular inflammation and shortened times to induced carotid artery thrombus formation (thrombosis). KC-Tie2 mice with skin disease were treated IP 1x/wk for 6wks with function-blocking antibodies (Abs) targeting murine IL-17A, IL-17F, IL-17RA, IL-12/23p40, IL-23p19 or isotype IgG (n=9-21/grp) and thrombosis, skin inflammation and splenic immunocytes were examined. KC-Tie2 mice treated with Abs targeting IL-17A, IL-17RA, IL-12/23p40 and IL-23p19, but not IL-17F had significantly decreased acanthosis, cutaneous T and myeloid cell infiltrates, STAT3, S100A9, and TNFα (p<0.05 vs. IgG), consistent with observed efficacy (or lack thereof) of these biologic therapies in psoriasis patients. Improvement (increase) in thrombosis times was seen in mice with significantly improved skin inflammation and this corresponded with decreases in splenic proinflammatory CD11b+Ly6Chi monocytes. Notably, KC-Tie2 mice treated with IL-17F Abs also showed significantly improved thrombosis (p<0.05 vs. IgG), despite sustained skin inflammation and CD11b+Ly6Chi monocytosis. Further examination of splenic immunocytes identified reduced CD11b+Ly6G+ neutrophils in all mice that showed improved thrombosis and this corresponded with decreases in cutaneous NF-κB (p<0.05 vs. IgG). Our data demonstrate that inhibiting IL-23/IL-17 cytokines associated with psoriasiform skin inflammation increases time to occlusive thrombosis and identifies a potential role for IL-17F in mediating CV outcomes. Moreover, splenic neutrophil number and skin NF-κB expression corresponded best with increased clotting times suggesting these may serve as surrogate measures of CV outcomes in psoriasis patients.