Nehal N. Mehta

Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database

AIMS Psoriasis is a common chronic inflammatory T-helper cell-1/17 mediated skin disease. Recent studies suggest that psoriasis, particularly if severe, may be an independent risk factor for atherosclerosis, myocardial infarction (MI), and stroke. We conducted a cohort study using the General Practice Research Database to determine if severe psoriasis patients have an increased risk of cardiovascular (CV) mortality. METHODS AND RESULTS Severe psoriasis was defined as patients who received a psoriasis diagnosis and systemic therapy consistent with severe psoriasis (n = 3603). Up to four unexposed patients without psoriasis were selected from the same practices and start dates for each psoriasis patient (n = 14 330). For every death, the cause was determined by review of the electronic medical record. Severe psoriasis was an independent risk factor for CV mortality (HR 1.57; 95% CI 1.26, 1.96) when adjusting for age, sex, smoking, diabetes, hypertension, and hyperlipidaemia. Overall, severe psoriasis patients experienced one extra CV death per 283 patients per year, even when adjusting for major CV risk factors. The relative risk of CV mortality was modified by age. For example, the RR of CV death for a 40-year-old and 60-year-old with severe psoriasis was 2.69 (1.45, 4.99) and 1.92 (1.41, 2.62), respectively. The findings were robust to multiple sensitivity analyses. CONCLUSION Patients with severe psoriasis have an increased risk of CV mortality that is independent of traditional CV risk factors. Additional studies are needed to determine the mechanism of this association and the impact that control of psoriasis has on CV risk.

Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies.

BACKGROUND We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

Prevalence of Metabolic Syndrome in Patients with Psoriasis: A Population-Based Study in the United Kingdom

Increasing epidemiological evidence suggests independent associations between psoriasis and cardiovascular and metabolic disease. Our objective was to test the hypothesis that directly-assessed psoriasis severity relates to the prevalence of metabolic syndrome and its components. Population-based, cross-sectional study using computerized medical records from The Health Improvement Network Study population included individuals aged 45-65 years with psoriasis and practice-matched controls. Psoriasis diagnosis and extent were determined using provider-based questionnaires. Metabolic syndrome was defined using National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria. 44,715 individuals were included: 4,065 with psoriasis and 40,650 controls. 2,044 participants had mild psoriasis (≤2% body surface area (BSA)), 1,377 had moderate (3-10% BSA), and 475 had severe psoriasis (>10% BSA). Psoriasis was associated with metabolic syndrome, adjusted odds ratio (OR) 1.41 (95% CI 1.31-1.51), varying in a “dose-response” manner, from mild (adj. OR 1.22, 95% CI 1.11-1.35) to severe psoriasis (adj. OR 1.98, 95% CI 1.62-2.43). Psoriasis is associated with metabolic syndrome and the association increases with increasing disease severity. Furthermore, associations with obesity, hypertriglyceridemia and hyperglycemia increase with increasing disease severity independent of other metabolic syndrome components. These findings suggest that screening for metabolic disease should be considered for psoriasis, especially when extensive.

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

OBJECTIVE An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n = 20, 50% male, 80% Caucasian, aged 27.3 ± 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (Si). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS Endotoxemia induced systemic IR as demonstrated by a 35% decrease in Si (3.17 ± 1.66 to 2.06 ± 0.73 × 10−4 [μU · ml−1 · min−1], P < 0.005), while there was no effect on pancreatic β-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems. CONCLUSIONS We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

Psoriasis Severity and the Prevalence of Major Medical Comorbidity: A Population-Based Study

IMPORTANCE Despite the growing literature on comorbidity risks in psoriasis, there remains a critical knowledge gap on the degree to which objectively measured psoriasis severity may affect the prevalence of major medical comorbidity. OBJECTIVE To examine the prevalence of major medical comorbidity in patients with mild, moderate, or severe psoriasis, classified objectively based on body surface area involvement, compared with that in patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS Population-based cross-sectional study of patient data from United Kingdom-based electronic medical records; analysis included 9035 patients aged 25 to 64 years with psoriasis and 90,350 age- and practice-matched patients without psoriasis. MAIN OUTCOMES AND MEASURES Prevalence of major medical comorbidity included in the Charlson comorbidity index. RESULTS Among patients with psoriasis, 51.8%, 35.8%, and 12.4%, respectively, had mild, moderate, or severe disease based on body surface area criteria. The mean Charlson comorbidity index was increasingly higher in patients with mild (0.375 vs 0.347), moderate (0.398 vs 0.342), or severe psoriasis (0.450 vs 0.348) (each P < .05). Psoriasis overall was associated with higher prevalence of chronic pulmonary disease (adjusted odds ratio, 1.08; 95% CI, 1.02-1.15), diabetes mellitus (1.22; 1.11-1.35), diabetes with systemic complications (1.34; 1.11-1.62), mild liver disease (1.41; 1.12-1.76), myocardial infarction (1.34; 1.07-1.69), peptic ulcer disease (1.27; 1.03-1.58), peripheral vascular disease (1.38; 1.07-1.77), renal disease (1.28; 1.11-1.48), and rheumatologic disease (2.04; 1.71-2.42). Trend analysis revealed significant associations between psoriasis severity and each of the above comorbid diseases (each P < .05). CONCLUSIONS AND RELEVANCE The burdens of overall medical comorbidity and of specific comorbid diseases increase with increasing disease severity among patients with psoriasis. Physicians should be aware of these associations in providing comprehensive care to patients with psoriasis, especially those presenting with more severe disease.

Measures of Insulin Resistance Add Incremental Value to the Clinical Diagnosis of Metabolic Syndrome in Association With Coronary Atherosclerosis

Background—Whether measures of insulin resistance provide incremental information regarding atherosclerotic cardiovascular disease beyond current National Cholesterol Education Program (NCEP) Adult Treatment Panel III metabolic syndrome (MetSyn) criteria or inflammatory markers is uncertain. Methods and Results—We examined the association of insulin resistance and MetSyn with coronary artery calcification (CAC) in 840 asymptomatic nondiabetic subjects. Both NCEP and World Health Organization–defined MetSyn were associated (ordinal regression odds ratio [OR] and 95% confidence intervals for NCEP-defined MetSyn) with CAC after controlling for age, non-MetSyn risk factors, and plasma CRP levels (OR, 1.93 [1.43 to 2.60], P<0.001) and after further controlling for homeostasis model assessment index (HOMA) (OR, 1.56 [1.14 to 2.15], P=0.006). Conversely, HOMA was significantly associated with CAC after adjusting for age, non-MetSyn risk factors, and CRP levels (OR, 1.62 [1.31 to 2.01], P<0.001) and after further adjusting for NCEP-defined MetSyn (OR, 1.45 [1.16 to 1.82], P=0.007). Addition of HOMA to the NCEP MetSyn significantly improved the association with CAC, but addition of CRP data to MetSyn or HOMA did not. Conclusions—Both MetSyn and HOMA index were associated with coronary atherosclerosis independent of established risk factors, including CRP. These findings support the use of biomarkers of insulin resistance in addition to NCEP MetSyn criteria in assessing cardiovascular disease risk.

Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study

Objectives We aimed to quantify the risk of major adverse cardiovascular events (MACE) among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis without known PsA compared with the general population after adjusting for traditional cardiovascular risk factors. Methods A population-based longitudinal cohort study from 1994 to 2010 was performed in The Health Improvement Network (THIN), a primary care medical record database in the UK. Patients aged 18–89 years of age with PsA, RA or psoriasis were included. Up to 10 unexposed controls matched on practice and index date were selected for each patient with PsA. Outcomes included cardiovascular death, myocardial infarction, cerebrovascular accidents and the composite outcome (MACE). Cox proportional hazards models were used to calculate the HRs for each outcome adjusted for traditional risk factors. A priori, we hypothesised an interaction between disease status and disease-modifying antirheumatic drug (DMARD) use. Results Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=81 573) were identified. After adjustment for traditional risk factors, the risk of MACE was higher in patients with PsA not prescribed a DMARD (HR 1.24, 95% CI 1.03 to 1.49), patients with RA (No DMARD: HR 1.39, 95% CI 1.28 to 1.50, DMARD: HR 1.58, 95% CI 1.46 to 1.70), patients with psoriasis not prescribed a DMARD (HR 1.08, 95% CI 1.02 to 1.15) and patients with severe psoriasis (DMARD users: HR 1.42, 95% CI 1.17 to 1.73). Conclusions Cardiovascular risk should be addressed with all patients affected by psoriasis, PsA or RA.

Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]-Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT): A Pilot Study

OBJECTIVE To evaluate the feasibility of using [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) to detect and quantify systemic inflammation in patients with psoriasis. DESIGN Case series with a nested case-control study. SETTING Referral dermatology and preventive cardiology practices. PARTICIPANTS Six patients with psoriasis affecting more than 10% of their body surface area and 4 controls age and sex matched to 4 of the patients with psoriasis for a nested case-control study. MAIN OUTCOME MEASURES The FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean standardized uptake value, a measure of FDG tracer uptake by macrophages and other inflammatory cells. RESULTS FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints was observed in a patient with psoriatic arthritis as well as in 1 patient with no history of joint disease or joint symptoms. In a nested case-control study, FDG-PET/CT imaging demonstrated increased vascular inflammation in multiple segments of the aorta compared with controls. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate analysis (mean β = 0.33; P < .001). Patients with psoriasis further demonstrated increased hepatic inflammation after adjusting for cardiovascular risk factors (β = 0.18; P < .001), but the association was no longer significant when adjusted for alcohol intake (β = -0.25; P = .07). CONCLUSION FDG-PET/CT is a sensitive tool for identifying inflammation and can be used to identify clinically observed inflammation in the skin and subclinical inflammation in the blood vessels, joints, and liver of patients with psoriasis.

Adipose Inflammation, Insulin Resistance, and Cardiovascular Disease:

Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll-like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro-inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator-activated receptor-gamma and NFkappaB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin-resistant state promoting meta-bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity.

A Genome-wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10−3. Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10−8; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10−96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10−3). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.