Prospective evaluation of cardiovascular risk and mortality in patients with psoriasis: A population-base study

doi:10.21203/rs.3.rs-3152170/v1

Background

The association between psoriasis and cardiovascular disease (CVD) has long been discussed and continually refined. However, there is currently a lack of prospective studies on the cardiovascular risk attributed to psoriasis in the general population.

Methods

Representative adult participants were selected from the National Health and Nutrition Examination Survey (NHANES). Risks of cardiovascular symptoms and diseases prevalence were evaluated between participants with and without psoriasis. The hazards for all-cause mortality and CVD mortality were stratified by psoriasis status. Mediation analysis was then conducted to identify potential mediators between psoriasis and cardiac death.

Results

Overall, 19,741 participants were included in the current study, 542 (2.7%) had psoriasis and 19,199 (97.3%) did not have psoriasis. After adjusting for known CVD risk factors, odds for hypertension (OR = 1.37, 95% CI: 1.13-1.66, p= 0.001), hypercholesterolemia (OR = 1.37, 95% CI: 1.13-1.64, p < 0.001) and angina pectoris (OR = 1.74, 95% CI: 1.11-2.60, p = 0.011) were higher in psoriasis patients. Compared with participants without psoriasis, moderate/severe but not mild patients showed significantly higher CVD mortality (HR = 2.55, 95% CI: 1.27-5.15, p = 0.009). This result was supported by subgroup analyses. Mediation analysis further suggested that the direct effect of moderate/severe psoriasis on CVD mortality accounted for 81.4% (65.8%-97.1%). Besides, the indirect effect might derive from disturbance of serum albumin, urea nitrogen and uric acid.

Conclusions

Moderate-to-severe psoriasis is an independent risk factor for cardiovascular disease, making it necessary to regularly conduct cardiovascular disease-related examinations for patients with higher severity of psoriasis in clinical settings.

NHANES

Psoriasis

Cardiovascular disease

Cardiovascular mortality

Psoriasis, a prevalent chronic inflammatory skin disease, can manifest at any age and affects an estimated 125 million individuals worldwide as of 2020. Psoriasis constitutes approximately 3% of the total population in the United States, posing a significant individual and societal burden(1,2). The most common clinical variant, plaque psoriasis, is typified by well-defined localized erythematous scaly papules or plaques. Psoriasis is currently understood to be a disease mediated by an interplay of multiple genes and immune factors, with an unidentified cause. Given its observed association with multisystem diseases, some research advocates managing psoriasis as a systemic disease(3,4). Among various comorbidities, the link between cardiovascular disease (CVD) and psoriasis has garnered considerable attention. As far back as 1961, Reed and others observed a high prevalence of heart disease-related mortality among psoriasis patients with psoriatic arthritis(5). Numerous studies have confirmed that the risk of various major cardiovascular events in psoriasis patients is increased, including coronary artery disease (CAD), myocardial infarction (MI), and chronic heart failure (CHF)(6–8). However, certain studies suggest that psoriasis may not independently contribute to CVD risk(9,10). To reconcile these disparate conclusions, some researchers argue that the inclusion of a large number of mild psoriasis patients could potentially confound risk factor assessments(11). Recent cohort studies and meta-analyses have emphasized that the risk of cardiovascular events is more significant in people with moderate-to-severe psoriasis compared to the general population and patients with mild psoriasis(12,13). Nevertheless, only one study based on general population data from Norway has corroborated this conclusion, indicating a dearth of related research(14).

Cardiovascular disease (CVD) remains a critical concern in human health, contributing to roughly one-third of all global mortality. Within the realm of evidence-based medicine, numerous risk factors have been identified and validated, such as age, gender, ethnicity, smoking, alcohol consumption, metabolic syndrome, and hyperuricemia, among others. Investigations into the comorbidity of other diseases necessitate a comprehensive consideration of these potential confounding factors in statistical analyses(15,16).

Considering the aforementioned issues, we designed this study using data from the National Health and Nutrition Examination Survey (NHANES), a large-scale comprehensive survey spearheaded by the National Center for Health Statistics (NCHS), a branch of the Centers for Disease Control and Prevention (CDC). The survey leverages multi-stage, probability sampling to ensure that the selected samples are representative of the entire U.S. population, encompassing geographical, racial, gender, age, and other demographic factors. It provides an abundant trove of demographic, laboratory examination, and questionnaire survey data, enabling the design of observational studies for multiple subgroups to minimize the impact of various confounding factors on the analytical outcomes. Simultaneously, it captures the interplay of common exposure factors influencing cardiovascular risk in psoriasis patients and employs mediation effect analysis to scrutinize the role of albumin and other factors in this association. To the best of our knowledge, this is the first prospective study analyzing the cardiovascular risk in psoriasis patients based on American general population.

Study design and population

Since 1999, the NHANES survey transitioned into a continuous program, with findings released biennially. To gather information on prevalence and severity of psoriasis, the present work used data from four cycles (2003-2006, 2011-2014), encompassing 40,228 general participants(17,18). The NHANES study protocol was approved by the NCHS research ethics review board, with all included participants providing written informed consent at enrollment.

The National Death Index documented the vital status of corresponding participants from the NHANES survey. The follow-up period for each study participant spanned from the NHANES baseline interview to either the participant’s death or the final date of follow-up (December 31, 2019). The cause of death was defined by ICD-10 codes.

This study was designed to explore the association between psoriasis and CVD. Considering the small number of participants with psoriasis, relatively lenient exclusion criteria were applied: participants younger than 20 years old (n = 18,089); missing data for psoriasis status (n = 1,928); missing data for psoriasis area (n = 6); missing data for mortality follow-up (n = 44); and pregnant participants (n = 420). After applying these criteria, a total of 19,741 participants, including 542 with psoriasis and 19,199 without, were incorporated into the study. The participant selection procedure was further elucidated in a flowchart in Figure 1.

Data collection

In a standard NHANES data collection procedure, demographic data and standardized questionnaires were collected by trained interviewers. Baseline information, including age, sex, race/ethnicity, family poverty income ratio (PIR), employment status, marital status, education, smoking status, drinking status, and medical condition, was self-reported without any leading questions. Subsequently, participants underwent physical examinations in mobile examination units, where anthropometric measurements were taken. Serum specimens were also sampled, stored and detected for biochemical profiles.

Data preprocess

Participants with psoriasis were identified based on a positive response to the question "Ever told had Psoriasis?". The severity of psoriasis was categorized according to the extent of the lesions. Participants with "little or no psoriasis" or "only a few patches" were classified as having mild psoriasis, while those with "scattered patches" or "extensive psoriasis" were considered moderate/severe cases. Likewise, cardiovascular symptoms or diseases were defined by the self-reported health condition questionnaires. In addition, we defined overweight as BMI ≥ 25 kg/m² and obesity as ≥ 30 kg/m², in accordance with the WHO classification(19). Due to sample size limitations, borderline diabetes population was classified as normal rather than a separate category.

In reference to previous studies, we recoded certain variables for the convenience of subsequent analyses. Race was categorized into Mexican, Hispanic, Black, White and others. Education levels were divided into three ordered levels: less than high school, high school or equivalent, more than high school. For marital status, widowed and divorced participants were considered as separated, and living with partner was merged with married. The economic status of participants was evaluated based on the annual family PIR, partitioned at 1.3 and 3.5(20). Additionally, we included multiple laboratory data files, using their respective concentration units. For indicators with international standardized unit format, we opted for their standardized format for further analysis

Statistical analyses

Following data collection and cleaning, variables with more than 30% missing values were removed, with the exception of the primary cause of death. Multiple imputation by chained equations was employed to complement missing values, and the interpolated results were validated.

We calculated differences in demographic variables, medical conditions, and biochemistry profiles. The Shapiro-Wilk test was performed on continuous variables to determine their distribution. Variables with a non-normal distribution were described using medians and interquartile ranges, and exact tests were applied for comparisons between participants with and without psoriasis. Categorical variables were reported using counts and percentages and compared using Pearson's Chi-squared tests.

The associations between psoriasis and the prevalence of hypertension, hypercholesterolemia, diabetes, obesity, CHF, CAD, angina pectoris, MI and stroke were evaluated using logistic regression. The risks attributable to psoriasis were presented as odds ratios (ORs) and 95% confidence intervals (CIs). Potential confounders such as age, sex, race, education and smoking status were adjusted during analysis.

In our prospective study, psoriasis patients were stratified into mild and moderate/severe subgroups. All-cause mortality and cause-specific mortality from CVD were calculated using the Kaplan–Meier (KM) method and represented as cumulative hazards. Differences between groups were estimated using the log-rank test. The proportional hazards assumption was tested by calculating Schoenfeld residuals. Cox regression models were fitted based on univariate and multivariate conditions and hazard ratios (HRs) were respectively calculated. Adjusted survival curves were visualized based on the multivariate Cox model, accounting for sex, age, race, education, marital status, family PIR, smoking and drinking status.

Subgroup analyses were conducted using univariate regression to balance potential clinical heterogeneity between participants with moderate/severe psoriasis and those without psoriasis. Subgroup analysis factors included sex, age brackets (<65, ≥65 years old), race, education, marital status, family PIR, drinking, smoking, hypertension, hypercholesterolemia, diabetes and obesity, which are known CVD risk factors. Interaction effects were assessed statistically between psoriasis and the above variables. Interaction effects between psoriasis and these variables were statistically assessed.

Potential causal associations from psoriasis to CVD mortality via serum biochemical indexes were explored using multiple mediation analysis. Using the "mma" package, Mediators and their mediation effects were statistically inferred, adjusting for baseline CVD risk factors(21). The bootstrapping method was employed to estimate effect sizes and 95% CIs.

All analyses were performed using R version 4.2.2. All statistical tests were two-sided, with a pre-set significance threshold of p < 0.05.

Baseline characteristics

From 4 NHANES circles, 21,697 participants aged between 20 and 80 were preliminarily included. After applying the exclusion criteria outlined in the methods section, we retained 19,741 eligible participants (19,199 without psoriasis and 542 with psoriasis) for further investigation. Among those with psoriasis, 428 had mild and 114 had moderate-to-severe manifestations of the disease. The psoriasis cohort was predominantly white (57.9% vs. 41.7%), older (median age: 51 vs. 46 years), more educated (59.8% vs. 54.6% completed more than high school), had a higher BMI (median: 28.55 vs. 27.70), and a larger waist circumference (median: 100.60 vs. 97.00 cm). Notably, we observed a higher prevalence of hypertension (44.1% vs. 34.6%), hypercholesterolemia (44.3% vs. 34.0%), diabetes (16.2% vs. 11.5%), CHF (5.0% vs. 2.9%), CAD (5.4% vs. 3.6%), angina pectoris (4.6% vs. 2.2%) and MI (5.9% vs. 3.5%) among participants with psoriasis (Table 1). When looking at serum biochemical indexes, psoriasis patients presented higher levels of uric acid, urea nitrogen, triglyceride, and lower levels of HDL-cholesterol and albumin, suggesting potential renal dysfunction and lipid metabolism disturbances (Table 2).

Logistic regression analyses

The associations between psoriasis and various cardiovascular symptoms and diseases were evaluated and were displayed in Table 3. Generally, the psoriasis population exhibited greater odds of hypertension (OR = 1.49, 95% CI: 1.25-1.77, p < 0.001), hypercholesterolemia (OR = 1.55, 95% CI: 1.30-1.84, p < 0.001), obesity (OR = 1.21, 95% CI: 1.01-1.44, p = 0.034), CHF (OR = 1.74, 95% CI: 1.15-2.54, p = 0.006), CAD (OR = 1.52, 95% CI: 1.02-2.19, p = 0.031), angina pectoris (OR = 2.17, 95% CI: 1.40-3.21, p < 0.001) and MI (OR = 1.72, 95% CI: 1.17-2.43, p = 0.004). However, adjusted models only supported similar relationships for hypertension (OR = 1.37, 95% CI: 1.13-1.66, p = 0.001), hypercholesterolemia (OR = 1.37, 95% CI: 1.13-1.64, p < 0.001), obesity (OR = 1.28, 95% CI: 1.07-1.53, p = 0.006) and angina pectoris (OR = 1.74, 95% CI: 1.11-2.60, p = 0.011).

Survival analyses

For survival analysis, participants with psoriasis were divided into mild and moderate/severe populations to avoid the potential neutralization effect. KM cumulative hazard curves for all-cause mortality (Figure 2A) and CVD mortality (Figure 2B) were plotted, showing the highest incidence rate of both all-cause and cardiac death in the moderate/severe group. We calculated HRs for psoriasis and its severity, adjusting for sex, age, race, education, marital status, family PIR, smoking and drinking. As indicated in Additional file 1: Table S1, non-stratified psoriasis appeared to have no effect on mortality risk, while moderate/severe psoriasis was significantly associated with higher risks of cardiac death (HR = 2.55, 95% CI: 1.27-5.15, p = 0.009) (Table 4). Based on the Cox models, the adjusted survival curves were depicted in Figure 2B, C.

Subgroup and interaction analyses

We further tested the elevated risk of CVD mortality from moderate/severe psoriasis across subgroups. Except for missing HRs due to the absence of events, results remained stable across subgroups. Consistently, there was no statistical interaction observed between psoriasis and the variables used for grouping (Figure 3).

Mediation effects

According to the above results, serum biochemical indexes that showed discrepancies between participants with and without psoriasis were selected as potential mediators. Mediation analysis revealed that the direct effect of moderate/severe psoriasis on CVD mortality accounted for 81.4% (65.8%-97.1%) of the total effects. The proportion of the indirect effect was 18.6% (2.9%-34.2%), which was primarily driven by albumin (14.7%), uric acid (2.9%), and urea nitrogen (0.5%) (Figure 4).

In our national data-based prospective study, we first evaluated the baseline data discrepancies between the groups with and without psoriasis. A significant positive correlation was noted between psoriasis and BMI, waist circumference, and triglycerides, while serum HDL-cholesterol levels were negatively associated with psoriasis, consistent with previous large-scale population-based studies(8). In the investigation of major metabolic diseases and cardiovascular event comorbidities, psoriasis demonstrated a positive correlation with hypertension, hypercholesterolemia, and obesity after adjusting for baseline status. Among the common cardiovascular risks, only angina pectoris (OR = 1.74, 95% CI: 1.11-2.60) exhibited a positive correlation with psoriasis. This finding aligns with a Rotterdam population-based study indicating no relationship between psoriasis and CAD, CHF, and stroke(22), but conflicts with the latest meta-analysis results derived from European and East Asian populations that suggested a significant association between psoriasis and higher CAD and MI event risk(23). Interestingly, several cardiovascular events, including CHF (OR = 1.74, 95% CI: 1.15-2.54), CAD (OR = 1.52, 95% CI: 1.02-2.19), angina pectoris (OR = 2.17, 95% CI: 1.40-3.21) and MI (OR = 1.72, 95% CI: 1.17-2.43), were positively correlated with psoriasis prior to OR adjustment. We speculate that these discrepancies may be attributed to several reasons: our psoriasis patient group sample size might not have been large enough to resist the influence of confounding factors during the analysis; the proportion of hospitalized patients in the studies included in the meta-analysis might have been higher, while our study and other population-based studies included fewer psoriasis patients, with a higher proportion of mild cases, leading to an unclear correlation after adjustment. This is supported by several studies distinguishing between mild and moderate-to-severe psoriasis, where moderate-to-severe psoriasis demonstrated a significantly stronger correlation with various major CVDs in comparison to mild psoriasis(24,25).

Subsequently, to our knowledge, we conducted the first prospective study on cardiovascular event risk stratified by psoriasis severity based on a national database of the general population. Our findings initially highlighted a significant positive correlation between moderate-to-severe psoriasis and cardiovascular event mortality (HR=2.55, 95%CI=1.27~5.15). This result aligns with a meta-analysis that encompassed 31 cohort studies prior to January 2022(13), underscoring the clinical importance of regular monitoring and screening for cardiovascular events in patients with moderate to severe psoriasis. A recent cohort study similar to ours, based on a hospitalized population and using PASI to distinguish the area and severity of psoriasis, drew similar conclusions(26). Another meta-analysis has already indicated that mild psoriasis does not elevate cardiovascular risk(27), consistent with our study results. Moreover, previous research suggested that the CVD risk for patients with severe psoriasis is not significantly amplified in comparison to the overall mortality risk increase(28) , while our group of moderate-to-severe psoriasis patients showed that all-cause mortality was not definitively affected in this group (P=0.064). Our subgroup analysis revealed that all included common epidemiological variables did not interact with the impact of moderate-to-severe psoriasis on CVD risk. This further emphasized the crucial role of cardiovascular events in attributing death in patients with moderate-to-severe psoriasis, reinforcing the notion of psoriasis severity as an independent risk factor for cardiovascular events. To further explore potential mediating factors in the relationship between moderate-to-severe psoriasis and CVD risk, we undertook a mediation analysis. Albumin, accounting for the largest proportion of the mediating effect in our study (14.7% of the total 18.6%), has received comparatively less attention in relation to psoriasis in past research. In cardiovascular diseases, albumin is considered a negative acute-phase reactant, potentially reflecting changes in vascular permeability under inflammatory conditions(29). We hypothesize that the systemic inflammatory state induced by psoriasis may partially account for such mediating effects. Additionally, blood urea nitrogen and uric acid may be associated with increased cardiovascular risk in psoriasis patients suffering from chronic kidney disease and hyperuricemia, respectively. This notion is supported by existing research evidence(30,31).

Numerous studies have delved into the mechanisms underlying cardiovascular events in psoriasis, potentially elucidating the results observed in our research. Several lipid metabolism markers, including serum total cholesterol and triglycerides, especially HDL-cholesterol, have been found to be significantly associated with cardiovascular risk in psoriasis patients in a targeted metabolomics study(32). A recent study discussed the relationship between impaired cholesterol efflux capacity (CEC) and CVD in psoriasis. Lower CEC was associated with more severe psoriasis and poorer vascular health, and was manifested by an increased proportion of low concentration, smaller volume HDL and LDL(33). This aligns with another recent study on non-calcified coronary burden (NCB) in psoriasis patients(34). A cohort study employing the random forest algorithm to identify the top 10 major predictors of NCB in psoriasis patients found congruence with our research findings, specifically in relation to BMI, total obesity, and HDL(35). This underscores the vital role of obesity, dyslipidemia, and other pro-inflammatory metabolic syndromes in major cardiovascular events, particularly coronary syndromes, in psoriasis patients.

The impact of psoriasis on the risk of chronic heart failure (CHF) has been noted in a previous national study and was also found to be positively correlated with the severity of psoriasis(36). However, left ventricular remodeling and a decrease in ejection fraction have only been discovered in studies on psoriatic arthritis(37). Packer and colleagues have summarized the inflammatory metabolic heart failure with preserved ejection fraction potentially caused by systemic inflammation such as psoriasis, suggesting that the related mechanisms may be akin to the pro-inflammatory metabolic syndrome that may predominate in coronary syndrome events(38).

Interleukin-17 (IL-17), Interleukin-23 (IL-23), and the type I inflammation they mediate are widely recognized as pivotal drivers of the systemic inflammatory response in psoriasis(1,4). Some researchers propose that IL-17A may serve as a critical link between psoriasis and atherosclerosis, given its consistent overexpression in both psoriatic lesions and atherosclerotic plaques(39), inducing systemic vasculitis, endothelial dysfunction, and arterial hypertension(40). New evidence suggests that the currently effective biological agents for psoriasis treatment, including IL-12/IL-17/IL-23/TNF-α inhibitors, may offer some degree of cardiovascular protection(41,42). However, given the potential risk of biologics themselves triggering cardiovascular disease, further high-level evidence research is required to assess this effect..

The advent of transcriptomics analysis and Mendelian studies in recent years has offered new methodologies for elucidating the mechanisms and causal relationships in some comorbidities observed in epidemiology. Current evidence from two Mendelian studies based on European and East Asian populations suggests that psoriasis and several major CVDs may share a common genetic origin, and targeted treatment for psoriasis could potentially improve cardiovascular outcomes(43,44). A whole-blood transcriptomics study identified that 40% of differentially expressed genes related to the severity of psoriasis are associated with future cardiovascular events, and pinpointed key regulatory transcription factors for psoriasis and CVD. The affected pathways include JAK-STAT, NF-κB, and IL-6. All of these processes are upregulated in psoriasis and play roles in the progression of atherosclerosis, suggesting their potential use in predicting future adverse cardiovascular events in patients with psoriasis(45).

Our study possesses several strengths. Firstly, our analyses were conducted on representative samples from the general U.S. population, allowing our estimates of the cardiovascular effects of psoriasis to be supported by real-world evidence. Secondly, our survival analyses, particularly in the dimension of CVD mortality, underscored the importance of stratifying psoriasis. Studies on psoriasis should strive to avoid the neutralization effect that can arise from the inclusion of an excessive number of mild cases. Thirdly, the stratification used in our study was based on the range of the lesion, thereby suggesting the possibility of a user-friendly method for assessing cardiovascular risk among psoriasis patients. Lastly, the comprehensive NHANES database and mediation analysis fostered a convergence of epidemiology and biochemistry. The potential mediators we identified might provide novel insights into the strategies for cardiovascular intervention in psoriasis patients.

Nonetheless, our study still has some limitations. Owing to the relatively low prevalence of psoriasis and the limited scale of our research, our estimates of the cardiovascular risk from psoriasis were not sufficiently precis. Concurrently, the paucity of events in stratified populations necessitated a conservative interpretation of results. For the same reason, we did not exclude certain participants with malignant diseases, potentially introducing latent confounding. In addition, the diagnoses of psoriasis and CVDs were acquired from self-reports, which might lead to reporting bias due to varying education and self-awareness. Regrettably, some meaningful indicators, such as LDL, were omitted during data cleaning due to a high proportion of missing values. Lastly, the NHANES is a cross-sectional survey, meaning it lacks chronological information on disease incidence and progression. Consequently, the majority of results in this study were inferred on the basis of statistics rather than causality, necessitating validation by subsequent studies.

In our large-scale, prospective study, we found significant correlations between psoriasis severity and cardiovascular risk factors. Our data suggested that obesity, hypertension, and hypercholesterolemia were positively associated with psoriasis. Despite adjusting for various factors, only angina pectoris remained significantly correlated with psoriasis among cardiovascular events. Intriguingly, severe psoriasis showed a strong positive correlation with the mortality rate of cardiovascular events. We identified albumin, blood urea nitrogen, and uric acid as potential mediators in the relationship between severe psoriasis and cardiovascular disease risk. These findings underscore the importance of monitoring and screening for cardiovascular events in patients with severe psoriasis and suggest psoriasis severity as an independent risk factor for these events.

CVD: Cardiovascular disease

CAD: Coronary artery disease

MI: Myocardial infarction

CHF: Chronic heart failure

NHANES: National Health and Nutrition Examination Survey

NCHS: National Center for Health Statistics

CDC: Centers for Disease Control and Prevention

OR: odds ratio

CI: confidence intervals

KM: Kaplan-Meier

HR: Hazard ratios.

Ethics approval and consent to participate

The protocols of the NHANES were approved by the NCHS Ethics Review Board. NCHS IRB/ERC Protocol numbers: 98-12, 2005-06, 2011-17. Written informed consent was obtained from individual or guardian participants.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and analyzed in the current study are available at NHANES website: https://www.cdc.gov/nchs/nhanes/index.htm.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported in part by grants from Investigation into the Molecular Mechanisms Underpinning Lymphocytic Scarring Alopecia with Inflammatory Fibrosis, HBBJ-012.

Author Contributions

S.C, Y.G and Y.G conceived the study design and are responsible for the overall content. Q.C and J.K analyzed and interpreted the data. L.W and D.W wrote the manuscript. Z.J and X.D edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank the participants of the NHANES databases.

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Table1. Baseline characteristics of study population

	Overall, N=19741	No psoriasis, N=19199	Psoriasis, N=542	P-value
	Overall, N=19741	No psoriasis, N=19199	Psoriasis, N=542	P-value
Female (%)	10024 (50.8)	9733 (50.7)	291 (53.7)	0.183
Age (year)	47.00 [33.00, 61.00]	46.00 [33.00, 61.00]	51.00 [37.00, 63.00]	<0.001
Race (%)				<0.001
Mexican	2594 (13.1)	2557 (13.3)	37 (6.8)
Hispanic	1677 (8.5)	1632 (8.5)	45 (8.3)
White	8317 (42.1)	8003 (41.7)	314 (57.9)
Black	4419 (22.4)	4348 (22.6)	71 (13.1)
Others	2734 (13.8)	2659 (13.8)	75 (13.8)
Education (%)				0.047
Less Than High School	4452 (22.6)	4348 (22.6)	104 (19.2)
High School or Equivalent	4487 (22.7)	4373 (22.8)	114 (21.0)
More Than High School	10802 (54.7)	10478 (54.6)	324 (59.8)
Marital Status (%)
Married	11448 (58.0)	11129 (58.0)	319 (58.9)	0.070
Separated	4206 (21.3)	4076 (21.2)	130 (24.0)
Never married	4087 (20.7)	3994 (20.8)	93 (17.2)
Family PIR (%)				0.137
<1.3	6762 (34.3)	6562 (34.2)	200 (36.9)
1.3-3.5	6791 (34.4)	6626 (34.5)	165 (30.4)
>3.5	6188 (31.3)	6011 (31.3)	177 (32.7)
Body mass index (kg/m2)	27.70 [24.00, 32.30]	27.70 [24.00, 32.30]	28.55 [25.50, 34.27]	<0.001
Waist Circumference (cm)	97.00 [86.80, 108.20]	97.00 [86.70, 108.15]	100.60 [89.40, 110.80]	<0.001
SBP (mmHg)	120.00 [110.00, 132.00]	120.00 [110.00, 132.00]	122.00 [112.00, 134.00]	0.140
DBP (mmHg)	72.00 [64.00, 78.00]	72.00 [64.00, 78.00]	72.00 [64.00, 78.00]	0.009
Pulse (n)	72.00 [64.00, 80.00]	72.00 [64.00, 80.00]	72.00 [64.00, 80.00]	0.195
Irregular pulse rhythm (%)	424 (2.1)	409 (2.1)	15 (2.8)	0.390
Alcohol (%)	5547/14194 (28.1)	5404/13795 (28.1)	143/399 (26.4)	0.394
Smoke (%)	8736 (44.3)	8452 (44.0)	284 (52.4)	<0.001
Hypertension (%)	6891 (34.9)	6652 (34.6)	239 (44.1)	<0.001
Hypercholesterolemia (%)	6760 (34.2)	6520 (34.0)	240 (44.3)	<0.001
Diabetes (%)	2304 (11.7)	2216 (11.5)	88 (16.2)	<0.001
CHF (%)	588 (3.0)	561 (2.9)	27 (5.0)	0.008
CAD (%)	716 (3.6)	687 (3.6)	29 (5.4)	0.039
Angina (%)	444 (2.2)	419 (2.2)	25 (4.6)	<0.001
MI (%)	709 (3.6)	677 (3.5)	32 (5.9)	0.005
Stroke (%)	669 (3.4)	643 (3.3)	26 (4.8)	0.086

Continues variables are presented as the median and interquartile range, category variables are presented as count and proportion.

SBP, systolic blood pressure; DBP, Diastolic blood pressure; CAD, coronary artery disease; MI, myocardial infarction; CHF, congestive heart failure; PIR, poverty income ratio.

Table 2 Baseline biochemistry profile of study population

	Overall, N=19741	No psoriasis, N=19199	Psoriasis, N=542	P-value
Glycohemoglobin (%)	5.50 [5.20, 5.80]	5.50 [5.20, 5.80]	5.50 [5.20, 5.90]	0.025
Total Cholesterol (mmol/L)	4.86 [4.22, 5.59]	4.86 [4.22, 5.59]	4.91 [4.32, 5.66]	0.064
Direct HDL-Cholesterol (mg/dL)	1.29 [1.09, 1.58]	1.29 [1.09, 1.58]	1.24 [1.03, 1.50]	0.008
ALT (U/L)	20.00 [16.00, 28.00]	20.00 [16.00, 28.00]	21.00 [16.00, 28.75]	0.803
AST (U/L)	23.00 [19.00, 27.00]	23.00 [19.00, 27.00]	23.00 [20.00, 28.00]	0.094
ALP (IU/L)	64.00 [52.00, 77.00]	64.00 [52.00, 77.00]	65.00 [53.00, 81.00]	0.066
GGT (U/L)	19.00 [14.00, 29.00]	19.00 [14.00, 29.00]	19.00 [14.00, 30.75]	0.586
Albumin (g/L)	43.00 [40.00, 45.00]	43.00 [40.00, 45.00]	42.00 [40.00, 44.00]	<0.001
Globulin (g/L)	28.00 [26.00, 31.00]	28.00 [26.00, 31.00]	29.00 [25.00, 32.00]	0.988
Total Bilirubin (umol/L)	10.26 [8.55, 13.68]	10.26 [8.55, 13.68]	10.26 [8.55, 13.68]	0.906
LDH (IU/L)	123.00 [109.00, 140.00]	123.00 [109.00, 140.00]	123.00 [109.00, 142.00]	0.8
Creatinine (umol/L)	76.02 [63.65, 89.28]	76.02 [63.65, 89.28]	76.02 [64.53, 88.40]	0.817
Uric acid (umol/L)	315.20 [261.70, 374.70]	315.20 [261.70, 374.70]	321.20 [273.60, 380.70]	0.045
BUN (mmol/L)	4.28 [3.21, 5.71]	4.28 [3.21, 5.71]	4.64 [3.57, 5.71]	0.005
Glucose (mmol/L)	5.16 [4.72, 5.77]	5.16 [4.72, 5.77]	5.16 [4.77, 5.83]	0.254
Cholesterol (mmol/L)	4.89 [4.22, 5.61]	4.89 [4.22, 5.61]	4.94 [4.29, 5.72]	0.094
Triglycerides (mmol/L)	1.31 [0.87, 2.03]	1.30 [0.87, 2.03]	1.40 [0.94, 2.07]	0.023
Total Protein (g/L)	71.00 [68.00, 74.00]	71.00 [68.00, 75.00]	71.00 [67.00, 74.00]	0.001
Sodium (mmol/L)	139.00 [138.00, 141.00]	139.00 [138.00, 141.00]	139.00 [138.00, 141.00]	0.745
Potassium (mmol/L)	4.00 [3.80, 4.20]	4.00 [3.80, 4.20]	4.00 [3.80, 4.20]	0.403
Total Calcium (mmol/L)	2.35 [2.30, 2.42]	2.35 [2.30, 2.42]	2.35 [2.30, 2.40]	0.278
Iron (umol/L)	14.30 [10.60, 18.60]	14.30 [10.60, 18.60]	14.00 [10.60, 17.90]	0.132
Phosphorus (mmol/L)	1.23 [1.10, 1.36]	1.23 [1.10, 1.36]	1.23 [1.10, 1.36]	0.244
Chloride (mmol/L)	104.00 [102.00, 106.00]	104.00 [102.00, 106.00]	104.00 [102.00, 105.75]	0.002
Bicarbonate (mmol/L)	25.00 [24.00, 27.00]	25.00 [24.00, 27.00]	25.00 [24.00, 27.00]	0.474
Osmolality (mmol/Kg)	279.00 [276.00, 282.00]	279.00 [276.00, 282.00]	279.00 [276.00, 282.00]	0.025

Continues variables are presented as the median and interquartile range.

HDL, high-density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen.

Table 3. ORs (95% CIs) for cardiovascular symptoms and disease among participants with psoriasis

	NHANES (N= 19741)
	No Psoriasis (n = 19199)	Psoriasis (n = 542)
	No Psoriasis (n = 19199)	Cases	Crude OR (95%Cl)	P-value	*Adjusted OR(95% CI)**	P-value
Hypertension	6652 (34.6)	239 (44.1)	1.49(1.25~1.77)	<0.001	1.37(1.13~1.66)	0.001
Hypercholesterolemia	6520 (34.0)	240 (44.3)	1.55(1.30~1.84)	<0.001	1.37(1.13~1.64)	< 0.001
Diabetes	2216 (11.5)	88 (16.2)	1.55(0.95~2.39)	0.058	1.45(0.89~2.24)	0.111
Obesity	7007 (36.5)	222 (41.0)	1.21 (1.01~1.44)	0.034	1.28 (1.07~1.53)	0.006
CHF	561 (2.9)	27 (5.0)	1.74(1.15~2.54)	0.006	1.48(0.96~2.20)	0.061
CAD	687 (3.6)	29 (5.4)	1.52(1.02~2.19)	0.031	1.19(0.78~1.75)	0.396
Angina	419 (2.2)	25 (4.6)	2.17(1.40~3.21)	<0.001	1.74(1.11~2.60)	0.011
MI	677 (3.5)	32 (5.9)	1.72(1.17~2.43)	0.004	1.37(0.92~1.98)	0.106
Stroke	643 (3.3)	26 (4.8)	1.45(0.95~2.13)	0.068	1.20(0.78~1.79)	0.386

Adjusted for age, sex (female, male), race (White, Asian, African, mixed background, unknown), education (less than high school, high school or equivalent, more than high school) and smoking status (no, yes).

CAD, coronary artery disease; MI, myocardial infarction; CHF, congestive heart failure.

Table 4. HRs (95% CIs) for all-cause and CVD mortality among participants with mild and moderate/severe psoriasis

Variables	All-cause Mortality		CVD Mortality
Variables	HR (95%Cl)	P-value	HR (95%Cl)	P-value
Psoriasis
No	ref		ref
Mild	0.92(0.69~1.23)	0.574	0.61(0.30~1.24)	0.171
Moderate/Severe	1.55(0.98~2.48)	0.064	2.55(1.27~5.15)	0.009
Female	0.67(0.60~0.74)	< 0.001	0.64(0.53~0.79)	< 0.001
Age	1.09(1.08~1.09)	< 0.001	1.10(1.09~1.11)	< 0.001
Race
Mexican	ref	ref
Hispanic	0.85(0.65~1.11)	0.226	0.51(0.29~0.90)	0.021
White	1.66(1.38~2.01)	< 0.001	1.54(1.10~2.17)	0.013
Black	1.41(1.16~1.71)	< 0.001	1.32(0.92~1.88)	0.131
Others	0.95(0.74~1.22)	0.679	0.67(0.41~1.11)	0.119
Education
Less Than High School	ref		ref
High School or Equivalent	0.95(0.83~1.08)	0.390	0.77(0.60~0.98)	0.034
More Than High School	0.84(0.75~0.95)	0.007	0.65(0.52~0.82)	< 0.001
Marital Status
Married	ref		ref
Separated	1.49(1.34~1.66)	< 0.001	1.76(1.43~2.16)	< 0.001
Never married	1.80(1.53~2.12)	< 0.001	2.04(1.49~2.80)	< 0.001
Family PIR
<1.3	ref		ref
1.3-3.5	0.75(0.67~0.84)	< 0.001	0.83(0.67~1.02)	0.073
>3.5	0.54(0.47~0.63)	< 0.001	0.57(0.43~0.74)	< 0.001
Alcohol	0.82(0.73~0.91)	< 0.001	0.88(0.71~1.08)	0.217
Smoke	1.51(1.36~1.68)	< 0.001	1.11(0.91~1.35)	0.288

PIR, poverty income ratio.

Additionalfile1TableS1.xls
Additional files Additional file 1:Table S1. Hazard ratios for all-cause mortality and CVD mortality among participants with or without psoriasis.

Prospective evaluation of cardiovascular risk and mortality in patients with psoriasis: A population-base study

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Abstract

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Background

Methods

Results

Discussion

Conclusions

Abbreviations

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