To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome.
To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome.
Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined.
A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08–2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78–5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001).
PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients.
Cardiovascular disease (CVD) represents a major cause of morbidity and mortality in patients with psoriatic diseases ([1, 2]). By the time clinical symptoms of CVD appear in these patients, atherosclerosis already may be in advanced stages. Using carotid intima-media thickness (CIMT) as a measure of early atherosclerotic changes and possible progression of atherosclerosis (), several cohort studies have shown abnormal CIMT measurements in patients diagnosed with psoriatic arthritis (PsA) and psoriasis, as compared to healthy controls ([4-6]).
Metabolic syndrome is a cluster of several known CV risk factors, including insulin resistance, obesity, atherogenic dyslipidemia, and hypertension (). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) definition is the most widely used criteria currently. There is a paucity of good data regarding the association of metabolic syndrome and rheumatic disease, particularly in PsA.
Psoriatic diseases may be associated with obesity, hypertension, dyslipidemia, and insulin resistance because of the shared inflammatory pathway. Furthermore, the severity of psoriatic disease is associated with an increased prevalence of obesity and risk factors for CVD. Although the prevalence of obesity and the metabolic syndrome is known to be increased in psoriasis and has been well documented (), there have been limited studies evaluating the association of metabolic syndrome with PsA versus psoriasis. The death rate of PsA has increased (standardized mortality ratio 1.3), with the majority due to CVDs compared with the general population ([9, 10]). However, the relationship of obesity and metabolic syndrome remains complex and is not well characterized in patients with PsA compared to psoriasis.
Incremental increases in inflammation in patients with PsA may contribute to a higher CV risk and the risk for metabolic syndrome as compared to psoriasis alone (). This potentially could be explained by an increase in inflammatory cells and cytokines, including tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), which are associated with central obesity, insulin resistance, hypertension, and dyslipidemia, leading to more endothelial dysfunction and subclinical atherosclerosis (). This suggests there is a close tie between the metabolic and immune systems. This study aimed to determine if metabolic syndrome with inflammatory arthritis is associated with increased CIMT among patients with psoriatic diseases.
We conducted a cross-sectional investigation comparing patients with psoriasis and PsA recruited for the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study. Patients were included if they were ages ≥18 years and able to provide consent for the study.
PsA patients were enrolled from 2 tertiary referral centers in Cleveland, Ohio (Cleveland Clinic [CC] and University Hospitals Case Medical Center [UHCMC], Murdough Family Center for Psoriasis and Department of Dermatology). PsA was diagnosed after satisfying the criteria of the Classification of Psoriatic Arthritis Study Group with confirmation by a board-certified rheumatologist. All patients were managed by their clinical rheumatologist for the duration of the study. Other forms of inflammatory arthritides were excluded. CC and UHCMC are tertiary hospitals that serve as the main referral centers for Ohio and the surrounding states.
Patients with psoriasis were diagnosed or received confirmation of diagnosis by a board-certified dermatologist. Patient symptoms of joint pain, history of joint involvement, or previous diagnosis of PsA were evaluated by a board-certified rheumatologist and enrolled in the PsA group. The Institutional Review Boards of CC and UHCMC approved this study. All subjects provided written informed consent prior to participation.
Metabolic syndrome was defined using the NCEP ATP III criteria, as affirmed and slightly modified by the American Heart Association and the National Heart, Lung, and Blood Institute (). The definition of metabolic syndrome requires any 3 of the following 5 criteria: increased waist circumference (≥102 cm in non-Asian men, ≥88 cm in non-Asian women, ≥90 cm in Asian men, and ≥80 cm in Asian women), elevated triglycerides (≥150 mg/dl or treatment with fibrates or nicotinic acid), reduced high-density lipoprotein (HDL) cholesterol (<40 mg/dl in men and <50 mg/dl in women or treatment with fibrates or nicotinic acid), elevated blood pressure (≥130 mm Hg systolic and ≥85 mm Hg diastolic or treatment for hypertension), or elevated fasting glucose (≥100 mg/dl or treatment for elevated glucose).
Demographics, medical history, traditional CV risk factors, and psoriatic disease history were collected using a standardized protocol. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at CC. REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry, 2) audit trails for tracking data manipulation and export procedures, 3) automated export procedures for seamless data downloads to common statistical packages, and 4) procedures for importing data from external sources.
Pertinent clinical information included demographic features; duration of disease (since onset of either/both PsA or psoriasis); family history of CVD, smoking status, diabetes mellitus (fasting glucose of ≥126 mg/dl, on a diabetes mellitus diet, taking hypoglycemic agents, or receiving insulin), hypertension (systolic blood pressure ≥140 mm Hg and diastolic blood pressure ≥90 mm Hg or use of antihypertensive agents), and hyperlipidemia (low-density lipoprotein [LDL] cholesterol ≥140 mg/dl or taking a lipid-lowering agent); and history of steroid and disease-modifying antirheumatic drug (DMARD) intake.
Physical examinations were performed to obtain height, weight, blood pressure (measured on both arms after being seated for at least 5 minutes and then averaged), hip and waist circumference, Schober test, joint count examinations (for PsA patients), and body surface area. Diagnostic studies included carotid duplex ultrasonography to obtain CIMT measurements and to document the presence of plaque. A fasting venous blood sample was obtained for C-reactive protein (CRP) level, total cholesterol, HDL cholesterol, triglycerides, LDL cholesterol, blood glucose, blood urea nitrogen, and creatinine, which were all quantified by the CC and UHCMC clinical laboratories. Rheumatoid factor and anti–cyclic citrullinated peptide antibodies were also obtained for PsA patients.
A subgroup of patients from both the PsA and psoriasis groups who consented were enrolled for carotid duplex ultrasound imaging. A standardized protocol was performed by 2 registered vascular sonographers who had been specifically trained in CIMT imaging. All imaging was obtained using the Philips iU22 ultrasound system using an 8–4 MHz linear transducer. A circumferential plaque screen was performed using both transverse and longitudinal views of the bilateral carotid arteries. Images of the right and left common carotid arteries were obtained at 3 distinct angles of insonation using Meijer's Arc and obtained in triplicate at each angle during the R wave of the electrocardiogram. Plaque was defined as a focal wall thickening ≥50% greater than the adjacent vessel wall or a focal protruding wall thickening at least 1.5 mm in CIMT. Images were stored digitally and transferred to a secure server for analysis by trained core laboratory readers.
The 10-mm segment of the far wall of the distal common carotid arteries was measured to determine the CIMT bilaterally using a semiautomated border detection program (Carotid Analyzer, Medical Imaging Applications). The mean–mean of the 9 CIMT measurements for each side were recorded and the thicker value for the 2 sides was recorded as the overall CIMT for the study participant. Vascular sonographers and CIMT analysts and readers were formally trained in CIMT imaging as described by the American Society of Echocardiography consensus statement ().
All continuous data are summarized as the mean ± SD for normally distributed data; the median and 25th and 75th percentiles (Q1, Q3) were used for non–normally distributed data. Categorical data are shown as the percentage of nonmissing data. Comparisons between PsA and psoriasis were performed using Student's t-test for normally distributed continuous data (Wilcoxon's rank sum test for non–normally distributed data) and chi-square tests for categorical data. Unadjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to determine the association of PsA and metabolic syndrome using logistic regression methods. A multivariable model was developed to adjust for other factors associated with metabolic syndrome. All baseline demographics and clinical characteristics were considered for adjustment. Variables that were univariately associated with metabolic syndrome (P < 0.20) were used to construct the model. Stepwise selection methods were used for the final model and all variables with a P value less than 0.05 remained in the final model. Interactions were tested using Wald's tests.
CIMT was summarized with medians (Q1, Q3) and comparisons were made using Wilcoxon's rank sum test or the Kruskal-Wallis test. A linear regression model was used to adjust for factors associated with CIMT. Since CIMT was not normally distributed, it was natural log–transformed. Regression coefficients (β) and P values are reported. All analyses were performed using SAS, version 9.2. P values less than 0.05 were considered statistically significant.
There were 343 patients with psoriatic diseases enrolled in the study, and the baseline clinical characteristics are summarized in Table 1. There was a significant difference in age distribution, with PsA patients being older compared to psoriasis patients (mean age 50.4 years versus 45.7 years; P = 0.002). As expected, PsA patients had a longer disease duration (P = 0.001) as compared to psoriasis patients. In addition, PsA patients also had a higher body mass index (BMI) compared to psoriasis patients (mean 31.8 kg/m2 versus 29.5 kg/m2; P = 0.010). PsA patients also had a significantly higher prevalence of elevated blood pressure and elevated CRP levels compared with psoriasis patients. PsA patients had significantly more CV procedures done (P = 0.045) as well as increased use of nonsteroidal antiinflammatory drugs and steroids (P < 0.001). There were no significant differences in prior CV events, family history of CV risk, and Framingham/ATP III Risk Score (P = 0.596) in both groups (Table 1).
|Psoriasis (n = 145)||PsA (n = 198)||P|
|Age, mean ± SD years||45.7 ± 15.28||50.4 ± 11.76||0.002|
|Men||73 (50.3)||101 (51.0)||0.90|
|Disease duration, mean ± SD years||15.5 ± 13.23||21.1 ± 14.87||0.001|
|BMI, mean ± SD kg/m2||29.5 ± 6.93||31.8 ± 7.89||0.01|
|Waist circumference, mean ± SD cm||98.5 ± 16.55||104.6 ± 17.93||0.006|
|Hip measurement, mean ± SD cm||106.2 ± 13.50||111.7 ± 15.05||0.001|
|Smoker||99 (68.3)||61 (32.4)||< 0.001|
|Alcohol use||135 (93.1)||145 (77.1)||< 0.001|
|Family history of CV risk||108 (74.5)||28 (63.6)||0.16|
|Diabetes mellitus||14 (18.2)||33 (17.6)||0.63|
|Systolic BP, mean ± SD mm Hg||127.4 ± 17.06||131.5 ± 14.79||0.03|
|Diastolic BP, mean ± SD mm Hg||79.8 ± 9.95||82.2 ± 10.27||0.04|
|CRP, median (Q1, Q3) mg/dl||0.2 (0.1, 0.9)||0.2 (0.1, 0.6)||0.001a|
|DMARDs ever used||45 (31)||160 (81)||0.001|
|Metabolic syndrome||35 (28.9)||66 (42)||0.024|
|Large waist circumference||66 (45.5)||122 (61.6)||0.003|
|Triglycerides ≥150 mg/dl||33 (27.3)||52 (36.4)||0.12|
|Low HDL cholesterol||43 (35.8)||53 (37.1)||0.84|
|High BP/hypertension||53 (36.6)||108 (54.5)||0.001|
|Hyperglycemia||23 (19.2)||42 (23.2)||0.41|
|Framingham/ATP III Risk Score, mean ± SD||9.7 ± 6.91||10.6 ± 5.63||0.6|
PsA patients had a significantly larger waist circumference (P = 0.003) and higher blood pressure (P = 0.001). Psoriatic disease patients with inflammatory arthritis were closely associated with a higher risk of metabolic syndrome (univariate OR 1.78 [95% CI 1.08–2.95], P = 0.025). Because of the potential effect of nonbiologic or biologic DMARDs on CV profiles (), an interaction between the patient groups and DMARD use was assessed and was found to be significant (unadjusted P = 0.038). After adjustment for age, natural log–transformation of CRP level, and diastolic blood pressure, the interaction between the patient groups and DMARD use remained statistically significant (P = 0.049). For patients taking DMARDs, PsA patients were half as likely to have metabolic syndrome (adjusted OR 0.57 [95% CI 0.25–1.33]). However, for patients not receiving DMARDs, PsA patients were twice as likely to be associated with metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78–5.59]) (Table 2).
|Covariates||Adjusted OR (95% CI)||P|
|No DMARDs (PsA vs. psoriasis)||2.09 (0.78–5.59)||0.049a|
|Taking DMARDs (PsA vs. psoriasis)||0.57 (0.25–1.33)|
|Age (per year)||1.04 (1.01–1.06)||0.002|
|Natural log (CRP)||1.56 (1.25–1.94)||< 0.001|
|Diastolic BP||1.07 (1.03–1.10)||< 0.001|
Imaging was performed in a subgroup of our population (n = 98 with PsA, n = 117 with psoriasis). Patients with PsA had thicker maximum IMT values compared to psoriasis patients (P < 0.001) (Figure 1). Additionally, patients with metabolic syndrome had thicker CIMT values as compared to patients without metabolic syndrome, but the difference was not statistically significant (P = 0.099; no evidence of an interaction). PsA patients with metabolic syndrome had the thickest CIMT values and the highest prevalence of plaque compared to any other group (Table 3). After adjustment for factors that were statistically different between the PsA and psoriasis groups (age, sex, metabolic syndrome, weight, diabetes mellitus, and natural log of CRP level), PsA patients had a significantly higher maximum CIMT than psoriasis patients (β = 0.077, P = 0.02).
|Psoriasis patients||PsA patients||P|
|No metabolic syndrome (n = 83)||Metabolic syndrome (n = 34)||No metabolic syndrome (n = 55)||Metabolic syndrome (n = 43)|
|Maximum IMT, median (Q1, Q3)||0.88 (0.75, 1.06)||1.05 (0.9, 1.19)||0.98 (0.88, 1.25)||1.13 (0.92, 1.31)||< 0.001|
|Plaque, no. (%)||28 (33.7)||12 (35.3)||13 (23.6)||22 (51.2)||0.43|
Our study demonstrated that patients with PsA have an increased prevalence of metabolic syndrome and significantly higher CIMT values compared to patients with psoriasis alone. Metabolic syndrome as a cluster of CVD risk factors is associated with increased CIMT among both PsA and psoriasis patients. More importantly, we found that PsA in the presence of metabolic syndrome had the highest overall maximum CIMT and prevalence of carotid plaques compared to other groups of PsA and psoriasis patients. These observations support our hypothesis that an incremental increase in inflammatory pathways in PsA may contribute to an even higher CV risk and metabolic syndrome as compared to psoriasis alone.
Psoriasis and PsA are both considered to be chronic T cell–mediated inflammatory diseases that carry unfavorable CV comorbidities (). More evidence has been accumulating regarding the vital role of chronic inflammation in the development of obesity, dyslipidemia, and other metabolic disturbances. Increases in inflammatory cells and cytokines, including TNFα and IL-6, which are associated with central obesity, insulin resistance, hypertension, and dyslipidemia, can lead to more endothelial dysfunction and subclinical atherosclerosis ().
Patients with PsA have substantially increased risks for ischemic heart disease, cerebral vascular disease, type 2 diabetes mellitus, hyperlipidemia, and hypertension ([2, 11, 17, 18]). Our study also reveals that PsA is associated with a higher prevalence of traditional CV risk factors, including hypertension, obesity, and metabolic syndrome, compared with psoriasis. This supports the findings of Husted et al, who reported that PsA patients have a higher risk for developing cardiometabolic complications than the general population and patients with psoriasis alone (). However, this association may not fully explain the CV risks related to the condition. Recent studies have found that 30–50% of PsA patients with atherosclerosis do not have traditional cardiac risk factors, suggesting a possible role for new or unconventional risk factors. These findings provide evidence against the notion that obesity and other CV morbidities are simply an effect of a sedentary lifestyle due to joint pain among PsA patients as compared to psoriasis patients. There may be additional factors that need to be monitored in these patients to better understand the mechanisms underlying accelerated atherosclerosis in PsA patients.
Metabolic syndrome is a cluster of several known CV risk factors, including insulin resistance, obesity, atherogenic dyslipidemia, and hypertension. These conditions are interrelated and share underlying mediators, mechanisms, and pathways. The presence of metabolic syndrome identifies patients who are at a higher risk of developing atherosclerotic CVD and type 2 diabetes mellitus (). However, the major use of metabolic syndrome is not primarily to identify patients at general risk of CVD and type 2 diabetes mellitus, but rather, it identifies a specific subgroup of patients with a shared disease pathophysiology. Metabolic syndrome ties together insulin resistance, visceral adiposity, dyslipidemia, and hypertension, and has been strongly associated with CV morbidity separate from traditional Framingham risk factors among patients with psoriatic diseases. Incremental increases in inflammatory pathways in PsA may contribute to an even higher CV risk and metabolic syndrome as compared to psoriasis alone. A recent Canadian study found that patients with PsA were found to have an increased prevalence of metabolic syndrome and adipokine level as compared to patients with psoriasis (). Our results demonstrate similar findings that PsA has a higher prevalence of metabolic syndrome as compared to psoriasis, particularly when not receiving any DMARD treatment; however, the prevalence was the same among patients taking DMARDs. These new findings could support the role of an increased inflammatory response in PsA compared to psoriasis. This potentially can be an important mechanism to consider that may lead to increased CV morbidity. Furthermore, this association may help to explain the higher CRP values and correlates of more serious Framingham scores in the PsA cohort compared to the psoriasis cohort.
CIMT has been used as a surrogate marker and measurement of early atherosclerotic changes with the capability of determining anatomic extent and progression of atherosclerosis ([3, 22]). The absolute value and progression in thickness of CIMT have been shown to predict the risk for coronary events (). Using the CIMT measurement, Kimhi et al and Gonzalez-Juanatey et al have shown a significant prevalence of subclinical atherosclerosis in PsA patients compared to matched healthy controls ([5, 18]). Our study demonstrated that CIMT values are higher in PsA patients as compared to psoriasis patients (even after adjusting for age, sex, metabolic syndrome, weight, diabetes mellitus, and natural log of CRP). This was further supported by a recent cross-sectional study that found PsA patients had more subclinical atherosclerosis with increased total plaque area as compared to patients with psoriasis alone. Interestingly, the CIMT from both groups was not statistically different (). This could be explained by the fact that our PsA patients were significantly older than our psoriasis patients. Our cohort also had higher BMI, more instances of diabetes mellitus and smoking, and more active joint symptoms (with a higher swollen joint count). Although carotid total plaque area progression may be a strong predictor of stroke, death, or myocardial infarction (), there is not a large epidemiologic study showing a strong association of total plaque area and CV risk as compared with CIMT. Nevertheless, these important findings should encourage rheumatologists and dermatologists to adopt a more aggressive approach in early diagnosis and treatment of PsA.
A recent population-based retrospective study found that PsA patients are 1.46-fold more likely to have incidence of vascular disease as compared to psoriasis patients. Although this recent study did not specifically assess the association of metabolic syndrome with subclinical atherosclerosis as in our study, it renders support to our conclusion that incremental increases in inflammatory pathways in patients with PsA may contribute to a higher vascular risk as compared to patients with psoriasis ().
New insights into the relationship between CVD risk and PsA include a strong association with metabolic syndrome, a known significant and independent determinant of increased risk for CVD ([7, 21]). Metabolic syndrome is positively associated with increased CIMT. Other risk factors such as disease activity, disease severity, diabetes mellitus, BMI, background ischemic heart disease, and smoking were not found to be associated with CIMT in PsA patients (). A more relevant clinical question is whether the presence of inflammatory arthritis together with metabolic syndrome increases the risk for accelerated atherosclerosis in PsA patients as measured by increased CIMT. To our knowledge, our study is one of the first to address this question. Our data suggest that PsA patients with metabolic syndrome have the highest overall maximum CIMT compared to other patients with psoriatic disease in the presence or absence of metabolic syndrome. Furthermore, they also have the highest prevalence of carotid plaque. This is likely related in part to the increases in inflammatory cells, cytokines, and adipokines, which can further lead to accelerated endothelial dysfunction and subclinical atherosclerosis.
There are limitations in our study. Since this is a cross-sectional study, the causality of the disease, metabolic syndrome, and atherosclerosis cannot be determined. Due to the inherent distinct pathophysiology of psoriatic diseases, we expected to have differences in patient age, disease duration, and severity. This pathophysiology also explains the varying treatment regimens and duration among patients with psoriasis versus PsA. We controlled for these variables using multivariable analysis.
Patients with PsA have an increased prevalence of metabolic syndrome with significantly higher CIMT compared to patients with psoriasis. Metabolic syndrome is also associated with increased CIMT among PsA and psoriasis patients. More importantly, PsA patients with metabolic syndrome have the highest overall maximum CIMT and prevalence of carotid plaques compared to other patients with psoriatic disease. All of these observations support our hypothesis that incremental increases in inflammatory pathways in PsA may contribute to an even higher CV risk and metabolic syndrome as compared to psoriasis alone. Early diagnosis and treatment of inflammatory arthritis in patients with psoriatic disease is vital because it may improve CV risk profile and morbidity in patients with psoriatic disease.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Husni had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Lin, Dalal, Korman, Husni.
Acquisition of data. Lin, Churton, Korman, Kim, Husni.
Analysis and interpretation of data. Lin, Dalal, Brennan, Kim, Husni.
The authors would like to thank Eva Balazs of the CC Angiographic Core Laboratory and Alia Grattan of the CC Non-Invasive Vascular Laboratory for their expert and timely assistance with this project. The authors also would like to thank Drs. Stephen Nicholls and Kiyoko Uno for their generous help in the initial design of the study concept and their expertise in CV imaging. We thank the contributions of Vaibhav Pawar, Neil Borkar, and Douglas Kast of the UHCMC Murdough Family Center for Psoriasis for collaboration.