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Increased Prevalence of Coronary Artery Disease in Severe Psoriasis and Severe Atopic Dermatitis

      Abstract

      Background

      Psoriasis and atopic dermatitis (AD) are immuno-inflammatory diseases that can result in lifelong systemic inflammation. Unlike AD, psoriasis has been associated with cardiovascular disease. The aim of this study was to examine the prevalence, severity, and subtype of coronary artery disease (CAD) in psoriasis and AD patients without known cardiovascular disease.

      Methods

      Consecutively enrolled patients (psoriasis n = 58, AD n = 31) and retrospectively matched controls (n = 33) were examined using cardiac computed tomography angiography (CCTA) and assessed using an 18-segment model of the coronary tree.

      Results

      The prevalence of a coronary artery calcium score >0 was 29.8% in psoriasis and 45.2% in AD, vs 15.2% in controls (P = .09 and P = .01, respectively). More patients with psoriasis had a coronary artery calcium score ≥100 (psoriasis 19.3%, controls 2.9%; P = .02). CCTA showed the presence of plaques in 38.2% of psoriasis patients and 48.1% of AD patients, vs 21.2% of controls (P = .08 and P = .03, respectively). Psoriasis was associated with an increased prevalence of significant coronary stenosis (stenosis >70%) (psoriasis 14.6%, controls 0%; P = .02) and 3-vessel coronary affection or left main artery disease (psoriasis 20%, controls 3%; P = .02), whereas AD was associated with mild (AD 40.7%, controls 9.1%; P = .005) single-vessel affection.

      Conclusions

      These findings suggest that psoriasis and AD are associated with an increased prevalence of CAD. Patients with psoriasis have an increased prevalence of severe CAD.

      Keywords

      Clinical Significance
      • Severe psoriasis is associated with increased prevalence of coronary artery disease.
      • Psoriasis patients had more proximal lesions and a higher prevalence of significant stenoses, as well as affection of 3 vessels and left main coronary artery disease.
      • Severe atopic dermatitis is associated with increased prevalence of coronary artery disease.
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      Atopic dermatitis is another common, multifactorial Th2-driven inflammatory skin disease with a frequently chronic or chronically relapsing course. The disease usually manifests in infancy, but can occur throughout childhood and adolescence, and, in a subgroup of patients, persist into adulthood.
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      Cardiac computed tomography (CT) is a well-established method for risk assessment and a diagnostic tool in suspected coronary artery disease. The low-radiation-dose noncontrast CT technique enables accurate measurements of the coronary artery calcium score, which is strongly associated with the risk of future cardiovascular events.
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      We aimed to examine the prevalence, severity, and subtype of coronary atherosclerosis as an indicator of cardiovascular risk in psoriasis and atopic dermatitis patients without known cardiovascular disease compared with age- and sex-matched subjects without known inflammatory diseases.

      Patients and Methods

      Study Design

      The clinical study was conducted as a single-center observational case-control study. The Central Denmark Region Committees on Biomedical Research Ethics and the Danish Data Protection Agency approved the study protocol before patient enrollment commenced. All prospectively enrolled participants provided written informed consent before entering the study. The Committee on Research Ethics waived the requirement for informed consent regarding the retrospectively matched control group. This trial was registered with http://ClinicalTrials.gov, identifier NCT01356758.

      Patients

      Participants were consecutively recruited from a tertiary referral clinic at the Department of Dermatology, Aarhus University Hospital. Subjects considered for inclusion were either patients referred for treatment at the clinic or people who responded to a study notification in the member's magazine published by the Danish Psoriasis Association.
      Eligible patients were men and women aged ≥18 years without symptoms of coronary artery disease, diagnosed with either severe psoriasis vulgaris or severe atopic dermatitis. The following criteria of severity were used: severe psoriasis group, severe plaque psoriasis with Psoriasis Area Severity Index (PASI) ≥10; severe atopic dermatitis group, diagnosis according to the criteria of Hanifin and Rajka,
      • Hanifin J.
      • Rajka G.
      Diagnostic features of atopic dermatitis.
      body surface area of inflamed skin ≥10%, and one or more of the following sub-criteria: history of hospital admission for the treatment of atopic dermatitis, current use of potent topical corticosteroids (EU/UK class III-IV), and history or current use of systemic immunosuppressive treatment (prednisone/cyclosporine/methotrexate/azathioprine).
      The exclusion criteria for both groups included: arterial hypertension, unless well controlled with antihypertensive medication for at least 3 months before inclusion (exclusion on blood pressure ≥180/100 mm Hg); lipid-lowering treatment, unless well controlled for at least 3 months before inclusion; plasma total-cholesterol ≥8 mmol/L; congestive heart failure (New York Heart Association group III and IV); reduced kidney function (estimated glomerular filtration rate below 60 mL/min); prior coronary artery intervention or coronary artery bypass grafting; prior myocardial infarction or stroke. For the patients suffering from psoriasis, additional exclusion criteria were: treatment with methotrexate, cyclosporin, acitretin, and fumarate esters within 6 months before inclusion unless less than a PASI-50% reduction had been observed during this treatment; ultraviolet type B phototherapy and psoralen ultraviolet type A photochemotherapy within 1 month before inclusion; prior or current treatment with biologic agents unless the treatment was discontinued due to insufficient efficacy (<PASI-50% reduction); investigational biological agents within 6 months before inclusion; or concurrent immunosuppressive or antiinflammatory treatment for other immune diseases. In the group of patients suffering from atopic dermatitis, patients receiving topical corticosteroids or systemic azathioprine could be included if exhibiting persistent disease activity (affected body surface area >10%) despite treatment. Atopic dermatitis patients receiving other immunosuppressive treatment including methotrexate and experimental drugs within 6 months were excluded.
      All of the patients underwent clinical evaluation (complete medical history and physical examination) and laboratory evaluation. The following information was recorded: demographic characteristics, psoriasis/atopic dermatitis disease duration, severity and current therapy, psoriasis-related arthritis or arthralgia, a medical history of traditional cardiovascular risk factors and therapy including family history of premature coronary artery disease in a first-degree relative, tobacco use, medically treated hypertension, dyslipidemia, and diabetes. Smoking status was regarded as nonsmoker or ever-smoker (current tobacco use or smoked at least 100 cigarettes/approximately 100 grams of tobacco during course of life). Physical examination included height, weight, and blood pressure. For patients suffering from psoriasis PASI, the number of nails with nail psoriasis and the presence of swollen or tender joints were assessed. Body surface area was assessed in patients suffering from atopic dermatitis. Blood tests included glucose, C-reactive protein, serum lipids, electrolytes, and creatinine.
      Controls were retrospectively obtained from a cohort of approximately 9000 patients referred to CCTA at Aarhus University Hospital, for noninvasive assessment of coronary artery disease, during an 8-year period (2006-2014). All investigations were conducted at the same center using the same technique as for the dermatology patients. Asymptomatic patients, patients with atypical clinical symptoms and patients referred for cardiovascular risk assessment were selected, whereas patients with symptoms compatible with coronary artery disease (high a priori risk with symptoms of typical angina) or known cardiovascular disease were excluded. Patients with a diagnosis of psoriasis or other inflammatory diseases also were excluded. Results of the CCTA were blinded from the investigators until the cohort was established. Baseline information about traditional risk factors and demographic data were recorded from the validated database.
      • Nielsen L.H.
      • Nørgaard B.L.
      • Tilsted H.H.
      • et al.
      The western Denmark Cardiac Computed Tomography Registry: a review and validation study.

      CT Procedures

      Subjects underwent noncontrast coronary artery calcium CT and contrast-enhanced CCTA (Figure 1). Electrocardiogram-gated CCTA was conducted during a single breath-hold using a dual-source CT system (SOMATOM Definition; Siemens Medical Solutions, Forchheim, Germany). Electrocardiogram-dependent tube current modulation (Care Dose 4D) was used as the default in all patients, reference, 320 mAs. Tube voltage was set at 100 or 120 kVp. Detector collimation was 2 × 64 × 0.6 mm; gantry rotation time was 330 ms. Patients were given 1-2 doses (0.4-0.8 mg) of glycerylnitrate spray solution administered sublingually before the procedure. Pharmacological heart rate control was used when appropriate. Noncontrast examination and contrast-enhanced CCTA were performed. The contrast medium comprised 70-80 mL of Optiray (Ioversol 350 mgI/mL, Mallinckrodt Medical Gmbh, Hennef, Germany).
      Figure thumbnail gr1
      Figure 148-year-old man with severe psoriasis and calcified coronary lesions on CCTA (left); 57-year-old man with severe lifelong atopic dermatitis and mixed coronary plaque in the LAD on CCTA (middle), and no plaques in the RCA (right). CCTA = cardiac computed tomography angiography; LAD = left anterior descending artery; RCA = right coronary artery.
      Data sets were reconstructed with a slice thickness of 0.75 mm (reconstruction increment, 0.4 mm) using dedicated cardiac filters (B35f and I26f).

      CT Image Analysis

      Images were analyzed using the imaging software syngo.via (Siemens Healthcare, Siemens AG, Erlangen, Germany). The transaxial, horizontal, and sagittal images were evaluated together with reconstructed images using multi-planar reformation. In case of artifacts, alternative reconstruction at a different cardiac phase was attempted.

      Coronary Artery Calcium Score

      Using the noncontrast data, identification was performed on each calcified lesion in each vessel distribution (right coronary artery [RCA], circumflex [Cx], left main coronary artery [LM], and left anterior descending arteries [LAD]). A coronary artery calcium score was obtained by a semi-automated algorithm in accordance with the Agatston method.
      • Agatston A.S.
      • Janowitz W.R.
      • Hildner F.J.
      • Zusmer N.R.
      • Viamonte Jr., M.
      • Detrano R.
      Quantification of coronary artery calcium using ultrafast computed tomography.
      Settings were: threshold 130 HU 96.5 mg/cm3 CaHA and mass calibration factor 0.743.

      Coronary Artery Angiography Analysis

      The coronary tree was divided into an 18-segment model
      • Raff G.L.
      • Abidov A.
      • Achenbach S.
      • et al.
      SCCT guidelines for the interpretation and reporting of coronary computed tomographic angiography.
      (Supplementary Figure, available online) based on the axial coronary segmentation model suggested by the American Heart Association.
      • Austen W.G.
      • Edwards J.E.
      • Frye R.L.
      • et al.
      A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association.
      Coronary anatomy was examined, coronary dominants and heart rate were noted, the quality of the acquired data was evaluated, and a 5-point quality score was applied (1. Excellent; 2. Good; 3. Moderate; 4. Poor; 5. Not assessable). Segments were analyzed and categorized as follows: 1) Segment analyzability, 2) presence of plaques, 3) luminal stenosis and quantitative stenosis grading (no plaque/normal 0% [no luminal stenosis]; mild 1%-49% area stenosis; moderate 50%-69% area stenosis; severe 70%-100% area stenosis), and 4) plaque composition (calcifying, mixed, noncalcifying). Plaques were identified visually on the contrast-enhanced CT scan. Noncalcified plaques were identified as structures adjacent to or compromising the coronary artery lumen with lower density than the contrast-enhanced vessel lumen. In addition, they should be distinguished clearly from the surrounding tissue. Calcified plaques were identified as structures placed adjacent to or compromising the coronary artery lumen, but with higher density than the contrast-filled lumen.
      Noncoronary cardiac findings were also evaluated. End-diastolic volume and left ventricular myocardial mass were recorded. Extracardiac structures were reviewed by a radiologist.

      Statistical Methods

      Statistical analysis was performed using STATA/IC ver. 12.1 for Mac (StataCorp LP, College Station, TX). The level of statistical significance was set at α = 0.05. Patient characteristics were compared using one-way analysis of variance for continuous variables and Fisher's exact test for categorical variables. Assumption of normal distribution was assessed using histograms and quantile-quantile plots. The CCTA results were not suitable for the measures of central tendency, mean, and median. The reason for this was that both coronary artery calcium scores and CCTA data were not distributed normally, and because a large proportion of the CT scans were normal (eg, coronary artery calcium = 0, plaque = 0). Furthermore, the sample sizes differed between groups. Instead, the data are shown in prevalence measures of CCTA findings in the study population and as pooled data of the segment analysis.
      Coronary artery calcium scores were analyzed as dichotomized categorical variables using Fisher's exact test. CCTA data on plaques and stenosis were analyzed using contingency tables and Fisher's exact test. The relationship between risk factors and positive cardiac CT findings were analyzed using Spearman's rank correlation tests for continuous and ordinal data and Mann-Whitney U test for dichotomous variables.
      Prevalence of risk factors in patients with CCTA luminal stenosis and patients without luminal stenosis were compared within each group using Student's t test.
      Risk estimates and adjusted risk estimates were calculated using logistic regression analysis.

      Results

      Patient Characteristics

      A total of 84 psoriasis patients were considered for enrollment. Five were excluded due to prior cardiovascular events or prior coronary interventions. Nineteen patients were excluded for other reasons (eg, low disease activity, concurrent diseases, personal reasons). Within atopic dermatitis patients, 46 subjects were considered for enrollment. One was excluded due to cardiovascular disease. Ten patients were excluded for other reasons. A total of 60 psoriasis and 35 atopic dermatitis patients met the initial criteria and signed the informed consent form. In the psoriasis group, 1 patient subsequently withdrew consent and 1 was excluded due to screening failure. Four atopic dermatitis patients were excluded subsequently due to screening failure. Of the 58 psoriasis patients examined with cardiac CT, 54 were examined with both coronary artery calcium CT and CCTA, 3 were examined with only coronary artery calcium CT, and one with only CCTA. Thirty-one atopic dermatitis patients were examined with cardiac CT, of whom 27 were examined with coronary artery calcium CT and CCTA and 4 with only coronary artery calcium CT. The reasons for conducting coronary artery calcium CT alone were obesity, a potential for allergy to the contrast media, patient anxiety, and arrhythmia. Of 35 controls, 33 were analyzed; 1 was excluded due to incorrect initial diagnosis and 1 was excluded due to scan failure. All 33 controls were examined with coronary artery calcium CT and CCTA.
      Baseline characteristics were similar across groups (Table 1). Body mass index (BMI) was slightly higher in psoriasis patients. Medically treated hyperlipidemia was more frequent among controls. Controls also had a more frequent family history of ischemic heart disease, but not statistically significantly. Overall, there was no significant difference in the mean number of traditional coronary artery disease risk factors (family history of coronary artery disease, tobacco exposure, medically treated hypertension or untreated blood pressure >140/90 mm Hg, medically treated dyslipidemia, obesity with BMI >30 kg/m2, and type 2 diabetes) between the 2 patient groups and controls (mean [SD]: psoriasis 2.1 [1.3], atopic dermatitis 1.5 [1.1], and controls 1.9 [1.1]; P = .11). In accordance with the natural history of the diseases, the disease duration in atopic dermatitis was significantly longer than in psoriasis. In atopic dermatitis, mean body surface area of inflamed skin was 39.6% (95% confidence interval, 27.6-51.5), and in psoriasis patients the mean PASI was 13.9 (95% confidence interval, 12.8-15.1).
      Table 1Patient Characteristics and Traditional Cardiovascular Risk Factors
      Data are presented as the mean (SD).
      VariablePsoriasis (n = 58)Atopic Dermatitis (n = 31)Controls (n = 33)P Value
      Age, y (SD)50.8 (10.5)47.0 (11.0)47.7 (8.9).19
      Men, n (%)40 (69.0%)24 (77.4%)24 (72.7%).73
      Left ventricular mass, g (SD)113.4 (22.8)122.4 (22.5)121.1 (25.0).41
      Systolic BP, mm Hg (SD)137.6 (15.2)135.3 (15.4)135.0 (13.4).68
      Diastolic BP, mm Hg (SD)86.0 (9.9)84.1 (9.0)83.3 (10.3).44
      Body mass index, kg/m2 (SD)29.1 (6.2)26.9 (4.7)26.4 (3.7).03
      Disease duration, years (SD)28.1 (14.2)38.2 (14.3)-.002
      Family history of IHD, n (%)26 (44.8%)10 (33.3%)19 (57.6%).17
      Tobacco, ever smoked, n (%)35 (60.3%)15 (48.4%)22 (66.7%).34
      Medically treated diabetes, n (%)4 (6.9%)1 (3.2%)1 (3.0%).76
      Medically treated hyperlipidemia, n (%)9 (15.5%)1 (3.2%)10 (30.3%).011
      Medically treated hypertension, n (%)14 (24.1%)4 (12.9%)4 (12.1%).32
      BP = blood pressure; IHD = ischemic heart disease.
      Data are presented as the mean (SD).

      Coronary Artery Calcium Scores

      Figure 2 shows the distribution of coronary artery calcium scores in the study groups. The range of coronary artery calcium scores was: 0-1257 in psoriasis, 0-773 in atopic dermatitis, and 0-100 in controls. Descriptive mean (SD) coronary artery calcium scores were: psoriasis 88 (231), atopic dermatitis 41 (140), and controls 5 (19).
      Figure thumbnail gr2
      Figure 2Scatter plot displaying the distribution of coronary artery calcium (CAC) scores in the various groups.
      Table 2 shows the number of subjects with any detectable coronary artery calcium (coronary artery calcium score >0) and moderate to severe calcifications (coronary artery calcium score ≥100). We found detectable coronary artery calcium in 17 subjects (29.8%) with psoriasis and 14 subjects (45.2%) with atopic dermatitis, and a coronary artery calcium score >100 in 11 subjects (19.3%) with psoriasis and 2 subjects (6.5%) with atopic dermatitis. Coronary artery calcium >0 was more prevalent in patients with psoriasis compared with controls, but the difference was not statistically significant (P = .09). However, the number of patients with coronary artery calcium >100 was higher in patients with psoriasis than in controls (P = .02). We found a higher prevalence of coronary artery calcium >0 in atopic dermatitis than in controls (P = .01), but only few atopic dermatitis patients with coronary artery calcium >100, and no difference compared with controls.
      Table 2Calcium CT and Coronary CT Angiography Findings
      Data are presented as number of subjects (percentage of group total).
      PsoriasisAtopic DermatitisControlsGroup ComparisonP Value
      Calcium CTn = 57n = 31n = 33
       CACS >017 (29.8%)14 (45.2%)5 (15.2%)Pso vs controls/AD vs controls.09/.01
       CACS >10011 (19.3%)2 (6.5%)1 (2.9%)Pso vs controls/AD vs controls.02/NS
      Coronary CT angiographyn = 55n = 27n = 33
       Coronary plaques, n
      034 (61.8%)14 (51.9%)26 (78.8%)Pso vs controls/AD vs controls.08/.03
      1-210 (18.2%)7 (25.9%)6 (18.2%)Pso vs controls/AD vs controlsNS/NS
      ≥311 (20%)6 (22.2%)1 (3%)Pso vs controls/AD vs controls.02/.03
       Coronary stenosis, No.
      039 (70.9%)16 (59.3%)28 (84.9%)Pso vs controls/AD vs controlsNS/.03
      1-27 (12.7%)6 (22.2%)4 (12.1%)Pso vs controls/AD vs controlsNS/NS
      ≥39 (16.4%)5 (18.5%)1 (3%)Pso vs controls/AD vs controls.05/.06
       Severity of luminal stenosis
      Plaque, no stenosis10 (18.2%)2 (7.4%)3 (9.1%)Pso vs controls/AD vs controlsNS/NS
      Mild15 (27.8%)11 (40.7%)3 (9.1%)Pso vs controls/AD vs controls.03/.005
      Moderate6 (10.9%)4 (14.8%)2 (6.1%)Pso vs controls/AD vs controlsNS/NS
      Severe8 (14.6%)0 (0%)0 (0%)Pso vs controls/AD vs controls.02/NS
       Distribution of disease
      Diffuse/mild4 (7.3%)2 (7.4%)2 (6.1%)Pso vs controls/AD vs controlsNS/NS
      Single vessel5 (9.1%)7 (25.9%)4 (12.1%)Pso vs controls/AD vs controlsNS/NS
      Two vessel4 (7.3%)3 (11.1%)1 (3%)Pso vs controls/AD vs controlsNS/NS
      Three vessel and/or LM11 (20%)1 (3.7%)1 (3%)Pso vs controls/AD vs controls.021/NS
      AD = atopic dermatitis; CACS = coronary artery calcium score; CT = computed tomography; LM = left main coronary artery; Pso = psoriasis; NS = nonsignificant.
      Data are presented as number of subjects (percentage of group total).

      Plaque Characteristics, CCTA

      A total of 1481 segments were analyzed: 707 segments in psoriasis, 336 segments in atopic dermatitis, and 438 segments in controls. There was no significant difference in the number of analyzable segments per patient between psoriasis, atopic dermatitis, and controls (mean [SD]: psoriasis 12.9 [1.4], atopic dermatitis 12.4 [2.1], and controls 13.2 [1.3]; P = .12). Moreover, we found no difference in the proportion of studies with an image quality score of at least 2 (good) (psoriasis 94.5%, atopic dermatitis 82.1%, and controls 94.0%; P = .21). Un-analyzable segments were due to triggering, movement, and respiration artifacts, a small diameter (<2.0 mm) in distal segments and segments not anatomically present due to anatomical variation.
      The prevalence of segments with disease in the 3 groups is displayed as pooled data in Figure 3A. The overall number of segments with disease was significantly higher in psoriasis and atopic dermatitis patients than in controls (psoriasis 9.3%, atopic dermatitis 8.4%, vs controls 3.1%; P < .0001 and P = .001, respectively). The overall proportion of segments with luminal abnormalities (area stenosis >1%) was higher in psoriasis and atopic dermatitis than in controls (psoriasis 7.3%, atopic dermatitis 6.9%, vs controls 2.3%; P < .001 and P = .002, respectively). The analysis of plaque composition is displayed in Figure 3A. We found more segments with calcified plaques in psoriasis and atopic dermatitis than in controls (psoriasis 5.7%, atopic dermatitis 4.2%, vs controls 0.7%; P = .0001 and P = .001, respectively). Segments with calcified stenoses were also more frequent in psoriasis and atopic dermatitis (psoriasis 4.7%, atopic dermatitis 4.2%, vs controls 0.5%; P < .0001 and P < .0001, respectively), whereas the number of segments with mixed or noncalcified plaques or stenosis was similar in psoriasis and atopic dermatitis patients and controls.
      Figure thumbnail gr3
      Figure 3Overall segment analysis demonstrating prevalence, subtype, and vessel distribution of segments with atherosclerosis and luminal abnormalities visualized as proportion of all analyzable segments. AD = atopic dermatitis; Cx = circumflex; LAD = left anterior descending artery; LM = left main coronary artery; RCA = right coronary artery.
      Figure 3B shows the vessel distribution and severity of luminal abnormalities in each group.
      CCTA findings on patient level are listed in Table 2. The number of segments with coronary plaques ranged from 0-7 in psoriasis, 0-4 in atopic dermatitis, and 0-5 in controls. The number of segments with luminal abnormalities (stenosis >1%) ranged from 0-7 in psoriasis, 0-4 in atopic dermatitis, and 0-4 in controls. Although not statistically significant, more psoriasis patients had detectable plaques (P = .08) or stenosis (P = .107) compared with controls. An excess of psoriasis patients had more than 3 coronary segments with plaques compared with controls (20% vs 3%; P = .02) and more than 3 plaques with detectable stenosis (16.4% vs 3%; P = .05). We found more atopic dermatitis patients with atherosclerotic plaques compared with controls (plaque: atopic dermatitis 48.1% vs controls 21.2%; P = .03 and stenosis: atopic dermatitis 40.7% vs controls 15.1%; P = .03). More atopic dermatitis patients than controls had coronary disease with >3 coronary plaques (22.2% vs 3%; P = .03) and more segments with detectable stenosis (18.5% vs 3%; P = .06). Mild stenosis (area stenosis 1%-49%) was more prevalent in psoriasis and atopic dermatitis compared with controls (psoriasis 27.8%, atopic dermatitis 40.7%, vs controls 9.1%; P = .03 and P = .005, respectively). Significant luminal abnormalities (area stenosis 70%-100%) were seen only in psoriasis, whereas no patients in the atopic dermatitis or control group had severe stenosis (psoriasis 14.6%, atopic dermatitis 0%, vs controls 0%; P = .02). More patients with psoriasis suffered from atherosclerotic plaques in 3 coronary vessels or affection of the left main coronary artery (20%, vs control 3%; P = .02). In contrast, most atopic dermatitis patients with coronary atherosclerosis suffered from single-vessel disease, but the distribution did not differ significantly from controls (atopic dermatitis 25.9%, vs controls 12.1%; P = .15).
      The distribution of segments with luminal abnormalities (stenosis >1%) in the 18-segment model of the coronary tree is displayed in the Supplementary Figure, available online. In psoriasis, 94% of luminal abnormalities were located in the proximal segments. The vessel distribution of segments with narrowing was: LM 8%, LAD 46%, Cx 20%, and RCA 26%. Among atopic dermatitis patients, 100% of the segments with narrowing were located in the proximal segments. The distribution of segments with narrowing was: LM 4%, LAD 72%, Cx 4%, and RCA 19%. In controls, all (100%) of segments with narrowing were located in the proximal segments. The distribution of segments with narrowing was: LM 10%, LAD 80%, Cx 0%, and RCA 10%.

      Association with Risk Factors

      Among psoriasis patients, coronary artery calcium score and luminal stenosis by CCTA correlated with age (r = 0.52, P < .001, and r = 0.43, P = .001, respectively), medically treated hyperlipidemia (P = .001 and P < .001, respectively) and diabetes (P = .002 and P = .01, respectively). Medically treated hypertension was correlated with CCTA luminal stenosis (P = .05). Other risk factors and clinical variables did not correlate with cardiac CT findings. Among atopic dermatitis patients, the coronary artery calcium score and luminal stenosis by CCTA correlated with age (r = 0.64, P < .001, and r = 0.53, P = .005, respectively), tobacco exposure (P = .04 and P = .04, respectively), and disease duration (r = 0.46, P < .01, and r = 0.26, P = .20, respectively), whereas other variables did not correlate with cardiac CT findings (see Supplementary Table, available online).
      Patients with psoriasis who exhibited luminal abnormalities by CCTA had more traditional coronary artery disease risk factors (family history of coronary artery disease, tobacco exposure, medically treated hypertension or untreated blood pressure >140/90 mm Hg, medically treated dyslipidemia, obesity with BMI >30 kg/m2, and diabetes type 2) than patients without luminal abnormalities (mean number of risk factors [SD]: stenosis ≥1: 2.7 [1.7] vs stenosis = 0: 1.7 [0.9]; P = .01). In atopic dermatitis, however, we observed no significant difference in the number of risk factors in patients with luminal abnormalities by CCTA compared with patients without luminal abnormalities (stenosis ≥1: 1.6 [1.1] vs stenosis = 0: 1.5 [1.1]; P = .9).
      Adjustment for age did not alter crude risk estimates on the association between psoriasis/atopic dermatitis and CCTA luminal abnormalities. Adjusted estimates were with wide ranges due to the limited number of patients (data not shown).

      Discussion

      While our pooled data on segment analysis confirm an increased prevalence of coronary artery disease in severe psoriasis, the most important finding in our study was obtained using cardiac CT beyond coronary artery calcium scoring. These findings showed that the prevalence of severe coronary artery disease was increased despite the absence of symptoms or a history of cardiovascular disease in patients with psoriasis. More patients than controls suffered from elevated calcium scores, multiple plaques and stenoses, significant stenoses and 3-vessel disease, or disease in the left main coronary artery. We used the same modality to demonstrate that atopic dermatitis also was associated with an increased prevalence of coronary artery disease; in contrast to psoriasis patients, coronary artery disease in patients with atopic dermatitis was characterized predominantly by mild disease and single-vessel affection.
      Our findings are consistent with a range of studies demonstrating that the relationship between psoriasis and surrogate markers of cardiovascular risk shift toward a proatherogenic state in patients with psoriasis.
      • Patel R.V.
      • Shelling M.L.
      • Prodanovich S.
      • Federman D.G.
      • Kirsner R.S.
      Psoriasis and vascular disease-risk factors and outcomes: a systematic review of the literature.
      Coherently, the prevalence of coronary artery disease risk genes are increased in patients with psoriasis.
      • Lu Y.
      • Chen H.
      • Nikamo P.
      • et al.
      Association of cardiovascular and metabolic disease genes with psoriasis.
      A retrospective study linking records of patients undergoing coronary angiography with dermatology records demonstrated that patients with psoriasis were more likely to have coronary artery disease (84.3%, vs nonpsoriatics 75.7%; P = .005) at coronary angiography.
      • Armstrong A.W.
      • Harskamp C.T.
      • Ledo L.
      • Rogers J.H.
      • Armstrong E.J.
      Coronary artery disease in patients with psoriasis referred for coronary angiography.
      Until now, cardiac CT has only been applied in patients with psoriasis using non-contrast-enhanced CT. Using a 16-row scanner, Ludwig et al
      • Ludwig R.J.
      • Herzog C.
      • Rostock A.
      • et al.
      Psoriasis: a possible risk factor for development of coronary artery calcification.
      reported an increased prevalence and amount of coronary artery calcium (59.4% vs 28.1%; P = .015) in patients with psoriasis. More recently, a non-contrast-enhanced CT study showed that psoriasis is associated with increased epicardial adipose tissue volume with an association of epicardial fat volume and coronary artery calcium.
      • Torres T.
      • Bettencourt N.
      • Mendonça D.
      • et al.
      Epicardial adipose tissue and coronary artery calcification in psoriasis patients.
      We excluded patients with symptoms of coronary artery disease or prior cardiac disease. Consequently, we have probably underestimated the true coronary artery disease severity in psoriasis compared with controls and atopic dermatitis. This difference in the cohorts might explain the lower prevalence of coronary artery disease in our data compared with previous publications that included patients with possible symptoms of ischemic heart disease or prior ischemic events. During the enrollment process, we excluded several psoriasis patients from the study due to prior cardiovascular disease. In the present study, we aimed to examine the pathology of coronary artery disease in psoriasis and atopic dermatitis without the interference by prior coronary interventions. Even so, we found that 20% of the psoriasis patients suffered from plaques in 3 coronary vessels or disease in the left main coronary artery, or both. These are manifestations that usually predict a severely elevated risk of future major cardiovascular events.
      • Pundziute G.
      • Schuijf J.D.
      • Jukema J.W.
      • et al.
      Prognostic value of multislice computed tomography coronary angiography in patients with known or suspected coronary artery disease.
      • Nakazato R.
      • Arsanjani R.
      • Achenbach S.
      • et al.
      Age-related risk of major adverse cardiac event risk and coronary artery disease extent and severity by coronary CT angiography: results from 15,187 patients from the International Multisite CONFIRM Study.
      Almost 15% of the patients with psoriasis had coronary plaques with significant luminal abnormalities (stenosis >70%), whereas similar abnormalities were not observed in any of the patients in the other groups. Accordingly, the results of the coronary artery calcium scores showed that almost 20% of the investigated patients had moderate to high coronary artery calcium scores above 100, which also indicates an elevated risk of cardiovascular disease. The coronary artery calcium score results of our study may be seen in the perspective of other large data sets on coronary artery calcium and mortality,
      • Blaha M.
      • Budoff M.J.
      • Shaw L.J.
      • et al.
      Absence of coronary artery calcification and all-cause mortality.
      concluding that the hazard ratios for all-cause mortality after adjustment for risk factors were 1.99, 4.05, and 5.56 for scores of 1-10, 11-100, and 101-400, respectively, compared with a score of 0. In another study,
      • Budoff M.J.
      • Shaw L.J.
      • Liu S.T.
      • et al.
      Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.
      10-year survival (after adjustment for risk factors, including age) was 99.4% for a coronary artery calcium score of 0 and deteriorated progressively to 87.8% for a score >1000.
      Our patients also demonstrated an increased prevalence of traditional cardiovascular risk factors among psoriasis patients with positive findings of coronary artery disease vs patients without signs of coronary artery disease. We observed no significant correlation between coronary artery disease and disease duration, indicating that the increased prevalence of coronary artery disease is seen not only in early-onset psoriasis but also in late-onset psoriasis.
      Being in agreement with the majority of previous publications, our results demonstrate that increased cardiovascular risk in psoriasis can be shown, not only in large-scale epidemiologic studies, but also in a clinical trial on smaller numbers of patients with direct visualization of the coronary atherosclerotic process.
      Another important finding is that the prevalence of coronary artery disease seems increased in patients with severe long-term atopic dermatitis. Patients with atopic dermatitis seem to exhibit a type of coronary atherosclerosis dominated by fewer plaques and stenosis, single-vessel disease, lower coronary artery calcium scores, and predominantly mild stenosis, while severe and widespread disease appears less prevalent. These findings indicate that atopic dermatitis might be associated with an increased risk of coronary artery disease. Atopic dermatitis has been associated with a slightly increased risk of ischemic stroke,
      • Su V.Y.
      • Chen T.J.
      • Yeh C.M.
      • et al.
      Atopic dermatitis and risk of ischemic stroke: a nationwide population-based study.
      and a similar association has been demonstrated most recently between eczema and selected cardiovascular disease risk factors.
      • Silverberg J.I.
      • Greenland P.
      Eczema and cardiovascular risk factors in 2 US adult population studies.
      Until now, atopic dermatitis has been linked to comorbidities such as allergy, asthma, and psychiatric disorders
      • Simpson E.L.
      Comorbidity in atopic dermatitis.
      rather than traditional cardiovascular risk factors. Atherosclerosis and Th2-mediated diseases do not appear to share a common immunological mechanism. Th2-related chemokines are represented sparsely in human advanced atherosclerotic plaques,
      • Frostegard J.
      • Ulfgren A.K.
      • Nyberg P.
      • et al.
      Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.
      indicating that Th2 activation is not quantitatively important. Studies on a murine model even indicated an atheroprotective effect of some newly described cytokines expressed by cells of the Th2 lineage.
      • Miller A.M.
      • Xu D.
      • Asquith D.L.
      • et al.
      IL-33 reduces the development of atherosclerosis.
      However, even though atopic dermatitis is the prototypical Th2-mediated disease and Th2-mediated cytokines predominate during the acute phase of the disease, the mechanisms driving atopic dermatitis are based on a complex interplay also involving Th17/Th22, Treg, and Th1-mediated cytokines.
      • Yamanaka K.
      • Mizutani H.
      The role of cytokines/chemokines in the pathogenesis of atopic dermatitis.
      In fact, an increase in Th1-mediated cytokines, which is of major importance for initiation of atherosclerosis, is probably of importance during the chronic phases of atopic dermatitis.
      • Bieber T.
      Atopic dermatitis.
      • Yamanaka K.
      • Mizutani H.
      The role of cytokines/chemokines in the pathogenesis of atopic dermatitis.
      A potential explanation for the increased prevalence of coronary artery disease is the long-term systemic inflammation in atopic dermatitis patients with chronic disease. It may even be a shared factor in atopic dermatitis and psoriasis, despite the differing genotype and phenotype of the diseases. The increased severity of coronary artery disease in psoriasis may be due to more aggressive systemic inflammation, more Th1/Th17-derived cytokines in psoriasis than in atopic dermatitis, shared traditional risk factors in psoriasis and cardiovascular disease, or some combination of these causes. The current findings may be clinically relevant when treating adults with life-long severe atopic dermatitis with long periods of inflammation in the skin. At present, our results do not allow any conclusion about the appropriateness of cardiovascular disease screening in atopic dermatitis patients because it remains to be confirmed whether these patients have a compromised prognosis due to cardiovascular events and, if so, whether it can be modified by any medical or interventional treatment.
      Our control group was not a true healthy population; they represent patients with atypical angina referred for CCTA through actual clinical practice patterns by a variety of physicians. Despite a low a priori risk of coronary artery disease (ie, atypical angina), the control cohort may have had an increased risk of coronary artery disease compared with a true asymptomatic background population. The increased number of controls treated with lipid-lowering drugs may reflect a potential referral bias. Consequently, our approach may have led to an overestimation of the risk of coronary artery disease in the general population and potentially reduced the differences between our control group and atopic dermatitis and psoriasis patients. The validity of our control group is supported by prevalences of coronary artery disease varying between 11.4%
      • Kim K.J.
      • Choi S.I.
      • Lee M.S.
      • Kim J.A.
      • Chun E.J.
      • Jeon C.H.
      The prevalence and characteristics of coronary atherosclerosis in asymptomatic subjects classified as low risk based on traditional risk stratification algorithm: assessment with coronary CT angiography.
      and 22%
      • Choi E.K.
      • Choi S.I.
      • Rivera J.J.
      • et al.
      Coronary computed tomography angiography as a screening tool for the detection of occult coronary artery disease in asymptomatic individuals.
      in CCTA studies in asymptomatic individuals.
      The patients in this study were evaluated extensively, but the number of subjects was limited. The sample size does not allow in-depth sub-group analysis, rendering any association with traditional coronary artery disease risk factors with limited power. All patients and controls were recruited from the same referral zone with 1.25 million inhabitants. The socioeconomic status was uniform; the study population was predominantly white, which may limit the external validity.
      In conclusion, our results indicate that severe psoriasis and severe atopic dermatitis are associated with an increased prevalence of coronary artery disease, as assessed by cardiac CT. Psoriasis patients had more proximal lesions and a higher prevalence of significant stenoses, as well as affection of 3 vessels and left main disease, while atopic dermatitis was associated with mild and single-vessel disease. Larger studies are required to clarify the clinical implications of these associations.

      Acknowledgment

      The authors thank the staff at the Cardiac Imaging Centre, Department of Cardiology, Aarhus University Hospital, Denmark, for their contribution.

      Supplementary Data

      Figure thumbnail fx1
      Supplementary Figure18-segment model of the coronary tree illustrating the distribution of segments with luminal abnormalities in psoriasis, atopic dermatitis, and controls (percentage of segments with stenosis within group). AD = atopic dermatitis; Con = controls; Cx = circumflex; D1/D2 = diagonal branch; LAD = left anterior descending artery; OM = obtuse marginal; PDA = posterior descending artery; PLB = posterior lateral branch; Pso = psoriasis; RI = ramus intermedius; RCA = right coronary artery.
      Supplementary TableAssociation Between Risk Factors and Clinical Measures and Cardiac CT Findings
      Data are presented as Spearman's rho and level of significance for continuous and ordinal data and significance level assessed by Mann-Whitney U test for dichotomous variables.
      PsoriasisAD
      CAC ScoreCCTA Luminal AbnormalitiesCAC ScoreCCTA Luminal Abnormalities
      rhoP-ValuerhoP-ValuerhoP-ValuerhoP-Value
      Age0.52<.0010.43.0010.64<.0010.53.005
      Male sex-.82-.24-.09-.25
      Family history of CAD-.38-.59-.55-.69
      Med. treated hypertension-.18-.05-.23-.17
      Med. treated hyperlipidemia-.001-<.001-.55-.43
      Diabetes-.02-.01-.39--
      Tobacco exposure-.64-.90-.04-.04
      Disease duration0.12.390.06.690.46.010.26.20
      PASI0.21.120.11.44----
      Body mass index0.10.440.10.46−0.26.16−0.14.47
      Weight0.09.490.12.40−0.08.660.08.68
      Height0.01.960.09.490.14.450.16.41
      Systolic BP0.20.160.18.200.25.210.28.18
      Diastolic BP0.08.590.08.590.23.240.17.42
      AD = atopic dermatitis; BP = blood pressure; CAC = coronary artery calcium; CAD = coronary artery disease; CCTA = coronary computed tomography angiography; PASI = Psoriasis Area Severity Index.
      Data are presented as Spearman's rho and level of significance for continuous and ordinal data and significance level assessed by Mann-Whitney U test for dichotomous variables.

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