Clinical trial
Are all patients with psoriasis at increased risk for coronary artery disease? Sila Seremet1, MD, Berhan Genc2, MD, Ahmet Tastan3, MD, Zehra Ilke Akyildiz4, MD, Cem Nazli4, MD, Sinan Ozcelik1, MD, Fatma Sule Afsar1, MD, Aynur Solak2, MD, and Volkan Emren4, MD
1 Department of Dermatology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey, 2 Department of Radiology, Faculty of Medicine, Sifa University, Izmir, Turkey, 3 Department of Cardiology, Faculty of Medicine, Sifa University, Izmir, Turkey, and 4Department of Cardiology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
Correspondence Sila Seremet, MD Department of Dermatology Izmir Katip Celebi University Ataturk Training and Research Hospital 35360 Basin Sitesi Izmir Turkey E-mail: [email protected] Conflicts of interest: None.
Abstract Associations have been recently recognized between psoriasis and an increased incidence of atherosclerotic diseases. However, there are scarce data on the prevalence of coronary lesions in patients with psoriasis. The aim of this study was to identify the calcified and non-calcified atherosclerotic coronary lesions in patients with psoriasis compared to controls. Forty patients with psoriasis and 42 control subjects matched for age, sex, and cardiovascular risk profile were included in this case–control study. Coronary lesions were evaluated by a 128-slice dual source multidetector computed tomography scanner. Coronary calcification scoring was calculated according to the Agatston score. The prevalence of atherosclerotic coronary lesions (psoriasis: 15%, controls: 16.7%; P = 0.83) and the mean coronary calcification scoring (psoriasis: 9.9 35.2 Agatston unit, controls 2.8 12.0 Agatston unit; P = 0.81) did not show a significant difference between the two groups. Multivariate analysis identified age ≥48 years and fasting blood glucose ≥99.0 mg/ dl as independent predictors of coronary artery disease in patients with psoriasis (F = 30.9; P = 0.001; adjusted R2 = 0.49). Patients with psoriasis had the same prevalence of calcified and non-calcified atherosclerotic coronary lesions as compared to controls. Our results demonstrated the necessity of considering the age and fasting blood glucose of patients with psoriasis in a decision for further cardiovascular evaluation.
doi: 10.1111/ijd.12673
Introduction Psoriasis is a common chronic inflammatory disease that mainly involves the skin and joints. Various immunologic and inflammatory mechanisms have been suggested for the pathogenesis of the disease. Similar inflammatory mechanisms have been proposed in the pathogenesis of coronary artery disease (CAD).1–3 Several epidemiologic studies have reported an increased risk of cardiovascular (CV) mortality and morbidity in patients with psoriasis,4,5 but other studies did not confirm these results.6,7 There is another epidemiologic study that has reported an increased rate of CV risk factors in the psoriatic population, and it has been suggested that the coexistence of CV risk factors and the immune-mediated inflammatory nature of the disease itself may play a role in the formation of CAD in these patients.8 Two other studies reported that psoriasis is an independent risk factor for coronary calcification.9,10 In these studies, coronary atherosclerosis was mainly determined by the coronary ª 2014 The International Society of Dermatology
calcification scoring (CCS) measured by computed tomography (CT); however, this technique does not show non-calcified coronary lesions and may underestimate the real extent of CAD.9,10 In our study, our aim was to evaluate the prevalence of calcified and non-calcified atherosclerotic coronary lesions in patients with psoriasis by using both CCS and contrast-enhanced CT coronary angiography techniques and to identify a subgroup of patients with psoriasis who should be referred for further cardiac evaluation due to an increased risk for subclinical CAD. Materials and methods Study cohorts The study group included eligible patients with chronic plaque psoriasis aged between 18 and 55 years old. The exclusion criteria were as follows: • Patients with past or present history and/or symptoms of any CV disease: myocardial infarction, stable or unstable angina International Journal of Dermatology 2014
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pectoris, stroke, congestive heart disease, cardiomyopathy, cardiac surgery, percutaneous coronary intervention, documented CAD on previous coronary angiography, or myocardial ischemia on stress tests. • Contraindications to coronary CT imaging: atrial fibrillation, atrial flutter, multiple premature ventricular beats, serum creatinine >1.5 mg/dl, history of severe allergic reaction to intravenous contrast agents, pregnancy, or contraindications to beta-blocker. • History of antioxidant or biologic therapy. From November 2011 to May 2012, 40 consecutive patients with chronic plaque-type psoriasis (from the dermatology outpatient clinic of Izmir Katip Celebi University, Ataturk Training and Research Hospital, Turkey) and age- and gendermatched 42 control subjects with similar Framingham risk scores (FRS) from the outpatient check-up clinics of the same hospital were recruited. All patients underwent physical examination and resting blood pressure measurements on two different office visits. Body mass index and waist circumference were measured. Psoriasis area and severity index (PASI) were calculated for patients with psoriasis.11 Conventional CV risk factors were recorded. Serum total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, creatinine, hemoglobin-A1c, and fasting and postprandial glucose were measured. All patients were screened for any sign of cardiac disease by electrocardiographic and echocardiographic examinations. The FRS was calculated, which estimates the 10-year CV risk of an individual by using CV risk factors.12 Individuals with low risk were defined to have 10% or less coronary heart disease risk at 10 years. Individuals with an estimated 10-year risk of 10–20% are considered to have intermediate risk, and those with an estimated 10-year risk of more than 20% are named as a member of the high-risk group. All patients with psoriasis and controls gave written informed consent for participation. The study protocol was approved by the local institutional ethics committee.
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Seremet et al.
Diagnostic interventions All cardiac examinations were performed with a 128-slice dual source multidetector CT scanner (Somatom Definition; Siemens Medical Solutions, Erlangen, Germany). Coronary arteriosclerosis (CAS) was evaluated by both CCS and contrast-enhanced CT coronary angiography. The CCS was calculated with ECG-gated unenhanced CT according to a method described by Agatston et al.13 ECG–gated contrast enhanced CT angiography was also performed during the same session. Before the procedure, the cardiac rate was reduced with 5–20 mg intravenous metoprolol tartrate in patients with a heart rate exceeding 80 beats/min. CT angiography was performed after a bolus injection of 75–90 ml contrast material (Ultravist; Schering, Berlin, Germany) via the antecubital vein with a flow rate of 5–6 ml/s followed by a 50 ml saline flush. Image acquisitions were performed with the following scan parameters: 120 kV tube voltage, 400–430 mA tube current, 0.35 ms rotation time, and 32 9 0.6 mm detector collimation. Image reconstructions were made in all cardiac phases at 50 ms intervals at a slice thickness of 0.75 mm and a reconstruction increment of 0.5 mm. Best systolic and best diastolic frames were automatically picked and transferred to a work station (MultiModality Workplace; Siemens Inc.) for postprocess advanced analysis. Images of all patients were assessed with multiplanar reconstruction, volume rendering technique, and maximum intensity projections (Fig. 1). The images were consensually reviewed by an experienced radiologist and a cardiologist who were blinded to the medical history of the patients. Coronary calcification scoring was determined by using software (Calcium Scoring, MultiModality Workplace; Siemens Inc.) that recognizes pixels greater than the threshold value of 130 Hounsfield units as “calcification” and expresses coronary calcification in Agatston units (AU) (Fig. 2). Coronary calcification scoring of more than 0 AU was defined as the presence of CAS. Patients with a normal CCS and a protruding coronary lesion within the coronary lumen (i.e., soft plaque) in CT angiography were also defined to have CAS.
(b)
Figure 1 Multiplanar reconstruction images of a patient with stenotic lesion (arrow) in the left anterior descending coronary artery (a) and a patient with normal coronary artery (b) International Journal of Dermatology 2014
ª 2014 The International Society of Dermatology
Seremet et al.
Psoriasis and coronary artery disease
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Figure 2 Computed tomography angiographic demonstration of calcific plaques (arrow) in the LAD artery of a patient with psoriasis (a). Calcium score is measured for each coronary artery and the total coronary calcification score is expressed in Agatston units (b). CX, circumflex; LAD, left anterior descending; LM, left main; RCA, right coronary artery
Statistical analysis The data are expressed as mean standard deviation for continuous variables and frequencies for categorical parameters. The Mann–Whitney U-test was used for comparing categorical variables. Pearson’s chi-squared test or Fisher’s exact test was used for comparing categorical variables. Univariate logistic regression analysis was used to evaluate the effect of different demographic and clinical variables for the presence of CAD. Subsequent multiple logistic regression analyses were performed to identify the independent predictors of CAD. Receiver operating characteristic analysis was performed to detect cut-off values for clinical variables that could be high-risk criteria for CAD in patients with psoriasis. P < 0.05 was considered as statistically significant in all analyses. All statistical analyses were performed using SPSS for Windows (version 15.0; SPSS, Chicago, IL, USA).
Results Demographic characteristics and CV risk factors of the study population are summarized in Table 1. Both groups were successfully matched for age and sex. There were no significant differences in blood pressure, body mass index, waist circumference, or serum lipid and glucose levels between patients with psoriasis and controls. Prevalence of hypertension, diabetes, smoking, family history of CV disease, and FRS were also similar in both groups. Patients with psoriasis had a mean disease duration of 16 10.2 years. The mean PASI index of the study group was 6.6 4.0. The treatment for psoriasis was as follows: drug therapy (14 patients, 35%), phototherapy (10 patients, 25%), and both drug therapy and phototherapy (eight patients, 20%). During therapy, the patients were receiving methotrexate (14 patients), cyclosporine (11), and acitretin (seven). Eleven patients (27.5%) had a history of inpatient treatment with a mean number of 1.2 1.0 episodes of hospitalization. ª 2014 The International Society of Dermatology
Table 1 Demographic characteristics and cardiovascular risk factors of the study population
Sex Male Female Age Hypertension Diabetes Current smoker Smoking duration (years) Ex-smoker Years since quitting smoking Family history of CVD Body mass index (kg/m2) Waist circumference (cm) Systolic BP (mmHg) Diastolic BP (mmHg) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Fasting glucose (mg/dl) Postprandial glucose (mg/dl) Hemoglobin A1c (%) hs-CRP (mg/dl)
Psoriasis (n = 40)
Controls (n = 42)
P value
20 20 41.2 8 4 21 11.8 17 3.8 11 27.7 97.8 122.6 76.0 201.8 163.9 46.5 128.0 102.4 113.6 5.5 0.4
18 24 42.2 11 2 15 9.5 16 3.1 12 29.7 97.2 124.6 77.7 205.2 141.5 44.3 130.7 102.5 119.3 5.3 0.4
0.51
(50%) (50%) 10.7 (20%) (10%) (52.5%) 12.3 (42.5%) 1.1 (27.5%) 5.4 13.7 11.0 7.4 41.6 103.0 8.7 55.0 21.6 39.4 0.7 0.27
(42.9%) (57.1%) 7.1 (26%) (4.8%) (35.7%) 10.7 (38.1%) 0.7 (29.3%) 8.9 15.1 19.0 10.9 37.5 54.8 13.0 34.9 10.8 30.0 0.4 0.34
0.90 0.50 0.42 0.12 0.33 0.68 0.36 0.86 0.35 0.91 0.86 0.36 0.82 0.65 0.07 0.51 0.49 0.23 0.26 0.34
BP, blood pressure; hs-CRP, high-sensitivity C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Coronary arteriosclerosis was demonstrated in six (15%) patients with psoriasis and in seven (16.7%) controls (P = 0.83). Non-calcified soft coronary plaques were observed in one patient with psoriasis and in two controls. The CCS of the two groups was not statistically significant: mean calcification scores was 9.9 35.2 AU (range: 0–174) for the patient group and 2.8 12.0 AU (range: 0–76) for the control group (P = 0.81). The International Journal of Dermatology 2014
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treatment regimens for psoriasis in patients with CAD were as follows: systemic drug therapy and phototherapy (three patients), systemic drug therapy (two), and phototherapy (one). Acitretin was used in one patient, cyclosporine in two, combination of methotrexate and cyclosporine in one, and combination of acitretin, methotrexate, and cyclosporine in one, for the systemic treatment of patients with psoriasis who had CAD. None of the patients with psoriasis and CAD were in the high-risk category for CV events according to FRS; two patients were in the low-risk category with an estimated risk of 20.0) psoriasis, and these scores were compared with the general population.15 Compared with the general population, 10-year risks of patients with both moderate and severe psoriasis were 28.0% greater for CAD. Gelfand et al. showed that the 5-year risk of myocardial infarction for patients with mild psoriasis was similar with the risk of a control population adjusted for CV risk factors whereas the same risk was higher than both groups in patients with severe psoriasis that required systemic therapy.24 It may be suggested that the severity of the psoriatic disease, rather than the disease itself, may be responsible for developing CAD, but this issue must be confirmed with prospective randomized studies comparing the prevalence of coronary heart disease in patients with mild, moderate, and severe psoriasis. Current data suggest that the long-term risk for CV events is higher in patients with severe psoriasis compared to patients with mild psoriatic disease; however, the prevalence of silent CAD in patients with mild psoriasis is still unclear. Age is one of the major well-known risk factors for the occurrence of CAD and was identified as one of the independent clinical predictors of CAD in the current study. This may be another reason for the lower prevalence of CAD in our patient group compared to those of the two previous studies, as our study group tended to be younger (mean age 41 years) than the patients with psoriasis in Ludwig et al. (mean age 49 years) and Yiu et al.9,10 (mean age 46 years). Systemic therapies used in the treatment of severe psoriasis may correct endothelial dysfunction by their anti-inflammatory effects and decrease the risk of CV events. For example, Prodanovich et al. International Journal of Dermatology 2014
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demonstrated a significant reduction in the incidence of vascular disease with methotrexate therapy in patients with psoriasis.25 In the current study, 35% of the patients were receiving methotrexate therapy with a mean 16.0 10.2 years, and the mean PASI score was 6.6 4.0.25 Although the patients in the study group of Yiu et al.10 had a similar mean duration of disease (15.7 7.1 years) and higher usage of methotrexate therapy (56%), mean PASI score was still higher (14.2 9.6) than the score of our group. Early identification of patients with psoriasis with silent CAD is an important issue. The usefulness of FRS in patients with psoriasis was validated in a former study.26 Gisondi et al. reported that the FRS of patients with chronic plaque psoriasis is significantly higher than the age- and sex-matched controls. Patients with psoriasis had an intermediate 10-year estimated risk of developing CV events (with a mean score of 11.0 8.0), which warrants early interventions aimed to correct modifiable risk factors such as antihypertensive, antidiabetic, and antilipidemic drugs, and the cessation of smoking.26 However, FRS may be insufficient to estimate risk in younger patients and women, and it may underestimate the risk in patients with inflammatory diseases. Mehta et al. suggested that the FRS will be insufficient to identify patients with increased risk for subclinical vascular disease that warrants early and aggressive risk factor modification,27 and they recommended the utilization of a modified FRS, which uses the addition of a 6.2% attributable risk of psoriasis to the calculated FRS.5,27 In the current study, the mean estimated 10year risk for CV events for patients with psoriasis with subclinical atherosclerosis was 9.17 6.79%, which corresponds to a low–moderate risk category according to the FRS. As none of these patients was in the high-risk category, early and aggressive treatment for modifying atherosclerotic risk factors may be neglected by only using the FRS. We have shown that silent CAD can be predicted in patients with psoriasis by using two simple parameters (age ≥48 years and FBG ≥99 mg/dl) with a very good sensitivity and specificity. In addition to patients with high-risk FRS, early and aggressive intervention for modifying CV risk factors may also be recommended for patients with psoriasis with an age of ≥48 years and FBG ≥ 99.0 mg/dl who are in low–moderate FRS. All patients with subclinical atherosclerosis in the study group were either receiving systemic drug therapy or phototherapy and, therefore, may be considered to have a severe psoriatic disease. This finding is also consistent with previous studies suggesting a strong correlation between the severity of the psoriasis and CV disease. Use of age and FBG criteria for early CV risk modification may be more valuable in patients with International Journal of Dermatology 2014
severe psoriasis to prevent the progression of a probable existing subclinical atherosclerosis. Study limitations
Because of the small sample size and exclusion criteria of the study group, the observed prevalence of CAD in patients with psoriasis may not reflect the exact value of the population with psoriasis. The effect of different treatment modalities on the prevalence of subclinical CAD was not analyzed due to the small sample size of the study group. Accuracy of the recommended criteria for identifying high-risk patients for subclinical CAD should be also validated with future prospective studies that include larger study cohorts. Conclusion In conclusion, this study shows that patients with mild psoriasis and controls have the same prevalence of calcified and non-calcified atherosclerotic coronary lesions. However, as early identification of atherosclerosis in young patients with psoriasis is important, age and FBG may be useful in choosing patients for further cardiovascular evaluation. As the data on prevalence of silent CAD and calcification in psoriasis are contradictory, we still need to have further prospective studies for a more accurate identification of patients with psoriasis at high risk for CAD. References 1 Armstrong AW, Voyles SV, Armstrong EJ, et al. Angiogenesis and oxidative stress: common mechanisms linking psoriasis with atherosclerosis. J Dermatol Sci 2011; 63: 1–9. 2 Methe H, Brunner S, Wiegand D, et al. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol 2005; 45: 1939– 1945. 3 Boehncke WH, Boehncke S, Tobin AM, et al. The psoriatic march: a concept of how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol 2011; 20: 303–307. 4 Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol 2004; 19: 225–230. 5 Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med 2011; 124: 775. 6 Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease hospitalizations: results of a large population-based Dutch cohort. J Invest Dermatol 2010; 130: 962–967. 7 Stern RS. Psoriasis is not a useful independent risk factor for cardiovascular disease. J Invest Dermatol 2010; 130: 917–919. ª 2014 The International Society of Dermatology
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8 Qureshi AA, Choi HK, Setty AR, et al. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol 2009; 145: 379–382. 9 Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol 2007; 156: 271–276. 10 Yiu KH, Yeung CK, Zhao CT, et al. Prevalence and extent of subclinical atherosclerosis in patients with psoriasis. J Intern Med 2013; 273: 273–282. 11 Berth-Jones J, Grotzinger K, Rainville C, et al. A study examining inter- and intrarater reliability of three scales for measuring severity of psoriasis: psoriasis Area and Severity Index, Physicians Global Assessment and Lattice System Physicians Global Assessment. Br J Dermatol 2006; 155: 707–713. 12 Third Report of the National Cholesterol Education Program. (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–3421. 13 Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 5: 827– 832. 14 Prodanovich S, Kirsner RS, Kravetz JD, et al. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol 2009; 145: 700–703. 15 Kimball AB, Guerin A, Latremouille-Viau D, et al. Coronary heart disease and stroke risk in patients with psoriasis: retrospective analysis. Am J Med 2010; 123: 350–357. 16 Tobin AM, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol 2010; 37: 1386–1394. 17 Love TJ, Qureshi AA, Karlson EW, et al. Prevalence of the metabolic syndrome in psoriasis: results from the
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National Health and Nutrition Examination Survey, 2003-2006. Arch Dermatol 2011; 147: 419–424. Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246. Raychaudhuri SP, Jiang WY, Raychaudhuri SK. Revisiting the Koebner phenomenon: role of NGF and its receptor system in the pathogenesis of psoriasis. Am J Pathol 2008; 172: 961–971. Florez H, Castillo-Florez S, Mendez A, et al. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Res Clin Pract 2006; 71: 92–100. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol 2008; 60: 218–224. Armstrong AW, Harskamp CT, Ledo L, et al. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol 2012; 109: 976–980. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: 1735–1741. Prodanovich S, Ma F, Taylor JR, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol 2005; 52: 262–267. Gisondi P, Farina S, Giordano MV, et al. Usefulness of the Framingham risk score in patients with chronic psoriasis. Am J Cardiol 2010; 106: 1754–1757. Mehta NN, Yu Y, Saboury B, et al. Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study. Arch Dermatol 2011; 147: 1031–1039.
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Are all patients with psoriasis at increased risk for coronary artery disease? Sila Seremet1, MD, Berhan Genc2, MD, Ahmet Tastan3, MD, Zehra Ilke Akyildiz4, MD, Cem Nazli4, MD, Sinan Ozcelik1, MD, Fatma Sule Afsar1, MD, Aynur Solak2, MD, and Volkan Emren4, MD
1 Department of Dermatology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey, 2 Department of Radiology, Faculty of Medicine, Sifa University, Izmir, Turkey, 3 Department of Cardiology, Faculty of Medicine, Sifa University, Izmir, Turkey, and 4Department of Cardiology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
Correspondence Sila Seremet, MD Department of Dermatology Izmir Katip Celebi University Ataturk Training and Research Hospital 35360 Basin Sitesi Izmir Turkey E-mail: [email protected] Conflicts of interest: None.
Abstract Associations have been recently recognized between psoriasis and an increased incidence of atherosclerotic diseases. However, there are scarce data on the prevalence of coronary lesions in patients with psoriasis. The aim of this study was to identify the calcified and non-calcified atherosclerotic coronary lesions in patients with psoriasis compared to controls. Forty patients with psoriasis and 42 control subjects matched for age, sex, and cardiovascular risk profile were included in this case–control study. Coronary lesions were evaluated by a 128-slice dual source multidetector computed tomography scanner. Coronary calcification scoring was calculated according to the Agatston score. The prevalence of atherosclerotic coronary lesions (psoriasis: 15%, controls: 16.7%; P = 0.83) and the mean coronary calcification scoring (psoriasis: 9.9 35.2 Agatston unit, controls 2.8 12.0 Agatston unit; P = 0.81) did not show a significant difference between the two groups. Multivariate analysis identified age ≥48 years and fasting blood glucose ≥99.0 mg/ dl as independent predictors of coronary artery disease in patients with psoriasis (F = 30.9; P = 0.001; adjusted R2 = 0.49). Patients with psoriasis had the same prevalence of calcified and non-calcified atherosclerotic coronary lesions as compared to controls. Our results demonstrated the necessity of considering the age and fasting blood glucose of patients with psoriasis in a decision for further cardiovascular evaluation.
doi: 10.1111/ijd.12673
Introduction Psoriasis is a common chronic inflammatory disease that mainly involves the skin and joints. Various immunologic and inflammatory mechanisms have been suggested for the pathogenesis of the disease. Similar inflammatory mechanisms have been proposed in the pathogenesis of coronary artery disease (CAD).1–3 Several epidemiologic studies have reported an increased risk of cardiovascular (CV) mortality and morbidity in patients with psoriasis,4,5 but other studies did not confirm these results.6,7 There is another epidemiologic study that has reported an increased rate of CV risk factors in the psoriatic population, and it has been suggested that the coexistence of CV risk factors and the immune-mediated inflammatory nature of the disease itself may play a role in the formation of CAD in these patients.8 Two other studies reported that psoriasis is an independent risk factor for coronary calcification.9,10 In these studies, coronary atherosclerosis was mainly determined by the coronary ª 2014 The International Society of Dermatology
calcification scoring (CCS) measured by computed tomography (CT); however, this technique does not show non-calcified coronary lesions and may underestimate the real extent of CAD.9,10 In our study, our aim was to evaluate the prevalence of calcified and non-calcified atherosclerotic coronary lesions in patients with psoriasis by using both CCS and contrast-enhanced CT coronary angiography techniques and to identify a subgroup of patients with psoriasis who should be referred for further cardiac evaluation due to an increased risk for subclinical CAD. Materials and methods Study cohorts The study group included eligible patients with chronic plaque psoriasis aged between 18 and 55 years old. The exclusion criteria were as follows: • Patients with past or present history and/or symptoms of any CV disease: myocardial infarction, stable or unstable angina International Journal of Dermatology 2014
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2
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Psoriasis and coronary artery disease
pectoris, stroke, congestive heart disease, cardiomyopathy, cardiac surgery, percutaneous coronary intervention, documented CAD on previous coronary angiography, or myocardial ischemia on stress tests. • Contraindications to coronary CT imaging: atrial fibrillation, atrial flutter, multiple premature ventricular beats, serum creatinine >1.5 mg/dl, history of severe allergic reaction to intravenous contrast agents, pregnancy, or contraindications to beta-blocker. • History of antioxidant or biologic therapy. From November 2011 to May 2012, 40 consecutive patients with chronic plaque-type psoriasis (from the dermatology outpatient clinic of Izmir Katip Celebi University, Ataturk Training and Research Hospital, Turkey) and age- and gendermatched 42 control subjects with similar Framingham risk scores (FRS) from the outpatient check-up clinics of the same hospital were recruited. All patients underwent physical examination and resting blood pressure measurements on two different office visits. Body mass index and waist circumference were measured. Psoriasis area and severity index (PASI) were calculated for patients with psoriasis.11 Conventional CV risk factors were recorded. Serum total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, creatinine, hemoglobin-A1c, and fasting and postprandial glucose were measured. All patients were screened for any sign of cardiac disease by electrocardiographic and echocardiographic examinations. The FRS was calculated, which estimates the 10-year CV risk of an individual by using CV risk factors.12 Individuals with low risk were defined to have 10% or less coronary heart disease risk at 10 years. Individuals with an estimated 10-year risk of 10–20% are considered to have intermediate risk, and those with an estimated 10-year risk of more than 20% are named as a member of the high-risk group. All patients with psoriasis and controls gave written informed consent for participation. The study protocol was approved by the local institutional ethics committee.
(a)
Seremet et al.
Diagnostic interventions All cardiac examinations were performed with a 128-slice dual source multidetector CT scanner (Somatom Definition; Siemens Medical Solutions, Erlangen, Germany). Coronary arteriosclerosis (CAS) was evaluated by both CCS and contrast-enhanced CT coronary angiography. The CCS was calculated with ECG-gated unenhanced CT according to a method described by Agatston et al.13 ECG–gated contrast enhanced CT angiography was also performed during the same session. Before the procedure, the cardiac rate was reduced with 5–20 mg intravenous metoprolol tartrate in patients with a heart rate exceeding 80 beats/min. CT angiography was performed after a bolus injection of 75–90 ml contrast material (Ultravist; Schering, Berlin, Germany) via the antecubital vein with a flow rate of 5–6 ml/s followed by a 50 ml saline flush. Image acquisitions were performed with the following scan parameters: 120 kV tube voltage, 400–430 mA tube current, 0.35 ms rotation time, and 32 9 0.6 mm detector collimation. Image reconstructions were made in all cardiac phases at 50 ms intervals at a slice thickness of 0.75 mm and a reconstruction increment of 0.5 mm. Best systolic and best diastolic frames were automatically picked and transferred to a work station (MultiModality Workplace; Siemens Inc.) for postprocess advanced analysis. Images of all patients were assessed with multiplanar reconstruction, volume rendering technique, and maximum intensity projections (Fig. 1). The images were consensually reviewed by an experienced radiologist and a cardiologist who were blinded to the medical history of the patients. Coronary calcification scoring was determined by using software (Calcium Scoring, MultiModality Workplace; Siemens Inc.) that recognizes pixels greater than the threshold value of 130 Hounsfield units as “calcification” and expresses coronary calcification in Agatston units (AU) (Fig. 2). Coronary calcification scoring of more than 0 AU was defined as the presence of CAS. Patients with a normal CCS and a protruding coronary lesion within the coronary lumen (i.e., soft plaque) in CT angiography were also defined to have CAS.
(b)
Figure 1 Multiplanar reconstruction images of a patient with stenotic lesion (arrow) in the left anterior descending coronary artery (a) and a patient with normal coronary artery (b) International Journal of Dermatology 2014
ª 2014 The International Society of Dermatology
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Psoriasis and coronary artery disease
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Figure 2 Computed tomography angiographic demonstration of calcific plaques (arrow) in the LAD artery of a patient with psoriasis (a). Calcium score is measured for each coronary artery and the total coronary calcification score is expressed in Agatston units (b). CX, circumflex; LAD, left anterior descending; LM, left main; RCA, right coronary artery
Statistical analysis The data are expressed as mean standard deviation for continuous variables and frequencies for categorical parameters. The Mann–Whitney U-test was used for comparing categorical variables. Pearson’s chi-squared test or Fisher’s exact test was used for comparing categorical variables. Univariate logistic regression analysis was used to evaluate the effect of different demographic and clinical variables for the presence of CAD. Subsequent multiple logistic regression analyses were performed to identify the independent predictors of CAD. Receiver operating characteristic analysis was performed to detect cut-off values for clinical variables that could be high-risk criteria for CAD in patients with psoriasis. P < 0.05 was considered as statistically significant in all analyses. All statistical analyses were performed using SPSS for Windows (version 15.0; SPSS, Chicago, IL, USA).
Results Demographic characteristics and CV risk factors of the study population are summarized in Table 1. Both groups were successfully matched for age and sex. There were no significant differences in blood pressure, body mass index, waist circumference, or serum lipid and glucose levels between patients with psoriasis and controls. Prevalence of hypertension, diabetes, smoking, family history of CV disease, and FRS were also similar in both groups. Patients with psoriasis had a mean disease duration of 16 10.2 years. The mean PASI index of the study group was 6.6 4.0. The treatment for psoriasis was as follows: drug therapy (14 patients, 35%), phototherapy (10 patients, 25%), and both drug therapy and phototherapy (eight patients, 20%). During therapy, the patients were receiving methotrexate (14 patients), cyclosporine (11), and acitretin (seven). Eleven patients (27.5%) had a history of inpatient treatment with a mean number of 1.2 1.0 episodes of hospitalization. ª 2014 The International Society of Dermatology
Table 1 Demographic characteristics and cardiovascular risk factors of the study population
Sex Male Female Age Hypertension Diabetes Current smoker Smoking duration (years) Ex-smoker Years since quitting smoking Family history of CVD Body mass index (kg/m2) Waist circumference (cm) Systolic BP (mmHg) Diastolic BP (mmHg) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Fasting glucose (mg/dl) Postprandial glucose (mg/dl) Hemoglobin A1c (%) hs-CRP (mg/dl)
Psoriasis (n = 40)
Controls (n = 42)
P value
20 20 41.2 8 4 21 11.8 17 3.8 11 27.7 97.8 122.6 76.0 201.8 163.9 46.5 128.0 102.4 113.6 5.5 0.4
18 24 42.2 11 2 15 9.5 16 3.1 12 29.7 97.2 124.6 77.7 205.2 141.5 44.3 130.7 102.5 119.3 5.3 0.4
0.51
(50%) (50%) 10.7 (20%) (10%) (52.5%) 12.3 (42.5%) 1.1 (27.5%) 5.4 13.7 11.0 7.4 41.6 103.0 8.7 55.0 21.6 39.4 0.7 0.27
(42.9%) (57.1%) 7.1 (26%) (4.8%) (35.7%) 10.7 (38.1%) 0.7 (29.3%) 8.9 15.1 19.0 10.9 37.5 54.8 13.0 34.9 10.8 30.0 0.4 0.34
0.90 0.50 0.42 0.12 0.33 0.68 0.36 0.86 0.35 0.91 0.86 0.36 0.82 0.65 0.07 0.51 0.49 0.23 0.26 0.34
BP, blood pressure; hs-CRP, high-sensitivity C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Coronary arteriosclerosis was demonstrated in six (15%) patients with psoriasis and in seven (16.7%) controls (P = 0.83). Non-calcified soft coronary plaques were observed in one patient with psoriasis and in two controls. The CCS of the two groups was not statistically significant: mean calcification scores was 9.9 35.2 AU (range: 0–174) for the patient group and 2.8 12.0 AU (range: 0–76) for the control group (P = 0.81). The International Journal of Dermatology 2014
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treatment regimens for psoriasis in patients with CAD were as follows: systemic drug therapy and phototherapy (three patients), systemic drug therapy (two), and phototherapy (one). Acitretin was used in one patient, cyclosporine in two, combination of methotrexate and cyclosporine in one, and combination of acitretin, methotrexate, and cyclosporine in one, for the systemic treatment of patients with psoriasis who had CAD. None of the patients with psoriasis and CAD were in the high-risk category for CV events according to FRS; two patients were in the low-risk category with an estimated risk of 20.0) psoriasis, and these scores were compared with the general population.15 Compared with the general population, 10-year risks of patients with both moderate and severe psoriasis were 28.0% greater for CAD. Gelfand et al. showed that the 5-year risk of myocardial infarction for patients with mild psoriasis was similar with the risk of a control population adjusted for CV risk factors whereas the same risk was higher than both groups in patients with severe psoriasis that required systemic therapy.24 It may be suggested that the severity of the psoriatic disease, rather than the disease itself, may be responsible for developing CAD, but this issue must be confirmed with prospective randomized studies comparing the prevalence of coronary heart disease in patients with mild, moderate, and severe psoriasis. Current data suggest that the long-term risk for CV events is higher in patients with severe psoriasis compared to patients with mild psoriatic disease; however, the prevalence of silent CAD in patients with mild psoriasis is still unclear. Age is one of the major well-known risk factors for the occurrence of CAD and was identified as one of the independent clinical predictors of CAD in the current study. This may be another reason for the lower prevalence of CAD in our patient group compared to those of the two previous studies, as our study group tended to be younger (mean age 41 years) than the patients with psoriasis in Ludwig et al. (mean age 49 years) and Yiu et al.9,10 (mean age 46 years). Systemic therapies used in the treatment of severe psoriasis may correct endothelial dysfunction by their anti-inflammatory effects and decrease the risk of CV events. For example, Prodanovich et al. International Journal of Dermatology 2014
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demonstrated a significant reduction in the incidence of vascular disease with methotrexate therapy in patients with psoriasis.25 In the current study, 35% of the patients were receiving methotrexate therapy with a mean 16.0 10.2 years, and the mean PASI score was 6.6 4.0.25 Although the patients in the study group of Yiu et al.10 had a similar mean duration of disease (15.7 7.1 years) and higher usage of methotrexate therapy (56%), mean PASI score was still higher (14.2 9.6) than the score of our group. Early identification of patients with psoriasis with silent CAD is an important issue. The usefulness of FRS in patients with psoriasis was validated in a former study.26 Gisondi et al. reported that the FRS of patients with chronic plaque psoriasis is significantly higher than the age- and sex-matched controls. Patients with psoriasis had an intermediate 10-year estimated risk of developing CV events (with a mean score of 11.0 8.0), which warrants early interventions aimed to correct modifiable risk factors such as antihypertensive, antidiabetic, and antilipidemic drugs, and the cessation of smoking.26 However, FRS may be insufficient to estimate risk in younger patients and women, and it may underestimate the risk in patients with inflammatory diseases. Mehta et al. suggested that the FRS will be insufficient to identify patients with increased risk for subclinical vascular disease that warrants early and aggressive risk factor modification,27 and they recommended the utilization of a modified FRS, which uses the addition of a 6.2% attributable risk of psoriasis to the calculated FRS.5,27 In the current study, the mean estimated 10year risk for CV events for patients with psoriasis with subclinical atherosclerosis was 9.17 6.79%, which corresponds to a low–moderate risk category according to the FRS. As none of these patients was in the high-risk category, early and aggressive treatment for modifying atherosclerotic risk factors may be neglected by only using the FRS. We have shown that silent CAD can be predicted in patients with psoriasis by using two simple parameters (age ≥48 years and FBG ≥99 mg/dl) with a very good sensitivity and specificity. In addition to patients with high-risk FRS, early and aggressive intervention for modifying CV risk factors may also be recommended for patients with psoriasis with an age of ≥48 years and FBG ≥ 99.0 mg/dl who are in low–moderate FRS. All patients with subclinical atherosclerosis in the study group were either receiving systemic drug therapy or phototherapy and, therefore, may be considered to have a severe psoriatic disease. This finding is also consistent with previous studies suggesting a strong correlation between the severity of the psoriasis and CV disease. Use of age and FBG criteria for early CV risk modification may be more valuable in patients with International Journal of Dermatology 2014
severe psoriasis to prevent the progression of a probable existing subclinical atherosclerosis. Study limitations
Because of the small sample size and exclusion criteria of the study group, the observed prevalence of CAD in patients with psoriasis may not reflect the exact value of the population with psoriasis. The effect of different treatment modalities on the prevalence of subclinical CAD was not analyzed due to the small sample size of the study group. Accuracy of the recommended criteria for identifying high-risk patients for subclinical CAD should be also validated with future prospective studies that include larger study cohorts. Conclusion In conclusion, this study shows that patients with mild psoriasis and controls have the same prevalence of calcified and non-calcified atherosclerotic coronary lesions. However, as early identification of atherosclerosis in young patients with psoriasis is important, age and FBG may be useful in choosing patients for further cardiovascular evaluation. As the data on prevalence of silent CAD and calcification in psoriasis are contradictory, we still need to have further prospective studies for a more accurate identification of patients with psoriasis at high risk for CAD. References 1 Armstrong AW, Voyles SV, Armstrong EJ, et al. Angiogenesis and oxidative stress: common mechanisms linking psoriasis with atherosclerosis. J Dermatol Sci 2011; 63: 1–9. 2 Methe H, Brunner S, Wiegand D, et al. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol 2005; 45: 1939– 1945. 3 Boehncke WH, Boehncke S, Tobin AM, et al. The psoriatic march: a concept of how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol 2011; 20: 303–307. 4 Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol 2004; 19: 225–230. 5 Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med 2011; 124: 775. 6 Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease hospitalizations: results of a large population-based Dutch cohort. J Invest Dermatol 2010; 130: 962–967. 7 Stern RS. Psoriasis is not a useful independent risk factor for cardiovascular disease. J Invest Dermatol 2010; 130: 917–919. ª 2014 The International Society of Dermatology
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8 Qureshi AA, Choi HK, Setty AR, et al. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol 2009; 145: 379–382. 9 Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol 2007; 156: 271–276. 10 Yiu KH, Yeung CK, Zhao CT, et al. Prevalence and extent of subclinical atherosclerosis in patients with psoriasis. J Intern Med 2013; 273: 273–282. 11 Berth-Jones J, Grotzinger K, Rainville C, et al. A study examining inter- and intrarater reliability of three scales for measuring severity of psoriasis: psoriasis Area and Severity Index, Physicians Global Assessment and Lattice System Physicians Global Assessment. Br J Dermatol 2006; 155: 707–713. 12 Third Report of the National Cholesterol Education Program. (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–3421. 13 Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 5: 827– 832. 14 Prodanovich S, Kirsner RS, Kravetz JD, et al. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol 2009; 145: 700–703. 15 Kimball AB, Guerin A, Latremouille-Viau D, et al. Coronary heart disease and stroke risk in patients with psoriasis: retrospective analysis. Am J Med 2010; 123: 350–357. 16 Tobin AM, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol 2010; 37: 1386–1394. 17 Love TJ, Qureshi AA, Karlson EW, et al. Prevalence of the metabolic syndrome in psoriasis: results from the
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National Health and Nutrition Examination Survey, 2003-2006. Arch Dermatol 2011; 147: 419–424. Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246. Raychaudhuri SP, Jiang WY, Raychaudhuri SK. Revisiting the Koebner phenomenon: role of NGF and its receptor system in the pathogenesis of psoriasis. Am J Pathol 2008; 172: 961–971. Florez H, Castillo-Florez S, Mendez A, et al. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Res Clin Pract 2006; 71: 92–100. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol 2008; 60: 218–224. Armstrong AW, Harskamp CT, Ledo L, et al. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol 2012; 109: 976–980. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: 1735–1741. Prodanovich S, Ma F, Taylor JR, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol 2005; 52: 262–267. Gisondi P, Farina S, Giordano MV, et al. Usefulness of the Framingham risk score in patients with chronic psoriasis. Am J Cardiol 2010; 106: 1754–1757. Mehta NN, Yu Y, Saboury B, et al. Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study. Arch Dermatol 2011; 147: 1031–1039.
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