Psoriasis is associated with increased risks of cardiovascular disease, diabetes, and obesity. Several population-based studies have suggested that patients suffering from psoriasis have an increased risk of metabolic syndrome (MS) 1.
The MS is a constellation of metabolic changes, in particular insulin resistance, which collectively confer a higher proinflammatory and prothrombotic risk. The most widely accepted criteria for MS definition have been issued by the Adult Treatment Panel III, which defines it as the presence of at least three of the following conditions: abdominal obesity [waist circumference: >102 cm (40 inch) men; >88 cm (35 inch) women]; elevated serum triglycerides (TGs) [>150 mg/dl (1.7 mmol/l) or under treatment]; low-density lipoprotein (LDL) cholesterol high-density lipoprotein (HDL) cholesterol [men: <40 mg/dl (1 mmol/l); women: <50 mg/dl (1.3 mmol/l) or under treatment]; elevated blood pressure (>130/85 mmHg or under treatment); and elevated fasting glucose (>110 mg/dl or under treatment) 2.
Previous studies have reported an association between psoriasis and an increased risk of atherosclerosis. Psoriasis and atherosclerosis are both characterized by T helper (Th)1 and Th17 activation and reduced T-regulatory cell function 3,4. The link between psoriasis and atherosclerosis may also be related to an increased prevalence of established atherosclerotic risk factors, as well as to the chronic inflammation that occurs in patients with psoriasis 5.
Endocan is a human endothelial cell-specific molecule (ESM). The history of endocan originates from the discovery of a soluble protein produced by endothelial cells: ESM-1. Later studies showed that post-translational modification of this molecule led to the identification of a dermatan sulfate chain on ESM-1 protein core, which was consequently included in the proteoglycan family, under the new name of endocan. Endocan is the product of one single gene, ESM, located in the proximal region of chromosome five long arm (5q11.2) 6.
In vivo, endocan is detected with an average concentration of ∼1 ng/ml in the serum of healthy persons 7. Endocan mRNA was first identified from cultures of human umbilical vein endothelial cells 6, and then reported in cultured human endothelial cells from the dermal microvasculature, the coronary and pulmonary arteries, and capillaries from adipose tissues 8–10. Surprisingly, endocan could not be detected in highly vascularized organs, such as brain, heart, pancreas, or liver 10, suggesting that endocan expression may be characteristic of activated rather than resting endothelial cells.
Expression of endocan is regulated by cytokines and growth factors. Tumor necrosis factor-α, interleukin-1, transforming growth factor-β1, fibroblast growth factor-2, and vascular endothelial growth factor have been shown to induce endocan expression in vitro, whereas interferon-γ inhibits tumor necrosis factor-α-induced upregulation of endocan 7. Experimental evidence indicates that endocan is a key player in the regulation of major processes such as cell adhesion in inflammatory disorders and tumor progression 11.
Endocan may play roles in the vascular contribution to organ-specific inflammation. It also interacts with and directly influences leukocyte function associated antigen (LFA)-1. Endocan may be implicated in the regulation of leukocyte extravasation at the inflammatory sites, because of the essential role of intercellular adhesion molecule-1/LFA-1 interactions during firm adhesion of human lymphocytes and monocytes 12.
Considering that only few previous studies 5,13 evaluated the role of endocan in the sera of psoriasis vulgaris patients, we aimed in this work to investigate serum and tissue levels of endocan in psoriatic patients, as it may have a role in the pathogenesis of psoriasis.
Patients and methods
This case–control study included 40 psoriatic patients and 40 age-matched and sex-matched nonpsoriatic controls. Sample size was calculated using STATA version 11 program (Statacorp., Lakeway, College Station, Texas, USA), setting the type-1 error (α) at 0.05 and the power (1-β) at 0.8 14.
All patients were randomly recruited from the outpatient clinics of the Dermatology and Venereology Department, Ain Shams University Hospitals. Informed consents were signed from all participants before the study. The study was approved by the research ethics committee, Ain Shams University.
Inclusion criteria were any patient with psoriasis vulgaris from both sexes and different age groups, with different grades of severity. Exclusion criteria were pregnancy, lactation, receiving topical or systemic therapy of psoriasis within the past 2 months before the study, psoriasis variants other than psoriasis vulgaris (erythrodermic or pustular), known malignancy, local or systemic infection, previous history of infection (<3 months), inflammatory bowel disease, hepatic, renal, or other systemic diseases, and medications (antihypertensive drugs, lipid-lowering therapy, chemotherapeutics, antidepressants, and antipsychotics).
Diagnosis of psoriasis vulgaris was based on clinical examination of all patients. All the participants in the study were subjected to full history taking; general and dermatological examination; and measurement of body height and weight, waist/hip circumference ratio, blood pressure, and BMI. The presence or absence of MS was determined according to the definition issued by the Adult Treatment Panel III 2. Psoriasis severity was evaluated by the same dermatologist according to the psoriasis area and severity index (PASI). Patients with PASI score less than 10 were considered to have mild disease, whereas those with PASI scores more than or equal to 10 were considered to have moderate-to-severe disease 15.
Venous blood samples (3 ml) were collected from both patients and controls. The samples were withdrawn without stasis at 7.00–8.00 a.m. after 20 min of supine rest, following a fasting period of 12 h, and allowed to clot for 30 min. Samples were then centrifuged and sera were stored in aliquots at −20°C until assayed. Total plasma cholesterol, TG, and HDL cholesterol were measured using an enzymatic calorimetric method with the Olympus AU 600 autoanalyser and reagents from Olympus Diagnostics GmbH (Hamburg, Germany). LDL cholesterol levels were calculated using the Friedewald formula. Blood glucose was measured with the glucose oxidase method.
Punch biopsies of a size of 4 mm were taken from patients and controls for evaluation of tissue endocan level in psoriatic plaques (patients) versus normal skin (nonpsoriatic controls). Tissue samples were homogenized by grinders and then centrifuged for 20 min at a speed of 2000–3000 rpm, and then the supernatant was removed.
Serum and tissue endocan levels had been estimated by using sandwich enzyme immunoassay (enzyme-linked immunosorbent assay) technique (GSCIENCE, Veterans Blvd, lab facilities China, hong kong office in USA). The procedure was performed according to the manufacturer’s instruction as supplied with the kit from Glory Science Company (lab facilities China, hong kong office in USA) (http://www.glorybioscience.com).
The collected data were revised, coded, tabulated, and introduced to a PC using statistical package for the social sciences (2001; SPSS 15.0.1 for Windows; SPSS Inc, Chicago, Illinois, USA). Quantitative variables are expressed as mean and SD or as median and interquartile range in cases of nonparametric variables. Qualitative variables are expressed as frequencies and percents. Student’s t-test was used to compare between continuous parametric variables, and Mann–Whitney test was used to compare between continuous nonparametric variables between the two study groups. χ2-Test was used to examine the relationship between categorical variables. Correlation analysis using Spearman’s method was used to assess the strength of association between two quantitative variables. Receiver operating characteristic curve was used to evaluate the sensitivity and specificity of serum endocan. Linear regression was used to test and estimate the dependence of a quantitative variable based on its relationship with a set of independent variables. P value less than 0.05 was considered statistically significant.
This case–control study included 40 psoriasis vulgaris patients – 24 (60%) male and 16 (40%) female – with age ranging from 15 to 61 years with a mean of 46.05±12.32 years, and 40 age-matched and sex-matched controls – 24 (60%) male and 16 (40%) female – with age ranging from 25 to 65 years with a mean of 43±11.44 years. As for PASI score, the patients’ score ranged between 3 and 63 (23.11±18.72). Sixteen (40%) patients showed mild disease with PASI score less than 10, and 24 (60%) patients suffered from moderate-to-severe disease with a PASI score more than or equal to 10. Sixteen (40%) patients showed positive MS criteria and 24 (60%) were negative for MS, and these numbers were the same in the controls as well.
In this study, serum endocan level in psoriatic patients ranged between 3.80 and 320.00 ng/ml and their tissue endocan values ranged between 25.00 and 43.50 ng/ml, respectively, whereas serum endocan level in controls ranged between 1.50 and 20.00 ng/ml and their tissue endocan values ranged between 6.50 and 25.00 ng/ml, respectively. The mean endocan level in serum and lesional skin biopsies showed statistically significant higher values in psoriasis vulgaris patients when compared with controls (Table 1).
The comparison between mild and moderate-to-severe psoriasis patients, as regards the mean serum and tissue endocan levels, showed a highly statistically significant increase in the levels of serum and tissue readings among the moderate-to-severe cases (P<0.01) (Table 2).
An receiver operating characteristic curve to discriminate cases from controls using serum endocan showed that the value more than or equal to 25 ng/ml could be used as a cutoff point, with 50% sensitivity and 100% specificity (Fig. 1), whereas using tissue endocan it was revealed that the value more than or equal to 23.5 ng/ml could be used as a cutoff point, with 100% sensitivity and 90% specificity (Fig. 2). In addition, serum endocan value more than or equal to 4.35 ng/ml could be used as a cutoff point between mild and moderate-to-severe patients, with 83.3% sensitivity and 75% specificity (Fig. 3), knowing that the median values of serum endocan of the controls, mild patients, and moderate-to-severe patients were as follows: 7.5 (4–10), 4 (4–4.6), and 45 (17.25–115) ng/ml, respectively.
In this study, 40% of the patients and controls showed MS-positive criteria whereas 60% were MS negative. Comparison of cases and controls as regards laboratory data [TGs, cholesterol, LDL, HDL, fasting blood sugar (FBS), systolic blood pressure (SBP), and diastolic blood pressure (DBP)] showed statistically nonsignificant differences concerning TG, cholesterol, LDL, HDL, FBS, and MS prevalence. However, there was a statistically significant increase in SBP and DBP in controls compared with cases (Table 3).
After adjustment of all factors in patients, using linear regression analysis, age, sex, disease duration, BMI, TG, cholesterol, LDL, HDL, FBS, and blood pressure, it was found that PASI score is the only determining factor that affects serum and tissue endocan levels of cases. Patients with higher PASI scores have higher serum endocan (Fig. 4) and tissue readings as well. There was also a statistically highly significant direct correlation between psoriasis duration and disease severity PASI.
However, after adjustment of all factors in the controls, using linear regression analysis, it was found that BMI, FBS, sex, hypertension, and TG were independent factors affecting serum and skin biopsy level of endocan readings. Controls with higher BMI and FBS had higher serum and tissue endocan levels, whereas female controls and those with higher levels of blood pressure and TG had lower endocan serum and tissue readings.
Endocan is a unique endothelium-derived circulating proteoglycan. Advances in biomarker research have uncovered its newer implications in health and disease 16. The pathophysiology of psoriasis is characterized by epidermal hyperproliferation, enhanced antigen presentation, Th1 cytokine production, T-cell expansion, and angiogenesis 17,18.
The results of the present study demonstrated that the mean serum and lesional skin biopsy levels of endocan were significantly higher in the psoriatic group compared with those of the control group, suggesting a role for endocan in the etiopathogenesis of psoriasis.
Our findings are in agreement with those of Balta et al. 5, who conducted a study on 29 patients with psoriasis vulgaris and 35 controls and similarly they found a significantly higher mean serum level of endocan in patients in comparison with the controls, with a significantly higher level with increased PASI score. On the other hand, ErekToprak et al. 13 found no statistically significant difference in serum endocan levels between psoriasis patients and the control group, but their correlation analyses in psoriasis patients showed that serum endocan levels were significantly correlated with PASI score. To our knowledge, no previous studies evaluated the tissue lesional level of endocan in psoriasis to compare with.
Moreover, this study showed a significant positive correlation between serum and tissue endocan readings in the psoriatic patients and PASI score. There was a significantly higher serum and tissue endocan level among patients with moderate-to-severe psoriasis than in those with mild disease, and this further supports its possible role in the etiopathogenesis of psoriasis and its additional contribution to the severity of the disease.
Endocan might contribute in the pathogenesis of psoriasis through its role in modification of cell adhesion. Endocan can enhance the production of proinflammatory cytokines by endothelial cells, increase microvascular permeability, and regulate leukocyte migration 19. It may play a role in the inflammatory process and the leukocytic adhesion to the endothelial cells and its migration to the dermis, as well as a potential role in cell proliferation. The mitogenic property of endocan has been described in several studies 16.
Endocan protein core binds to lymphocytes and monocytes through a high-affinity interaction with the integrin CD11a/CD18, also called lymphocyte function associated antigen-1 (LFA-1). In addition, Endocan has been shown to promote the mitogenic and migratory activities of vascular endothelial growth factor-A, a key molecule in angiogenesis, which is a key step in psoriasis pathogenesis 20. Endocan additionally promotes cell proliferation and thus may have a vital role in wound repair and tumor progression 16.
Multiple epidemiologic studies have consistently demonstrated higher prevalence of MS in patients with psoriasis 1,21. The underlying pathophysiology linking psoriasis and MS may involve overlapping inflammatory pathways and genetic predisposition. Endocan is a marker of endothelial dysfunction, and thus it may play a role in cardiovascular disorder and atherosclerosis tendency as confirmed by Balta et al. 5, who found a strong relation between serum endocan level, severity of psoriasis vulgaris, and atherosclerosis.
However, we surprisingly found equal prevalence of MS in psoriatic patients and nonpsoriatic controls, mostly because of the increased BMI of the Egyptian population – a phenomenon needing to be thoroughly evaluated by further studies. Similar results were reached by Praveenkumar et al. 22, who found a statistically insignificant difference between psoriatic patients and nonpsoriatic controls as regards the prevalence of the MS. Our study also revealed that MS has no statistically significant effect on the serum or tissue endocan readings neither in cases nor controls.
In this study, we compared serum and tissue endocan levels with laboratory data ‘criteria of MS’ (TGs, cholesterol, LDL, HDL, FBS, SBP, DBP, and BMI) in patients and controls. After adjustment of all factors, using linear regression test, it was found that sex, BMI, TG, FBS, and hypertension were independent factors affecting serum and tissue endocan readings in controls. On the other hand, after adjustment of all factors in the cases, it was found that PASI score is the only variable affecting the serum and tissue endocan levels.
In conclusion, this case–control study shows that endocan levels are elevated in serum and tissue of psoriatic patients more than controls, and it also reveals a positive correlation between endocan and psoriasis severity, suggesting that this molecule may play a role in the pathogenesis of psoriasis. Thus, it is worthy to investigate the use of antiendocan therapy in the treatment of psoriasis vulgaris. Antiendocan therapeutic strategy might serve to inhibit neoangiogenesis, cell migration, and alteration of cell adhesion properties, which are the main steps in the etiopathogenesis of psoriasis vulgaris.
Conflicts of interest
There are no conflicts of interest.
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