ORIGINAL ARTICLE. Introduction. Kumari Asha 1, Suman B. Sharma 1, Archana Singal 2, Amitesh Aggarwal 3

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1 ORIGINAL ARTICLE ASSOCIATION OF CAROTID INTIMA-MEDIA THICKNESS WITH LEPTIN AND APOLIPOPROTEIN B/APOLIPOPROTEIN A-I RATIO REVEALS IMMINENT PREDICTORS OF SUBCLINICAL ATHEROSCLEROSIS IN PSORIASIS PATIENTS Kumari Asha 1, Suman B. Sharma 1, Arhana Singal 2, Amitesh Aggarwal 3 University College of Medial Sienes and G.T.B. Hospital, Dilshad Garden, University of Delhi, India: Department of Biohemistry 1, Department of Dermatology 2 and Department of Mediine 3 Summary: Psoriasis patients are often suseptible to ardiovasular diseases (CVD), inluding atheroslerosis. Traditional markers (biohemial and inflammatory) and diagnosti tools ould detet olusive but not sublinial atheroslerosis. Carotid intima-media thikness (CIMT), has reently been reognised as a non invasive diagnosti tool for identifiation of premature atheroslerosis. Therefore we evaluated 80 psoriasis patients and 80 age sex mathed healthy ontrols for serum leptin levels and apolipoprotein B/apolipoprotein A-I ratio (apob/apoa-i ratio) in relation with CIMT of arotid artery. Carotid intima-media thikness and arotid plaques were simultaneously measured by arotid sonography. Serum onentration of leptin and apolipoprotein were measured using enzyme-linked immuno sorbent assay (ELISA) and nephelometry respetively. Raised CIMT orrelated to age of onset of the disease, serum leptin and apob/apoa-i ratio in psoriasis patients. Taking into aount, values that were above the 75 perentile of the three markers (leptin, apob/apoa-i ratio and CIMT) the odds ratio was 4.26 ( CI). Leptin and apob/apoa-i ratio showed signifiant umulative assoiation with CIMT. Results of preditive analysis supports measurement of CIMT along with estimation of serum leptin and apob/apoa-i ratio for predition of premature atheroslerosis in psoriasis patients. Key words: Apolipoprotein; apob/apoa-i, Leptin; Psoriasis; CIMT; Atheroslerosis Introdution Psoriasis is an immune intervened inflammatory disorder of skin that affets nearly 23% of the total world s population. The disease is aused by unusual differentiation and hyper proliferation of the keratinoytes and an be identified by presene of red, saly, sharp demarated plaques mostly over extremities and salp. Psoriasis is a systemi disease and studies suggest that patients with psoriasis are at inreased risk of ardiovasular diseases, inluding sublinial atheroslerosis (1). The inreased inidenes of ardiovasular disease in these patients annot be explained by onventional risk fators (older age, high blood pressure (BP), dyslipidemia, smoking, obesity, diabetes mellitus) alone (1, 2). There is an urgent need to study role of other ontributory fators ommon to both psoriasis and ardiovasular disease. Reently, Amerian Assoiation of Clinial Endorinologists has approved routine measurement of apolipoprotein to assess risk of ardiovasular disease (3). Serum apoa-i (apolipoprotein A-I) is an index of onentration of HDL-C (high-density lipoprotein-holesterol) in plasma and apob (apolipoprotein B) is primary apolipoprotein assoiated with LDL-C (low-density lipoprotein-holesterol). Thus the balane between the pro-atherogeni apob and the anti-atherogeni apoa-i an help in the estimation of ardiovasular risk. Previous studies have shown that both immune ell response and hroni inflammatory ells are involved in aelerating atherosleroti risk in patients of psoriasis. Immune ell dysfuntion in psoriasis produes systemi inflammation. Cytokines involved in inflammation further inreases serum leptin, a 16 kda obese protein, whih in turn inreases proinflammatory mediators, thus induing viious irle of inflammation (4). Thus, we evaluated patients for serum leptin whih is known to regulate body weight, metabolism and immunity. Additionally, leptin indues proliferative and anti-apoptoti ativities in T ell (5). Sine psoriasis is an immune mediated disease, haraterized by hyperproliferation of skin ells and infiltration of T lymphoytes, leptin may provide a link between T ell funtion and inflammation in psoriasis (6). Clinial studies done so far gave ontraditory results, suggesting a multifaeted role of leptin, as an obese protein and/or immunomodulator (dereased immune ell response), in immune-mediated inflammatory onditions in humans. ACTA MEDICA (Hrade Králové) 2014; 57(1):

2 CIMT measurement has been validated as a surrogate non invasive diagnosti tool to identify atheroslerosis at sub linial stage (7, 8). Thus, we measured CIMT and evaluated its potential relation with apob/apoa-i ratio and serum leptin in patients of psoriasis. Material and Methods Human subjets The study involved 80 adult patients ( 18 years) of either sex, diagnosed to have psoriasis, from Dermatology Outpatient Department, UCMS & GTB Hospital, Delhi and 80 age, sex and BMI mathed healthy volunteers with no known systemi disease. Norms of National Cholesterol Eduation Program Expert Panel Adult Treatment Panel III for Asian definition was adapted for defining onventional ardiovasular risk fators (smoking, entral obesity, dyslipidemia, diabetes, hypertension) in these patients (9). Inlusion and exlusion riteria Patients below the age of 18 years, pregnant and latating female patients and subjets who had systemi treatment of retinoids in last six months for the management of their psoriasis were exluded from the study. Those who were on lipid-lowering mediation were also not inluded in the study. The ontrol group omprised healthy hospital staff and patients from dermatology outpatients linis who were not undergoing any systemi therapy nor had been diagnosed with lipid metaboli disorders. Physial and linial evaluation of study groups Sine the present study involves investigations of various onventional and nononventional risk fators so onfounding fators whih are known to have an effet on blood lipids value, were reorded. All patients were subjeted to detailed personal interview and standardized linial examination using a detailed questionnaire to obtain information inluding: Physial assessment Age, sex, Body Mass Index (BMI) [wt (kg) / height (m) 2 ] (10), Waist/ Hip ratio (11). Clinial evaluation Detailed medial and treatment history inluding the use of lipid-lowering mediations, urrent igarette smoking status and alohol onsumption. Clinial severity of disease was assessed using Psoriasis Area and Severity Index (PASI) (12). The study was approved by institutional human ethial ommittee and a written onsent was obtained from all partiipants of the study. Sample olletion Following an overnight fasting, 5 ml of blood sample was drawn from partiipants using venipunture, under asepti onditions. Blood was entrifuged at 2000g for 10 minutes and serum sample thus obtained was preserved at 80 C until assayed. Assay of biohemial parameters Fasting and post prandial gluose levels were measured spetrophotometrially at 500 nm using gluose oxidase-peroxidase method. Fasting serum lipid profile estimation was done by measuring the level of total serum holesterol (TC) (enzymati-alorimetri CHOP-PAP method), serum triglyerides (TG) (enzymati GPO-PAP method), high density lipoprotein-holesterol (HDL-C), very low density lipoprotein-holesterol (VLDL-C) and low density lipoprotein-holesterol (LDL-C) (alulated using Friedwald and Fredrikson s formula). Serum onentration of apolipoprotein (apoa-i and apob) and leptin were measured using kits based on nephelometry (Goldsite Diagnostis In, China) and ELISA (BioVendor) respetively as per manufaturer s instrutions. Measurement of Carotid intima media thikness (CIMT) CIMT and plaques of both right and left arotid arteries were measured to assess sublinial atheroslerosis and strutural hanges in the vasular wall using a high resolution B mode ultrasound with a 10 MHZ linear vasular probe (13). All arotid ultrasound measurements were performed by an expert ardiologist. Values above 0.7 mm were defined as elevated CIMT (14). The mean CIMT was alulated as the arithmetial mean of two measurements of the left and right arotid arteries. Statistial analysis Statistial analysis was arried out using standard statistial software (SPSS software version 20). Quantitative data were expressed as mean ± standard deviation. Comparison between patients and ontrols for different parameters was done using t-test. Pearson orrelation analysis was used to determine the relation of CIMT with other risk variables. The differene between patients with psoriasis and ontrol group under study has been explained using test of equality of orrelations oeffiients. We generated reeiver operator harateristi (ROC) urve for serum leptin, apob/ apoa-i ratio and mean CIMT. Speifiity, sensitivity and preditive values were alulated using MedCal statistial software. Assoiation of PASI with CIMT was investigated using adjusted logisti regression model. Multivariate regression analysis was used to study the effet of inde- 22

3 pendent (preditor) variables on one dependant (CIMT) variables. For all statistial tests, P < 0.05 was onsidered signifiant. Results Clinial harateristis A total of 80 patients of psoriasis and an equal number of age-sex mathed ontrols were inluded in the study, to rule out any possible role of onfounding fators. Most of the patients (30% eah) were either from the 3140 years or 5160 years age group. The demographi and linial data of study subjets has been summarized in the Tab. 1. Eighty perent of patients were suffering with psoriasis vulgaris, the most ommon variant of psoriasis. Assoiation of atherogeni risk fators with disease in patients The main atherogeni harateristis of patient and ontrol groups are shown in Tab. 2. Conventional risk fators Of the total 80 psoriati patients studied, 4 (5.0 %) had diabetes, 4 (5 %) had hypertension, 54 (60 %) had dyslipidemia and 38 patients (47.5%) were still atively smoking with mean smoking index (number of igarettes or beedi/ day total duration in years) of ± The mean of the severity of disease (PASI) (15.60 ± 10.79) in patient group was found to be signifiantly assoiated with duration of disease (p = 0.001) (r = 0.638) and waist: hip ratio Tab. 1: Demographi and linial evaluation in psoriasis patients and healthy ontrols. Variables Control (n = 80) Psoriasis Patients (n = 80) P value Demographi variables Sex (male/female) Age (years) Lifestyle Fators Alohol use (%) Smoking (%) Anthropometri Variables (mean ± SD) Waist/hip ratio Body Mass Index (kg/m 2 ) Disease speifi harateristis (mean ± SD) Age of onset of disease Duration of Disease (months) Psoriasis Area Severity Index 60/ ± ± ± / ± ± ± ± ± ± Tab. 2: Atherogeni risk fator and CIMT measurements in psoriasis patients and healthy ontrols <0.050 <0.001 < Variables Controls (n = 80) Psoriasis Patients (n = 80) P value Systoli Blood Pressure(mmHg) 113 ± ± Diastoli Blood Pressure (mmhg) 70 ± ± Blood Sugar (Fasting) (mg/dl) ± ± Blood Sugar (PP) (mg/dl) ± ± Total Cholesterol (mg/dl) ± ± <0.001 HDL-C (mg/dl) ± ± LDL-C (mg/dl) ± ± <0.010 Triglyerides (mg/dl) ± ± <0.010 apolipoprotein A-I (g/l) 1.96 ± ± apolipoprotein B (g/l) 0.79 ± ± apob/apoa-i ratio ± ± 0.23 <0.001 Serum Leptin (ng/ml) 8.43 ± ± 7.68 <0.001 Mean CIMT (mm) 0.48 ± ± 0.14 <0.001 HDL-C High-density lipoprotein-holesterol; LDL-C Low-density lipoprotein-holesterol; mean CIMT mean Carotid intima-media thikness. 23

4 (r = 0.412, p < 0.01). Smoking Index was signifiantly orrelated (r = 0.483), (p < 0.05) to severity (PASI) of disease. The data shows that disease gets severe with time and a hange in lifestyle may help in urbing the disease. Nononventional risk fators Serum apob levels (P < 0.05) and apob/apoa-i (P < 0.001) ratio in patients were signifiantly higher as ompared to ontrol subjets while the differene in serum apoa-i onentration of two groups were statistially insignifiant. Serum leptin levels in patients of psoriasis (16.57 ± 7.68) was signifiantly higher (p < 0.001) than those of healthy ontrols (8.43 ± 3.64) (Tab. 2). The study shows onsiderable orrelation (r = 0.603, p < 0.05) between higher serum leptin level and raised waist/hip ratio in patients. However no orrelation was observed between serum leptin levels and lipid profile. CIMT measurement and its orrelation with atherogeni parameters The mean CIMT values of the right and left arotid artery of the patients were found to be signifiantly higher (p < 0.001) ompared with the ontrols (0.658 ± 0.13 mm vs ± 0.09 mm and ± 0.13 mm vs ± 0.08 mm respetively). Among patients, 26 (32.5 %) reported an abnormal inrease in CIMT i.e. above 0.7 mm. Data in Tab. 3 shows intra group omparison in patients of psoriasis, based on whether or not the CIMT was more than 0.7 mm. There was signifiant differene between two subgroups (based on CIMT ut off of 0.7mm) of patients for CIMT (p < 0.001), apob/ apoa-i ratio (p < 0.001) and serum leptin (p < 0.05) levels. We analysed the assoiation between CIMT and other variables studied in the patient and in the ontrol group (Tab. 4). All orrelations were standardized for age and BMI. Signifiantly different trends were found for the orrelation of CIMT with leptin in patient group than those in the ontrol group. Data in Fig. 1 suggests that greater CIMT values were signifiantly assoiated with age of patient, age of onset of disease (p < 0.001), smoking index, systoli blood pressure, diastoli blood pressure, serum leptin, apob onentration (p < 0.05) and apob/apoa-i (p < 0.001) in patient group. However, CIMT was not found to be orrelated to either duration, severity of the disease or serum apoa-i onentration in the patients of psoriasis. Even after adjustment for other onfounding fators (smoking index and disease duration) no signifiant assoiation (partial R = 0.067, p = 0.07) was observed between CIMT and severity of psoriasis (PASI). Tab. 3: Anthropometri and laboratory values lassified by CIMT in psoriasis patients. Variable CIMT > 0.70 mm (N = 26) CIMT < 0.70 mm (N = 54) P value Age (years) ± ± Waist/hip ratio 0.92 ± ± Body Mass Index (kg/m 2 ) ± ± Age of onset (years) ± ± <0.001 Duration (months) ± ± PASI ± ± Smoking Index ± ± Systoli blood pressure (mmhg) 125 ± ± Diastoli blood pressure (mmhg) 82 ± ± Blood Sugar (Fasting) (mg/dl) ± ± Blood Sugar (pp) (mg/dl) ± ± Total holesterol (mg/dl) ± ± HDL-C (mg/dl) ± ± LDL-C (mg/dl) ± ± Triglyerides (mg/dl) ± ± apolipoprotein B (g/l) 1.23 ± ± apolipoprotein A-I (g/l) 1.58 ± ± apob/apoa-i ratio 0.81 ± ± 0.19 <0.001 Leptin (ng/ml) ± ± Mean CIMT (mm) 0.82 ± ± 0.05 <0.001 PASI Psoriasis Area Severity Index; HDL-C High-density lipoprotein-holesterol; LDL-C Low-density lipoprotein-holesterol; CIMT Carotid intima-media thikness. 24

5 Tab. 4: Correlation of Carotid intima media thikness with ardiovasular risk fators in patients of psoriasis and ontrols. Variables Controls (n = 80) Psoriasis Patients (n = 80) Equality of orrelation oeffiients P value Systoli blood pressure Diastoli blood pressure Total Cholesterol Triglyerides HDL holesterol LDL holesterol apolipoprotein A apolipoprotein B apob/apoa-i ratio Leptin < Pearson orrelation oeffiient a a a Age BMI W/H Onset age Duration PASI SI DBP SBP TC LDL HDL TG apoa-i apob apob/apoa-i Leptin Fig. 1: Bar diagram showing orrelation between CIMT and several variables. BMI Body Mass Index; W/H waist/hip ratio; PASI Psoriasis Area Severity Index; SI smoking index; DBP Diastoli blood pressure; SBP Systoli blood pressure; TC Total holesterol; LDL Low-density lipoprotein; HDL High-density lipoprotein; TG Triglyerides; apoa-i apolipoprotein A-I; apob apolipoprotein B; apob/apoa-i apob/apoa-i ratio. Non signifiant; Correlation was signifiant at the a P < 0.001, b P < 0.01, P < Results from regression analysis (F = 8.945, P < 0.001) suggested that inreased CIMT in patients may be assoiated to umulative hroni inflammation and impaired apolipoprotein and thus it an serve as a reliable indiator of sublinial disease and may help in early diagnosis of CVD risk fators assoiated with psoriasis. The 75th perentile values used to determine high risk values for apob/apoa-i ratio, leptin levels and mean CIMT were 0.73, ng/ml and 0.70 mm respetively. We alulated preditive values (sensitivity, speifiity, positive preditive value (PPV) and negative preditive value (NPV) for eah biomarker. The results are as follows: 30%, 92.5%, 80% and 56.92% for apob/apoa-i ratio; 25%, 90%, 71.43% and 54.55% for leptin and 30%, 92.5%, 80% and 56.92% for mean CIMT. The preditive values inreased (47.50%, 82.50%, 73.08% and 61.11%) when we took three biomarkers into aount (Tab. 5). A fairly signifiant kappa value of 0.3 depited that the three biomarkers an be used to assess early risk of ardiovasular disease in psoriasis patients. Assuming 75th perentile value as ut off for leptin, apob/apoa-i ratio and CIMT, the odds ratio alulated was 4.26 ( CI). Aording to results of ROC urves (Fig. 2), the variable with highest AUC (area under urve) was mean CIMT followed by serum leptin and apob/apoa-i ratio respetively. Disussion Psoriasis and atheroslerosis are systemi inflammatory disease. Psoriasis is not a life-threatening disease by itself 25

6 Tab. 5: Preditive values for biomarkers (Leptin, apob/apoa-i ratio and CIMT) 95% CI Lower limit Higher limit Disease prevalene 50.00% 42.00% 58.00% Sensitivity 47.50% 36.21% 58.98% Speifiity 82.50% 72.38% 90.08% Positive preditive value 73.08% 58.97% 84.42% Negative preditive value 61.11% 51.25% 70.34% Sensitivity (%) however ardiovasular risk fators assoiated with the disease, at times, make it fatal (15, 16, 17). Reently few studies from western ountries have reported that psoriasis may be independently assoiated with myoardial infartion (18, 19). Anthropometri and serum lipid measurement has been reommended in psoriasis patients, but their role is not ertain till date (2, 19, 20, 21). Thus, we evaluated psoriasis patients for both onventional and non onventional ardiovasular risk fators. Reently, CIMT has been reognised as reliable non invasive diagnosti tool to identify premature atheroslerosis. We studied potential role of apob/apoa-i ratio and serum leptin levels as preditor for sublinial atheroslerosis, in assoiation with CIMT. We mathed age, sex and BMI in patients and ontrols to rule out their possible role in evaluation of atherogeni parameters studied. It was observed that 47.5% patients were ative smoker and nearly 60% of patients were either overweight (BMI > 25 kg/m 2 ), hypertensive or had abnormal serum lipid profile. Obesity ould be sign of inativeness in these patients. In addition, waist/hip ratio was signifiantly higher in patients than ontrols (p < 0.001). In 1995, Henseler and Christophers also reported that patients with severe psoriasis were mostly overweight (22). In a similar study Naldi et al., observed that a moderate inrease in BMI was assoiated with inreased risk of psoriasis and linially obesity doubled the risk of psoriasis (23). Serum leptin (OB protein) in patient group was signifiantly related to raised waist hip ratio, PASI sore and inreased CIMT, thus providing its assoiation with psoriasis. These findings were in agreement with previous results of Enany et al. (24), Cerman et al. (25) and Hamminga et al. (26) who suggested that leptin may serve a role of marker in psoriasis. Thus we may infer that inreased serum leptin in obese patients may be orrelated to events of metaboli dysfuntion. In the study, apob levels and apob/apoa-i ratio were elevated in psoriasis and abnormal apolipoprotein metabolism may be related to the high inidene of atheroslerosis. Among patients, 32.5% had high CIMT (above 0.7 mm) with the mean CIMT (0.65 ± 0.02 mm). Reent study by Kimhi et al. (27) showed that psoriati arthritis patients had signifiantly higher CIMT ompared with ontrols (0.76 ± 0.11 versus 0.64 ± 0.27, P < ) whih was similar Speifiity (%) Mean CIMT apob/apoa-i ratio Leptin Fig. 2: Comparison of ROC urves among leptin, apob/apoa-i ratio and CIMT variable. AUC values were 0.81 (95% CI, ); 0.78 (95% CI, ) and 0.85 (95% CI, ) respetively and there was no signifiant pair wise differene for AUC values (P > 0.05). to results given by Gonzalez et al. and Mongi et al. (28, 29). In our urrent study, we have observed a similar trend with signifiantly higher CIMT (P < 0.001). Grobbee et al. (30) and Tam et al. (31, 32) have shown that presene of arotid lesions and thikened intima an be onsidered as a surrogate marker for the detetion of early atheroslerosis in sublinial stage of disease and an be orrelated to ardiovasular risks among patients and this inrease is signifiantly assoiated with linial (age of onset of the disease) and atherogeni (apob/apoa-i ratio) parameters as also revealed in our study. We did not find any orrelation of CIMT with disease duration or severity whih was similar to reports given by Youssef et al. (33). This was perhaps due to quite young age group of our patients and flutuating ourse of the disease. Our finding was onordant to those of Huang et al. who found that both apob levels and apob/apoa-i ratio were assoiated to inreased CIMT (34). As reported by Dahlen et al. we also observed that high apob/apoa-i ratio, and not serum lipid profile, were assoiated with inreased CIMT (35). Previous studies from various ountries have also demonstrated that an inreased CIMT value often orrelates to atherogeni risks in various hroni diseases (36). By regression analysis, we found a signifiant umulative effet of apob/apoa-i ratio and serum leptin (as preditors) on mean value of arotid artery reords of psoriasis patients studied (as dependent variables) (F = 8.945, P < 0.001). Thus a signifiant orrelation of ardiovasular risk fators and 26

7 inflammatory biomarkers with inreased CIMT in present population may be linked to inreased risk of sublinial atheroslerosis in the diseased group. The study further shows that CIMT along with leptin and apob/apoa-i ratio an be used as biomarkers to estimate ardia risk in patients of psoriasis. Conlusions We may onlude that the measurement of apob/apoa-i ratio rather than serum apolipoprotein estimation, an help in diagnosis of premature atheroslerosis in patients of psoriasis. Chroni inflammation plays a major ontributing role in both psoriasis and atheroslerosis. This study demonstrates the need to sreen patients for serum leptin, apob/apoa-i ratio and CIMT along with known onventional risk fators, to predit sublinial atheroslerosis and hene the future risk of CVD in patients of psoriasis. Aknowledgements This work was supported by grants from the University Grants Commission, Government of India. Referenes 1. Prodanovih S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. 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Ann Rheum Dis 2003; 62: Reeived: 02/09/2013 Aepted in revised form: 08/01/2014 Suman Bala Sharma, Department of Biohemistry, University College of Medial Sienes (University of Delhi) and G. T. B. Hospital, Dilshad Garden, Delhi, India; drsbs08@hotmail.om 27