The Relationship between Lichen Planus and Carotid Intima Media Thickness

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1 Brief Report Acta Cardiol Sin 2016;32: doi: /ACS A The Relationship between Lichen Planus and Carotid Intima Media Thickness Koseoglu C, 1 Erdogan M, 2 Koseoglu G, 3 Kurmus O, 4 Ertem AG, 2 Efe TH, 5 Kurmus GI, 6 Durmaz T, 2 Keles T 2 and Bozkurt E 2 Background: Lichen planus (LP) is a chronic inflammatory disease. Although the association between chronic inflammation and subclinical atherosclerosis has been reported in the literature, the relationship between LP and carotid intima media thickness (CIMT) has not been previously investigated. The aim of this study was to investigate the relationship between LP and CIMT. Methods: One hundred eleven LP patients and 105 controls were enrolled in the study. Then, CIMT examination was performed with an ultrasonography device. Cross-sectional associations of LP with CIMT were analyzed using linear regression models adjusted for related confounders. Results: No statistical difference was found between LP and the controls except for the female gender, white blood cell, LDL cholesterol and triglycerides (p = 0.046, p = 0.019, p = and p = 0.013, respectively). Significant difference was found between the groups in terms of CIMT ( mm vs mm, p = 0.001). CIMT was correlated with longevity of the LP, but we did not find LP to be an independent predictor of increased CIMT in logistic regression analysis (r = 0.449, p < 0.001, = , p = 0.092; respectively). Conclusions: The results of our study suggested that LP was associated with increased mean CIMT, and furthermore that CIMT was correlated with longevity of LP. However, LP was not an independent predictor of increased CIMT. Key Words: Carotid intima media thickness Lichen planus Subclinical atherosclerosis INTRODUCTION Received: May 20, 2015 Accepted: February 24, Deparment of Cardiology, Ankara Training and Research Hospital; 2 Department of Cardiology, Ataturk Training and Research Hospital; 3 Department of Dermatology, Ankara University Faculty of Medicine, Ankara; 4 Department of Cardiology, Tarsus State Hospital, Mersin; 5 Department of Cardiology; 6 Department of Dermatology, D skap Y ld r mbeyaz t Training and Research Hospital, Ankara, Turkey. Address correspondence and reprint requests to: Dr. Cemal Koseoglu, Ankara Training and Research Hospital, Alt ndag, Ankara, Turkey. Tel: ; drcemalkoseoglu@hotmail.com Lichen planus (LP) is a chronic, idiopatic, immunemediated inflammatory disease that affects the skin and mucous membranes. 1 The disease occurs in % of the population and mostly influences middle-aged women. 2 It has been described in the literature that chronic inflammation in LP may predispose to dyslipidemia, diabetes mellitus, and increased oxidative stress, and also that these factors and inflammation are associated with endothelial dysfunction and atherosclerosis. 2,3-5 Clinical and subclinical cardiovascular involvement have been reported in patients with psoriasis, which is recognised as a chronic inflammatory skin disease that displays a similar physiopathology as LP. 6 However, there is considerable lack of evidence of a relationship between LP and the subclinical atherosclerotic process. Carotid intima media thickness (CIMT) is an indicator of subclinical atherosclerosis, and studies have shown that it points out cardiovascular events and mortality. 7,8 CIMT has also been found to be associated with coronary artery disease and coronary atherosclerotic load. 9,10 In this study, we aimed to evaluate the subclinical atherosclerotic process with measurement of CIMT in patients with LP. Acta Cardiol Sin 2016;32:

2 Carotis Intima Media Thickness and Lichen Planus MATERIAL AND METODS Patient selection A total of 153 patients with lichen planus, who were admitted to the outpatient clinic of the department of dermatology according to exclusion and inclusion criterias described below, were consecutively enrolled in this study. Additionally, 105 age-matched controls were admitted to the outpatient clinic of department of cardiology and consecutively enrolled in the study. Inclusion criteria for the study group were as follows: 1) men or women > 18 years of age, and 2) LP that was confirmed according to clinical and histopathologic criteria established by World Health Organisation criteria. LP was assessed clinically in a standardized dermatological examination by experienced, trained physicians, including dermatological consultants. The patient examinations involved the entire body, including the scalp and nails. Longevity of LP is defined as length of the time from first diagnosis of LP to the study enrollment. Patients with renal failure, hepatic insufficiency, a history of cardiovascular, cerebrovascular disease or connective tissue disease, hypertension and presence of epithelial dysplasia were excluded from the study. Thirty-five patients with systemic treatment, such as steroid, immune-suppresive treatment, retinoids, lipidlowering therapy, antihypertensive or antiaggregant drugs, were excluded from the study. Seven patients from the LP group (two men and five women) were excluded as they had lichenoid drug eruptions. Ultimately, the final number of patients included in our study was 111. Cutaneous involvement was presented in 62 (55.8%) patients, mucosal lesions were presented in 39 (35.1%) patients and 10 (9.0%) patients had mucocutaneous involvement. The study was approved by the local ethics committee,andinformedconsentwasobtainedfromall of the participants. Clinical and biochemical parameters For this study, we first measured body height and weight, blood pressure and body mass index. Thereafter, serum triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, glucose levels were determined in samples collected after a 12-hour fasting period. Total plasma cholesterol, triglyceride, and HDL cholesterol were measured by an enzymatic colorimetric method using an autoanalyzer and reagents from (Olympus AU 600, Olympus Diagnostics GmbH, Hamburg, Germany). The LDL cholesterol levels were calculated using the Friedewald formula, and blood glucose was measured by the glucose oxidase method. The blood was collected in tripotassium EDTA tubes, and blood counts were measured on a Sysmex XT-1800i Hematology Analyzer (Sysmex Corporation, Kobe, Japan). CIMT The carotid artery B-mode ultrasonography examinations were carried out with a Vivid 7 Pro ultrasonography device (Vingmed System Seven GE ultrasound, Horten, Norway) using a 5-12 MHz linear array transducer. All ultrasonography examinations were performed by the same operator who was unaware of the patients diagnosis. Those images obtained during ultrasonographic imaging were recorded electronically and then evaluated. The carotid artery imaging was performed while the patient was lying in a supine position lifting his neck at an angle of approximately 20 to the front. The far walls of the right and left common carotid arteries were evaluated. The intima media thickness was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo. CIMT measurements were carried out from the longitudinal plane during the B-mode examination. The averages of the CIMT values obtained from the far walls of the right and left common carotid arteries were then calculated. Statistical analysis We used the Kolmogorov-Smirnov test to evaluate normal distrubition. Continuous variables were expressed as mean standard deviation (SD), and categorical variables were defined as numbers and percentages. Student s t-test was used to compare continuous variables and the Mann-Whitney U test was used for non-normally distributed data. Differences in the distrubition of categorical variables were assessed by chi-square analysis. Pearson s and Spearman s analyses were used for correlation analysis, and multiple logistic regression analysis was performed for parameters affecting the CIMT. The SPSS (SPSS, 16.0, Chicago, IL, USA) package 739 Acta Cardiol Sin 2016;32:

3 Koseoglu C et al. program was used for all statistical analyses. p values less than 0.05 were tabulated as statistically significant. RESULTS Demographical, clinical and biochemical parameters of patients are shown in Table 1. Patients in the two groups were well balanced with regard to age, body mass index, smoking history, diabetes mellitus, systolic blood pressure, and diastolic blood pressure. Hematological variables of both groups and the comparisons are also summarized in Table 1. No statistical differences were found between LP and the controls except for the gender (73.8% vs. 40%, p = 0.046), white blood cell (WBC) ( / L, / L, p = 0.019), LDL cholesterol ( mg/dl vs mg/dl, p = 0.011) and triglycerides ( mg/dl vs mg/dl, p = 0.013). There was a significant difference between the groups in terms of CIMT ( mm vs mm, p = 0.001). There was a positive correlation between the CIMT and WBC, male sex and longevity of the LP (r = 0.421, p = vs. r = 0.278, p = 0.021; r = 0.449, p < 0.001; respectively) (Table 2). After adjustments for relevant confounders (age, sex, smoking, diabetes mellitus, systolic blood pressure, diastolic blood pressure, LDL cholesterol, triglycerides), LP was not an independent predictor of increased CIMT ( = , p = 0.092). Only age and diastolic blood pressure were found to be independent predictors of increased CIMT ( = 0.248, p = vs. = , p = 0.040) (Table 3). In subgroup analysis regarding involment of LP, CIMT was higher in both mucosal LP, cutaneouslpandmucocutaneouslppatientscomparedtothe controls (p = 0.002, p < 0.001, p = 0.001, respectively). DISCUSSION This prospective case-control study showed that CIMT was increased in patients with LP who had no clinical evidence of heart disease. There was a positive correlation between the CIMT and longevity of the LP. Additionally, LP was not an independent predictor of increased CIMT after adjustments for relevant confounders (age, sex, smoking, diabetes mellitus, systolic blood Table 1. Baseline characteristics of the study population Variables Patients with lichen planus (n = 111) Control patients (n = 105) p value Age (years) Female, n (%) 82 (73.8) 42 (40) Body mass index (kg/m 2 ) Systolic blood pressure, (mmhg) Dystolic blood pressure, (mmhg) Diabetes mellitus, n (%) 19 (17.1) 20 (19.0) Smoking, n (%) 31 (27.9) 30 (28.5) Hypercholesterolemia, n (%) 47 (42.3) 28 (26.6) Low density lipoprotein, (mg/dl) High density lipoprotein, (mg/dl) Triglycerides, (mg/dl) Total cholesterol, (mg/dl) Creatinine, (mg/dl) Glucose, (mg/dl) Heamoglobine, (g/l) White blood cell, (10 3 / L SD) Left ventricule ejection fraction, n (%) Mean time with lichen planus, (month) Carotid intima media thickness, (mm) Mucosal lichen planus, n = 39 (35.1%) Cutaneous lichen planus, n = 62 (55.8%) < < Mucocutaneous lichen planus, n = 10 (9.0%) Acta Cardiol Sin 2016;32:

4 Carotis Intima Media Thickness and Lichen Planus Table 2. Correlation of carotid intima media thickness in patients with lichen planus Variables *r p value Age, (years) Male sex Body mass index (kg/m 2 ) Diabetes mellitus Smoking SBP, (mmhg) DBP, (mmhg) LDL cholesterol, (mg/dl) Trigyceride, (mg/dl) White blood cell, (10 3 / L SD) Longevity of LP < < * Coefficient of correlation. DBP, diastoilc blood pressure; LDL, low density lipoprotein; LP, lichen planus; SBP, systolic blood pressure. pressure, diastolic blood pressure, LDL cholesterol, triglycerides). CIMT is recognized as a marker of subclinical atherosclerosis. A population-based study of 15,792 subjects established the association of CIMT with incident coronary heart disease. 11 InastudybyO Learyetal.,itwas found that increased CIMT was associated with increased risk of new myocardial infarction in subjects without clinical cardiovascular disease. 12 Nambi et al. stated that measurement of intima media thickness of common carotid arteries in concert with plaque information improved coronary heart disease risk prediction. 7 Increased CIMT has been reported in several chronic inflammatory diseases such as androgenetic alopecia and psoriasis. 13,14 A similar mechanism probably explains the increased CIMT in LP. It has been hypothesizedthattheassociationbetweenlpandcardiovascular (CV) risk is due to chronic systemic inflammation. 3,15 It is generally accepted that cell-mediated immune dysfunction is implicated in LP etiology and pathophysiology. Antigens are processed by Langerhans cells and then presented to T lymphocytes. This stimulated T lymphocytic infiltrate attacks keratinocytes. Then, a larger number of cytokines is released by wounded keratinocytes. This induces further release of cytokines and chemokines belonging to either T helper-1 or T helper-2 groups. 16 It was found by Mattsson et al. that serum levels of interleukin IL-2, IL-6 and IL-10 [besides tumor Table 3. Independent predictors of carotid intima media thickness in all study patients Variable * pvalue Age, (years) Male sex Body mass index (kg/m 2 ) Diabetes mellitus Smoking SBP, (mmhg) DBP, (mmhg) LDL cholesterol, (mg/dl) Trigyceride, (mg/dl) White blood cell, (10 3 / L SD) LP * Coefficient of logistic regression analysis. DBP, diastoilc blood pressure; LDL, low density lipoprotein; LP, lichen planus; SBP, systolic blood pressure. necrosis factor- (TNF- ) and transforming growth factor- (TGF- )] were elevated within the subepithelial infiltrate in patients with LP. 17 In LP patients, increased levels of TNF-, interleukin IL-2, and IL-6 have been reported. In our study, indicators of inflammation such as white blood cell were significantly higher in patients with LP. We also found positive correlation between CIMTandWBCinpatientswithLP,andwesurmisedthat thereasonforthismaybeattributabletochronicinflammation in that similar results were demonstrated in patients with psoriasis by Yurtdas et al. 18 Yiu et al. demostrated that severity and area of psoriasis were associated with CIMT. 19 We found that CIMT was higher in all involvement types of LP than in the controls. But there were only ten patients with mucocutaneous involvement in our study, and this small sample size limited our investigation to evaluating the correlation between CIMT and severity of disease. Dyslipidemia constitutes a risk factor for atherosclerosis. Cabellero et al. showed a correlation between familial dyslipidemia and CIMT. 20 Recently, a case-control study demonstrated that lichen planus was associated with dyslipidemia in a large series of patients. 3 Furthermore, we also found significantly higher LDL cholesterol and trigylceride levels in patients with LP. To identify whether LP can be associated with increased CIMT through dyslipidemia, we performed correlation and regression analysis. However, LDL and triglyceride values were not correlated with CIMT and they were not pre- 741 Acta Cardiol Sin 2016;32:

5 Koseoglu C et al. dictors of increased CIMT in LP patients. Although a higher prevalence of dyslipidemia was detected in patients with LP, data revealing the association between dyslipidemia and LP were limited. Lipid profile screening in patients with LP may be useful in detecting individuals at risk but further large scale studies are required to identify aggressive and early risk modification in men andwomenwithlp. CONCLUSIONS Carotid intima media thickness was increased in patients with LP who had no clinical evidence of heart disease. Although LP was not found to be an independent predictor of increased CIMT, these results may be important in the early detection of subclinical atherosclerotic process and subsequent cardiovascular events in patients with LP. This is the first study which investigated the relationship with LP and CIMT, and further large studies are necessary for this relation to be better illuminated. Study limitation The small number of study patients and lack of long-term clinical follow-up are the major limitations of this investigation. In our study, age is an independent predictor of CIMT, and longevity of LP is correlated with CIMT. The other limitation is that older patients may have a longer duration of LP and the association between longevity of LP and CIMT may be confounded by age. Further studies with large sample size are neccessary to evaluate the relation between LP, severity of disease and subclinical atherosclerotic risk. CONFLICT OF INTEREST None. REFERENCES 1. Arias-Santiago S, Buendia-Eisman A, Aneiros-Fernandez J, et al. Lipid levels in patients with lichen planus: a case-control study. J Eur Acad Dermatol Venereol 2011;25: Seyhan M, Ozcan H, Sahin I, et al. High prevalence of glucose metabolism disturbance in patients with lichen planus. Diabetes Res Clin Prac 2007;77: Dreiher J, Shapiro J, Cohen AD. Lichen planus and dyslipidaemia: a case control study. Br J Dermatol 2009;161: Aly DG, Shahin RS. Oxidative stress in lichen planus. Acta Dermatovenerol Alp Pannonica Adriat 2010;19: Balta S, Cakar M, Demirkol S, et al. Arterial stiffness itself without other inflammatory markers may not provide information to clinicians. J Clin Hypertens 2013;15: Rocha-Pereira P, Santos-Silva A, Rebelo I, et al. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta 2001;303: Nambi V, Chambless L, He M, et al. Common carotid artery intima-media thickness is a good as carotid intima-media thickness of all carotid artery segments in improving prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study. Eur Heart J 2012;33: Lorenz MW, Schaefer C, Steinmetz H, et al. Is carotid intima media thickness useful for individual prediction of cardiovascular risk? Ten-year results from the Carotid Atherosclerosis Progression Study (CAPS). Eur Heart J 2010;31: Amato M, Montorsi P, Ravani A, et al. Carotid intima-media thickness by B-mode ultrasound as surrogate of coronary atherosclerosis: correlation with quantitative coronary angiography and coronary intravascular ultrasound findings. Eur Heart J 2007; 28: Guaricci AI, Arcadi T, Brunetti ND, et al. Carotid intima media thickness and coronary atherosclerosis linkage in symptomatic intermediate risk patients evaluated by coronary computed tomography angiography. Int J Cardiol 2014;176: Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, Am J Epidemiol 1997;146: O Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. NEngJMed1999;340: Arias-Santiago S, Gutiérrez-Salmerón MT, Castellote-Caballero L, et al. Elevated aldosterone levels in patients with androgenetic alopecia. Br J Dermatol 2009;161: Arias-Santiago S, Gutierrez-Salmerón MT, Buendía-Eisman A, et al. Hypertension and aldosterone levels in women with earlyonset androgenetic alopecia. Br J Dermatol. 2009;162: Fedele S, Sabbah W, Donos N, et al. Common oral mucosal diseases, systemic inflammation and cardiovascular diseases in a large cross-sectional US survey. Am Heart J 2011;161: Pezelj-Ribaric S, Prso IB, Abram M, et al. Salivary levels of tumor necrosis factor-alpha in oral lichen planus. Mediators Inflamm 2004;13: Simark-Mattsson C, Bergenholtz G, Jontell M, et al. Distribution of interleukin-2, -4, -10, tumor necrosis factor-alpha and transforming growth factor beta mrnas in oral lichen planus. Arch Acta Cardiol Sin 2016;32:

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