E P I DE M I O L O G Y A N D HE A L T H S E R V IC E S RE SE AR CH
BJD
British Journal of Dermatology
Lichen planus and dyslipidaemia: a case–control study J. Dreiher,* J. Shapiro and A.D. Cohen*§ *Hospitals Division, Clalit Health Services, Tel Aviv, Israel Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 84150, Israel Dermatology Department, Soraski Medical Center, Tel Aviv, Israel §Research and Health Planning Department, Health Planning and Policy Wing, Clalit Health Services, Tel Aviv, Israel
Summary Correspondence Jacob Dreiher. E-mail:
[email protected]
Accepted for publication 18 February 2009
Key words comorbidity, dyslipidaemia, hyperlipidaemia, lichen planus, metabolic syndrome
Conflicts of interest None declared. DOI 10.1111/j.1365-2133.2009.09235.x
Background Previous reports have demonstrated an association between psoriasis and dyslipidaemia. Objectives As lichen planus (LP) is also a chronic inflammatory disorder, we investigated the association between LP and dyslipidaemia in Israel. Methods A case–control study was performed utilizing the database of Clalit Health Services, a large healthcare provider organization in Israel. Patients aged 20–79 years who were diagnosed as having LP were compared with a sample of enrollees without LP regarding the prevalence of dyslipidaemia. Data on other health-related lifestyle factors and comorbidities were collected. Results The study included 1477 patients with LP and 2856 controls without LP. The prevalence of dyslipidaemia was significantly higher in patients with LP (42Æ5% vs. 37Æ8%, P = 0Æ003; odds ratio, OR 1Æ21, 95% confidence interval, [CI]: 1Æ06–1Æ38). A multivariate logistic regression model demonstrated that LP was significantly associated with dyslipidaemia even after controlling for confounders, including age, sex, smoking, hypothyroidism, diabetes, hypertension, socioeconomic status and obesity (multivariate OR 1Æ34, 95% CI: 1Æ14–1Æ57, P < 0Æ001). Conclusions In the present study, LP was found to be associated with dyslipidaemia.
Lichen planus (LP) is a chronic inflammatory disease that affects the skin, mucous membranes and appendages.1–3 LP occurs in 0Æ4–1Æ9% of the population, mostly over 45 years old, and is more common among women.2,4 Psoriasis, a chronic inflammatory skin disorder morphologically related to LP, is associated with a high frequency of cardiovascular events.5 An increased risk for traditional cardiovascular risk factors, such as smoking, low physical activity, hypertension, obesity, diabetes mellitus, dyslipidaemia and the metabolic syndrome has been reported in patients with psoriasis.5–9 Various disorders of plasma lipid and lipoprotein pattern,5,8,10–13 most often including an increase of triglycerides and a decrease in high-density lipoprotein (HDL) cholesterol, have been shown in patients with psoriasis.7,11,13 In some studies, significant increases in total cholesterol and low-density lipoprotein cholesterol have also been found.5,11,12 Epidermal cells in LP have shown abnormalities in enzymatic activity, as well as defective carbohydrate expression. An increased prevalence of diabetes and carbohydrate intolerance has been observed in patients with LP,14,15 suggesting its possible role in the pathogenesis of this aetiologically obscure
disease.2 Oral LP has also been associated with diabetes.16,17 However, not all studies found similar results: in one study, the incidence of systemic diseases including hypertension (21%), arthritis (14%) and diabetes (5%) was not higher than expected from the incidence in the general population.18 To the best of our knowledge, no studies have investigated the association between LP and dyslipidaemia. We have previously described the association between psoriasis and dyslipidaemia.19 The purpose of the current study was to assess the association between LP and dyslipidaemia utilizing the large medical dataset of Clalit Health Services (CHS).
Materials and methods For the current case–control study, data mining techniques utilizing the CHS database were used. CHS is the largest health provider organization in Israel, serving a population of approximately 3 800 000 enrollees. A comprehensive computerized database with continuous real-time input from pharmaceutical, medical and administrative computerized operating systems facilitates epidemiological studies such as the current analysis. 2009 The Authors
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The study included all patients aged 20–80 years with LP. Cases were defined as having LP when there was at least one documented diagnosis of LP in the medical records registered by a CHS dermatologist. Controls were randomly selected from the list of CHS enrollees, with a ratio of 2 : 1 regarding cases, excluding patients with a diagnosis of LP, and frequency-matched to cases on age and sex. As only patients aged 20–80 years were included in the study, the final number of subjects included in the study is 1477 cases and 2856 controls. Data available from the CHS database included age, sex, ethnicity (Jewish or Arab), chronic diagnoses such as diabetes, hypertension, obesity, current smoking, ischaemic heart disease, cerebrovascular disease and dyslipidaemia, as well as a large variety of diagnoses (109 different codes for chronic disease). The diagnoses of chronic diseases, including dyslipidaemia, were taken from CHS chronic diseases registry, which is based on utilization of lipid-lowering medications and data withdrawn from hospital and primary care physicians’ reports. A dyslipidaemia code is registered in the database when a diagnosis of dyslipidaemia is made by a primary care physician or during hospitalization, when patients are prescribed statins or fibrates, or when total cholesterol levels exceed 250 mg dL)1. The registry is validated by primary care physician confirmation of registered diagnoses of chronic diseases. The validity of diagnoses in the register was previously estimated and found to be high for important chronic diagnoses.20 The proportions of patients with dyslipidaemia were compared between cases and controls by univariate analyses, using v2 tests to compare categorical parameters between the groups and t-tests for comparison of continuous variables. Mantel– Haenszel stratified analysis was performed in order to test for confounding and effect modification. Effect modification was identified when the P-value in Tarone’s test of homogeneity was < 0Æ05. Logistic regression models were used to measure the association between LP and dyslipidaemia in a multivariate analysis. In all types of multivariate models, covariates were selected for multivariate analysis if the univariate P-value for the association between the potential confounder and dyslipidaemia was < 0Æ1, and remained in the model if the multivariate P-value was < 0Æ05. Statistical analysis was performed using SPSS software, version 15 (SPSS, Chicago, IL, U.S.A.). The study was approved by the institutional review board of Soroka University Medical Center.
Results The study included 1477 patients with LP and 2856 controls between the ages of 20 and 79 years. Due to matching, patients with LP had the same age distribution as controls and the same sex composition. They were more likely to be of low to intermediate socioeconomic status, and to be diagnosed with hypothyroidism. No differences in the frequency of other conditions associated with dyslipidaemia, such as obesity, smoking, diabetes and hypertension, were noted (Table 1). Overall, dyslipidaemia was diagnosed among 42Æ5%
Table 1 Demographic and clinical characteristics of the study population (n = 4333)
Characteristic Age (years) Mean ± SD Median (range) Male, n (%) Socioeconomic status, n Low Intermediate High Current smoker, n (%) Obesity, n (%) Diabetes, n (%) Hypothyroidism, n (%) Hypertension, n (%) Dyslipidaemia, n (%)
Patients with lichen planus Controls (n = 1477) (n = 2856) 52Æ8 55Æ0 600 (%) 565 641 246 289 265 192 148 369 627
± 15Æ3 53Æ1 ± 14Æ5 (21–79) 55Æ0 (21–79) (40Æ6) 1156 (40Æ5) (38Æ9) (44Æ1) (16Æ9) (19Æ6) (17Æ9) (13Æ0) (10Æ0) (25Æ0) (42Æ5)
1040 1143 640 548 523 352 164 746 1080
(36Æ8) (40Æ5) (22Æ7) (19Æ2) (18Æ3) (12Æ3) (5Æ7) (26Æ1) (37Æ8)
P-value 0Æ52 0Æ93
< 0Æ001 0Æ76 0Æ76 0Æ52 < 0Æ001 0Æ42 0Æ003
Significant P-values are shown in bold face.
of cases, compared with 37Æ8% of controls (P = 0Æ003; odds ratio, OR 1Æ21, 95% confidence interval [CI]: 1Æ06–1Æ38). A stratified analysis of the association between LP and dyslipidaemia is presented in Table 2. The association was more prominent among subjects in the 55–64 year age group, women, people of intermediate socioeconomic status, nonobese, nonsmokers, and people without diabetes, hypertension and hypothyroidism. However, none of the variables presented in Table 2 was found to be a significant confounder, and only age group was found to be an effect modifier of the association between LP and dyslipidaemia (P = 0Æ035 for interaction). A multivariate logistic regression model demonstrated that LP was associated with dyslipidaemia, even after controlling for confounders, including age, sex, socioeconomic status, smoking, obesity, diabetes, hypertension and hypothyroidism (Table 3). Actually, the strength of the association was stronger in the multivariate model (OR 1Æ34, 95% CI 1Æ14–1Æ57; P < 0Æ001; Table 3).
Discussion In the present study LP was found to be associated with a higher prevalence of dyslipidaemia. After controlling for confounders, patients with LP had a higher prevalence of dyslipidaemia. LP was previously reported to be associated with an abnormal carbohydrate metabolism in epidermal cells and a higher prevalence of diabetes than in the general population.14–17 In an extensive search of the literature, no studies of the association between LP and dyslipidaemia have been identified. Of note, hypothyroidism, which is known to be associated with dyslipidaemia, was also found to be associated with LP in the
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628 Lichen planus and dyslipidaemia, J. Dreiher et al.
Subgroups
n
All, n (%) 4333 Age, n (%) 20–54 years 2081 55–64 years 1190 65–80 years 1062 Sex, n (%) Female 2577 Male 1756 Socioeconomic status, n (%) Low 1605 Intermediate 1784 High 886 Smoking, n (%) Nonsmokers 3496 Smokers 837 Obesity, n (%) No 3545 Yes 788 Diabetes, n (%) No 3789 Yes 544 Hypothyroidism, n (%) No 4021 Yes 312 Hypertension, n (%) No 3218 Yes 1115
Table 2 Stratified analysis of the association between lichen planus (LP) and dyslipidaemia in different subgroups (n = 4333)
Dyslipidaemia prevalence in LP cases (n = 1477)
Dyslipidaemia prevalence in controls (n = 2856)
OR (95% CI)
627 (42Æ5)
1080 (37Æ8)
1Æ21 (1Æ06–1Æ38)
130 (18Æ3) 235 (59Æ3) 262 (70Æ6)
227 (16Æ6) 374 (47Æ1) 479 (69Æ3)
1Æ13 (0Æ89–1Æ44) 1Æ64 (1Æ28–2Æ10) 1Æ06 (0Æ80–1Æ41)
407 (46Æ4) 220 (36Æ7)
677 (39Æ8) 403 (35Æ0)
1Æ31 (1Æ11–1Æ55) 1Æ08 (0Æ88–1Æ32)
206 (36Æ5) 307 (47Æ9) 112 (45Æ5)
360 (34Æ6) 448 (39Æ2) 264 (41Æ3)
1Æ08 (0Æ87–1Æ35) 1Æ43 (1Æ17–1Æ73) 1Æ19 (0Æ88–1Æ61)
495 (41Æ7) 132 (45Æ7)
833 (36Æ1) 247 (45Æ1)
1Æ27 (1Æ09–1Æ46) 1Æ03 (0Æ77–1Æ37)
459 (37Æ9) 168 (63Æ4)
760 (32Æ6) 320 (61Æ2)
1Æ26 (1Æ09–1Æ46) 1Æ10 (0Æ80–1Æ50)
471 (36Æ7) 156 (81Æ3)
783 (31Æ3) 297 (84Æ4)
1Æ27 (1Æ10–1Æ47) 0Æ80 (0Æ50–1Æ28)
534 (40Æ2) 93 (62Æ8)
981 (36Æ4) 99 (60Æ4)
1Æ17 (1Æ02–1Æ35) 1Æ10 (0Æ70–1Æ76)
349 (31Æ5) 279 (75Æ3)
542 (25Æ7) 538 (72Æ1)
1Æ33 (1Æ13–1Æ57) 1Æ18 (0Æ88–1Æ58)
CI, confidence interval; OR, odds ratio. Significant associations are shown in bold face.
Table 3 Logistic regression for dyslipidaemia (n = 4333) Variable
OR
95% CI
P-value
Lichen planus (vs. controls) Age (per year) Male sex (vs. female) Current smoker Obesity Hypothyroidism Diabetes mellitus Hypertension High SES (vs. low SES) Intermediate SES (vs. low SES)
1Æ34 1Æ07 0Æ91 1Æ40 1Æ31 1Æ62 4Æ59 2Æ34 1Æ50 1Æ28
1Æ14–1Æ57 1Æ06–1Æ09 0Æ77–1Æ06 1Æ15–1Æ69 1Æ06–1Æ60 1Æ22–2Æ16 3Æ52–5Æ99 1Æ95–2Æ82 1Æ21–1Æ85 1Æ07–1Æ52
< 0Æ001 < 0Æ001 0Æ231 0Æ001 0Æ010 0Æ001 < 0Æ001 < 0Æ001 < 0Æ001 0Æ005
CI, confidence interval; OR, odds ratio; SES, socioeconomic status.
present study. To the best of our knowledge, this association has been reported in only a single case report.21 The association with psoriasis, a chronic inflammatory disorder which is morpholically related to LP, has been previously reported but is somewhat controversial. Several mechanisms for the increased lipid levels in psoriasis have been suggested. Psoriasis is a chronic inflammatory state,22 and chronic
inflammation has been suggested as part of the metabolic syndrome. Both psoriasis and the metabolic syndrome are characterized by increases in the immunological activity of type 1 helper T cells. Cytokines such as tumour necrosis factor (TNF)-a and interleukin (IL)-6 seem to play a central role. TNF-a may lead to insulin resistance by inhibiting insulinmediated tyrosine phosphorylation of the insulin receptor.9 Although its aetiology remains unknown, the current trend is to consider LP as an autoimmune process. A delayed hypersensitivity immune reaction, in which the release of cytokines by activated T cells attracts inflammatory cells and leads to the destruction of keratinocytes, resulting in generation of reactive oxygen species, may play a role in the pathogenesis of LP.1,3,23,24 LP is characterized by the upregulation of inflammatory CXCR3 ligands associated with the recruitment of effector cytotoxic T cells and plasmacytoid dendritic cells.3 Various cytokines including IL-2, IL-4, IL-6, IL-10, TNF-a, interferon (IFN)-a, IFN-c and transforming growth factor-b1 are involved in LP.3,24 Induction of the IFN-a-inducible CXCR3 ligands CXCL9, CXCL10 and CXCL11 has been reported. These inflammatory processes could potentially explain the link between LP and dyslipidaemia, and possibly other components of the metabolic syndrome, because chronic inflammation has been suggested as a component of the 2009 The Authors
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metabolic syndrome. For example, an increased activity of type 1 helper T cells has been noted in the metabolic syndrome, with cytokines such as IL-6 and TNF-a playing a key role,9,10,12 and TNF-a inhibitors were shown to be associated with a beneficial increase in HDL cholesterol.7 The present study has some potential limitations. Directionality of the association cannot be established by the study design. No information on lipid-lowering drugs or systemic medication for LP was available. We also had no information regarding lipid levels. While most of the patients (including controls) were probably monitored for lipid levels as part of a national programme for quality indicators in primary care, a selection bias cannot be completely excluded. To conclude, an association between LP and dyslipidaemia was observed in the current study. Further prospective studies, including studies in other populations, are needed to establish our observation. Nevertheless, we suggest that, similar to psoriasis, LP might also have a role as a marker for dyslipidaemia. If this observation is extended and confirmed in additional studies, it may be prudent to follow up patients with LP for the development of cardiovascular risk factors.
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