Psoriasis and metabolic syndrome
Hidetoshi Takahashi, M.D., Department of Dermatology, Asahikawa Medical University, 2-1-1-1 Midorigaokahigashi, Asahikawa 078-8510, Japan. Email: firstname.lastname@example.org
Psoriasis is a chronic inflammatory and immune-mediated disease associated with several comorbidities, such as obesity, hypertension, diabetes mellitus, dyslipidemia and cardiovascular disorder. These comorbidities are components of metabolic syndrome. The pathogenesis of metabolic syndrome is supposed to be related to increased levels of adipocytokines, such as tumor necrosis factor-α (TNF-α) and adiponectin. Recent study has revealed a high prevalence of metabolic syndrome in psoriatics compared with other skin diseases. Biologic agents, including anti-TNF-α antibodies, are recommended as the first-line treatment for psoriatics with metabolic syndrome. This article reviews the association of psoriasis and metabolic syndrome in terms of adipocytokines and evaluates the role of biologic agents in the treatment of psoriasis.
Psoriasis is a chronic skin disease characterized by inflammatory cell infiltration, hyperproliferation of epidermal cells and dilated microvessels. The prevalence of psoriasis is varied at approximately 0.1–3% of the population.1–3 Both genetic and environmental factors are involved in its pathomechanism.4–6
Metabolic syndrome is a combination of central obesity, dyslipidemia, glucose intolerance and elevated blood pressure. The pathophysiology of metabolic syndrome is attributed to insulin resistance mediated by adipocytokines, such as tumor necrosis factor (TNF)-α leptin, and adiponectin.7–13 The syndrome is associated with cardiovascular disease and type 2 diabetes mellitus (DM).14 The predominant underlying risk factor is visceral adiposity.15–17
Epidemiological surveys in the USA, Europe and Japan revealed the association of psoriasis with metabolic syndrome.18–20 Furthermore, several reports suggest that psoriasis is an independent risk factor of cardiovascular disease.21–23 Factors related to cardiovascular events, such as smoking, obesity, physical inability and psychological stress, are prevalent among psoriasis patients.24
In this review, we assess the association of psoriasis and metabolic syndrome and discuss the prevalence and risk of psoriasis-associated comorbidities in terms of metabolic syndrome.
In 1988, Reaven proposed the term “syndrome X” for the combination of glucose intolerance, hypertension, hyperinsulinemia, low high-density lipoprotein (HDL) cholesterol and high triglycemia.25 However, Reaven did not include abdominal obesity. In 1989, Kapran proposed “the deadly quartet”, which is the constellation of upper body obesity, glucose intolerance, high triglycemia and hypertension.26 In 1991, DeFronzo named the clustering of metabolic disorders, including non-insulin-dependent DM, obesity, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease as “insulin resistance syndrome”.27 Nakamura and Tokunaga28 showed the contribution of visceral fat accumulation in the development of coronary artery disease and Lamarche et al.29 proposed the combination of hyperinsulinemia, high apolipoprotein B levels and high small, dense low-density lipoprotein (LDL) as risk factors for ischemic heart disease and designated as “the atherogenic metabolic triad”. Finally, in 1999, the World Health Organization designated metabolic syndrome as the constellation of disorders including obesity, dyslipidemia, hypertension and glucose intolerance that increases the risk of cardiovascular disease and diabetes.30
Among several diagnostic criteria of metabolic syndrome, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) is widely used in the USA and Europe (Table 1). In contrast, the Japan Society for the Study of Obesity (JASSO) has defined Japanese metabolic syndrome, which is similar to that of the International Diabetes Foundation (IDF) (Table 1). Contrary to the definition of JASSO, central obesity determined by waist circumference is not essential for the diagnosis of NCEP ATP III. The definition of increased waist circumference is different among ethnicities (Table 2). Metabolic syndrome affects 25% of people in the USA, and the prevalence increases with age.31 In Japan, according to the criteria of the Japan Committee for the Diagnostic criteria of Metabolic Syndrome,14 the incidence of metabolic syndrome in 2007 was 18.4%.
Table 1. Definition of metabolic syndrome
|Definition criteria||DM or insulin resistance plus >2 risk factors (below)||>3 risk factors (below)||Increased waist circumstance plus >2 risk factors (below)||Increased waist circumstance plus >2 risk factors (below)|
|Obesity||Waist-to-hip ratio||Waist circumference||Waist circumference criteria depend on ethnicity||Waist circumference|
|Men: >0.9||Men: >102 cm||Men: >85 cm|
|Women: >0.85||Women: >88 cm||Women: >90 cm|
|And/or BMI: 30 kg/cm|| || |
|Triglyceride||>150 mg/dL||>150 mg/dL or drug treatment for elevated levels||>150 mg/dL or drug treatment for elevated levels||Triglyceride >150 mg/dL|
|HDL cholesterol||Men: <35 mg/dL||Men: <40 mg/dL||Men: <40 mg/dL||<40 mg/dL|
|Women: <39 mg/dL||Women: <50 mg/dL or drug treatment for elevated levels||Women: <50 mg/dL or drug treatment for elevated levels|| |
|Blood pressure||>140/90 mmHg||>130 mmHg systolic or >85 mmHg diastolic or drug treatment for hypertension||>130 mmHg systolic or >85 mmHg diastolic or drug treatment for hypertension||>130 mmHg systolic or >85 mmHg diastolic or drug treatment for hypertension|
|Fasting plasma glucose||Impaired fasting glucose or DM type 2||>100 mg/dL or drug treatment for DM||>100 mg/dL or drug treatment for DM||>100 mg/dL or drug treatment for DM|
|Microalbuminuria||>30 mg albumin/g creatinine|| || || |
Table 2. Standard waist circumference of obesity among ethnicity
|Central, South America|
|Mediterranean, Middle East|| |
METABOLIC SYNDROME AND PSORIASIS
The majority of T cells infiltrating in psoriasis was assumed to belong to the T-helper cell (Th)1 subset, producing interferon (IFN)-γ and TNF-α.32,33 Recently, the aberrant activation of dendritic cells in the skin has been found to play a critical role in the pathogenesis of psoriasis.34 Activated dendritic cells affect Th17 cells which produce interleukin (IL)-17 and IL-22, and IL-22 induces keratinocyte proliferation.35 Psoriasis, a chronic inflammatory skin disorder, shows systemic involvement affecting joints in some patients. Systemic inflammation is associated with a number of adipocytokines such as TNF-α, adiponectin, leptin and plasminogen activator inhibitor-1 (PAI-1). Among the inflammatory cytokines, TNF-α plays a pivotal role in both psoriasis and metabolic syndrome.36–38
Several reports indicate the association between psoriasis and metabolic syndrome.24,39–42 Sommer et al.39 showed that psoriasis patients have a significantly increased association with metabolic syndrome compared with melanoma patients (odds ratio [OR] = 5.92; 95% confidence interval [CI] = 2.78–12.8). They showed that the risk of metabolic syndrome was increased in those aged 40–49 years and the phenomena were not explained by increased frequency of smoking or alcohol intake. Gisondi et al.24 demonstrated that the prevalence of metabolic syndrome in plaque-type psoriasis was significantly higher than general skin diseases, even after age and sex adjustment (30.1% vs 20.6%, OR = 1.65; 95% CI = 1.16–2.35). A Japanese study also showed that the prevalence of metabolic syndrome is increased in psoriatics compared with general skin diseases (OR = 1.72; 95% CI = 0.98–3.01).43 Following studies of large numbers of cases found a significant increase in metabolic syndrome of Japanese psoriatics (OR = 1.82; 95% CI = 1.12–3.21) (Table 3). In contrast, OR of metabolic syndrome in the Taiwanese psoriasis population is 0.84.42 This could be related to the lower prevalence of metabolic syndrome in these populations. While the incidence of metabolic syndrome is increasing among the general Chinese population, the tendency is much less apparent in other Asians. These reports were all compared with other skin diseases. Using the health service database in Israel, a cross-sectional study disclosed a significant association of psoriasis with metabolic syndrome (OR = 1.3; 95% CI = 1.1–1.4).41 Recently, Love et al.44 reported a significant increase in prevalence of metabolic syndrome in the USA (OR = 1.96; 95% CI = 1.02–3.77), after adjustment for age, sex, race/ethnicity, smoking and C-reactive protein levels.
Table 3. Prevalence of comorbidities in Japanese psoriatics
|Patient no.||175||154|| ||NS|
|Age, years||55.8 ± 20.2 (21–88)||57.3 ± 23.6 (19–92)|| ||NS|
|Insulin resistance/DM||36 (20.6)||14 (9.1)||1.71 (1.05–2.79)||<0.05|
|Dyslipidemia||60 (34.3)||25 (16.2)||2.73 (1.59–4.69)||<0.01|
|Hypertension||48 (27.4)||23 (14.9)||2.03 (1.15–3.59)||<0.01|
|Metabolic syndrome||48 (27.4)||25 (16.2)||1.82 (1.12–3.21)||<0.05|
Body mass index (BMI) is generally used as the evaluation of obesity level. Overweight and obesity are designated as BMI of more than 25 kg/m2 and more than 30 kg/m2, respectively. According to the data from Ministry of Health, Labor and Welfare in 2009, 30.4% of the male and 20.2% of the female adult population are overweight in Japan. However, only 3% of the adult Japanese are obese. In contrast, 66% and 32% of the adult population in the USA are overweight and obese, respectively.45,46 In the European population, 30–80% and 30% were diagnosed as overweight and obese, respectively.47
Substantial evidence indicates that psoriasis is closely associated with increased risk of obesity. However, it remains unknown whether obesity is a result or a cause of psoriasis. Herron et al.48 retrospectively examined bodyweight before the onset of psoriasis and concluded that obesity follows psoriasis. Mallbris et al.49 also showed no significant difference in BMI between a psoriatic patient within a year of onset and a matched control suggesting that obesity follows psoriasis. In contrast, comparison of psoriasis patients within 2 years of onset and other dermatological disease patients revealed that the risk of psoriasis was related to BMI50 suggesting that obesity may be among the causative factors for psoriasis.
Hensler and Christophers18 reported the positive correlation between psoriasis and obesity in Caucasians, which was confirmed by various studies.24,39,40,51–53 In recent study of Japanese psoriatics, obesity/overweight was significantly increased compared with healthy controls and the severity (Psoriasis Area and Severity Index [PASI] score) was positively correlated with the BMI.54
Several studies have shown the link between psoriasis and insulin resistance/DM.18,39,55,56 German studies disclosed that psoriatics showed an increased prevalence of DM, especially in women.18,55 Furthermore, the prevalence of psoriatics with DM is twice than that of melanoma (OR = 2.5; 95% CI = 1.7–3.6).39 Qureshi et al.57 showed that psoriasis was independently associated with DM (relative risk [RR] = 1.63). Brauchli et al.58 showed the RR of DM in psoriatics to be 1.36 compared with non-psoriatic patients. The OR of developing DM was 2.56 and the risk correlated with psoriasis severity. In Japan, DM was also significantly associated with psoriasis with an OR of 1.71 (95% CI = 1.05–2.79) (Table 3). Although numerous reports support the association of psoriasis with DM, it should be noted that obesity, which is closely associated with DM, is among the comorbidities in psoriatics. Precise elucidation of the relation between psoriasis and insulin resistance/DM remains to be determined.
Several studies showed that psoriasis is associated with atherogenic dyslipidemia with increased blood levels of total cholesterol, triglycerides, LDL, very LDL and lipoprotein A, and low HDL and apolipoprotein B.54,55,59–64 Mallbris et al.49 reported that psoriasis patients with a duration of less than 1 year show significantly elevated LDL and apolipoprotein A-1 and altered cholesterol/triglyceride ratio compared with healthy controls. The study in Japan also revealed that dyslipidemia was significantly associated with psoriasis with an OR of 2.73 (95% CI = 1.59–4.69) (Table 3). Because psoriasis is associated with obesity and the excess adipose tissue might contribute to dyslipidemia, the exact relation of dyslipidemia in psoriasis is not clear. However, overproduction of adipocyte-derived lipolytic inflammatory cytokines such as TNF-α, IL-6 and leptin65,66 is known to induce dyslipidemia.
Several reports indicate the prevalence of hypertension in psoriasis.18,19,39,56,67 Swedish psoriasis patients showed a significantly higher rate of hypertension (observed/expected [O/E] ratio = 3.6; P < 0.001) compared with other dermatological patients.56 A similar tendency was observed in a German study (O/E ratio = 1.9; P < 0.01).18 Furthermore, Sommer et al. reported that psoriasis patients show threefold higher prevalence of hypertension compared with other skin disease patients (OR = 3.3; 95% CI = 2.4–4.4). The Japanese psoriasis patients also showed increased prevalence of hypertension compared with other dermatological patients (OR = 2.03; 95% CI = 1.15–3.59) (Table 3). Hypertension is presumed to be an independent comorbidity of psoriasis.19
Ena et al.67 reported that angiotensin-converting enzyme (ACE) and renin activity are increased in psoriatics. Angiotensin II is produced by ACE following renin-dependent production of angiotensin I.68 Although hypertension might be prevalent in psoriatics, the mechanism of this association remains to be determined.
CARDIOVASCULAR DISORDER (CVD)
Cardiovascular disorders such as myocardial infarction and stroke are closely associated with psoriasis.18,21,22,56,69–71 McDonald and Calabresi70 showed that the risk of arterial and venous vascular diseases such as myocardial infarction, thrombophlebitis, pulmonary embolism and cerebrovascular disease is 2.2-fold higher in psoriasis patients compared with other dermatological disorders. Gelfand et al.22 reported that mild or severe psoriatics show a significantly increased risk of myocardial infarction. The RR of myocardial infarction was higher for young psoriasis patients (<30 years old) with hazard ratios (HR) of 1.29 and 3.10 for mild and severe psoriasis, respectively. In contrast, HR of mild and severe psoriasis in patients who were aged 60 years or older were 1.08 and 1.36, respectively. Brauchli et al.72 demonstrated that the incidence of myocardial infarction, stroke and transient ischemic attack were not significantly increased in psoriatics compared with controls. The adjusted OR of developing myocardial infarction for patients with psoriasis aged less than 60 years was 1.66 (95% CI = 1.03–2.66) compared with non-psoriatic patients. In contrast, myocardial infarction of psoriatics aged more than 60 years was not significantly increased. In Japanese psoriatics aged 19–92 years, the OR of ischemic myocardial disorders was significantly increased (OR = 5.51; 95% CI = 1.86–16.5). However, the OR of cerebrovascular disorders was not significantly different in these populations (OR = 1.75; 95% CI = 0.67–4.5).
METABOLIC SYNDROME AND ADIPOCYTOKINES
Recent studies have revealed that adipose tissue, especially visceral adipose tissue, functions as not only an energy store, but also as an endocrine organ contributing to the regulation of body functions such as glucose, lipid- and insulin-dependent metabolism, vascular tonus, coagulation and inflammation.73,74 Various adipocytokines involved in these process such as adiponectin, leptin, IL-6, TNF-α and PAI-1 are produced in the adipose tissue.73,74
Adiponectin is an adipocyte-specific secretary protein abundantly present in circulation. A negative correlation between BMI and plasma adiponectin levels has been reported.75 Plasma levels of adiponectin are decreased in obesity, insulin resistance and type 2 DM,76–78 and hypoadiponectinemia is assumed to be closely associated with metabolic syndrome.79,80In vitro studies disclosed that adiponectin is suppressed by other adipokines, TNF-α and IL-6.81,82 Okamoto et al.83 reported decreased plasma adiponectin levels in patients with coronary artery disease suggesting the anti-atherosclerotic effect of adiponectin. Furthermore, patients with decreased levels of adiponectin show increased risk of developing DM, hypertension and dyslipidemia.83,84 Kaur et al.85 showed decreased levels of adiponectin in psoriatics of normal weight compared with healthy controls of normal weight. In Japanese psoriatics, decreased adiponectin levels were observed with negative correlation with psoriasis severity, and blood TNF-α and IL-6 levels.78,86 Adiponectin suppresses secretion of TNF-α from keratinocytes and TNF-α, IL-6, IL-17, IL-22 and IFN-γ from T lymphocytes in vitro.88
Leptin is another adipocyte-specific secretary protein which acts primarily through a specific receptor in the hypothalamus.89 It decreases appetite and increases energy expenditure90 reflected in body fat mass.91 The leptin receptor is also expressed in various tissues including adipocytes, endothelial cells, monocytes, and keratinocytes of injured skin.92 Elevation of leptin levels is known to affect arterial intima-media thickness93 and leptin is assumed to be an independent predictor of CVD and coronary heart disease.94,95 Johnston et al.96 showed a positive correlation between BMI and waist circumference with serum leptin levels. However, there exists no significant difference of leptin levels between psoriatics and matched healthy controls. Contrary to the results of Johnston et al.,96 we and others demonstrated the increased leptin levels in psoriatics compared with other skin disease patients and matched healthy controls.86,97 The discrepancy might be due to the difference in the patient number of each study. Johnston’s study was performed with only 30 psoriasis patients, while the following studies were performed in 144 and 122 patients, respectively. In vitro study disclosed that leptin increases keratinocyte and lymphocyte proliferation. This is accompanied by increased secretion of TNF-α and IL-6 from keratinocytes, and TNF-α, IL-6, IL-17, IL-22 and IFN-γ from T lymphocytes.88
TNF-α ANTAGONIST TREATMENT AND PREVENTION OF CVD
Tumor necrosis factor-α plays an essential role in the pathophysiology of psoriasis. Our recent study demonstrated that the serum TNF-α levels are increased in psoriatics compared with healthy controls, and furthermore, the increase was significantly correlated with PASI score.98 It is now recognized that psoriasis is not a simple skin disease, but rather a chronic inflammatory systemic disease mediated by various inflammatory cytokines including TNF-α. Now, anti-TNF-α or anti-TNF-α receptor agents show remarkable therapeutic effects on psoriasis.
Recently, Boehncke et al.99 proposed a concept of “psoriatic march”; psoriasis may cause insulin resistance, which in turn triggers endothelial cell dysfunction, leading to atherosclerosis and finally myocardial infarction or stroke. Studies of rheumatoid arthritis and psoriatic arthritis showed that anti-TNF-α treatment resulted in an anti-proatherogenic effect, and decreased LDL and triglyceride levels.100,101 Furthermore, Bernstein et al.102 reported that etanercept treatment for 4 weeks significantly decreased the inflammatory (C-reactive protein) and prothrombotic factor (fibrinogen) levels in metabolic syndrome. Jacobsson et al.103 reported that CVD was significantly suppressed in rheumatoid arthritis by anti-TNF-α treatment. These studies may suggest that anti-TNF-α treatment might prevent CVD in psoriasis. Strober et al.104 strongly recommended the use of anti-TNF-α modalities, adalimumab and infliximab, for the treatment of obese psoriatics or those with metabolic syndrome.
Psoriasis is a chronic systemic inflammatory disease associated with metabolic syndrome and other comorbidities including CVD. Pro-inflammatory cytokines and adipocytokines contribute to these comorbidities. Thus, psoriasis should not be regarded as a simple skin disease but rather as a systemic inflammatory disease. In this context, anti-TNF-α treatment for psoriasis would be useful not only for the skin lesions but also for the prevention of CVD and other metabolic syndrome associated comorbidities.