|Year : 2016 | Volume
| Issue : 2 | Page : 168-176
Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management
Yugal Kishor Sharma, Naren Prakash, Aayush Gupta, Prakhar Bansal
Department of Dermatology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
|Date of Web Publication||1-Mar-2016|
Flat No. 603, Anandibaug Phase-2, Kharalwadi, Pimpri, Pune - 411 018, Maharashtra
Source of Support: None, Conflict of Interest: None
Metabolic syndrome, a constellation of interrelated risk factors of metabolic origin namely, abdominal obesity, insulin resistance, dyslipidemia and hypertension, confers greater risk of cardiovascular disease on its patients than the sum of the individual components. It is increasingly being associated with inflammatory dermatoses, especially psoriasis. Determination of the diagnostic criteria of this syndrome is conditioned by the changing views regarding its pathogenesis. Approximately, a quarter of the world's population harbors this syndrome, whose reported prevalence in India (5-30%) has escalated with an increase in urbanization and socioeconomic status. Due to, up to 3 times, the risk of cardiovascular mortality and up to 24 times risk of diabetes mellitus, the epidemiological significance of metabolic syndrome ideally necessitates formulation of preventive guidelines by public health authorities. Chronic inflammation, involving several cytokines and adipokines, forms the bridge between this syndrome and psoriasis and underlies the formation of atherosclerotic plaque, the primary lesion of coronary artery disease, in whose pathogenesis oxidative stress and genetic factors also play a role. Up to 4-fold increase in the prevalence of metabolic syndrome and 3-fold increased risk of cardiovascular mortality is reported globally in psoriatics. Increasing index of suspicion of this syndrome by the dermatologists, prevention of cardiovascular damage by lifestyle modifications, smoking cessation and redressal of the inherent depression in these patients is as imperative in management as is the specific therapy of the skin lesions of this systemic, rather than "just a skin," disease as well as the lipid-lowering, antihypertensive and antidiabetic agents.
Keywords: Abdominal obesity, cardiovascular disease, dyslipidemia, insulin resistance, metabolic syndrome, psoriasis
|How to cite this article:|
Sharma YK, Prakash N, Gupta A, Bansal P. Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management. Med J DY Patil Univ 2016;9:168-76
|How to cite this URL:|
Sharma YK, Prakash N, Gupta A, Bansal P. Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management. Med J DY Patil Univ [serial online] 2016 [cited 2023 Jan 31];9:168-76. Available from: https://www.mjdrdypu.org/text.asp?2016/9/2/168/177653
| Introduction|| |
Psoriasis, an immune-mediated inflammatory disease, characterized by epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis, blood vessel dilatation and excess Th1/Th17 inflammation, affects 2-3% of the population worldwide.  The inexorable inflammation underlying its chronic course also predisposes its patients to a number of disorders having an inflammatory component, most notably cardiovascular and metabolic, collectively christened "metabolic syndrome." Hence rather than a mere dermatosis, psoriasis is increasingly being considered a systemic illness.
First described by Kylin in 1923 as the clustering of hypertension, hyperglycemia and gout,  metabolic syndrome is a constellation of interrelated risk factors of metabolic origin that appear to promote directly the development of atherosclerotic cardiovascular disease (CVD).  Gerald Reaven introduced the concept of "syndrome X" in 1988 proposing insulin resistance to be the underlying cause of all other components.  In the diagnostic criteria for the metabolic syndrome proposed by the World Health Organization task force on diabetes, presence of insulin resistance is mandatory.  With the growing evidence of its critical role, abdominal obesity has now become pivotal for the diagnosis of metabolic syndrome. Though the unequivocal final consensus on the criteria of this syndrome is yet to be arrived at, most commonly used diagnostic guidelines are summarized in [Table 1].
| Components of Metabolic Syndrome|| |
The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) 2001,  the most widely used guidelines for epidemiological studies, recognized a constellation of the following cardiovascular risk factors of metabolic (lipid and nonlipid) origin as definitive criteria for diagnosing metabolic syndrome and considered it desirable, rather than mandatory, to also estimate proinflammatory (C-reactive protein [CRP]) and prothrombotic (plasma plasminogen activator inhibitor [PAI]-1/fibrinogen) markers, as additional components.  The rise in these acute phase reactants due to a high cytokine state observed in the setting of obesity, insulin resistance and other features of metabolic syndrome, has been shown in large prospective studies to correlate with increased cardiovascular risk in these patients. ,
In contrast to other criteria, all consequences of insulin resistance, obesity is a lifestyle variable that along with physical inactivity has an adverse effect on insulin-mediated glucose disposal. More specifically obesity, rather than being a result of insulin resistance, leads to its increased causation in these individuals.  Different fat depots exhibit varying metabolic activity, intra-abdominal obesity being most strongly associated with insulin resistance. 
Insulin resistance/glucose intolerance
The term "insulin resistance syndrome" was proposed with the belief in the priority of deranged glucose disposal, its association with other metabolic risk factors and independent correlation with CVD.  The selection by the NCEP ATP III of impaired fasting glucose as a diagnostic aid of the metabolic syndrome is based on the use of plasma fasting glucose concentrations to diagnose diabetes, a disease unequivocally known to increase CVD risk. 
Atherogenic dyslipidemia in routine lipoprotein analysis is characterized by raised triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C). While the ability of the latter to predict CVD risk has been known for many years, some authors have raised concerns regarding the inclusion of raised TG as an "independent" CVD risk factor in view of the equivocal evidence. However, a decrease in particle diameter of low density lipoprotein (LDL) and increase in postprandial TG-rich remnant lipoproteins, though included in an atherogenic lipoprotein profile, are not cited as part of the criteria for diagnosing the metabolic syndrome. 
Raised blood pressure
The most widely debated component of metabolic syndrome and considered by many to be "less metabolic" than the others, is the role of essential hypertension. Though no more than 50% of patients with essential hypertension are insulin resistant,  these are the ones at greatest CVD risk.  Mechanisms proposed for hypertension in the setting of insulin resistance include the loss of vasodilatory affect of insulin with its affect on sodium reabsorption and the sympathetic system remaining intact. 
| Prevalence of Metabolic Syndrome|| |
Worldwide prevalence of metabolic syndrome ranges from <10% to as much as 84%, depending on the region, urban or rural environment, composition (sex, age, race, and ethnicity) of the population studied, and the definition of the syndrome used.  It is estimated to be ∼25 % in the United States, 23% in Europe, and 20-25% in South Asians.  Surveys in large cities in different parts of India suggest about one-third of the urban population to have this syndrome, with the prevalence in the rural population, as low as 5%.  Even within the urban environment significantly increased prevalence is seen with improved socioeconomic status.  In the Indian migrant populations in other countries, the occurrence of metabolic syndrome and its components is reported to be even higher than in the indigenous populations. ,,
| Metabolic Syndrome and Atherosclerosis|| |
Impressive evidence has accumulated over the past decade suggesting the regulation of the atherosclerotic process by inflammatory mechanisms.  Several components of metabolic syndrome, including visceral obesity and insulin resistance, are also associated with a low-grade inflammatory state.  The interaction between different components of the metabolic syndrome (insulin resistance, dyslipidemia, etc.), contributes to the development of a proinflammatory state characterized by increased oxidative stress and chronic subclinical vascular inflammation. The adipose tissue is a source of several adipokines-leptin, PAI-1, tumor necrosis factor alpha (TNF-α), angiotensinogen and interleukin-6 (IL-6)-that directly contribute to this process  resulting in endothelial dysfunction followed by formation of unstable atherosclerotic plaque,  the leading cause of death and morbidity worldwide  [Figure 1].
|Figure 1: Possible mechanism leading to unstable atherosclerotic plaque in metabolic syndrome|
Click here to view
| Impact of Metabolic Syndrome|| |
For the development of preventive and therapeutic guidelines of this rapidly spreading syndrome, it is crucial to learn its impact on cardiovascular and overall mortality of the general population.
Though each component of the metabolic syndrome is an established cardiovascular risk factor, the presence of multiple components confers greater risk than the sum total of the risks associated with the individual components. Using data from the Kuopio Ischaemic Heart Disease Risk Factor Study of middle-aged Finnish men, the relative risk of almost four for coronary artery disease (CAD) mortality and 3.5 for CVD mortality was demonstrated in patients with metabolic syndrome. A sub-study of the Botnia trial demonstrated a 2-fold increase in CAD in the presence of this syndrome while this was shown to be 1.5 times by analysis of data from the Scandinavian Simvastatin Survival Study (4S) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). ,,
Individuals with metabolic syndrome were found to have a 5-fold higher relative risk for diabetes in the Framingham Heart data.  A 24-fold increased risk of diabetes was demonstrated in the West of Scotland Coronary Prevention Study in those with metabolic syndrome at 5 years follow-up.  In a 4-year longitudinal study of 890 nondiabetic Pima Indians, those with this syndrome were almost 3 times more likely to develop diabetes. 
The metabolic syndrome has been shown to be present in 88% of patients with nonalcoholic steatohepatitis (NASH), with up to 98% having insulin resistance, occurring independent of obesity. Hepatic fat content, a hallmark of NASH, was found to correlate most strongly with increased fasting insulin and plasma TG levels. 
Polycystic ovary syndrome
Insulin resistance is critical in the pathogenesis of both polycystic ovary syndrome (PCOS) and metabolic syndrome. Thus, it is not surprising that the two frequently coexist. A study showed that fasting blood glucose and insulin levels were significantly higher (P < 0.02 and P < 0.000001) in both lean and obese PCOS patients compared with a control group. 
The view that sleep apnea and excessive sleepiness in obese patients may be manifestations of the metabolic syndrome is supported by findings of: first, obesity, PCOS and type 2 diabetes are independently associated with excessive daytime sleepiness without sleep apnea; second, hypercytokinemia and insulin resistance indices in obese patients with sleep apnea are unaffected by continuous positive airway pressure; and finally, the prevalence of symptomatic sleep apnea, in general, random samples parallels that of the metabolic syndrome. 
An increased risk of breast cancer of ∼40% in postmenopausal women with body mass index (BMI) in the highest quartile has been shown by several case-control studies.  In addition to a higher endogenous estrogen production, insulin and/or insulin-like growth factors may also contribute to this increased risk. A study of 860 patients with prostate cancer demonstrated that young obese (more likely insulin resistant) patients had a higher grade of cancer.  Increasing evidence also implicates insulin-like growth factors in the evolution of prostate and colorectal cancer. Liver cancer, perhaps as a result NASH and subsequent cirrhosis, also appears to be more common in metabolic syndrome patients. 
| Chronic Inflammation - The Bridge between Psoriasis, Metabolic Syndrome and Atherosclerosis?|| |
Chronic inflammation is thought to be the etiopathogenetic mechanism underlying metabolic syndrome, atherosclerosis, and psoriasis, the last being an independent risk factor for subclinical atherosclerosis and subsequent adverse cardiovascular events. , In psoriasis as well as the metabolic syndrome, similar inflammatory markers such as Th1 cytokines (intracellular adhesion molecule-1, TNF-α), osteopontin, leptin, adiponectin, homocysteine, and CRP, play a pathogenetic role.  Not only are the Th1/Th2 imbalances common to psoriasis and atherosclerosis, but also similar proinflammatory cytokines - interferon-γ, TNF-α, IL-1, IL-6, etc.,-may operate in their evolution. Osteopontin, an inflammatory glycoprotein, that exerts a Th1 cytokine effect and is thought to play a role in the development of atherosclerosis, is also elevated in psoriasis. 
Chronic psoriasis also impacts oxidative metabolic pathways through the generation of free radicals, reactive oxygen species, and superoxide anion. The resultant oxidative stress, believed to play a central role in the pathogenesis of metabolic syndrome, has systemic implications with respect to atherosclerosis and myocardial infarction. , Genetics also play a critical role with several psoriasis susceptibility loci, namely, PSORS2, PSORS3, and PSORS4 also known to associate with the metabolic syndrome, type 2 diabetes, familial hyperlipidemia, and CVD. 
| Psoriasis and Components of Metabolic Syndrome|| |
Obesity and psoriasis
Psoriasis and obesity not only share similar mediators of inflammation such as TNF-α and IL-6, but also have the common mesothelial origin of the macrophage and adipocyte-the engines of psoriatic and adipocytic inflammation, respectively. Importantly, psoriasis, like obesity, is associated with high systemic and local levels of TNF-α. , This suggests that obesity may potentiate the TNF-α and IL-6-driven inflammation seen in psoriasis, additionally vitiating glucose regulation, dyslipidemia, endothelial dysfunction and hypertension and cumulatively heightening the inherent cardiovascular risk of cutaneous psoriatic inflammation. Patients with severe psoriasis also have a higher BMI that is directly related to the risk of cardiovascular mortality.  A randomized, controlled, investigator-blinded clinical trial suggested an increased therapeutic response to a low dose of cyclosporine in psoriasis patients with moderate reduction in body weight (5-10%), by demonstrating a PASI 75 response in 66.7% patients treated with cyclosporine plus a low-calorie diet as compared to 29.0% in patients treated with cyclosporine alone (P < 0.001).  Many inflammatory products synthesized in skin lesions of psoriasis have the potential to interact with adipose tissue, which is expanded in obese psoriatics, at the dermal/adipose interface. 
Diabetes and psoriasis
Diabetes is related to psoriasis independent of obesity, hypertension, and hyperlipidemia and is more prevalent in patients with severe psoriasis than in those with the mild disease. Inflammation could be a biologically plausible mechanism underlying this association. Insulin resistance has previously been attributed to inflammation,  and elevated CRP levels are predictive of diabetes.  Data from large cross-sectional studies have revealed substantial risk of diabetes in psoriasis patients, with a 62% increase in risk with severe disease. 
Hypertension and psoriasis
Though the precise pathophysiologic mechanisms that underlie psoriasis and hypertension are unknown, the link may be attributed to the increased levels of the angiotensin-converting enzyme, endothelin-1 and rennin in patients with psoriasis.  Elevated CRP (as seen in psoriasis) has been shown to foretell the development of hypertension on follow-up in multiple cohorts.  The association may also be attributed to the increased oxidative stress in psoriasis patients.  Sommer et al. reported that inpatients with psoriasis had more than a 3-fold higher prevalence of hypertension compared with inpatients without psoriasis (odds ratio: 3.3; 95% confidence interval: 2.4-4.4).  One prospective study demonstrated an increased risk of diabetes and hypertension in women with psoriasis, even after adjustment for age, BMI, alcohol intake, and smoking status. 
Dyslipidemia and psoriasis
There is conflicting information about how lipid profiles might be affected by psoriasis. An atherogenic lipid profile comprising, high cholesterol, LDL and TG and low HDL levels was noted in psoriasis patients in some studies, , with no significant difference between patients and controls noted in others. ,, Lipoprotein (a), whose role has been implied in cardiovascular pathology, has also been reported to be elevated.  Oxidized LDL (ox-LDL), a molecule thought to contribute to initiation as well as the progression of atherosclerosis,  is produced by oxidative damage of lipids and proteins in response to increased production of oxygen metabolites as seen in psoriatics. Anti-ox-LDL antibodies demonstrated by Vanizor Kura  and Φrem  in psoriatics, have been suggested to reflect the in vivo oxidation of LDL.
| Psoriasis, Metabolic Syndrome, and Cardiovascular Disease|| |
Given the evidence for the association between psoriasis and the core components of the metabolic syndrome, it is no surprise that psoriasis has been proved to be associated with increased risk of the complete syndrome by several studies in India and abroad.  Recently, a study in Italy found the risk of being diagnosed with metabolic syndrome to be double in the psoriasis group when compared to the control group with the risk increasing with disease severity.  A higher prevalence was also observed in an Indian study by Ali et al. (P = 0.005), although they did not find any association with disease severity or duration. The same authors also found psoriatic arthritis to be significantly more common in psoriatic patients with metabolic syndrome (40.5%) than in those without it (19%). ,
Overall epidemiological data unanimously support the link between psoriasis and cardiovascular risk.  The several possible biological factors that may explain such a link include a higher prevalence of conventional cardiovascular risk factors (e.g., smoking, obesity, low physical activity) in psoriatics, systemic medications used to treat psoriasis and the underlying inflammatory activity in psoriasis.  A study by Gelfand et al.  in 2006, which included 130,976 psoriasis patients, demonstrated an increased risk of myocardial infarction, more so in the younger patients with severe disease (e.g., a 30-year-old with severe psoriasis had a relative risk of 3.10). However, these observations need to be confirmed by larger studies.
Understanding the specific relationships between its components and their link to subsequent macrovascular disease is an important prerequisite for developing public health policy to reduce clinical risk. Particular vigilance is advised as is early clinical intervention to prevent the complications of this syndrome. First line therapy for this syndrome recommended by the American Heart Association comprises of lifestyle modifications including weight loss (BMI <25 kg/m 2 ), 30 min of moderate-intensity activity most days of the week and healthy eating habits.  Finnish Diabetes Prevention Study involving overweight individuals with impaired glucose intolerance demonstrated a 58% reduced risk of diabetes at 4-years follow-up with modest weight loss by dietary changes and exercise.  Concurrent hypertension, diabetes, and hypercholesterolemia should be adequately managed. The Veterans Affairs HDL Intervention Trial demonstrated a 35% reduction in risk of cardiovascular death in patients with metabolic syndrome who received gemfibrozil.  In the AFCAPS/TexCAPS study, those with the metabolic syndrome had a 37% reduced risk of an acute coronary event with lovastatin therapy.  In psoriasis patients, several studies have shown remission of the disease with weight loss. , Furthermore, smoking cessation (a well-established CVD risk factor and shown to be associated with psoriasis in many studies) and redressal from depression consequent to the disease, have the potential to at least partially offset the increased inherent risk of cardiovascular catastrophes and complications of diabetes present in these patients. 
Some skin conditions other than psoriasis, less commonly associated with metabolic syndrome are summarized in [Table 2], along with the mechanism of their association and findings of the relevant studies.
| Conclusion|| |
Metabolic syndrome, though not considered to represent a distinct disease entity, due to its chronic underlying inflammation has the importance of conferring greatly increased risk for a number of comorbidities, e.g., CAD, myocardial infarction, stroke, and type 2 diabetes.  Though further large-scale studies are needed to definitively quantify the cardiovascular risk in psoriasis patients, it is imperative for a dermatologist, who also doubles as a primary care physician in many cases of psoriasis, to suspect, manage and adequately counsel these patients regarding the potential comorbidities due to concomitant metabolic syndrome rather than letting them get away with the belief that their diseases are "just a skin disease." Practicing clinicians also should be aware of this syndrome as timely control of its components can add some years to the patient's life by early detection and management of the associated cardiovascular comorbidities. Large-scale population-based studies could provide help in promulgation of country specific preventive health as well as management guidelines by the concerned authorities.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Langley RG, Krueger GG, Griffiths CE. Psoriasis: Epidemiology, clinical features, and quality of life. Ann Rheum Dis 2005;64 Suppl 2:ii18-23.
Kylin E. Studies on hypertension-hyperglycemia-hyperuricemia-syndrome. Zentralblatt Fuer Inn Med 1923;44:105-27.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al.
Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52.
Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.
Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome - A new worldwide definition. Lancet 2005;366:1059-62.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, et al.
Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004;24:e13-8.
Devaraj S, Singh U, Jialal I. Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol 2009;20:182-9.
Reaven GM. The metabolic syndrome: Requiescat in pace. Clin Chem 2005;51:931-8.
Day C. Metabolic syndrome, or what you will: Definitions and epidemiology. Diab Vasc Dis Res 2007;4:32-8.
Zavaroni I, Mazza S, Dall′Aglio E, Gasparini P, Passeri M, Reaven GM. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med 1992;231:235-40.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415-28.
Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014;2014:943162.
Sawant A, Mankeshwar R, Shah S, Raghavan R, Dhongde G, Raje H, et al.
Prevalence of metabolic syndrome in urban India. Cholesterol 2011;2011:920983.
Pandit K, Goswami S, Ghosh S, Mukhopadhyay P, Chowdhury S. Metabolic syndrome in South Asians. Indian J Endocrinol Metab 2012;16:44-55.
Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroja R; Chennai Urban Population Study (CUPS No.). Intra-urban differences in the prevalence of the metabolic syndrome in southern India - The Chennai Urban Population Study (CUPS No 4). Diabet Med 2001;18:280-7.
McKeigue PM, Pierpoint T, Ferrie JE, Marmot MG. Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in south Asians and Europeans. Diabetologia 1992;35:785-91.
Tan CE, Ma S, Wai D, Chew SK, Tai ES. Can we apply the national cholesterol education program adult treatment panel definition of the metabolic syndrome to Asians? Diabetes Care 2004;27:1182-6.
Libby P. Inflammation in atherosclerosis. Nature 2002;420:868-74.
Festa A, D′Agostino R Jr, Howard G, Mykkänen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: The Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42-7.
Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005;111:1448-54.
Falk E, Fuster V. Angina pectoris and disease progression. Circulation 1995;92:2033-5.
Weber C, Noels H. Atherosclerosis: Current pathogenesis and therapeutic options. Nat Med 2011;17:1410-22.
Standl E. Aetiology and consequences of the metabolic syndrome. Eur Heart J Suppl 2005;7 Suppl D:D10-3.
Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, Nissén M, et al.
Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-9.
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al.
The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16.
Sattar N, Gaw A, Scherbakova O, Ford I, O′Reilly DS, Haffner SM, et al.
Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108:414-9.
Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the "metabolic syndrome" and incidence of type 2 diabetes. Diabetes 2002;51:3120-7.
Machado M, Cortez-Pinto H. Non-alcoholic steatohepatitis and metabolic syndrome. Curr Opin Clin Nutr Metab Care 2006;9:637-42.
Vrbíková J, Cibula D, Dvoráková K, Stanická S, Sindelka G, Hill M, et al.
Insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:2942-5.
Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005;9:211-24.
Pathak DR, Whittemore AS. Combined effects of body size, parity, and menstrual events on breast cancer incidence in seven countries. Am J Epidemiol 1992;135:153-68.
Amling CL, Kane CJ, Riffenburgh RH, Ward JF, Roberts JL, Lance RS, et al.
Relationship between obesity and race in predicting adverse pathologic variables in patients undergoing radical prostatectomy. Urology 2001;58:723-8.
Ross R. Atherosclerosis - An inflammatory disease. N Engl J Med 1999;340:115-26.
Mallbris L, Granath F, Hamsten A, Ståhle M. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol 2006;54:614-21.
Padhi T, Garima. Metabolic syndrome and skin: Psoriasis and beyond. Indian J Dermatol 2013;58:299-305.
Aurangabadkar SJ. Comorbidities in psoriasis. Indian J Dermatol Venereol Leprol 2013;79 Suppl 7:S10-7.
Azfar RS, Gelfand JM. Psoriasis and metabolic disease: Epidemiology and pathophysiology. Curr Opin Rheumatol 2008;20:416-22.
Bonifati C, Carducci M, Cordiali-Fei P, Trento E, Sacerdoti G, Fazio M, et al
. Correlated increases of tumour necrosis factor-a, interleukin-6 and granulocyte monocyte colony stimulating factor levels in suction blister fluids and sera of psoriatic patients - Relationships with disease severity. Clin Exp Dermatol 1994;19:383-7.
Nickoloff BJ, Karabin GD, Barker JN, Griffiths CE, Sarma V, Mitra RS, et al.
Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol 1991;138:129-40.
Sterry W, Strober BE, Menter A; International Psoriasis Council. Obesity in psoriasis: The metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol 2007;157:649-55.
Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G. Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: A randomized, controlled, investigator-blinded clinical trial. Am J Clin Nutr 2008;88:1242-7.
Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, et al.
Psoriasis and systemic inflammatory diseases: Potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 2010;130:1785-96.
Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, et al.
Low-grade systemic inflammation and the development of type 2 diabetes: The atherosclerosis risk in communities study. Diabetes 2003;52:1799-805.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-34.
Ena P, Madeddu P, Glorioso N, Cerimele D, Rappelli A. High prevalence of cardiovascular diseases and enhanced activity of the renin-angiotensin system in psoriatic patients. Acta Cardiol 1985;40:199-205.
Hage FG. C-reactive protein and hypertension. J Hum Hypertens 2014;28:410-5.
Sowers JR. Hypertension, angiotensin II, and oxidative stress. N Engl J Med 2002;346:1999-2001.
Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res 2006;298:321-8.
Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 cases. Arch Dermatol 1991;127:1339-45.
Rocha-Pereira P, Santos-Silva A, Rebelo I, Figueiredo A, Quintanilha A, Teixeira F. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta 2001;303:33-9.
Tekin NS, Tekin IO, Barut F, Sipahi EY. Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm 2007;2007:78454.
Farshchian M, Zamanian A, Farshchian M, Monsef AR, Mahjub H. Serum lipid level in Iranian patients with psoriasis. J Eur Acad Dermatol Venereol 2007;21:802-5.
Vahlquist C, Michaëlsson G, Vessby B. Serum lipoproteins in middle-aged men with psoriasis. Acta Derm Venereol 1987;67:12-5.
Pietrzak A, Kadzielewski J, Janowski K, Rolinski J, Krasowska D, Chodorowska G, et al.
Lipoprotein (a) in patients with psoriasis: Associations with lipid profiles and disease severity. Int J Dermatol 2009;48:379-87.
Nakajima K, Nakano T, Tanaka A. The oxidative modification hypothesis of atherosclerosis: The comparison of atherogenic effects on oxidized LDL and remnant lipoproteins in plasma. Clin Chim Acta 2006;367:36-47.
Vanizor Kural B, Orem A, Cimsit G, Yandi YE, Calapoglu M. Evaluation of the atherogenic tendency of lipids and lipoprotein content and their relationships with oxidant-antioxidant system in patients with psoriasis. Clin Chim Acta 2003;328:71-82.
Orem A, Cimsit G, Deger O, Orem C, Vanizor B. The significance of autoantibodies against oxidatively modified low-density lipoprotein (LDL) in patients with psoriasis. Clin Chim Acta 1999;284:81-8.
Ali NM, Maria K, Bhaskaran U. Prevalence of metabolic syndrome in psoriatic arthritis compared with psoriasis: A cross-sectional study in a South Indian population. Egypt J Dermatol Venerol 2015;35:20-2.
Parodi A, Aste N, Calvieri C, Cantoresi F, Carlesimo M, Fabbri P, et al.
Metabolic syndrome prevalence in psoriasis: A cross-sectional study in the Italian population. Am J Clin Dermatol 2014;15:371-7.
Ali NM, Kuruvila M, Unnikrishnan B. Psoriasis and metabolic syndrome: A case control study. Indian J Dermatol Venereol Leprol 2014;80:255-7.
Vena GA, Vestita M, Cassano N. Psoriasis and cardiovascular disease. Dermatol Ther 2010;23:144-51.
Kremers HM, McEvoy MT, Dann FJ, Gabriel SE. Heart disease in psoriasis. J Am Acad Dermatol 2007;57:347-54.
Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735-41.
Kimball AB, Gladman D, Gelfand JM, Gordon K, Horn EJ, Korman NJ, et al.
National psoriasis foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol 2008;58:1031-42.
Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al.
Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22.
Wolters M. Diet and psoriasis: Experimental data and clinical evidence. Br J Dermatol 2005;153:706-14.
De Menezes Ettinger JE, Azaro E, de Souza CA, dos Santos Filho PV, Mello CA, Neves M Jr, et al.
Remission of psoriasis after open gastric bypass. Obes Surg 2006;16:94-7.
Arias-Santiago S, Gutiérrez-Salmerón MT, Castellote-Caballero L, Buendía-Eisman A, Naranjo-Sintes R. Androgenetic alopecia and cardiovascular risk factors in men and women: A comparative study. J Am Acad Dermatol 2010;63:420-9.
Ahouansou S, Le Toumelin P, Crickx B, Descamps V. Association of androgenetic alopecia and hypertension. Eur J Dermatol 2007;17:220-2.
Ice CL, Murphy E, Minor VE, Neal WA. Metabolic syndrome in fifth grade children with acanthosis nigricans: Results from the CARDIAC project. World J Pediatr 2009;5:23-30.
Rendon MI, Cruz PD Jr, Sontheimer RD, Bergstresser PR. Acanthosis nigricans: A cutaneous marker of tissue resistance to insulin. J Am Acad Dermatol 1989;21(3 Pt 1):461-9.
El Safoury OS, Abdel Hay RM, Fawzy MM, Kadry D, Amin IM, Abu Zeid OM, et al.
Skin tags, leptin, metabolic syndrome and change of the life style. Indian J Dermatol Venereol Leprol 2011;77:577-80.
Sudy E, Urbina F, Maliqueo M, Sir T. Screening of glucose/insulin metabolic alterations in men with multiple skin tags on the neck. J Dtsch Dermatol Ges 2008;6:852-5.
El Safoury O, Fawzi M, Abdel Hay RM, Hassan AS, El Maadawi Z, Rashed L. Increased tissue leptin hormone level and mast cell count in skin tags: A possible role of adipoimmune in the growth of benign skin growths. Indian J Dermatol Venereol Leprol 2010;76:538-42.
Sabat R, Chanwangpong A, Schneider-Burrus S, Metternich D, Kokolakis G, Kurek A, et al.
Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One 2012;7:e31810.
Nagel G, Bjørge T, Stocks T, Manjer J, Hallmans G, Edlinger M, et al.
Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can). Br J Dermatol 2012;167:59-67.
Shu X, Ji J, Li X, Sundquist J, Sundquist K, Hemminki K. Cancer risk among patients hospitalized for Type 1 diabetes mellitus: A population-based cohort study in Sweden. Diabet Med 2010;27:791-7.
Rosengren A, Himmelmann A, Wilhelmsen L, Branehög I, Wedel H. Hypertension and long-term cancer incidence and mortality among Swedish men. J Hypertens 1998;16:933-40.
Arias-Santiago S, Buendía-Eisman A, Aneiros-Fernández J, Girón-Prieto MS, Gutiérrez-Salmerón MT, Mellado VG, et al.
Cardiovascular risk factors in patients with lichen planus. Am J Med 2011;124:543-8.
Chung CP, Avalos I, Oeser A, Gebretsadik T, Shintani A, Raggi P, et al.
High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: Association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007;66:208-14.
Nascimento IS, Quaio CR, Sinicato NA, Appenzeller S, de Carvalho JF. Aspects of atherosclerosis and metabolic syndrome in lupus erythematosus. Acta Reumatol Port 2010;35:294-300.
Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: A summary of the evidence. Diabetes Care 2005;28:1769-78.
[Table 1], [Table 2]