You cannot just treat the skin

Traditionally thought of as a disease solely of the skin, psoriasis is a chronic, systemic, inflammatory autoimmune disease affecting 2% to 3% of the US population, making it the most common autoimmune disease in the country.1 Current understanding of the shared pathogenesis of psoriasis, obesity, and cardiovascular disease (CVD), coupled with the associated comorbidities of psoriasis should alert cardiologists and primary care providers to aggressively monitor cardiovascular risk factors in patients with psoriasis, so that prevention and treatment can be started early. EPIDEMIOLOGY Patients with psoriasis typically present with erythematous plaques on extensor surfaces of the upper and lower extremities and scalp, and the peak incidences of age are the 20s and 50s.2 The incidence is equal in men and women, with the lowest incidence occurring in patients of West African, Japanese, and North and South American Indian heritage.3 An estimated 10% to 30% of patients will develop psoriatic arthritis, and the incidence of obesity is twice that of the general population.4,5 According to the National Psoriasis Foundation (NPF), the 2008 estimated cost of psoriasis was $11.25 billion, with the largest portion attributed to work absenteeism. The effect of the disease on quality of life is analogous to other chronic illnesses such as hypertension, cancer, and heart disease.6 Even patients with mild disease describe having an impaired quality of life.7 CARDIOVASCULAR RISK AND PSORIASIS Psoriasis also is associated with other chronic, severe medical conditions such as CVD, diabetes, hypertension, metabolic syndrome, depression, obesity, stroke, and cancer. The life expectancy of patients with severe disease is shortened by 5 years, largely attributed to CVD.7 Common lifestyle factors among patients with psoriasis include smoking and excessive alcohol consumption.8 These patients also tend to consume more health care resources than the general population. The excess mortality from CVD has traditionally been credited to the comorbid diseases associated with psoriasis, but recent research indicates that obesity and CVD share a common inflammatory pathway and mediators as in psoriasis pathogenesis.9 The specific cause of psoriasis is inadequately understood, but seems to involve a genetic predisposition with an environmental trigger, and chronic inflammation mediated by T helper cell 1 (Th1) and 17 (Th17) autoimmune dysfunction.9,10 Many other inflammatory mediators also play a role in psoriasis, such as tumor necrosis factor alpha (TNF-alpha); interleukins (IL) 6, 23, 17, 20 and 22; platelet hyperactivity; and hyperhomocysteinemia.4 In addition, patients with psoriasis are known to have high levels of C-reactive protein (CRP), and more importantly higher levels of high sensitivity C-reactive protein (hs-CRP) in addition to the other inflammatory cytokines.4 Although plasma levels of hs-CRP decrease during treatment remission, they do not usually return to normal.2 Similarly, inflammation plays a crucial part in all phases of atherosclerosis development, and CVD is now recognized as a systemic inflammatory disorder.9,10 The initiating event in atherosclerosis begins with endothelial cell dysfunction, which can be triggered by diseases such as hypertension, diabetes, dyslipidemia, and metabolic syndrome, and adverse lifestyle choices such as smoking and obesity.9 The bulk of published data indicates CRP is a contributor to atherogenesis and an independent risk marker for CVD.9 Elevated hs-CRP levels are a predictor of future MI, stroke, and hypertension independent of lipid levels. IL-6, IL-8, IL-10, IL-18, and TNF-alpha have also been implicated in acute coronary syndrome.2 Obesity is now considered a chronic inflammatory state. Adipose tissue contains an excessive production of inflammatory mediators such as TNF-alpha, IL-1, IL-6, and IL-8, and a positive correlation has been established between abdominal obesity and CRP.5,9 Menter and colleagues found that obese patients have increased levels of pro-inflammatory adipokines such as leptin (an adipose metabolism regulatory hormone and immune response modifier) and decreased levels of adiponectin (an anti-inflammatory hormone).4 Leptin receptors are expressed on many cells associated with inflammation, such as T cells, monocytes, and macrophages. The elevated levels of leptin correlate with increased inflammation, atherosclerosis, and insulin resistance.9 The inflammatory pathway common to psoriasis, atherosclerosis, obesity, and CVD starts with the activation and upregulation of Th1. This produces a cascade of events crucial for the development of CVD.10 Increased inflammation and insulin resistance from inflammatory adipokines may be the stimulus for the initial assault on endothelial cells, leading to the formation of atherosclerotic plaques in patients with psoriasis.9 Furthermore, the adipocytokine leptin enhances CRP formation in endothelial cells incubated with IL-1 and IL-6 and the elevated levels of CRP seem to promote atherogenesis.9 Additional inflammatory cells and pro-inflammatory cytokines stimulate the formation of psoriatic plaques and can cause rupture of atherosclerotic plaques.9 This potentially synergistic cycle of intensified inflammation between obesity and psoriasis may suggest the presence of other comorbidities such as CVD.4 OBESITY, CVD, AND PSORIASIS The incidence of obesity among patients with psoriasis became evident in the mid-1990s.4 Since then, several studies with pediatric and adult patients have found that patients with psoriasis tend to be more obese than patients who do not have psoriasis.4 Abdominal obesity is known to increase morbidity risk in patients with hypertension, hyperlipidemia, diabetes, and other CVD.4 Increasing abdominal obesity has shown to be directly correlated with an increased incidence of psoriasis.5 As body mass index (BMI) increases, the risk of developing psoriasis also increases. Setty and colleagues found that a BMI of 30 or greater caused psoriasis in 50% of study participants and a BMI of 35 or greater was responsible for 63% of psoriasis diagnoses.5 In addition, obesity seems to play a role in psoriasis treatment response. Patients with higher BMIs tend to have a poorer clinical response to medications, and there have been anecdotal reports that gastric bypass surgery and aggressive lifestyle modification regimens lessened plaque psoriasis severity even in the absence of pharmacological management.4 The link between psoriasis and CVD was first discussed in 1961, and two more recent large population studies confirmed that even patients with mild psoriasis had an increased prevalence of CVD and risk factors.2 More recently, a landmark prospective cohort study found psoriasis to be an independent risk factor for nonfatal CVD in women even after adjusting for traditional cardiovascular risk factors.10 A recent study used the Nurses' Health Study (NHS II) to evaluate the link between psoriasis and CVD.10 The NHS II is an ongoing study that was started in 1989 with the recruitment of over 100,000 registered female nurses ages 24 to 42 from 15 states in the United States. Participants have been followed with biennial questionnaires with return rate of more than 90% for each 2-year period. The primary endpoints evaluated were nonfatal CVD, nonfatal MI, and stroke. For each participant, information was collected about their use of tobacco, use of postmenopausal hormones and oral contraceptives, menopausal status, history of diabetes, cancer, hypercholesterolemia, and hypertension. Even after adjusting for traditional cardiovascular risk factors, patients with psoriasis had significantly higher risk of MI and stroke compared to controls.10 Furthermore, patients who developed psoriasis before age 40 or have had the disease more than 9 years had an even greater chance of having a nonfatal cardiovascular event, regardless of disease severity.10 To establish a basis for risk stratification and treatment indications, Mehta and colleagues performed a cohort study using the General Practice Research Database (GPRD) from the United Kingdom to evaluate the risk severe psoriasis played in occurrence of major cardiac events.7 The primary endpoints were also nonfatal MI, nonfatal stroke, or death due to cardiovascular causes. The researchers conferred a 6.2% absolute risk of 10-year rate of major cardiac events in patients with severe psoriasis, after adjusting for age, gender, and comorbid conditions. Mild cases of psoriasis did not pose as serious a 10-year cardiovascular risk. DISCUSSION Psoriasis affects about 75 million Americans and can no longer be considered just a disease of the skin.1 This systemic inflammatory disease requires a multidisciplinary approach for optimal monitoring and treatment. Traditionally, patients with psoriasis are managed by dermatologists and rheumatologists with treatment focused on controlling the extent of plaque formation and minimizing joint destruction from psoriatic arthritis. Initial treatment for mild disease generally begins with topical therapy; systemic medications (such as methotrexate, cyclosporine, and acitretin) are added as the disease progresses.11 Newer biological therapies include TNF-alpha inhibitors and IL-12/IL-23 antagonists, which have expanded treatment options for patients. Systemic therapies that control the inflammatory process (methotrexate and TNF-alpha antagonists) hold significant promise in decreasing cardiovascular risk in patients with severe or long-standing psoriasis.12 Health care providers must become familiar and stay abreast of potentially beneficial pleiotropic effects these agents may provide as the understanding of the pathogenesis of psoriasis, obesity, and CVD is further elucidated. The broader medical community needs to be involved in assessing patients with psoriasis for cardiovascular risk and intervening to minimize comorbid conditions. Comorbid conditions associated with psoriasis have implications in CVD development. Patients with psoriasis tend to have higher rates of type 2 diabetes, hyperlipidemia, hypertension, metabolic syndrome, obesity, and depression, in addition to increased incidence of smoking and excessive alcohol intake. Quality of life measurements are now a critical aspect in the evaluation of patients with psoriasis; awareness has increased among dermatologists about the increased incidence of depression and suicide ideation in these patients. Depression is known to be a significant predictor of CVD and even death up to 1 year after an MI.8 Multiple studies have established the increased incidence of type 2 diabetes in patients with psoriasis, independent of obesity, and increased rates of insulin resistance even in the absence of overt diabetes.2 Patients with psoriasis are twice as likely to suffer from hypertension than patients without psoriasis, and are often treatment-resistant.1,2 In addition, patients with psoriasis tend to have a higher rate of metabolic syndrome that is independent of disease severity.8 Metabolic syndrome influences the development of type 2 diabetes, hyperlipidemia, and arterial hypertension.2 Unlike patients with other systemic inflammatory diseases, patients with psoriasis have a higher incidence of obesity. Hyperlipidemia is also related to psoriasis disease severity. Patients commonly have lower levels of high-density lipoprotein and higher levels of low-density lipoprotein.2 As previously discussed, patients have higher levels of hs-CRP, homocysteine, and many other inflammatory cytokines that are common to both CVD and psoriasis. Together, the increased incidence of comorbid conditions and the inflammatory disease process itself makes cardiovascular risk stratification a necessity in patients with psoriasis (Figure 1).FIGURE 1: Psoriasis and CVD risk algorithmIn addition to an increased risk for serious, life-threatening diseases, patients with psoriasis are more likely to smoke and drink excessive amounts of alcohol. Cigarette smoking has been reported in about 80% of patients before the onset of psoriasis, and was directly linked to psoriasis development in women involved in the NHS II.8 Alcohol use and abuse has been linked with disease onset, severity, and decreased response to treatment.8 Many providers are unaware of the link between psoriasis and CVD. Mounting evidence of the direct association between psoriasis and nonfatal CVD coupled with the increased 10-year absolute risk for cardiovascular events in severe psoriasis requires the involvement of primary care providers and cardiologists in patient care. Management of patients with psoriasis should begin with informing them of the increased risk of cardiovascular events. At every patient visit, encourage appropriate lifestyle modifications. Emphasize reducing BMI, smoking cessation, and decreasing alcohol consumption, which have been shown to decrease CVD and psoriasis disease severity and improve patients' response to pharmacologic treatment. Because no specific changes have been made to the current cardiovascular risk assessment guidelines, experts recommend following the guidelines rigorously.13 The NPF recommends screening patients based on the American Heart Association (AHA) guidelines as early as age 20, regardless of any known cardiovascular risk factors.8 Patients with known risk factors, such as family history or other comorbid conditions, should be monitored more closely.8 The 2008 American Journal of Cardiology editors' consensus report recommends that patients with moderate to severe psoriasis have complete annual screenings, including full personal and family medical history, physical exam, and assessment of BP, lipid levels, hs-CRP, blood glucose, and lifestyle habits (Table 1).2 Patients found to have abnormal serum lipid levels and/or increased plasma hs-CRP should be treated according to the Adult Treatment Panel (ATP) III guidelines.2 Hypertension management should follow current Joint National Committee (JNC-7) guidelines to reach target BP.TABLE 1: Recommended screening for cardiovascular risk in patients with psoriasis2 , 8Patients diagnosed with metabolic syndrome should be managed for weight reduction and treated for concomitant cardiovascular risk factors.2 Patients being treated with methotrexate, cyclosporine, corticosteroids, acitretin, or biologic medications should be monitored for additional cardiovascular risks or drug interactions as indicated by the specific treatment. CONCLUSION As the pathogenesis and shared inflammatory pathways of psoriasis and CVD continue to be researched, primary care providers are in an excellent position to aid in the prevention and treatment of cardiovascular events in patients with psoriasis. Further research and changes to current cardiovascular screening guidelines may be needed as psoriasis continues to be shown as an independent risk factor for nonfatal cardiovascular events.