There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis.
Key points
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Patients with moderate to severe psoriasis have a reduced life expectancy of approximately 5 years because of cardiovascular disease.
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There is an increased prevalence of traditional cardiovascular risk factors in patients with moderate to severe psoriasis; these include hypertension, cigarette smoking, dyslipidemia, diabetes mellitus, and obesity.
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Alcohol misuse and depression are also increased in this population and may contribute to excess cardiovascular mortality.
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In diseases such as rheumatoid arthritis, systemic inflammation plays a role in the development of cardiovascular disease; this may also be the case in psoriasis.
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It is recommended that patients with moderate to severe psoriasis should be screened for cardiovascular risk factors and that these should be managed according to national guidelines.
Introduction
Once considered to be solely a cutaneous disease, there is now robust evidence that psoriasis is associated with systemic inflammation and a significantly increased risk of cardiovascular disease. Moderate to severe psoriasis is associated with a higher incidence of cardiovascular risk factors such as diabetes mellitus, obesity, smoking, and the metabolic syndrome. It is now well established that patients with severe psoriasis have an excess mortality compared with the general population. The spectrum of comorbidities observed in patients with psoriasis is described by Garshick and Kimball elsewhere in this issue. It has yet to be established whether these comorbidities occur as a direct result of the systemic inflammation associated with psoriasis, as a consequence of genetically determined selection, or whether other factors are involved.
Introduction
Once considered to be solely a cutaneous disease, there is now robust evidence that psoriasis is associated with systemic inflammation and a significantly increased risk of cardiovascular disease. Moderate to severe psoriasis is associated with a higher incidence of cardiovascular risk factors such as diabetes mellitus, obesity, smoking, and the metabolic syndrome. It is now well established that patients with severe psoriasis have an excess mortality compared with the general population. The spectrum of comorbidities observed in patients with psoriasis is described by Garshick and Kimball elsewhere in this issue. It has yet to be established whether these comorbidities occur as a direct result of the systemic inflammation associated with psoriasis, as a consequence of genetically determined selection, or whether other factors are involved.
Epidemiology
Cardiovascular Risk in Patients with Psoriasis
Although the association of psoriasis with cardiovascular disease was first described more than 40 years ago, the significance of the association between psoriasis and cardiovascular disease has only become apparent over the past decade. A seminal, population-based cohort study using the United Kingdom General Practice Research Database (GPRD) showed that patients with psoriasis had an increased adjusted relative risk for myocardial infarction, after controlling for other cardiovascular risk factors. The relative risk increased with increasing psoriasis severity, with a 3-fold increase in the risk of myocardial infarction for male patients with psoriasis at the age of 30 years. This increased risk was observed in all age groups, although it decreased with age. Patients with psoriasis at the age of 60 years still had an increased risk of cardiovascular disease even when the data were controlled for traditional cardiovascular risk factors. This finding suggests that psoriasis may be an independent risk factor for premature cardiovascular disease. Other studies have confirmed an increase in cardiovascular disease, peripheral vascular disease, stroke, and overall mortality, and these studies also show a correlation between the risk of cardiovascular morbidity and psoriasis severity. Another study using the GPRD showed that the incidence of risk factors for cardiovascular disease, including incident diabetes, hypertension, obesity, and hyperlipidemia, were increased compared with the general population after a first recorded diagnosis of psoriasis. A systematic review and meta-analysis of observational studies examining cardiovascular risk in 201,239 patients with mild psoriasis and 17,415 patients with severe psoriasis showed an estimated excess of 11,500 major adverse cardiovascular events each year. A cohort study using the GPRD showed that patients with severe psoriasis have a 6-year reduction in life expectancy, with cardiovascular death accounting for the greatest proportion of excess mortality.
In contrast, 2 large studies did not show an increase in cardiovascular risk. A 30-year cohort study in 1376 patients concluded that only patients with exceptionally severe psoriasis had an increased risk of overall noncardiovascular mortality and that severe psoriasis was not an independent risk factor for cardiovascular disease. These findings are unusual because no association was observed between obesity and cardiovascular mortality, or between severe psoriasis and obesity, despite robust evidence to the contrary in other populations. In an article refuting these findings, it was suggested that the epidemiologic study design was flawed. However, most studies have reported a link between psoriasis and premature cardiovascular disease. The mechanisms underpinning this increased risk are unclear. Patients with psoriasis have an excess prevalence of cardiovascular risk factors. There is evidence of systemic inflammation in psoriasis. Systemic inflammation has been identified as causing excess cardiovascular disease in other immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis. Further long-term, population-based, epidemiologic studies are needed to define more accurately the risk of cardiovascular disease in patients with psoriasis. Inception cohort studies of patients with newly diagnosed psoriasis, which comprehensively record patient demographics, risk factors, and psoriasis history, will minimize survivorship bias and confounding caused by cardiovascular comorbidities.
The results from epidemiology studies have prompted smaller studies to try to address whether psoriasis is causal rather than associated with cardiovascular disease. A study of 39 patients with psoriasis compared with 38 healthy controls showed evidence of increased arterial stiffness, independent of other cardiovascular risk factors, and this stiffness increased with duration of disease. Another study showed increased coronary artery calcification in 32 asymptomatic patients with psoriasis compared with healthy controls. Epicardial fat thickness, measured by transthoracic echocardiography, is another risk factor for atherosclerosis. In a small case-control study, epicardial fat thickness was significantly higher in 31 patients with psoriasis compared with 32 controls, independently of other cardiometabolic risk factors.
Cardiovascular risk factors and psoriasis
Hypertension
Several studies have reported a strong association between hypertension and moderate to severe psoriasis. In a large meta-analysis examining the prevalence of hypertension in 309,469 patients with psoriasis, the odds ratio (OR) for hypertension in patients with mild psoriasis was 1.30 (95% confidence interval [CI], 1.15–1.47) and 1.49 (95% CI, 1.20–1.86) in those with severe psoriasis compared with healthy controls. In a subgroup analysis, patients with psoriatic arthritis also had an increased prevalence of hypertension (OR, 2.07; 95% CI, 1.41–3.04).
Diabetes Mellitus
Psoriasis is associated with an increased prevalence and incidence of type II diabetes mellitus. A recent meta-analysis and systematic review concluded that the prevalence of diabetes was increased in patients with psoriasis with an OR of 1.53 (95% CI, 1.06–1.24) for mild disease and 1.97 (95% CI, 1.48–2.62) for severe disease. The incidence of diabetes in patients with psoriasis had an OR of 1.27 (95% CI, 1.16–1.4).
Obesity and the Metabolic Syndrome
Although it has been well established that patients with psoriasis are more likely to be obese, it is unclear whether obesity antedates or occurs after the development of psoriasis. A prospective study in 78,626 women followed for 14 years showed a biological gradient between increasing body mass index (BMI) and the risk of incident psoriasis, suggesting that obesity precedes the development of the disease. Another study showed that patients with newly diagnosed psoriasis have lipid abnormalities at the onset of disease, compared with healthy controls. In contrast, a large cross-sectional study using a self-reported questionnaire showed that patients became overweight after the onset of psoriasis and concluded that obesity was a consequence of psoriasis rather than a risk factor for development of the disease. It has been shown more recently in a large international study that children and adolescents with psoriasis are more obese than age-marched and sex-matched controls, with a tendency toward central adiposity.
Patients with moderate to severe psoriasis have an increased prevalence of the metabolic syndrome in a constellation of comorbidities that includes visceral obesity, insulin resistance, dyslipidemia, and hypertension ( Box 1 ). This association increases with increasing disease severity. In addition, the increased risk of individual components of the metabolic syndrome also shows a dose-response relationship with psoriasis severity, independently of other metabolic syndrome components. Children with psoriasis have a significantly higher risk of developing the metabolic syndrome, with 30% of children meeting the criteria in one small study.
Patient has at least 3 of the following 5 conditions:
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Fasting glucose greater than or equal to 100 mg/dL (or receiving drug therapy for hyperglycemia)
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Blood pressure greater than or equal to 130/85 mm Hg (or receiving drug therapy for hypertension)
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Triglycerides greater than or equal to 150 mg/dL (or receiving drug therapy for hypertriglyceridemia)
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High-density lipoprotein C (HDL-C) less than 40 mg/dL in men or less than 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)
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Waist circumference greater than or equal to 102 cm (40 inches) in men or greater than or equal to 88 cm (35 inches) in women; if Asian American, greater than or equal to 90 cm (35 inches) in men or greater than or equal to 80 cm (32 inches) in women
There is substantial evidence of dyslipidemia in patients with psoriasis. A study of 95,540 participants from the Nurses’ Health Study II showed that hypercholesterolemia is associated with an increased risk of incident psoriasis, particularly in those who had a diagnosis of hypercholesterolemia for greater than 7 years. There was no association between psoriasis and the use of lipid-lowering drugs. Important differences have also been observed in lipoprotein composition and particle size, and cholesterol efflux mechanisms in patients with psoriasis. Patients with psoriasis have lower levels of protective high-density lipoprotein (HDL), with an increased proportion of more atherogenic small low-density lipoprotein (LDL) and HDL particles, similar to that observed in diabetic patients. It has been shown that abnormal HDL particle size is associated with aortic vascular inflammation in patients with psoriasis after correction for other cardiovascular risk factors, when measured by PET–computed tomography (CT), a validated surrogate marker of cardiovascular disease. Compositional alterations of HDL in patients with psoriasis result in impaired ability to promote cholesterol efflux from macrophages, and this worsens with increasing psoriasis severity. Note that successful treatment of psoriasis results in recovery of HDL particle size and cholesterol efflux capacity.
Cigarette Smoking and Excessive Alcohol Use
The frequencies of smoking and excess alcohol consumption, which are independent risk factors for the development of cardiovascular disease, are increased in patients with psoriasis. However, it remains unclear whether these lifestyle factors influence the development of psoriasis or occur as a result of disease-related psychological distress. A recent meta-analysis of 25 prevalence studies (146,934 patients with psoriasis) and 3 incidence studies showed an association between psoriasis and current or former smoking and suggested that smoking is an independent risk factor for the development of psoriasis. Recent evidence has shown that cigarette smoke increases the percentage of circulating T helper 17 (Th17) cells in the peripheral blood of patients with psoriasis compared with nonsmokers.
Excess alcohol intake has been reported in up to 30% of patients with psoriasis and is likely associated with psychological distress. Excess alcohol intake can lead to a wide spectrum of cardiovascular complications, including alcoholic cardiomyopathy, atrial fibrillation, sudden death, and hemorrhagic stroke. Alcohol-related diseases accounted for a significant proportion of excess mortality in a population of Finnish patients with psoriasis.
Other associated comorbid conditions in patients with psoriasis may also contribute indirectly to cardiovascular disease. Obstructive sleep apnea and chronic obstructive pulmonary disease are associated with excessive cardiovascular disease and are commoner in patients with moderate to severe psoriasis. Patients with psoriasis have also been shown to have increased levels of homocysteine, which is an independent risk factor for cardiovascular disease. Moderate to severe psoriasis is associated with increased levels of depression, which is another independent risk factor for cardiovascular disease. In summary, there seems to be an excess of lifestyle factors and medical conditions in patients with psoriasis that predispose to premature cardiovascular disease.
Pathomechanisms underlying the association of psoriasis with cardiometabolic comorbidites and cardiovascular risk
Further research is needed to investigate the complex relationship between psoriasis and metabolic comorbidities at a clinical and molecular level. Multiple hypotheses have been suggested. Although it is possible that patients with psoriasis are genetically predisposed to develop obesity, diabetes, and premature atherosclerosis, genome-wide association scans of patients with psoriasis have not shown an increased inheritance of genes associated with metabolic comorbidities.
Common inflammatory pathways are likely involved in the pathophysiology of psoriasis and cardiovascular inflammation, both of which are associated with a chronic proinflammatory, proangiogenic, and prothrombotic state. The proinflammatory cytokine profile of psoriasis lesions is remarkably similar to that of atherosclerotic lesions, with a similar inflammatory cell infiltrate of T cells, macrophages, and monocytes observed in both conditions ( Fig. 1 ). Psoriasis plaques and unstable atherosclerotic plaques both have an increased frequency of activated T cells with both Th1 and Th17 patterns of cytokine production. Th17 cells and their inflammatory mediators, including interleukin (IL)-17, IL-6, and IL-8, are also increased in the blood of patients with unstable coronary artery disease. Increased expression of known cardiovascular biomarkers, such as monocyte chemoattractant protein-1 (MCP-1) and macrophage-derived chemokine, has been observed in the lesional skin and serum of patients with psoriasis compared with healthy controls, suggesting shared inflammatory pathways linking psoriasis and cardiometabolic disease.
Although there is significant evidence that systemic inflammation drives the increased cardiovascular risk in psoriasis, it is unclear whether psoriatic inflammation primarily contributes to the development of cardiometabolic comorbidities, or whether preexisting metabolic dysfunction causes immunologic dysregulation that then leads to the development of psoriasis. The former explanation has been described as the metabolic march of psoriasis, in which systemic inflammation caused by psoriasis affects the function of other cells and tissues driving the metabolic dysregulation, dyslipidemia, obesity, and increase in cardiovascular risk observed in patients with psoriasis. Release of skin-derived cytokines and inflammatory mediators from psoriasis lesions into the circulation and upregulation of cell adhesion molecules may result in compartmental shifts in inflammatory cells between lesional psoriatic skin, the peripheral circulation, and atheromatous plaques of the coronary vasculature.
Adipokines
Inflammation of adipose tissue caused by psoriasis-related systemic inflammation likely leads to metabolic dysregulation. Monocytes and macrophages infiltrating adipose tissue in obese patients create an inflammatory microenvironment through the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-6, and MCP-1. When adipose tissue becomes inflamed, adipokines, which are a family of inflammatory mediators, are released into the circulation. Adipokines, such as leptin and adiponectin, play an important role in the pathogenesis of the metabolic syndrome, which is a proinflammatory, prothrombotic state, characterized by an increase in C-reactive protein (CRP), TNF-α, IL-6, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) ( Box 2 ). Increased leptin levels and low adiponectin levels in patients with psoriasis are thought to contribute to the development of the metabolic syndrome, independently of BMI.
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Proinflammatory state: increased levels of C-reactive protein, TNF-α, and IL-6
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Prothrombotic state: increased PAI-1 and fibrinogen
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Adipokines: increased levels of leptin, resistin, and retinol-binding protein 4, with lower level of adiponectin
Leptin has a proinflammatory effect, causing inflammatory cytokine production, angiogenesis, increased expression of activation markers on T cells and monocytes, and upregulation of adhesion molecules on endothelial cell walls. Increased levels of leptin in patients with psoriasis have been shown to be independent of obesity, and correlate with disease severity and disease duration. Some studies have suggested that increased levels of leptin contribute to the initial development of psoriasis through the release of proinflammatory mediators.
Adiponectin inhibits the production of proinflammatory cytokines such as IL-6 and TNF-α, downregulates cell adhesion molecule expression in endothelial cells, and induces antiinflammatory cytokines IL-10 and IL-1 receptor antagonist in monocytes and macrophages. Plasma levels of adiponectin are decreased in obesity and type 2 diabetes and studies have suggested that adiponectin plays an antiinflammatory role in cardiovascular disease. Circulating levels of adiponectin are reduced in patients with psoriasis, even after adjusting for cardiometabolic risk factors, and negatively correlate with TNF-α and IL-6 levels.
Resistin is another proinflammatory adipokine produced by macrophages in adipose tissue, which is associated with atherosclerosis and is increased in patients with psoriasis. Adipocyte-derived retinol-binding protein 4 is thought to play a role in insulin resistance and is increased in the serum of patients with psoriasis. Together, adipokines in obese patients with psoriasis perpetuate this chronic inflammatory state.
Microparticles
Microparticle formation has recently been shown to contribute to accelerated atherogenesis in patients with psoriasis and other inflammatory conditions. Microparticles are membrane vesicles containing nucleic acids and inflammatory mediators, such as IL-1, Cluster of Differentiation 40 (CD40) ligand, and intercellular adhesion molecule 1 (ICAM-1), which are released following cell activation or apoptosis and contribute to vascular inflammation, thrombosis, and angiogenesis. Leukocyte-derived microparticles contribute to atherosclerotic plaque rupture and subsequent cardiovascular events, and have been shown to be predictive of cardiovascular outcomes. Studies have shown significantly higher microparticle concentrations in the blood of patients with psoriasis, even after adjusting for cardiovascular risk factors.
Hypercoagulability
Upregulation of platelets and coagulation factors may produce a hypercoagulable state contributing to an increase in thromboembolic events in psoriasis. There is increased activation of platelets in patients with psoriasis compared with healthy controls, with increased levels of beta-thromboglobulin and platelet factor 4, increased platelet volume, and hyperaggregability, all of which normalize with resolution of disease. There is an increase in platelet expression of p-selectin and increased release of platelet-derived microparticles in patients with psoriasis, which correlate with disease severity. Circulating levels of PAI-1 are also increased in patients with psoriasis.
Management of Cardiovascular Risk
Education and primary prevention
Until alternative evidence is available, the presence of severe psoriasis should be considered an independent cardiovascular risk factor. It is the responsibility of physicians and dermatologists to counsel patients with psoriasis regarding the increased risk of cardiometabolic conditions and the need for lifestyle modifications, including smoking cessation, weight reduction, and regular screening for diabetes and hypertension. Patients with moderate to severe psoriasis should have annual monitoring of blood pressure, BMI, waist circumference, lipid profile, fasting glucose, glycosylated hemoglobin, and smoking status. In addition, appropriate weight-loss and lifestyle advice should be given by dermatologists in the routine management of patients with psoriasis. This advice is of particular importance in the pediatric population, in which there is a high risk of both metabolic and psychosocial comorbidities, thus stressing the need for early monitoring for cardiac risk factors and aggressive lifestyle modification in this patient population.
In a cohort study using the GPRD, the presence of severe psoriasis (defined as patients receiving systemic therapy) conferred an additional 6.2% absolute risk of 10-year major adverse cardiac events, after adjusting for age, gender, diabetes, hypertension, tobacco use, and hyperlipidemia. A further study showed that the Framingham Risk Score underestimated cardiovascular risk in patients with psoriasis, and, when the attributable risk associated with psoriasis was applied to calculate the risk, most patients were reclassified into a higher risk category. This finding has important implications for cardiovascular risk stratification and preventative strategies, further reinforcing the view that dermatologists are key to ensuring that both patients and their physicians are informed of this increased risk. Studies are required to ensure that patients are aware of these associated conditions and are making lifestyle modifications accordingly.
Further research to determine how to optimize primary prevention of cardiovascular events in patients with psoriasis is also required. It is of vital importance that standardized screening tools are developed to identify cardiometabolic comorbidities in routine clinical practice. Collaboration with primary care physicians, internists, cardiologists, endocrinologists, and dieticians is essential to optimally manage this increase in cardiometabolic risk in these patients.
The impact of weight reduction on the clinical course of psoriasis and treatment response needs further investigation. Weight reduction may improve psoriasis and small case series have shown a beneficial effect of gastric bypass surgery on psoriasis severity. Several studies have suggested that weight loss may supplement the response to psoriasis therapies. In a study of 303 overweight or obese patients with psoriasis on stable-dose systemic treatment randomized to receive a 20-week quantitative and qualitative dietary and exercise intervention or basic counseling at baseline, patients in the intervention group showed a significantly greater decrease in psoriasis severity. In another study, obese patients with psoriasis showed a superior response when cyclosporine was combined with a low-calorie diet. A small study of 10 patients showed an improved response to topical treatment in obese patients with psoriasis on a low-calorie diet. These findings emphasize the need for more holistic management of patients with psoriasis and the incorporation of lifestyle interventions into treatment regimens.
Biomarkers
In recent years, much research has focused on identifying biomarkers of systemic inflammation and cardiovascular risk in patients with psoriasis. Although patients with more severe psoriasis seem to have an increased risk of cardiometabolic comorbidities, the degree of cutaneous involvement does not necessarily correlate with the level of systemic or cardiovascular inflammation. For example, patients with psoriatic arthritis may only have mild cutaneous involvement, despite significant extracutaneous tissue inflammation and increased inflammatory markers. Validated biomarkers would provide a more reliable means of screening for increased cardiovascular risk. For example, in a recent study, increases in known cardiovascular biomarkers, including soluble ICAM-1 (sICAM-1), soluble E (sE)-selectin, matrix metalloproteinase (MMP)-9, myeloperoxidase (MPO), and total PAI-1 (tPAI-1), did not correlate significantly with Psoriasis Area and Severity Index (PASI), and it was suggested that this represented increased systemic inflammation rather than increases resulting from local cutaneous inflammation.
Because the pathomechanisms leading to increased cardiovascular risk in patients with psoriasis may differ from mechanisms in the nonpsoriatic population, it is not known whether conventional inflammatory biomarkers of atherosclerotic disease are reliable predictors of risk in patients with psoriasis. Studies have shown that conventional biomarkers of inflammation and cardiovascular disease, such as CRP, human soluble CD40 ligand (sCD40L), human matrix gla-protein, and fetuin-A, are significantly altered in patients with psoriasis after controlling for age and BMI. CRP is a serum protein produced by the liver and is increased by infection and systemic inflammation. Patients with immune-mediated diseases such as rheumatoid arthritis have increased levels of CRP compared with normal controls. CRP is increased in patients with psoriatic arthritis and to a lesser extent in those with cutaneous psoriasis alone. High-sensitivity CRP is an independent risk factor for the development of coronary artery disease and is increased in patients with psoriasis.
The use of activated myeloid cell–derived and neutrophil-derived biomarkers has also been examined in several studies. One study showed the neutrophil/lymphocyte ratio (NLR) to be the most reliable predictor of subclinical atherosclerosis in patients with psoriasis, as measured by the aortic velocity propagation and carotid intima media thickness, and NLR also correlated with PASI. In several studies patients with psoriasis have shown significant increases in serum MPO, which is a known biomarker of cardiovascular inflammation that mediates its effects through lipid oxidation and endothelial dysfunction. MPO is also highly expressed in psoriasis plaques. In one of these studies, serum levels of MPO correlated with coronary artery calcification, carotid plaque burden, carotid intima media thickness, and flow-mediated dilatation in patients with psoriasis but showed no association with psoriasis severity.
The Effect of Systemic Treatments on Cardiovascular Risk and Treatment Recommendations
Systemic and biologic treatments used to treat psoriasis may modulate cardiovascular risk. Although certain traditional systemic drugs may have a negative impact on cardiovascular risk factors such as hyperlipidemia or hypertension, it has been suggested that the suppression of systemic inflammation may reduce cardiovascular risk. Careful evaluation of a patient’s cardiovascular risk factor profile is needed when selecting individual therapies. When medication-related adverse effects such as hypertension and dyslipidemia occur, dermatologists should be adept at initiating antihypertensive and lipid-lowering agents for the optimal management of cardiovascular risk.
Although growing evidence suggests that the aggressive management of moderate to severe psoriasis may mitigate cardiovascular risk, it is still unclear whether this is caused by the effect of individual systemic treatments on circulating immune cells, or whether clearance of cutaneous disease by any means decreases the systemic inflammatory burden. In a retrospective cohort study of 8845 patients in the Kaiser Permanente health care database followed for a median of 4.1 years, the use of either TNF inhibitors or oral agents/phototherapy was associated with statistically significant reductions (50% and 46%, respectively) in the risk of myocardial infarction risk, compared with patients treated with topical agents alone, suggesting that systemic treatment of psoriasis decreases systemic inflammation. In a previously mentioned small study of 15 patients, successful treatment with either topical or systemic psoriasis therapies significantly improved HDL-cholesterol efflux capability and normalized HDL composition and function. This finding also suggested that the observed lipid abnormalities were secondary to systemic inflammation. In contrast, another study examining the effect of treatment on multiple biomarkers of cardiovascular risk showed considerable decreases in serum levels of these biomarkers following etanercept treatment but no change after phototherapy.
Methotrexate
Methotrexate (MTX) has been the first-line systemic agent for psoriasis for more than 40 years. There is considerable evidence to support the beneficial effect of MTX on cardiovascular risk in both the psoriasis and rheumatoid arthritis populations. In a retrospective cohort study of 7615 patients with psoriasis and 6707 patients with rheumatoid arthritis at the Veterans Integrated Service network, MTX significantly reduced the risk of vascular disease compared with those who were not treated with MTX, particularly in those treated with low-dose MTX and concomitant folic acid.
As a result of the growing evidence suggesting the possible cardioprotective effect of MTX, the National Institutes of Health (NIH) are currently conducting the Cardiovascular Inflammation Reduction Trial (CIRT; clinicaltrials.gov identifier NCT01594333 ) to examine the effect of low-dose MTX on the rate of heart attacks, strokes, or death in 7000 patients with type 2 diabetes or metabolic syndrome who have known coronary artery disease. The results of this study will be relevant to the psoriasis population.
Cyclosporine
Cyclosporine is a highly effective oral medication, but has an unfavorable side effect profile. In addition to nephrotoxicity, cyclosporine can adversely affect the cardiovascular risk factor profile by increasing the risk of hypertension and dyslipidemia. The reported incidence of new-onset hypertension with short-course cyclosporine therapy typically ranges from 0% to 24%, and is generally reversible with dose reduction or the use of antihypertensives. The onset of hypertension did not seem to be dose related, suggesting that there may a subset of patients with increased individual sensitivity to cyclosporine.
Hyperlipidemia, particularly hypertriglyceridemia, develops in approximately 15% of patients with psoriasis on cyclosporine therapy. If hyperlipidemia develops, a lipid-lowering diet should be introduced, followed by dose reduction of cyclosporine or commencement of a lipid-lowering agent if dietary measures fail. The use of cyclosporine in moderate to severe psoriasis is currently limited to short-term to medium-term interventional treatment courses in order to achieve rapid disease control before transitioning to another systemic therapy with a more favorable long-term toxicity profile. The potential adverse effects of cyclosporine on cardiovascular risk factors such as hypertension have to be balanced by the short duration of modern cyclosporine therapy regimens and the need to achieve rapid control of skin disease in appropriate patients.
Acitretin
Acitretin is a vitamin A derivative that has been used to treat psoriasis since the early 1980s. Although less effective than other traditional systemic agents when used as a monotherapy, acitretin can play a valuable role in patients with generalized pustular psoriasis and palmoplantar disease. Chronic increase of triglyceride levels may increase the risk of atherosclerosis, so monitoring of hyperlipidemia is necessary, but this should not be considered a contraindication because it is usually readily managed with dietary modification and lipid-lowering agents.
Fumaric Acid Esters
Fumaric acid esters are compounds derived from the unsaturated dicarbonic acid, fumaric acid, which have been used in Europe since the late 1970s for the treatment of psoriasis. Patients with psoriasis treated with fumaric acid esters show a reduction in circulating CRP and an increase in adiponectin following treatment. A similar study showed a beneficial effect of continuous treatment with fumaric acid esters on biomarkers of cardiovascular risk.
Tumor Necrosis Factor-Alpha Inhibitors
A large body of evidence from psoriasis and rheumatoid arthritis populations suggests that TNF-α inhibitors have a beneficial effect on cardiovascular risk. In the previously mentioned retrospective cohort study using the Kaiser Permanente health care database in California, patients receiving TNF-α inhibitors had a 50% reduction in the risk of myocardial infarction compared with those treated with topical agents, but there was no significant difference in TNF-α inhibitor use compared with traditional systemic agents or phototherapy. However, a study of 2400 patients with severe psoriasis in nationwide administrative databases in Denmark showed that patients treated with biologic agents or MTX had lower cardiovascular event rates compared with patients treated with other antipsoriatic therapies (cyclosporine, acitretin, and phototherapy).
Larger studies in patients with rheumatoid arthritis also support the cardioprotective effect of TNF-α inhibition. In a longitudinal cohort study of 10,156 patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) rheumatoid arthritis registry, treatment with TNF-α inhibitors was associated with a reduced risk of cardiovascular events (hazard ratio, 0.39) compared with disease-modifying antirheumatic drugs, and MTX was not associated with a reduction in risk.
The effect of etanercept on inflammatory biomarkers in psoriasis has been evaluated in several studies. In a previously mentioned study, etanercept treatment resulted in a highly significant reduction in all investigated biomarkers of cardiovascular risk including soluble vascular cell adhesion molecule-1, sICAM-1, sE-selectin, MMP-9, MPO, and tPAI-1, although these parameters did not improve in patients who had successful treatment with phototherapy. Another study showed a significant decrease in CRP in patients with psoriasis and psoriatic arthritis treated with etanercept. Significant reductions in fibrinogen, ferritin, high-sensitivity CRP, erythrocyte sedimentation rate, haptoglobin, ceruloplasmin, and alpha1-antitrypsin have also been observed after etanercept treatment.
Another large-scale, retrospective cohort study of patients with rheumatoid arthritis or psoriasis showed that the adjusted risk of diabetes was lower for individuals starting TNF-α inhibitors and hydroxychloroquine compared with other nonbiologic disease-modifying agents, including MTX, suggesting that these agents may reduce the risk of metabolic dysfunction.
Ustekinumab
There has been considerable controversy regarding the association between the use of anti–IL-12p40 agents in patients with psoriasis and major adverse cardiovascular events (MACE). Ustekinumab has been approved for clinical use in psoriasis for more than 5 years, whereas briakinumab was withdrawn from clinical trials because of concerns over cardiovascular safety. Two meta-analyses examined the association of anti–IL-12p40 inhibitors and cardiovascular events in patients with psoriasis. The first compared the excess probability of MACE in 22 randomized controlled trials (RCTs) in patients receiving active treatment of anti–IL-12p40 agents (ustekinumab and briakinumab) and TNF-α inhibitors. Although the apparent increase in MACE observed with patients receiving anti–IL-12p40 antibodies was not statistically significant, the findings raised questions about the cardiovascular safety of the anti–IL-12p40 agents. A subsequent meta-analysis examining the rate of MACE in patients in RCTs of IL-12/23 antibodies using different statistical methods showed a significantly higher risk of MACE in patients treated with anti–IL-12p40 agents compared with placebo. Note that these studies analyzed short-term use (up to 16 weeks) of anti–IL-12p40 agents in patients in clinical trials. However, a 5-year safety study conducted by the manufacturers of ustekinumab has shown no increase or decrease in the rate of MACE over time and compares favorably with population-based rates of MACE.
There are several ongoing studies to assess the role of systemic inflammation in accelerated cardiovascular disease. These studies will further define the relationship between psoriasis, traditional cardiovascular risk factors, systemic inflammation, and accelerated coronary artery disease. Two large-scale, prospective cohort studies are currently underway at the National Institutes of Health in the United States. The first, entitled the Psoriasis, Atherosclerosis and Cardiometabolic Disease Initiative ( NCT01778569 ), is a longitudinal cardiometabolic phenotyping program of 1800 patients who will be followed for up to 5 years. These patients will undergo comprehensive cardiovascular and metabolic risk assessment using high-level multimodal imaging (fluorodeoxyglucose PET-CT, PET-MRI, and cardiac CT angiography) to assess vascular inflammation ( Fig. 2 ), along with comprehensive analysis of blood, skin, and adipose tissue samples. The second study, entitled A Trial to Determine the Effect of Psoriasis Treatment on Cardiometabolic Disease: Vascular Inflammation in Psoriasis Trial ( clinicaltrials.gov identifier NCT01553058 ), is designed to assess the effects of biologic treatment and phototherapy on systemic inflammation and cardiovascular disease risk factors in patients with moderate to severe psoriasis. It is hoped that these studies will provide further insight into the mechanistic links between inflammation and the development of cardiometabolic disease in patients with psoriasis.
