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Keywords:

  • atherosclerosis;
  • inflammation;
  • pathogenesis;
  • psoriasis;
  • treatment

Summary

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Inflammation plays a key role in the pathogenesis of a number of chronic inflammatory systemic diseases (CISDs), including psoriasis, rheumatoid arthritis, systemic lupus erythematosus and Crohn’s disease, and also in the pathogenesis of atherosclerosis. CISDs and cardiovascular diseases, such as atherosclerosis, share common pathogenic features, and cardiovascular disease is an important cause of morbidity and mortality in patients with CISDs. Activated inflammatory cells and pro-inflammatory cytokines contribute to the development of psoriatic lesions and play an important role in the breakdown of atherosclerotic plaques. Psoriasis and atherosclerosis also have similar histological characteristics involving T cells, macrophages and monocytes. In particular, the extravasation of T cells through the epithelium is characteristic of both psoriatic and atherosclerotic plaques. Cardiovascular disease is an important cause of morbidity and mortality in patients with psoriasis, which is associated with an increased cardiovascular risk profile compared with the general population. Patients with psoriasis are at increased risk of arterial hypertension, coronary heart disease, hyperlipidaemia, obesity and type II diabetes, which are more prevalent than in control patients. This increased risk could be due to the effects of chronic inflammatory changes, particularly the infiltration of T cells and subsequent secretion of pro-inflammatory cytokines. Some drugs used in the treatment of cardiovascular disease, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors have anti-inflammatory activity. In addition, systemic treatments for psoriasis may, by decreasing inflammation, reduce the risk of cardiovascular disease. It is suggested, therefore, that an integrated approach to the treatment of the inflammatory processes underlying both psoriasis and atherosclerosis may be beneficial in reducing cardiovascular risk in patients with psoriasis. The newer targeted biological therapies, such as efalizumab and infliximab, which offer the potential for long-term disease control in psoriasis, may be of particular use in this setting.

Chronic inflammatory systemic diseases (CISDs), such as psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn’s disease, are part of a spectrum of chronic diseases in which inflammation plays an important role in pathogenesis. Central to this pathogenesis is an imbalance in inflammatory cytokines.1 The possibility that CISDs share common underlying inflammatory processes is suggested by epidemiological evidence showing that patients with one CISD are more likely than control patients to have another CISD.2

Inflammation also plays an important role in the pathogenesis of atherosclerosis,3–7 which is an important risk factor for vascular disease.8 Evidence from a number of sources, including genetic studies, suggests that CISDs and cardiovascular diseases, including atherosclerosis, share common pathogenic features in which inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) play an important role.9 In addition, atherosclerosis has been found to be more common in patients with RA and SLE than in healthy controls.10

Common pathogenic features shared by psoriasis, cardiovascular disease and atherosclerosis include immunological processes, inflammatory cytokine profiles and the presence of inflammatory markers both locally and systemically.3–5,7,11–22 Activation of these inflammatory cells together with the release of inflammatory cytokines and proteases contributes to the development of psoriatic lesions and plays a major role in the breakdown of atherosclerotic plaques.4,5,23,24 Both atherosclerosis and psoriasis are diseases mediated by T-helper 1 (Th1) cells.25–27 Unstable psoriatic and atherosclerotic plaques both have an increased percentage of activated T cells expressing a Th1 pattern of cytokines.5,26 In addition, both diseases have a common pattern of T-cell activation, including chemokines,5,24 local and systemic expression of adhesion molecules,24,28 and endothelins.29,30 Both conditions also share similar histological features with the involvement of T cells, macrophages, monocytes, mast cells, connective tissue cells and extracellular matrix.3,31–33

Cardiovascular disease has been found to be an important cause of morbidity and mortality in patients with CISDs and is associated with decreased life expectancy.34–38 Cardiovascular disease, which is the most common cause of death in the general population, is also the most common cause of death in patients with rheumatoid arthritis.39 Studies have suggested a link between systemic inflammation and cardiovascular events in diseases such as RA and SLE,35,40,41 and systemic inflammation may accelerate the atherosclerotic process.8 Psoriasis is associated with an increased cardiovascular risk profile and the chronic inflammation of this disease has an adverse effect on this risk.9 Several cardiovascular risk factors appear to be influenced, including blood pressure, platelet adhesion, endothelial-cell dysfunction, oxidative stress, waist circumference and dyslipidaemia. In addition, cardiovascular risk factors, such as obesity and smoking, also increase the cardiovascular risk profile by stimulating psoriasis activity.9,42

This review examines the evidence for an increased risk of cardiovascular disease in patients with psoriasis and the commonalities in the pathogenesis of atherosclerosis and psoriasis. It also discusses the possible benefits of an integrated approach to the treatment of the underlying inflammatory processes that are common to both psoriasis and atherosclerosis.

Inflammation and atherosclerosis

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Atherosclerosis, a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries, is the main cause of heart disease and stroke, and the underlying cause of approximately half of all deaths in westernized countries.43 The development of an atherosclerotic plaque is a multistep process and inflammation contributes to both the development of atheroma itself and the eventual rupture of the plaque (Fig. 1).6,7,43,44

image

Figure 1.  Immunological basis of (a) psoriatic and (b) atherosclerotic plaque formation. 1. Antigen-presenting cells (APCs) activate naive T cells within the lymph node to increase expression of leucocyte-function-associated antigen-1 (LFA-1); 2. Activated T cells migrate to blood vessel; 3. Activated T cells adhere to endothelium; 3a. Activated T cells and macrophages collect on endothelium; 4. Extravasation occurs mediated by LFA-1 and intercellular adhesion molecule-1 (ICAM-1); 5. Activated T cell interacts with macrophages, dendritic cells and smooth muscle cells/keratinocytes; 6. Re-activated T cells and macrophages secrete chemokines and cytokines that contribute to the inflammatory environment, resulting in the formation of (a) psoriatic plaque, or (b) atherosclerotic plaque; 7. Macrophages are transformed into lipid-laden foam cells by uptake of oxidized LDL; 8. Formation of ‘fatty streaks’ in the subendothelium and, eventually, atherosclerotic plaques. IP = inducible protein.

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The first step in the formation of an atherosclerotic plaque is altered endothelial function with a change in the normal homeostatic responses. Low-density lipoprotein (LDL) cholesterol, which is progressively oxidized, accumulates in the artery wall and smooth muscle cell proliferation occurs. The next step involves the recruitment of leukocytes (monocytes and T cells) to the region with transendothelial migration (diapedesis) into the developing lesion and the accumulation of lipid-laden macrophages (foam cells) to form a fatty streak. Transendothelial migration of T cells is a key early step that is mediated by cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1, on the vascular endothelium. The accumulating macrophages release cytokines and enzymes, including matrix metalloproteinases (MMP), which degrade the connective tissue matrix. The next step is the formation of a more advanced fibrous lesion, which is characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells. These lesions normally have a fibrous cap composed of smooth muscle cells and extracellular matrix that surrounds a lipid-rich necrotic core. The plaque, which is covered by a fibrous cap, then gradually develops into an advanced and complex lesion. Continuing inflammatory processes gradually result in thinning of the fibrous cap to create a potentially unstable plaque that can eventually rupture, with thrombosis and clinical evidence of vascular occlusion.

Risk factors

There are numerous genetic and environmental risk factors for atherosclerosis.43 Factors with a strong genetic component include increased levels of LDL cholesterol, decreased levels of high-density lipoprotein cholesterol, hypertension, increased levels of homocysteine, family history, diabetes, obesity, metabolic syndrome and increased levels of inflammatory molecules such as C-reactive protein (CRP). Environmental factors include a high-fat diet, smoking, lack of exercise, low levels of antioxidants and infectious agents.

Screening

In the U.S.A., the Screening for Heart Attack Prevention and Education (SHAPE) Task Force has formulated a set of practice guidelines for cardiovascular screening of asymptomatic patients at risk of atherosclerosis.45 A number of screening tests are available, such as measurement of coronary artery calcification by computed tomography scanning and measurement of carotid artery intima-media thickness and plaque by ultrasound, that can provide direct evidence for the presence and extent of atherosclerosis. Other, newer tests, such as magnetic resonance imaging of the great arteries, investigation of arterial stiffness, and assessment of systemic endothelial dysfunction, require validation. The results of screening together with risk-factor assessment are used for risk stratification to identify at-risk patients and initiate appropriate therapy.

Arterial stiffness is characteristic of patients with atherosclerosis and CISDs

Arterial stiffness is one of the most important determinants of increasing systolic blood pressure and pulse pressure and is thus a major cause of cardiovascular complications and events.46 A number of studies have shown that there is a relationship between arterial stiffness and cardiovascular mortality, cardiovascular events, strokes and all-cause mortality.46–50 Arterial stiffness is also a characteristic finding in patients with CISDs, such as SLE and RA,39,51–53 and appears to be related to a number of factors, including age, disease duration, serum cholesterol, CRP and IL-6.52

Vascular dysfunction is also evident in RA patients, even at the level of the cutaneous vasculature, and is also linked to atherosclerosis.54 Skin microvascular function has been found to be impaired in patients with active RA and to respond to anti-inflammatory treatment.54

Inflammation and psoriasis

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Psoriasis is a complex CISD, with environmental and genetic components, that affects the skin, scalp, nails and occasionally the joints, with periods of exacerbation and remission. It is a common disease, with estimates of prevalence ranging from < 1–5%.55 Psoriasis is characterized by epidermal hyper-proliferation, abnormal differentiation of epidermal keratinocytes and lymphocyte infiltration (mainly T cells), which result in the formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. Numerous inflammatory cells and mediators are involved in the pathogenesis of psoriasis, particularly T cells, cytokines and chemokines (Fig. 1).31–33,56 At the site of inflammation, activated T cells predominantly release type 1 cytokines such as interferon-α (IFN-α), TNF-α and IL-2. IFN-α may contribute to hyper-proliferation of keratinocytes in the skin by inhibiting apoptosis.57 IL-2 stimulates T-cell proliferation and TNF-α activates and increases keratinocyte proliferation. TNF-α also stimulates T-cell and macrophage cytokine production, macrophage chemokine production and the expression of adhesion molecules on vascular endothelial cells.31–33

Risk factors

There are several risk factors that may provide the environmental stimulus for T-cell proliferation leading to the development of psoriasis. They include psychological stress, certain medications, such as antimalarial drugs, beta-blockers, lithium and nonsteroidal anti-inflammatory drugs, a history of skin disorders and skin infection, obesity, smoking and alcohol consumption.58–62

Comorbidities

Psoriasis is associated with a number of comorbid conditions, some of which also occur in patients with other CISDs such as RA. These include obesity,63 metabolic syndrome,42,64,65 diabetes,66 dyslipidaemia66–68 and cardiovascular disease.65,66,69,70

Cardiovascular-related risk factors

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

For over 20 years it has been known that patients with RA are at increased risk of hypertension, hyperlipidaemia, type II diabetes, the metabolic syndrome and cardiovascular mortality.34,37,71,72 As a result, clinical practice guidelines have been developed for the evaluation and management of cardiovascular risk in these patients.73

Cardiovascular disease, heart disease, stroke and cerebrovascular disease, and their risk factors, are also more common in patients with psoriasis compared with the general population.9,18,74–81 Patients with psoriasis are at increased risk of arterial hypertension, coronary heart disease, hyperlipidaemia, obesity and type II diabetes, which are key components of the metabolic syndrome, stroke and cerebrovascular disease, and the presence of these conditions has been shown to be more prevalent in psoriasis patients than in control patients.42,76,78,80,81 Cardiovascular risk factors, stroke and cerebrovascular disease are more strongly associated with severe than with mild psoriasis.76,80,81 The increased risk for these comorbid conditions could be due to the effects of chronic inflammatory changes, particularly the secretion of pro-inflammatory cytokines.78

Several case-control studies have shown that patients with psoriasis are more likely to have cardiovascular disease than patients without psoriasis.74,77,79 In a study in Israel, the association between psoriasis, diabetes mellitus and atherosclerosis was investigated by examining the records of 46 095 patients with psoriasis and 1 579 037 control patients without psoriasis in a healthcare database.77 The prevalence of diabetes and atherosclerosis was significantly higher in patients with psoriasis compared with control patients [odds ratio (OR) 1·27 and 1·28, respectively]. In a US study, the relationship between psoriasis and cardiovascular disease and/or risk factors was assessed by analysing healthcare claims.74 The prevalence of atherosclerosis, congestive heart failure, type II diabetes, and peripheral vascular disease was higher in patients with psoriasis than control patients (OR ≥ 1·20). In a second US study, the association between psoriasis and cardiovascular disease and other comorbidities was analysed using data collected from the National Health and Wellness Survey (NHWS) on 1127 patients with psoriasis and a matched control group of patients without psoriasis.79 Patients with psoriasis were significantly more likely to have cardiovascular comorbidities, including hypertension, hypercholesterolaemia and diabetes, compared with control patients.

Cardiovascular morbidity and mortality

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

A link between psoriasis and increased cardiovascular mortality has been suspected for many years. A large, 10-year, prospective, cohort study of outpatients with psoriasis, conducted in the 1980s, showed no increase in cardiovascular mortality in patients with psoriasis compared with the general population.82 However, more recent studies have demonstrated such a link.69,83 In a historical cohort study conducted in Sweden, cardiovascular mortality was assessed in 8991 hospitalized patients with psoriasis plus 19 757 outpatients with psoriasis and compared with that in the general population.83 There was no increased cardiovascular mortality among outpatients with psoriasis [standardized mortality ratio (SMR) 0·94], but there was in patients hospitalized at least once (SMR 1·52), and the risk increased with increasing number of hospital admissions (P < 0·001). In addition, cardiovascular mortality was higher among patients admitted at a younger age (SMR 2·62, P < 0·001 for patients aged 20–39 years at first admission) and young age at first admission appeared to further increase the risk in patients with repeated admissions.

Perhaps the strongest data to date are from a large, prospective, population-based study in the UK.69 In a cohort of more than half a million, patients with psoriasis had an increased relative risk (RR) for myocardial infarction, compared with matched controls.69 The increase in risk was greater in patients with severe psoriasis compared with mild psoriasis and the increase also varied with age. For a 60-year-old patient with mild psoriasis, the adjusted RR of having a myocardial infarction was 1·08 (95% CI: 1·03–1·13), while in a 30-year-old patient with severe psoriasis, the adjusted RR was 3·10 (95% CI: 1·98–4·86). The authors suggest that psoriasis is an independent risk factor for myocardial infarction and that the study adds to the increasing evidence linking Th1-associated diseases to atherosclerosis and coronary artery disease.

Long-term treatment

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Atherosclerosis

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, are used to reduce plasma cholesterol levels and thus the risk of cardiovascular disease. They lower cholesterol by inhibiting HMG-CoA reductase, which is a rate-limiting enzyme in the synthesis of cholesterol in the liver. Statins have been shown to reduce the annual incidence of stroke by approximately 30% in patients with coronary artery disease, an effect that may be due to anti-inflammatory actions in addition to lowering cholesterol levels.84 The anti-inflammatory effects may be due to inhibition of the inflammatory activity of macrophages85 or a reduction of tissue factor (TF) and MMP expression.86,87 In addition, statins have down-regulatory effects on systemic markers of inflammation, such as CRP and serum amyloid A, in patients with atherosclerosis.88

Angiotensin-converting enzyme (ACE) inhibitors, which are primarily used for the treatment of hypertension, have been shown to have beneficial effects on plaque progression in animal models of atherosclerosis.89 A possible mechanism is a reduction in the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) and consequent plaque infiltration by macrophages. Reduced MCP-1 levels have been found in some studies of patients with myocardial infarction treated with ACE inhibitors.90

Psoriasis

Systemic treatments for psoriasis, such as methotrexate and cyclosporin, may reduce the risk of cardiovascular disease by decreasing inflammation. However, because most therapeutic agents induce adverse cardiovascular effects, such as hypertension, dyslipidaemia and hyperhomocysteinaemia, preventive measures may be required during long-term treatment.9

The long-term treatment of moderate-to-severe psoriasis with traditional systemic therapies is limited by the potential for adverse effects, such as renal and hepatic toxicity, teratogenicity and malignancy.91 The development of targeted biological therapies, such as efalizumab, a humanized monoclonal IgG1 antibody against CD11a, the α-subunit of leukocyte function-associated antigen 1 (LFA-1),92–95 and TNF-α blocking agents, such as infliximab,96,97 has been a major advance in the treatment of the disease. LFA-1 and ICAM-1 are co-stimulatory molecules expressed on T cells and antigen-presenting cells, respectively, that facilitate multiple T-cell-mediated events.98 By interfering with LFA-1 and ICAM-1 binding, efalizumab inhibits key steps in the immunological cascade that leads to the generation of psoriasis plaques, including T-cell activation and migration of T cells from the circulation into dermal and epidermal tissues.92,99 Efalizumab has also been shown to have activity against CD11c+ cells with many of the markers of dendritic cells, which express the inflammatory mediators inducible nitric oxide synthase and TNF-α.94 The long-term efficacy of efalizumab in the treatment of psoriasis has been demonstrated in a number of phase III clinical studies.100–104

Integrated approach to the treatment of atherosclerosis and psoriasis

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Disease-modifying antirheumatic drugs, such as the folate analogue methotrexate, have been shown to reduce the risk of cardiovascular disease in patients with psoriasis or RA.105,106 Evidence also suggests that the treatment of CISDs with targeted biological therapies, such as etanercept, infliximab and adalimumab, may have a beneficial effect on cardiovascular function in addition to reducing systemic markers of inflammation, such as erythrocyte sedimentation rate and CRP levels.107–111 In a study of patients with RA, treatment with the TNF-α blocker infliximab improved endothelial function: flow-mediated vasodilatation was significantly improved, and CRP and the disease activity score were significantly reduced.108 RA is associated with increased aortic stiffness, which correlates with measures of inflammation.110 In a study by Mäki-Petäjäet al., median aortic pulse-wave velocity was significantly higher in subjects with RA compared with control subjects and was significantly reduced by TNF-α-blocking therapy with a concomitant improvement in endothelial function to a level that was comparable to that in control subjects.110

Similarly, some drugs used to treat cardiovascular disease have been shown to have an effect on systemic inflammatory markers, such as CRP and oxidized LDL cholesterol.112 In a study by Koulouris et al., the effects of ramipril (an ACE inhibitor) and telmisartan (an angiotensin-II type 1 receptor blocker), administered separately or in combination, on inflammation and lipid peroxidation were assessed in patients with type II diabetes but without coronary artery disease.112 Treatment with ramipril and telmisartan either alone or in combination was associated with a significant reduction in serum levels of CRP and oxidized LDL cholesterol.

The statins also have potential immunosuppressive benefits that are additional to their lipid-lowering effects.113–116 The direct anti-inflammatory effects of the statins are mediated through different processes, including the suppression of antigen-specific T-cell activation,117 inhibition of LFA-1/ICAM-1 binding116 and inhibition of T-cell activation via inhibition of small guanosine triphosphatase activity and induction of apoptosis.118 Interestingly, different statins have been shown to have different, and in some cases opposing, effects on T-cell regulation.119 Atorvastatin treatment has been shown to result in modest but clinically apparent anti-inflammatory effects, with modification of vascular risk factors in RA.120

Conclusions

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

Atherosclerosis and psoriasis have a number of common pathogenic features with pro-inflammatory cytokines playing a central role in both diseases. Pro-inflammatory cytokines, together with the activation of inflammatory cells, contribute to the development of psoriatic lesions and play an important role in the breakdown of atherosclerotic plaques. Both conditions also share similar histological features with the involvement of T cells, macrophages, monocytes, mast cells, connective tissue cells and extracellular matrix. Cardiovascular disease is an important cause of morbidity and mortality in patients with psoriasis, and psoriasis is associated with an increased cardiovascular risk profile. An integrated approach to the treatment of the inflammatory processes underlying both psoriasis and atherosclerosis may have a beneficial effect on reducing the cardiovascular risk factors in psoriasis. Newer biological therapies may fulfil a dual role in treating both psoriasis and cardiovascular disease.

Acknowledgments

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References

The author would like to thank Kevin De-Voy (supported by Merck Serono International S.A., Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany) for editorial assistance in the preparation of the manuscript.

References

  1. Top of page
  2. Summary
  3. Inflammation and atherosclerosis
  4. Inflammation and psoriasis
  5. Cardiovascular-related risk factors
  6. Cardiovascular morbidity and mortality
  7. Long-term treatment
  8. Integrated approach to the treatment of atherosclerosis and psoriasis
  9. Conclusions
  10. Acknowledgments
  11. References