Abstract
Psoriasis is often associated with other diseases, substantially adding to the patient’s burden of disease. Recent epidemiologic studies have demonstrated an increased cardiovascular morbidity among patients with psoriasis and psoriatic arthritis (PsA), which contributes to their reduced life expectancy. At the meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) adjacent to the International Federation of Psoriasis Associations (IFPA) congress, members discussed the pathogenetic aspects of this association and resulting consequences for the management of patients with psoriasis and PsA. A future research agenda was considered.
- PSORIATIC ARTHRITIS
- PSORIASIS
- INSULIN RESISTANCE
- ATHEROSCLEROSIS
- MYOCARDIAL INFARCTION
- ANTI-TUMOR NECROSIS FACTOR AGENTS
Given the central role of the immune system in pathogenesis1,2,3,4, psoriasis and psoriatic arthritis (PsA) are currently considered to be immune-mediated inflammatory disorders (IMID), alongside numerous others such as rheumatoid arthritis (RA)5. Despite their distinct clinical presentation, these diseases share many common features such as their chronic course, inflammatory expression, and several pathogenetic aspects, including the central role of the immune system; a Th1-like cytokine milieu in the affected tissue, dominated by interferon-γ and interleukins 2 and 22; and the key role of tumor necrosis factor-α (TNF-α). The profound therapeutic effect of strategies to neutralize TNF-α have revolutionized the management of RA and have begun to alter the way psoriasis and PsA are being treated6,7.
Another shared feature of IMID is their association with other diseases, namely cardiovascular diseases (CVD) such as atherosclerosis and myocardial infarction. It is these comorbidities that have a direct impact on the mortality associated with IMID8. The exact mechanism by which these diseases predispose a patient to CVD is unclear, but may involve various cellular and humoral inflammatory mediators, namely TNF-α9. Recently, circulating concentrations of TNF receptors were shown to be highly predictive of mortality in patients with RA10, and treating RA with TNF-α blockers substantially reduced the cardiovascular morbidity and mortality in responding patients11.
Clinical aspects of cardiovascular comorbidity in psoriasis
In a landmark report12 describing the findings in a cohort of almost 3000 patients, Henseler and Christophers discussed the association of psoriasis with diabetes mellitus, obesity, heart failure, and hypertension. Their observations have since been reproduced in multiple studies. Cardiovascular morbidity has a substantial influence on patients’ life expectancies, which are 3.5 years shorter in men and 4.4 years shorter in women with severe psoriasis13. Mallbris, et al were able to establish an association between psoriasis severity and cardiovascular mortality14, which was confirmed by Gelfand, et al, who reported up to 3-fold increased risk for psoriasis patients to develop myocardial infarction, depending on age and disease severity15. In a carefully performed case-control study, Ludwig, et al observed coronary artery calcification to be much more frequent and pronounced in patients with psoriasis compared to controls matched for all known risk factors16. As coronary artery calcification reflects coronary artery disease, these results further substantiate the research of Mallbris and Gelfand.
Clinical aspects of cardiovascular comorbidity in PsA
Although large-scale epidemiologic studies in PsA are not available, clinic-based studies have shown that PsA is associated with increased mortality risk17,18. CVD were the primary cause of death for a large proportion of the cases in this prospective study18, and the standardized prevalence ratios for myocardial infarction, angina, and hypertension were reported to be significantly higher in patients with PsA than the general population19. Factors associated with CVD included diabetes, hyperlipidemia, and high Psoriasis Area and Severity Index (PASI) scores19. Thus, severe psoriasis is an important predictor for CVD in patients with PsA.
PsA is associated with subclinical atherosclerosis. The association of hyperuricemia with hypercholesterolemia and renal impairment in PsA was reported in 200020. A subsequent study in PsA patients without clinically evident CVD showed that there is a correlation between serum uric acid concentration and subclinical atherosclerosis as measured by carotid intima-media wall thickness (IMT)21. Hyperuricemia is an independent risk factor for CVD and may be a marker of subclinical atherosclerosis in PsA22. Tam, et al found that subclinical atherosclerosis, defined using carotid IMT, was increased in PsA patients compared to matched controls23. Increased blood sugar and total triglyceride levels were independently associated with subclinical atherosclerosis in PsA. Of interest, the Framingham risk score was similar in PsA patients with and without subclinical atherosclerosis; 35% of the patients had subclinical atherosclerosis despite having a low cardiovascular risk score23. Similar results were obtained by Eder, et al from Israel24 and Gonzalez-Juanatey, et al from Spain25.
An additional factor in the predisposition to CVD among patients with PsA is the use of nonsteroidal antiinflammatory drugs (NSAID). Both Cox-2-selective and nonelective NSAID have been associated with an increased risk for CVD26. Because many patients with PsA use NSAID, their risk for cardiovascular complications may be increased.
The effect of anti-TNF therapy with onercept on traditional and novel biochemical cardiovascular risk factors was evaluated at baseline and at the end of the treatment in a double-blind, placebo-controlled study in 127 patients with PsA27. Onercept 100 mg induced significant reductions in concentrations of C-reactive protein, lipoprotein(a), and homocysteine, and an increase in the serum sex hormone-binding globulin, apolipoprotein (Apo) AI, Apo B, and triglycerides. These results suggested that it was not possible to prove that TNF blockade would provide cardioprotection on the basis of biochemical changes in isolation, and direct measures of atherosclerotic progression, such as carotid ultrasound, may be better27. In a pilot study, Tam, et al showed that short-term TNF-α blockade may be associated with reduction of IMT in PsA patients, along with improvement in clinical and laboratory indices of inflammation, but independent of changes in lipid profiles28. Anti-TNF-α therapy was also shown to improve aortic stiffness in patients with inflammatory arthropathies, including PsA29. These findings support the favorable effect of anti-TNF treatment on cardiovascular risk in patients with PsA.
Pathogenetic aspects of cardiovascular comorbidity in psoriasis and PsA
Pathophysiologically, the increased cardiovascular mortality of psoriasis patients is a consequence of what has been termed the “psoriatic march” (Figure 1)30. Psoriasis and its comorbidities, primarily obesity, contribute to the inflammatory burden of the affected patient. Systemic inflammation in turn causes insulin resistance, where the equilibrium between pro- and antiatherogenic effects of insulin is shifted toward the former (Figure 2)31. Insulin resistance results in endothelial dysfunction, which in turn leads to atherosclerosis and subsequent myocardial infarction, if coronary arteries are involved32.
The “psoriatic march.” Psoriasis and its comorbidities, primarily obesity, contribute to the inflammatory burden of the affected patient. Systemic inflammation in turn causes insulin resistance. This results in endothelial dysfunction, which provides the basis for atherosclerosis and subsequently myocardial infarction, if coronary arteries are involved.
Insulin resistance as a cause for endothelial cell dysfunction. Physiologically, endothelial cells respond to insulin by producing vasodilating nitric oxide (NO) via the endothelial nitric oxide synthase (eNOS) pathway (left). With insulin resistance, this pathway is blunted, but insulin’s mitogenic actions, which are mediated via the mitogen-activated protein kinase (MAPK) pathway, remain intact, potentially leading to increased production of adhesion molecules, thereby predisposing insulin-resistant patients to hypertension and atherosclerosis (right) (adapted from Boehncke, et al. Br J Rheumatol 2007;157:1249–5131); with permission.
Clinical consequences
Lifestyle interventions
The data reviewed here suggest a substantially elevated risk for CVD in patients with psoriasis and PsA. As psoriasis and PsA can only be controlled and not cured, it is of utmost importance for these patients to eliminate any additional risk factors for CVD that they can influence directly, particularly obesity and smoking. As both are prevalent among psoriasis patients33, clinicians need to convince their patients to normalize body weight and to quit smoking. Lifestyle interventions such as those practiced in the management of diabetes mellitus should be recommended.
Considerations regarding systemic therapies
When considering treatment options for psoriasis, it is evident that several systemic antipsoriatic therapies may cause or worsen cardiovascular comorbidity. This is particularly true for acitretin, which may increase serum triglycerides and cholesterol, and cyclosporin A, which may cause difficult-to-control hypertension. Side effects must be taken into account, and appropriate monitoring must be conducted to minimize these additional risks34.
Comorbidity necessitates comedication
In a survey of 1200 psoriasis patients, Mrowietz and coworkers found that only one-third took no other comedications, whereas one-quarter took more than 3 other systemic therapies35. Many of these concomitant medications are known to trigger psoriasis; this has been well established for beta-blockers and angiotensin-converting enzyme (ACE) inhibitors (Table 1). Of note, 8% of the psoriasis patients surveyed were taking a beta-blocker, and 12% an ACE inhibitor.
Drugs as trigger factors for psoriasis.
In patients taking multiple systemic therapies, drug interactions are another potential problem that must be considered when choosing the best option for the patient with numerous concomitant diseases. Of the available systemic antipsoriatic therapies, cyclosporin A and methotrexate bear a higher risk of drug interactions, whereas the biologics and fumaric acid esters have less (Table 2). All systemic medications for the treatment of psoriasis as well as existing comorbidities must be reviewed, and drugs potentially triggering psoriasis should be avoided if possible.
The risk of drug interactions.
The European League Against Rheumatism (EULAR) recently published recommendations for cardiovascular risk management in patients with RA and other forms of inflammatory arthritis including PsA36. EULAR recommends annual cardiovascular risk assessment using national guidelines for all patients with PsA. Any cardiovascular risk factors identified should be managed according to local guidelines; however, if local guidelines are not available, cardiovascular risk management should follow the Systematic Coronary Risk Evaluation (SCORE) model37, which is similar to the Framingham risk score. In addition to appropriate cardiovascular risk management, aggressive suppression of the inflammatory process was recommended to further lower the cardiovascular risk.
Comprehensive monitoring
Managing the comorbidities associated with psoriasis and PsA should not be limited to patients’ skin and joint symptoms. Dermatologists in private practice can detect developing comorbidities early. According to a recent consensus under the guidance of the National Psoriasis Foundation, a comprehensive investigation of psoriasis patients should include measurement every 2 years of blood pressure, pulse, and body mass index (BMI); measurement every 5 years [every 2 years in patients with additional risk factors (e.g., positive family history, diabetes mellitus, smoking)] of fasting blood glucose and lipids; and assessment of joint status with validated screening questionnaires at every visit32,38. Validated screening questionnaires such as ToPAS (Toronto Psoriatic Arthritis Screening) or PASE (Psoriatic Arthritis Screening and Evaluation) should also be utilized to observe signs of developing joint involvement32. These simple observations will promote early detection and targeted transferral when necessary, protecting patients from avoidable health problems.
Future research agenda
It is well understood that psoriasis and PsA are associated with comorbidities that have a substantial influence on patients’ well-being. Future research will need to clarify the pathogenetic links between psoriasis/PsA and its comorbidities. As there is evidence for the former driving the latter, the comorbidities may simply be complications of undertreated psoriasis and PsA. Consequently, the hypothesis that continuous systemic antipsoriatic therapy may reduce cardiovascular risk should be addressed in prospective clinical trials. A single-center open-label pilot trial is under way, and preliminary observations from it are encouraging; a multicenter followup study will be required to validate the results.
Recent publications have identified some biomarkers that identify psoriasis as a chronic systemic inflammatory disorder31,39. Thus, clinical assessment of the skin and joints in psoriasis and PsA, such as with the PASI, may need to be complemented with laboratory measures. Future projects should validate potential biomarkers for the systemic inflammatory burden of patients with psoriasis and PsA.
