Abstract
Psoriatic arthritis (PsA) is associated with serious comorbidities such as increased cardiovascular risk, hypertension, depression, and reduced quality of life. Patients with psoriasis have been observed to have an increased incidence of metabolic syndrome compared with the general population; recently, this has also been observed in patients with PsA. This review focuses on the comorbidities associated with PsA, with an emphasis on risks of coronary artery disease and metabolic syndrome. We also discuss the development of a comprehensive approach for the management of comorbidities of PsA. The review summarizes a presentation at the 2010 annual meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis).
Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease associated with psoriasis; in addition to the involvement of the cutaneous system, it often involves extraarticular sites that may be neglected in clinical practice.
Recent reports suggest that patients with PsA have an increased risk for cardiovascular disease (CVD) and mortality, as well as metabolic syndrome and its components1,2,3,4,5,6,7. The simplest explanation for increased cardiovascular risk is the prevalence of traditional risk factors such as age, gender, smoking, and history of diabetes. However, this is not the case with psoriatic disease, where many studies have found that up to 30%–50% of patients with atherosclerosis do not have these risk factors8,9. Therefore, treatment regimens for PsA patients must be tailored to comorbidities associated with PsA, including metabolic abnormalities. The objective of this review is to discuss the constellation of comorbid conditions associated with PsA, with an emphasis on atherosclerosis and metabolic syndrome.
Relationship Between Systemic Inflammation, Obesity, and Atherosclerosis
Psoriatic disease is uniquely associated with obesity, insulin resistance, and hypertension10,11,12,13, which are capable of inducing inflammatory cascades on the endothelial lining to initiate the process of atherosclerosis. Although no pathophysiological mechanism for this association has been identified to date, the observation that psoriatic disease is a risk factor for coronary artery disease (CAD) provides a unique opportunity to study the contributing role of systemic inflammation to atherosclerosis.
The influence of obesity on psoriatic disease appears to stem from a complex interaction of inflammatory and metabolic factors. Under normal conditions, the endothelial cells of the arterial wall resist adhesion and aggregation of leukocytes and promote fibrinolysis. When activated by stimuli such as obesity, insulin resistance, hypertension, or inflammation, the endothelial cells express adhesion molecules that selectively recruit various classes of leukocytes. Inflammatory cells such as blood monocytes now adhere to the endothelial surface by binding to leukocyte adhesion molecules. Activated white adipose tissue increases the synthesis of proinflammatory cytokines, such as interleukins (IL-1, IL-6, IL-17) and tumor necrosis factor-α (TNF-α)14,15. IL-6 stimulates the hepatic production of C-reactive protein (CRP), which stimulates macrophages to produce tissue factor, an important procoagulant found in atherosclerotic plaques. Further, proinflammatory cytokines stimulate adipocytes to synthesize neuropeptides, which are critical in the pathogenesis of psoriatic disease16. In addition, adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease. Adipocytokines are cytokines associated with adipose tissue including TNF-α; the most widely studied are leptin, adiponectin, resistin, and visfatin14,15.
Other Comorbidities in PsA
PsA is associated with inflammatory bowel disease17, uveitis18,19, valvular heart disease20, fatigue, osteoporosis, and comorbidities secondary to therapy or to chronic pain, disability (Table 1) and reduced quality of life.
Comorbidities in psoriatic arthritis.
Individual components of metabolic syndrome such as obesity1,2, hypertension1,2,3, insulin resistance1,2, and dyslipidemia1,3,4,5 have been reported by several studies in patients with PsA. The leading cause of death in 428 Canadian patients with PsA was cardiovascular diseases (36.2%)21,22. In a followup study of patients with PsA (n = 648), a significantly higher prevalence of angina, myocardial infarction, and hypertension was observed6. In a cross-sectional comparative study of patients with PsA (n = 3066), the prevalences of ischemic heart disease, congestive heart failure, atherosclerosis, type II diabetes mellitus (T2DM), hyperlipidemia, and hypertension were significantly higher in patients with PsA than in controls (p < 0.05)1. In a study of 47 patients with PsA and 100 healthy controls, PsA patients had significantly higher levels of hypertension, hyperlipidemia, erythrocyte sedimentation rate, CRP, and fibrinogen3. A nationwide Danish registry study found that the cardiovascular risk from severe psoriasis or PsA is of similar magnitude to that of DM23.
Recently, we observed an increased prevalence of metabolic syndrome in patients with PsA (61/105 patients; 58.1%) compared to 35.2% reported for the Third National Health and Nutrition Examination Survey (NHANES III) data13. Of the patients with metabolic syndrome, 15 (24.6%) had CAD, 24 (39.3%) had T2DM, and 11 (18.0%) had chronic kidney disease.
Can We Prevent Metabolic Syndrome and Cardiovascular Comorbidities of PsA?
It is essential to monitor risk factors of CAD and provide necessary care to prevent the progress of atherosclerosis in patients with PsA. Standard care includes avoiding tobacco, lowering blood pressure to below 140/90 mm Hg, lowering serum cholesterol to below 200 mg/dl (more specifically LDL cholesterol to below 100 mg/dl), weight reduction, a healthy diet, and ≥ 30 min/day of physical activity, all of which have been recommended for the general population by the National Psoriasis Foundation and the American Heart Association24,25, and have been confirmed in guidelines from the European League Against Rheumatism for patients with RA, ankylosing spondylitis (AS), or PsA (Table 2)26.
The 10 recommendations for cardiovascular (CV) risk management in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).
In patients with PsA, the severity of skin inflammation may be an indicator of increased cardiovascular disease6; thus, early diagnosis and treatment targeting the inflammatory cascades associated with PsA may halt disease progression and reduce mortality and morbidities.
Reports suggest that treatment with disease-modifying antirheumatic drugs (DMARD), such as methotrexate, appear to provide a substantial benefit in reducing risk of vascular disease in psoriasis and RA27,28,29,30. However, although methotrexate is beneficial for RA-associated metabolic syndrome and appears to reduce atherosclerosis29,30, it has not been shown to reduce inflammation in PsA. Further, prolonged treatment with DMARD may increase the risks of infectious and malignant diseases.
Similarly, the use of biologics has inherent risks for mycobacterial infection, deep fungal infection, lymphoma, and other malignancies31,32,33. The cardioprotective role of TNF blockers provides a new dimension for the treatment of RA, PsA, and AS because of their prominent antiinflammatory action. Recent publications demonstrated an improvement of arterial stiffness with etanercept in patients with RA34 and with infliximab in patients with AS35, and data from the British Biologics Registry suggest RA patients who responded to anti-TNF agents may have reduced risks for myocardial infarction36. These data may justify usefulness of biologics in reducing/preventing the cardiovascular comorbidities associated with psoriatic disease, but randomized controlled trials are needed for confirmation.
Conclusion: The Concept of Total Care
Given the increased prevalence of comorbidities in patients with psoriatic disease, it is essential to approach the disease as a potentially multisystem disorder. An ideal treatment regimen for PsA would provide comprehensive and effective care similar to the proposed Total Care Program for psoriasis37. Table 3 provides an outline of a comprehensive program that includes exemplary care of joints and skin and of the comorbidities associated with PsA.
The concept of total care.
