Dermatology Online Journal
Psoriasis: Can statins play a dual role?
- Author(s): Rajpara, Anand N
- Goldner, Ronald
- Gaspari, Anthony
- et al.
Psoriasis: Can statins play a dual role?1. School of Medicine, University of Maryland, Baltimore, Maryland. firstname.lastname@example.org
Anand N Rajpara MSIV1, Ronald Goldner MD2, Anthony Gaspari MD2
Dermatology Online Journal 16 (2): 2
2. Department of Dermatology, University of Maryland, Baltimore, Maryland
Recently, a strong association between “psoriasis” and “atherosclerosis” has emerged. Psoriasis patients have an increased prevalence of atherosclerotic disease including coronary artery, cerebrovascular, and peripheral vascular diseases. The exact connection between psoriasis and atherosclerosis remains unclear, but it is thought that inflammation, which plays an important role in both diseases, may be the causative link. Nevertheless, psoriasis patients suffer from an increased burden of atherosclerotic disease and most commonly die from “coronary artery disease” (CAD). Psoriatic patients have an increased prevalence of CAD risk factors and an increased risk of myocardial infarction (MI). One CAD risk factor in psoriasis patients that can easily be managed is “hyperlipidemia.” “Statins” are safe, cost-effective, and have been proven to be highly effective in preventing CAD, including MI, in patients with hyperlipidemia. Furthermore, in addition to their lipid lowering properties, statins have anti-inflammatory immunomodulator activities that may be beneficial in several autoimmune diseases including psoriasis. Considering the safety and cost-effectiveness of statins, we feel that it is worth investigating if statins can play a dual role in psoriasis by treating the increased atherosclerotic disease burden in these patients through their lipid lowering effects and by decreasing psoriatic disease activity through their anti-inflammatory immunomodulatory properties.
Psoriasis is a chronic inflammatory disease of the skin, scalp, nails, and sometimes joints, that affects 1-2 percent of the general population [1, 2, 3, 4]. Psoriasis typically first affects patients between the ages of 15 and 35 and can cause major physical and psychological morbidity, leading to a significant economic burden on the health care system and the patient [5, 6, 7, 8]. Psoriasis was originally thought of as an inflammatory disorder solely affecting the skin, but it is now recognized as a systemic inflammatory disease, much like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) . Research suggests that patients with chronic systemic inflammatory diseases like SLE and RA are at increased risk for atherosclerosis and heart disease [10, 11, 12, 13]. With new evidence supporting the inflammatory basis for atherosclerosis and coronary artery disease (CAD), researchers hypothesize that systemic inflammation may be one potential mechanism linking chronic inflammatory diseases to atherosclerosis and heart disease [14, 15]. Not surprisingly then, recent observational studies show an increased risk of cardiovascular disease in patients with psoriasis [16-22]. In a clinic-based study with over 600 subjects, McDonald and Calabresi found that psoriasis patients had a 2.2 times higher relative risk of arterial and venous vascular disease (MI, PE, stroke, thrombophlebitis) than controls with other dermatologic conditions . Further, recent analysis of 2 large health plan databases in the United States confirmed findings from earlier studies, that the prevalence of cardiovascular disease is increased in the psoriasis population .
Psoriasis and atherosclerosis
|Figure 1||Figure 2|
One of the likely mechanisms responsible for the increased risk of heart disease in psoriasis patients is the increased prevalence of cardiovascular (CV) disease risk factors in this population (Figure 1) . Proven risk factors for CV disease, such as dyslipidemia, obesity, diabetes, smoking, hypertension, and metabolic syndrome, are more prevalent in patients with psoriasis, as compared to healthy controls and patients with other dermatologic disorders [26-32]. Recently, it has been proposed that psoriasis itself may be an independent risk factor for CV disease, through systemic inflammation and exacerbation of the atherosclerotic process [33, 34]. In fact, psoriasis shares many similar pathogenic mechanisms with atherosclerosis, such as the immunological processes involved, inflammatory cytokine profiles, and both local and systemic inflammatory markers (Figure 2 and Table 1) [9, 35-51]. For example, psoriasis and atherosclerosis are both T-helper 1 cell (Th-1) mediated diseases [52, 53, 54]. Both diseases have the same pattern of T-cell activation and expression of adhesion molecules [38, 55, 56]. Both unstable psoriatic and atherosclerotic plaques have predominance of Th-1 cytokines [38, 53]. In addition, psoriasis and atherosclerosis share common histological features with involvement of T-cells, monocytes, macrophages, connective tissue cells, and extracellular matrix [36, 57, 58, 59].
Thus, by utilizing common pathogenic mechanisms, psoriasis-induced systemic inflammation may very well be an independent risk factor for atherosclerosis and heart disease. As new research on this subject emerges, it will be interesting to see if treatment of psoriasis itself, leading to decreased systemic inflammation, lowers the risk of atherosclerotic disease in these patients. Interestingly, a retrospective study by Prodanovich et al. showed that patients with psoriasis and rheumatoid arthritis treated with methotrexate had decreased rates of vascular disease as compared to controls .
A recent observational study by Prodanovich et al. in 2009 examined the association between psoriasis and atherosclerosis . The study was conducted at the Miami VA medical center and included 3236 patients with psoriasis and 2500 control patients without psoriasis. After controlling for CAD risk factors, the authors found that psoriasis patients had a higher prevalence of ischemic heart disease (OR 1.78), cerebrovascular disease (OR 1.70), and peripheral vascular disease (OR 1.98). Psoriasis was also found to be an independent risk factor for mortality (OR 1.86). The authors concluded that psoriasis patients have a higher prevalence of atherosclerotic disease including coronary artery disease, cerebrovascular disease, and peripheral vascular disease, which contributes to their increased mortality .
Psoriasis and cardiovascular disease
Indeed, recent studies suggest that psoriasis is an independent risk factor for CV disease. In the largest study of non-hospitalized patients with psoriasis and CAD to date, Gelfand et al. concluded that psoriasis is an independent risk factor for acute myocardial infarction (MI) . The study was a large retrospective cohort study performed at the University of Pennsylvania that used the validated General Practice Research Database (GPRD), which contained longitudinal medical records on over 130,000 psoriasis patients, from about 450 primary care centers throughout England. Gelfand et al. found that the relative risk of MI was significantly higher in patients with both mild and severe psoriasis, with a relative risk of 1.29 (95% CI 1.14-1.46) for 30-year-old patients with mild psoriasis and 3.10 (95% CI 1.98-4.86) for 30-year-old patients with severe psoriasis . However, the authors failed to mention the absolute risk of MI in these patients, which is most likely not clinically relevant for young patients. Nevertheless, the evidence linking psoriasis and CAD led the American Journal of Cardiology (AJC) to publish a consensus statement addressing the matter in 2008 . The consensus statement declares that patients with moderate to severe plaque psoriasis have an increased prevalence of CAD and an increased risk for MI. The AJC recommends that “patients with moderate to severe psoriasis should be informed that they may be at increased risk for CAD and that they should undergo appropriate medical evaluation” .
Psoriasis and Hyperlipidemia
As part of the medical evaluation for CV diseases, the AJC recommends that patients with moderate to severe plaque psoriasis undergo blood lipid profiles . The AJC also recommends that, once identified, psoriasis patients with hyperlipidemia should be treated according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines, which serve as the gold standard for cholesterol management for all patients with dyslipidemia . The NCEP ATP III guidelines for cholesterol management state that based on multiple lines of evidence, there is a strong causal relationship between LDL levels and CAD, which is to be expected, considering the major role LDL plays in atherosclerotic plaque formation (Figure 2) . The ATP III guidelines recommend that LDL levels should be the primary target of cholesterol lowering therapy and lipid lowering therapy should be initiated based on LDL levels and CAD risk factors (Table 2 and Table 3) . At this time, psoriasis is not considered as a CAD risk factor by the most recent ATP III guidelines revised in 2004. Thus psoriasis patients with hyperlipidemia are to be treated no differently than the general population. The ATP III advocates that initial treatment of hyperlipidemia in most cases should start with therapeutic lifestyle changes (TLC), consisting of diet, exercise, and weight loss for a period of 3 months. However, most people will end up requiring lipid lowering drug therapy .
Statins and treatment of hyperlipidemia
The NCEP advocates the use of statins as first-line drugs when LDL-lowering drugs are indicated to achieve LDL goals. Results from five major clinical trials showed statins decreased CHD, total mortality, MI's, strokes, and peripheral vascular disease in patients that met NCEP criteria for lipid-lowering therapy treated with statins vs. placebo [62, 63, 64, 65, 66, 67]. These five trials included about 30,000 people randomized to either placebo or statin and in the trials, statins proved to be safe, with no major or unexpected adverse side effects. In addition, short-term clinical trials involving statins have demonstrated that every 1 percent decrease in LDL levels provides a 1 percent decrease in the risk for MI and CHD death [68, 69, 70]. The NCEP ATP III concludes that “statin therapy reduces the risk of essentially every clinical manifestation of the atherosclerotic process; they are easy to administer, with good patient acceptance, they have few drug-drug interactions, and they have a good record for safety” .
Although statins are considered relatively safe, they are not without side-effects and patients require monitoring. One of the most common side-effects of statins is liver toxicity. Asymptomatic elevation of AST and/or ALT greater than 3 times the upper limit of normal occur in <1 percent of patients receiving statins, with progression to liver failure occurring in 1 case per 1 million statin prescriptions . Accordingly, statins are absolutely contraindicated in patients with acute or chronic liver disease and baseline liver function tests (LFTs) are needed before initiating therapy. Regarding psoriasis patients, the AJC recommends that patients who have been treated in the past, or are currently being treated with methotrexate should be monitored closely for hepatic dysfunction .
The most common side-effect of statins is muscle toxicity. Myalgia occurs in 1.5-3.0 percent of individuals on statins, myositis occurs in 0.3-2.2 cases per million prescriptions, and rhabdomyolysis occurs in 0.3-13.5 cases per million prescriptions . Rhabdomyolysis is a life threatening condition and thus it is recommended that any patient on statin therapy that complains of muscle pain undergo measurement of serum creatine kinase to monitor for this condition. In regards to psoriasis patients, the AJC recommends that patients receiving cyclosporine and a statin should be monitored closely for signs of rhabdomyolysis . Of note, we did find one report in the literature in which statins caused worsening of psoriatic skin disease in a patient with psoriasis .
The mechanisms by which statins lower LDL levels, thereby, decreasing the progression of atherosclerosis and CHD, is relatively well known. Statins decrease cholesterol synthesis in the liver by inhibiting 3-hydroxy-3-3methylglutaryl coenzyme A (HMG-CoA), which is a rate-limiting enzyme involved in the synthesis of cholesterol . Further, decreased levels of intracellular cholesterol in liver cells leads to up-regulation of the LDL receptor gene and ultimately, more LDL receptors on the surface of the liver, thereby, decreasing circulating LDL levels.
Statins and autoimmune disease
However, the cardio-protective effects of statins cannot be attributed solely to lipid lowering alone [72, 73]. In addition to their lipid lowering effects, statins may exhibit anti-inflammatory immunomodulator activity that could be beneficial in atherosclerosis and CAD, which have important inflammatory components [74, 75]. Statins down regulate adhesion molecules such as LFA-1 and I-CAM-1 on leukocytes and endothelial cells, which are necessary for leukocyte activation, leukocyte migration to inflammatory sites, and immunologic cytotoxicity . Statins inhibit the inducible expression of MHC II molecules, further decreasing leukocyte activation. Statins also inhibit the expression of chemokine receptors on Th-1 cells, which interferes with their ability to migrate to inflammatory sites. In addition, statins block the production of NO synthase and production of several inflammatory cytokines, like TNF-alpha and IFN-gamma by macrophages . Figures 3 and 4 from Greenwood et al. summarizes the many anti-inflammatory immunomodulator effects of statins .
|Figure 3||Figure 4|
Based on their anti-inflammatory immunomodulator properties, researchers have started to use statins in the treatment of autoimmune disease. The use of statins to treat animal models of autoimmune diseases like MS, arthritis, and SLE shows promise (Table 4) . Recent human clinical trials indicate statins may be beneficial in the treatment of MS, rheumatoid arthritis, and SLE [77, 78, 79]. Currently, there are only a limited number of studies looking at the use of statins in human autoimmune diseases.
Pathogenesis of psoriasis
Psoriasis, like SLE and RA, is a chronic systemic inflammatory disease in which the immune system is thought to play a major role in disease initiation and maintenance (Figure 5) . The initial event in psoriasis involves an unknown environmental trigger, acting on a genetically sucesptible host to trigger an inflammatory and immunologic cascade. Stressed keratinocytes release factors that activate dermal dendritic cells, which in turn travel to lymph nodes to activate T-cells. T-cells then differentiate into Th-1 and Th-17 cells and migrate back to the dermis and epidermis, via chemokines and adhesion molecules. The activated T-cells next activate macrophages in the dermis and release numerous inflammatory cytokines, including TNF-alpha, IFN-gamma, and IL-17, which leads to keratinocyte activation and hyper-proliferation, manifesting clinically as psoriatic plaques . Biologic therapies that inhibit TNF-alpha (infliximab, entanercept, and adalimumab) and inhibit T-cells (efalizumab and alefacept), have proven to be efficacious in the treatment of psoriasis (Table 5) .
Statins and Psoriasis
Thus, based purely upon the mechanisms of disease in psoriasis, it is biologically plausible that statins may be beneficial in the treatment of psoriasis through their anti-inflammatory immunomodulator effects. For example, statins have been found to down regulate adhesion molecules, such as LFA-1, which is the target of efalizumab. Statins also inhibit the production of inflammatory cytokines like TNF-alpha, which is targeted by infliximab, entanercept, and adalimumab. Further, statins inhibit the production of IL-17, which is the target of new psoriasis drugs currently in phase 2 clinical trials. Lastly, statins inhibit activation and migration of Th-1 cells, which are major players in the pathogenesis of psoriasis. The potential use of statins to treat psoriasis currently has only biological plausibility and needs the support of actual clinical data.
We could only find one report in the literature in which statins have been used specifically for the treatment of psoriasis. The pilot study was done by Shirinsky et al. in Russia in 2007, looking at the efficacy of simvastatin in treating plaque psoriasis . Patients selected for the study were at least 18 years of age, with plaque psoriasis covering >10 percent of their bodies and a psoriasis area and severity (PASI) score of at least 12. Seven patients were prescribed simvastatin 40 mg/d for 8 weeks and were followed up at week 4 and week 8, using the PASI and dermatology quality of life index (DLQI) to assess severity of disease. At the end of 8 weeks, the researchers found a statistically significant decrease in the mean PASI score by 47.34 percent and downward trends beginning in DLQI scores. Two patients achieved 50 percent PASI response and two patients achieved 75 percent PASI response. Although the study had a small number of patients, was uncontrolled, and failed to assess lipid levels, their findings suggest that statins could have clinical utility in the treatment of psoriasis.
In summary, patients with moderate to severe plaque psoriasis have an increased prevalence of hyperlipidemia, an increased prevalence of atherosclerotic disease including CAD, cerberovascular disease, and peripheral vascular disease, and they are at increased risk for MI. It is known that inflammation is an important pathogenic mechanism underlying both atherosclerosis and psoriasis. However, it still remains to be proven whether the systemic inflammation in psoriasis is responsible for the increased prevalence of atherosclerosis and CAD in these patients. Nevertheless, it is clear that patients with psoriasis, for whatever reason, have an increased atherosclerotic disease burden, with CAD being the most common cause of death in these patients. Accordingly, it is essential that psoriasis patients should be screened for CAD risk factors according to the AJC 2008 consensus report on psoriasis and heart disease.
We emphasize screening for hyperlipidemia in psoriatic patients due to the major role lipids play in the pathogenesis of atherosclerosis and because hyperlipidemia is relatively easy to treat. Once indentified, psoriasis patients with hyperlipidemia meeting criteria for lipid-lowering drug therapy should be started on statin therapy in order to decrease their CV mortality. Unfortunately, psoriasis is not yet considered as a risk factor for CAD by the current lipid-lowering guidelines so psoriasis patients should be treated like any other patient with hyperlipidemia. Further, it is presently unknown whether treatment of hyperlipidemia with statins in psoriasis patients will decrease their risk of CAD or other atherosclerotic diseases to any greater or lesser extent than the general population. Theoretically, statins should benefit psoriasis patients as these drugs are proven to decrease the risk of essentially every clinical manifestation of the atherosclerotic process.
In addition to their lipid lowering effects, statins have many anti-inflammatory immunomodulator properties. Based on these properties it seems biologically plausible that statins could potentially decrease psoriasis disease activity. However, this remains only speculation because there has been only one pilot study showing modest effect of statins on psoriatic disease. Nevertheless, considering the safety and cost-effectiveness of statins, we feel that it is worth investigating if statins can play a dual role in psoriasis by treating the increased atherosclerotic disease burden in these patients through their lipid lowering effects and by decreasing psoriatic disease activity through their anti-inflammatory immunomodulatory properties.
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