Introduction
Psoriasis is a systemic inflammatory disorder that involves complex pathogenic interactions between the innate and adaptive immune systems, affecting approximately 2% of the population [
1].
Several important diseases occur more often in patients with psoriasis than expected based on their respective prevalence in the general population. Individuals with psoriasis have an increased risk of developing other chronic health diseases such as psoriatic arthritis, metabolic syndrome (MetS), depression, non-alcoholic fatty liver disease, Crohn’s disease, lymphoma and cardiovascular disorders [
2].
The relationship between psoriasis and an increased incidence of major adverse cardiovascular events has been observed in multiple epidemiologic studies. McDonald and Calabresi first demonstrated that the risk associated with vascular diseases was 2.2 times higher in more of 300 hospitalized patients with psoriasis than in controls with other dermatologic conditions [
3,
4].
The higher incidence of cardiovascular events in the population with psoriasis could be explained by several mechanisms. The high prevalence of traditional cardiovascular risk factors and metabolic abnormalities contributes to the high cardiovascular burden in patients with psoriasis. Likewise, the presence of systemic inflammation in combination with metabolic abnormalities may act in a synergistic manner to increase cardiovascular risk in these patients [
5].
This review focused on epidemiologic and clinical evidence linking psoriasis to cardiovascular risk factors and cardiovascular disease. We described the possible pathophysiologic mechanisms that justify this association and analyzed the best way to stratify the cardiovascular risk in patients with psoriasis (clinical scores, imaging techniques used to assess subclinical atherosclerosis). We also described the usefulness of the therapies frequently used in cardiovascular prevention (aspirin, lipid-lowering drugs, antihypertensive therapy, hypoglycemic agents) and analyzed the impact of the specific medication of the psoriasis on cardiovascular risk factors or major atherosclerotic events.
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Association Between Psoriasis and Cardiovascular Risk Factors
Smoking
Smoking is associated with an increased risk of cardiovascular disease, and prior studies have suggested that patients with psoriasis are more likely to be active smokers. Moreover, smoking is a possible risk factor for the onset of psoriasis, although the evidence remains limited and contradictory [
6‐
8].
A previously published meta-analysis determined that that smoking is an independent risk factor for the development of psoriasis and that patients with established psoriasis continue to smoke more than patients without psoriasis [
9]. Another meta-analysis showed not only a positive association between the presence of psoriasis and the prevalence of smoking, but also between tobacco and the severity of psoriasis [
10].
Several pathophysiologic mechanisms may explain the association of smoking with psoriasis [
11‐
13]. The nicotinic acetylcholine receptors are found not only in the nervous system and adrenal medulla, but have also been identified in other tissues, such as skin keratinocytes and inflammatory cells. Smoking causes oxidative stress and production of dangerous free radicals, interfering with signal pathways relevant in psoriasis such as mitogen-activated protein kinase, nuclear factor kappa B and JAK-STAT pathways. Nicotine also induces an increased secretion of several cytokines such as interleukin (IL)-12, tumor necrosis factor (TNF), IL-2 and granulocyte-monocyte colony-stimulating factor, which play a crucial role in the pathogenesis of psoriasis [
14]. The action of nicotine on the skin and inflammatory cells could facilitate keratinocyte adhesion and upward migration in the epidermis and may have an immunomodulatory effect, interfering with immune cell signaling [
15].
Finally, tobacco could negatively influence the response to treatment. In that sense, an observational study showed that heavy smoking could decrease the treatment effect of anti-TNF drugs in patients with psoriatic arthritis [
16]. Similarly, a small retrospective study showed that current smoking at the start of anti-TNF therapy was associated with non-response to TNF blockers [
17].
Obesity and MetS
MetS consists of a group of metabolic risk factors including central obesity, glucose intolerance, hypertension, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) and insulin resistance. The MetS is associated with a twofold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality [
18].
The association between psoriasis and obesity has been largely supported by evidence. In Argentina, a cross-sectional study (1286 psoriasis patients and 2547 controls) showed that the prevalences of overweight (43% vs. 40%,
p < 0.01) and obesity (30% vs. 24%,
p < 0.01) were higher in the psoriasis group compared with controls [
19]. In a Danish study, more adolescents with mild psoriasis were obese (8.6% vs. 1.7%,
p = 0.008), and physical measures of abdominal obesity were also significantly higher compared with the control group [
20].
On the other hand, some authors described that the risk of psoriasis being increased in the obese population, and this clinical scenario may negatively affect systemic treatment of psoriasis [
21].
A recent meta-analysis (63 studies encompassing 15,939 psoriasis patients and 103,984 controls) showed that 30.3% of psoriasis patients were reported with MetS compared with 21.7% subjects in the control group [OR 2.18 (95% CI 1.84–2.34)] [
22]. Similarly, another meta-analysis showed that the association between psoriasis and MetS is high in Latin America [
23].
As with obesity, in a large prospective study from a general population, the presence of MetS was associated with increased risk of incident psoriasis, and the authors suggest that this positive association could, at least partly, be attributed to adiposity [
24].
Consequently, the relationship between MetS and psoriasis is bidirectional, where inflammation is the common pathophysiologic substrate between both entities. In that sense, growing knowledge suggests that the Th17 cells and IL-23 may be a link between cutaneous and metabolic manifestations of psoriasis [
25].
Hypertension
Data from epidemiologic studies show that hypertension is more prevalent among psoriasis patients, and prevalence is associated with psoriasis severity [
19,
26‐
28]. A recently published meta-analysis demonstrates that psoriasis is associated with an increased risk of hypertension compared with those without psoriasis [
29].
Additionally, psoriasis patients are prone to suffer difficult-to-control hypertension. A case-control study showed that, compared with hypertensive patients without psoriasis, psoriasis patients with hypertension were five times more likely to be on a monotherapy antihypertensive regimen, 9.5 times more likely to be on dual antihypertensive therapy and 16.5 times more likely to be on a triple antihypertensive regimen after adjusting for traditional cardiac risk factors [
30].
As previously described for other risk factors, hypertension was significantly associated with an increased risk of psoriasis incidence [
31].
Again, it is accepted that inflammation underlies the pathogenesis of hypertension, and activated immune cells are critical factors within this process [
32,
33].
Dyslipidemia
“Atherogenic dyslipidemia” is associated with increased cardiovascular risk [
34]. Its main findings include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in low-density lipoprotein (LDL) particles (size reduction, increase in density, oxidation), accumulation of remnant lipoproteins and postprandial hyperlipidemia. Small LDL particles can accumulate in the tunica intima to initiate atherosclerosis. These LDL particles undergo oxidative modification producing oxidized LDL (oxLDL) that may enter macrophages to get transformed into foam cells, leading to the development of atherosclerotic plaques. Products of oxLDL may injure vascular wall cells to produce cytokines and inflammatory mediators, thereby promoting low-grade inflammation and progression of atherosclerotic plaques.
Psoriasis is associated with an atherogenic lipid profile and significant lipid abnormalities have been noted even during 5 years preceding onset of psoriasis [
35]. Similarly, another study reported that the mean oxLDL levels in patients with psoriasis were significantly higher than those of healthy controls [
36].
On the other hand, HDL is involved in reverse cholesterol transport, inhibition of monocytic infiltration and thus suppression of atherogenicity. In patients with psoriasis, not only lipoprotein levels can be altered, but also their composition and function may be significantly different from controls. This is an important observation because the composition and function of HDL are actually considered more important than the quantity of HDL itself. In that sense, Mehta et al. showed that the HDL efflux capacity in psoriasis patients compared with controls was diminished beyond cardiovascular risk factors [
37].
The plasma concentration of the major apoprotein of LDL cholesterol, apolipoprotein B, is associated with the development of atherosclerosis and higher cardiovascular risk. Also, lipoprotein (a), a genetic variant of LDL with apolipoprotein B linked to apolipoprotein-a by a disulfide bond, is also susceptible to lipid peroxidation and is said to have both thrombogenic and atherogenic roles. A recently published meta-analysis showed that lipoprotein (a) and apolipoprotein B levels were significantly higher in patients with psoriasis compared with controls [
38].
Importantly, all lipid abnormalities observed in the patient with psoriasis have systemic inflammation and insulin resistance as a substrate. Consequently, the association with other risk factors such as obesity and MetS is strong.
Diabetes
A systematic review reported that the average prevalence of type 2 diabetes in psoriasis patients was 11.6% (15 epidemiologic cohorts evaluated) [
39]. The same study showed an increased prevalence of type 2 diabetes in subjects with psoriasis compared with controls (11 studies evaluated). The mean type 2 diabetes prevalence was 10.3% in psoriasis patients and 6.2% in controls. The heterogeneous findings complicate a reliable estimate of the true prevalence of diabetes in patients with psoriasis but the prevalence of diabetes observed in the psoriasis patients was systematically higher than in the healthy population.
However, many new cases of diabetes have been reported in the population with psoriasis compared with subjects without the disease. In a study of 108,132 patients with psoriasis, the adjusted hazard ratios for incident type 2 diabetes were 1.11 (95% CI 1.07–1.15) in the mild psoriasis group and 1.46 (1.30–1.65) in the severe psoriasis group [
40]. Similarly, a meta-analysis (eight cohort studies included) reported a relative risk of 1.50 (95% CI 1.27–1.77) for diabetes incidence in patients with psoriasis [
41].
The relationship between psoriasis and diabetes can be partially explained by the increase in obesity and unhealthy lifestyles and possibly can be related to insulin resistance associated with inflammation. However, other mechanisms have been proposed to explain this association. Genetically, several genes (CDKAL1, PTPN22, ST6GAL1, JAZF1) have been linked to both type 2 diabetes and psoriasis [
42,
43]. Additional emerging pathways that are implicated include those of the glucagon-like peptide-1 receptor and the incretin effect [
44,
45].
However, at present, the exact mechanistic links between the two diseases are not entirely understood and warrant further investigations.
Physical Activity
While numerous studies have suggested an association between psoriasis and physical activity, others have yielded contradictory results.
A recently published meta-analysis combined data of 13 studies including a total of 149,499 participants [
46]. There was no significant difference in the level of exercise between people without and with psoriasis when analyzed for the overall effect but the subgroup analysis showed that patients with psoriasis performed vigorous exercises significantly less than controls (RR 0.76; 95% CI 0.67–0.85;
p < 0.00001). Also, patients with a higher proportion of psoriatic lesions and self-awareness were associated with lower intensity exercises.
Similarly, another systematic review showed that individuals with psoriasis are less likely to participate in vigorous physical activity compared with individuals without psoriasis [
47].
In a large cohort of women in the USA, the association between physical activity and incident psoriasis was evaluated (1026 incident psoriasis cases during 1,195,703 person-years of follow-up) [
48]. In this study, vigorous physical activity was independently associated with a reduced risk of incident psoriasis [multivariate RR for the highest quintile, 0.66 (95% CI 0.54–0.81;
p < 0.001)]. The mechanism whereby physical activity reduces psoriasis risk deserves further study. It is biologically plausible that physical activity may affect psoriasis risk through effects on systemic inflammatory mediators.
Association Between Psoriasis and Cardiovascular Events
An estimated prevalence of cardiovascular heart disease of 14.3% has been observed in North American patients with psoriasis, which is higher (11.3%) than that of the general population [
49]. A cross-sectional study developed in Argentina showed that regardless of age and the presence or absence of diabetes, hypertension or smoking, there was a significant association between coronary artery disease and psoriasis (OR 1.48, 95% CI 1.04–2.11,
p = 0.03) [
19].
Likewise, a prospective, population-based cohort study of patients with psoriasis in the UK showed that the incidences of myocardial infarction per 1000 person-years for control patients and patients with mild and severe psoriasis were 3.58 (95% CI 3.52–3.65), 4.04 (95% CI 3.88–4.21) and 5.13 (95% CI 4.22–6.17), respectively. The relative risk was greatest in young patients with severe psoriasis [
50].
Furthermore, patients with psoriasis, particularly if severe, have an increased risk of stroke that is not explained by major stroke risk factors identified in routine medical care [
51,
52].
Additionally, a retrospective cohort of patients with psoriasis showed higher mortality rates during follow-up compared with the control group [
53]. In the same way, another study showed that patients with severe psoriasis have an increased risk of cardiovascular mortality that is independent of traditional cardiovascular risk factors [
54].
Finally, Pietrzak et al. developed a meta-analysis that indicates an elevated risk of cardiovascular events in psoriatic patients in relation to non-psoriatic controls (OR 1.28; 95% CI 1.18–1.38) [
55]. In another recently published meta-analysis, Saumya et al. obtained results supporting a significant association between psoriasis and incidence of major adverse cardiovascular events. The incidence of cardiovascular events among psoriasis patients was dominant in the Middle East population compared with other geographic locations considered in this study. The differences found may be related to variations in genetic structure, environmental exposures or issues related to healthcare use [
56].
Pathogenetic mechanisms of cardiovascular disease in psoriasis patients appear to be of a complex nature. The development of atherosclerosis and its increased prevalence may be partially explained by the presence of atherosclerotic risk factors as well as by the chronic inflammatory processes that are commonly observed in psoriasis. Previous studies have established psoriasis primarily as a T cell-mediated disorder. While initial evidence implicated a predominant role of helper T cells type 1 (Th1), recent research shows the importance of the Th17 and other IL-17 producing cell types [
57]. All the subtypes of T cells involved in the pathogenesis of psoriasis are also involved in atherosclerosis [
58]. Therefore, the main hypothesis is that the chronic inflammation that occurs in psoriasis is more than skin deep and results in multiple systemic mechanisms that are shared with other chronic inflammatory diseases, including atherosclerosis. In addition, Flammer and Ruschitzka proposed the theory of “two plaques for one syndrome” since molecular mechanisms as well as the pro-inflammatory cytokine profile of psoriatic lesions are remarkably similar to those of atherosclerotic ones, with a comparable inflammatory infiltrate of T cells, macrophages and monocytes [
59].
Impact of Specific Treatments for Psoriasis on Cardiovascular Risk
The choice of topical or systemic treatment depends on the severity, extent, risk-benefit ratio, patient preferences and the response to the therapy employed. Being a recurring pathology, it is common that multiple periods of treatments are required to maintain control of the disease. Systemic conventional treatments should be used with caution in psoriatic patients with MetS, because they could adversely affect the coexisting metabolic disorders, especially in the case of their chronic use [
114]. Biologics appear to have a different safety profile compared with conventional treatments, and so they are usually tolerated.
A meta-analysis of observational studies that mostly analyzed works on rheumatoid arthritis but that included six studies conducted in patients with psoriasis demonstrated a cardioprotective effect of methotrexate, reducing cardiovascular events and acute myocardial infarction [
115].
Retinoids can increase the value of triglycerides and cholesterol, and decrease the values of HDL cholesterol [
116]. The effect is dose dependent and can be managed in most cases with diet or dose adjustment.
Some reports showed an increase in the level of triglycerides and total cholesterol, and a systematic review found a significant (dose-dependent) increase in blood pressure with the use of cyclosporine in patients with psoriasis [
117].
The aforementioned meta-analysis also demonstrated a cardioprotective effect of anti-TNF, reducing cardiovascular events and acute myocardial infarction [
115]. Specifically, in patients with psoriasis, Wu et al. showed that the incidence of acute myocardial infarction was significantly lower in the group treated with anti-TNF compared with those who received topical treatments (3.05 vs. 6.73 events every 1000 patients/year), without finding differences from the group treated by other systemic treatments [
118]. Likewise, another recent meta-analysis considering only studies that included patients with psoriasis or psoriatic arthritis showed that the use of anti-TNF was associated with a lower risk of acute myocardial infarction and cardiovascular events regarding topical treatment or phototherapy [
119]. However, infliximab therapy was associated with an increase in hospitalizations and higher mortality in patients with heart failure, although etanercept did not show such effects [
120]. In another analysis of psoriasis patients treated with etanercept, the appearance of heart failure was rare and a real increase in risk could not be demonstrated [
121]. In a meta-analysis conducted by Singh et al., the rate of heart failure was not statistically different when comparing therapy with biologics and controls [
122].
IL-17A inhibitors (secukinumab and ixekizumab) do not appear to be associated with an increased risk of cardiovascular events, although the data are still limited [
123]. Some small randomized trials showed a greater number of cardiovascular events with one of the IL-12/23 inhibitors, briakinumab, already discontinued in the market [
124,
125]. However, a systematic review did not find this association with another drug in the same group (ustekinumab) [
123].
Finally, while treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several cardiovascular risk factors, and the incidence of major cardiovascular events is low [
126].
Conclusion
Psoriasis is a chronic inflammatory skin disease associated with increased cardiovascular morbidity and mortality. Patients with psoriasis have an increased prevalence of classic cardiovascular risk factors, but psoriasis may provide an additional and independent cardiovascular risk factor: inflammation. Knowledge of the application of different strategies in cardiovascular prevention could mean an advantage in performing the difficult task of estimating cardiovascular risk and treating cardiovascular risk factors in this particular group of patients.
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