By: Aiham Dheyaa Ahmed

Introduction:
Psoriasis is a prevalent inflammatory skin condition, affecting approximately 2% of the population in
Western countries. It's characterized by red scaly plaques that can appear on various parts of the body,
reflecting the underlying pathogenic mechanisms of inflammation, hyperproliferation, and angiogenesis.
Psoriasis is considered an immune-mediated disease, involving complex interactions between the innate
and adaptive immune systems.
This condition is associated with a wide range of comorbidities, including cardiovascular diseases, and its
impact goes beyond the skin. The connection between psoriasis and cardiovascular issues is a subject of
ongoing debate. This review focuses on epidemiological, genetic, and mechanistic studies exploring the
link between psoriasis and cardiovascular comorbidity. It also delves into the hypothesis of psoriasis
potentially acting as an independent cardiovascular risk factor, potentially driving atherosclerosis
through inflammation-induced endothelial dysfunction. The goal is to identify strategies for managing
psoriasis patients to reduce their excess cardiovascular risk.

EPIDEMIOLOGY:
The overview highlights the complex relationship between psoriasis and cardiovascular diseases. While
some early studies questioned the association, numerous subsequent epidemiological studies have
reaffirmed a clear link between psoriasis and cardiovascular comorbidities. This connection is supported
by the presence of shared risk factors, such as diabetes, obesity, hypertension, and dyslipidemia, which
are not only major cardiovascular risk factors but are also observed in psoriasis patients.
Furthermore, evidence suggests that psoriasis may act as an independent cardiovascular risk factor, with
the severity and duration of the disease contributing to elevated cardiovascular risk. Studies have shown
a dose-effect relationship, where more severe psoriasis corresponds to higher cardiovascular risk.
Additionally, research indicates a substantial increase in coronary artery calcification among severe
psoriasis patients compared to controls with matching cardiovascular risk factors.
In clinical terms, psoriasis is quantified as an attributable risk for major cardiovascular events, akin to the
risk associated with diabetes mellitus or other well-established risk factors. These findings underscore
the importance of recognizing psoriasis as a potential independent cardiovascular risk factor.
It's essential to note that the chronic skin inflammation characteristic of psoriasis does not singularly
explain this association, as other chronic skin conditions, such as atopic dermatitis, do not exhibit similar
effects. Genetic and pathogenetic investigations are needed to better understand the underlying
mechanisms and establish the precise nature of the link between psoriasis and cardiovascular diseases.

GENETICS:
The association between psoriasis and its comorbid conditions, particularly cardiovascular disease, has
prompted investigations into potential shared genetics. Psoriasis exhibits a clear genetic predisposition,
with familial history and a higher concordance rate among monozygotic twins. The first susceptibility
locus, PSORS-1, located on chromosome 6 in the major histocompatibility complex (MHC) region,
explains a substantial portion of psoriasis heritability.
Genome-wide association studies (GWASs) have identified over 50 regions on the human genome
associated with psoriasis, linked to pathways involving antigen presentation, interleukin-23 (IL-23)
signaling, T-lymphocyte development, innate immunity, and immune response regulation.
While chronic skin inflammation alone doesn't fully account for increased cardiovascular risk in psoriasis,
some GWAS findings reveal genetic overlap between psoriasis and atopic dermatitis, though they exhibit
distinct pathogenic pathways. Conversely, rheumatoid arthritis, another chronic inflammatory disease
with cardiovascular comorbidity, shares genetic characteristics with psoriasis, particularly in the MHC
region and immune-related genes.

Pathogenesis:
The text discusses the potential link between psoriasis, a skin condition, and cardiovascular comorbidity,
emphasizing the need for mechanistic studies to understand this connection. While genetic factors alone
cannot explain the increased cardiovascular risk in severe psoriasis patients, research is exploring the
role of the immune system.
1- Epidemiological Evidence: There is epidemiological evidence suggesting a connection between
psoriasis and cardiovascular comorbidity, potentially making psoriasis an independent cardiovascular risk
factor.
2-Need for Mechanistic Studies: To clarify the link between psoriasis and cardiovascular issues,
mechanistic studies are essential. Animal models are often used to explore these mechanisms.
3- Role of the Immune System: Previous models focused on the adaptive immune system, but newer
approaches, like mannan-induced psoriasis, highlight the significance of the innate immune system.
4- Inflammatory Pathways: Both psoriasis and atherosclerosis are considered inflammation-driven
conditions. Shared mechanisms, such as lymphocyte extravasation and the involvement of T-helper-1
lymphocytes, have been studied.
5- TH1 and TH17 Lymphocytes: TH1 lymphocytes are believed to play a crucial role in both
atherosclerosis and psoriasis, with evidence also suggesting the involvement of TH17 lymphocytes in
these conditions.
6- Innate Immune System: Recent research has rekindled interest in the innate immune system's role in
psoriasis, with evidence supporting the involvement of neutrophils and their interaction with the
endothelium in atherosclerosis.
7- Monocytes and Macrophages: Both psoriasis and atherosclerosis involve monocytes and
macrophages, which are regularly found in psoriatic lesions.
8- Role of IL-17A: The text highlights IL-17A as a potential pro-atherogenic factor, with studies suggesting
its association with plaque stability and cardiovascular events.
9- Direct Link in Mouse Model: It mentions a direct link found in a mouse model involving psoriatic
arthritis induced by type-II collagen-specific antibodies. This model demonstrated that IL-23 drove
inflammation in the aortic root through the activation of specific T-lymphocytes, which are associated
with both atherosclerosis and psoriasis.

Psoriatic Inflammation as a Driver for Atherosclerosis:

Over the past decade, researchers have uncovered shared pathogenic mechanisms between psoriasis
and atherosclerotic plaque formation. However, these commonalities do not fully explain why psoriasis
appears to be an independent cardiovascular risk factor, as indicated by numerous epidemiological
studies.
A pivotal factor in understanding this relationship is the recognition that psoriasis is not solely a skin
condition but rather a chronic systemic inflammatory disease. This systemic inflammation is
substantiated by the presence of inflammatory biomarkers in the blood of psoriasis patients, including C-
reactive protein, erythrocyte sedimentation rate, and the platelet activation marker P-selectin.
Notably, (18)F-fluorodeoxyglucose positron emission tomography computed tomography (PET-CT)
imaging in psoriasis patients has shown evidence of vascular inflammation, suggesting that psoriatic
inflammation extends to blood vessels and induces inflammation in the vessel walls. Studies in mouse
models further support the idea that skin-specific inflammation can lead to vascular inflammation.
The link between psoriasis and cardiovascular comorbidity likely arises from insulin resistance and
endothelial dysfunction, both known drivers of atherosclerosis. Insulin resistance, characterized by
reduced sensitivity to insulin's metabolic actions promoting glucose disposal, is a common feature of
diabetes and cardiovascular disorders, often associated with endothelial dysfunction. Insulin's vascular
actions include the stimulation of nitric oxide production, leading to vasodilation, which, in turn, affects
glucose disposal in skeletal muscles.
However, inflammation disrupts this balance by inducing insulin resistance through cytokines that alter
insulin signaling in endothelial cells. This results in reduced production of vasodilating nitric oxide and,
subsequently, endothelial dysfunction. Notably, TNF-α, a central cytokine in many inflammatory
diseases, including psoriasis, acts as a significant insulin antagonist.
The concept of the "psoriatic march" proposes that psoriatic inflammation contributes to cardiovascular
comorbidity via atherosclerosis independently of other cardiovascular risk factors. Psoriasis's chronic
systemic inflammation is reflected in elevated biomarkers of systemic inflammation, including resisting
and leptin, insulin-antagonizing adipokines. These adipokines, along with insulin resistance, may
contribute to atherosclerosis by upregulating adhesion molecules on endothelial cells.
Multiple studies have found evidence of endothelial dysfunction in psoriasis patients, characterized by
impaired flow-mediated vascular dilation. Insulin resistance, as measured by the homeostasis model
assessment of insulin resistance (HOMA-IR) index, is significantly higher in psoriasis patients compared
to non-psoriatic controls, reinforcing the connection between insulin resistance and endothelial
dysfunction in psoriasis.
This cascade of events ultimately drives atherosclerosis, increasing the risk of cardiovascular diseases
such as myocardial infarction and stroke in individuals with psoriasis.

Consequences for the management of psoriasis:

The management of psoriasis should include close monitoring of cardiovascular risk factors, as severe
psoriasis is associated with increased cardiovascular comorbidity. However, studies have shown that
many healthcare providers do not routinely screen psoriasis patients for these risk factors.
Recommendations for monitoring and managing cardiovascular risk factors in psoriasis patients are
largely in line with those for the general adult population. This includes assessing traditional
cardiovascular risk factors such as cholesterol levels, blood pressure, diabetes, and smoking status.
Lifestyle interventions like weight loss and smoking cessation should be encouraged, particularly for
obese and smoking psoriasis patients
There is evidence that a comprehensive approach to psoriasis treatment can yield better outcomes, as
demonstrated by a controlled clinical trial showing improved responses to psoriasis treatment when
including a calorie-reduced diet, especially for obese patients with moderate-to-severe psoriasis.

The chronic systemic inflammation in psoriasis is believed to contribute to atherosclerosis by promoting

insulin resistance and endothelial dysfunction, thereby increasing cardiovascular risk. This has prompted
investigations into whether continuous systemic anti-inflammatory treatments could help mitigate this
risk.
Recent data from the CANTOS trial demonstrated the potential benefits of anti-inflammatory therapy in
reducing recurrent cardiovascular events in a high-risk population, suggesting that it is feasible. Early
indications of this concept's applicability to psoriasis patients came from retrospective studies that
showed a reduced incidence of cardiovascular diseases in individuals treated with methotrexate or TNF-
α inhibitors for their psoriasis.
Numerous observational studies and controlled trials have evaluated changes in cardiovascular risk
markers under systemic anti-psoriatic treatment. These studies reported improvements in cytokines,
adipokines, endothelial dysfunction, and carotid intima-media thickness. However, the results have been
mixed, with some studies failing to show significant protective effects.
Pharmaceutical companies sponsored larger studies, investigating the effects of various biologic drugs.
These trials have shown mixed results, with some indicating improvements in vascular inflammation and
others showing no significant impact.
Overall, there is some evidence supporting the idea that systemic anti-inflammatory therapy can reduce
the excess cardiovascular risk in psoriasis patients. Potential targets for this therapy include TNF-α and IL-
17A, which have been associated with insulin resistance and atherogenic effects. However, the effect size
of such treatments may be relatively small, and the effectiveness can vary depending on the population
studied and the duration of treatment.
While anti-inflammatory therapy remains an appealing approach, addressing other major cardiovascular
risk factors associated with psoriasis, such as the metabolic syndrome and lifestyle interventions like
smoking cessation, may also be effective in reducing excess cardiovascular risk in a real-world scenario.

CONCLUSION:

Psoriasis is currently regarded as a chronic-recurrent, systemic inflammatory disease, driven by an

intense cross talk between cells of the innate and adaptive immune system. It is associated with
substantial cardiovascular comorbidity, which can only partially be explained through shared a genetic
control. Evidence in favor of psoriasis as an independent cardiovascular risk factor comes from
epidemiologic studies showing a “dose effect” of psoriasis on the patients’ cardiovascular risk as well as
from case–control studies looking at biomarkers for cardiovascular risk and specific manifestations of
atherosclerosis. Inflammation-induced insulin resistance and endothelial dysfunction provide a
pathogenetic link between psoriasis and atherosclerosis. Whether systemic anti-inflammatory therapy
can reduce the patients’ excess cardiovascular risk remains one of the hot research topics in the field.
Independent of this discussion, a comprehensive approach to the management of psoriasis at least in
patients with severe disease is mandatory based on current knowledge. This must include regular
screening and monitoring of traditional cardiovascular risk factors as well as their guideline-oriented
treatment.

Boehncke, W. (2018). Systemic inflammation and cardiovascular comorbidity in psoriasis

patients: Causes and consequences. Frontiers in Immunology, 9.
https://doi.org/10.3389/fimmu.2018.00579