Psoriasis: why does it come with a greater risk of heart attack and stroke?

Keywords::

• atherosclerosis
• inflammation
• myocardial infarction
• psoriasis
• stroke
• vascular inflammation

The association between psoriasis and occlusive cardiovascular events is generating a tremendous amount of interest in the medical and scientific community. This association is not a novel discovery as reports published almost 40 years ago suggested that patients with psoriasis were at a higher risk of myocardial infarction (MI) and stroke [1,2]. However, it is the article published by Gelfand et al. in 2006 that attracted the attention of physicians across various medical specialties and triggered intense research in that area [3]. Using the General Practice Research Database (GPRD™), Gelfand et al. compared the risk of MI in more than 130,000 patients with psoriasis to more than 500,000 control patients without psoriasis. They showed that the risk of MI was higher in patients with psoriasis, but not all subsequent studies confirmed the findings that patients with psoriasis were at increased risk of heart attack and stroke. The association between psoriasis and occlusive cardiovascular events has important implications, including therapeutic implications, as many of our current systemic treatments for psoriasis could either increase or decrease the risks of MI and stroke. Cohort studies performed using various databases suggest that treatment of rheumatoid arthritis with TNF-α antagonists or methotrexate could decrease the risks of MI or stroke [4]. A few studies in patients with psoriasis have also been conducted and one has observed a decrease in MI and/or stroke for patients treated with TNF-α antagonists whereas another did not [5,6]. The role of IL-12/IL-23 antagonists is more controversial as a numerical imbalance between patients receiving placebo and those receiving anti-IL-12/IL-23 in the number of major arterial cardiovascular events has been reported with ustekinumab and briakinumab. Analysis combining data for both biologics suggests either a trend or a statistically significant increase in cardiovascular events [7,8].

The exact reasons for the increased risks of MI and stroke in patients with psoriasis are still under intense study. The prevalence of several risk factors for MI and stroke such as diabetes, obesity, hypertension, metabolic syndrome and hypercholesterolemia is increased in patients with psoriasis. Several studies using Cox regression models to correct for differences in those risk factors between psoriatic patients and control groups of patients without psoriasis have suggested that psoriasis is an independent risk factor for MI and stroke. The main problem with these studies is that they mostly use data from claims or medical databases. As there is a limit to the information present in these databases the increased risk of MI and stroke reported in patients with psoriasis could theoretically be related to differences in the intensity or control of traditional risk factors (such as differences in lipid levels for patients with hypercholesterolemia or in tobacco use for smokers) for which more granular information is lacking in the database.

The observation made almost 200 years ago that psoriasis was associated with a specific type of inflammatory arthritis showed that psoriasis is more than only a skin disease. Psoriasis may also induce inflammation beyond skin and joints. Markers of inflammation such as C-reactive protein and sedimentation rate have been shown to be elevated in patients with psoriasis. Vascular inflammation has been reported to be increased in patients with moderate to severe psoriasis using a technique combining PET and CT scans [9]. The same technique is now being used by us and others to study the effect of systemic treatments for psoriasis on vascular inflammation [10]. Therefore, psoriasis could be viewed as a systemic inflammatory disease that increases vascular inflammation leading to MI and stroke. Interestingly, atherosclerosis is being increasingly viewed as an inflammatory disease. Increased infiltration of T cells and elevated levels of Th1 and Th17 cytokines such as TNF-α, IL-17 and IL-6 have also been reported in patients with atherosclerosis [11–13]. However, even if there are similarities between the inflammatory processes in atherosclerosis and in psoriasis there are important differences such as the central role of monocytes and macrophage infiltration in atherosclerosis and the involvement of keratinocytes in psoriasis [14].

Several questions related to psoriasis and vascular inflammation remain unanswered. Patients with psoriasis have increased circulating levels of several proinflammatory cytokines such as TNF-α and IL-6. Is the increase in vascular inflammation related to the effects of these cytokines on arterial walls? Psoriasis is characterized by massive infiltration of the skin and joints by activated T cells. Could these T cells re-enter circulation, enter the arterial walls and react with antigen-presenting cells to increase local vascular inflammation? Could the putative antigens involved in T-cell activation in psoriatic patients be present both in the skin and the heart? Single nucleotide polymorphisms for several genes, including genes coding for the TNF-α pathway, the IL-12/IL-23 pathway and for proteins involved in the formation of the cornified envelope, have been associated with psoriasis [15,16]. Could the proteins encoded by these gene variants have a direct role in vascular inflammation or in other risk factors of MI or stroke?

Gaining more knowledge on the mechanisms involved in the association between MI/stroke and psoriasis should be a priority as this information can translate into strategies that can have a significant impact on patient survival. Physicians may eventually choose a systemic treatment not only based on the efficacy/safety profile, drug coverage and patient preference, but also on its potential effects on comorbidities such as coronary artery disease. Vascular inflammation may not be directly related to skin inflammation and the use of systemic treatments targeting vascular inflammation may be required to decrease risks of MI and stroke. If this turns out to be true the situation would be reminiscent of psoriasis and psoriatic arthritis treatments, where methotrexate has good efficacy on joint and skin inflammation whereas the efficacy of acitretin on joints is limited. It is also possible that vascular inflammation is directly linked to cutaneous and articular inflammation. If this is the case, aggressive local treatments such as potent topical corticosteroids may improve vascular inflammation by decreasing the number of activated T cells and cytokine release in the skin, therefore preventing vascular wall inflammation.

The next few years will certainly bring us more information on the mechanisms involved in the association between occlusive cardiovascular events and psoriasis. Several cohort studies are currently underway to explore the impact of various treatments for psoriasis on MI and stroke. In addition, prospective randomized studies using surrogate markers for MI and stroke, such as vascular inflammation, will provide additional information on the impact of various systemic treatments on those risks.

Financial & competing interests disclosure

The author has been a consultant, speaker and/or investigator and has received compensation in the form of grants and/or honoraria from Janssen, Abbott, Amgen, Astellas, Novartis, Pfizer, Celgene, Tribute, Isotechnika and Lilly. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.