The results of this study demonstrate that patients with severe psoriasis have a clinically significant 57% increased risk of CV death beyond the risk of death associated with traditional CV risk factors. On the basis of our data, a patient with severe psoriasis has an excess risk of CV death attributable to psoriasis of 1 in 283 patients per year. The risk of CV mortality in patients with severe psoriasis was not explained by major cardiac risk factors identified in routine medical practice, suggesting that severe psoriasis may be an independent risk factor for CV death. Moreover, the relative risk of CV death associated with severe psoriasis was highest in younger individuals suggesting a process of accelerated CVD in younger severe psoriasis patients. Therefore, it is of utmost importance that patients with severe psoriasis and their providers are aware of this increased risk and that these patients undergo appropriate risk assessment and implementation of prevention strategies.
The strengths of the current study include the utilization of a large population-based database that is well accepted for CV epidemiological studies and well-validated for psoriasis.1,9,17,18
In addition, the increased risk of CV death and point estimates were robust to a variety of sensitivity analyses (Table
). We attempted to ensure that we were capturing patients who were seen regularly, minimizing the risk that information bias could explain the findings. In addition, even when patients with highest risk for CV death (i.e. those with history of MI, stroke or transient ischaemic attack, or atherosclerotic disease) were excluded, there was still a 56% increase in CV death associated with severe psoriasis. The results also persisted when examining the risk based on different treatments that theoretically could increase (e.g. cyclosporine, oral retinoids) or decrease (e.g. methotrexate) the risk of CVD.21,22
Thus, these findings suggest that the increased CV mortality is not due to treatment effect. The results also persisted when restricting the severe group to patients treated with therapy specific to severe psoriasis (e.g. oral retinoids), and when excluding patients with psoriatic arthritis suggesting that the findings are associated with severe skin psoriasis as opposed to misclassification with other diseases in which our systemic therapies may be indicated. Our data are consistent with recent studies that demonstrate that psoriasis is an independent risk factor for coronary artery disease,12–15
Our study builds upon previous findings that severe psoriasis patients have an increased relative risk CV mortality that is highest in younger individuals by evaluating outpatients, as opposed to hospitalized patients while also controlling for major CV risk factors.24
Psoriasis is a prototypical Th-1, 17 inflammatory disease, and Th-1 cellular secreted factors (e.g. intracellular adhesion molecule-1, TNF-α) are indeed involved in the pathogenesis of atherosclerosis and MI.25
Furthermore, given the accumulating evidence of inflammation playing a key role in development, progression, and complications of atherosclerosis,26
our findings have biological plausibility. Another Th-1 disease, rheumatoid arthritis, has also been shown to be associated with increased risk of MI27
and multi-vessel coronary disease.28
Recent studies have shown coronary microvascular dysfunction in patients who have chronic inflammation such as in rheumatoid arthritis or systemic lupus erythematosus.29
Patients with psoriasis have elevated high-sensitivity C-reactive protein30
which has been independently associated as a marker for increased risk of CV events.31,32
Finally, a recent study showed increased CVD defined as coronary artery disease, peripheral arterial disease, and stroke in patients with psoriasis,15
however this was not population-based and did not evaluate for CV mortality.
In addition to the inflammatory burden driving CAD risk in these disease states, there may be shared genetic risk which contributes as well. Genetics have been shown to play a key role in susceptibility to psoriasis33
and metabolic disorders, such as diabetes34
as well as coronary artery disease.36
Interestingly, replicated genetic loci identified in psoriasis such as CDKALI
have been shown to be associated with Type 2 diabetes.37
Diabetes has long been known to be a potent risk factor for MI,38
and a shared genetic component between diabetes and psoriasis may contribute to our findings. Recent studies have found that psoriasis is an independent risk factor for developing diabetes and therefore, it is possible that metabolic affects of psoriasis may mediate the association of psoriasis and CVD.9,39
Furthermore, a gene related to blood cholesterol levels, APOE4
was recently shown to be associated with psoriasis, and this too may be a shared mechanism for increasing coronary risk through lipid pathways. Interestingly, two key inflammatory signalling molecules, TNFAIP3
(tumour necrosis factor inducible protein A20) and its interacting protein TNIP141
were discovered using genome-wide association to be strongly associated with psoriasis. Variation in the TNFAIP3
gene in mice42
and in humans43
has been shown to increase coronary artery disease.
As with all studies, there are important limitations to consider. In database studies, there remains the possibility for misclassification of CV death. If misclassification of CV death is present, such errors would be expected to be non-differential and therefore would bias our results toward the null. Another potential limitation of our study is that we did not examine patients with exclusively incident (new onset) psoriasis. Ideally, an inception cohort study could be performed. However, in diseases such as psoriasis which may not come to medical attention for many years, it is difficult to validly identify truly incident (new onset) cases in a medical records database setting. Finally, although our study suggests that severe psoriasis is an independent risk factor for CV death, it is possible that incomplete measurement of confounders or unknown confounding factors could explain some of the observed association. For example, we did not control for use of specific medications that may alter CV mortality risk, such as angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitors (statins), and non-steroidal anti-inflammatory drugs. However, our external adjustment analysis reveals that such unmeasured confounding is unlikely to be driving our results.
This study adds to the growing literature suggesting that patients with severe psoriasis are at increased risk of CVD that is not explained by traditional risk factors. This is the first paper to report increased CV mortality in this group of patients while controlling for major cardiovascular risk factors. In this study, severe psoriasis was at least as potent a risk factor for CV death as other major known risk factors such as smoking,44
Our results did not show an increase in CV mortality in the presence of hyperlipidaemia, although the results were not statistically significant and therefore should be interpreted cautiously. Although treatment of hyperlipidaemia has been shown to decrease CVD events and subsequent mortality at 1 year,47
no study has shown that hyperlipidaemia is an independent risk factor for CV death after controlling for age, diabetes, tobacco use, and hypertension. In further analyses (data not shown), when we limited the outcome to only MI, consistent with the literature, hyperlipidaemia was an independent risk factor for MI.
This increase in CVD and mortality is important for clinicians to recognize so that counselling and appropriate screening for CVD and its risk factors in patients with severe psoriasis can be implemented.48,49
Future studies are necessary to determine how psoriasis should influence cholesterol treatment targets as outlined by guidelines such as Adult Treatment Panel III, in which clinicians are advised to consider emerging CV risk factors in their treatment decisions. Additionally, future studies are indicated to determine what degree of psoriasis severity translates into clinically significant CV risk, as well as to determine if controlling psoriasis results in reduction of CV risk.