The results of this study demonstrate that patients with severe psoriasis have a 44% increased risk of stroke, a potentially devastating co-morbidity. The risk of stroke in patients with psoriasis was not explained by both common and rare major risk factors for stroke as identified in routine medical practice, suggesting that psoriasis may be an independent risk factor for stroke. Patients we classified as having mild psoriasis had a statistically significant increased risk of stroke, however, this association was very modest and of limited clinical significance for the individual patient. For example, based on our data, a patient with mild psoriasis has an excess risk of stroke attributable to psoriasis of 1 in 4115 per year, whereas a patient with severe psoriasis has an excess risk of stroke attributable to psoriasis of 1 in 530 per year.
The increased risk of stroke persisted in a variety of sensitivity analyses designed to insure that we were capturing incident, not prevalent strokes, and that insured that all patients were seen regularly, minimizing the risk that information bias could explain the findings. Furthermore, the results persisted when excluding patients with psoriatic arthritis, restricting the severe group to patients treated with therapy specific to severe psoriasis (e.g. oral retinoids), and 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 stroke(Lebwohl and Ali 2001
; Prodanowich, Ma et al. 2005
). Our findings are in agreement with recent studies that have found that psoriasis is an independent risk factor for cardiovascular disease in general (e.g. MI and coronary artery disease) and cerebrovascular disease in particular(Gelfand, Neimann et al. 2006
; Ludwig, Herzog et al. 2007
; Balci, Balci et al. 2008
). Our study also extends the findings of previous studies that observed an association between psoriasis and cerebrovascular disease or stroke but did not account for psoriasis severity or confounding factors(Kaye, Li et al. 2008
As with all studies, there are important limitations to consider. In database studies, there remains the possibility for misclassification of stroke due to coding errors or misdiagnosis. The overall incidence of stroke in our study was similar in the two control groups and is similar to rates of stroke reported using national statistics from England and Wales (Carroll K.). Although several studies have used GPRD to evaluate the epidemiology of stroke, a small validation study demonstrated that for 25 patients in the GPRD referred for a diagnostic code of stroke, there was a confirmation of stroke by the specialist in 64% of cases and a diagnosis of TIA in 16% of cases, giving an overall agreement in the opinion of an acute cerebrovascular diagnosis of 80%(Gibbs, Newson et al. 2001
). If misdiagnosis of stroke is present, such errors would be expected to be non-differential misclassification and therefore would bias our results toward the null. Furthermore, it is difficult to differentiate between ischemic and hemorrhagic strokes in large population-base studies of medical record data, and therefore cannot determine directly how psoriasis influences the risk of various subtypes of strokes. Since the majority of strokes are ischemic in nature, the results are likely driven by the association of psoriasis and ischemic stroke. The association between severe psoriasis and stroke was similar in a sensitivity analysis restricting the outcome of stroke to those whom received therapy consistent with an ischemic etiology. Another potential limitation of our study is that we did not examine patients with exclusively incident (new onset) psoriasis. Therefore, we could not determine how duration of psoriasis affects stroke risk, and it is possible that some bias towards null findings could be introduced through the depletion of susceptible patients (e.g., some patients with psoriasis will have died from stroke prior to being captured in our study population). 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. Furthermore, we did not directly determine severity of psoriasis based on extent of skin disease, which may introduce misclassification of mild and severe psoriasis when using therapy as a marker of psoriasis phenotype. It is likely that our mild psoriasis group contains a small subset of patients with severe skin disease, as systemic therapies are used infrequently for psoriasis in the general population, and that our severe group contains a small subset of patients with mild skin disease despite the use of systemic therapy. This misclassification would result in an over estimation and under estimation of the risk of stroke in the mild and severe psoriasis patients, respectively. Moreover, the generalizability of our results to patients with severe psoriasis who are not treated with the agents we used to identify severe disease needs to be determined in future studies. Finally, although our study suggests that psoriasis, particularly if severe, is an independent risk factor for stroke, it is possible that incomplete measurement of confounders or unknown confounding factors could explain some of the observed association. We did not adjust for alcohol in this analysis as validly measuring alcohol intake in any setting is challenging, the relationship between alcohol consumption and stroke is a complex “J shaped” curve, and the relationship between stroke and alcohol intake is believed to be mediated by hypertension (which was adjusted for in our models)(Reynolds, Lewis et al. 2003
; CDC 2007
). Analyzing our data using an external adjustment approach suggests that such an unknown or unmeasured confounder would have to be common in the general population, and have a strong association with psoriasis and a stronger association with stroke than the known stroke risk factors in order to render our findings null(Greenland 1996
This study adds to the growing literature suggesting that patients with psoriasis, particularly if disease is severe, are at increased risk of cardiovascular events that is not explained by traditional risk factors. Clinicians are advised to alert psoriasis patients, particularly if disease is severe, to have assessment and treatment of their cardiovascular risk factors as recommended by current guidelines(Friedewald, Cather et al. 2008
; Kimball, Gladman et al. 2008
). More research is necessary to directly determine the mechanisms by which psoriasis may lead to adverse cardiovascular outcomes, as well has how psoriasis severity and treatment influence cardiovascular risk.