Risk of Myocardial Infarction in Patients With Psoriasis FREE

Psoriasis is a common, chronic, immune-mediated disease that affects about 2% to 3% of the adult population.^1- 2 Approximately 6% to 11% of patients with psoriasis also have an associated inflammatory arthropathy (psoriatic arthritis).^3- 4 The extent of body surface area affected by psoriasis is variable, ranging from limited disease (<2% body surface area) in approximately 80% of patients to more extensive skin involvement in approximately 20% of patients.⁵ Psoriasis has serious impacts on health-related quality of life, even in patients with limited body surface area involvement.⁶

The pathophysiology of psoriasis is characterized by an increase in antigen presentation, T-cell activation, and T-helper cell type 1 (T_H1) cytokines, resulting in thick scaly red plaques and in some patients, arthritis.^7- 8 Psoriasis is also associated with markers of systemic inflammation, such as increased C-reactive protein levels.^9- 11 The immunological abnormalities that lead to the development of psoriasis suggest that these patients may be at increased risk for other diseases associated with an inflammatory state. For example, increasing evidence suggests that a T_H1 immune response, including activated T cells, antigen presenting cells, cytokines, and markers of systemic inflammation such as C-reactive protein, are important to the development of atherosclerosis and ultimately, myocardial infarction (MI).^12- 13 The observation that other T_H1-mediated diseases, such as rheumatoid arthritis, are associated with an increased risk of MI supports the theory that T_H1-mediated diseases predispose patients to MI.^14- 16

Several hospital-based studies have indicated that psoriasis is associated with a higher prevalence of cardiovascular diseases, including MI.^17- 21 These studies did not control for any potentially associated risk factors for MI and therefore it is unclear if psoriasis itself, or comorbidities and behaviors associated with psoriasis, explain this association. The goal of our study was to examine a broadly representative population-based cohort to determine the risk of MI in patients with psoriasis.

More than 1500 general practitioners in the United Kingdom, who were unaware of the hypothesis to be tested, collected data prospectively in this population-based cohort study between 1987 and 2002. Data were collected as part of the patient's electronic medical record and were maintained in the General Practice Research Database (GPRD). The GPRD contains data on more than 8 million persons with more than 35 million years of follow-up time and is broadly representative of the UK population.²² General practitioners receive specific training, financial inducements, and penalties to ensure data accuracy. The GPRD has been used extensively for epidemiological studies. In the UK health care system, all of the patients’ care is coordinated by the general practitioner. The ability of the GPRD to capture data from specialists, and validly identify psoriasis, MI, and the covariates used for this study, has been demonstrated previously.^23- 29

The study population consisted of all patients with psoriasis aged 20 to 90 years who had at least 1 day of observation time. Each patient with psoriasis was matched to up to 5 control patients (as available, based on matching criteria) who did not have diagnostic codes consistent with psoriasis, who were observed in the same practice, and who had a date of observation in the practice (the latest of either the date when the patient registered with the practice or the date when the practice was designated “up to standard”) within 60 days. Therefore, we ensured that those patients with and without psoriasis were followed up by the same practices during similar time periods. For control patients, observation start time was the latest of the patient registration and up to standard dates. For patients with psoriasis, observation start time was the latest of the patient registration, up to standard, and psoriasis diagnosis dates. Practices are designated up to standard when audits demonstrate that at least 95% of relevant patient encounters are recorded and data are determined to be of suitable quality for epidemiological research. For all patients, follow-up time ended (ie, patients were censored) when they developed an MI, died, transferred out of the practice, or the practice was no longer up to standard, whichever came first.

Diseases are classified in the GPRD by using Oxford Medical Information System (OXMIS) and Read codes. The OXMIS and Read codes are diagnostic codes that general practitioners use as part of the patient's electronic medical record. Patients were classified as having psoriasis if they ever received a diagnostic code for psoriasis. Patients with psoriasis were defined as having severe disease if they received a code consistent with severe disease (eg, treatment with psoralen or phototherapy, methotrexate, azathioprine, cyclosporine, etretinate, acitretin, hydroxyurea, or mycophenolate), as determined by the British National Formulary and the opinion of 2 dermatologists (D.J.M. and J.M.G.). The treatment codes were selected without any knowledge of whether or not the patients with psoriasis ever had an MI. Patients with psoriasis were classified as having mild disease if the patients never received a code consistent with severe disease. Patients were classified as controls if they never received a diagnostic code consistent with psoriasis.

Patients were classified as having diabetes mellitus, hyperlipidemia, hypertension, or being a current smoker if they ever received a code for these conditions during the time that the practice was considered up to standard. Patients were determined to have a history of MI if they ever received a code for MI on or before their start date. Age was determined at the maximum of the patient registration and up to standard dates. Body mass index was determined based on the recorded height and weight that occurred closest to the start date and calculated as weight in kilograms divided by height in meters squared.

Patients were classified as having an acute MI if they received a medical code consistent with this diagnosis after the start date and on or before the end date.

The sample size was determined by including the maximum eligible number of patients with psoriasis eligible based on the age criteria. We randomly selected and matched up to 5 control patients, as additional matching yields minimal statistical power. All eligible controls were not included to allow for analyses to be performed using standard hardware and software given the massive size of the database. Data were summarized descriptively. Associations between the presence of psoriasis and various covariates were tested by using the Fisher exact test for categorical variables and t test for continuous variables. All statistical tests were 2-tailed.

The rates of MI in the mild and severe psoriasis groups were compared with the rate of MI in the control population by using an unadjusted Cox proportional hazards regression model. Patients who died without MI were considered censored for the primary analysis; we also conducted sensitivity analyses considering the composite outcome of the earlier of MI and death. The rates were then adjusted for age, sex, and the presence of diabetes, hyperlipidemia, hypertension, or current smoking. Body mass index was not included in the primary model as it was recorded in only 61% of patients, but was included in a sensitivity analysis. We also assessed interactions between age and psoriasis and sex and psoriasis on the risk of MI. Each dichotomous variable in the model was checked for proportionality while adjusting for the other covariates in the model by examining diagnostic log-log survival plots.

We performed a sensitivity analysis in which patients had to have at least 6 months of follow-up time and could not have had an MI in the first 6 months to ensure the capture of incident, not prevalent, MIs. Additional sensitivity analyses were performed to ensure that all patients were actively followed up. First, we altered the end date such that it was defined as the earliest date at which the patient experienced MI, or received a last prescription or diagnosis; and second, we restricted the population to only include patients observed at least once per year by the general practitioners. One other sensitivity analysis was performed to demonstrate that the association of psoriasis with MI was not affected by the reason for censoring.

All statistical analyses were performed by using Stata version 8.2 (StataCorp LP, College Station, Tex). All P values are 2-sided and P<.05 was considered statistically significant.

Data were stripped of personally identifiable information. The study was approved by the Office of Regulatory Affairs of the University of Pennsylvania, Philadelphia, and by the Scientific and Ethical Advisory Group of the Medicines Control Agency, United Kingdom. The requirement of informed consent was waived as the study included only anonymized data.

We identified 130 976 patients with psoriasis and 556 995 corresponding control patients, followed up for a mean of 5.4 years (Table 1). Patients with psoriasis were less likely to be censored by transferring out of the practice than were control patients. Among patients with psoriasis, 3837 (2.9%) were classified as having severe disease based on having received systemic treatment. The frequency of oral treatment for psoriasis was similar to that reported in other population-based studies from the United Kingdom.³⁰ The majority of patients classified with severe psoriasis received methotrexate (Table 2). Documentation of psoralen and phototherapy use was low, because these therapies are restricted to specialists and are not well captured by the GPRD.

Patients with psoriasis were more likely to be men and older; however, the distribution of these variables was similar between patients with psoriasis and controls. Consistent with previous studies,^{19- 20,31- 32} patients with psoriasis were more likely to have diabetes, hyperlipidemia, hypertension, a history of MI, have a higher body mass index, and be a current smoker.

The incidence rates of MI are shown in Table 3. Patients with psoriasis had a higher incidence of MI compared with control patients, with patients who had severe psoriasis having the highest rate. Table 4 provides the hazard ratios for all of the factors in the adjusted model. As expected, all of the usual risk factors result in increased risk of MI in this population. Examination of log-log plots for each of the variables in our model demonstrated that assumptions of proportional hazards were met.

The increased relative risk of having an MI adjusted for potentially confounding variables was similar in men and women. However, there was effect modification by age on the relative risk of patients with psoriasis developing an MI (Table 4). The highest relative risk for patients with psoriasis having an MI occurred in younger patients, and the relative risk was attenuated in older patients (Figure). For example, for a 30-year-old patient with mild or severe psoriasis, the relative risk of having an MI is 1.29 (95% confidence interval [CI], 1.14-1.46) and 3.10 (95% CI, 1.98-4.86), respectively. However, for a 60-year-old patient with mild or severe psoriasis, the relative risk of having an MI is 1.08 (95% CI, 1.03-1.13) and 1.36 (95% CI, 1.13-1.64), respectively. However, the attributable and excess risk of MI due to psoriasis, when controlling for major cardiovascular risk factors, increases as patients with psoriasis age due to the fact that the baseline risk of MI increases with age (Table 3).

We performed a series of sensitivity analyses (Table 5) to further ensure the validity of our results. Similar results were found in analyses that excluded MIs occurring within the first 6 months of follow-up to ensure capture of incident, not prevalent MI; or that required the last prescription or diagnosis be used as the end date to ensure that all patients were actively followed up and censored for the same reason; or that were restricted to patients who were observed at least once per year by the general practitioners to further ensure active follow-up. Additional sensitivity analyses demonstrated no evidence of confounding by body mass index when the models were limited to patients with a recorded height and weight. We also performed 2 additional analyses in the severe group. In the first model, we excluded patients ever treated with methotrexate and, in a second model, we excluded patients ever treated with oral retinoids or cyclosporine. The relative risk of MI in patients with severe psoriasis remained increased in both of these models and was statistically similar to our primary analysis. Finally, an increase in the adjusted relative risk for patients with psoriasis persisted in a model that included a composite end point of MI or death due to any cause.

Our study results suggest that psoriasis is an independent risk factor for MI. The risk of MI associated with psoriasis is greatest in young patients with severe psoriasis, is attenuated with age, and remains increased even after controlling for traditional cardiovascular risk factors. The findings demonstrate a dose-response effect, given that patients classified as severe had a higher risk of MI than patients with mild psoriasis, consistent with the hypothesis that greater immune activity in psoriasis is related to a higher risk of MI.

The reason for the higher risk ratio of MI in younger patients with psoriasis may relate to the observation that psoriasis is a heterogeneous disease. For example, it has been hypothesized that those persons with earlier onset disease (before age 40 years) have more severe disease and a stronger association with human leukocyte antigen (HLA)-Cw6 than patients with onset of psoriasis after age 40 years.^33- 34 Additionally, because most patients with psoriasis develop the disease before age 40 years (approximately 75%), there may be a survivorship effect in which after decades of psoriasis, those patients predisposed to MI would less likely be available in the older age groups of our study due to the mortality associated with MI.

Our study advances the literature establishing the association of psoriasis and MI in that it is a broadly representative population-based study, which controlled for major risk factors that are typically measured in epidemiological studies of cardiovascular disease. Our study also has the advantage of being large enough to allow for detailed analyses, which have yielded novel findings. The study is broadly representative of patients with psoriasis. The magnitude of association between severe psoriasis and MI in those patients younger than 50 years is similar to the magnitude of association for other major cardiac risk factors.

Observational studies may be limited by bias and confounding. Selection bias is unlikely to explain the results described herein as the patients with psoriasis and control patients were identified and included from the same well-defined source population. Information (ascertainment) bias is unlikely to explain the results as patients with psoriasis and control patients had information collected in the same manner (by general practitioners matched by practice) and the results were robust to multiple sensitivity analyses. Control patients were more likely to be censored by transferring out of the practice; however, the results were similar in sensitivity analyses in which patients were censored at the time of their last prescription or diagnosis to ensure that all patients were actively followed up and censored for the same reason. Because MI is a major objective medical event, it is very unlikely that documentation of MI in the electronic medical record would vary between patients with psoriasis and those observed by general practitioners for diagnoses other than psoriasis.

The results also persisted when controlling for the major risk factors for MI. However, it is possible that unknown or unmeasured confounding variables may explain some of the observed association. For example, recent literature has found modest associations between obesity, smoking, stress, and psoriasis when evaluating patients from referral centers or hospitals.^31,35- 36 Information on body mass index was available for approximately 61% of patients, and patients with psoriasis had increases in body mass index compared with control patients. Other population-based studies have not found a significant association between psoriasis and body mass index.³⁷ In our study, we did not find any evidence of confounding by body mass index in the patients (>410 000) who had this information recorded. Furthermore, we measured smoking status as current or never and therefore could not determine if history of smoking or number of cigarettes smoked introduced any potential confounding.

Additionally, we defined severe psoriasis based on a history of having received systemic therapies and therefore cannot differentiate between the impact of psoriasis severity and systemic therapy on the risk of MI. The most commonly used systemic therapy was methotrexate, which recently has been shown to lower the incidence of cardiovascular outcomes, and therefore it is possible that our algorithm classifying severe psoriasis may underestimate the independent risk of MI in patients with severe psoriasis.³⁸ Oral retinoids and cyclosporine may induce certain cardiovascular risk factors, such as hypertension and hyperlipidemia, in some patients; however, these variables were measured in our analysis and would be unlikely to alter MI risk in an independent manner.^39- 40 Furthermore, the findings in the severe group were robust to sensitivity analyses that excluded patients treated with methotrexate or cyclosporine and oral retinoids. We also did not directly assess psoriasis activity in our mild psoriasis group; therefore, it is possible that the risk of MI in those patients we classified as having mild disease varies based on psoriasis activity (eg, extent of skin involvement). Finally, we did not examine if having psoriatic arthritis and the possible use of nonsteroidal anti-inflammatory drugs in addition to skin psoriasis further altered the risk of having an MI.

The results add to the growing evidence linking T_H1 diseases to atherosclerosis and coronary artery disease. Psoriasis is the most prevalent T_H1 autoimmune disease. The immune abnormalities in psoriasis are profound, leading to an estimated 20 billion T cells infiltrating the skin of a patient with severe psoriasis as well as profound increases in dendritic cells, T_H1 cytokines (eg, TNF-α, interferon), and chemokines.⁷ Other T_H1 diseases, such as rheumatoid arthritis, have also been shown to be an independent risk factor for acute MI and multivessel coronary artery disease, when adjusting for coronary risk factors, such as diabetes, hyperlipidemia, hypertension, and smoking.^14- 16 Additional studies have indicated that the severity of rheumatoid arthritis, measured by markers of systemic inflammation, is associated with an increased risk of cardiovascular death, even when controlling for traditional cardiovascular risk factors and comorbidities.¹⁶ The exact mechanism by which T_H1-mediated diseases such as psoriasis and rheumatoid arthritis predispose a patient to cardiovascular disease is unclear, but may be due to the common immunological pathways that function abnormally in these diseases. Furthermore, it is possible that the link between psoriasis and MI may be mediated by other factors beyond inflammation, such as psychological stress, sedentary lifestyle, or possibly poor compliance with management of cardiovascular risk factors.

Our findings are novel and therefore it is important that additional studies be performed to confirm these results and determine their therapeutic implications. In particular, it is important to determine the impact of clinical markers of psoriasis activity, such as body surface area, as well as biomarkers of systemic inflammation (eg, C-reactive protein) on the risk of MI in patients with psoriasis. In the meantime, as part of good medical care, patients with psoriasis should be encouraged to aggressively address their modifiable cardiovascular risk factors.