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Departments of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United StatesCharlie Norwood VA Medical Center, Augusta, GA, United States
Departments of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United StatesPhysiology, Medical College of Georgia at Augusta University, Augusta, GA, United StatesCharlie Norwood VA Medical Center, Augusta, GA, United States
Previous research in non-dialysis patients suggests that the inflammatory skin disease psoriasis is associated with an increased risk of severe vascular events like myocardial infarction (MI). Thus, we determined whether psoriasis represents a significant risk factor for MI in end-stage renal disease (ESRD) patients.
Methods
We queried the United States Renal Data System for ESRD patients starting dialysis between 2004 and 2015. ICD-9 and ICD-10 codes were used to identify those with at least two diagnoses of psoriasis, a diagnosis of MI, and other clinical risk factors. Logistic regression was used to examine the association of psoriasis and various risk factors with MI.
Results
Of a cohort of 1,062,693, we identified 6823 (0.6%) subjects with psoriasis and 181,960 (17.1%) with MI. Of the 6823 patients with psoriasis, 1671 (24%) developed an MI. Psoriasis was associated with an increased risk of MI in an unadjusted model [odds ratio (OR) = 1.34; confidence interval (CI) = 1.26–1.42]. However, after controlling for demographics, dialysis modality, access type, and various conditions related to the Charlson Comorbidity Index, psoriasis was not associated with MI (OR = 0.95, CI = 0.89–1.01). Confounders of the association of psoriasis with MI included congestive heart failure (OR = 5.26, CI = 5.17–5.36), pulmonary disease (OR = 1.25, CI = 1.23–1.26), and diabetes with complications (OR = 1.82, CI = 1.79–1.85).
Conclusions
Contrary to prior research in the general population, in the ESRD population psoriasis was not associated with an increased risk of MI after controlling for various demographic and clinical parameters. These data emphasize the importance of an integrated approach since comorbidities may influence the choice of therapy for psoriasis and outcomes.
Psoriasis is a chronic inflammatory disease that is characterized by the development of scaly, erythematous plaques on the skin. Approximately 7.4 million people in the United States are affected by psoriasis and its associated comorbidities, which greatly impact quality of life.
Psoriasis patients have a greater prevalence of cardiovascular disease risk factors, including hypertension, diabetes, obesity, dyslipidemia, and atherosclerosis.
Psoriasis has also been associated with an increased prevalence of severe coronary artery calcification (CAC), with CAC scores elevated to a similar extent as is observed in type II diabetes.
Inflammation, secretion of adipokines, insulin resistance, enhanced angiogenesis, oxidative stress, and hypercoagulability may contribute to the association between psoriasis and cardiometabolic disorders.
In addition, renal dysfunction may potentially be attributed to comorbidities associated with psoriasis, including atherosclerosis, arterial hypertension, and diabetes.
Systemic inflammation may also provide a mechanistic link between psoriasis and kidney disease, as well as cardiometabolic disorders. Patients with severe psoriasis were found to have a 5-year decreased life expectancy, with cardiovascular disease contributing significantly to this disparity.
Psoriasis patients also showed an increased risk of stroke, atherosclerosis, myocardial infarction, coronary artery disease, and endothelial dysfunction even when cardiovascular risk factors were accounted for.
Thus, the presence of psoriasis may represent a significant additive risk factor for developing cardiovascular diseases in ESRD patients. To address this question, we queried the United States Renal Data System (USRDS) for ESRD patients with psoriasis to investigate psoriasis as a potential risk factor for myocardial infarction (MI).
Methods
Approvals
This study protocol has been deemed “non-human subjects research” by the Augusta University Institutional Review Board. The manuscript has been reviewed and found to fulfill USRDS privacy requirements by the National Institute of Diabetes and Digestive and Kidney Diseases. As per USRDS guidelines, no patient consent was required.
Dataset and study cohort
The USRDS is a national data system that collects, analyzes, and distributes information about chronic kidney disease and ESRD.
United States Renal Data System. 2019 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019.
The dataset includes demographics on ESRD patients and Centers for Medicare Services (CMS) medical claims submitted to Medicare. Using data from the USRDS, we employed a retrospective cohort design to analyze psoriasis and its association with MI. All ESRD patients in the USRDS who started dialysis between 2004 and 2015 were eligible for inclusion into the study. The study sample size was 1,062,693. ICD-9 and ICD-10 codes were used to identify those with at least two diagnoses of psoriasis, a diagnosis of MI, and other demographic and clinical risk factors. Patients were excluded if they were less than 18 years of age, had missing data on age, race, sex, ethnicity, access type, or dialysis type, had only one diagnosis of psoriasis, had a history of MI on CMS Form 2728, or had no follow-up as they died at the time of entry into the USRDS. This study protocol has been deemed “non-human subjects research” by the Augusta University Institutional Review Board. The manuscript has been reviewed and found to fulfill USRDS privacy requirements by the National Institute of Diabetes and Digestive and Kidney Diseases. As per USRDS guidelines, no patient consent was required.
Demographic and other clinical risk factors
Demographic data including age at incident dialysis, race, sex, ethnicity, and access type were determined from the patient data or CMS Form 2728. ICD-9 and ICD-10 codes from hospital, detailed, and physician/supplier claims were used to identify those with at least two diagnoses of psoriasis, a diagnosis of MI, and other clinical risk factors. Various clinical covariates or confounders of MI from the Charlson Comorbidity index (CCI) were identified. The CCI is a prognostic index designed to predict the risk of mortality attributable to comorbid diseases by measuring major systemic comorbidities.
These clinical diagnoses include stroke, congestive heart failure, dementia, pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver disease, non-complicated diabetes, complicated diabetes, paraplegia, cancer, metastatic cancer, moderate to severe liver disease, and AIDS, as well as MI; diagnoses other than MI were used to control for CCI-related co-morbidities. Other clinical covariates included tobacco and alcohol dependence. All clinical covariates must have occurred following the start of dialysis but before the first MI diagnosis or for those without an MI diagnosis, before death, determined using CMS Form 2746 (ESRD Death Notification) or December 31, 2015.
Statistical analysis
All statistical analysis was performed using SAS 9.4 and statistical significance was assessed using an alpha level of 0.05. Descriptive statistics including frequencies and percentages or means and standard deviations, where appropriate, on all variables overall, by psoriasis, and by MI were determined.
To examine the association of each demographic or clinical risk factor with psoriasis and to examine the association of psoriasis, demographic, and clinical risk factors with MI, logistic regression was used. For psoriasis, each risk factor was assessed in a simple bivariate model to assess potential confounding. For MI, psoriasis and each demographic or clinical risk factor were examined in simple bivariate models and then all variables were entered into a more comprehensive multivariable model. An offset parameter of the natural log of the number of person years at risk was used in the estimation of the odds ratio for MI. To build the final multivariable model for MI, a backward model building strategy was used to arrive at the final comprehensive model. Starting with the full model, the least significant demographic or clinical risk factor was removed from the model. The Akaike's Information Criterion (AIC) and -2Log likelihood (-2LL) test were used to determine whether the reduced model fit was as good as the previous model. A lower AIC and non-statistically significant -2LL test indicated whether the reduced model was as good as the previous model. If the reduced model was not as good as the previous model, the variable was re-entered in the model and the next least significant variable was examined for removal. The final model included any demographic or clinical risk factor that was statistically significant and/or needed in the model using the model building criteria. The adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) are presented for the final models.
Results
Demographics and clinical characteristics associated with psoriasis
From 2004–2015, 1,062,693 patients from the USRDS met the inclusion criteria and 6823 (0.6%) received two diagnoses of psoriasis. Briefly, of those with psoriasis, 57% were male and 43% were female, 66.1% were White, 28.3% were Black and 5.6% were of other race, and 99.8% were on hemodialysis and 0.2% were on peritoneal dialysis. As seen in Tables 1 and 2, many demographic and clinical variables were associated with psoriasis. In simple models, variables associated with an increased odds of psoriasis included increasing age, stroke, congestive heart failure, dementia, pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver disease, non-complicated diabetes, complicated diabetes, paraplegia, cancer, metastatic cancer, moderate to severe liver disease, AIDS, tobacco dependence, and alcohol dependence. Female sex, Black race, Hispanic ethnicity, hemodialysis, and catheter access were associated with decreased risk of psoriasis.
TABLE 1Descriptive statistics and simple logistic regression results on psoriasis for demographic variables.
Demographics and clinical characteristics associated with MI
Of the total cohort, 181,960 (17.1%) patients had an MI. As seen in Table 3, those with MI were older [66.4 years (SD = 12.8) vs 62.9 years (SD = 15.3)], had higher percentages of psoriasis (0.9% vs 0.6%), female sex (43.6% vs 42.9%), non-Hispanic ethnicity (86.0% vs 85.2%), and graft access (3.7% vs 3.3%) in comparison to those without MI. In addition, they had higher percentages of all clinical diagnoses: stroke, congestive heart failure, dementia, pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver disease, non-complicated and complicated diabetes, paraplegia, cancer, metastatic cancer, AIDS, and tobacco and alcohol dependence.
TABLE 3Descriptive statistics and final multivariable logistic regression on myocardial infarction.
Of the 6823 patients with psoriasis, 1671 (24%) had an MI. In simple models (Table S3), psoriasis was associated with increased odds of MI [OR = 1.34; 95% CI = 1.26–1.42]. Other variables associated with increased odds of MI in simple models included age, female sex, hemodialysis, catheter access, and graft access. Increased risk of MI was associated with the following clinical diagnoses in simple models: stroke, congestive heart failure, dementia, pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver disease, non-complicated diabetes, complicated diabetes, paraplegia, cancer, metastatic cancer, moderate to severe liver disease, AIDS, and tobacco dependence.
In the final model (Table 3 and Fig. 1), psoriasis was not associated with MI (adjusted OR = 0.95, CI = 0.89–1.01) after controlling for demographic and clinical covariates. The following variables were associated with increased risk of MI: increasing age, hemodialysis, catheter access, graft access, stroke, congestive heart failure, pulmonary disease, peptic ulcer disease, non-complicated diabetes, diabetes with complications, paraplegia, AIDS, and tobacco dependence. Confounders of the association of psoriasis with MI included congestive heart failure, pulmonary disease, and diabetes with complications. The following variables were associated with decreased odds of MI in the final model: female sex, Black race, other race, Hispanic ethnicity, dementia, connective tissue disease, mild liver disease, cancer, metastatic cancer, and alcohol dependence.
Figure 1Forest plot of the adjusted odds ratios and 95% confidence intervals for the final model examining the association of psoriasis and other risk factors on MI.
This study utilized data from the USRDS to investigate the association between psoriasis and MI in the ESRD population. Among the total cohort, 0.6% were diagnosed with psoriasis. These patients were more likely to be male, White race, non-Hispanic ethnicity, on hemodialysis, and use a catheter for dialysis access. In addition, all demographic and clinical variables in Table 2 were associated with increased odds of psoriasis. Among the total cohort, 17.1% had an MI. These patients were older and more likely to be female, of non-Hispanic ethnicity, have a graft for dialysis access, or carry a diagnosis of psoriasis in comparison to those without MI. This group of MI patients also had higher percentages of all clinical diagnoses in Table 3 compared to those without MI. Of the patients with psoriasis, 24% developed an MI. Prior to adjusting for confounding variables, the unadjusted association initially suggested an increased risk of MI associated with psoriasis.
A relationship between systemic inflammatory disease, like psoriasis, and increased cardiovascular risk has been suggested.
Shared inflammatory pathways, including type 1 helper T-cells, macrophages, and inflammatory cytokines, are involved in the development of both psoriasis and atherosclerosis.
Our finding of no association between psoriasis and MI in ESRD patients is contrary to prior research in the general population. Gelfand's prospective, population-based cohort study in the United Kingdom found that psoriasis may confer an independent risk of MI after making adjustments for hypertension, diabetes, history of MI, hyperlipidemia, age, sex, smoking, and body mass index.
A 5-year population-based study in Taiwan found that psoriasis may confer an independent risk of MI in Asian populations after adjusting for coronary risk factors, such as diabetes, hyperlipidemia, and hypertension, as well as demographic risk factors.
However, after controlling for various demographic and clinical parameters in our final model, psoriasis was not associated with an increased risk of MI in the ESRD population. In a separate study, the association between psoriasis and stroke in the USRDS database was also examined and showed a similar association between psoriasis and an increased risk of stroke in simple models, which disappeared in the multivariable final model (manuscript in review).
Confounders of the association of psoriasis with MI included congestive heart failure (CHF), pulmonary disease, and diabetes with complications. A confounder is a variable that independently affects the exposure and the outcome, consequently modifying the association between them.
In this study, the indicated confounders independently affected psoriasis, the exposure, and MI, the outcome. The confounding effect of CHF in the association of psoriasis with MI is the most marked compared to other factors (Table 3, Fig. 1). Inflammation plays a role in the pathogenesis of both psoriasis and CHF. Studies have shown that increased inflammatory cytokines, such as tumor necrosis factor α (TNF-α), in patients with HF are associated with worsened prognosis and may contribute to myocardial dysfunction.
TNF-α is also the central inflammatory mediator in psoriasis pathogenesis, and elevated circulating levels of TNF-α have been reported in psoriasis patients.
Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis.
Psoriasis has been associated with endothelial dysfunction and increased arterial stiffness, which may lead to CHF by increased myocardial afterload and decreased coronary flow reserve.
The findings of this study further support the proposition of the independent effects of psoriasis on the risk of CHF progression mediated through systemic inflammatory mechanisms. Thus, patients with psoriasis should undergo annual evaluation of cardiovascular risk factors.
There are several potential explanations for the discrepancy between previous research supporting an association between psoriasis and MI and this study finding no association between the two. In this study, the comorbidities comprising the Charlson Comorbidity Index, other than MI as the outcome of interest, were controlled.
These included stroke, congestive heart failure, dementia, pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver disease, non-complicated diabetes, complicated diabetes, paraplegia, cancer, metastatic cancer, moderate to severe liver disease, AIDS, tobacco dependence, and alcohol dependence. As this study adjusted for a high number of comorbidities relative to other studies, the lack of association between psoriasis and MI in this query may represent the high degree of confounding between psoriasis and other comorbidities for the outcome of MI.
Conversely, psoriasis may predispose patients to comorbidities that might have been controlled for in this study. A population-based, cross-sectional study found that patients with psoriasis had higher odds of having at least one major comorbid disease in comparison to patients without psoriasis.
Other emerging comorbidities of psoriasis include chronic obstructive pulmonary disease, peptic ulcer disease, sexual dysfunction, and obstructive sleep apnea.
Although a correlation between psoriasis and comorbidities has been established, it is unclear whether psoriasis induces these comorbidities or whether these comorbidities lead to psoriasis.
There are several limitations to this study since the USRDS dataset was utilized. The diagnoses were not the result of clinical data as they were inferred from billing codes submitted to Medicare or derived from CMS form 2728. The positive predictive value (PPV) of the components of the CCI have been shown to range from 62.5–100%,
when validated using chart reviews. This current study required two psoriasis diagnoses, which most likely increased the PPV. Furthermore, this study could not account for the clinical gravity of a psoriasis diagnosis; consequently, we were unable to stratify patients by psoriasis severity nor did we identify medications that may have been used for treatment in this study. Indeed, the treatment status of patients with psoriasis was not determined, which is also a limitation of the study. However, in an earlier study in ESRD patients from the USRDS database between 2004 and 2011, we found that only 2.7% of psoriasis patients were prescribed treatment with systemic drugs, 5.8% with light therapy, and 3.6% with local therapy (e.g., intralesional administration of corticosteroids).
This result is consistent with the idea that psoriasis is generally under-treated, although it should be noted that only treatments with ICD-9 or procedure codes were investigated in our study.
Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011.
Therefore, it is possible that patients who have been treated or are currently receiving therapy for psoriasis may have different clinical outcomes than those who are receiving no treatment. Although we did not examine MI specifically in our prior study, the fact that our study looking at the effect of treatment on mortality showed that prescribed treatment was associated with increased survival suggests the overall health benefits of therapy for this inflammatory skin disease.
Nevertheless, the limitations of the USRDS are countered by the extensive volume of data contained in the database, which captures billed diagnoses and therapies on all ESRD patients in the United States and offers strong statistical power.
Although psoriasis has traditionally been considered a disease that predominantly affects the skin and joints, increasing evidence suggests that it has far-reaching systemic effects. Research about the risk of comorbidities in psoriasis patients may increase our understanding of psoriasis and improve clinical practice. The presence of comorbid diseases may influence therapeutic choice since some treatments for psoriasis may exacerbate comorbid conditions and vice versa.
Thus, appropriate management of psoriasis, particularly in the ESRD population in which psoriasis treatment was found to decrease the risk of mortality, should involve an integrated approach to ensure comprehensive care with proper health screening, evaluation, and management.
Previous research in the general population suggests that psoriasis is associated with an increased risk of MI. We queried the USRDS to investigate if psoriasis represents a significant risk factor for developing MI in ESRD patients. ICD codes were used to query the outcome of interest, MI, and other clinical risk factors. Among the total cohort, 0.6% were diagnosed with psoriasis, and 24% of these patients developed an MI. In simple models, psoriasis was associated with MI. However, after adjusting for demographic and clinical parameters in the final model, there was no association between psoriasis and MI. This finding is contrary to previous research in the general population and may be due to controlling for more factors than other studies or differences between the general population and the ESRD population.
This work was supported by the Augusta University Department of Medicine Translational Research Program, the Charlie Norwood Veterans Affairs Medical Center, a grant from Dialysis Clinic, Inc., and the MCG Medical Scholars Program. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the United States Government.
United States Renal Data System. 2019 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019.
Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis.
Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011.
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