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Association of psoriasis with myocardial infarction in end-stage renal disease patients

Published:August 28, 2022DOI:https://doi.org/10.1016/j.amjms.2022.08.003

      Abstract

      Background

      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.

      Key Indexing Terms

      Introduction

      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.
      • Rachakonda T.D.
      • Schupp C.W.
      • Armstrong A.W.
      Psoriasis prevalence among adults in the United States.
      Classic comorbidities include psoriatic arthritis, psychological/psychiatric disorders, and uveitis.
      • Oliveira Mde F.
      • Bde O.R
      • Duarte G.V.
      Psoriasis: classical and emerging comorbidities.
      Psoriasis patients have a greater prevalence of cardiovascular disease risk factors, including hypertension, diabetes, obesity, dyslipidemia, and atherosclerosis.
      • Hu S.C.S.
      • Lan C.C.E.
      Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment.
      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.
      • Tinggaard A.B.
      • et al.
      Prevalence and severity of coronary artery disease linked to prognosis in psoriasis and psoriatic arthritis patients: a multi-centre cohort study.
      ,
      • Mansouri B.
      • et al.
      Comparison of coronary artery calcium scores between patients with psoriasis and type 2 diabetes.
      CAC, in turn, is associated with cardiovascular disease, including myocardial infarction (MI).
      • Tinggaard A.B.
      • et al.
      Prevalence and severity of coronary artery disease linked to prognosis in psoriasis and psoriatic arthritis patients: a multi-centre cohort study.
      ,
      • Mansouri B.
      • et al.
      Comparison of coronary artery calcium scores between patients with psoriasis and type 2 diabetes.
      Furthermore, meta-analysis studies have suggested that psoriasis is associated with an increased risk of severe vascular events, particularly MI.
      • Hu S.C.S.
      • Lan C.C.E.
      Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment.
      ,
      • Xu T.
      • Zhang Y.H.
      Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies.
      Inflammation, secretion of adipokines, insulin resistance, enhanced angiogenesis, oxidative stress, and hypercoagulability may contribute to the association between psoriasis and cardiometabolic disorders.
      • Hu S.C.S.
      • Lan C.C.E.
      Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment.
      Patients with psoriasis are also at significantly increased risk for chronic kidney disease and end-stage renal disease (ESRD).
      • Ungprasert P.
      • Raksasuk S.
      Psoriasis and risk of incident chronic kidney disease and end-stage renal disease: a systematic review and meta-analysis.
      ,
      • Lee E.
      • et al.
      Risk of end-stage renal disease in psoriatic patients: real-world data from a nationwide population-based cohort study.
      One possible mechanism proposes that tubular injury may be induced by increased levels of uric acid.
      • Ungprasert P.
      • Raksasuk S.
      Psoriasis and risk of incident chronic kidney disease and end-stage renal disease: a systematic review and meta-analysis.
      ,
      • Lee E.
      • et al.
      Risk of end-stage renal disease in psoriatic patients: real-world data from a nationwide population-based cohort study.
      In addition, renal dysfunction may potentially be attributed to comorbidities associated with psoriasis, including atherosclerosis, arterial hypertension, and diabetes.
      • Lee E.
      • et al.
      Risk of end-stage renal disease in psoriatic patients: real-world data from a nationwide population-based cohort study.
      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.
      • Mehta N.N.
      • et al.
      Attributable risk estimate of severe psoriasis on major cardiovascular events.
      ,
      • Ni C.
      • Chiu M.W.
      Psoriasis and comorbidities: links and risks.
      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.
      • Mehta N.N.
      • et al.
      Attributable risk estimate of severe psoriasis on major cardiovascular events.
      ,
      • Ni C.
      • Chiu M.W.
      Psoriasis and comorbidities: links and risks.
      Psoriasis remains undertreated in the ESRD population when compared to the already undertreated general population.
      • Schwade M.J.
      • et al.
      Treatment of psoriasis in end-stage renal disease patients is associated with decreased mortality: a retrospective cohort study.
      • Armstrong A.W.
      • et al.
      Under-treatment of patients with moderate to severe psoriasis in the united states: analysis of medication usage with health plan data.
      • Horn E.J.
      • et al.
      Are patients with psoriasis undertreated? Results of national psoriasis foundation survey.
      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.
      • Charlson M.E.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      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.
      VariableOverallPsoriasisNo PsoriasisOR95% CIp-value
      Total population1,062,6936823 (0.6)1055870 (99.4)
      Age, mean (SD)63.5 (14.9)64 (13.2)63.5 (14.9)1.0021.001–1.0040.0050
      Race, n (%)
       Black301110 (28.3)1036 (15.2)300074 (28.4)0.450.42–0.48<0.0001
       Other59430 (5.6)423 (6.2)59007 (5.6)0.930.84–1.03
       White702153 (66.1)5364 (78.6)696789 (66)1.00
      Sex, n (%)
       Female457356 (43.0)2852 (41.8)454504 (43.1)0.950.91–0.990.0383
       Male605337 (57.0)3971 (58.2)601366 (57)1.00
      Ethnicity, n (%)
       Hispanic155972 (14.7)850 (12.5)155122 (14.7)0.830.77–0.89<0.0001
       Non-Hispanic906721 (85.3)5973 (87.5)900748 (85.3)1.00
      First Dialysis Modality, n (%)
       Hemodialysis1060624 (99.8)6800 (99.7)1053824 (99.8)0.570.38–0.870.0082
       Peritoneal2069 (0.2)23 (0.3)2046 (0.2)1.00
      Access Type, n (%)
       Catheter860902 (81.0)5376 (78.8)855526 (81.0)0.860.81–0.91<0.0001
       Graft35552 (3.4)237 (3.5)35315 (3.3)0.920.80–1.05
       AV Fistula166239 (15.6)1210 (17.7)165029 (15.6)1.00
      TABLE 2Descriptive statistics and simple logistic regression results on psoriasis for clinical variables.
      VariableOverallPsoriasis Diagnosis
      PsoriasisNo PsoriasisOR95% CIp-value
      Stroke/Cardiovascular Disease, n (%)338679 (31.9)2895 (42.4)335784 (31.8)1.581.51–1.66<0.0001
      Congestive Heart Failure, n (%)646183 (60.8)5297 (77.6)640886 (60.7)2.252.12–2.38<0.0001
      Dementia, n (%)72984 (6.9)537 (7.9)72447 (6.9)1.161.06–1.270.0010
      Pulmonary Disease, n (%)452353 (42.6)4231 (62.0)448122 (42.4)2.212.11–2.33<0.0001
      Connective Tissue Disease, n (%)60191 (5.7)872 (12.8)59319 (5.6)2.462.29–2.64<0.0001
      Peptic Ulcer Disease, n (%)98876 (9.3)1000 (14.7)97876 (9.3)1.681.57–1.80<0.0001
      Mild Liver Disease, n (%)39564 (3.7)583 (8.5)38981 (3.7)2.442.24–2.66<0.0001
      Non-Complicated Diabetes, n (%)139791 (13.2)959 (14.1)138832 (13.2)1.081.01–1.160.0272
      Diabetes with Complications, n (%)550821 (51.8)4612 (67.6)546209 (51.7)1.951.85–2.05<0.0001
      Paraplegia, n (%)58346 (5.5)496 (7.3)57850 (5.5)1.351.24–1.48<0.0001
      Cancer, n (%)136305 (12.8)1206 (17.7)135099 (12.8)1.461.38–1.56<0.0001
      Metastatic Cancer, n (%)54248 (5.1)433 (6.4)53815 (5.1)1.261.15–1.39<0.0001
      Moderate to Severe Liver Disease, n (%)48204 (4.5)641 (9.4)47563 (4.5)2.202.03–2.39<0.0001
      AIDS, n (%)15234 (1.4)124 (1.8)15110 (1.4)1.281.07–1.530.0075
      Tobacco Dependence, n (%)364101 (34.3)3683 (54.0)360418 (34.1)2.272.16–2.37<0.0001
      Alcohol Dependence, n (%)59129 (5.6)642 (9.4)58487 (5.5)1.771.63–1.92<0.0001

      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.
      MINo MIOR95% CIp-value
      Total Population, n (%)181960 (17.1)880733 (82.9)
      Psoriasis Diagnosis1671 (0.9)5152 (0.6)0.950.89–1.010.0964
      Age, mean (SD)66.4 (12.8)62.9 (15.3)1.0291.029–1.030<0.0001
      Race, n (%)
       Black46573 (25.6)254537 (28.9)0.710.70–0.72<0.0001
       Other10376 (5.7)49054 (5.6)0.950.93–0.98
       White125011 (68.7)577142 (65.5)1.00
      Sex, n (%)
       Female79235 (43.6)378121 (42.9)0.900.89–0.91<0.0001
       Male102725 (56.5)502612 (57.1)1.00
      Ethnicity, n (%)
       Hispanic25413 (14.0)130559 (14.8)0.820.80–0.83<0.0001
       Non-Hispanic156547 (86.0)750174 (85.2)1.00
      First Dialysis Modality, n (%)
       Hemodialysis181591 (99.8)879033 (99.8)1.361.20–1.54<0.0001
       Peritoneal369 (0.2)1700 (0.2)1.00
      Access Type, n (%)
       Catheter146754 (80.7)714148 (81.1)1.311.29–1.33<0.0001
       Graft6739 (3.7)28813 (3.3)1.111.08–1.15
       AV Fistula28467 (15.6)137772 (15.6)1.00
      Stroke/Cardiovascular Disease, n (%)91577 (50.3)247102 (28.1)1.451.43–1.46<0.0001
      Congestive Heart Failure, n (%)164797 (90.6)481386 (54.7)5.265.17–5.36<0.0001
      Dementia, n (%)19722 (10.8)53262 (6.0)0.940.92–0.96<0.0001
      Pulmonary Disease, n (%)114236 (62.8)338117 (38.4)1.251.23–1.26<0.0001
      Connective Tissue Disease, n (%)13677 (7.5)46514 (5.3)0.940.92–0.97<0.0001
      Peptic Ulcer Disease, n (%)28255 (15.5)70621 (8.0)1.151.13–1.17<0.0001
      Mild Liver Disease, n (%)9187 (5.1)30377 (3.5)0.960.93–0.990.0021
      Non-Complicated Diabetes, n (%)24851 (13.7)114940 (13.0)1.521.49–1.56<0.0001
      Diabetes with Complications, n (%)131065 (72)419756 (47.7)1.821.79–1.85<0.0001
      Paraplegia, n (%)16251 (8.9)42095 (4.8)1.531.50–1.57<0.0001
      Cancer, n (%)29217 (16.1)107088 (12.2)0.830.82–0.84<0.0001
      Metastatic Cancer, n (%)9793 (5.4)44455 (5.0)0.780.76–0.80<0.0001
      Moderate to Severe Liver Disease, n (%)10182 (5.6)38022 (4.3)
      AIDS, n (%)2827 (1.6)12407 (1.4)1.101.05–1.15<0.0001
      Tobacco Dependence, n (%)87559 (48.1)276542 (31.4)1.151.14–1.17<0.0001
      Alcohol Dependence, n (%)11479 (6.3)47650 (5.4)0.940.92–0.96<0.0001

      Psoriasis association with 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.
      Fig 1
      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.

      Discussion

      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.
      • Xu T.
      • Zhang Y.H.
      Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies.
      ,
      • Yeung H.
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      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
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      • Davidovici B.B.
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      Several lines of evidence have indicated that psoriasis is associated with the risk of cardiovascular disease, a hallmark of which is atherosclerosis.
      • Xu T.
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      Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies.
      ,
      • Yeung H.
      • et al.
      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
      • Takeshita J.
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      Psoriasis and comorbid diseases: epidemiology.
      • Ghazizadeh R.
      • et al.
      Pathogenic mechanisms shared between psoriasis and cardiovascular disease.
      • Gelfand J.M.
      • et al.
      Risk of myocardial infarction in patients with psoriasis.
      • Davidovici B.B.
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      Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions.
      Consistent with this idea is the increased CAC scores observed in patients with psoriasis.
      • Tinggaard A.B.
      • et al.
      Prevalence and severity of coronary artery disease linked to prognosis in psoriasis and psoriatic arthritis patients: a multi-centre cohort study.
      ,
      • Mansouri B.
      • et al.
      Comparison of coronary artery calcium scores between patients with psoriasis and type 2 diabetes.
      Shared inflammatory pathways, including type 1 helper T-cells, macrophages, and inflammatory cytokines, are involved in the development of both psoriasis and atherosclerosis.
      • Xu T.
      • Zhang Y.H.
      Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies.
      ,
      • Takeshita J.
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      Psoriasis and comorbid diseases: epidemiology.
      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.
      • Gelfand J.M.
      • et al.
      Risk of myocardial infarction in patients with psoriasis.
      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.
      • Lin H.W.
      • et al.
      Increased risk of acute myocardial infarction in patients with psoriasis: a 5-year population-based study in Taiwan.
      A meta-analysis of 7 cohort studies suggested that psoriasis significantly increases the risk of stroke and MI.
      • Xu T.
      • Zhang Y.H.
      Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies.
      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.

      Catalogue of bias collaboration, Aronson JK, Bankhead C, Nunan D. Confounding. In Catalogue Of Biases. 2018. www.catalogueofbiases.org/biases/confounding.

      ,
      • Skelly A.C.
      • Dettori J.R.
      • Brodt E.D.
      Assessing bias: the importance of considering confounding.
      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.
      • Khalid U.
      • et al.
      Psoriasis and risk of heart failure: a nationwide cohort study.
      TNF-α is also the central inflammatory mediator in psoriasis pathogenesis, and elevated circulating levels of TNF-α have been reported in psoriasis patients.
      • Khalid U.
      • et al.
      Psoriasis and risk of heart failure: a nationwide cohort study.
      Indeed, anti-TNF-α medications have successfully been used to treat psoriasis.
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      Additionally, studies suggest that anti-TNF-α therapies decrease the risk of acute MI,
      • Lee J.L.
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      Biologics and cardiovascular events in inflammatory arthritis: a prospective national cohort study.
      ,
      • Low A.S.
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      although this idea remains somewhat controversial.
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      ,
      • Nguyen T.
      • Wu J.J.
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      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.
      • Khalid U.
      • et al.
      Psoriasis and risk of heart failure: a nationwide cohort study.
      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.
      • Sundararajan V.
      • et al.
      New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.
      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.
      • Yeung H.
      • et al.
      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
      Increasing psoriasis severity was associated with a higher mean CCI.
      • Yeung H.
      • et al.
      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
      Psoriasis overall was associated with higher prevalence of chronic pulmonary disease, diabetes, diabetes with systemic complications, mild liver disease, myocardial infarction, peptic ulcer disease, peripheral vascular disease, renal disease, and rheumatologic disease.
      • Yeung H.
      • et al.
      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
      Furthermore, associations have been reported between psoriasis and major cardiovascular events, obesity, hypertension, diabetes, dyslipidemia, metabolic syndrome, inflammatory bowel disease, hepatic disease, chronic kidney disease, malignancy, infection, mood disorders, and psoriatic arthritis.
      • Takeshita J.
      • et al.
      Psoriasis and comorbid diseases: epidemiology.
      Other emerging comorbidities of psoriasis include chronic obstructive pulmonary disease, peptic ulcer disease, sexual dysfunction, and obstructive sleep apnea.
      • Takeshita J.
      • et al.
      Psoriasis and comorbid diseases: epidemiology.
      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%,
      • Quan H.
      • et al.
      Assessing validity of ICD-9-CM and ICD-10 administrative data in recording clinical conditions in a unique dually coded database.
      and ICD-9 diagnoses for psoriasis have been shown to have a PPV of 78%
      • Asgari M.M.
      • et al.
      Validity of diagnostic codes and prevalence of psoriasis and psoriatic arthritis in a managed care population, 1996-2009.
      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).
      • Schwade M.J.
      • et al.
      Treatment of psoriasis in end-stage renal disease patients is associated with decreased mortality: a retrospective cohort study.
      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.
      • Armstrong A.W.
      • et al.
      Under-treatment of patients with moderate to severe psoriasis in the united states: analysis of medication usage with health plan data.
      ,
      • Armstrong A.W.
      • et al.
      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.
      • Schwade M.J.
      • et al.
      Treatment of psoriasis in end-stage renal disease patients is associated with decreased mortality: a retrospective cohort study.
      We were also unable to account for idiosyncrasies in coding or inaccurate or missed codes from the dataset.
      • Eggers P.W.
      CMS 2728: what good is it?.
      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.
      • Ni C.
      • Chiu M.W.
      Psoriasis and comorbidities: links and risks.
      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.
      • Schwade M.J.
      • et al.
      Treatment of psoriasis in end-stage renal disease patients is associated with decreased mortality: a retrospective cohort study.
      ,
      • Yeung H.
      • et al.
      Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
      ,
      • Gulliver W.
      Long-term prognosis in patients with psoriasis.
      ,
      • Kimball A.B.
      • et al.
      National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening.

      Conclusion

      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.

      CRediT authorship contribution statement

      Naomi Siddiquee: Conceptualization, Data curation, Writing – original draft, Writing – review & editing, Supervision. Jennifer L. Waller: Conceptualization, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Supervision, Project administration. Stephanie L. Baer: Conceptualization, Writing – review & editing. Azeem Mohammed: Conceptualization, Writing – review & editing, Funding acquisition. Sarah Tran: Conceptualization, Writing – review & editing. Budder Siddiqui: Conceptualization, Writing – review & editing. Sandeep Padala: Conceptualization, Writing – review & editing. Lufei Young: Conceptualization, Writing – review & editing. Mufaddal Kheda: Conceptualization, Writing – review & editing, Funding acquisition. Wendy B. Bollag: Conceptualization, Data curation, Writing – original draft, Writing – review & editing, Supervision, Project administration.

      Declaration of Competing Interest

      None declared.

      Acknowledgments

      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.

      Data availability statement

      The data underlying this article are available in the USRDS Database, at https://www.usrds.org/for-researchers/simple-data-requests/ and can be accessed by submitting a Simple Data Request form.

      Appendix. SUPPLEMENTARY MATERIALS

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