Introduction ... Aims. Methods The study included the entire Danish population aged 18 years followed from 1 January 1997 until HF, death or 31

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1 European Journal of Heart Failure (2014) 16, doi: /ejhf.113 Psoriasis and risk of heart failure: a nationwide cohort study Usman Khalid 1 *, Ole Ahlehoff 1,2, Gunnar Hilmar Gislason 1,3,4, Søren Lund Kristensen 1,LoneSkov 4,5, Christian Torp-Pedersen 4,6, and Peter Riis Hansen 1,4 1 Department of Cardiology, Gentofte Hospital University of Copenhagen, Hellerup; 2 Department of Cardiology, Roskilde Hospital University of Copenhagen, Roskilde; 3 National Institute of Public Health, University of Southren Denmark, Copenhagen; 4 Faculty of Health Sciences, University of Copenhagen, Copenhagen; 5 Department of Dermatology, Gentofte Hospital University of Copenhagen, Hellerup; and 6 Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark Received 29 January 2014; revised 22 April 2014; accepted 2 May 2014; online publish-ahead-of-print 5 June 2014 Aims Psoriasis is a common inflammatory disease that is associated with increased risk of cardiovascular disease, including myocardial infarction. Heart failure (HF) is independently associated with several cardiovascular risk factors and is a major cause of cardiovascular morbidity and mortality. The association between psoriasis and HF is unclear and we therefore investigated the risk of new-onset HF in a nationwide cohort of psoriasis patients compared with the background population.... Methods The study included the entire Danish population aged 18 years followed from 1 January 1997 until HF, death or 31 December Information on comorbidity and concomitant medication was identified by individual-level linkage of administrative registers. New-onset HF was defined as first hospital admission for HF. Incidence rates of new-onset HF were calculated and adjusted hazard ratios were estimated by multivariable Cox regression models adjusted for age, gender, comorbidity and cardiovascular medications.... Results A total of subjects were eligible for analysis. In the study period patients with new-onset psoriasis, including patients with severe psoriasis, were identified. The overall incidence rates of new-onset HF were 2.82, 4.22 and 4.70 per 1000 person-years for the reference population, mild psoriasis and severe psoriasis, respectively. Compared with the reference population, the fully adjusted hazard ratios for new-onset HF were increased in patients with psoriasis with a hazard ratio 1.22 (95% confidence interval ) and hazard ratio of 1.53 (95% confidence interval ) for those with mild and severe disease, respectively.... Conclusion In this nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of new-onset HF.... Keywords Cardiovascular risk Epidemiology Inflammation Heart failure Psoriasis Introduction Psoriasis is a chronic systemic inflammatory disease with a worldwide prevalence ranging from 1 to 4%. 1,2 Increasing evidence has suggested that psoriasis is associated with an increased prevalence of traditional cardiovascular risk factors and cardiovascular disease, including ischaemic heart disease, and it appears that inflammatory mechanisms in psoriasis and atherosclerosis show a significant overlap. 3 7 Heart failure (HF) is a major global health burden that is also associated with cardiovascular risk factors (e.g. hypertension, obesity and diabetes), ischaemic heart disease and inflammation 8,9... Specifically, systemic inflammation may contribute to the development and progression of HF by promoting myocardial damage and abnormalities in other tissues observed in patients with HF (e.g. endothelial dysfunction, muscle wasting, renal impairment and anaemia) Few studies have examined the association between psoriasis and risk of developing HF independently of traditional cardiovascular risk factors with inconsistent results. Nationwide data have also not been presented previously. 6,14 18 Therefore, the aim of the present study was to investigate the association between new-onset HF and psoriasis, including the impact of the severity of *Corresponding author: Department of Cardiology, Gentofte Hospital, Post 635, Niels Andersens Vej 65, 2900 Hellerup, Denmark. Tel: , Fax: ; usman.khalid@regionh.dk

2 744 U. Khalid et al. psoriasis, in a nationwide, unselected cohort of psoriasis patients using the Danish nationwide registers. Methods Data sources and study population The study was conducted and reported in accordance with cohort study guidelines outlined in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations. 19. Health care in Denmark is government-financed and principally free of charge, and equally accessible to all citizens. Danish residents are assigned individual and permanent personal civil registration numbers at birth. This enables linkage of data across the respective registers on an individual level. The present study was based on data obtained from the civil registration system, the Danish National Patient Registry, the Danish Registry of Medicinal Product Statistics (National Prescription Registry), and the National Causes of Death Registry. Information on all drug prescriptions dispensed from Danish pharmacies recorded since 1995 was available in National Prescription Registry. This register holds information on dispensing date, quantity dispensed, strength of the drug, and the affiliation of the physician dispensing the prescription. The register is very accurate as the partial reimbursement of drug expenses by the government ensures registration of all dispensed prescriptions in the National Prescription Registry. 20. Data on morbidity were retrieved from Danish National Patient Register, which contains information on all hospital admissions, outpatient consultations, diagnoses, and procedures, recorded since 1978 and listed according to the international classification of diseases (ICD i.e. ICD-8) until 1994 (ICD-10) and thereafter. All deaths and causes of deaths are registered in National Causes of Death Registry within 14 days of occurrence. Comorbidity was continuously updated throughout follow-up with evaluation of the following comorbidities: diabetes, hypertension, atrial fibrillation, chronic obstructive pulmonary disease, renal disease, vascular disease, and thromboembolism. An age-standardized index of socioeconomic status from 0 to 4 was defined as the individual average annual income during a 5-year period before the start of the study. The study cohort consisted of the entire Danish population, where each subject was included in the cohort when aged 18years,starting from 1 January 1997 and followed until 31 December 2011, diagnosis of HF, migration, or death. Prescriptions claimed for topical vitamin D derivatives [Anatomical Therapeutical Chemical (ATC) code D05AX], i.e. first-line treatment used exclusively for psoriasis that is not accessible without prescription in Denmark, were used to identify patients with psoriasis. Patients were first included when claiming their second prescription for these agents to ensure persistent medical treatment for psoriasis. Patients were categorized as having severe psoriasis at the time of their third hospitalisation or outpatient consultation for psoriasis (ICD-10 L40) or psoriatic arthritis (M070-M073). This method for identification of psoriasis and classification of severity has previously been used and validated. 4,21,22. Patients with a history of admissions for psoriasis and/or HF were excluded at baseline to more accurately determine time at risk and the chronological sequence of the onset of disease. Pharmacotherapy Drugs are registered in the National Prescription Registry according to the ATC classification system. Baseline treatment with beta-blockers... (C07), loop diuretics (C03C), spironolactone (C03D), thiazides (C03AA), angiotensin-converting enzyme inhibitors/angiotensin 2 receptor blockers (ACEI/ARB) (C09), calcium channel blockers (C08), vitamin K antagonists (B01AA), digoxin (C01AA), anti-diabetic drugs (A10), platelet inhibitors (B01AC), cholesterol-lowering drugs (C10A), glucocorticoids (H02AB), retinoids (D05BB), and methotrexate (L01BA01) was defined by prescriptions dispensed at least one claimed prescription for each respective drug(s) up to 6 months before the study inclusion date. Outcome The primary endpoint for the study was new-onset HF, defined as first hospital admission for HF (ICD-codes: I110, I42, 150, J819 and ICD-8 code 428) recorded in the National Patient Registry. The accuracy of the HF diagnosis in the National Patient Registry has been shown to be high. 23,24. Statistical analysis Baseline characteristics are presented as means with standard deviations or frequencies and percentages, as applicable. Psoriasis and age were considered as time-dependent variables and thus subjects who developed psoriasis contributed risk time in the reference group until time of diagnosis. Comorbidity was updated continuously throughout follow-up, whereas concomitant medications were included as fixed variables at baseline. Hazard ratios (HRs) for the study endpoint were estimated with Cox proportional hazards models adjusted for confounding factors including age, sex, comorbidity, socioeconomic status, and concomitant medications (except for anti-diabetic drugs to avoid over-adjustment as diabetes is also a diagnosis adjusted for as a comorbidity) as given in Table 1. Incidence rates were summarized as events per 1000 person-years at risk. Sensitivity analyses with altered criteria for psoriasis diagnosis at study inclusion were conducted to address the impact of bias caused by increased health-care consumption associated with the diagnosis of psoriasis. In these analyses, patients with psoriasis were identified by their first prescription claim for vitamin D derivatives and were classified as having severe psoriasis at the time of their first inpatient or outpatient hospitalisation for psoriasis. This definition of psoriasis is considerably less conservative and is inherently associated with fewer health-care contacts than the one used in the primary analyses. The primary analysis was not adjusted for medications used for treatment of HF (i.e. loop diuretics, spironolactone, beta-blockers, and ACEI/ARB), and additional analysis was carried out with inclusion of HF medications to estimate its impact on the HRs of HF. Furthermore we performed an additional sensitivity analysis, where we excluded all subjects receiving medications used for HF (i.e. beta-blockers, ACEI/ARB, and loop-diuretics at baseline). To assess the influence of inclusion of secondary diagnoses we also performed a further analysis where subjects were only included if the HF diagnosis was recorded as primary diagnosis. For all analyses, a two-tailed P-value less than 0.05 was considered statistically significant and 95% confidence intervals (CIs) were also reported. Model assumptions, including absence of interaction between covariates were tested and found to be valid. All statistical analyses were performed with the SAS statistical software version 9.2 (SAS Institute Inc. Cary, NC, USA) and STATA software version 11.0 (StataCorp, College Station, TX, USA).

3 Psoriasis and risk of heart failure: a nationwide cohort study 745 Table 1 Baseline characteristics of the study population Reference population Mild psoriasis Severe psoriasis Psoriasis overall P-value (n = ) (n = ) (n = ) (n = )... Mean (SD) age (years) 40.7 (19.6) 44.2 (16.6) 42.6 (15.1) 43.9 (16.3) <0.001 Men (%) (49.3) (48.9) (47.5) (48.9) <0.001 Mean (SD) socio-economic status 2.0 (1.4) 2.5 (1.3) 2.5 (1.2) 2.5 (1.3) <0.001 Comorbidity (%) COPD (0.5) 184 (0.3) 56 (0.5) 240 (0.3) <0.001 Diabetes mellitus (0.7) 384 (0.7) 101 (0.9) 485 (0.7) <0.006 Hypertension (0.7) 458 (0.8) 133 (1.2) 591 (0.8) <0.001 Previous atrial fibrillation (0.5) 265 (0.5) 48 (0.4) 308 (0.5) <0.072 Renal disease (0.1) 32 (0.1) 12 (0.1) 44 (0.1) <0.068 Thromboembolism (0.9) 394 (0.7) 68 (0.6) 462 (0.7) <0.001 Vascular disease (0.8) 486 (0.9) 84 (0.8) 570 (0.9) <0.173 Medications (%) ACEI/ARB (2.0) (2.8) 281 (2.5) (2.8) <0.001 Acetylsalicylic acid (2.8) (2.8) 247 (2.2) (2.7) <0.001 Anti-diabetic drugs (1.4) 834 (1.5) 201 (1.8) (1.6) <0.001 Beta-blocker (2.6) (3.7) 347 (3.0) (3.6) <0.001 Calcium channel blocker (2.7) (3.4) 356 (3.2) (3.3) <0.001 Cholesterol-lowering drugs (0.5) 496 (0.9) 90 (0.8) 586 (0.9) <0.001 Digoxin (1.0) 368 (0.7) 53 (0.5) 421 (0.6) <0.001 Loop diuretic (2.1) 976 (1.8) 233 (2.1) (1.8) <0.001 Methotrexate (0.1) 139 (0.2) 315 (2.8) 454 (0.7) <0.001 Retinoid 314 (0.0) 61 (0.1) 59 (0.5) 120 (0.2) <0.001 Spironolactone (0.3) 135 (0.2) 25 (0.2) 160 (0.2) <0.001 Systemic glucocorticoids (1.7) (2.0) 376 (3.2) (2.0) <0.001 Thiazide diuretic (2.7) (3.3) 335 (3.0) (3.2) <0.001 Vitamin K antagonist (0.4) 186 (0.3) 38 (0.3) 224 (0.3) <0.853 ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin 2 receptor blocker; COPD, chronic obstructive pulmonary disease. Results Baseline characteristics The study comprised a total of subjects, aged 18years. Owing to previous psoriasis (n = ) and HF (n = ) subjects were excluded from the analysis at baseline. During the study period subjects with mild psoriasis and with severe psoriasis were identified. These patients were compared with the reference population of individuals. A flowchart of the study population selection is shown in Figure 1. In comparison with the reference population, patients who developed psoriasis had similar use of cardiovascular medications and comparable comorbidity at baseline (Table 1). Median follow-up time was estimated to be 11.9 years, 6.1 years and 5.4 years for the reference population, mild psoriasis, and severe psoriasis, respectively. The mean duration from diagnosis of psoriasis to incidence of HF was 4.9 years for subjects with mild psoriasis and 3.5 years for those with severe psoriasis, compared with 7.1 years from study inclusion to diagnosis of HF in the reference population. Risk of new-onset HF The results showed an association between psoriasis and an increased risk of new-onset HF (Table 2). The overall incidence... rates per 1000 person-years were 2.82 (95% CI ), 4.22 (95% CI ), and % (CI ) for the reference population, and patients with mild and severe psoriasis, respectively. The multivariable Cox regression model analyses, adjusted for age and sex, confirmed increased HRs for HF in patients with psoriasis compared with the reference population with HR 1.33 (95% CI ) and HR 1.73 (95% CI ) for mild and severe psoriasis, respectively. The HRs associated with psoriasis remained statistically significant in the fully adjusted statistical models controlling for age, sex, comorbidity, concomitant medications, and socioeconomic status (Table 3). Sensitivity analyses When the criteria for identifying psoriasis were altered to the first vitamin D prescription claim for mild psoriasis and first hospitalization for severe psoriasis, respectively, a total of patients with mild psoriasis and with severe psoriasis were identified. In this analysis the results were fully comparable with results of the primary analyses, with HR 1.52 (95% CI ) and HR 1.95 (95% CI ) for mild and severe psoriasis, respectively. Similarly, inclusion of HF medication in the analyses and exclusion of all subjects who used these drugs yielded

4 746 U. Khalid et al. Figure 1 Flowchart of the selection of the study population. Table 2 Incidence rates (IRs) with 95% confidence intervals (CIs) per 1000 person-years of new-onset heart failure and number of events Reference Mild Severe population psoriasis psoriasis... New-onset heart failure, IR (CI) 2.82 ( ) 4.22 ( ) Number of events ( ) results similar to the primary analyses. Also, when we excluded all subjects with HF as secondary diagnosis and used exclusively HF as the primary diagnosis to identify new-onset HF, the association between psoriasis and HF was not altered significantly. Discussion In this study we investigated the risk of new-onset HF in patients with psoriasis compared with the general population in an unselected, nationwide real-world cohort. After adjustments for age, sex, concomitant medications, comorbidity and socioeconomic status, the HRs of HF were significantly increased in patients with psoriasis compared with the general population. Notably, the risk of HF demonstrated a dose response relationship with severity of psoriasis. Psoriasis is a common chronic inflammatory disease with a strong genetic component characterized by a systemic immunological response, which is mainly driven by T helper (Th) 1 and 17 lymphocytes. 25,26 Like other chronic inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematous, psoriasis shares inflammatory... Table 3 Risk of new-onset heart failure (HF) associated with psoriasis New-onset HF Hazard 95% Confidence ratio interval... Crude estimates Mild psoriasis Severe psoriasis Adjusted for age and sex Mild psoriasis Severe psoriasis Adjusted for age, sex, comorbidity, medications (without HF medication) and socioeconomic status Mild psoriasis Severe psoriasis Adjusted for age, sex, comorbidity, medications (including HF medication) and socioeconomic status Mild psoriasis Severe psoriasis mechanisms with atherosclerosis and confers an independent risk of various cardiovascular diseases, including myocardial infarction and stroke. 4,5,21,27 31 According to current guidelines, patients with rheumatoid arthritis and other forms of inflammatory arthritis, including psoriatic arthritis, should therefore undergo annual evaluation of cardiovascular risk factors and there is evidence to suggest that such a recommendation should be extended to most patients with psoriasis. 3,32 Heart failure is a major cause of cardiovascular morbidity and mortality, and the prognosis after discharge for HF is comparable to or worse than that of several malignant disorders (i.e. approximately 50% of subjects diagnosed with HF die within 5years). 33 Importantly, recent research has supported the proposition that inflammatory mechanisms play a role in pathogenesis of HF Interest has focused on inflammatory cytokines, where, for example, elevated cardiac and circulating levels of tumour necrosis factor α (TNF-α) in patients with HF are associated with worsened prognosis and may contribute to myocardial dysfunction and other pathogenic manifestations of HF through an array of mechanisms, including endothelial dysfunction Further, TNF-α is also considered to be a central inflammatory mediator in psoriasis pathogenesis and elevated circulating levels of TNF-α have been reported in patients with psoriasis. 3,34 Moreover, psoriasis has been associated with endothelial dysfunction and increased arterial stiffness (which may contribute to HF by increased myocardial afterload and decreased coronary flow reserve), and preliminary evidence suggests that endothelial dysfunction in patients with psoriasis may be ameliorated by TNF-α inhibitors. 35,36 Therefore, it is conceivable that a systemic inflammatory state in patients with psoriasis may confer an increased risk of HF that is independent of traditional risk factors. Limited evidence has also indicated that patients with psoriasis and psoriatic arthritis have a high prevalence

5 Psoriasis and risk of heart failure: a nationwide cohort study 747 of subclinical left ventricular dysfunction in absence of clinically evident cardiovascular disease or classical risk factors. 37,38 A few observational studies have previously demonstrated an increased risk of HF in patients with psoriasis while others have found no such association. 6, These conflicting results may be explained, in part, by methodological issues (e.g. differences in population size and adjustments for important covariates). Moreover, previous studies are mainly based on selected populations and so the impact of the severity of psoriasis on the risk of HF has also not been fully investigated. However, the results of the present study, which is by far the largest to date, add to the evidence provided in the earlier studies demonstrating an association between psoriasis and increased risk of HF. 15,16,18 Moreover, our data expand these previous results considerably by demonstrating that this association remained even after adjustments for comorbidities, cardiovascular medications and socioeconomic status, and that the risk of new-onset HF is increased with increasing severity psoriasis. Together, these results support the proposition of independent effects of psoriasis on the risk of HF mediated through inflammatory mechanisms. Therefore, it is possible that even asymptomatic patients with psoriasis could be considered to be in stages A or B of the development of HF i.e. at high risk of HF without (stage A) or with (stage B) structural heart disease but more research is clearly warranted to shed light on this issue. 39 In view of the established association between psoriasis and coronary artery disease, where inflammatory mechanisms are also believed to play an important role, it is notable that a higher prevalence of subclinical coronary artery disease has been observed in patients with psoriasis and may have contributed to our results. 40,41 Study strengths and limitations The large number of participants, use of prospectively recorded nationwide data, completeness of follow-up, adjustment for important confounders, and use of validated measures of exposure and diagnoses are the major strengths of the study. Importantly, surveillance bias is unlikely because of the use of nationwide registers of drug prescriptions and hospitalizations in Denmark where health care is essentially free of charge and equally accessible to all inhabitants. Inclusion of the entire Danish population aged 18years reduced the possibility of selection bias related to, for example, age, gender, health insurance, and socioeconomic status. Moreover, exclusion of subjects with a history of psoriasis and/or HF at baseline ensured a reasonably accurate allocation of time at risk. There are, however, some important limitations to be acknowledged when interpreting the present findings. The identification of patients with psoriasis was based on prescriptions dispensed for vitamin D derivatives (first-line treatment for psoriasis in Denmark) and does not account for other topical psoriasis therapies. We have previously validated this method and any bias related to potential misclassification is anticipated to be negligible. 4 In addition, the small proportion of psoriasis patients who were not treated with vitamin D would have been included as controls and thus probably lead to underestimation of the rates of new-onset HF in psoriasis patients. Nevertheless, our results cannot be extrapolated... directly to patients with psoriasis treated with topical corticosteroids alone. Classification of severe psoriasis was based on number of hospitalizations, which may have decreased the threshold for detection of new-onset HF and comorbidities in this patient group. Although we have previously validated this method for classifying severe psoriasis, we also made multiple adjustments for confounding variables, including concomitant medications and comorbidities related to HF. Furthermore, the registers used in the study do not hold information on several important cardiovascular risk factors such as smoking, obesity, blood pressure, left ventricular ejection fraction, and lipid and glucose levels. The inclusion of socioeconomic data and a number of cardiovascular drugs and comorbidities in the analyses, however, is likely to control for some of this unmeasured confounding, although we cannot refute an impact of residual confounding on the results. Similarly, information on treatment with biologics (e.g. TNF-α inhibitors) is not accessible in the registers and could therefore not be controlled for in our analyses. However, studies of TNF-α inhibition in patients with HF have shown no consistent effects on clinical outcomes (hospitalization for HF and death). 42,43 Finally, the population in Denmark is predominantly composed of white people and this may limit the generalizability of the results to more ethnically diverse populations. Conclusion The results of this nationwide cohort study indicate a disease severity-dependent increased risk of new-onset HF in patients with psoriasis independent of traditional cardiovascular risk factors. The results add to evidence linking psoriasis with increased risk of cardiovascular disease and suggest that assessment of symptoms and signs of HF should be included in the clinical evaluation of cardiovascular risk factors in these patients. Funding The work was financially supported by unrestricted grants from the LEO foundation. G.G. is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation. Conflict of interest: none declared. References 1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361: Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. JAmAcadDermatol2014;70: Alexandroff AB, Pauriah M, Camp RD, Lang CC, Struthers AD, Armstrong DJ. 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