The Risk of Mortality among Psoriatic Patients with Varying Severity: A Nationwide Population-Based Cohort Study in Taiwan

Background: Previous studies showed conflicting results regarding the mortality risk in psoriasis patients with respect to disease severity and presence of psoriatic arthritis. This study aimed to determine the mortality risk in patients with mild and severe psoriasis and patients with psoriatic arthritis (PsA). Methods: A nationwide population-based cohort study was conducted based on data from the Taiwan National Health Insurance Research Database between 2002 and 2012. Incident psoriasis subjects were classified into two groups: psoriasis without arthritis and psoriasis with arthritis. Patients who had received systemic therapy and/or phototherapy were classified as having severe psoriasis; otherwise, patients were classified as having mild psoriasis. Control subjects without psoriasis were selected to match each psoriasis patient from the database within the same observational period. Cox proportional hazards analysis was used to compare the hazard ratio (HR) of time to death. Results: A total of 106,701 patients with psoriasis were included in this study. After controlling for demographics and comorbidities, psoriasis patients had a higher mortality risk compared with the control group (HR 1.41; 95% confidence interval (CI) 1.36 to 1.46). Compared with psoriasis alone, the mortality risk was not increased for PsA (HR = 1.01; 95% CI 0.93 to 1.10). Besides, severe psoriasis did not increase mortality risk compared with mild psoriasis (HR = 1.0; 95% CI 0.95 to 1.06). Conclusions: Patients with psoriasis had a higher mortality risk compared with control subjects, whereas psoriasis severity and presence of PsA had no impact on mortality risk in psoriasis patients.


Introduction
Psoriasis and psoriatic arthritis (PsA) are chronic disabling diseases that have a substantial negative impact on a patients' quality of life, resulting in a great physical, emotional, and social burden [1]. An increasing trend in psoriasis and psoriatic arthritis prevalence has been observed in several countries [2][3][4][5][6][7], making them serious global problems.
Over the past decade there has been greater recognition of increased mortality associated with psoriasis [7][8][9][10], particularly due to cardiovascular disease [10,11]. Mortality studies have been carried out for psoriatic arthritis as well [8,10,[12][13][14][15][16][17]. Most of the studies have been limited by their small sample size and selection bias in community-or hospital-based studies [12,[14][15][16][17][18]. Besides, it is unclear whether disease severity and presence of PsA are associated with mortality risk in psoriasis patients. This study aimed to investigate the mortality risk in psoriasis patients with respect to the psoriasis severity and presence of PsA.

Data Source
A cohort study was conducted using data from the National Health Insurance Research Database (NHIRD), which covered over 99.9% of the nearly 23 million people in Taiwan between 2000 and 2012. The NHIRD database contains registration files and original reimbursement claims data, including demographic characteristics, outpatient and inpatient services, diagnostic codes, procedures performed, and details of prescriptions and comorbidities. The NHIRD has been widely used in epidemiological studies [19][20][21][22][23][24][25][26]. Previous studies have confirmed the high accuracy and validity of the NHIRD in recording psoriasis [10]. This study was performed in accordance with the Helsinki Declaration and was approved by the National Health Research Institutes and the Institutional Review Board of Taipei Veterans General Hospital (IRB: 2015-02-011CC).

Study Population and Study Design
We enrolled patients with a new diagnosis of psoriasis in the NHIRD between 1 January 2000, and 31 December 2001. Subjects with prior psoriasis diagnosis were excluded. The date of the first psoriasis diagnosis was defined as the index date, which was the start of follow-up for these patients. Subjects were considered to have psoriasis only if the diagnosis was made by dermatologists or rheumatologists and the condition occurred in an inpatient setting or required three or more outpatient visits. Psoriasis was identified by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes 696.0, 696.1, and 696.8. Patients were classified into groups with PsA, which were identified using ICD-9-CM code 696.0 during the same period; otherwise, patients were considered to have psoriasis without PsA (PsO). Psoriasis severity was classified as mild and severe. Severe psoriasis was defined as disease requiring systemic therapy and/or phototherapy. All other cases were classified as mild psoriasis.

Matched Controls without Psoriasis
For each patient with psoriasis, one matched control without psoriasis were randomly selected from the database within the same observational period. These subjects were matched for age and sex.

Outcome Measurement
Since the National Health Insurance is a mandatory universal health insurance program open to all Taiwanese residents, withdrawal from the insurance is almost always due to death. All study subjects were followed from the index date to withdrawal from the insurance or 31 December 2012, whichever date came first. Subjects with the condition mentioned were considered censored in the analysis.

Statistical Analysis
The demographic information of patients was compared by using χ 2 tests for categorical variables and t-tests for continuous variables. Death rates per 1000 patient-years and 95% confidence intervals (CIs) were calculated according to psoriasis status. Cox proportional hazards analysis was used to compare the mortality risks. The model was adjusted for age, sex, socioeconomic status, residence (urban, suburban, or rural), and comorbidities (hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, stroke, connective tissue disease, renal disease, chronic liver disease including cirrhosis and hepatitis, chronic obstructive pulmonary disease, and cancer). A two-sided p value of <0.05 was considered to represent a statistically significant difference. All data processing and statistical analyses were performed with Stata version 12 (Stata Corporation, College Station, TX, USA) and statistical analysis software (SAS) version 9.1 (SAS Institute, Cary, NC, USA).
During an average of 5.2 (SD 3.1) years of follow-up, the mortality rate was 15.8 per 1000 person-years in psoriasis patients. Compared with control subjects, psoriasis patients had a significantly higher risk of mortality (incidence rate ratio = 1.46; 95% CI 1.41 to 1.51) after multivariable adjustment (hazard ratio (HR) = 1.41; 95% CI 1.36 to 1.46) ( Table 4). Both mild and severe psoriasis and presence and absence of PsA are associated with an increased mortality risk. Patients with PsA did not have a higher mortality risk compared with those with PsO (HR = 1.01; 95% CI 0.93 to 1.10). There was no significant difference in mortality risk between patients with severe psoriasis and those with mild psoriasis (HR = 1.00; 95% CI 0.95 to 1.06).  Table 4. Risk of mortality in psoriatic patients.

Number of Deaths per 1000
Person-Years

Discussion
In this nationwide population-based study, we found that psoriasis patients with or without arthritis and with mild or severe psoriasis have a significantly increased risk of mortality compared with the control subjects. Our findings are in agreement with those of prior studies [8,10,27,28].
In the studies by Wong et al. [15], Ali et al. [16], and Mok et al. [18], PsA patients had a 1.62-fold, a 1.36-fold, and 1.59-fold increased mortality risk, respectively. However, Wilson et al. [17] and Buckley et al. [12] did not find a significant increase in mortality in PsA patients compared with the general population. Two recent population-based cohort studies showed conflicting results. Ogdie et al. [8] found that the death rate in 8706 PsA subjects did not differ from that of the general population, whereas Lee et al. [10] found increased mortality in 9572 PsA patients.
Several studies investigated the mortality risk in psoriasis patients with respect to disease severity [8,10,11,[26][27][28]. Among these studies, four suggested an increased mortality in both patients with mild and severe psoriasis compared with the general population [8,10,27,28]; one reported a significant higher risk of mortality in patients with severe psoriasis [11]. Another study identified that severe but not mild psoriasis as associated with an increased risk of death [29]. Growing evidence suggests a link between psoriasis and other comorbidities. Psoriasis patients are more likely to have malignancy, cardiovascular disease, metabolic syndrome, obesity, and diabetes mellitus, particularly in those with PsA and severe skin disease [27,28,[30][31][32], which could explain the higher mortality risk observed in psoriasis patients. However, in our study, the psoriasis severity and presence of PsA had no impact on the overall mortality risk in psoriasis patients. The non-significant mortality difference between PsO patients and PsA patients could be explained by higher prevalence of cardiovascular disease and malignancy in PsO patients. Compared with the studies of Ogdie et al. [8] and Lee et al. [10] which enrolled only adult patients (age ≥18 years), our study included patients aged under 18 years. Since younger patients are less vulnerable to morbidity and mortality, the inclusion of these patients in our cohort might partially explain the nonsignificant effects of psoriasis severity on mortality risk in psoriasis patients. However, further studies are needed to determine the underlying explanations for our findings.
The strengths of our study include the large sample size, a population-based cohort study design, reliable psoriasis diagnosis made by dermatologists and rheumatologists, and a more comprehensive control of potential confounding factors. However, potential limitations of our study should be considered. First, since the NHIRD data did not include clinical assessments, it is not possible to classify psoriasis severity based on clinical measures such as the Physician Global Assessment and Psoriasis Assessment Severity Index. The use of treatment patterns as a marker for psoriasis severity may introduce misclassification bias. It is possible that some untreated patients with severe psoriasis were misclassified as having mild psoriasis. Nevertheless, previous studies have affirmed the reliability and validity of using these methods for grouping severe psoriasis [33][34][35][36]. Second, there could be a "healthy user" effect in that patients with severe psoriasis need to be healthy enough to be prescribed the therapies, which would result in an underestimate of mortality risk. Third, instead of confirming death with the death certificate data, we identified death using the subjects' withdrawal from insurance. Withdrawal from insurance could be due to a renunciation of citizenship. However, this method has been validated in a previous study [37]. Fourth, the information regarding causes of mortality is lacking in our database, therefore, precluding us from further analysis in this study. Finally, the Taiwanese population is predominantly of Chinese descent and caution is needed in extrapolating the results to other ethnic groups.

Conclusions
In summary, our study demonstrated that there was a significantly increased risk of mortality in psoriasis patients. Both mild and severe psoriasis and presence and absence of PsA were associated with an increased mortality risk, whereas the psoriasis severity and presence of PsA had no impact on mortality risk in psoriasis patients. These findings urge physicians to provide comprehensive health assessments and preventive health practices to psoriasis patients even with mild skin disease and no PsA.

Conflicts of Interest:
The authors declare no conflict of interest.