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HIV Infection Increases the Risk of Incident Psoriasis

A Nationwide Population-Based Cohort Study in Taiwan

Yen, Yung-Feng MD, MPH, PhD*,†,‡; Jen, I-An MD, MPH‡,§; Chen, Marcelo MD, PhD‖,¶; Lan, Yu-Ching PhD#; Lee, Chun-Yuan MD**; Chuang, Pei-Hung PhD‡,††,‡‡; Lee, Yun MPH; Arthur Chen, Yi-Ming MD, ScD‡,§§

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2017 - Volume 75 - Issue 5 - p 493–499
doi: 10.1097/QAI.0000000000001431
Epidemiology
Free

Background: HIV can cause an imbalance of T lymphocytes, which may contribute to the onset of psoriasis. However, the association of HIV with incident psoriasis has not been extensively studied.

Objectives: The aim of this nationwide population-based cohort study was to determine the association of HIV with incident psoriasis.

Methods: Since January 1, 2000, we identified adult people living with HIV/AIDS (PLWHA) from the Taiwan National Health Insurance Research Database. A control cohort without HIV infection, matched for age and sex, was selected for comparison. All patients were followed until December 31, 2012, and observed for the occurrence of psoriasis. The time-dependent Cox proportional hazards model was used to determine the association of HIV with incident psoriasis, while considering death as a competing risk event.

Results: Of the 102,070 patients (20,294 PLWHA and 81,776 matched controls), 248 (0.24%) had incident psoriasis during a mean follow-up period of 5.53 years, including 81 (0.40%) PLWHA and 171 (0.21%) controls. After adjusting for age, sex, and comorbidities, HIV infection was found to be an independent risk factor for incident psoriasis (adjusted hazard ratio, 1.80; 95% confidence interval: 1.38 to 2.36).

Conclusions: The population of PLWHA is living longer; clinicians need to be aware of their higher risk of psoriasis.

*Section of Infectious Diseases, Taipei City Hospital, Taipei City, Taiwan;

School of Medicine, National Yang-Ming University, Taipei, Taiwan;

Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan;

§Department and Institute of Public Health, National Yang-Ming University, Taipei, Taiwan;

Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan;

Department of Cosmetic Applications and Management, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan;

#Department of Health Risk Management, China Medical University, Taiwan;

**Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;

††Center for Prevention and Treatment of Occupational Injury and Diseases, Taipei Veterans General Hospital, Taipei, Taiwan;

‡‡Division of Clinical Toxicology and Occupational Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; and

§§Department of Microbiology and Institute of Medical Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Correspondence to: Yi-Ming Arthur Chen, MD, ScD, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan (e-mail: arthur@kmu.edu.tw).

The authors have no funding or conflicts of interest to disclose.

Received January 30, 2017

Accepted April 12, 2017

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INTRODUCTION

Psoriasis is a chronic immune-mediated skin disease affecting approximately 0.5%–4.6% of the world's populations.1 Psoriasis is a multifactorial disease that results from complex interactions of environmental and genetic risk factors.2,3 Previous reports have shown that HIV can provoke the development of psoriasis.4 Also, patients with psoriasis and HIV infection often present with more severe and treatment-refractory cutaneous disease.5

In the infected host, HIV can cause an imbalance of T lymphocytes, characterized by the depletion of CD4+ T cells and a relative increase in CD8+ T cells. This HIV-induced imbalance of T lymphocytes negatively impacts the selection of self-reactive antibody repertoires and may contribute to the onset of psoriasis.6 The HIV virion may also have a direct effect on the pathogenesis of psoriasis. A previous study showed that HIV RNA transcripts can be identified in the skin of patients with psoriasis,7 which suggests that HIV may play an important role in the development of psoriasis. Despite some evidence suggesting that HIV infection might be associated with the onset of psoriasis, the association of HIV with incident psoriasis has not been extensively studied. Therefore, we conducted a nationwide population-based cohort study of Taiwanese subjects with and without HIV from 2000 to 2012 to determine the association of HIV with incident psoriasis.

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METHODS

Data Source

The Taiwan National Health Insurance is a mandatory universal health insurance program that has provided comprehensive medical care to more than 99% of Taiwanese citizens since 1995.8 In this nationwide cohort study, we analyzed patient data obtained from the National Health Insurance Research Database (NHIRD). The NHIRD, a large-scale computerized database derived from the national health insurance system by the Bureau of National Health Insurance, is provided to investigators for research purposes. The identification codes of patients in the NHIRD are scrambled and deidentified before release to any investigator. This study was approved by the Institutional Review Board of Kaohsiung Medical University (KMUHIRB-20140073).

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Study Subjects

In this cohort study, we selected subjects who were ≥ 15 years old and were newly diagnosed with HIV between January 1, 2000, and December 31, 2012. The diagnosis of new HIV cases required (1) the presence of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code (042-044, 7958, or V08) in an inpatient setting or at 3 or more outpatient visits and (2) the presence of an examination for viral load or CD4 count (order codes: 26017A1, 14074B, 12071A, 12071B, 12073A, 12073B, 12074A, and 12074B).9 Patients who had received a diagnosis of psoriasis (ICD-9CM codes 696.0 and 696.1) before the HIV diagnosis were excluded.

The control group was matched by age, sex, and date of enrollment (±7 days). Four controls were randomly selected for each HIV patient.10,11 Control subjects were excluded if they had received a diagnostic code for HIV or psoriasis before inclusion in the study. The patients with HIV and control groups were both followed until a diagnosis of psoriasis, death, or until December 31, 2012. Death events were determined by the death certificate database of Taiwan.

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Variables and Measures

The outcome new psoriasis was defined by ICD-9CM code (696.0 and 696.1). A person was considered to have a new onset of psoriasis only if (1) the condition occurred in an inpatient setting or at 3 or more outpatient visits and (2) the psoriasis diagnosis was assigned by a board-certified physician in dermatology in Taiwan.

The control variables included sociodemographic data, comorbidities, opportunistic infection (OI) after HIV diagnosis, and highly active antiretroviral therapy (HAART). The sociodemographic data included income level and urbanization. Income level was calculated from the average monthly income of the insured person and grouped into 3 levels: low [≤19,200 New Taiwan Dollars (NTD)], intermediate (19,201 NTD to < 40,000 NTD), and high (≥40,000 NTD). Urbanization was categorized as residing in an urban or rural area. People living with HIV/AIDS (PLWHA) were considered to receive HAART if they received HAART before the new onset of psoriasis. The comorbidities in study subjects included diabetes (ICD9 code 250), chronic kidney disease (ICD9 code 580-587), hypertension (HTN; ICD9 code 401-405), coronary heart disease (ICD9 code 410-414), cancer (ICD9 code 140-208), and congestive heart failure (ICD9 code 428.0). The OIs after the diagnosis of HIV included cytomegalovirus infection (ICD9 code 078.5), Mycobacterium tuberculosis infection (ICD9 code 011-018), disseminated Mycobacterium avium complex infection (ICD9 code 0312), Pneumocystis jirovecii pneumonia (ICD9 code 1363), Penicillium marneffei infection (ICD9 code 1179), and herpes zoster (ICD9 code 053). A person was considered to have a comorbidity or OI only if the condition occurred in an inpatient setting or at 3 or more outpatient visits.12

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Statistical Analysis

First, the demographic data of the study subjects were analyzed. Continuous data are presented as a mean (SD), and the 2-sample t test was used for comparisons between groups. Categorical data were analyzed by the Pearson χ2 test, where appropriate.

The incidence of psoriasis per 1000 person-years was calculated in patients with and without HIV infection. The relative hazards of incident psoriasis in patients with HIV compared with patients without HIV infection were estimated from Cox proportional hazards models.

To determine the association between HIV infection and incident psoriasis, a Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for age, sex, and comorbidities. In these models, death was considered as a competing risk event.13 This study also evaluated the factors associated with incident psoriasis among PLWHA. In these models, HAART and OIs were regarded as time-dependent covariables,14 whereas other confounders such as age, sex, and comorbidities, which were collected at baseline, were considered as fixed covariates. Adjusted HRs (AHRs) with 95% CIs are reported to indicate the strength and direction of associations.

To examine the robustness of the main findings, sensitivity analyses were conducted after stratifying study subjects by age, sex, comorbidities, and OIs. All data management and analyses were performed using the SAS 9.4 software package (SAS Institute, Cary, NC).

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RESULTS

Participant Selection

We identified 22,327 individuals who had received a new diagnosis of HIV during the period from January 1, 2000, through December 31, 2012. After excluding those younger than 15 years old (n = 317), those with antecedent psoriasis (n = 149), and those with incomplete data (n = 1567), the remaining 20,294 patients with HIV were included in the analysis (Fig. 1). Another 81,776 subjects without HIV were randomly selected for the control group. The overall mean (SD) age was 34.0 (11.0) years and 91.5% of the subjects in the HIV group were male. Mean (SD) follow-up time was 4.99 (3.37) years in the HIV cohort and 5.71 (3.33) years in the control group. The demographic characteristics and comorbidities of the 2 groups are shown in Table 1. There were no significant differences in age or sex between the groups. As compared to control subjects, PLWHA had a significantly higher proportion of comorbidities (eg, chronic kidney disease, congestive heart failure, and malignancy).

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

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Incident Rate of Psoriasis

During the study follow-up period, 252 individuals had a new onset of psoriasis, including 81 (0.40%) study patients and 171 (0.21%) controls. The incidence rate of psoriasis per 1000 person-years was 0.80 in the PLWHA and 0.37 in the control group (P < 0.001). The relative hazard of incident psoriasis was 1.80 (95% CI: 1.38 to 2.36) between PLWHA and the control group. The time to diagnosis of incident psoriasis was significantly shorter in PLWHA than in those without HIV infection (P < 0.001, log-rank test; Fig. 2).

FIGURE 2

FIGURE 2

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Association of HIV Infection With Incident Psoriasis

A Cox proportional hazards model was used to identify independent risk factors for psoriasis. After adjusting for age, sex, and comorbidities, HIV infection significantly increased the risk of incident psoriasis (AHR 1.80; 95% CI: 1.38 to 2.36) (Table 2). In addition, other risk factors of incident psoriasis included male sex (AHR 2.04; 95% CI: 1.20 to 3.49), diabetes (AHR 1.67; 95% CI: 1.13 to 2.47), and HTN (AHR 2.18; 95% CI: 1.60 to 2.96). As compared to patients with low incomes, those with high incomes (AHR 0.53; 95% CI: 0.35 to 0.78) had a lower risk of incident psoriasis.

TABLE 2

TABLE 2

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Sensitivity Analysis for the Association Between HIV Infection and Psoriasis

Figure 3 shows the results of sensitivity analysis of the association between HIV and psoriasis, after adjustment for patient demographics and comorbidities. HIV infection was significantly associated with a higher risk of psoriasis in all patient subgroups, except those age ≥50 years, female patients, patients with intermediate or high income, and those living in a rural area.

FIGURE 3

FIGURE 3

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Factors Associated With Incident Psoriasis Among PLWHA

A time-dependent Cox proportional hazards model was used to determine the risk factors for incident psoriasis among PLWHA. After adjusting for age, sex, comorbidities, and OIs, risk factors for incident psoriasis included HTN (AHR 2.54; 95% CI: 1.49 to 4.34), HAART (AHR 1.72; 95% CI: 1.03 to 2.86), and Penicillium marneffei infection (AHR 6.21; 95% CI: 1.51 to 25.5) (Table 3). Moreover, PLWHA with high income had a lower risk of incident psoriasis (AHR 0.37; 95% CI: 0.15 to 0.95).

TABLE 3-a

TABLE 3-a

TABLE 3-b

TABLE 3-b

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DISCUSSION

This nationwide cohort study found that PLWHA had a higher risk for developing incident psoriasis as compared to controls, after adjusting for demographic data and comorbidities. T-cell imbalance and HIV-related superantigens may explain the increased risk of incident psoriasis in PLWHA. The T-cell imbalance in patients with HIV is characterized by decreased CD4 T cells and a relative increase in CD8 T cells. The depletion of CD4 suppressor T cells results in unchecked proinflammatory pathways, leading to psoriasis.15 Also, increased CD8 memory T cells enhance the production of interferon γ, which plays an important role in the development of psoriasis.16,17 Previous studies also demonstrated that the number of CD8 T cells and the memory subset of CD8 T cells were increased in the epidermis and dermis of psoriatic skin and were associated with the onset of psoriasis.18,19

HIV-related superantigens (eg, HIV nef protein) may also lead to the development of psoriasis.4 Previous reports indicated that HIV-related superantigens can induce the polyclonal activation of T cells that recognize autoantigens in the skin, initiating the cascade of cellular and molecular events that produce psoriasis.4,20,21

This study is a large-cohort study to address the association between HIV infection and the subsequent development of psoriasis. Because the cross-sectional study to examine the association between HIV infection and psoriasis was likely to have the problem of obscured temporality,22 the prospective cohort design in this report could provide reliable estimates of the strength of the association. Also, the design of our study, which included unbiased subject selection and strict HIV diagnosis, supports the validity of these findings. Moreover, this nationwide population-based study traced all PLWHA and control patients with minimal referral bias because all medical care was covered by the Taiwan National Health Insurance.

Nevertheless, this study has some limitations. First, psoriasis is a multifactorial disease in which environmental factors, infectious etiologies, and genetics may play dynamic roles in its pathogenesis. However, the data regarding the susceptibility gene (eg, HLA-Cw*0602 allele)23 for the psoriasis was not available in this study. Second, the diagnoses of HIV and psoriasis that rely on administrative claims data recorded by physicians or hospitals may be less accurate than diagnoses made in a prospective clinical setting. However, there is no reason to suspect that the validity of claims data would differ with a patient's HIV status. Furthermore, to improve the ascertainment of psoriasis diagnosis, new cases of psoriasis were defined as those assigned by the dermatologists and the outcome of incident psoriasis may have been misclassified. This nondifferential misclassification of outcome would most likely lead to an underestimation of the association between HIV infection and incident psoriasis. Third, the CD4 counts—the index of an advanced stage of HIV infection—were unavailable in our database. However, our study used OIs as a proxy for an advanced stage of HIV infection. All OIs among PLWHA were included in the multivariate analysis. Finally, the external validity of our findings may be a concern because almost all of our enrollees were Taiwanese. The generalizability of our results to other non-Asian ethnic groups requires further verification. However, our findings suggest new avenues for future research.

In conclusion, this nationwide, long-term cohort study established a link between HIV infection and psoriasis. HIV infection was an independent risk factor for incident psoriasis, after adjusting for demographic data and comorbidities. Because the population of PLWHA is living longer, clinicians need to be aware of their higher risks of psoriasis.

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ACKNOWLEDGMENTS

This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes.

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Keywords:

psoriasis; HIV; cohort

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