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.
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).
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.
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
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).
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).
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).
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.
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.
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).
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.
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.
1. Lebwohl M. Psoriasis
. Lancet. 2003;361:1197–1204.
2. Harden JL, Krueger JG, Bowcock AM. The immunogenetics of psoriasis
: a comprehensive review. J Autoimmun. 2015;64:66–73.
3. Prieto-Perez R, Cabaleiro T, Dauden E, et al. Genetics of psoriasis
and pharmacogenetics of biological drugs. Autoimmune Dis. 2013;2013:613086.
4. Morar N, Willis-Owen SA, Maurer T, et al. HIV
: pathogenesis, clinical features, and management. Lancet Infect Dis. 2010;10:470–478.
5. Parker SR. The skin and HIV
: no superficial matter. Top Antivir Med. 2014;22:680–684.
6. Stahl D, Lacroix-Desmazes S, Misra N, et al. Alterations of self-reactive antibody repertoires in HIV
disease: an insight into the role of T cells in the selection of autoreactive B cells. Immunol Lett. 2005;99:198–208.
7. Mahoney SE, Duvic M, Nickoloff BJ, et al. Human immunodeficiency virus (HIV
) transcripts identified in HIV
and Kaposi's sarcoma lesions. J Clin Invest. 1991;88:174–185.
8. Cheng TM. Taiwan's new national health insurance program: genesis and experience so far. Health Aff (Millwood). 2003;22:61–76.
9. Chen M, Jen IA, Chen YM. Nationwide study of cancer in HIV
-infected Taiwanese children in 1998–2009. J Acquir Immune Defic Syndr. 2015;69:e117–e118.
10. Wacholder S, McLaughlin JK, Silverman DT, et al. Selection of controls in case-control studies. I. Principles. Am J Epidemiol. 1992;135:1019–1028.
11. Beaumont JJ, Steenland K, Minton A, et al. A computer program for incidence density sampling of controls in case-control studies nested within occupational cohort
studies. Am J Epidemiol. 1989;129:212–219.
12. Yen YF, Chung MS, Hu HY, et al. Association of pulmonary tuberculosis and ethambutol with incident depressive disorder: a nationwide, population-based cohort
study. J Clin Psychiatry. 2015;76:e505–e511.
13. Jason PF, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
14. Collett D. Modelling Survival Data in Medical Research. 2nd ed. Chapman & Hall; 2003.
15. Fife DJ, Waller JM, Jeffes EW, et al. Unraveling the paradoxes of HIV
: a review of T-cell subsets and cytokine profiles. Dermatol Online J. 2007;13:4.
16. Smoller BR, McNutt NS, Gray MH, et al. Detection of the interferon-gamma-induced protein 10 in psoriasiform dermatitis of acquired immunodeficiency syndrome. Arch Dermatol. 1990;126:1457–1461.
17. Fuchs D, Hausen A, Reibnegger G, et al. Psoriasis
, gamma-interferon, and the acquired immunodeficiency syndrome. Ann Intern Med. 1987;106:165.
18. Vissers WH, Arndtz CH, Muys L, et al. Memory effector (CD45RO+) and cytotoxic (CD8+) T cells appear early in the margin zone of spreading psoriatic lesions in contrast to cells expressing natural killer receptors, which appear late. Br J Dermatol. 2004;150:852–859.
19. Austin LM, Coven TR, Bhardwaj N, et al. Intraepidermal lymphocytes in psoriatic lesions are activated GMP-17(TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis. J Cutan Pathol. 1998;25:79–88.
20. Nickoloff BJ, Wrone-Smith T. Superantigens, autoantigens, and pathogenic T cells in psoriasis
. J Invest Dermatol. 1998;110:459–460.
21. Torres BA, Johnson HM. Identification of an HIV
-1 Nef peptide that binds to HLA class II antigens. Biochem Biophys Res Commun. 1994;200:1059–1065.
22. Kanada KN, Schupp CW, Armstrong AW. Association between psoriasis
and viral infections in the United States: focusing on hepatitis B, hepatitis C and human immunodeficiency virus. J Eur Acad Dermatol Venereol. 2013;27:1312–1316.
23. Mallon E, Young D, Bunce M, et al. HLA-Cw*0602 and HIV
. Br J Dermatol. 1998;139:527–533.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
psoriasis; HIV; cohort