Association Between Psoriasis and Asthma: A Population-Based Retrospective Cohort Analysis
Running title: Psoriasis Increases Risk of Asthma
Word counts: abstract 185 words, text 2002 words
Hsin-Yu Fang, MD,a,1 Wei-Chih Liao, MD,b,c,1 Cheng-Li Lin, MSc,d,e Chia-Hung Chen, MD,b,c,* Chia-Hung Kao, MD,c,f,＊
aDepartment of Dermatology, China Medical University Hospital, Taichung, Taiwan
bDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine,
China Medical University Hospital, Taichung, Taiwan
cGraduate Institute of Clinical Medical Science and School of Medicine, College of
Medicine, China Medical University, Taichung, Taiwan
dManagement Office for Health Data, China Medical University Hospital, Taichung,
Taiwan
eCollege of Medicine, China Medical University, Taichung, Taiwan
Hospital, Taichung, Taiwan
1Contributed equally to this article. ＊Corresponding authors:
Chia-Hung Kao, MD, Professor, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174 E-mail address: d10040@mail.cmuh.org.tw
Chia-Hung Chen, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan. Tel.: +886 4 22052121x3485; fax: +886 4 22038883
E-mail address: hsnu758@gmail.com
Author Contributions:
Conception/Design: Hsin-Yu Fang, Wei-Chih Liao, Chia-Hung Chen, Chia-Hung Kao
Provision of study materials: Chia-Hung Kao Collection and/or assembly of data: Cheng-Li Lin
Chia-Hung Kao
Manuscript writing: All authors
Final approval of manuscript: All authors
Acknowledgments:
The study was supported in part by the study projects (018 and DMR-103-020) in China Medical University Hospital and Taiwan, Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111-03, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest:
Abstract
Background: Both of psoriasis and asthma are chronic immune-mediated inflammatory diseases. We evaluate the risk of asthma development in patients with psoriasis compared with controls.
Methods: This cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD). Patients with psoriasis (n = 10 288) and matched comparison patients without psoriasis (n = 41 152) were evaluated. A Cox proportional hazard regression analysis was used to determine the risk of asthma in patients with and without psoriasis.
Results: The risk of asthma was 1.38-fold higher (95% confidence interval (CI) =
1.23–1.54) in the psoriasis cohort than in the reference cohort, after adjusting for age, sex, and comorbidities. The incidence of asthma in male and female patients with psoriasis exhibited nonsignificant differences. Among all patients aged > 50 years,
psoriasis was associated with higher risk of asthma compared without psoriasis (adjusted hazard ratio (HR), 1.49 (95% CI = 1.18–1.88) in patients aged 50–64 years; adjusted HR, 1.63 (95% CI = 1.34–1.99) in patients aged > 65 years).
Conclusion: Our study results indicate that patients with psoriasis are associated with increased risk of asthma development.
Keywords: psoriasis, asthma, National Health Insurance Research Database (NHIRD), cohort study.
What's already known about this topic?
1. Both of psoriasis and asthma are chronic immune-mediated inflammatory diseases.
2. Studies have shown that psoriasis is associated with systemic comorbidities. 3. Recent studies have defined psoriasis as a systemic chronic inflammatory disease.
What does this study add?
1. The risk of asthma was 1.38-fold higher in the psoriasis cohort than in the reference cohort, after adjusting for age, sex, and comorbidities.
2. The incidence of asthma in male and female patients with psoriasis exhibited nonsignificant differences.
3. Among all patients aged > 50 years, patients with psoriasis were more likely to have higher risk of asthma compared without psoriasis.
Introduction
Psoriasis is a chronic immune-mediated inflammatory disease characterized by keratinocyte abnormalities and immune dysfunction. Psoriasis typically presents as erythematous scaly papules and plaques. The prevalence of psoriasis varies in different populations and is higher in men than in women.1,2 Studies have shown that psoriasis is associated with systemic comorbidities,3,4 including cardiovascular events, chronic kidney disease (CKD), ischemic stroke, and metabolic syndrome.5-8 Recent studies have defined psoriasis as a systemic chronic inflammatory disease,
characterized by dysregulation of the T-cell response and proinflammatory cytokines. Asthma is a chronic inflammatory disease of the airways. The most common
characteristics of asthma are airway hyperresponsiveness, and variable airflow obstruction and reversibility, associated with intense persistent airway inflammation and structural remodeling.9 The incidence rate of asthma ranges from 1 to 5 cases per 1000 person-years, with a higher incidence range in women than in men.10 Numerous asthma patients also suffer from chronic conditions such as hypertension, ischemic heart disease, diabetes, gastroesophageal reflux disease (GERD), and osteoarthritis.11 The causes of asthma are multifactorial and include environmental, immunological,
and host genetic factors. Several types of inflammation can occur in the lungs and many of the cytokines and chemokines produced are related to asthma.12
According to Chiang and Lin (2012), psoriasis is significantly associated with chronic obstructive pulmonary disease (COPD).13 Therefore, we hypothesized that psoriasis might increase the risk of asthma development. In this study, we investigated the risk of asthma development in psoriasis patients by using claims data from the National Health Insurance Research Database (NHIRD) of Taiwan. We also evaluated the effects of age, sex, coexisting cardiovascular risk factors, rhinitis, and sinusitis on asthma development in psoriasis patients.
Methods Data source
Taiwan’s National Health Insurance (NHI) program was established in 1995. It has enrolled up to 99% of the Taiwan population and contracted with 97% of the medical providers since 1998.14 The National Health Insurance Research Database (NHIRD) stores the NHI program reimbursement claims data, includes data on outpatient visits, hospital admissions, prescriptions, disease status for all insurants, and is maintained
and updated by the National Health Research Institute. All personal information in the NHIRD is anonymized before release for administrative use and research, in the interest of patient privacy. This study was conducted using the Longitudinal Health Insurance Database (LHID), a subset of the NHIRD. The LHID contains annual historical claims data on 1 000 000 randomly sampled beneficiaries enrolled in the NHI program in 2010, including all records on these beneficiaries from 1996 to 2010.
There were no significant differences in the distribution of gender, age, or health costs between the LHID and all insurance enrollees. In this study, disease diagnoses were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in outpatient and inpatient data.
Ethical Considerations
The NHIRD encrypts patient personal information to protect privacy and
provides researchers with anonymous identification numbers associated with relevant claim information, including patients’ sex, dates of birth, medical services utilized, and prescriptions. Patient consent is not required for accessing the NHIRD. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012). Our IRB specifically waived the consent requirement.
Study sample
Patients aged ≥ 20 years with newly diagnosed psoriasis (ICD-9-CM Codes 696,
696.0, 696.1, and 696.8) were included in the psoriasis cohort, and the date of diagnosis
of psoriasis was defined as the index date. For each psoriasis patient, 4 reference patients without a diagnosis of psoriasis were selected as the nonpsoriasis comparison cohort, frequency matched according to sex, age (within 5 years), and index year. In both cohorts, patients with asthma (ICD-9-CM Code 493) who were diagnosed prior
to the index date were excluded. The baseline comorbidity history was determined for
each patient, including coronary artery disease (CAD) (ICD-9-CM Codes 410–414), hypertension (ICD-9-CM Code 401–405), rhinitis (ICD-9-CM Codes 477 and 472.0), chronic sinusitis (ICD-9-CM Code 473), GERD (ICD-9-CM Codes 530.11 and 530.81), psychological disorder, including depression and anxiety (ICD-9-CM Codes
300.0 and 311), atopic dermatitis (ICD-9-CM Codes 691) and chronic obstructive
pulmonary disease (COPD) (ICD-9-CM codes 496). Severe psoriasis was defined by the presence of a prescription code for treatments consistent with severe psoriasis on or after the diagnosis of psoriasis (such as phototherapy including ultraviolet B or
psoralen and ultraviolet A (PUVA); immunomodulator, including methotrexate, azathioprine, cyclosporine, oral retinoids, hydroxyurea, mycophenolate mofetil, tacrolimus, etanercept, adalimumab, and ustekinumab). Patients without treatment codes for systemic or biologic treatment or phototherapy for psoriasis were classified as having mild disease.6
Main outcomes
The psoriasis patients (n = 10 288) and control patients without psoriasis (n = 41 152) were followed up until a diagnosis of asthma, loss to follow-up, withdrawal from the NHI, or the end of 2010.
Statistical analysis
Data are presented as mean ± standard deviation (SD) for continuous variables, and frequency and percentage for categorical variables. Chi-square and t tests were used to compare the baseline characteristics of the 2 cohorts. The asthma-free Kaplan-Meier curves of the 2 cohorts were compared using the log-rank test. Follow-up time (in person-years) was used to estimate incidence density rates and psoriasis cohort to non-psoriasis cohort hazard ratio (HR) with 95% confidence interval (CI), by gender,
age and comorbidities. The HR was determined using univariable and multivariable Cox proportional hazard regression model. The Cox proportion hazard regression analyses were also used to evaluate the effects of risk factors on risk of asthma, simultaneously adjusted for age, sex, and the comorbidities associated with significant differences in univariable Cox proportion hazard regression analyses. Further analysis was performed to verify the impact of psoriasis severity on asthma. All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA). Two-tailed p < 0.05 was considered statistically significant.
Results
Table 1 presents the demographic characteristics and comorbidities of the 2 cohorts. Men accounted for 52.7% of the study sample. The mean age of the nonpsoriasis cohort was 43.2 ± 17.1 years and that of the psoriasis cohort was 43.5 ± 17.0 years, with 68.3% of all patients aged < 50 years. The psoriasis cohort was more likely to have CAD (10.3% vs. 8.14%, p < 0.0001), hypertension (21.3% vs. 17.8%, p < 0.0001), rhinitis (16.6% vs. 13.0%, p < 0.0001), GERD (1.33% vs. 0.98%, p = 0.002), psychological disorder (7.86% vs. 6.10%, p < 0.0001), atopic dermatitis (4.50% vs. 1.46%, p < 0.0001) and COPD (1.64% vs. 1.22%, p < 0.0001) compared with the
nonpsoriasis cohort. The mean follow-up was 6.37 ± 3.75 years in the psoriasis cohort and 6.39 ± 3.77 years in the nonpsoriasis cohort (data not shown). The incidence of asthma was 6.41 per 1000 person-years in the psoriasis cohort, which was 1.38-fold higher than that in the nonpsoriasis cohort (4.38 per 1000 person-years), with an adjusted HR of 1.38 (95% CI = 1.23–1.54) (Table 2). The incidence of asthma was higher in men than in women and increased with age in both cohorts. We analyzed the sex-specific risk of asthma in patients with psoriasis and observed significantly higher risk of asthma for both women (adjusted HR = 1.29, 95% CI = 1.09–1.53) and men (adjusted HR = 1.46, 95% CI = 1.25–1.70). The age-specific risk of psoriasis was highest in the patients age ≥ 65 years (adjusted HR = 1.63; 95% CI = 1.34–1.99). We analyzed the association between psoriasis and the risk of asthma stratifying by comorbidity and found the similarly about 1.42-fold of asthma risk were significantly observed in patients without comorbidity (adjusted HR=1.42, 95% CI = 1.24-1.62) or
with comorbidity (adjusted HR=1.43, 95% CI=1.16-1.76).The results of univariable
and multivariable Cox proportional hazard analyses for association between asthma and psoriasis are shown in table 3.The risk of developing asthma was 1.11 time (95% CI = 1.00-1.23) for women patients and 1.02 times (95% CI = 1.02-1.03)
increased with age (every one year).The risk of developing asthma was greater for patients with comorbidity of hypertension (adjusted HR=1.29, 95% CI = 1.13-1.48), rhinitis (adjusted HR=1.57, 95% CI = 1.37-1.80), atopic dermatitis (adjusted
HR=1.54, 95% CI = 1.17-2.03), and COPD (adjusted HR=2.87, 95% CI=2.31-3.56). Furthermore, we divided the psoriasis cohort into 2 subgroups according to received treatment with immuomodulator or phototherapy to examine the combined effects of psoriasis and treatment. We observed that patients with psoriasis who received immnomodulator or phototherapy (severe psoriasis) had a significantly lower risk of asthma than mild psoriasis, as shown in Table 4. Patients with psoriasis who had received treatment of phototherapy had a significantly higher risk of asthma than did those with psoriasis who had received no treatment of phototherapy. The Kaplan-Meier plot revealed that the probability of remaining asthma-free was lower in the psoriasis cohort than in the nonpsoriasis cohort (log-rank p < 0.001) (Fig. 1).
Discussion
Our retrospective population-based cohort study, conducted using data from the NHIRD of Taiwan, suggests that patients with a clinical diagnosis of psoriasis are
associated with increased risk of asthma development compared with nonpsoriasis patients, after adjusting for age, sex, and medical comorbidities. The incidence rate of asthma was higher in men than in women, and increased with age in both cohorts. In the psoriasis patients, increased incidence rate of asthma was associated with medical comorbidities (such as CAD, hypertension, rhinitis, chronic sinusitis, GERD, and psychological disorder). In all patients aged > 50 years, patients with psoriasis are associated with higher risk of asthma compared without psoriasis; adjusted HR, 1.49
(95% CI = 1.18–1.88) in patients aged 50–64 years; adjusted HR, 1.63 (95% CI =
1.34–1.99) in patients aged > 65 years).
Psoriasis is a type of chronic inflammatory dermatosis that can restrict patients’ work, social, family, leisure, and sexual activities.15,16 Psoriasis is associated with multiple comorbidities and has been described as a systemic chronic inflammatory disorder.4 Tumor necrosis factor alpha, dendritic cells, cytokines, and T cells all contribute substantially to psoriasis pathogenesis, and increase the risk of systemic diseases.17 The associations between psoriasis and comorbidities have been well described; however, an emerging concern is the association between psoriasis and cardiovascular disease.18 Few studies have evaluated the relationship between
pulmonary disorder and psoriasis. Chiang and Lin (2012) reported that psoriasis patients are associated with increased risk of developing the chronic inflammatory airway disease COPD.13
Patients with asthma are associated with increased risk of coronary heart disease, diabetes mellitus, hypertension, and CKD.19-22 Various factors have been suggested as contributors to asthma, including immune regulation, genetic susceptibility, infection, and environmental factors. Studies have described the immune reaction in asthma as allergic, eosinophilic, IgE-dependent, and Th2-driven.23 The crucial role of another subset of CD4+ T cells, the Th17 cells, in inflammatory and autoimmune diseases has also been reported.24,25Th1 and Th17 phenotypes reportedly correlate with airway neutrophilic inflammation frequently found in the lungs of patients with severe or corticosteroid-resistant asthma.26 Studies have also identified increased concentration of interleukin-17, which is predominantly produced by Th17 cells, in the sputum of asthma patients.27
The leucocyte infiltrate in psoriasis predominantly consists of CD4-positive and CD8-positive T cells, and might precede epidermal hyperplasia.17,28 The imbalance
Psoriasis is classified as a Th1 disease, which is consistent with the relative underrepresentation of Th2 diseases, such as atopic dermatitis, in patients with psoriasis.29A study reported that mesenchymal stem cells solated from psoriasis showed an imbalance between the Th1-Th17 and Th2 pathways, which reflects the well-known abnormal balance observed in differentiated skin cells.30 Systemic inflammation is involved in both psoriasis and asthma. Dendritic cells are also associated with both conditions,31,32 and might partially explain their immunological similarities. Although asthma is a representative atopic disorder, its underlying pathophysiological mechanisms are complex. Multiple factors can contribute to asthma development, including genetic and environmental factors, infection, occupational exposure, air pollution, and diet. Race and ethnicity, lifestyle, and socioeconomic status have also been associated with asthma development. Further investigation of the pathophysiology of psoriasis and asthma is warranted.
The strengths of our study include its use of population-based data, which are highly representative of the general population. However, it also has limitations. First, the NHIRD does not contain detailed information on smoking habits, body mass index (BMI), dietary preference, occupational exposure, reproductive history, drug history,
family history of systemic diseases, and socio-economic status, all of which can be risk factors for asthma. Even BMI is an important in psoriasis and asthma and socio-economic status is associated to asthma. Second, evidence deriving from a
retrospective cohort study is generally of lower statistical quality than that from randomized trials because of potential biases related to adjustment for confounding variables. Although our study design was meticulous, including control for
confounding factors, bias resulting from unknown confounders could have affected our results. Third, all data in the NHIRD are anonymous. Therefore, relevant clinical variables, such as serum laboratory data, pulmonary function tests, and imaging and pathology results were unavailable. So, we have difficult to differentiate between allergic and non-allergic asthma. However, all insurance claims in the NHI are scrutinized by medical reimbursement specialists and subject to peer review. Data on the diagnoses of psoriasis and asthma can thus be considered reliable.
Conclusion
In conclusion, the results from our nationwide retrospective cohort study indicate
for CAD, hypertension, rhinitis, GERD, and psychological disorder (anxiety and depression). We observed higher incidence of asthma in the psoriasis patients aged ≧ 50 years. However, additional prospective studies are required to elucidate the
detailed underlying pathophysiology of asthma and psoriasis. We suggest that dermatologists should remain aware of increased risk of asthma in psoriasis patients, and refer to a specialist at an early stage if a patient exhibits chronic respiratory symptoms.
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Figure Legend:
Figure 1. Probability free of Asthma for patients with (dashed line) or without (solid line) Psoriasis
