Association between psoriasis and asthma: a population-based retrospective cohort analysis.

Association between psoriasis and asthma: a

populationbased

retrospective cohort analysis*

H.-Y. Fang,

W.-C. Liao,

C.-L. Lin,

C.-H. Chen

and C.-H. Kao

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), ischaemic 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 remodelling.9 The incidence rate of asthma ranges

from one to five cases per 1000 person-years, with a higher incidence in women than in men.10 Numerous asthma

patients also suffer from chronic conditions such as hypertension, ischaemic heart disease, diabetes, gastro-oesophageal

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,13 psoriasis is significantly

associated with chronic obstructive pulmonary disease (COPD). Therefore, we hypothesized that psoriasis might

increase the risk of asthma development. In this study, we investigated the risk of asthma development in patients with psoriasis 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 patients with psoriasis.

Materials and methods

Taiwan’s National Health Insurance (NHI) programme was established in 1995. Since 1998, it has enrolled up to 99% of the Taiwanese population and contracted with 97% of

Taiwan’s medical providers.14 The NHIRD stores the NHI programme

reimbursement claims data; includes data on outpatient visits, hospital admissions, prescriptions and disease

status for all insurants; and is maintained and updated by the National Health Research Institute. In the interest of patient privacy, all personal information in the NHIRD is anonymized before release for administrative use and research. 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 programme in 2010, including all records on these beneficiaries from 1996 to 2010.

There were no significant differences in the distribution of sex, 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 patients’ 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 to

access the NHIRD. This study was approved by the institutional review board of China Medical University

(CMU-REC-101-012), which specifically waived the requirement for consent.

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 cohort with psoriasis, and the date of diagnosis of psoriasis was defined as the index date. For each patient with psoriasis, four reference patients without a diagnosis of psoriasis

were selected as the nonpsoriasis comparison cohort, and 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 COPD (ICD-9-CM code

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 (e.g. phototherapy, including ultraviolet B, or psoralen and ultraviolet A; or

immunomodulator drugs, including methotrexate, azathioprine, ciclosporin, oral retinoids, hydroxyurea, mycophenolate

mofetil, tacrolimus, etanercept, adalimumab and

ustekinumab). Patients without treatment codes for systemic or biological treatment, or phototherapy for psoriasis were classified as having mild disease.6

Main outcomes

Patients with psoriasis (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 _ SD for continuous variables,

and Student’s t-tests were used to compare the

baseline characteristics of both cohorts. The asthma-free

Kaplan–Meier curves of both cohorts were compared using the log–rank test. Follow-up time (in person-years) was used

to estimate incidence density rates and psoriasis cohort with nonpsoriasis cohort hazard ratio (HR) with 95% confidence interval (CI) by sex, age and comorbidities. The HR was determined using uni- and multivariable Cox proportional

hazard regression models. The Cox proportional 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 proportional 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, U.S.A.). A two-tailed P-value < 0_05 was considered statistically significant.

Results

Table 1 presents the demographic characteristics and comorbidities of both 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. Compared with the cohort with no psoriasis cohort, the psoriasis cohort was more likely to have CAD (10_3% vs. 8_14%; P < 0_01); hypertension (21_3% vs. 17_8%; P < 0_01); rhinitis (16_6% vs. 13_0%; P < 0_01); GERD (1_33% vs. 0_98%; P < 0_01); psychological disorder (7_86% vs. 6_10%, P < 0_01); atopic dermatitis (4_50% vs. 1_46%; P < 0_01); and COPD (1_64% vs. 1_22%; P < 0_01). The mean length of follow-up was 6_37 _ 3_75 years in the psoriasis cohort and 6_39 _ 3_77 years in the cohort without psoriasis (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 cohort without psoriasis (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 analysed the sex-specific risk of asthma in patients with psoriasis and observed a 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 patients aged ≥ 65 years (adjusted HR 1_63, 95% CI 1_34–1_99). We analysed the association between psoriasis and the risk of asthma, stratifying by comorbidity, and observed a similar (about 1_42-fold), significant risk of asthma 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 uni- and multivariable Cox proportional hazard analyses for association between asthma and psoriasis are shown in Table 3. The risk of developing asthma was increased by 1_11-fold (95% CI 1_00–1_23) for women and 1_02-fold (95% CI 1_02–1_03) with age (every year). The risk of developing asthma was greater for patients with 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, in order to examine the combined effects of psoriasis and treatment, we divided the cohort with psoriasis into two subgroups according to having received treatment with immunomodulators or phototherapy. We observed that patients with psoriasis who received immunomodulator or phototherapy (severe psoriasis) had a significantly lower risk of asthma than those with mild psoriasis (Table 4). Patients with psoriasis who had received phototherapy had a significantly higher risk of asthma than did those with no psoriasis.

A 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_01) (Fig. 1).

Discussion

Our retrospective population-based cohort study, conducted using data from the NHIRD of Taiwan, suggests that, after adjusting for age, sex and medical comorbidities, patients with a clinical diagnosis of psoriasis are associated with an

increased risk of developing asthma compared with patients without psoriasis. The incidence rate of asthma was higher in men than in women, and increased with age in both cohorts. In patients with psoriasis, an increased incidence rate of

asthma was associated with medical comorbidities (e.g. CAD, hypertension, rhinitis, chronic sinusitis, GERD and psychological

disorder). In all patients aged > 50 years, those with psoriasis were associated with a higher risk of asthma compared with those 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, and 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 Tumour necrosis factor-a, 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 are 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 reported that patients with psoriasis are associated with increased risk of developing COPD.13

Patients with asthma are associated with an increased risk of coronary heart disease, diabetes mellitus, hypertension and CKD.19–22 Various factors have been suggested as contributing

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 T helper cell (Th) 2 driven.23 The

crucial role of another subset of CD4+ T cells, the Th17 cells, in inflammatory and autoimmune diseases has also been reported.24,25 Th1 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 an increased concentration

Th17 cells, in the sputum of asthma patients.27

The leucocyte infiltrate in psoriasis predominantly consists of CD4+ and CD8+ T cells, and might precede epidermal hyperplasia.17,28 The imbalance between Th1 and Th2 cells is

critical in inflammatory and immune disorders. Psoriasis is

classified as a Th1 disease, which is consistent with the relative under-representation of Th2 diseases, such as atopic dermatitis,

in patients with psoriasis.29 One study has reported that mesenchymal

stem cells isolated 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 populationbased data, which are highly representative of the general

population. However, it also has limitations. Firstly, 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 socioeconomic status, all of which can be risk factors for asthma. Even BMI is important in psoriasis and asthma,

and socioeconomic status is associated with asthma. Secondly, because of potential biases related to adjustment for confounding variables, evidence deriving from a retrospective cohort

study is generally of lower statistical quality than that from randomized trials. Although our study design was meticulous,

including control for confounding factors, bias resulting from unknown confounders could have affected our results. Thirdly, 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. Therefore, it is difficult to differentiate between allergic and nonallergic asthma. However, all insurance claims in the NHI are scrutinized by medical reimbursement specialists and subject to peer review. Thus, data on the diagnoses of psoriasis

and asthma can be considered reliable.

In conclusion, the results from our nationwide retrospective cohort study indicate that, after adjusting for CAD, hypertension, rhinitis, GERD and psychological disorder (anxiety and

depression), psoriasis is associated with increased risk of developing asthma. We observed a higher incidence of asthma in patients with psoriasis 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 patients with psoriasis, and refer to a specialist at an early stage if a patient exhibits chronic respiratory symptoms.