Q J Med 2014; 107:537–543 doi:10.1093/qjmed/hcu027 Advance Access Publication 3 February 2014
Increased risk of chronic obstructive pulmonary disease in patients with rheumatoid arthritis: a population-based cohort study T.-C. SHEN1,2, C.-L. LIN3,4, C.-H. CHEN1, C.-Y. TU1, T.-C. HSIA1, C.-M. SHIH1, W.-H. HSU1 and F.-C. SUNG3 From the 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital and China Medical University, Taichung, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chu Shang Show Chwan Hospital, Nantou, 3Department of Public Health, College of Public Health, China Medical University, Taichung and 4Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan Address correspondence to W.-H. Hsu, Department of Internal Medicine, China Medical University Hospital and China Medical University, No. 2 Yude Road, Taichung, Taiwan. email: [email protected]; F.-C. Sung, Department of Public Health, College of Public Health, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan. email: [email protected]
Summary Background: The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly popular. Our aim was to assess the association between patients with rheumatoid arthritis (RA) and subsequent COPD risk in a nationwide population. Method: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The RA cohort included patients who were newly diagnosed and recruited between 1998 and 2008. Each patient was randomly frequency-matched for age, sex and the year of index date with people without RA from the general population. The newly diagnosed COPD was followed up until the end of 2010. The relative risks of COPD were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. Result: The overall incidence rate of COPD was 1.74-fold higher in the RA cohort than in the
non-RA cohort (5.25 vs. 3.01 per 1000 personyears, 95% confidence interval (CI) = 1.68–1.81). Age-related risk analysis showed an increased incidence of COPD with age in both RA and non-RA cohorts. However, adjusted hazard ratio (HR) maximum was witnessed in the age range of 20–34 years (adjusted HR: 7.67, 95% CI=1.94–30.3), whereas adjusted HR minimum was observed in the oldest age group (>65 years). Conclusion: Patients with RA have a significantly higher risk of developing COPD than that of the control population. Further, age-related risk analysis indicated much higher adjusted HR in younger patients although COPD incidence increased with age. It can be hypothesized that in addition to cigarette smoke, RA may be a determining factor for COPD incidence and/or facilitates shortening of the time course for developing COPD. However, further investigation is needed to corroborate this hypothesis.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]
Downloaded from by guest on February 12, 2015
Received 9 January 2014 and in revised form 22 January 2014
538
T.-C. Shen et al.
Introduction
Methods
Rheumatoid arthritis (RA) is a disease involving an inflammatory reaction of the immune system against body tissues, leading to joint destruction and physical disability. RA imposes substantial social costs, including an increased risk of work-related disability and accelerated mortality.1 It has been estimated that nearly 50% of RA patients will develop some form of respiratory abnormality during their lifetime.2 In fact, a study by Toyoshima et al.3 listed pulmonary disease as the second leading cause of death in RA patients, accounting for nearly 20% of their mortality. Although RA-associated interstitial lung disease remains the most debilitating and known complication, airway disorders may also play an important role in respiratory abnormality.4 Chronic obstructive pulmonary disease (COPD) is defined as a persistent and progressive airflow limitation, which is associated with an enhanced chronic inflammatory response in the airways and lungs due to noxious particles or gases. It is the fourth leading cause of death worldwide, with reported prevalence rates between 5% and 13%.5,6 Among the possible influencing factors, cigarette smoking is the most important one in the development of COPD. However, there remains a substantial group of COPD patients who have never smoked.7,8 Other contributing factors must therefore exist and one of them could be autoimmunity. The role of autoimmune pathology in the development and progression of COPD is becoming increasingly popular.9 It is known that smoking is a common environmental risk factor for both RA and COPD. However, the reason why patients with RA develop COPD cannot be solely attributed to cigarette smoke. RA may play an independent role in COPD incidence. Even smokers with RA could have a different time course for developing COPD as compared with nonRA individuals who are addicted to smoking. Some studies have concluded that majority of COPD patients have increased levels of serum antibodies to self-antigens,10–16 and appearance of antibodies to specific autoantigens correlates with disease severity.12–14,16 However, the mechanism of interaction between autoimmunity and COPD is still inconclusive. This study attempts to determine if there is a differential risk of COPD in adults with or without RA by examining a relatively large cohort in Taiwan. The results in this study were generated from a population-based retrospective cohort obtained from the National Health Insurance (NHI) system’s database.
Data sources The Bureau of National Health Insurance set up the Taiwan NHI program on 1 March 1995. The NHI program had covered over 99% of the 23.7 million population by the end of 2009.17,18 The National Health Research Institute is responsible for managing the claims data and established the Taiwan National Health Insurance Research Database (TNHIRD) for public use. We conducted a nationwide cohort study using the Taiwan National Health Institute Research Database (NHIRD). In this study, we used the inpatients dataset, catastrophic illness dataset and registry of beneficiaries, which were all part of NHIRD. These datasets were linked using the encrypted unique personal identification number to obtain longitudinal medical history of each individual. This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
Patients newly diagnosed with RA (ICD-9-CM 714) during 1998–2008 were eligible for enrollment in our study cohort. To ensure the diagnostic validity of new RA cases, we selected only those RA patients with first-ever issued catastrophic illness certificates. In Taiwan NHI system, the government defined RA as a ‘catastrophic illness’ and provided regulations for the affected insurants to apply for catastrophic illness certificates. Patients with catastrophic illness certificates get free care for their illness or related conditions within the validity period of their certificates. This means that patients need a clinical physician to confirm their illness before applying for a catastrophic illness certificate. We excluded patients who had missing data on date of birth and sex, or had pre-existing COPD (ICD-9-CM 491, 492 and 496). Thus, we listed 28 725 RA patients as study subjects defined as the RA cohort. For every RA patient, we randomly selected four non-RA patients from the same study period, used the same exclusion criteria and frequency-matched with the RA cohort for age, gender and index year to form the non-RA cohort with a total of 114 900 subjects.
Outcome measures The study patients were followed until they were diagnosed with COPD, which was identified based on the hospitalization records. The follow-up period was the period from the index date to the date of
Downloaded from by guest on February 12, 2015
Study subjects
Risk of COPD in rheumatoid arthritis
539
COPD diagnosis, withdrawal from the insurance system, death, or till the end of 2010.
Table 1 Demographic characteristics and comorbidity in patient with and without RA
Exposure variables
Variable
In addition to RA, demographic characteristics such as sex, age and comorbidities were analyzed. The baseline comorbidity histories of hypertension (ICD9 codes 401–405), diabetes (ICD-9 code 250), hyperlipidemia (ICD-9 code 272), coronary artery disease (CAD) (ICD-9 codes 410–414), cerebral vascular accident (CVA) (ICD-9 codes 430–438) and end-stage renal disease (ESRD) (ICD-9 code 585) were identified according to their diagnoses in the hospitalization records prior to the index date.
Statistical analysis
Results Demographic characteristics are shown in Table 1. Both cohorts had similar sex and age distribution. There were more female patients (78.0%) and elderly, aged 50 years or older (60.5%) in our study. The RA cohort was more likely to have hypertension, diabetes, hyperlipidemia and CAD than the non-RA cohort. With a mean follow-up time of about 5.15 years for both cohorts, the cumulative incidence of COPD was significantly higher in the RA patients (log-rank P < 0.001) than in the non-RA patients (Figure 1). The incidence densities and adjusted hazard ratio (AHR) between the RA and non-RA cohorts are shown in Table 2. The overall incidence of COPD was 74% higher in the RA cohort than in the non-RA cohort (5.25 vs. 3.01
P-value
No N = 114 900 Sex Female Male Age, mean(SD)a Age group 20-34 years 35-49 years 50-64 years 65+ years Comorbidity Hypertension Diabetes Hyperlipidemia CAD CVA ESRD
Yes N = 28 725
n 89 612 25 288 53.2
(%) n (78.0) 22 403 (22.0) 6322 (14.3) 53.8
(%) (78.0) (22.0) (13.9)
10 952 34 428 43 620 25 900
(9.53) 2738 (30.0) 8607 (38.0) 10 905 (22.5) 6475
(9.53) (30.0) (38.0) (22.5)
18 188 10 423 4653 7199 7126 1072
(15.8) (9.07) (4.05) (6.27) (6.20) (0.93)
(20.5)
Increased risk of chronic obstructive pulmonary disease in patients with rheumatoid arthritis: a population-based cohort study T.-C. SHEN1,2, C.-L. LIN3,4, C.-H. CHEN1, C.-Y. TU1, T.-C. HSIA1, C.-M. SHIH1, W.-H. HSU1 and F.-C. SUNG3 From the 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital and China Medical University, Taichung, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chu Shang Show Chwan Hospital, Nantou, 3Department of Public Health, College of Public Health, China Medical University, Taichung and 4Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan Address correspondence to W.-H. Hsu, Department of Internal Medicine, China Medical University Hospital and China Medical University, No. 2 Yude Road, Taichung, Taiwan. email: [email protected]; F.-C. Sung, Department of Public Health, College of Public Health, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan. email: [email protected]
Summary Background: The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly popular. Our aim was to assess the association between patients with rheumatoid arthritis (RA) and subsequent COPD risk in a nationwide population. Method: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The RA cohort included patients who were newly diagnosed and recruited between 1998 and 2008. Each patient was randomly frequency-matched for age, sex and the year of index date with people without RA from the general population. The newly diagnosed COPD was followed up until the end of 2010. The relative risks of COPD were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. Result: The overall incidence rate of COPD was 1.74-fold higher in the RA cohort than in the
non-RA cohort (5.25 vs. 3.01 per 1000 personyears, 95% confidence interval (CI) = 1.68–1.81). Age-related risk analysis showed an increased incidence of COPD with age in both RA and non-RA cohorts. However, adjusted hazard ratio (HR) maximum was witnessed in the age range of 20–34 years (adjusted HR: 7.67, 95% CI=1.94–30.3), whereas adjusted HR minimum was observed in the oldest age group (>65 years). Conclusion: Patients with RA have a significantly higher risk of developing COPD than that of the control population. Further, age-related risk analysis indicated much higher adjusted HR in younger patients although COPD incidence increased with age. It can be hypothesized that in addition to cigarette smoke, RA may be a determining factor for COPD incidence and/or facilitates shortening of the time course for developing COPD. However, further investigation is needed to corroborate this hypothesis.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]
Downloaded from by guest on February 12, 2015
Received 9 January 2014 and in revised form 22 January 2014
538
T.-C. Shen et al.
Introduction
Methods
Rheumatoid arthritis (RA) is a disease involving an inflammatory reaction of the immune system against body tissues, leading to joint destruction and physical disability. RA imposes substantial social costs, including an increased risk of work-related disability and accelerated mortality.1 It has been estimated that nearly 50% of RA patients will develop some form of respiratory abnormality during their lifetime.2 In fact, a study by Toyoshima et al.3 listed pulmonary disease as the second leading cause of death in RA patients, accounting for nearly 20% of their mortality. Although RA-associated interstitial lung disease remains the most debilitating and known complication, airway disorders may also play an important role in respiratory abnormality.4 Chronic obstructive pulmonary disease (COPD) is defined as a persistent and progressive airflow limitation, which is associated with an enhanced chronic inflammatory response in the airways and lungs due to noxious particles or gases. It is the fourth leading cause of death worldwide, with reported prevalence rates between 5% and 13%.5,6 Among the possible influencing factors, cigarette smoking is the most important one in the development of COPD. However, there remains a substantial group of COPD patients who have never smoked.7,8 Other contributing factors must therefore exist and one of them could be autoimmunity. The role of autoimmune pathology in the development and progression of COPD is becoming increasingly popular.9 It is known that smoking is a common environmental risk factor for both RA and COPD. However, the reason why patients with RA develop COPD cannot be solely attributed to cigarette smoke. RA may play an independent role in COPD incidence. Even smokers with RA could have a different time course for developing COPD as compared with nonRA individuals who are addicted to smoking. Some studies have concluded that majority of COPD patients have increased levels of serum antibodies to self-antigens,10–16 and appearance of antibodies to specific autoantigens correlates with disease severity.12–14,16 However, the mechanism of interaction between autoimmunity and COPD is still inconclusive. This study attempts to determine if there is a differential risk of COPD in adults with or without RA by examining a relatively large cohort in Taiwan. The results in this study were generated from a population-based retrospective cohort obtained from the National Health Insurance (NHI) system’s database.
Data sources The Bureau of National Health Insurance set up the Taiwan NHI program on 1 March 1995. The NHI program had covered over 99% of the 23.7 million population by the end of 2009.17,18 The National Health Research Institute is responsible for managing the claims data and established the Taiwan National Health Insurance Research Database (TNHIRD) for public use. We conducted a nationwide cohort study using the Taiwan National Health Institute Research Database (NHIRD). In this study, we used the inpatients dataset, catastrophic illness dataset and registry of beneficiaries, which were all part of NHIRD. These datasets were linked using the encrypted unique personal identification number to obtain longitudinal medical history of each individual. This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
Patients newly diagnosed with RA (ICD-9-CM 714) during 1998–2008 were eligible for enrollment in our study cohort. To ensure the diagnostic validity of new RA cases, we selected only those RA patients with first-ever issued catastrophic illness certificates. In Taiwan NHI system, the government defined RA as a ‘catastrophic illness’ and provided regulations for the affected insurants to apply for catastrophic illness certificates. Patients with catastrophic illness certificates get free care for their illness or related conditions within the validity period of their certificates. This means that patients need a clinical physician to confirm their illness before applying for a catastrophic illness certificate. We excluded patients who had missing data on date of birth and sex, or had pre-existing COPD (ICD-9-CM 491, 492 and 496). Thus, we listed 28 725 RA patients as study subjects defined as the RA cohort. For every RA patient, we randomly selected four non-RA patients from the same study period, used the same exclusion criteria and frequency-matched with the RA cohort for age, gender and index year to form the non-RA cohort with a total of 114 900 subjects.
Outcome measures The study patients were followed until they were diagnosed with COPD, which was identified based on the hospitalization records. The follow-up period was the period from the index date to the date of
Downloaded from by guest on February 12, 2015
Study subjects
Risk of COPD in rheumatoid arthritis
539
COPD diagnosis, withdrawal from the insurance system, death, or till the end of 2010.
Table 1 Demographic characteristics and comorbidity in patient with and without RA
Exposure variables
Variable
In addition to RA, demographic characteristics such as sex, age and comorbidities were analyzed. The baseline comorbidity histories of hypertension (ICD9 codes 401–405), diabetes (ICD-9 code 250), hyperlipidemia (ICD-9 code 272), coronary artery disease (CAD) (ICD-9 codes 410–414), cerebral vascular accident (CVA) (ICD-9 codes 430–438) and end-stage renal disease (ESRD) (ICD-9 code 585) were identified according to their diagnoses in the hospitalization records prior to the index date.
Statistical analysis
Results Demographic characteristics are shown in Table 1. Both cohorts had similar sex and age distribution. There were more female patients (78.0%) and elderly, aged 50 years or older (60.5%) in our study. The RA cohort was more likely to have hypertension, diabetes, hyperlipidemia and CAD than the non-RA cohort. With a mean follow-up time of about 5.15 years for both cohorts, the cumulative incidence of COPD was significantly higher in the RA patients (log-rank P < 0.001) than in the non-RA patients (Figure 1). The incidence densities and adjusted hazard ratio (AHR) between the RA and non-RA cohorts are shown in Table 2. The overall incidence of COPD was 74% higher in the RA cohort than in the non-RA cohort (5.25 vs. 3.01
P-value
No N = 114 900 Sex Female Male Age, mean(SD)a Age group 20-34 years 35-49 years 50-64 years 65+ years Comorbidity Hypertension Diabetes Hyperlipidemia CAD CVA ESRD
Yes N = 28 725
n 89 612 25 288 53.2
(%) n (78.0) 22 403 (22.0) 6322 (14.3) 53.8
(%) (78.0) (22.0) (13.9)
10 952 34 428 43 620 25 900
(9.53) 2738 (30.0) 8607 (38.0) 10 905 (22.5) 6475
(9.53) (30.0) (38.0) (22.5)
18 188 10 423 4653 7199 7126 1072
(15.8) (9.07) (4.05) (6.27) (6.20) (0.93)
(20.5)
