Sjögren syndrome (SS) is an autoimmune condition in which the immune system reacts abnormally and attacks healthy cells and tissue. The typical symptom in patients with SS is dryness, which mainly attacks the eyes and mouth. In addition to affecting the tear and saliva glands, the immune system also attacks other secretary glands in the body. More than 90% of patients with SS are women.1 The etiology of SS remains largely unknown, but it is likely triggered by a combination of genetic, environmental, and hormonal factors.2 When the syndrome develops without a known cause, it is defined as primary SS (pSS); when the syndrome develops in association with other autoimmune disorder such as lupus or rheumatoid arthritis, it is known as secondary SS.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory response in the airways and the lungs. Patients suffer from persistent airflow obstruction which is usually progressive. Spirometry is usually required to diagnose the disease in clinics. The postbronchodilator ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were generally measured. A FEV1 to FVC ratio of <0.70 was considered as having persistent airflow limitation.3 Cigarette smoking is a known risk factor in the development of COPD; however, a substantial number of COPD patients have never smoked.4,5 Other contributing factors must therefore exist, one of which could be autoimmunity. Indeed, studies have reported that autoimmune pathology plays a role in the development and progression of COPD.6–12
Among studies for the association between autoimmune diseases and COPD, some evidences suggest that SS has the pulmonary involvement.13–15 Mandl et al recently reported that pSS patients showed deterioration in FEV1 and in the ratio of FEV1 to FVC after a mean follow-up time of 11 years.16 In addition, they found that 37% of the pSS patients developed COPD during the follow-up. However, their study lacked a comparison group and included only a small number of cases; therefore, the relationship between pSS and COPD deserves more studies.
The National Health Insurance (NHI) database of Taiwan is a nationwide database with the longitudinal medical data of ∼23 million people. The claims data are reliable and have been used for various studies, including those on SS or COPD.17–20 The present study attempts to use the data to determine if there is a higher risk of COPD in adult women with pSS.
MATERIALS AND METHODS
Taiwan's NHI program has offered a universal health insurance coverage to >99% of all residents of Taiwan since 1995. Taiwan's National Health Research Institute (NHRI) has been responsible to manage the claims data and to establish the National Health Insurance Research Database (NHIRD) containing medical claims from 1996 to 2011 for public uses. To protect all individuals’ privacy, identifications of insured individuals had been encrypted before the data files were released. The NHIRD contains outpatient and inpatient information on demographic status, dates of cares, diagnostic codes, and details of prescriptions. The diseases were coded using the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) in the NHIRD. In the present study, the diagnosis of SS was defined according to the American-European Consensus Group diagnostic criteria21 and was confirmed by experts specialized in the disease field. This study was approved by the Research Ethic Review committee of China Medical University and Hospital (CMUH104-REC2-115).
We conducted a population-based retrospective cohort study with 2 cohorts: the pSS group and the non-SS group. Using the NHIRD, females newly diagnosed with SS (ICD9-CM 710.2) during 2000 to 2005 were identified (n = 4475) for the potential study cohort of pSS. Those with a secondary SS (n = 335) at the baseline were excluded. We further excluded patients <20 years of age (n = 39) and with the history of COPD (ICD-9-CM 491, 492, and 496) (n = 1088) from the pSS cohort. A secondary SS was defined as a diagnosis of SS in patients with a previous history of rheumatoid arthritis (ICD-9-CM 714), systemic lupus erythematosus (SLE; ICD-9-CM 710.0), systemic sclerosis (ICD-9-CM 701.1), or primary biliary cirrhosis (ICD-9-CM 571.6). The date with pSS diagnosed was defined as the index date. From the same period of 2000 to 2005, we randomly selected 4-fold of women without the history of SS and COPD from the NHIRD as the non-SS group, matched by the propensity score to increase their comparability between the 2 groups. Subjects <20 years of age were also excluded for the non-SS group. We used a logistic regression model, including year of index date, age, and comorbidities of hypertension, diabetes, hyperlipidemia, coronary artery disease (CAD), stroke and chronic kidney disease (CKD), to estimate the probability of assigning a women to the study cohorts.
Covariates and Outcome
The medical records of comorbidities were obtained before the index date; these comorbidities included hypertension (ICD-9-CM 401–405), diabetes (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272), CAD (ICD-9-CM 410–414), stroke (ICD-9-CM 430–438), and CKD (ICD-9-CM 585). The primary outcome was COPD, which was determined by linking outpatient and/or inpatient care data from the NHIRD. To increase the validity of COPD diagnoses, we included only those patients who had been diagnosed with COPD and treated with relevant medication. Both groups were followed from the index date to the date of COPD diagnosis, withdrawal from the NHI system, or the end of 2011.
Data were expressed as frequencies and percentages for categorical data and as means and standard deviations (SD) calculated for continuous variables. We compared the distributions of age and comorbidity between the pSS group and the non-SS group. The standardized mean difference (SMD) was calculated by the pooled value to determine whether the difference between the 2 group significant. A value of 0.1 or less was considered as a negligible difference between 2 groups.22 Incidence density rates of COPD were calculated for both groups (per 1000 person-years) stratified by age and comorbidity. The Kaplan–Meier method was used to plot the cumulative incidences of COPD during the follow-up period, and the log-rank test was used to assess the differences between the survival curves. Univariate and multivariate Cox proportion hazards regression models were used to examine the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident COPD and COPD-associated risk factors. HRs between age groups and between groups with and without comorbidity were calculated. We also performed age- and comorbidity-specific stratified analyses to measure the pSS group to the non-SS group HRs of developing COPD. All analyses were performed using SAS software version 9.4 (SAS Institute, Inc., Cary, NC), and a 2-sided P < 0.05 was considered statistically significant.
The pSS group consisted of 3013 female adults diagnosed with pSS from 2000 to 2005, and the non-SS group comprised 12,052 women without SS. Table 1 compares the distributions of age and comorbidities between the pSS and non-SS groups. There were no significant differences between the pSS group and non-SS group in the distributions of age and comorbidity.
Figure 1 shows that the cumulative incidence of COPD was significantly higher in the pSS group than in the non-SS group during the follow-up period (P < 0.001) in the log-rank test. After an average follow-up period of 7.99 years, the incidence density rate of COPD was greater in the pSS group than in the non-SS groups (3.87 vs 2.77 per 1000 person-years, respectively) (Table 2). Women with pSS had an aHR of 1.39 to develop COPD (95% CI = 1.10–1.75, P = 0.007) compared with those without SS after adjusting for age and comorbidities. The risk of developing COPD appears to increase with age. Individuals aged >50 had an aHR of 4.24 (95% CI = 3.06–5.88, P < 0.001) compared with individuals aged 20 to 49. The incidence of COPD was higher for individuals with hypertension (HR = 2.12, 95% CI = 1.65–2.72, P < 0.001) and CAD (HR = 1.50, 95% CI = 1.18–1.91, P = 0.001).
Table 3 shows incidences and hazard ratios of COPD for the pSS group compared with non-SS group by age and comorbidities. The impact of pSS on developing COPD was greater for younger pSS subgroup (aged 20–49 years) than for older pSS subgroup (aged ≥ 50 years) and slightly greater for pSS subjects without comorbidity than for those with comorbidities. The hazards of COPD for the pSS group compared with non-SS group were also significant for individuals with hyperlipidemia (aHR = 1.66, 95 % CI = 1.13–2.45, P = 0.01), hypertension (aHR = 1.56, 95% CI = 1.12–2.16, P = 0.008), and CAD (aHR = 1.52, 95% CI = 1.01–2.30, P = 0.04).
However, Table 4 shows that the risk of COPD had a stronger association with comorbidity than with pSS. Women with both pSS and comorbidity had an aHR of 3.11 (95% CI = 2.23–4.33, P < 0.001) for COPD, compared with those free of both pSS and comorbidity.
To the best of our knowledge, this is the first nationwide population-based cohort study evaluating patients with pSS for their subsequent risk of developing COPD. The study demonstrates that female adults with pSS have an increased risk of developing COPD, compared with female adults without SS. Furthermore, we found that incidence of COPD was substantially higher in older people (aged ≥ 50 years) in both the pSS and non-SS groups. However, the aHR of COPD for the pSS group compared with non-SS group was greater in younger patients (aged 20–49 years) than in the older patients (aged ≥ 50 years), indicating that SS alone has a greater impact for younger patients to develop COPD, whereas the overall hazard was greater for older women. A possible explanation for this might be that older people, whether affected by pSS or not, tend to have prolonged and sufficient exposure to risk factors and be affected by more comorbid diseases than younger people, and these are risk factors of COPD. Another possibility is that using a fixed ratio (FEV1/FVC = 70%) to define obstructive ventilation defeat often causes an overestimation of COPD prevalence in the elderly population.
Several hypotheses can be postulated on the relationship between SS and COPD. Mandl et al have suggested that the inflammation of exocrine glands and mucosal dryness in the airways, dysfunction of mucociliary clearance, and interaction between sicca and smoking may increase the risk of developing COPD.16 In addition, some other theories support autoimmune pathogenesis of COPD.23,24 Consistent with the results of the present study, Hemminki et al reported that the risk of COPD increased in patients with several autoimmune diseases, including SS with an observed to expected incidence ratio of 1.89 (95 % CI = 1.12–2.99).25
Tobacco smoking may be the most important potential confounding factor in the present study because the NHIRD does not contain data on personal smoking habits. However, Karabulut et al reported a weak association between cigarette smoking and the development of pSS.26 In addition, most studies reported no significant difference in smoking between pSS patients and controls27–29 or even significantly fewer smokers in SS patient groups.30,31 Therefore, patients with SS do not necessarily have a significantly higher smoking rate than those without SS.
In the present study, we also evaluated the risk of COPD in association with several cardiovascular-related diseases. We found that HRs of COPD were significant for hypertension, diabetes, hyperlipidemia, CAD, and stroke in our univariate analysis. But the HRs of COPD remained significant only for hypertension and CAD in the multivariate analysis. These data are valuable for further studies because the incidence of COPD has risen in women in recent years.32
The strength of this study comes from providing a longitudinal population-based evaluation of pSS patients and their risk of developing COPD. It is generally costly to conduct a population-based prospective cohort study. On the other hand, a retrospective cohort study, using the existing data, is a suitable alternative that is economical and meets the necessary follow-up requirements. However, several limitations of the study must be considered when interpreting the study findings. First, this study used the ICD-9-CM algorithm to define SS, COPD, and comorbidities. The diagnosis depends on the performance of clinical physicians. However, an ad hoc committee established by the insurance authority has been responsible to monitor the claims data to prevent errors and violations. In addition, SS is categorized as a “catastrophic illness” in the insurance system and patients diagnosed with SS are entitled to receive the “catastrophic illness certification” issued by the insurance authority. The certification process requires the confirmation from experts specialized in the disease field based on medical records including serological and/or pathological evidences. The diagnosis of SS is likely correct, regardless that data of pathological reports were unavailable in the claims data. Second, the NHIRD does not provide detailed information on socioeconomic status, environmental factors, smoking habits, alcohol consumption, diet preference, or family history, but these are all potential confounding factors for this study. In addition, this study followed the 2 study cohorts for 6 to 11 years, which might be not long enough to observe the development of all COPD cases, particularly our study groups were relatively young. Therefore, we might underestimate the risk of COPD for patients with SS.
Our study suggests that women with pSS apparently have a greater risk of developing COPD than women without SS. This finding may lead to develop monitor strategy for patients with SS more emphasis on COPD screening, particularly for SS patients with comorbidity.
1. Jonsson R, Vogelsang P, Volchenkov R, et al. The complexity of Sjögren's syndrome: novel aspects on pathogenesis. Immunol Lett
2. Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome. Nat Rev Rheumatol
3. Global strategy for diagnosis, management, and prevention of COPD. December 2015. http://www.goldcopd.org
4. Birring SS, Brightling CE, Bradding P, et al. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med
5. Hagstad S, Ekerljung L, Lindberg A, et al. COPD among non-smokers—report from the obstructive lung disease in Northern Sweden (OLIN) studies. Respir Med
6. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, et al. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
7. Karayama M, Inui N, Suda T, et al. Antiendothelial cell antibodies in patients with COPD. Chest
8. Núñez B, Sauleda J, Antó JM, et al. Anti-tissue antibodies are related to lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
9. Packard TA, Li QZ, Cosgrove GP, et al. COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype. Immunol Res
10. Shen TC, Lin CL, Chen CH, et al. Increased risk of chronic obstructive pulmonary disease in patients with systemic lupus erythematosus: a population-based cohort study. PLoS One
11. Bieber V, Cohen AD, Freud T, et al. Autoimmune smoke and fire—coexisting rheumatoid arthritis and chronic obstructive pulmonary disease: a cross-sectional analysis. Immunol Res
12. Shen TC, Lin CL, Chen CH, et al. Increased risk of chronic obstructive pulmonary disease in patients with rheumatoid arthritis: a population-based cohort study. QJM
13. Hatron PY, Tillie-Leblond I, Launay D, et al. Pulmonary manifestations of Sjogren's syndrome. Presse Med
14. Soto-Cardenas MJ, Perez-De-Lis M, Bove A, et al. Bronchiectasis in primary Sjögren's syndrome: prevalence and clinical significance. Clin Exp Rheumatol
15. Papiris SA, Maniati M, Constantopoulos SH, et al. Lung involvement in primary Sjögren's syndrome is mainly related to the small airway disease. Ann Rheum Dis
16. Mandl T, Diaz S, Ekberg O, et al. Frequent development of chronic obstructive pulmonary disease in primary SS—results of a longitudinal follow-up. Rheumatology
17. Lu MC, Jheng CH, Tsai TY, et al. Increased dental visits in patients prior to diagnosis of primary Sjögren's syndrome: a population-based study in Taiwan. Rheumatol Int
18. Chung WS, Lin CL, Sung FC, et al. Increased risks of deep vein thrombosis and pulmonary embolism in Sjögren syndrome: a nationwide cohort study. J Rheumatol
19. Chiang YY, Lin HW. Association between psoriasis and chronic obstructive pulmonary disease: a population-based study in Taiwan. J Eur Acad Dermatol Venereol
20. Hsu JH, Chien IC, Lin CH, et al. Increased risk of chronic obstructive pulmonary disease in patients with schizophrenia: a population-based study. Psychosomatics
21. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis
22. Mamdani M, Sykora K, Li P, et al. Reader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding. BMJ
23. Shabana MM, Mohameda SA, Kamelb MA. Role of autoimmunity in the pathogenesis of chronic obstructive pulmonary disease. Egypt J Chest Dis Tuberc
24. Tzouvelekis A, Kostikas K, Bouros D. Autoimmunity and chronic obstructive pulmonary disease: thinking beyond cigarette smoke. Am J Respir Crit Care Med
25. Hemminki K, Liu X, Ji J, et al. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur Respir J
26. Karabulut G, Kitapcioglu G, Inal V, et al. Cigarette smoking in primary Sjogren's syndrome: positive association only with ANA positivity. Mod Rheumatol
27. Gravani F, Papadaki I, Antypa E, et al. Subclinical atherosclerosis and impaired bone health in patients with primary Sjogren's syndrome: prevalence, clinical and laboratory associations. Arthritis Res Ther
28. Schein OD, Hochberg MC, Muñoz B, et al. Dry eye and dry mouth in the elderly: a population-based assessment. Arch Intern Med
29. Priori R, Medda E, Conti F, et al. Risk factors for Sjögren's syndrome: a case-control study. Clin Exp Rheumatol
30. Pérez-De-Lis M, Akasbi M, Sisó A, et al. Cardiovascular risk factors in primary Sjögren's syndrome: a case-control study in 624 patients. Lupus
31. Bartoloni E, Baldini C, Schillaci G, et al. Cardiovascular disease risk burden in primary Sjögren's syndrome: results of a population-based multicentre cohort study. J Intern Med
32. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet