Increased Risks of Deep Vein
Thrombosis and
Pulmonary Embolism in Sjögren
Syndrome:
A Nationwide Cohort Study
Wei-Sheng Chung, Cheng-Li Lin, Fung-Chang Sung, Wu-Huei
Hsu, Yung-Fu Chen,
and Chia-Hung Kao
Sjogren syndrome (SS) is a systemic autoimmune disease that primarily affects the tear and saliva glands. The hallmark symptoms of SS are generalized dryness, which typically includes dry skin and dry eyes. However, the kidney, blood vessels, lungs, liver, pancreas, peripheral nervous system, and brain may also be affected by SS. Although SS occurs in men and women of all ages, most patients are postmenopausal women1.
A primary SS (pSS) diagnosis requires symptoms that meet 4 of the 6 American-European Consensus Group (AECG) criteria or 3 of the 4 objective diagnostic criteria. A diagnosis of secondary SS requires the presence of a well-defined major connective tissue disease, 1 subjective SS symptom, and symptoms meeting 2 of the 3 objective AECG diagnostic criteria for SS2.
Venous thromboembolism (VTE) includes deep vein
thrombosis (DVT) and pulmonary embolism (PE). A potentially fatal complication, VTE is a major health problem
worldwide3. Multiple acquired and genetic factors are associated with VTE. Traditional risk factors included pregnancy, oral contraceptives, hormone replacement therapy, immobilization, trauma, and specific genetic
cerebrovascular disease (CVA) are risk factors of VTE4,5,6. Diabetes, congestive heart failure, leg fractures, and major
surgery are also associated with an increased risk of VTE7,8,9,10,11. Many cancers have also been shown to correlate with VTE12,13.
Autoimmune disorders associated with inflammation might also increase the risk of VTE. Epidemiological
studies have shown that certain autoimmune diseases are associated with VTE14,15,16. Most studies on SS have focused on treatment and improving the quality of life of patients with SS17,18,19,20. However, relatively little information is available regarding the relationship between SS
and the development of DVT and PE, particularly among Asian patients with SS. We conducted a longitudinal
nationwide cohort study in Taiwan to investigate whether SS increases the risks of DVT and PE.
MATERIALS AND METHODS
Data sources. We conducted a retrospective, longitudinal study of a
nationwide, population-based cohort in Taiwan, using the National Health Institute Research Database (NHIRD). The NHIRD has been described in our previous studies16,21. The NHIRD consists of comprehensive
healthcare data that are representative of almost 100% of the 23.7 million residents of Taiwan22. The disease diagnoses used in the NHIRD were coded according to the criteria of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). A diagnosis of SS was defined according to AECG diagnostic criteria, and was confirmed through the Registry for Catastrophic Illness Patient Database (RCIPD), which is maintained by the Taiwan National Health Insurance (NHI) system. Our study was approved by the ethics review board at China Medical University (approval no. CMU-REC-101-012).
Participants. We identified 8920 patients with SS (ICD-9-CM code 710.2)
in the NHIRD and the RCIPD who were newly diagnosed between January 1, 2000, and December 31, 2008. Patients with a history of DVT
(ICD-9-CM 453.8) or noniatrogenic PE (ICD-9-CM 415.1, excluding ICD-9-CM 415.11) and those who lacked complete information in the NHIRD were excluded. The date of the diagnosis of SS was used as the index date. For each patient in our SS cohort, 4 controls without SS
on age category (5-year span), sex, and the year of the index date. Controls with a history of DVT or noniatrogenic PE were also excluded from the comparison cohort. A secondary SS was defined as a diagnosis of SS in patients with a previous diagnosis of rheumatoid arthritis (ICD-9-CM code 714), systemic lupus erythematosus (SLE; ICD-9-CM code 710.0), systemic sclerosis (ICD-9-CM code 701.1), or primary biliary cirrhosis (ICD-9-CM code 571.6).
Outcome measurement. The primary outcomes were newly diagnosed PE
or DVT from hospitalization records. All of the participants were followed from the index date to the date of a primary outcome, withdrawal from the NHI program, or the end of 2010, whichever came first. Nearly all patients with DVT or PE underwent a comprehensive examination before receiving intensive care. In Taiwan, DVT and PE patients’ medical reimbursements and discharge notes are scrutinized in a peer-review process.
Exposure variables. In addition to SS, the demographic characteristics such
as sex, age, and the comorbidities were analyzed. The pre-existing comorbidities included atrial fibrillation (ICD-9-CM 427.31), diabetes
(ICD-9-CM 250), CVA (ICD-9-CM 430–438), heart failure (ICD-9-CM 428), lower leg fracture or surgery (ICD-9-CM 820–823 and procedure codes 81.51, 81.52, 81.53, and 81.54, respectively), cancer (ICD-9-CM 140–208), and pregnancy (ICD-9-CM procedure 72–74 or ICD-9-CM code 640.x1-676.x1, 640.x2-676.x2, 650–659).
Statistical analysis. We compared the differences in demographic characteristics,
including age, sex, and the comorbidities, of the SS cohort with those of the comparison cohort, using a chi-squared analysis for the categorical variables and t tests for the continuous variables. The followup duration was estimated as the incidence density rate in both cohorts by using a Poisson regression model to estimate the incidence rate ratios (IRR) and 95% CI. A multivariate Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and 95% CI of the risks of DVT and PE in patients with SS, relative to those of the comparison cohort, after adjustments for age, sex, frequency of admission visits and comorbidities of atrial fibrillation, diabetes, CVA, heart failure, lower leg fracture or surgery, cancer, and pregnancy. We also estimated the interaction between comorbidity and SS on the development of PE or DVT by using the Cox model. Further analysis was performed to estimate the risks of DVT and PE among subgroups of SS. Cumulative incidence analyses were conducted using the Kaplan-Meier method, and the differences between the curves
were assessed using the log-rank test. Data management and analysis were performed using SAS, version 9.2 (SAS Institute). The cumulative
incidence curves were constructed using the R computer software (R Foundation for Statistical Computing). A 2-tailed p < 0.05 was considered statistically significant.
RESULTS
The SS cohort included 8920 patients, and the comparison cohort included 35,680 patients without SS (Table 1). Women comprised 88.9% of the SS and control patients. The mean ages of the SS and controls were 53.5 ± 14.4 years and 53.1 ± 14.6 years, respectively, and 59.6% of the
patients with SS were 50 years of age or older. Patients with SS had a higher prevalence of atrial fibrillation, heart
failure, cancer, and pregnancy than did the controls. The median followup period was 5.09 and 5.13 years for the SS and comparison cohorts, respectively. The overall incidence of DVT was 5.81 and 3.11 per 104 person-years for the SS and comparison cohorts, respectively (Table 2). The
cumulative DVT incidence curve for the SS cohort revealed a significantly higher incidence of DVT in the patients with SS, compared with those in the comparison cohort (log-rank p = 0.005).
After adjusting for age, sex, frequency of admission, and comorbidities, the patients with SS had an increased risk of DVT compared with the comparison cohort (adjusted HR 1.83, 95% CI 1.16–2.89). The sex-specific DVT incidence for patients with SS was highest among women (6.08 per 104 person-yrs). Compared to women in the comparison cohort, the women with SS had a greater relative risk of DVT (adjusted HR 2.03, 95% CI 1.26–3.28). The
age-specific relative risk of DVT was greatest among patients aged ≤ 65 years (adjusted HR 2.27; 95% CI 1.18–4.37). Among patients with no comorbidity, the incidence of DVT was 2.70 times greater in the SS cohort than in the comparison cohort (2.89 vs 0.82 per 104
person-yrs).
The incidence densities and the adjusted HR of PE in the SS and comparison cohorts are shown in Table 2. The
overall incidence of PE was 6.43 and 1.97 per 104 personyears in the SS and comparison cohorts, respectively. The
cumulative incidence of PE was significantly higher for the patients with SS (log-rank p < 0.001) than that for patients
without SS (Figure 1). Patients with SS had a 3.29-fold greater risk of PE (95% CI 2.03–5.31) than the controls did, after adjusting for age, sex, and the comorbidities. The sex-specific adjusted HR of PE was 5.76-fold higher for men in the SS cohort than for men in the comparison cohort (95% CI 1.74–19.2). The incidence of PE increased with increasing age in both cohorts. The effect of SS on the development of DVT or PE was greater in patients aged ≤
65 years (adjusted HR 4.22, 95% CI 1.95–9.13) than in patients aged ≥ 65 years (adjusted HR 2.66, 95% CI
1.43–4.97). The patients with SS without comorbidities had a greater risk of PE than the controls without comorbidities (adjusted HR: 4.51, 95% CI: 1.36–14.9).
Table 3 shows that, among the patients with SS and comorbidity, the risks of DVT (adjusted HR 3.66; 95% CI 2.61–8.33) and PE (adjusted HR 11.4; 95% CI 5.12–25.2) were significantly greater than those of the controls without a comorbidity. We observed that 8482 (95%) of the patients in the SS cohort were pSS, and 438 (5%) of the patients in the SS cohort were secondary SS. After adjusting for the covariates, the IRR and adjusted HR of DVT among the patients with a primary SS were significantly greater than those of the controls (adjusted HR 1.77; 95% CI 1.11-2.82). The risk of PE among patients with a pSS diagnosis was 3.21 times greater (95% CI 1.96-5.23) than that for the comparison cohort, whereas patients with a secondary SS diagnosis had a 5.06 times greater risk of PE than did the comparison cohort (95% CI 1.22-21.1).
DISCUSSION
Our study showed that the average annual incidence rate of SS in Taiwan was 4.3 per 100,000 persons in the population. Most of the patients with SS in our study were women with an age of onset > 50 years. These data are consistent with
had 1.83-fold and 3.29-fold greater
risks of developing DVT or PE, respectively, compared with people in the general population.
Ramagopalan, et al14 studied the patients with various immune-mediated diseases who were admitted to hospitals in England and showed that patients with SS had a 2.02-fold greater risk of VTE. However, Ramagopalan, et al14
estimated the risk of VTE without adjusting for comorbidities. Zoller, et al24 performed a large-scale study of the
relationship between PE and autoimmune diseases in Sweden, and determined that patients with a history of SS had a 2.19-fold greater risk of PE. However, Zoller, et al24
did not examine the difference in the risk of PE between patients with a pSS and those with a secondary SS. Our nationwide population-based cohort study in Taiwan revealed increased risks of DVT and PE among Asian patients with SS, compared with those in the general population, after adjusting for the potential covariates. Genetic and environmental factors might have contributed to the inconsistencies between our findings and those of other studies25,26.
Although the patients with SS in our study had a higher prevalence of comorbidities associated with DVT and PE than the comparison cohort did, SS remained an
independent risk factor for developing DVT and PE after adjusting for the covariates. The inflammatory response triggered by SS may drive arterial, venous, and microvascular thrombosis27,28. Cytokine induction of tissue factor
expression, endothelial dysfunction, the inhibition of the protein C system, and the inhibition of fibrinolysis are
central features of inflammation-induced hypercoagulability, and thus may contribute to the development of DVT
or PE28,29.
Most of our patients with SS were women, and both men and women with SS had a greater risk of PE, which is
consistent with the findings of previous studies24. The effect of SS on the development of DVT or PE was greater in
people age, they become less active, and their cardiopulmonary systems deteriorate. Thus, age-related changes in
blood hemostasis and coagulation in the deep veins of people ≥ 65 years of age might exert greater effects on the development of DVT than those related to SS3,30,31.
The incidence of both DVT and PE increased in patients with any comorbidity in both our SS and comparison cohorts. The multiplicative risks of DVT and PE were
significantly greater in patients with SS and any comorbidity. These results are significant using Cox proportional
hazards regression analysis for the increased risks of DVT and PE in SS with joint effect of any comorbidity (Table 3). The patients in our study who had pSS had 1.77-fold and 3.21-fold greater risks of DVT and PE, respectively,
compared with those for the comparison cohort (Table 4). In addition, patients with secondary SS had a greater risk of PE (adjusted HR 5.06; 95% CI 1.22-21.1) than patients with pSS (adjusted HR 3.21; 95% CI 1.96-5.23). Cervera, et al32
indicated that antiphospholipid antibodies are present in a lower proportion of patients with pSS than that of patients with secondary SS. Antiphospholipid antibodies are
associated with arterial and venous thrombosis33. Thromboembolic events are common in SLE, but not in pSS34.
Our study is the first, to our knowledge, to investigate the risks of DVT and PE in a cohort of Asian patients with SS. The strengths of our findings lie in the nationwide
population-based design of a longitudinal study and a followup period of about 50,000 person-years for our SS cohort. In addition, the diagnoses of all the patients with SS identified in the NHIRD were confirmed through their
inclusion in the RCIPD, which establishes a high level of reliability for our results. To avoid selection bias, we estimated the risks of DVT and PE only in patients newly diagnosed with SS who had no previous history of DVT and PE. Because each NHI beneficiary is assigned a unique personal identification number, every patient could be traced through the records of the NHIRD for the entire followup period. Thus, our findings can be generalized to
the entire population of Taiwan.
However, several limitations to the interpretation our findings should be considered. Hospitalized patients with
SS were enrolled in our study, which might have resulted in an overestimate of the risks of DVT and PE in our SS
cohort. Ramagopalan, et al14 suggested that people admitted to hospitals for autoimmune disorders may have an
increased risk of subsequent VTE. However, our comparison cohort also comprised inpatients and we
estimated the risk of SS on the development of DVT and PE, adjusting for comorbidities and frequency of hospitalization35. The SS cases based on AECG classification
criteria2, essentially a clinical diagnosis, may not be properly confirmed. The NHIRD does not provide family history of VTE and detailed lifestyle information such as smoking habits, body mass index, and physical activity, which are all potential confounding factors for our study. The lack of prescription drug data, such as that for hormone replacement therapy, contraceptive drugs, glucocorticosteroid treatments, and biological therapies, may also have
influenced the risk of DVT or PE among the patients in our SS cohort20,36. The lack of information regarding genetic factors [i.e., specific genetic deficiencies, such as Factor V Leiden (G 1691A), Factor II G20210A], and deficiencies of the natural anticoagulants (i.e., antithrombin, protein C, and protein S) in our study cohorts may become another
limitation.
Our nationwide population-based cohort study of 8920 patients with SS showed that patients with SS have a 1.83-fold greater risk of DVT and a 3.29-fold greater risk of PE, compared with the risks of DVT and PE among people in the general population. In addition, the multiplicative risks of DVT and PE were also significantly greater among patients with SS and a comorbidity. Therefore, providing adequate care for comorbidities is critical to the prevention of DVT and PE in patients with SS. Thus, a multidisciplinary team should guide the assessment, treatment, and
biological mechanisms of SS are warranted to determine its contribution to the development of DVT and PE.
