Journal of Thrombosis and Haemostasis, 12: 452–458 DOI: 10.1111/jth.

12518

ORIGINAL ARTICLE

Systemic lupus erythematosus increases the risks of deep vein

thrombosis and pulmonary embolism: a nationwide cohort
study
W . - S . C H U N G , * C . - L . L I N , † S . - N . C H A N G , ‡ C . - C . L U * and C . - H . K A O § ¶
*Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare; †Management Office for Health Data, China Medical
University Hospital; ‡Department of Medical Research, Taichung Veterans General Hospital; §Graduate Institute of Clinical Medicine Science
and School of Medicine, College of Medicine, China Medical University; and ¶Department of Nuclear Medicine and PET Center, China
Medical University Hospital, Taichung, Taiwan

To cite this article: Chung WS, Lin CL, Chang SN, Lu CC, Kao CH. Systemic lupus erythematosus increases the risks of deep vein thrombosis
and pulmonary embolism: a nationwide cohort study. J Thromb Haemost 2014; 12: 452–8.

risks of DVT and PE are significantly higher in SLE

Summary. Background: Studies on the risks of deep vein
thrombosis (DVT) and pulmonary embolism (PE) in
patients with systemic lupus erythematosus (SLE) are lim-
ited. We evaluated the effects of SLE on the risks of
developing DVT and PE in a nationwide, population-
based cohort study in Taiwan. Methods: We randomly
selected patients without SLE from the National Health
Insurance database (N = 23.74 million), and frequency-
matched four of them, on the basis of age, sex, and index
year, to each SLE patient in the catastrophic illness regis-
try of the NHI who was diagnosed with SLE between
1998 and 2008. Using a follow-up period ending in 2010,
we analyzed the risks of DVT and PE with a Cox propor-
tional-hazards regression analysis. Results: The 13 084
SLE patients (87.9% women; mean age of 35.6 years)
and 52 336 controls were followed for 90 237 and
379 185 person-years, respectively. After adjustment for
age, sex, and comorbidities, the SLE patients’ risks of
developing DVT and PE were 12.8-fold and 19.7-fold
higher, respectively, than those of the comparison cohort.
The risks of DVT and PE increased in both study groups
when the data were stratified on the basis of sex, age, and
comorbidities. The SLE patients aged ≤ 35 years had the
highest risks of developing DVT and PE. The multiplica-
tive increased risks of DVT and PE were also significant
in SLE patients with any comorbidity. Conclusion: The
Correspondence: Chia-Hung Kao, Graduate Institute of Clinical
Medicine Science and School of Medicine, College of Medicine,
China Medical University, Taichung, Taiwan, No. 2, Yuh-Der
Road, Taichung 404, Taiwan.
Tel.: +886 4 22052121 ext. 7412; fax: +886 4 22336174.
E-mail: d10040@mail.cmuh.org.tw
Received 10 November 2013
Manuscript handled by: F. R. Rosendaal
Final decision: F. R. Rosendaal, 22 January 2014
patients than in the general population.
Keywords: comorbidity; deep vein thrombosis; pulmonary
embolism; risk; systemic lupus erythematosus.
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoim-
mune, multiorgan inflammatory disorder that primarily
affects young women, but as many as 20% of SLE
patients are ≥ 50 years. Affecting nearly every organ sys-
tem in the body, SLE symptoms vary widely in severity,
from mild to progressively more serious symptoms that
can result in fatal complications. The average annual inci-
dence and average prevalence of SLE in Taiwan were
4.87 and 97.5 per 100 000 persons, respectively, between
2003 and 2008 [1].
Deep vein thrombosis (DVT) and pulmonary embolism
(PE) are manifestations of potentially lethal venous
thromboembolism (VTE). Patients affected by DVT most
often present with swelling, discoloration and discomfort
of the affected leg. Clinicians can diagnose DVT by using
non-invasive venous ultrasound, venography, magnetic
resonance imaging (MRI), or pathology of the thrombus
following its removal during surgery. With concomitant
PE, DVT can be a dangerous condition [2]. Patients with
PE may present with hypoxemia and/or dyspnea, chest
pain, and anxiety or nervousness. The diagnosis of PE
can be made on the basis of the results of the D-dimer
blood test, lung scan, spiral computed tomography scan,
pulmonary angiography, MRI, or pathology of the
thrombus following its removal during surgery [3].
According to the Virchow triad, VTE results from
altered blood coagulation, stasis, or abnormalities in the
vessel wall [4,5]. Hypercoagulable states and endothelial

© 2014 International Society on Thrombosis and Haemostasis


dysfunction may result from multiple interactions between
inherited and acquired risk factors. Several studies have
identified age, immobilization following cerebrovascular
accidents (CVAs), heart failure, lower leg fracture, surgery,
diabetes and cancer as acquired risk factors for VTE
[6–13]. Some studies have indicated that autoimmune
disorders, such as inflammatory bowel disease [14], rheu-
matoid arthritis [15], and Wegener granulomatosis [16], are
associated with an increased risk of VTE. Inflammation is
a common feature of the autoimmune diseases, and may
drive arterial, venous and microvascular thrombosis [17].
Mok et al. [18] found an 11.9-fold higher risk of VTE
in SLE patients than in the general population. Weng
et al. [19] reported a 0.8% incidence of pulmonary infarc-
tion in patients with SLE. However, the generalizability
of these findings of Mok et al. and Weng et al. is limited,
because of the relatively small samples used in their stud-
ies. Avi~na-Zubieta et al. [20] demonstrated increased risks
of DVT and PE in a population-based SLE cohort in
Canada. Therefore, we investigated whether the risks of
DVT and PE are higher among SLE patients in a nation-
wide, population-based cohort in Taiwan.
Methods
Data sources
The National Health Insurance (NHI) program was initi-
ated in 1995, and covers ~ 99% of the population of
Taiwan (23.74 million people) [21]. The NHI reimburses
patients for the costs of outpatient, inpatient, emergency
and traditional Chinese medical services, including the
costs of prescription medications. We used the longitudinal
health insurance database (LHID) of the NHI, which is
managed and released for research purposes by the
National Health Research Institute. The hospitalization
data obtained from the LHID contained information
regarding sex, date of birth, encrypted patient identification
numbers, dates of admission and discharge, discharge diag-
noses (up to five), surgical procedures (up to five), and dis-
charge status. The diagnoses and procedures recorded in
the LHID are coded according to the criteria of the Inter-
national Classification of Disease, Ninth Revision, Clinical
Modification (ICD-9-CM). We ensured that all data were
deidentified and analyzed anonymously. In addition, this
study was also approved by the Ethics Review Board of
China Medical University (CMU-REC-101-012).
Study participants
Patients newly diagnosed with SLE (ICD-9-CM 710.0)
between 1998 and 2008 were eligible for enrollment in
our study. To ensure the reliability of SLE cases, we
selected only newly diagnosed SLE patients (n = 13 319)
from the Registry for Catastrophic Illness Patient Data-
base (RCIPD). In the NHI system, SLE patients receive a
© 2014 International Society on Thrombosis and Haemostasis
SLE increase risks of DVT and PE 453
catastrophic illness certificate and are exempt from copay-
ment for their SLE-related medical care. The SLE
patients with missing data regarding date of birth or sex
(n = 36) and those with a history of DVT (ICD-9-
CM 453.8) or PE (ICD-9-CM 415.1) (n = 199) before the
index date were excluded from our study. For each SLE
patient, four controls without SLE during the study per-
iod were frequency-matched to each of the SLE patients
on the basis of age, sex, and the index year, to serve as
the comparison cohort. The same exclusion criteria were
applied to non-SLE controls.
Diagnostic criteria for SLE
The currently accepted diagnostic criteria for SLE were
established in 1971, revised in 1982, and updated to the
classification of SLE by the American College of Rheuma-
tology in 1997 [22], and include the following 11 criteria:
malar rash; discoid rash; photosensitivity; oral ulcers; non-
erosive arthritis; pleuritis or pericarditis; renal disorder,
persistent proteinuria, or cellular casts in the urine; neuro-
logic disorder, seizures, or psychosis; hematologic disorder,
including hemolytic anemia, leukopenia, lymphopenia, or
thrombocytopenia; the production of anti-nuclear anti-
body (Ab); and other immunologic disorders, including the
production of anti-DNA, anti-Smith or anti-phospholipid
Abs (Table S1). A person can receive a diagnosis of SLE if
four or more of the 11 criteria are observed in series or
simultaneously during any period of observation. In Tai-
wan, patients who receive a diagnosis of SLE on the basis
of these criteria can receive a catastrophic illness certificate
from the Bureau of National Health Insurance.
Outcome measurement and comorbidities
The primary outcomes were newly diagnosed DVT or PE
from hospitalization records. All of the patients were fol-
lowed from the index date to the date of a primary out-
come, 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. The pre-existing
comorbidities included atrial fibrillation (ICD-9-CM
427.31), hypertension (ICD-9-CM 401–405), diabetes
(ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272), 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), and can-
cer (ICD-9-CM 140–208).
Statistical analysis
We compared the distributions of the baseline characteris-
tics between the SLE and comparison cohorts by using a
454 W.-S. Chung et al

chi-square test. The incidence rate ratios (IRRs) and 95% of atrial fibrillation (0.52 vs. 0.15%, P < 0.0001),
confidence intervals (CIs) for DVT and PE were esti- hypertension (7.59 vs. 2.31%, P < 0.0001), diabetes (2.15
mated for each study group. The IRR was determined on vs. 1.49%, P < 0.0001), hyperlipidemia (2.13 vs. 0.70%,
the basis of the Poisson assumption. To estimate the P < 0.0001), CVA (2.45 vs. 0.90%, P < 0.0001), heart
cumulative incidence of DVT and PE risks, we performed failure (1.88 vs. 0.30%, P < 0.0001) and cancer (1.00 vs.
a survival analysis of both cohorts by using the Kaplan– 0.65%, P < 0.0001) than did the comparison cohort.
Meier method, and the significance of the results was
assessed with the log-rank test. Multivariate Cox propor-
Comparison of the risks of DVT and PE stratified by sex,
tional-hazards regression models were used to calculate
age, and comorbidity
the hazard ratios (HRs), with stratification based on age,
sex, the presence of comorbidity, and follow-up duration. For DVT, the median follow-up for the SLE cohort was
All statistical analyses were performed with SAS Ver- 6.92 years, and that for comparison cohort was
sion 9.2 (SAS Institute, Cary, NC, USA). A P-value of 7.29 years. In total, 136 SLE patients were diagnosed with
< 0.05 was considered to indicate a statistically significant DVT, yielding an incidence of 15.1 per 10 000 person-
result. years, whereas 43 cases of DVT occurred in the compari-
son cohort, yielding an incidence of 1.13 per 10 000
person-years (Table 2). The IRR for DVT in the SLE
Results
cohort was 13.3 (95% CI 12.5–14.2), and the adjusted HR
for DVT was 12.8 (95% CI 9.06–32.8), indicating that the
Demographic characteristics and comorbidities
SLE patients were at increased risk of DVT. The highest
A total of 13 084 SLE patients and 52 336 controls with- HRs were observed for women with SLE (adjusted
out SLE were enrolled in our study. The mean ages of HR 14.9, 95% CI 10.0–22.3) and the SLE patients aged
the comparison and SLE cohorts were 35.4  16.4 years ≤ 35 years (adjusted HR 52.8, 95% CI 23.0–121.3). The
and 35.6  16.1 years, respectively, and 54.1% of the SLE patients without comorbidity had a 14.9-fold higher
patients were ≤ 35 years of age (Table 1). Females risk of DVT than the patients in the comparison cohort
accounted for 87.9% of the patients. Table 1 presents a (adjusted HR 14.9, 95% CI 10.2–21.8).
summary of the baseline comorbidities of the SLE and Table 2 also shows the PE incidence densities and the
comparison cohorts. The SLE cohort included more cases adjusted HR for PE in the SLE and comparison cohorts.
For PE, the median follow-up for the SLE cohort was
6.96 years, and that for the comparison cohort was
7.29 years. PE occurred more frequently in the SLE
Table 1 Demographic characteristics and comorbidity between sys-
patients than in the controls (10.2 vs. 0.47 per 10 000 per-
temic lupus erythematosus (SLE) patients and controls
son-years), with an IRR of 21.4 (95% CI 19.9–23.1) and
SLE an adjusted HR of 19.7 (95% CI 11.9–32.8). In addition,
the highest adjusted HRs were observed for women with
No Yes
Variable N = 52 336 N = 13 084 P-value SLE (adjusted HR 21.2, 95% CI 12.2–36.9) and the
SLE patients aged ≤ 35 years (adjusted HR 71.5,
Sex, n (%) 95% CI 22.3–228.9). The SLE patients without comor-
Female 46 012 (87.9) 11 503 (87.9) 0.99
bidity had a 26.9-fold higher risk of PE than the controls
Male 6324 (12.1) 1581 (12.1)
Age (years), 35.4 (16.4) 35.6 (16.1) 0.28 (adjusted HR 26.9, 95% CI 14.6–49.5). Figure 1 shows
mean (SD)* the results of the comparison of the cumulative incidence
Stratification by age (years), n (%) rates of DVT and PE between the SLE and comparison
≤ 35 28 336 (54.1) 7084 (54.1) 0.99 cohorts. The incidence rates of DVT (Fig. 1A) and PE
35–50 14 604 (27.9) 3651 (27.9)
(Fig. 1B) were significantly higher in the SLE patients
50–65 6176 (11.8) 1544 (11.8)
≥ 65 3220 (6.15) 805 (6.15) than in the comparison cohort (P < 0.001 for both; log-
Comorbidity, n (%) rank test).
Atrial fibrillation 78 (0.15) 68 (0.52) < 0.0001
Hypertension 1210 (2.31) 993 (7.59) < 0.0001
Diabetes 781 (1.49) 281 (2.15) < 0.0001 The effect of the interaction between comorbidity and SLE
Hyperlipidemia 364 (0.70) 279 (2.13) < 0.0001 on the risks of DVT and PE development
CVA 473 (0.90) 320 (2.45) < 0.0001
Heart failure 157 (0.30) 246 (1.88) < 0.0001 Table 3 shows that the SLE patients with comorbidity
Lower leg fracture or 379 (0.72) 107 (0.82) 0.26 had a significantly higher risk of DVT (adjusted HR 22.1,
surgery 95% CI 13.0–37.6) than the comparison cohort with com-
Cancer 339 (0.65) 131 (1.00) < 0.0001
orbidity (adjusted HR 4.4, 95% CI 1.98–9.78) or without
CVA, cerebrovascular accident; SD, standard deviation. Chi-square comorbidity (reference). The risk of PE was also signifi-
test. *Two-sample t-test. cantly higher among the SLE patients with comorbidity

© 2014 International Society on Thrombosis and Haemostasis

 SLE increase risks of DVT and PE 455

Table 2 Comparison of deep vein thrombosis (DVT) and pulmonary embolism (PE) development stratified by sex, age and comorbidity
between systemic lupus erythematosus (SLE) patients and controls

SLE

No Yes
Adjusted HR
Variables Event PY Rate* Event PY Rate* IRR (95% CI) (95% CI)†

DVT 43 379 185 1.13 136 90 237 15.1 13.3 (12.5–14.2) 12.8 (9.06–18.1)
Sex
Female 31 335 032 0.93 117 80 203 14.6 15.8 (14.7–16.9 14.9 (10.0–22.3)
Male 12 44 153 2.72 19 10 035 18.9 6.97 (5.91–8.21) 7.21 (3.47–15.0)
Stratification by age (years)
≤ 35 6 205 530 0.29 82 50 938 16.1 55.1 (47.8–63.6) 52.8 (23.0–121.3)
35–50 9 109 639 0.82 34 25 882 13.1 16.0 (14.1–18.2) 13.9 (6.60–29.4)
50–65 14 44 645 3.14 12 9821 12.2 3.90 (3.32–4.57) 3.56 (1.62–7.85)
≥ 65 14 19 371 7.23 8 3596 22.3 3.08 (2.45–3.86) 2.97 (1.23–7.20)
Comorbidity‡
No 35 365 835 0.96 112 80 806 13.9 14.5 (13.6–15.5) 14.9 (10.2–21.8)
Yes 8 13 350 5.99 24 9431 25.5 4.25 (3.34–5.40) 4.15 (1.79–9.62)
PE 18 379 268 0.47 92 90 410 10.2 21.4 (19.9–23.1) 19.7 (11.9–32.8)
Sex
Female 15 335 086 0.45 83 80 356 10.3 23.1 (21.2–25.1) 21.2 (12.2–36.9)
Male 3 44 182 0.68 9 10 054 8.95 13.2 (10.8–16.0) 12.2 (3.25–46.1)
Stratification by age (years)
≤ 35 3 205 543 0.15 58 51 056 11.4 77.8 (65.6–92.4) 71.5 (22.3–228.9)
35–50 6 109 642 0.55 24 25 919 9.26 16.9 (14.8–19.4) 14.8 (5.97–36.4)
50–65 2 44 678 0.45 5 9843 5.08 11.3 (9.35–13.8) 7.48 (1.38–40.5)
≥ 65 7 19 406 3.61 5 3591 13.9 3.86 (3.11–4.78) 3.81 (1.15–12.7)
Comorbidity‡
No 12 365 910 0.33 71 80 965 8.77 26.7 (24.6–29.1) 26.9 (14.6–49.5)
Yes 6 13 358 4.49 21 9444 22.2 4.95 (3.86–6.35) 4.34 (1.67–11.3)

CI, confidence interval; HR, hazard ratio; IRR, incidence rate ratio; PY, person-years. *Rate: incidence rate per 10 000 person-years.
†Adjusted HR: multivariable analysis including age, sex, and comorbidity. ‡Comorbidity: one of the comorbidities used to classify the
comorbidity group.

(adjusted HR 66.3, 95% CI 32.2–136.3) than in the
comparison cohort with comorbidity (adjusted HR 13.4,
95% CI 4.81–37.3) or without comorbidity (reference).
Trends of DVT and PE event risk stratified by follow-up
years
Table 4 shows the results of the comparison of the risks
of DVT and PE stratified according to follow-up dura-
tion. During the first year of follow-up, the adjusted HRs
for DVT and PE were 66.7 (95% CI 16.0–278.7) and 91.5
(95% CI 12.3–677.4), respectively. However, the adjusted
HRs for DVT and PE decreased to 5.76 (95% CI 2.68–
12.3) and 6.66 (95% CI 2.15–20.6), respectively, for
patients who were followed up for > 8 years.
Discussion
The average prevalence of SLE was 97.5 per 100 000 per-
sons in Taiwan in 2003–2008 [1], which is higher than the
prevalence rates of 20 and 45 per 100 000 reported in the
USA and Canada, respectively [23–25]. Our results show
that the SLE patients had a 12.8-fold higher adjusted HR
for DVT and a 19.7-fold higher adjusted HR for PE than
the general population in Taiwan. Avi~ na-Zubieta et al.
[20] reported that, in Canada, SLE patients had relative
risks of 4.1 for DVT and 4.6 for PE, as compared with
the general population, after adjustment for covariates.
Although the underlying cause of the risk disparities
remains unclear, it might be associated with racial differ-
ences and environmental factors [26,27]. The fact that the
patients in our study had been admitted to the hospitals
might indicate more severe cases, in which SLE with
acute illness and high disease activity may have a higher
risk of thrombosis than that in patients with mild disease
activity.
In Taiwan, the incidence and prevalence of SLE
patients presenting with anti-phospholipid syndrome
(APS) are high [19,28]. The APS is an Ab-mediated pro-
thrombotic disorder associated with blood clots in both
arteries and veins [29]. However, APS alone cannot
explain the increased thrombotic risk in SLE. Chronic
inflammation and other contributing thrombovascular
risk factors also play vital roles in subsequent DVT and
PE development. Inflammation modulates thrombotic
responses by upregulating the activity of procoagulants,
downregulating that of anticoagulants, and suppressing
fibrinolysis [17]. Because of periodic episodes of inflam-

© 2014 International Society on Thrombosis and Haemostasis

456 W.-S. Chung et al

Table 3 Cox proportional-hazards regression analysis for the risks of

0.020
A
systemic lupus erythematosus (SLE)-associated deep vein thrombosis
Cumulative incidence with deep vein thrombosis

(DVT) and pulmonary embolism (PE) with interaction of comorbidity

Without systematic lupus Event Adjusted HR

0.015

erythematosus SLE Comorbidity N n (95% CI)† P-value*

With systematic lupus
DVT 0.007
erythematosus
No No 49 959 35 1 (Reference)
Log-rank Test : P-value < 0.001 No Yes 2377 8 4.40 (1.98–9.78)
0.010

Yes No 11 313 112 14.8 (10.1–21.6)

Yes Yes 1771 24 22.1 (13.0–37.6)
PE 0.003
No No 49 959 12 1 (Reference)
No Yes 2377 6 13.4 (4.81–37.3)
0.005

Yes No 11 313 71 26.6 (14.5–49.1)

Yes Yes 1771 21 66.3 (32.2–136.3)

CI, confidence interval; HR, hazard ratio. *P-value for interaction.

†Adjusted HR: adjusted for age and sex.
0.000

0 2 4 6 8 10 12
Time to deep vein thrombosis (years) The risks of DVT and PE increased in both men and
women with SLE when age and comorbidities were con-
0.020

B trolled for. Furthermore, the SLE patients had higher

Cumulative incidence with pulmonary embolism

risks of DVT and PE than did the comparison cohort,

regardless of age, after adjustment for the covariates.
However, the incidence of SLE was especially high in
0.015

Without systematic lupus

erythematosus
women aged ≤ 35 years, and the younger SLE patients
With systematic lupus had the highest risk of DVT and PE. Thus, clinicians
erythematosus should be especially vigilant regarding the treatment of
younger women with SLE. Aspirin and antimalarial medi-
0.010

Log-rank Test : P-value < 0.001

cations may have a protective thrombotic effect in these
SLE patients [33].
Our study shows that the incidence of DVT and PE
0.005

increased in patients with comorbidity in both cohorts.

The multiplicative increased risks of developing DVT and
PE were also significant in patients with concomitant
SLE and any comorbidity. These results are robust
0.000

according to Cox proportional-hazards regression analysis

0 2 4 6 8 10
Time to pulmonary embolism (years)
Fig. 1. Cumulative incidence of deep vein thrombosis and pulmo-
nary embolism. (A) Patients with systemic lupus erythematosus. (B)
Comparison cohort.
mation in multiple organ systems and a hypercoagulable
status, SLE leads to arterial, venous and microvascular
thromboses [30,31]. The highest risks of DVT and PE in
the SLE patients in our study occurred during the first
year of follow-up. Although the risks decreased over time,
the overall risk remained higher for the SLE patients than
for the controls for up to 8 years of follow-up. Our find-
ings are consistent with those of previous studies showing
an association between SLE and an increased risk of
venous thrombosis [20,32].
Although the SLE patients in our study had a higher
prevalence of comorbidities associated with the develop-
ment of DVT and PE than did the comparison cohort,
SLE remained an independent risk factor for the develop-
ment of DVT and PE after adjustment for the covariates.
12 for the increased risks of DVT and PE in SLE with inter-
action of any comorbidity, as shown in Table 3.
The strength of our findings is the nationwide, popula-
tion-based design of our longitudinal study on the risks
of DVT and PE in Asian SLE patients. In addition, the
diagnoses of all of the SLE cases identified in the NHIR
database claims data were confirmed through their inclu-
sion in the RCIPD, which establishes a high level of reli-
ability for our data. Because each resident in Taiwan is
assigned a unique personal identification number, every
patient could be traced through the records of the NHI
for the entire follow-up period. Thus, our findings can be
generalized to the entire population of Taiwan.
However, several limitations to the interpretation of our
findings should be considered. A higher proportion of
SLE patients than of controls were hospitalized, which
might have resulted in an overestimate of the risks of
DVT and PE. Ramagopalan et al. [34] suggested that peo-
ple admitted to hospitals for autoimmune disorders may
be at increased risk of subsequent VTE. However, our
comparison cohort also included inpatients, which may

© 2014 International Society on Thrombosis and Haemostasis

 SLE increase risks of DVT and PE 457

Table 4 Trends of deep vein thrombosis (DVT) and pulmonary embolism (PE) event risk stratified by duration of follow-up

Non-SLE cohort SLE cohort

Follow-up Adjusted
duration (years) Event PY Rate* Event PY Rate* IRR (95% CI) HR (95% CI)†

DVT
≤1 2 51 953 0.38 34 12 628 26.9 69.9 (61.3–79.8) 66.7 (16.0–278.7)
2–4 15 143 187 1.05 58 34 168 17.0 16.2 (15.1–17.4) 15.4 (8.72–27.4)
5–8 14 128 770 1.09 28 30 450 9.20 8.46 (7.89–9.07) 8.33 (4.35–15.9)
>8 12 55 275 2.17 16 12 992 12.3 5.67 (5.18–6.21) 5.76 (2.68–12.3)
PE
≤1 1 51 953 0.19 24 12 635 19.0 98.7 (84.5–115.3) 91.5 (12.3–677.4)
2–4 4 143 207 0.28 40 34 204 11.7 41.9 (37.8–46.4) 38.9 (13.9–109.1)
5–8 8 128 798 0.62 19 30 516 6.23 10.0 (9.31–10.8) 8.82 (3.81–20.4)
>8 5 55 311 0.90 9 13 055 6.89 7.63 (6.91–8.42) 6.66 (2.15–20.6)

CI, confidence interval; HR, hazard ratio; IRR, incidence rate ratio; PY, person-years; SLE, systemic lupus erythematosus. *Rate: incidence
rate, per 10 000 person-years. †Adjusted HR: multiple analysis, including age, sex, and comorbidities.

have reduced the potential for overestimating the risk,
because VTE is a common complication during and after
hospitalization for acute medical illness or surgery [35].
Although the healthcare claims data may contain potential
a misclassification bias concerning primary outcomes, the
auditing mechanism of the Bureau of National Health
Insurance can help to minimize the diagnostic uncertainty
and misclassification [36]. The lack of drug and laboratory
data, such as those for hormone replacement therapy, the
use of contraceptive drugs, glucocorticosteroid treatments,
and the levels of autoantibodies, may also have influenced
the primary outcomes in our study.
In conclusion, our nationwide, population-based cohort
study examining 13 084 SLE patients with a follow-up
period of ~ 90 400 person-years shows that SLE patients
have a 12.8-fold increased risk of DVT and a 19.7-fold
increased risk of PE as compared with such risks in the
general population. These findings highlight the impor-
tance of a multidisciplinary approach to the management
of the potential risk factors for DVT and PE among SLE
patients. Future studies on the biological mechanisms of
SLE and their effect on the development of DVT and PE,
as well as on the autoantibodies of the SLE patients and
the risk of DVT and PE development (such as renal dis-
ease, chronic inflammation, and medication), are encour-
aged and warranted.
Addendum
W.-S. Chung and C.-H. Kao: conception and design. C.-
L. Lin: administrative support. W.-S. Chung, C.-L. Lin,
and C.-H. Kao: data analysis and interpretation. All
authors: collection and assembly of data, manuscript writ-
ing, and final approval of manuscript.
Funding
This work was supported by the study projects (DMR-
103-012) in our hospital: Taiwan Ministry of Health and
Welfare Clinical Trial and Research Center for Excellence
(DOH102-TD-B-111-004), Taiwan Ministry of Health
and Welfare Cancer Research Center for Excellence
(MOHW103-TD-B-111-03), and International Research-
Intensive Centers of Excellence in Taiwan (I-RiCE)
(NSC101-2911-I-002-303). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript. No additional
external funding was received for this study.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Diagnostic criteria of systemic lupus erythemat-
osus.
References
1 Yeh KW, Yu CH, Chan PC, Horng JT, Huang JL. Burden of
systemic lupus erythematosus in Taiwan: a population-based
survey. Rheumatol Int 2013; 33: 1805–11.
2 Tzoran I, Saharov G, Brenner B, Delsart D, Roman P, Visona
A, Jimenez D, Monreal M. Silent pulmonary embolism in
patients with proximal deep vein thrombosis in the lower limbs.
J Thromb Haemost 2012; 10: 564–71.
3 Goldhaber SZ, Morrison RB. Cardiology patient pages. Pulmo-
nary embolism and deep vein thrombosis. Circulation 2002; 106:
1436–8.
4 Esmon CT. Basic mechanisms and pathogenesis of venous
thrombosis. Blood Rev 2009; 23: 225–9.
5 Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of
risk factors for venous thromboembolism. Arterioscler Thromb
Vasc Biol 2012; 32: 563–8.
6 Kelly J, Rudd A, Lewis RR, Coshall C, Moody A, Hunt BJ.
Venous thromboembolism after acute ischemic stroke: a prospec-
tive study using magnetic resonance direct thrombus imaging.
Stroke 2004; 35: 2320–5.

© 2014 International Society on Thrombosis and Haemostasis

458 W.-S. Chung et al
7 Bembenek J, Karlinski M, Kobayashi A, Czlonkowska A. Early
stroke-related deep venous thrombosis: risk factors and influence
on outcome. J Thromb Thrombolysis 2011; 32: 96–102.
8 Dean SM, Abraham W. Venous thromboembolic disease in con-
gestive heart failure. Congest Heart Fail 2010; 16: 164–9.
9 Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE,
Schulman S, Ortel TL, Pauker SG, Colwell CW Jr. Prevention
of VTE in orthopedic surgery patients: antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest 2012; 141: e278S–325S.
10 Noel P, Gregoire F, Capon A, Lehert P. Atrial fibrillation as a
risk factor for deep venous thrombosis and pulmonary emboli in
stroke patients. Stroke 1991; 22: 760–2.
11 Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spen-
cer FA. Venous thromboembolism in patients with diabetes mell-
itus. Am J Med 2012; 125: 709–16.
12 Prandoni P, Falanga A, Piccioli A. Cancer and venous thrombo-
embolism. Lancet Oncol 2005; 6: 401–10.
13 Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for
venous thrombosis – current understanding from an epidemio-
logical point of view. Br J Haematol 2010; 149: 824–33.
14 Murthy SK, Nguyen GC. Venous thromboembolism in inflam-
matory bowel disease: an epidemiological review. Am J Gastroen-
terol 2011; 106: 713–18.
15 Choi HK, Rho YH, Zhu Y, Cea-Soriano L, Avina-Zubieta JA,
Zhang Y. The risk of pulmonary embolism and deep vein throm-
bosis in rheumatoid arthritis: a UK population-based outpatient
cohort study. Ann Rheum Dis 2013; 72: 1182–7.
16 Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis
JC Jr, Hoffman GS, McCune WJ, St Clair EW, Specks U, Spi-
era R, Petri M, Stone JH. Brief communication: high incidence
of venous thrombotic events among patients with Wegener gran-
ulomatosis: the Wegener’s Clinical Occurrence of Thrombosis
(WeCLOT) Study. Ann Intern Med 2005; 142: 620–6.
17 Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and
blood coagulation. Hamostaseologie 2010; 30: 5–6 8–9
18 Mok CC, Ho LY, Yu KL, To CH. Venous thromboembolism in
southern Chinese patients with systemic lupus erythematosus.
Clin Rheumatol 2010; 29: 599–604.
19 Weng CT, Chung TJ, Liu MF, Weng MY, Lee CH, Chen JY,
Wu AB, Lin BW, Luo CY, Hsu SC, Lee BF, Tsai HM, Chao
SC, Wang JY, Chen TY, Chen CW, Chang HY, Wang CR. A
retrospective study of pulmonary infarction in patients with sys-
temic lupus erythematosus from southern Taiwan. Lupus 2011;
20: 876–85.
20 Avi~na-Zubieta JA, Lacaille D, Sayre EC, Kopec J, Choi HK,
Esdaile JM. Risk of pulmonary embolism and deep vein throm-
bosis in systemic lupus erythematosus: a population-based cohort
study. Arthritis Res Ther 2012; 14: A53.
21 Chen L, Yip W, Chang MC, Lin HS, Lee SD, Chiu YL, Lin
YH. The effects of Taiwan’s National Health Insurance on
access and health status of the elderly. Health Econ 2007; 16:
223–42.
22 Hochberg MC. Updating the American College of Rheumatol-
ogy revised criteria for the classification of systemic lupus erythe-
matosus. Arthritis Rheum 1997; 40: 1725.
23 Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM.
Prevalence of adult systemic lupus erythematosus in California
and Pennsylvania in 2000: estimates obtained using hospitaliza-
tion data. Arthritis Rheum 2007; 56: 2092–4.
24 Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper
GS. Understanding the epidemiology and progression of sys-
temic lupus erythematosus. Semin Arthritis Rheum 2010; 39:
257–68.
25 Bernatsky S, Joseph L, Pineau CA, Tamblyn R, Feldman DE,
Clarke AE. A population-based assessment of systemic lupus
erythematosus incidence and prevalence – results and implica-
tions of using administrative data for epidemiological studies.
Rheumatology (Oxford) 2007; 46: 1814–18.
26 Mok CC, Tang SS, To CH, Petri M. Incidence and risk factors
of thromboembolism in systemic lupus erythematosus: a compar-
ison of three ethnic groups. Arthritis Rheum 2005; 52: 2774–82.
27 Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic
lupus erythematosus: a comparison of worldwide disease burden.
Lupus 2006; 15: 308–18.
28 Tsai MH, Tsai WP, Liao ST, Liou LB. Anticardiolipin antibod-
ies in various diseases in Taiwan: a retrospective analysis. Lupus
2003; 12: 747–53.
29 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ,
Hughes GR. The management of thrombosis in the antiphosp-
holipid-antibody syndrome. N Engl J Med 1995; 332: 993–7.
30 Lipinski S, Bremer L, Lammers T, Thieme F, Schreiber S,
Rosenstiel P. Coagulation and inflammation. Molecular insights
and diagnostic implications. Hamostaseologie 2011; 31: 94–102,
4.
31 Zoller B, Li X, Sundquist J, Sundquist K. Risk of pulmonary
embolism in patients with autoimmune disorders: a nationwide
follow-up study from Sweden. Lancet 2012; 379: 244–9.
32 Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, La-
villa P, Mejıa JC, Aydintug AO, Chwalinska-Sadowska H, de
Ram on E, Fernandez-Nebro A, Galeazzi M, Valen M, Mathieu
A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M,
Hughes GR. Morbidity and mortality in systemic lupus erythe-
matosus during a 10-year period: a comparison of early and late
manifestations in a cohort of 1,000 patients. Medicine (Balti-
more) 2003; 82: 299–308.
33 Burgos PI, Alarcon GS. Thrombosis in systemic lupus erythe-
matosus: risk and protection. Expert Rev Cardiovasc Ther 2009;
7: 1541–9.
34 Ramagopalan SV, Wotton CJ, Handel AE, Yeates D, Goldacre
MJ. Risk of venous thromboembolism in people admitted to
hospital with selected immune-mediated diseases: record-linkage
study. BMC Med 2011; 9: 1.
35 Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar
AK, Deslandes B, Huang W, Zayaruzny M, Emery L, Anderson
FA Jr. Venous thromboembolism risk and prophylaxis in the
acute hospital care setting (ENDORSE study): a multinational
cross-sectional study. Lancet 2008; 371: 387–94.
36 Lee CH, Lin LJ, Cheng CL, Kao Yang YH, Chen JY, Tsai
LM.Incidence and cumulative recurrence rates of venous throm-
boembolism in the Taiwanese population. J Thromb Haemost
2010; 8: 1515–23.
37 Chung WS, Peng CL, Lin CL, Chang YJ, Chen YF, Chiang JY,
Sung FC, Kao CH.; Rheumatoid arthritis increases the risk of
deep vein thrombosis and pulmonary thromboembolism: a
nationwide cohort study. Ann Rheum Dis 2013; doi: 10.1136/
annrheumdis-2013-203380. [Epub ahead of print].
© 2014 International Society on Thrombosis and Haemostasis