Increased Risk of Venous Thromboembolism in Patients with
Dermatomyositis/Polymyositis: A Nationwide Cohort Study
Wei-Sheng Chung
a,b, Cheng-Li Lin
c, Fung-Chang Sung
c,d,⁎
, Chuan-Chin Lu
a,b,
Chia-Hung Kao
d,e,⁎⁎
Introduction
Together, deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) constitute venous thromboembolism (VTE), which has a
30-day case fatality rate of 11%–30% [1–3]. Previous studies have identifed
multiple acquired risk factors for VTE, including age, previous VTE
episodes, atrial fbrillation, and cerebrovascular disease (CVA) [4–7].
Diabetes, congestive heart failure, leg fractures, and major surgery are
also associated with an increased risk of VTE [8–12]. Studies have also
indicated the association between certain cancers and VTE [13,14]. In
addition, pregnancy, prolonged bed rest, and oral contraceptives use may also contribute to an increased risk for VTE.
Dermatomyositis (DM) is a connective tissue disease related to polymyositis
(PM), and is characterized by chronic idiopathic infammation of the skin and muscles. Both DM and PM are systemic disorders and
affect the muscles, skin, joints, esophagus, lungs, and heart. Previous studies on pulmonary involvement in patientswith DM/PMhave focused
on interstitial lung disease [15,16]. However, DM/PM is not traditionally
considered a risk factor for DVT and PE. Studies have demonstrated that chronic infammation is associated with prothrombotic factors and endothelial
dysfunction during atherothrombosis development [17,18].
Recent studies have identifed associations between autoimmune
diseases and the risk of VTE [19–21]. The number of epidemiological research
on the relationship between DM/PM and VTE is limited [19].
Therefore, we conducted a nationwide retrospective cohort study to investigate the effects of DM/PMon the risk of VTE development in Taiwan.
Methods Data Source
Data were accessed from the National Health Insurance Research Database (NHIRD) of the National Health Institute (NHI). Information on the identity of an insurant is encrypted in the NHIRD to ensure patient privacy. A committee of the Bureau of National Health Insurance is responsible for randomly selecting and checking the accuracy of
claims. The NHI program was initiated in 1995 and covers N 99% of
the 23.74 million people living in Taiwan [22]. The insurant identifcation
codes were used to link 3 data fles: inpatient claims, the Registry for Catastrophic Illness Patient Database (RCIPD), and demographic information. The International Classifcations of Disease, 9th Revision, Clinical Modifcation (ICD-9-CM) codes were used to defne diseases documented in the claims data. All of the data were deidentifed and analyzed anonymously. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012). Diagnostic Criteria of DM/PM
The classifcation criteria ofDM/PMis based on [1] a typical skin rash of DM, including a heliotrope rash, Gottron sign, and Gottron papules; [2] symmetrical proximal muscle weakness; [3] elevation of serum skeletal muscle enzyme; [4] a characteristic electromyographic pattern;
[5] a muscle biopsy consistent with myositis [23].
Participants
We identifed 2063 patients with newly diagnosed DM/PM
(ICD-9-CMcodes 710.3 and 710.4) from2000 to 2010. These patientswere confrmed in the RCIPD as the DM/PM cohort. The date on which a DM/PM
patient registered for a catastrophic illness was defned as the index date. The patients with DM/PM were diagnosed with VTE (ICD-9 codes 453.8 and 415.1, except iatrogenic PE, ICD-9-CM 415.11) prior to the index date (n=18), or thosewithmissing information regarding age or sex (n=14),were excluded fromour study. A non-DM/PMcomparison cohort randomly selected from all of the NHI benefciaries was
frequency matched with the DM/PM cohort at a 4:1 ratio based on age (in 5-y spans), sex, and year of DM/PM diagnosis. The same exclusion criteria were also applied to non-DM/PM controls.
Outcome Measurement
The person-years of the follow up for each participantwere estimated from the index date until theywere hospitalized for VTE,withdrew from the NHI, lost to follow up, or until December 31, 2010.
Exposure Measurement
In addition to DM/PM, demographic characteristics such as age, sex, and comorbidities were evaluated. Patient histories of atrial fbrillation (ICD-9-CM code 427.31), hypertension (ICD-9-CM codes 401-405), diabetes (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), CVA (ICD-9-CM codes 430-438), heart failure (ICD-9-CM code 428),
lower leg fracture or surgery (ICD-9-CM codes 820, 821; 823; 81.51, 81.52, 81.53, 81.54), cancers (ICD-9-CMcodes 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) were identifed according to hospital admissions prior to the endpoint to control for any potential confounding effects of VTE risk factors.
Statistical Analysis
All analyses were performed using SAS, version 9.2, computer software (SAS Institute Inc, Cary, NC, USA), with P b 0.05 being considered signifcant for a 2-tailed test. The demographic characteristics and comorbidities of the DM/PM and non-DM/PM comparison cohorts were presented using the total number (percentage) for the categorical variables and the median (with IQR) for the continuous variables. The differences were examined using the Chi-square test for the categorical variables and the Mann-Whitney U test for the continuous variables. The sex-, age- and comorbidity-specifc incidence rates and 95% confdence interval (CI) of VTE per 10 000 person-years of follow up were
calculated for each cohort. A Poisson regression model was applied to measure the incidence rate ratio (IRR) and 95% CIs of VTE for the DM/PM cohort compared with that of the non-DM/PM cohort. Hazard
ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazardmodels, using the non-DM/PMcohort as the reference,
to evaluate the association between DM/PM and the risk of VTE development. The multivariable models were simultaneously adjusted for
demographic characteristics and comorbidities. The joint effects of sex, age, comorbidities, and DM/PM were also assessed using Cox proportional hazard models. The cumulative incidence of VTE was calculated
using the Kaplan-Meier method. Statistical signifcance was evaluated by using the log-rank test.
Results
Table 1 shows the demographic characteristics and comorbidities of the 2 cohorts.Women outnumbered men (67.8% vs 32.2%) for both cohorts. The median age of the non-DM/PM cohort was 47.1 years and
that of the DM/PM cohort was 48.0 years, with 55.2% of the patients aged≤49 years. The DM/PMcohortwasmore likely to have atrial fbrillation,
hypertension, diabetes, hyperlipidemia, CVA, heart failure, lower leg fracture or surgery, cancer and pregnancy compared with the
DM/PM cohort and 5.96 years for the non-DM/PM cohort (data not shown).
Table 2 summarizes the VTE incidence rates of the 2 cohorts during the 11-year follow-up period, and the DM/PM cohort to non-DM/PM cohort IRR and adjusted HRs. The incidence of VTE was 12.0-fold higher in the DM/PM cohort than in the non-DM/PM cohort (25.0 vs 2.08 per 10 000 person-y), with an adjusted HR of 11.1 (95% CI = 5.21–23.6). The sex-specifc analysis demonstrated a 13.4-fold signifcantly higher risk of developing VTE in women in the DM/PM cohort compared with women in the non-DM/PM cohort (95% CI = 5.18–34.6). We observed a higher risk of VTE in men in the DM/PM cohort compared with men in the non-DM/PM comparison cohort (adjusted HR= 8.01, 95% CI = 2.26–28.4). The age-specifc analysis revealed that the DM/PM patients had a greater incidence of VTE development than the non-DM/PM patients in all of the age groups did, and that the IRR of VTE increased with age. Patients with DM/PM aged N 65 years exhibited a 15.2-fold higher risk of VTE than patients in the non-DM/PM cohort aged N 65 years (95% CI= 3.81–60.8). In patientswithout comorbidities, the incidence of VTE was 15.8-fold higher in the DM/PM cohort than in the non-DM/PM cohort (18.2 vs 1.15 per 10 000 person-y), with an adjusted HR of 16.5 (95% CI = 5.97–45.5).
When considering the joint effects of DM/PM and sex on the risk of VTE development, we discovered that women with DM/PMexhibited the highest risk of VTE development (adjusted HR = 13.1, 95% CI = 5.09–33.5), followed by men with DM/PM (adjusted HR = 10.5, 95% CI = 3.45–32.0), compared with that of women without
DM/PM (Table 3). Patients with DM/PMaged N 65 years exhibited a signifcantly
higher risk of VTE development compared with patients without DM/PM aged ≤ 65 years (adjusted HR= 26.8, 95% CI= 8.55–84.2). Patients with DM/PM aged ≤ 65 years also exhibited a signifcantly higher risk of VTE development compared with that of patients without DM/ PMaged≤65 years (adjusted HR= 9.39, 95% CI= 3.84–23.0). The DM/PMpatientswith comorbidities demonstrated a considerably higher
risk of VTE development than the non-DM/PM patients without any comorbidities did (adjusted HR = 33.3, 95% CI= 11.2–99.4). The DM/PM
patients without any comorbidities also exhibited a signifcantly higher risk of VTE development compared with that of the non-DM/PM patients without any comorbidities (adjusted HR = 16.4, 95% CI = 5.94–45.2).
As shown in Fig. 1, the cumulative incidence of VTEwas 1.75% higher in the DM/PM cohort than that in the non-DM/PM cohort (1.95% vs 0.02%; P b .001) by the end of the follow up.
Discussion
In previous studies, the prevalence of DM/PM was 2.9 per 100 000 people in Taiwan, which was lower than the prevalence of 5–70 per
100 000 people in Western countries [24–26]. In this study, women exhibited
a higher risk of developing DM/PMthanmen did. This fnding is
consistentwith the fndings of previous studies [19,23]. TheDM/PMpatients
had an 11.3-fold increased risk of VTE development compared with that of the non-DM/PMcomparison cohort, after adjusting for age,
sex, and comorbidities. In a study on DM/PM patients from a single
hospital in Spain, Selva O'Callaghan et al [27] observed a trend toward
VTE. Ramapogalan et al [19] evaluated patients admitted to hospitals
in England with various immune-mediated diseases, and observed that the DM/PM patients had a 3.04-fold higher risk of developing VTE compared with that of the control patients. However, they did not adjust for comorbid medical illnesses when calculating the risk of VTE.
Zoller et al [21] conducted a large-scale study to evaluate PE in patients
with autoimmune disorders in Sweden, and observed that the patients with a history of DM/PMexhibited a 3.4-fold higher risk of PE compared with that of the general population. The discrepancies in the described fndings might refect true variations in disease occurrence among
various populations [28,29].
Although the DM/PM patients in this study exhibited a higher prevalence of comorbidities and coexistent conditions associated with the
development of VTE than the comparison cohort did, DM/PMremained an independent risk factor for developing VTE after adjusting for covariates. Chronic infammation and microvascular endothelial injury
are pivotal features of DM/PM [21,27]. Infammation and endothelial
dysfunction result in the loss of the anticoagulant, antiaggregant, and vasodilatory properties of the endothelium, and subsequently leads to
atherosclerosis [30,31].
In this study, the majority of the DM/PM patients were women. However, the DM/PM patients exhibited a higher risk of VTE compared with that of the non-DM/PM patients, irrespective of sex. This fnding is
consistent with those of previous studies [19,32]. Older people with
age, activity levels decrease and cardiopulmonary systems deteriorate. The risk factors for thrombosis associated with advancing age might thus accentuate the effects of DM/PM on the risk of VTE development
[33].
The incidence of VTE increased in the presence of comorbidities in both the DM/PM and non-DM/PM cohorts. The DM/PM patients with any comorbidity demonstrated an additive risk of VTE development compared with that of the control cohort without comorbidities. The results obtained using multiple models to analyze the increased risk of VTE in the DM/PM cohort, and the joint effects of the comorbidities,
were robust and consistent with those of previous studies [20].
This study is the frst inwhich the increased risk of VTE development in an Asian population with DM/PM was evaluated. The primary strengths of this study are the nationwide cohort longitudinal design and a follow-up period of approximately 10 000 person-years for the DM/PM cohort. In addition, the DM/PM diagnoses were identifed using the NHIRD and confrmed by their inclusion in the RCIPD, which conferred a high level of reliability to the results. To avoid selection bias, we estimated the risk of VTE in only newly diagnosed DM/PM patients with no previous history of VTE. Because each NHI benefciary is assigned a unique personal identifcation number, each patient can be traced using the NHIRD records throughout the follow-up period. The NHI program covers N 99% of the 23.74 million people living in
Taiwan [22]. Thus, the fndings of this study are generalizable to the
population of Taiwan.
Further data analysis showed that DM/PM patients in the present study had a VTE prevalence of 8.7 per 100,000 people.With the relative risk of 12.0, the estimated population attributable risk (PAR) of VTE
associatedwithDM/PMpatients is 9.5 per 10,000 or 0.095% for the population. It means that (despite the risk of VTE associated with DM/PMis
high on an individual basis, as indicated by the RR of 12), of 10,000 cases of VTE only 9 to 10 will be prevented if DM/PM completely disappears from the general population.
However, several limitations should be considered when interpreting these fndings. The NHIRD does not provide detailed lifestyle information, such as smoking, body mass index, and physical activity, which
are all potential confounding factors for this study. In addition, information on DM/PMseverity scale such as disease activity, functional impairment,
and physical damage was unavailable in our data. The lack of prescription drug data (eg, hormone replacement therapy, the use of contraceptive drugs, immunoglobulin therapy, and glucocorticosteroid treatments) might also have infuenced the VTE risk evaluations of the patients in the DM/PM cohort.
In conclusion, this nationwide population-based cohort study of 2031 DM/PM patients indicates that DM/PM patients exhibit an
11.3-fold increased risk of VTE compared with that of non-DM/PM patients. In addition, the multiplicative risks of VTE are signifcantly increased
among DM/PM patients with comorbidities. Therefore, adequately treating comorbidities is critical for preventing VTE in DM/PM patients, andmultidisciplinary teams should guide the assessment and treatment of these patients. Future studies on the antibody levels and disease activity of DM/PMand howthey affect VTE development arewarranted.
