RHEUMATOLOGY

Rheumatology 2014;53:1639–1645 doi:10.1093/rheumatology/keu133 Advance Access publication 8 April 2014

Original article Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study Wei-Sheng Chung1,2, Cheng-Li Lin3,4, Fung-Chang Sung3,4, Wu-Huei Hsu2, Wen-Ta Yang1, Chuan-Chin Lu1 and Chia-Hung Kao2,5

Methods. We identified patients with an SSc diagnosis in Taiwan between 1998 and 2010 using the Catastrophic Illness Patient Database and the National Health Insurance Research Database. Each SSc patient was frequency matched to four control patients based on age, sex and index year and all patients were observed from the index date until the appearance of a DVT or PTE event or 31 December 2010. We calculated the hazard ratios and 95% CIs of DVT and PTE in the SSc and comparison cohorts using the Cox proportional hazards regression model. Results. We observed 1895 SSc patients and 7580 control patients for 10 128 and 46 488 person-years, respectively. The mean ages of the SSc and comparison cohorts were 50.3 and 49.9 years, respectively. After adjusting for age, sex and co-morbidities, the risks of DVT and PTE among the SSc patients were 10.5- and 7.00-fold higher than those of the control patients. The probability of developing DVT and PTE increased in the years following the SSc diagnosis. Conclusion. SSc patients exhibited a significantly higher risk of developing DVT and PTE compared with the general population. Thus multidisciplinary teams should guide the assessment, treatment and holistic care of SSc patients. Key words: systemic sclerosis, deep vein thrombosis, pulmonary thromboembolism, nationwide cohort study.

Introduction SSc, scleroderma is an autoimmune CTD that varies considerably in the extent and severity of skin and visceral organ involvement [1]. Limited cutaneous scleroderma

1 Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, 2Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, 3Management Office for Health Data, China Medical University Hospital, 4Department of Public Health, China Medical University and 5Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan.

Submitted 11 October 2013; revised version accepted 30 January 2014. Correspondence to: Chia-Hung Kao, Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2 Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected]

may restrict fibrosis to the hands, arms and face. Diffuse cutaneous scleroderma is a rapidly progressive disease that may affect a large area of skin and compromise one or more internal organs [2, 3]. Endothelial dysfunction, fibroblast dysfunction and dysregulation of the immune system are the three major events thought to contribute to the pathogenesis of SSc [4]. Chronic inflammation and fibrosis in SSc alter the blood vessels, skin, skeletal muscles and internal organs. Lung involvement is a frequent complication and a leading cause of morbidity and mortality in SSc patients. The most frequent type of lung involvement is interstitial lung disease, which results in pulmonary fibrosis or nonspecific interstitial pneumonia [5, 6]. However, inflammation and scarring fibrosis can be localized in the blood vessels. In addition, the inflammation mediators connected with prothrombotic factors and endothelial

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CLINICAL SCIENCE

Objectives. Few Asian studies have evaluated the risks of deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) in patients with SSc. We conducted a nationwide population-based cohort study to evaluate how SSc affected the incidence of DVT and PTE in Taiwan.

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Abstract

Wei-Sheng Chung et al.

dysfunction are involved in the development of atherosclerosis and thrombosis [7, 8]. Deep vein thrombosis (DVT) is a condition associated with the formation of blood clots in one or more of the deep veins. Pulmonary thromboembolism (PTE) is the sudden occlusion of a pulmonary artery by a blood clot dislodged from elsewhere in the body. If not treated appropriately, PTE can cause respiratory or circulatory collapse and death. Although the major PTE risk factors are recognized, the pathology often develops in people that lack traditional risk factors. Based on a longitudinal investigation of thromboembolism aetiology, Cushman et al. [9] reported that half of PTE cases were idiopathic. Studies have shown that chronic inflammatory diseases are associated with coagulation activation and increased DVT and PTE risk [10–12]. Because SSc is not a traditional risk factor for DVT and PTE, studies investigating the risks of DVT and PTE in patients with SSc are scant. We conducted a longitudinal nationwide cohort study in Taiwan to investigate whether SSc increases the risks of DVT and PTE.

Review Board of the China Medical University and Hospital (CMU-REC-101-012).

Patients and methods

Outcome measurement

The National Health Insurance (NHI) programme was launched in Taiwan on 1 March 1995 and covers nearly 100% of the Taiwanese population [13]. In this study we used data from the National Health Institute Research Database (NHIRD), which has been described in previous studies [10, 11]. 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). The ACR proposed classification criteria for SSc in 1980: the major criterion was proximal scleroderma, and the minor criteria comprised sclerodactyly; digital pitting, scars or loss of substance on the finger pads; and bibasilar pulmonary fibrosis. Patients that fit the major criterion and two minor criteria can be diagnosed with SSc [14]. An SSc diagnosis was defined according to the ACR diagnostic criteria and was confirmed through the Registry for Catastrophic Illness Patient Database (RCIPD). In Taiwan, rheumatologists can apply for a catastrophic illness card for patients who fit the ACR diagnostic criteria of SSc and applications for a catastrophic illness card should be scrutinized by peer review. To ensure vulnerable populations have access to necessary care, the NHI programme exempts beneficiaries from obligations for NHI-defined catastrophic illnesses. SSc patients who carry catastrophic illness cards are exempted from co-payments. The NHRID encrypts the patients’ personal information for privacy protection and provides researchers with anonymous identification numbers associated with the relevant claim information, which includes the patient’s sex, date of birth, registry of medical services and medication prescriptions. Patient consent is not required to access the NHIRD. This study was approved by the Institutional

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We conducted a retrospective cohort study to investigate the association between SSc and PTE. Patients with newly diagnosed SSc (ICD-9-CM 710.1), identified using the NHIRD and confirmed in the RCIPD during 1998–2010, were selected as the SSc cohort. The index date for SSc patients was the SSc diagnosis date. We identified patients with a diagnosis of DVT (ICD-9 453.8) or non-iatrogenic PTE (ICD-9 415.1, excluding ICD-9 415.11) to evaluate the association among DVT and non-iatrogenic PTE and SSc. Patients with a history of DVT or PTE diagnosed before the index date or missing information for age or sex were excluded. For each patient in our SSc cohort, four patients (control patients) were randomly selected from insurants who were not diagnosed with SSc and frequency matched based on age (every 5-year spans), sex and the year of the index date. Control participants with a history of DVT or PTE or missing information for age or sex were also excluded.

The primary outcome was newly diagnosed DVT or PTE, obtained from hospitalization records. All patients were observed from the index date to the date of the primary outcome, withdrawal from the NHI programme or the end of 2010, whichever occurred first. Nearly all DVT and PTE patients underwent comprehensive examinations before receiving intensive care. In Taiwan, the medical reimbursements and discharge notes of patients are scrutinized in a peer review process.

Exposure variables In addition to SSc, demographic characteristics such as sex, age and co-morbidities were analysed. Pre-existing co-morbidities included atrial fibrillation (ICD-9-CM 427.31), hypertension (ICD-9-CM 401–405), diabetes (ICD-9-CM 250), hyperlipidaemia (ICD-9-CM 272), cerebrovascular diseases (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), cancer (ICD-9-CM 140–208) and pulmonary hypertension (ICD-9-CM 416.0, 416.8 and 416.9).

Statistical analysis All statistical analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC, USA). Kaplan–Meier curves were constructed using R computer software (R Foundation for Statistical Computing, Vienna, Austria). The levels of significance were set at a two-tailed P-value of 65 years of age with SSc (35.6 per 10 000 person-years). The co-morbidity-specific analyses indicated that patients without co-morbidity in the SSc cohort exhibited the highest DVT incidence rate (12.6 per 10 000 person-years). Multivariate Cox proportional hazards regression analyses indicated that patients with SSc had a 10.5-fold higher risk of DVT compared with the non-SSc patients after controlling for age, sex and co-morbidities (95% CI 3.64, 30.3). Sex-specific analysis showed an 8.57-fold significantly higher risk of developing DVT in the SSc cohort compared with the non-SSc cohort in women (95% CI 2.86, 25.7).

TABLE 1 Demographic characteristics and co-morbidity in patients with and without SSc SSc Variable Sex Female Male Age group, n (%), years 434 35–49 50–64 >65 Mean (S.D.)a Co-morbidity, n (%) Atrial fibrillation Hypertension Diabetes Hyperlipidaemia Cerebrovascular diseases Heart failure Lower leg fracture or surgery Cancer Pulmonary hypertension

No n = 7580

Yes n = 1895

n (%) 5676 (74.9) 1904 (25.1)

n (%) 1419 (74.9) 476 (25.1)

1208 (15.9) 2476 (32.7) 2408 (31.8) 1488 (19.6) 49.9 (16.1) 46 491 303 145 204 67 93 137 8

(0.61) (6.48) (4.00) (1.91) (2.69) (0.88) (1.23) (1.81) (0.11)

302 (15.9) 619 (32.7) 602 (31.8) 372 (19.6) 50.3 (15.9) 27 203 98 54 49 72 24 35 63

(1.42) (10.7) (5.17) (2.85) (2.59) (3.80) (1.27) (1.85) (3.32)

P-value

0.99

0.99

0.28 0.0003 65 years Co-morbidityd No Yes PTE All Female Male Stratified age 465 years >65 years Co-morbidityd No Yes

Yes

Wei-Sheng Chung et al.

Rheumatology key messages SSc patients exhibit an 8.11-fold pulmonary thromboembolism risk. . The risk of pulmonary thromboembolism increases in the years following SSc diagnosis. . Pulmonary thromboembolism risk significantly increases among SSc patients with co-morbidities. .

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Acknowledgements Individual author contributions were as follows: conception and design: W.-S.C. and C.-H.K.; administrative support: C.-L.L.; collection and assembly of data: all authors; data analysis and interpretation: W.-S.C., C.-L.L. and C.H.K.; manuscript writing and final approval of manuscript: all authors. Funding: This work was supported by study projects (DMR-101-036) in our hospital, the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center and for Excellence (DOH102-TD-B-111-004), the Taiwan Ministry of Health and Welfare Cancer Research Center for Excellence (MOHW103-TD-B-111-03), and the International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. No additional external funding was received for this study. Disclosure statement: The authors have declared no conflicts of interest.

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Deep vein thrombosis and pulmonary thromboembolism in SSc

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