Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular complications, including venous thromboembolism (VTE) events. |
Despite substantial heterogeneity across studies, this meta-analysis showed evidence of an increased risk of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients with SLE compared with the general population. |
A considerably higher incidence of VTE events was also observed in the SLE population than the general population and patients with concomitant antiphospholipid syndrome. |
The absolute risk and incidence rate of VTE events were also found to be higher in younger (< 40 years) patients with SLE versus those aged 41–64 years. |
Future research is needed to inform on the impact of traditional and SLE-specific risk factors for VTE to further identify patients with SLE at highest risk, allowing for improved prevention and treatment strategies. |
Introduction
Methods
Search Strategy and Eligibility Criteria
Data Extraction and Quality Assessment
Statistical Methods
Meta-analysis Methods for Relative Effects
Meta-analysis Methods for Proportions
Meta-analysis Methods for Incidence Rates
Results
Study Selection Process
Study Characteristics
Author (year) | Country | Study design | Inclusion criteria | Exclusion criteria | Population (s) | Reference group | Follow-up | Overall quality appraisal |
---|---|---|---|---|---|---|---|---|
Ahlehoff et al. [16] | Denmark | Retrospective cohort study | All Danish individuals ≥ 18 years from 1997 to 2011 | Patients with history of CLE or SLE before the start of the study; patients treated with oral anticoagulants or with previous cardiovascular events | SLE | General population | 11.36 years | High |
Akimoto et al. [17] | Japan | Prospective cohort study | Patients fulfilling the 1982 ACR criteria for SLE | NR | Subgroups: | NA | 5 years | High |
§ aPL+ | ||||||||
§ aPL− | ||||||||
Aviña-Zubieta et al. [5] | Canada | Retrospective cohort study | Incident SLE cohort with cases diagnosed for the first time between January 1996 and December 2010 defined as follows: | Cases that did not have an ICD code for SLE within the last 5 years prior to the end of follow-up, as long as they remained alive and residents of the province | SLE | Non-SLE reference population | 5 years | High |
(a) Two ICD-9-CM 710.0 codes for SLE at least 2 months apart and within a 2-year period by a nonrheumatologist physician | Subpopulations: | |||||||
(b) One ICD code for SLE by a rheumatologist or from hospital (ICD-9-CM 710.0 or ICD-10 M32.1, M32.8, and M32.9) | § Age/sex/entry matched | |||||||
(c) Absence of a prior SLE diagnosis between January 1990 and December 1995 (to ensure incident SLE cases) | § CCI/age/sex/entry matched | |||||||
§ Glucocorticoid/age/sex/entry matched | ||||||||
§ Number of medical service plan visits/age/sex/entry matched | ||||||||
§ Fully matched | ||||||||
Hansen and Jacobsen [18] | Denmark | Retrospective cohort study | Adult patients with SLE fulfilling the modified ACR 1982 or 1997 classification criteria | NR | SLE | NA | 8.9 ± 7.6 years | High |
Becker-Merok and Nossent [19] | Norway | Retrospective cohort study | All patients met the revised and/or updated ACR 1982 or 1997 classification criteria | NR | SLE | NA | 11.9 years (mean) | High |
Bizzaro et al. [20] | Italy | Prospective cohort study | At least 4 of the ACR revised criteria for the classification of SLE | NR | SLE | NA | 15 years | Medium |
Brouwer et al. [21] | The Netherlands | Prospective cohort study | Fulfilled at least 4 criteria for the classification of SLE, as defined by the ACR | NR | SLE | NA | 12.7 years | High |
Subgroups: | ||||||||
§ No aPL | ||||||||
§ LAC | ||||||||
§ aCL | ||||||||
Burgos et al. [22] | USA | Prospective cohort study (LUMINA cohort) | Meeting ACR criteria for SLE; disease duration ≤ 5 years; ≥ 16 years of age; defined ethnicity; living in recruitment area of 3 medical centers | NR | SLE | NA | 4.6 years | High |
Calvo-Alén et al. [23] | USA | Prospective cohort study (LUMINA cohort) | Meeting ACR criteria for SLE; disease duration ≤ 5 years; ≥ 16 years of age; defined ethnicity; living in recruitment area of 3 medical centers | NR | SLE | NA | 53 months | High |
Chabbert-Buffet et al. [24] | France | Prospective cohort study | Women who fulfilled the diagnostic criteria for SLE as defined by the American Rheumatism Association | NR | All | NA | 46 months | Medium |
Subgroups: | ||||||||
§ CPA | ||||||||
§ CMA | ||||||||
Chang et al. [25] | Canada | Prospective cohort study | Having ≥ 4 ACR criteria | NR | SLE | NA | 11.88 years | Unclear |
Subgroups: | ||||||||
§ 0–1 year after diagnosis | ||||||||
§ ≤ 30 days after diagnosis | ||||||||
§ 30 days to 1 year after diagnosis | ||||||||
§ 1–5 years after diagnosis | ||||||||
§ 5–10 years after diagnosis | ||||||||
§ 10–20 years after diagnosis | ||||||||
§ 20–30 years after diagnosis | ||||||||
§ 30–40 years after diagnosis | ||||||||
§ 40–50 years after diagnosis | ||||||||
Chen et al. [26] | China | Retrospective cohort study | Patients fulfilling the classification criteria of the ACR for SLE | NR | SLE | NA | 30.01 months (range 23–48 months) | Medium |
Choojitarom et al. [27] | Thailand | Prospective cohort study | Patients with SLE (diagnosed as SLE by the 1997 revised ACR criteria) who were regularly followed up at the outpatient department and gave consent to screen for b2GP1Ab in addition to LAC and aCL antibodies during the 1-year enrollment period | NR | SLE | NA | 8.4 years | High |
Only patients who had a positive test for at least 1 type of the aPL were included in this study | ||||||||
All included patients must have had another positive test of the same aPL at least 6 weeks apart from the first instance | ||||||||
All enrolled patients must have had no previous evidence of vascular thrombosis | ||||||||
Chung et al. [28] | Taiwan | Retrospective cohort study | Patients newly diagnosed with SLE (ICD-9-CM: 710.0) | Patients with SLE with missing data for date of birth or sex and those with a history of DVT or PE before the index date | SLE | No SLE | NR | High |
Domingues et al. [29] | USA | Prospective cohort study | Patients with SLE | < 3 measures of anticardiolipin; history of thrombosis prior to SLE diagnosis or of unknown date | All | NA | 12.2 years | Medium |
García-Villegas et al. [15] | Mexico | Prospective cohort study | Women, age ≥ 18 years, premenopausal women who qualified as SLE (≥ 4 after American Rheumatology College criteria) and who signed the FALTA | Exclusion criteria were pregnancy, nonstabilized thyroid disease, acute physical stress (< 3 months), amputation of limbs, generalized edema and/or recent liposuction (< 1 year), and having fulfilled the ACR criteria for the diagnosis of antiphospholipid syndrome | SLE | NA | NR | High |
Hinojosa-Azaola et al. [30] | Mexico | Prospective cohort study | Recent onset SLE defined as ≤ 1 year since the accrual of ≥ 4 ACR revised and updated classification criteria | Patients receiving anticoagulants for severe pulmonary HTN without thrombosis, who presented with thrombosis 7 months prior to diagnosis of SLE, and patients with malignancies | SLE | NA | 5.21 years | High |
Hsu et al. [31] | Taiwan | Prospective cohort study | Patients with SLE (ICD-9: 710.0) | Patients diagnosed before 2001; patients whose diagnosis did not pass the catastrophic illness certification procedure; patients with acute coronary syndrome, any stroke, PE, DVT, or PAD before the diagnosis of SLE; patients with follow-up < 1 year; patients who developed vascular events in the first year; patients with HCQ use between 0 and 80% | Subgroups: | NA | 7.4 years | High |
§ HCQ | ||||||||
§ No HCQ | ||||||||
Johannesdottir et al. [32] | Denmark | Case–control study | Cases of VTE | NR | SLE | Controls | NR | High |
Kaiser et al. [33] | USA | Retrospective cohort study | SLE based on ACR criteria | NR | SLE | NA | NR | High |
Kaiser et al. [34] | USA | Retrospective cohort study | Patients fulfilled the ACR criteria for SLE, completed an extensive questionnaire, gave permission for medical record review, and provided a DNA sample | NR | § Discovery cohort | NA | NR | High |
§ Replication cohort | ||||||||
Manger et al. [35] | Germany | Retrospective cohort study | All patients fulfilled the 1982 and 1997 revised criteria of the ACR for the diagnosis of SLE | NR | SLE | NA | 5.4 years | Medium |
Martínez-Berriotxoa et al. [36] | Spain | Prospective cohort study | All patients fulfilled the 1997 ACR criteria for SLE | NR | Subgroups: | NA | 10 years | Medium |
§ LAC | ||||||||
§ Persistent aCL | ||||||||
§ Transient aCL | ||||||||
§ aPL | ||||||||
McMahon et al. [37] | Ireland | Retrospective cohort study | Diagnosis of SLE based on ACR criteria | NR | SLE | NA | NR | Medium |
Mok et al. [38] | China, USA | Prospective cohort study | Patients who fulfilled at least 4 of the ACR criteria for SLE | NR | SLE | NA | 4.95 years | High |
Subgroups: | ||||||||
§ Chinese | ||||||||
§ African American | ||||||||
§ Caucasian | ||||||||
Mok et al. [39] | China | Retrospective cohort study | Patients who fulfilled ≥ 4 ACR criteria for SLE | NR | SLE | General population | 9.9 years (with DVT) and 9.3 years (no DVT) | High |
Subgroups: | ||||||||
§ < 30 years | ||||||||
§ 30–40 years | ||||||||
§ 40–50 years | ||||||||
§ 50–60 years | ||||||||
Mok et al. [40] | China | Prospective cohort study | Patients who were newly diagnosed as having SLE in the outpatients clinic of the hospital or during hospitalization or referred to the unit within 12 months of diagnosis of SLE | NR | Subgroups: | NA | 9.7 ± 7.3 years | Unclear |
§ APS | ||||||||
§ No APS | ||||||||
Mok et al. [41] | China | Retrospective cohort study | Patients who satisfied the 1982 revised ACR classification criteria for SLE | Therapeutic termination of pregnancy | SLE | NA | 11 years | High |
Moroni et al. [42] | Italy | Prospective cohort study | All patients met more than 4 criteria for SLE per ACR and had clinical manifestations of lupus nephritis | NR | SLE | NA | 173 months | Medium |
Subgroups: | ||||||||
§ aPL | ||||||||
Ramirez et al. [43] | Italy | Prospective cohort study | All patients with SLE met the revised ACR or the 2012 SLICC classification criteria | NR | SLE | NA | 1.8 years | Medium |
Reddy and Chand (2014)[44] | India | Prospective cohort study | Patients who fulfilled the ACR criteria | NR | Subgroups: | NA | < 1 year to 4 years | Low |
§ With APS | ||||||||
§ Without APS | ||||||||
Regéczy et al. [45] | Hungary | Retrospective cohort study | Patients with SLE and with or without FV Leiden mutation | NR | Subgroups: | NA | 11 years | High |
§ Heterozygous FV | ||||||||
§ Normal FV | ||||||||
§ Heterozygous FV, aPL+ | ||||||||
§ Heterozygous FV, aPL− | ||||||||
§ Normal FV, aPL+ | ||||||||
§ Normal FV, aPL− | ||||||||
Romero-Díaz et al. [46] | Mexico | Retrospective cohort study | All the patients with a diagnosis of SLE of recent onset, defined as less than 1 year since diagnosis | Patients with an episode of thrombosis of any kind prior to the study and those who were receiving anticoagulants for any reason | SLE | Other disease | 6.1 years | High |
Sciascia et al. [47] | UK | Prospective cohort study | (1) the presence of aPL (medium or high titers of aCL, defined as > 20 IgG phospholipid units and/or > 20 IgM phospholipid units and/or LAC positive) on at least 2 occasions, with an interval of 6 weeks, during the year previous to the inclusion into the study; (2) patients with SLE meeting 4 or more ACR criteria for the classification of SLE; and (3) being aged between 18 and 65 years | Positivity for aPL but without SLE, previous thrombotic events, uncontrolled hypertension, active gastric, or duodenal ulcer, severe thrombocytopenia (platelets < 50,000 mm3), hepatic failure, severe illness (e.g., cancer), allergy to aspirin, allergy to warfarin, or being currently pregnant | SLE | NA | 32.94 months | Medium |
Singh et al. [48] | India | Prospective cohort study | Patients who fulfilled the ACR criteria | NR | AR of DVT and stroke by APS for those with SLE | NR | 4 years | Unclear |
Somers et al. [49] | USA | Prospective cohort study | All patients met the ACR classification criteria for SLE | NR | SLE | NA | < 5 years | High |
Taraborelli et al. [50] | Italy | Retrospective cohort study | All the patients with a diagnosis of SLE, classified according to the 1997 ACR criteria and SLICC, who had been followed for at least 5 years and with complete aPL profiles available at the beginning of the follow-up (within ± 1 year of registry entry) | NR | All | NA | 14 years | High |
Subgroups: | ||||||||
§ Significant aPL | ||||||||
§ No significant aPL | ||||||||
Tarr et al. [51] | Hungary | Prospective cohort study | All patients met 4 or more of the revised ACR classification criteria for SLE | NR | Subgroups: | NA | 5 years | Low |
§ aCL-IgG | ||||||||
§ aCL-IgM | ||||||||
§ aCL-IgG + IgM | ||||||||
Tektonidou et al. [52] | Greece | Retrospective cohort study | Patients with SLE and biopsy-proven renal involvement who were followed up on a regular basis at the Department of Pathophysiology and for whom at least 2 measurements of aPL were performed before or at the time of kidney biopsy | Patients with the appearance of thrombotic microangiopathy lesions | Subgroups: | NA | 7.07 years | Medium |
§ Without APSN | ||||||||
§ With APSN | ||||||||
Tektonidou et al. [53] | Greece | Retrospective cohort study | All patients with SLE fulfilled at least 4 of the ACR criteria for the classification of SLE | Previous thrombosis or pregnancy morbidity | Subgroups: | NA | 108 months | High |
§ aPL + | ||||||||
§ aPL- | ||||||||
To et al. [54] | USA | Prospective cohort study | Patients fulfilled the 1982 ACR revised classification criteria for SLE | Autoantibody profiles were incomplete at the time of the study | Subgroups: | NA | 9.2 years | High |
§ Sm/RNP | ||||||||
§ DNA/Ro/La | ||||||||
§ DNA/LAC/aCL | ||||||||
Wang and Liu [55] | China | Retrospective cohort study | Patients with SLE and APS | Pregnant women | Subgroups: | NA | 39.3 months | Medium |
§ SLE + APS | ||||||||
Watanabe et al. [56] | Japan | Retrospective cohort study | All patients with SLE diagnosed according to the 1997 ACR revised criteria for SLE | Patients with a history of thrombosis and those who had received any antithrombotic agent prior to or at the time of SLE diagnosis | Subgroups: | NA | 65 months | High |
§ aPL+ | ||||||||
§ aPL− | ||||||||
Yusuf et al. [57] | USA | Retrospective cohort study | All adults 18–64 years of age who were enrolled in the health insurance plans included in the MarketScan Commercial Claims databases during any time in 2007 and remained continuously enrolled for any length of time (with the cutoff for assessing continuity occurring on 31 December 2010) and who also had diagnoses of 1 or more of the 4 autoimmune diseases of interest (AIHA, ITP, RA, or SLE) during 2007 | NR | All | No autoimmune disease | 2.6 years | High |
Subpopulations: | ||||||||
§ All, 18–40, 41–64 at 90 days | ||||||||
§ All, 18–40, 41–64 at 180 days | ||||||||
§ All, 18–40, 41–64 at 1 year | ||||||||
§ All, 18–40, 41–64 at 2 years | ||||||||
§ All, 18–40, 41–64 at 3 years | ||||||||
§ All, 18–40, 41–64 at 4 years | ||||||||
Subgroups: | ||||||||
§ 18–40 years | ||||||||
§ 41–64 years | ||||||||
Zöller et al. [58] | Sweden | Retrospective cohort study | Patients with a primary or secondary diagnosis of autoimmune disorders | Previous admission for VTE | All | No autoimmune disease | NR | High |
Subpopulations: | ||||||||
§ < 1 year of follow-up | ||||||||
§ 1–5 years of follow-up | ||||||||
§ 5–10 years of follow-up | ||||||||
§ ≥ 10 years of follow-up |