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Asymptomatic coronary artery disease assessed by coronary computed tomography in patients with systemic lupus erythematosus: A systematic review and meta-analysis

Published:April 08, 2022DOI:https://doi.org/10.1016/j.ejim.2022.04.001

      Highlights

      • In our systematic review and meta-analysis, we demonstrated that subclinical CAD by CCS is more prevalent in patients with SLE compared to controls.
      • However, the extent of CAC by CCS was not higher in patients with SLE than controls.
      • Moreover, analysis for limited studies showed that CAC measured by CCTA showed non-calcified plaque burden is increased SLE compared to controls.

      Abstract

      Background

      Coronary artery disease (CAD) assessed by coronary computed tomography (CT) in patients with systemic lupus erythematosus (SLE) has been investigated in several studies, but with conflicting results. The aim of this systematic review and meta-analysis of the literature was synthesize the evidence on this topic.

      Methods

      The relevant literature was identified and evaluated from inception until January 2021 in PubMed, Embase, Web of Science and Cochrane library. Studies reporting coronary artery calcification (CAC), and its prevalence and extent using the coronary calcium score (CCS) were included. Data extracted from eligible studies were used to calculate effect estimates (ESs) and 95% confidence intervals (95%CI) and weighted mean differences (WMD) with 95%CI.

      Results

      Twenty-four studies were eligible for inclusion. For the CAC prevalence, 11 studies were included (918 SLE patients and 3952 controls) and the pooled prevalence for the random effect was 29.8% (95%CI 25.7–32.9%) for SLE patients and 11.8% (95%CI 16.2-20.4%) in controls (RR 2.22, 95%CI 1.42 to 3.48; p= 0.0005) and no significant increase in the WMD for CCS (MD= 0.32, 95%CI −5.55 to 6.20, p= 0.91) compared with controls in seven studies. Greater organ damage and glucocorticoid use has been associated with a higher CCS. According to two studies, the coronary CT angiography calcified and non-calcified plaque burden were increased in SLE patients compared with controls.

      Conclusions

      In SLE, asymptomatic CAD by CAC is more prevalent and there is more multivessel disease compared with controls without lupus. However, the extent of CAC was not increased in SLE patients.

      Systematic Review registration

      PROSPERO CRD42021228710.

      Keywords

      1. Introduction

      Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with female predominance: cardiovascular disease (CVD) is the leading cause of morbidity and mortality. Accelerated atherosclerosis and coronary artery disease (CAD) are major contributors to the pathogenesis of CVD in SLE patients [
      • Manzi S
      • Meilahn EN
      • Rairie JE
      • Conte CG
      • Medsger TAJ
      • Jansen-McWilliams L
      • et al.
      Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.
      ,
      • Esdaile JM
      • Abrahamowicz M
      • Grodzicky T
      • Li Y
      • Panaritis C
      • Du Berger R
      • et al.
      Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.
      ]. Previously, it was thought that CAD was a condition affecting exclusively older men; however, patients with SLE (young female-predominant) have an increased risk of CVD compared with the general population [
      • Esdaile JM
      • Abrahamowicz M
      • Grodzicky T
      • Li Y
      • Panaritis C
      • Du Berger R
      • et al.
      Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.
      ].
      Traditional risk models, such as the Framingham risk score, do not capture the CV risk in patients with SLE. Therefore, new markers for subclinical CVD are required for stratification of these high-risk patients. The use of imaging has the potential to improve this stratification for future CV events and may determine personalized effective CVD management and medical therapy. Arterial calcium development is closely related to vascular injury, inflammation, and repair. Various factors have been considered as components of the arterial calcification pathophysiological process in patients with autoimmune diseases such as SLE, including traditional cardiovascular risk factors, lipid oxidation, endothelial damage, which can lead to accelerated vascular aging, in which the inflammatory cascade, which might be called "inflammaging", can play an important role [
      • Santos-Moreno P
      • Burgos-Angulo G
      • Martinez-Ceballos MA
      • Pizano A
      • Echeverri D
      • Bautista-Niño PK
      • et al.
      Inflammaging as a link between autoimmunity and cardiovascular disease: the case of rheumatoid arthritis.
      ].
      Coronary artery calcium (CAC) is most commonly evaluated by non-contrast electrocardiographic-gated cardiac electron beam computerized tomography (EBCT) or multidetector computerized tomography (MDCT). The coronary calcium score (CCS) is associated with the plaque burden and provides insight into the level of CV risk [
      • Erbel R
      • Möhlenkamp S
      • Moebus S
      • Schmermund A
      • Lehmann N
      • Stang A
      • et al.
      Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study.
      ]. CAC may also be measured by coronary computed tomography angiography (CCTA), which is a reliable non-invasive method to characterize the coronary artery burden and has been validated against intravascular ultrasound, the gold standard for imaging coronary plaque [
      • Papadopoulou S-L
      • Neefjes LA
      • Schaap M
      • Li H-L
      • Capuano E
      • van der Giessen AG
      • et al.
      Detection and quantification of coronary atherosclerotic plaque by 64-slice multidetector CT: a systematic head-to-head comparison with intravascular ultrasound.
      ]. CCTA permits volumetric quantification of coronary artery plaque, luminal stenosis, arterial remodelling and plaque subcomponents, which include calcified and non-calcified coronary plaque [
      • Batty JA
      • Subba S
      • Luke P
      • Gigi LWC
      • Sinclair H
      • Kunadian V.
      Intracoronary imaging in the detection of vulnerable plaques.
      ]. The latest American Heart Association and American College of Cardiology (AHA/ACC) guidelines for the primary prevention of atherosclerotic CVD permit the use of CAC scores in intermediate-risk patients, and may consider additional individual risk-enhancing clinical factors such as chronic inflammatory disease like SLE if the risk level is uncertain [
      • Arnett DK
      • Blumenthal RS
      • Albert MA
      • Buroker AB
      • Goldberger ZD
      • Hahn EJ
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ]. Thus, the CAC score could be useful in determining CV risk in patients with SLE.
      Several recent studies have investigated the association between SLE and CAC. Therefore, to better characterize the prevalence and magnitude of asymptomatic CAD in patients with SLE, as determined by the CCS measured by computed tomography, we conducted a systematic review and meta-analysis of all published studies.

      2. Methods

      This systematic review and meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) [
      • Shamseer L
      • Moher D
      • Clarke M
      • Ghersi D
      • Liberati A
      • Petticrew M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
      ] and was registered in PROSPERO (registration number: CRD42021228710).

      2.1 Search strategy and screening

      Two authors (CMP and KGB) independently searched published studies indexed in PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane library databases from inception to January 2021 using a search strategy that comprised papers that reported the prevalence and magnitude of CAD measured by CCS in patients with SLE, without language, country of origin or age restrictions. We combined the search term “SLE” in all fields with each of the following keywords: coronary calcification, coronary calcium, computed tomography angiography, and coronary artery atherosclerosis. Supplementary table 1 shows the search strategy. References of selected retrieved articles were also manually reviewed to identify any studies missed during the search strategy.
      After all duplicate studies were identified, electronically-detected published papers were screened by title and/or abstracts and by reviewing full-text papers if these were considered relevant for inclusion. Two investigators independently evaluated the full texts of selected records. Discrepancies were resolved by consensus. Agreement between the two investigators was estimated using Cohen's kappa coefficient [
      • Viera AJ
      • Garrett JM.
      Understanding interobserver agreement: the kappa statistic.
      ]. All references detected were saved electronically in Rayyan QCRI software (specific for systematic reviews) [
      • Ouzzani M
      • Hammady H
      • Fedorowicz Z
      • Elmagarmid A.
      Rayyan-a web and mobile app for systematic reviews.
      ]. If multiple articles from the same cohort were found, only the article with the most complete data was included.

      2.2 Eligibility criteria

      Randomized and non-randomized controlled studies were considered for inclusion if they reported the prevalence of CAD and CCS in adults or children with SLE compared with controls without SLE. The classification criteria for SLE had to be based on either the American College of Rheumatology (ACR) [
      • Hochberg MC.
      Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
      ], Systemic Lupus International Collaborating Clinic (SLICC) [
      • Petri M
      • Orbai A-M
      • Alarcón GS
      • et al.
      Derivationand validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus.
      ]or European League Against Rheumatism (EULAR) [
      • Aringer M
      • Costenbader K
      • Daikh D
      • Brinks R
      • Mosca M
      • Ramsey-Goldman R
      • et al.
      2019 European league against rheumatism/American college of rheumatology classification criteria for systemic lupus erythematosus.
      ] criteria.
      Eligible controlled studies had to provide at least one of the following datasets: absolute numbers of patients with prevalent CAD (CCS >0) and total patient numbers to estimate CAD prevalence and/or mean or median CCS measured as Agatston units with standard deviations (SD) or ranges, in order to estimate the extent of CAD disease, respectively. We excluded all studies that reported insufficient data, case reports, comments, editorials and reviews. Studies involving patients with previous CAD or stroke were excluded as were studies published in languages other than English or Spanish. Abstracts without full-text publication in peer-reviewed journals or studies that lacked relevant data needed to compute the prevalence of either CAD or CCS were excluded.

      2.3 Quality assessment

      The quality of each study was independently evaluated by two authors (KGB and CMP) using the Newcastle-Ottawa quality assessment scale (NOS), which assessed each study in three areas: 1) selection of the study groups; 2) comparability of the groups; and 3) ascertainment of the exposure or outcome of interest in case-control or cohort studies, respectively [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ]. The maximum NOS score is 9 and a score of ≥ 6 was considered indicative of good quality. Discrepant opinions between authors were resolved by consensus.

      2.4 Data extraction

      Two investigators independently extracted data to minimize reporting errors and disagreements were solved by consensus. Data concerning the author, year of publication, study design and study location were extracted. We also extracted all data on demographic characteristics, key baseline clinical variables and diagnostic method of CAD. Absolute numbers of patients who had CAD (CCS >0) and means with the SD of CCS, measured as Agatston units, were extracted. Additional angiographic data on coronary plaque composition, characterized by CCTA, was extracted whenever available. Values reported as medians with ranges or means with standard errors were imputed to the corresponding means with SDs. The values presented as percentages were recalculated to absolute numbers.

      2.5 Statistical analysis

      To assess the prevalence of CAD, the number of SLE patients with CCS > 0 and the total number of SLE patients were pooled and compared with similar data for controls without SLE to estimate the risk ratio (RR) for CAD. CCS means with SDs reported in the included studies were pooled to estimate the weighted mean difference between patients with SLE and controls. Due to data heterogeneity, we reported the results of analyses using a random effects model (Mantel-Haenszel method). Forest plots were used to show the final effect model. For overall estimated RR or weighted mean differences, a p-value < 0.05 was considered statistically significant. Heterogeneity between studies was tested using the chi-square method, where a p-value < 0.05 was considered statistically significant. The I2 value indicates the percentage of variation in the pooled study results and an I2 value above 20% was considered statistically significant. A sensitivity analysis was performed to determine the robustness of the results. Publication bias was visually estimated and assessed through funnel plots and confirmed by Egger's regression test. All analyses were performed using the meta-analysis statistical software Review Manager (Version 5.4.1). A narrative synthesis was the alternative option to report findings when meta-analysis was impossible.

      3. Results

      3.1 Results of literature search

      The initial search yielded 691 articles, of which 290 were screened; 217 articles were excluded based on title and abstract review. Seventy-three articles underwent full-length review. Fifty-nine articles were excluded (Supplementary table 2 shows reasons for exclusion). Fourteen articles, which all were cross-sectional, involving 918 SLE patients and 3952 controls were finally included. Agreement between the authors was high (kappa= 0.83) Details of the literature search and excluded studies are shown in Fig. 1. Eleven studies contributed to the meta-analysis of the prevalence of CAD [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Greco CM
      • Kao AH
      • Sattar A
      • Danchenko N
      • Maksimowicz-McKinnon KM
      • Edmundowicz D
      • et al.
      Association between depression and coronary artery calcification in women with systemic lupus erythematosus.
      ,
      • Gartshteyn Y
      • Braverman G
      • Mahtani S
      • Geraldino-Pardilla L
      • Bokhari S
      • Askanase A.
      Prevalence of coronary artery calcification in young patients with SLE of predominantly Hispanic and African-American descent.
      ,
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ,
      • Bicakcigil M
      • Tasan D
      • Tasdelen N
      • Mutlu N
      • Yavuz S.
      Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients.
      ,
      • Romero-Diaz J
      • Vargas-Vorackova F
      • Kimura-Hayama E
      • Cortazar-Benitez LF
      • Gijon-Mitre R
      • Criales S
      • et al.
      Systemic lupus erythematosus risk factors for coronary artery calcifications.
      ,
      • Somers EC
      • Zhao W
      • Lewis EE
      • Wang L
      • Wing JJ
      • Sundaram B
      • et al.
      Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.
      ,
      • Kiani AN
      • Magder LS
      • Post WS
      • Szklo M
      • Bathon JM
      • Schreiner PJ
      • et al.
      Coronary calcification in SLE: comparison with the multi-ethnic study of atherosclerosis.
      ,
      • Heshmat TS
      • Khalil NM
      • Elhamid HA
      • Labib S
      • Mahfouz M.
      Assessment of premature coronary atherosclerosis in patients with systemic lupus erythematosus disease.
      ,
      • Kakuta K
      • Dohi K
      • Sato Y
      • Yamanaka T
      • Kawamura M
      • Ogura T
      • et al.
      Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition.
      ,
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ] and seven studies contributed to the meta-analysis of mean CCS [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ,
      • Somers EC
      • Zhao W
      • Lewis EE
      • Wang L
      • Wing JJ
      • Sundaram B
      • et al.
      Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.
      ,
      • Heshmat TS
      • Khalil NM
      • Elhamid HA
      • Labib S
      • Mahfouz M.
      Assessment of premature coronary atherosclerosis in patients with systemic lupus erythematosus disease.
      ,
      • Kakuta K
      • Dohi K
      • Sato Y
      • Yamanaka T
      • Kawamura M
      • Ogura T
      • et al.
      Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition.
      ,
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Kao AH
      • Wasko MCM
      • Krishnaswami S
      • Wagner J
      • Edmundowicz D
      • Shaw P
      • et al.
      C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis.
      ].
      Fig 1
      Fig. 1Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram.

      3.2 Study characteristics

      All studies included were observational. One study included women only [
      • Greco CM
      • Kao AH
      • Sattar A
      • Danchenko N
      • Maksimowicz-McKinnon KM
      • Edmundowicz D
      • et al.
      Association between depression and coronary artery calcification in women with systemic lupus erythematosus.
      ] and another included only men [
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ]. Although selection was not restricted by age, all studies identified as candidates for selection were in adults. The diagnosis of SLE was based on fulfilment of the ACR [
      • Hochberg MC.
      Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
      ] or SLICC criteria [
      • Petri M
      • Orbai A-M
      • Alarcón GS
      • et al.
      Derivationand validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus.
      ]. The demographic and clinic characteristics of the study populations are shown in Table 1 and Table 2. For CCS quantification, two older studies used EBTC scanners [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Greco CM
      • Kao AH
      • Sattar A
      • Danchenko N
      • Maksimowicz-McKinnon KM
      • Edmundowicz D
      • et al.
      Association between depression and coronary artery calcification in women with systemic lupus erythematosus.
      ], while eight used MDCT [
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ,
      • Bicakcigil M
      • Tasan D
      • Tasdelen N
      • Mutlu N
      • Yavuz S.
      Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients.
      ,
      • Romero-Diaz J
      • Vargas-Vorackova F
      • Kimura-Hayama E
      • Cortazar-Benitez LF
      • Gijon-Mitre R
      • Criales S
      • et al.
      Systemic lupus erythematosus risk factors for coronary artery calcifications.
      ,
      • Somers EC
      • Zhao W
      • Lewis EE
      • Wang L
      • Wing JJ
      • Sundaram B
      • et al.
      Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.
      ,
      • Kiani AN
      • Magder LS
      • Post WS
      • Szklo M
      • Bathon JM
      • Schreiner PJ
      • et al.
      Coronary calcification in SLE: comparison with the multi-ethnic study of atherosclerosis.
      ,
      • Heshmat TS
      • Khalil NM
      • Elhamid HA
      • Labib S
      • Mahfouz M.
      Assessment of premature coronary atherosclerosis in patients with systemic lupus erythematosus disease.
      ,
      • Kakuta K
      • Dohi K
      • Sato Y
      • Yamanaka T
      • Kawamura M
      • Ogura T
      • et al.
      Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition.
      ,
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Gartshteyn Y
      • Braverman G
      • Mahtani S
      • Geraldino-Pardilla L
      • Bokhari S
      • Askanase A.
      Prevalence of coronary artery calcification in young patients with SLE of predominantly Hispanic and African-American descent.
      ]. CCS was quantified using the conventional Agatston method [
      • Agatston AS
      • Janowitz WR
      • Hildner FJ
      • Zusmer NR
      • Viamonte MJ
      • Detrano R.
      Quantification of coronary artery calcium using ultrafast computed tomography.
      ]. CCTA was acquired according to recommended protocols [
      • Abbara S
      • Blanke P
      • Maroules CD
      • Cheezum M
      • Choi AD
      • Han BK
      • et al.
      SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography: a report of the society of cardiovascular computed tomography guidelines committee: endorsed by the north American society for cardiovascular imaging (NASCI.).
      ] in two studies ([29,30]). On assessment of study quality based on the NOS (see Supplementary table 3), only four studies had a high risk of bias, and the remaining studies had a low risk.
      Table 1Characteristics of the studies included.
      Author and publication yearN (SLE/Controls)Type of controlsAge SLE/Controls, yearsEthnicity SLE%/Controls %Type of CT scanner
      Asanuma 200365/69Age, sex and race-matched controls40.3±11.6/42.7±12.6Caucasian 72/75EBCT
      Kao 2008105/105Age and race-matched healthy controls51.1±9.3/51.6±8.6Caucasian 96.2/96.2EBT
      Greco 2009161/161Age and race- matched healthy women from population study50.1±10/51.0±9.6Caucasian 88/90EBCT
      Yiu 200950/50Age and sex-matched controls45.7±8.8/47.7±4.8Chinese 100/100MDCT
      Bicakcigil 2011106/98Age, sex, BMI, waist/hip-matched controls41.1±11.9/38.7±6.6NAMDCT
      Romero-Diaz 2012139/100Age and sex-matched controls31.8±10.1/32.5±9.7Hispanics 100/100MDCT
      Somers 201295/38Age and sex-matched controls from population study37.6±9.1/39.3±10.2White 84.2/89.5MDCT
      Heshmat 201530/30Age and sex-matched control32.1±5.1/32.3±5.4Egyptian 100/100MDCT
      Kiani 201580/241Controls from population studyNACaucasians 65/41

      African American 31/59
      MDCT
      Kakuta 201621/23NA60±11/65±10Japanese 100/100MDCT
      Romero-Diaz 201895/100 (only men)Age-matched controls34.7±10.1/34.8±9.7Hispanics 100/100MDCT
      Gartshteyn 2001976/3042Age and sex-matched control40.0±13.0/NAAfrican America 40/45.2

      Caucasians 16/54.8

      Hispanics 33/0
      MDCT
      Purmalek 201964/30Age and gender-matched controls45±12/37±11Caucasians 39/53

      African American 20/17
      MDCT
      Stojan 202072/100No matched controls51.1±1.4/66.3±9.6Caucasians 70.8/71.3

      African American 23.6/5.3
      MDCT
      EBCT: electron beam computed tomography; MDCT: multi-detector computed tomography; NA: not available.
      Table 2SLE-related characteristics and morbidities of included studies.
      Author and publication yearSLE duration, yearsSLEDAI score, mean or medianAntiphospholipid antibodies, %Antimalarials use, %Glucocorticoid use, %Hypertension, %Diabetes mellitus, %
      Asanuma 20039.9±8.73.2±3.3 with CAC and 3.9±3.6 without CAC10 with CAC and 39 without CACNANA48NA
      Kao 200816.5±7.2NANA49.537.153.30
      Greco 200916.3±7.02.0±2.3NANANA55NA
      Yiu 2009NANANANANA204
      Bicakcigil 20117.0±4.11.1±1.3*23.5NA6927.36.6
      Romero-Diaz 20125.5±2.94.5±4.870 with CAC and 36 without CACNANA241
      Somers 2012NA4 (IQR 0-6)11.662.161.1NANA
      Heshmat 2015NANANANANANA0
      Kiani 2015NANANANANA515
      Kakuta 2016NANANANANA5229
      Romero-Diaz 20187.8±6.93.9±2.5 with CAC and 4.7±2.8 without CAC24 with CAC and 19 without CACNANA398
      Gartshteyn 200197 (2-13)NA3796904310.5
      Purmalek 201915±123.8±3.0NA8975586
      Stojan 202012±1.9*1.7±2.171.887.520.865.32.8
      IQR: interquartile range; NA: not available; SLEDAI: systemic lupus erythematosus disease activity index; *SELENA-SLEDAI

      3.3 Meta-analysis of the prevalence of CAD and mean CCS

      As show in Fig. 2, pooled data from ten studies showed that the risk of CAD (CCS > 0) was significantly higher in patients with SLE compared with controls (274/918 [29.8%] vs. 468/3952 [10.6%]; RR 2.22 [95%CI 1.42-3.48]; p= 0.0005) with substantial heterogeneity (I2= 86%, p < 0.0001) (Fig. 2). Seven studies provided data on the severity of CAD in patients with SLE and controls [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ,
      • Somers EC
      • Zhao W
      • Lewis EE
      • Wang L
      • Wing JJ
      • Sundaram B
      • et al.
      Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.
      ,
      • Heshmat TS
      • Khalil NM
      • Elhamid HA
      • Labib S
      • Mahfouz M.
      Assessment of premature coronary atherosclerosis in patients with systemic lupus erythematosus disease.
      ,
      • Kakuta K
      • Dohi K
      • Sato Y
      • Yamanaka T
      • Kawamura M
      • Ogura T
      • et al.
      Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition.
      ,
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Kao AH
      • Wasko MCM
      • Krishnaswami S
      • Wagner J
      • Edmundowicz D
      • Shaw P
      • et al.
      C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis.
      ]. No significant increase in the WMD for CCS (MD= 0.32, 95%CI −5.55 to 6.20, p= 0.91 and I2= 50%, p= 0.06) was found compared with controls (Fig. 3).
      Fig 2
      Fig. 2Forest plot showing meta-analysis on prevalence of asymptomatic coronary artery disease (CAD) in patients with SLE compared with controls.
      Fig 3
      Fig. 3Forest-plot showing meta-analysis of the weighted mean differences (WMD) of coronary calcium score in patients with SLE compared with controls.

      3.4 Qualitative analyses

      One study indicated that patients with SLE had more multivessel CAD [
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ]. Patients with CAD were more likely to be older [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Yiu KH
      • Wang S
      • Mok MY
      • Ooi GC
      • Khong PL
      • Mak KFH
      • et al.
      Pattern of arterial calcification in patients with systemic lupus erythematosus.
      ,
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Gartshteyn Y
      • Braverman G
      • Mahtani S
      • Geraldino-Pardilla L
      • Bokhari S
      • Askanase A.
      Prevalence of coronary artery calcification in young patients with SLE of predominantly Hispanic and African-American descent.
      ,
      • Kiani AN
      • Magder L
      • Petri M.
      Coronary calcium in systemic lupus erythematosus is associated with traditional cardiovascular risk factors, but not with disease activity.
      ] and hypertensive [
      • Gartshteyn Y
      • Braverman G
      • Mahtani S
      • Geraldino-Pardilla L
      • Bokhari S
      • Askanase A.
      Prevalence of coronary artery calcification in young patients with SLE of predominantly Hispanic and African-American descent.
      ,
      • Baker JF
      • Zhang L
      • Imadojemu S
      • Sharpe A
      • Patil S
      • Moore JS
      • et al.
      Circulating endothelial progenitor cells are reduced in SLE in the absence of coronary artery calcification.
      ] according to data from at least two studies. Some SLE-disease factors were associated with the presence or progression of CAD in at least two studies, including greater organ damage [
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Lertratanakul A
      • Wu P
      • Dyer AR
      • Kondos G
      • Edmundowicz D
      • Carr J
      • et al.
      Risk factors in the progression of subclinical atherosclerosis in women with systemic lupus erythematosus.
      ] and the use or duration of corticosteroids [
      • Romero-Díaz J
      • Acosta-Hernández RI
      • Criales-Vera S
      • Kimura-Hayama E
      • Domínguez-Quintana M
      • Morán-Contla R
      • et al.
      Asymptomatic coronary artery calcifications in men with systemic lupus erythematosus.
      ,
      • Lertratanakul A
      • Wu P
      • Dyer AR
      • Kondos G
      • Edmundowicz D
      • Carr J
      • et al.
      Risk factors in the progression of subclinical atherosclerosis in women with systemic lupus erythematosus.
      ,
      • Hu L
      • Chen Z
      • Jin Y
      • Jiang B
      • Wang X
      • Yu H
      • et al.
      Incidence and predictors of aorta calcification in patients with systemic lupus erythematosus.
      ,
      • Manger K
      • Kusus M
      • Forster C
      • Ropers D
      • Daniel WG
      • Kalden JR
      • et al.
      Factors associated with coronary artery calcification in young female patients with SLE.
      ]. CAC may be not affected by SLE activity [
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • Turner E
      • Olsen N
      • Fazio S
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Kiani AN
      • Fang H
      • Akhter E
      • Quiroga C
      • Simpson N
      • Alaupovic P
      • et al.
      Apolipoprotein-containing lipoprotein subclasses and subclinical atherosclerosis in systemic lupus erythematosus.
      ]. Osteoprotegerin (OPG) was associated with CAD in SLE patients in two studies [
      • Kiani AN
      • Aukrust P
      • Ueland T
      • Hollan I
      • Barr E
      • Magder LS
      • et al.
      Serum osteoprotegrin (OPG) in subclinical atherosclerosis in systemic lupus erythematosus.
      ,
      • Poornima IG
      • Shields K
      • Kuller LH
      • Manzi SM
      • Ramsey-Goldman R
      • Richardson C
      • et al.
      Associations of osteoprotegerin with coronary artery calcification among women with systemic lupus erythematosus and healthy controls.
      ]. The role of immunosuppressants on CAC in these patients is unclear [
      • Hu L
      • Chen Z
      • Jin Y
      • Jiang B
      • Wang X
      • Yu H
      • et al.
      Incidence and predictors of aorta calcification in patients with systemic lupus erythematosus.
      ,
      • Kiani AN
      • Vogel-Claussen J
      • Arbab-Zadeh A
      • Magder LS
      • Lima J
      • Petri M.
      Semiquantified noncalcified coronary plaque in systemic lupus erythematosus.
      ].

      3.5 Results of CCTA

      CCTA was performed in two studies with SLE patients without previous CVD. In the study by Purmalek et al. [
      • Purmalek MM
      • Carlucci PM
      • Dey AK
      • Sampson M
      • Temesgen-Oyelakin Y
      • Sakhardande S
      • et al.
      Association of lipoprotein subfractions and glycoprotein acetylation with coronary plaque burden in SLE.
      ] the dense calcified plaque burden was significantly elevated in SLE patients compared with controls and the non-calcified plaque burden was increased in SLE [
      • Carlucci PM
      • Purmalek MM
      • Dey AK
      • Temesgen-Oyelakin Y
      • Sakhardande S
      • Joshi AA
      • et al.
      Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus.
      ]. Stojan et al.[
      • Stojan G
      • Li J
      • Budoff M
      • Arbab-Zadeh A
      • Petri MA.
      High-risk coronary plaque in SLE: low-attenuation non-calcified coronary plaque and positive remodelling index.
      ] found that low attenuation non-calcified plaque (LANCP) was significantly greater in patients with SLE compared with controls and the LANCP volume was significantly higher in patients aged > 60 years and those with a prednisone dose > 10 mg/day.

      3.6 Publication bias

      The funnel plots demonstrated symmetrical distributions and Egger's tests confirmed the lack of publication bias for either prevalence or mean differences analysis (p= 0.69 and p= 0.22, respectively) (Supplemental Fig. 1). In the sensitivity analyses, no study significantly modified the effect estimator, either in the prevalence or in the mean differences analysis random model (Supplementary Fig. 2).

      4. Discussion

      Our results show that SLE patients had an increased prevalence of asymptomatic CAD evaluated by coronary computed tomography. CAD by CT was defined as a CSS >0, the cut-off used in all original articles included in our analysis: higher CCS scores are associated with an elevated CV risk and the absence of coronary calcium is a negative marker that confers a favourable prognosis [
      • Sarwar A
      • Shaw LJ
      • Shapiro MD
      • Blankstein R
      • Hoffmann U
      • Cury RC
      • et al.
      Diagnostic and prognostic value of absence of coronary artery calcification.
      ]. On the other hand, the use of the total calcium score as a measure of the extent of atherosclerosis raises the question of whether it accurately correlates with the amount of calcified plaque present pathologically [
      • Janowitz WR
      • Agatston AS
      • Kaplan G
      • Viamonte MJ.
      Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women.
      ]. Calcium screening has been shown to predict stenotic disease [
      • Haberl R
      • Becker A
      • Leber A
      • Knez A
      • Becker C
      • Lang C
      • et al.
      Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients.
      ] and some authors have suggested using CAC continuously [
      • McClelland RL
      • Jorgensen NW
      • Budoff M
      • Blaha MJ
      • Post WS
      • Kronmal RA
      • et al.
      10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) study and the DHS (Dallas Heart St.
      ]. Therefore, we decided to evaluate the extent of CAC by the mean CCS. However, we did not find that the burden of disease with a higher mean CCS was increased in SLE patients compared with controls. This is probably due to the few studies, with small sample sizes, evaluating mean differences between SLE patients and controls. Data from limited evidence shows that patients with SLE had more multivessel CAD than controls and that greater organ damage and GCT use might be associated with a higher CCS and progression in CAC, respectively.
      The importance of absolute risk assessment in determining the net benefit of preventive therapy through CAC measurement was focused on patients at low/moderate risk of CV events, who received less benefit from therapy [
      • Kavousi M
      • Desai CS
      • Ayers C
      • Blumenthal RS
      • Budoff MJ
      • Mahabadi A-A
      • et al.
      Prevalence and prognostic implications of coronary artery calcification in low-risk women: a meta-analysis.
      ]. However, large prospective studies have also addressed the prognostic value of CAC for more adverse CV events in subsets considered at high risk, such as patients with diabetes and renal diseases, etc. [
      • Malik S
      • Budoff MJ
      • Katz R
      • Blumenthal RS
      • Bertoni AG
      • Nasir K
      • et al.
      Impact of subclinical atherosclerosis on cardiovascular disease events in individuals with metabolic syndrome and diabetes: the multi-ethnic study of atherosclerosis.
      ]. Although, there are no specific studies evaluating the prognostic value of CAC deposition in patients with SLE, which affects mainly young individuals, these conditions were shown as high risk in diabetic patients and, more recently, evidence has shown they have a higher risk than diabetes [
      • Barbhaiya M
      • Feldman CH
      • Chen SK
      • Guan H
      • Fischer MA
      • Everett BM
      • et al.
      Comparative risks of cardiovascular disease in patients with systemic lupus erythematosus, diabetes mellitus, and in general medicaid recipients.
      ]. Beyond the prognostic value, CAC has emerged as an effective investigational tool to complement traditional risk stratification in this high-risk inflammatory disease [
      • Choi H
      • Uceda DE
      • Dey AK
      • Mehta NN.
      Application of non-invasive imaging in inflammatory disease conditions to evaluate subclinical coronary artery disease.
      ].
      Although there was a previous systematic review and meta-analysis including nine studies [
      • Li H
      • Tong Q
      • Guo L
      • Yu S
      • Li Y
      • Cao Q
      • et al.
      Risk of coronary artery disease in patients with systemic lupus erythematosus: a systematic review and meta-analysis.
      ], this the first study to explore the association between SLE and CAD in studies which only included patients without a previous clinical CVD risk assessment. Li et al. found that SLE patients were significantly at risk of developing CAD. A recent systematic review evaluating six autoimmune diseases (AID) found that the quantitative CAC score is higher in patients with AID, including SLE [
      • Martínez-Ceballos M
      • Sinning-Rey J
      • Alzate-Granados JP
      • Mendoza-Pinto C
      • Garcia-Carrasco M
      • Montes-Zabala L
      • et al.
      Coronary calcium in autoimmune diseases. a systematic literature review and meta-analysis.
      ]. We included studies using different generations of CT technology, EBCT and MDCT scanners. Although the latter offers a higher spatial resolution and overall improved image quality, both scanners are comparable and have equivalent reproducibility for measuring CCS [
      • Detrano RC
      • Anderson M
      • Nelson J
      • Wong ND
      • Carr JJ
      • McNitt-Gray M
      • et al.
      Coronary calcium measurements: effect of CT scanner type and calcium measure on rescan reproducibility–MESA study.
      ]. Therefore, we believe that the results obtained from the inclusion of both methods in our meta-analysis were not seriously affected by this decision.
      Our results support the increased risk of CAD observed in extensive epidemiological studies of patients with SLE [
      • Manzi S
      • Meilahn EN
      • Rairie JE
      • Conte CG
      • Medsger TAJ
      • Jansen-McWilliams L
      • et al.
      Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.
      ,
      • Schoenfeld SR
      • Kasturi S
      • Costenbader KH.
      The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review.
      ,
      • Urowitz MB
      • Gladman DD
      • Anderson NM
      • Su J
      • Romero-Diaz J
      • Bae SC
      • et al.
      Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.
      ], the restricted evidence on increased CAD assessed by invasive coronary angiography in SLE [
      • Sella EMC
      • Sato EI
      • Barbieri A.
      Coronary artery angiography in systemic lupus erythematosus patients with abnormal myocardial perfusion scintigraphy.
      ,
      • Kaul MS
      • Rao S V
      • Shaw LK
      • Honeycutt E
      • Ardoin SP
      • St Clair EW.
      Association of systemic lupus erythematosus with angiographically defined coronary artery disease: a retrospective cohort study.
      ] and reports of a higher risk of subclinical atherosclerosis in other vascular territories in SLE such as increased carotid intima-media thickness and carotid plaque [
      • Henrot P
      • Foret J
      • Barnetche T
      • Lazaro E
      • Duffau P
      • Seneschal J
      • et al.
      Assessment of subclinical atherosclerosis in systemic lupus erythematosus: a systematic review and meta-analysis.
      ], and reduced artery flow-mediated dilatation [
      • Mendoza-Pinto C
      • Rojas-Villarraga A
      • Molano-González N
      • García-Carrasco M
      • Munguía-Realpozo P
      • Etchegaray-Morales I
      • et al.
      Endothelial dysfunction and arterial stiffness in patients with systemic lupus erythematosus: a systematic review and meta-analysis.
      ].
      Despite a comprehensive body of supporting evidence, barriers have slowed the adaption of CAC testing in routine care. Cost and radiation exposure are concerns, but several features of the CAC score show its value as an optimal tool for atherosclerotic CVD risk stratification. Firstly, CT is a highly sensitive imaging test for the detection of dense calcium structures, including small calcifications in the coronary walls. Second, detection of CAC is almost pathognomonic for atherosclerotic plaque. Third, non-contrast CT cannot detect non-calcified plaque, and there is a strong correlation with the histopathologic plaque area [
      • Rumberger JA
      • Simons DB
      • Fitzpatrick LA
      • Sheedy PF
      • Schwartz RS.
      Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study.
      ]. Finally, as a marker of coronary plaque, CAC functions as a summary measure of individual lifetime exposure to coronary risk factors [
      • Erbel R
      • Budoff M.
      Improvement of cardiovascular risk prediction using coronary imaging: subclinical atherosclerosis: the memory of lifetime risk factor exposure.
      ]. The evidence suggests that patients with chronic systemic inflammatory disease, such as SLE, may benefit from the CAC for CVD risk stratification [
      • Farshad S
      • Halalau A
      • Townsend W
      • Schiopu E.
      Utility of Coronary Calcium Scoring (CCS) in Connective Tissue Disorders (CTDs) for the evaluation of subclinical coronary atherosclerosis - a systematic review.
      ].
      Given that measuring the non-calcified burden, a marker for coronary wall thickening, enables early detection of atherosclerosis even before clinically detectable plaque, research efforts in chronic systemic inflammatory disease have focused on semiautomatic quantification of the non-calcified burden to better capture rupture-prone CAD, which prompt more aggressive primary prevention management [
      • Patel NH
      • Dey AK
      • Sorokin A V
      • Teklu M
      • Petrole R
      • Zhou W
      • et al.
      Chronic inflammatory diseases and coronary heart disease: Insights from cardiovascular CT.
      ]. Stojan et al. [
      • Stojan G
      • Li J
      • Budoff M
      • Arbab-Zadeh A
      • Petri MA.
      High-risk coronary plaque in SLE: low-attenuation non-calcified coronary plaque and positive remodelling index.
      ] showed that low-attenuation non-calcified plaque and positive remodelling by CCTA are common in patients with SLE. Recent evidence has shown that coronary plaque features detected on CCTA rather than CAC may enhance the risk prediction of CAC. However, the data on the use of CAC for image-guiding therapy is still more developed than data on plaque features.
      Clinically, having a chronic inflammatory disease with an increased risk of mortality, like SLE, is enough of a risk-enhancing condition to warrant early statin therapy for primary prevention of atherosclerotic CVD by the AHA/ACC [
      • Grundy SM
      • Stone NJ
      • Bailey AL
      • Beam C
      • Birtcher KK
      • Blumenthal RS
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ]. Given chronic inflammatory diseases greatly increase atherosclerotic progression, measurement of CAC by CV CT is currently recommended in individuals with borderline intermediate risk categories [
      • Arnett DK
      • Blumenthal RS
      • Albert MA
      • Buroker AB
      • Goldberger ZD
      • Hahn EJ
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ]. A large study [
      • Ahmadi N
      • Nabavi V
      • Hajsadeghi F
      • Flores F
      • French WJ
      • Mao SS
      • et al.
      Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography.
      ] found that non-calcified and mixed coronary plaque in women, compared with men, is associated with worse clinical outcomes, an extremely pertinent finding for the treatment of young women with SLE. The integration of CCTA as a marker may capture residual CVD risk in patients with SLE, particularly severe initial disease and/or lupus nephritis, which has recently been associated with greater mortality [
      • Li D
      • Yoshida K
      • Feldman CH
      • Speyer C
      • Barbhaiya M
      • Guan H
      • et al.
      Initial disease severity, cardiovascular events and all-cause mortality among patients with systemic lupus erythematosus.
      ,
      • Hermansen M-L
      • Lindhardsen J
      • Torp-Pedersen C
      • Faurschou M
      • Jacobsen S.
      The risk of cardiovascular morbidity and cardiovascular mortality in systemic lupus erythematosus and lupus nephritis: a Danish nationwide population-based cohort study.
      ]. From a therapeutic perspective, CCTA can be used to assess the impact of treatments on atherosclerosis longitudinally, especially those which may have anti-inflammatory effects on CV events in large studies [
      • Ridker PM
      • Everett BM
      • Thuren T
      • MacFadyen JG
      • Chang WH
      • Ballantyne C
      • et al.
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      ]. Furthermore, the use of biologic disease-modifying drugs in rheumatoid arthritis (RA) has been associated with protective calcification of non-calcified lesions and a lower likelihood of new plaque formation [
      • Karpouzas GA
      • Ormseth SR
      • Hernandez E
      • Budoff MJ.
      Biologics may prevent cardiovascular events in rheumatoid arthritis by inhibiting coronary plaque formation and stabilizing high-risk lesions.
      ]. Similarly, the proportion of time SLE patients are on immunosuppressive agents was associated with a decrease in non-calcified plaque [
      • Khan A
      • Arbab-Zadeh A
      • Kiani AN
      • Magder LS
      • Petri M.
      Progression of noncalcified and calcified coronary plaque by CT angiography in SLE.
      ]. These findings highlight the contribution of systemic inflammation in CAD and support CCTA-measured coronary findings as endpoints for larger randomized, clinical trials. Moreover, the use of CAC scoring has been associated with significant improvements in the reclassification and discrimination of incident ASVD [
      • Patel J
      • Pallazola VA
      • Dudum R
      • Greenland P
      • McEvoy JW
      • Blumenthal RS
      • et al.
      Assessment of coronary artery calcium scoring to guide statin therapy allocation according to risk-enhancing factors: the multi-ethnic study of atherosclerosis.
      ], supporting the utility of CAC scoring as an adjunct to risk-enhancing factor assessment to more accurately classify individuals with an intermediate risk of ASCVD who might benefit from statin therapy.
      The study has some limitations. Firstly, most studies included had a small sample size and statistical heterogeneity, which might be due to differences in the population enrolled and the diagnostic method of CAC. Our results may have been skewed by the inclusion of SLE patients with different medications, such as glucocorticoids, hydroxychloroquine (HCQ) and/or statins (Table 2). The use of statins can reduce the risk of clinical CAD and influences CCS and CCTA findings [
      • Andelius L
      • Mortensen MB
      • Nørgaard BL
      • Abdulla J.
      Impact of statin therapy on coronary plaque burden and composition assessed by coronary computed tomographic angiography: a systematic review and meta-analysis.
      ]. HQC use also has an impact on different CV markers [
      • Munguía-Realpozo P
      • Mendoza-Pinto C
      • García-Carrasco M
      • Berra-Romani R
      • Sierra-Benito C
      • Méndez-Martínez S
      • et al.
      The impact of antimalarial agents on traditional and non-traditional subclinical atherosclerosis biomarkers in systemic lupus erythematosus: a systematic review and meta-analysis.
      ] and substantially improves survival in SLE patients [
      • Jorge A
      • McCormick N
      • Lu N
      • Zheng Y
      • Esdaile J
      • De Vera M
      • et al.
      Hydroxychloroquine and mortality among patients with systemic lupus erythematosus in the general population.
      ]. However, most studies included had no data on statins or antimalarials. Secondly, the absence of adjustment for traditional and non-traditional CAD risk factors, such as depression, and physical inactivity, and anti-phospholipid antibodies, among others, which are more prevalent in patients with SLE [
      • Bruce IN
      • Urowitz MB
      • Gladman DD
      • Ibañez D
      • Steiner G.
      Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto risk factor study.
      ], may lead to an overestimate of the effects of the disease. Third, most studies included were cross-sectional and, therefore, the prognostic value of CAD assessment by coronary computed tomography remains unclear. Finally, although our search strategy did not restrict by age, all studies retrieved from the search were in adults. Therefore, our results cannot be generalizable to all patients with SLE. Efforts should be made to identify novel biomarkers, such as CAC, that would assist physicians in quantifying the atherosclerotic burden and follow the trajectory.

      5. Conclusions

      This systematic review and meta-analysis found that, in patients with SLE, subclinical CAD by CCS and CCTA is more prevalent compared with controls. Studies should focus on the longitudinal analysis of CAD assessed by CT and its relationship with injury markers, lipid function and immune cells, to understand inflammatory atherosclerosis and the effects of anti-inflammatory therapies.

      Funding

      The authors have not declared a specific grant for this study from any funding agency in the public, commercial or not-for-profit sectors.

      Conflict of interest

      The authors have no ethical conflicts to declare.

      Acknowledgment

      The abstract of this work was published as a poster at the 2021 American College of Rheumatology meeting. We thank David Buss and Ms. Fernanda Solis for technical assistance.

      Appendix. Supplementary materials

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