You are here

  • Home
  • Archive
  • Volume 9, Issue 3
  • Application of EULAR and European Society of Cardiology recommendations with regard to blood pressure and lipid management in antiphospholipid syndrome

Article Text

Article menu

Download PDFPDF

Autoimmunity
Original research
Application of EULAR and European Society of Cardiology recommendations with regard to blood pressure and lipid management in antiphospholipid syndrome
  1. George C Drosos1,
  2. George Konstantonis1,
  3. Petros P Sfikakis1,2,3 and
  4. Maria G Tektonidou1,2,3
  1. 1Cardiovascular Risk Research Laboratory, First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
  2. 2Rheumatology Unit, First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
  3. 3Joint Academic Rheumatology Program, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
  1. Correspondence to Professor Maria G Tektonidou; mtektonidou{at}gmail.com

Abstract

Background To examine blood pressure (BP) and lipid treatment eligibility in antiphospholipid syndrome (APS) according to European Alliance of Associations for Rheumatology (EULAR) and European Society of Cardiology (ESC) recommendations.

Methods Systematic Coronary Risk Evaluation (SCORE), modified-SCORE, diabetes mellitus (DM)-equivalent risk classifiers (DIME) and disease-related classifiers –type of thrombotic events (APSevents), antiphospholipid-antibody profile (aPLprofile) and adjusted Global APS Score for cardiovascular disease– were used to calculate predicted low-moderate, high and very-high cardiovascular risk (CVR) in 111 patients with APS without prior atherosclerotic cardiovascular events or DM. Actual CVR (AR) was determined according to ESC guidelines, including carotid/femoral plaque presence. In low-moderate SCORE-predicted risk patients, classification ability and agreement for BP or lipid treatment was tested with Matthews’ correlation coefficient (MCC) and Cohen’s kappa, respectively, using the AR classes as reference qualifiers.

Results SCORE underestimated high/very-high-AR in >50% of cases. SCORE-guided BP/lipid treatment eligibility was 4.2%/12.6% for high, 10.5%/16.8% for very-high AR patients, while 5.3% of low-moderate AR cases were eligible for lipid-lowering therapy. For BP treatment, MCC was higher using DIME for low-moderate and very-high-risk (0.33 and 0.32, respectively), and using modified-SCORE+APSevents (MCC=0.25) for high-risk patients. Eligibility agreement was better with DIME+APSevents or aPLprofile (kappa=0.51) for high-risk, and DIME (kappa=0.31) for very-high-risk patients. For lipid treatment, both classification ability and eligibility agreement were stronger with SCORE (or modified-SCORE)+APSevents in low-moderate (MCC/kappa=0.43/0.41) and very-high risk (MCC/kappa=0.30/0.30), and with DIME+aPLprofile (MCC/kappa=0.50/0.50) in high-risk patients, respectively.

Conclusion Multimodal risk assessment including disease-related and cardiometabolic features used for high-risk diseases such as DM can improve CVR management in APS.

  • Antiphospholipid Syndrome
  • Cardiovascular Diseases
  • Hypertension
  • Lipids
  • Atherosclerosis

Data availability statement

Data are available upon reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003326

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • According to European Alliance of Associations for Rheumatology (EULAR) recommendations for cardiovascular risk (CVR) management, succeeding CVR assessment that contemplates both disease-related and traditional risk factors, blood pressure (BP) and lipid management in antiphospholipid syndrome (APS) should follow general population guidelines. The European Society of Cardiology recommends the use of the Systematic Coronary Risk Evaluation (SCORE) to guide BP and lipid-lowering treatment.

    WHAT THIS STUDY ADDS

    • In addition to SCORE and modified SCORE, we used for the first time the diabetes mellitus-equivalent risk cardiometabolic traits, the type of thrombotic events, the antiphospholipid antibody (aPL) profile and the adjusted Global APS Score for cardiovascular disease as potential CVR classifiers.

    • Consideration of type of thrombotic events, aPL profile and diabetes mellitus-equivalent risk cardiometabolic traits improves risk classification to guide BP and lipid management in patients with APS at low-moderate CVR as assessed by the SCORE tool.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Use of both disease-related variables and cardiometabolic traits typical of high-CVR disorders such as diabetes mellitus can inform SCORE-guided BP and lipid management in APS.

    Introduction

    Antiphospholipid syndrome (APS) is an autoimmune rheumatic and musculoskeletal disorder (RMD) characterised by a plethora of macrovascular and microvascular thrombotic manifestations.1 2 APS is associated with life-threatening complications due to arterial thrombosis in the coronary, cerebrovascular and/or pulmonary circulation,3 supporting the need for strict control of risk factors associated with their development and recurrence.2 4

    Hypertension and hyperlipidaemia have been recognised as independent predictors of recurrent thromboses in APS,5–9 including cardiovascular events.8 10 However, a high prevalence of unachieved blood pressure (BP) and lipid targets has been documented in patients with APS.8 11–13 The 2022 EULAR recommendations for cardiovascular risk (CVR) management in RMDs4 proposed that, after assessment of both traditional and disease-related CVR features, BP and lipid treatment in APS should follow general population guidelines. The European Society of Cardiology (ESC) recommends that optimal CVR management, including BP and lipid modification therapy, should be tailored to individual patient risk assessment.14–16

    Numerical estimates calculated with the Systematic Coronary Risk Evaluation (SCORE) are recommended by the ESC15–17 to risk-stratify patients for CVR factor management, including modifications of baseline risk for systemic autoimmune disorders.14 17 Qualitative clinical risk modifiers have also been introduced to refine risk in high-CVR disorders,14 16 including diabetes mellitus (DM).14 18 Cardiometabolic risk phenotypes associated with DM14 16 18 may also prevail in APS compared with other high-CVR disorders such as rheumatoid arthritis.19 Identification of subclinical atherosclerotic plaques on vascular ultrasound (VUS) is also proposed by the ESC14–16 as a risk classifier to modify clinical risk estimated by SCORE. A 2.5–4-fold higher risk for subclinical atherosclerosis has been described in APS versus the general population,8 20 21 comparable to that observed in patients with DM.22 23

    Hypertension and hyperlipidaemia are included, along with the antiphospholipid antibody (aPL) profile, in the adjusted Global APS Score (aGAPSS) which was developed to predict recurrent thrombotic events in APS.4 7 A more recent version of the aGAPSS focusing on the prediction of arterial events, the aGAPSS for cardiovascular disease (aGAPSSCVD), further included obesity, smoking and DM as independent predictors for CVR assessment in APS.10 24 Hitherto, the contribution of any of the aforementioned general and disease-related risk assessment modalities to guide BP and lipid management in APS remains unknown.

    In this study, we aimed to investigate the impact of multiple risk assessment strategies based on traditional and disease-related CVR factors to inform decision-making to initiate treatment for BP and lipids in APS, according to recommendations issued by EULAR and ESC.

    Methods

    Study population

    All patients fulfilling the updated classification criteria for definite APS1 who are followed in our department, were screened by two expert rheumatologists (PPS, MGT) for eligibility to participate in this study. Patients with systemic lupus erythematosus (SLE)-associated APS met also the Systemic Lupus International Collaborating Clinics classification criteria.25 Participants with a history of atherosclerotic cardiovascular events, DM, chronic kidney disease or acute illness or pregnancy at the time of enrolment, were excluded from the study (online supplemental figure S1).

    Baseline clinical and laboratory assessment

    Examination took place in the Cardiovascular Risk Research Laboratory of our Department. At enrolment, the following clinical data were collected for all patients: age; gender; clinical events informing the diagnosis of APS according to the updated classification criteria1; weight and height to calculate the body mass index; waist circumference; BP (measured according to the ESC guidelines15 with an automated electronic device); smoking history; and current use of antiplatelets, anticoagulants, glucocorticoids, immunosuppressants, hydroxychloroquine, antihypertensives and hypolipidaemics.

    Blood lipid variables measured in the fasting state included total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, while non-HDL-cholesterol was calculated by subtraction of HDL-cholesterol from TC.16 Atherogenic dyslipidaemia was defined as non-HDL-cholesterol ≥130 mg/dL and low HDL-cholesterol (men: <40 mg/dL; women: <50 mg/dL).16 26 27 Immunological tests included IgG and IgM anti-cardiolipin antibodies (aCL), IgG and IgM anti-beta-2 glycoprotein I antibodies (anti-β2GPI) and lupus anticoagulant (LA). Patients were considered aPL positive if LA, and/or medium or high-titres of IgG or IgM aCL and/or medium or high-titres of IgG or IgM anti-β2GPI were present in two consecutive measurements at least 12 weeks apart.1

    CVR assessment

    VUS imaging

    VUS was performed at the time of patients’ clinical and laboratory assessment by an experienced operator (GK) blinded to participants’ medical history and clinical assessment. A high-resolution device (Vivid 7 Pro, GE HealthCare, Chicago, Illinois, USA) with a linear 14-MHz transducer was used to examine eight vascular anatomical sites: left and right common carotid arteries; left and right carotid bulbs; left and right carotid bifurcation; and left and right common femoral arteries. Following the Mannheim consensus,28 subclinical atherosclerotic plaques were defined as a focal intraluminal thickening at the near and far arterial wall with intima-media thickness (IMT)≥1.5 mm, or increased by at least 0.5 mm or 50% compared with the IMT value of the adjacent vascular wall.

    CVR classification

    An internist (GCD) blinded to the results of the VUS examination performed patients’ clinical risk classification and assessment of BP and lipid status. Participants were risk-stratified into low-moderate, high and very-high-risk classes using six different classification modalities to estimate predicted risk. Three sets of classifiers focused on atherosclerotic CVR (ASCVR) factors as included in the SCORE and modified SCORE (mSCORE) equations,14 16 17 and the ASCVR features proposed by ESC for DM (ie, diabetes mellitus-equivalent atherosclerotic cardiovascular risk (DIME)).14 18 The other three risk classification approaches involved disease-related risk factors including a history of arterial versus non-arterial thrombotic APS manifestations (ie, APSevents), as well as the presence of major cardiovascular events (ie, non-atherosclerotic stroke and/or transient ischaemic attack, acute myocardial infarction or peripheral artery thrombosis); the aPL profile (ie, aPLprofile); and the aGAPSSCVD equation.

    SCORE, mSCORE and DIME classes were defined according to the ESC guidelines.14 16 18 mSCORE was calculated by multiplying SCORE by a 1.5 and 2.0 factor for patients with primary APS (PAPS)14 16 and SLE-APS,29 30 respectively.

    Disease-specific risk classifiers for CVR assessment in patients with APS are currently lacking.4 Thus, we included the type of thrombotic events (arterial vs venous) and the aPL profile as potential risk classifiers based on the evidence that patients with a history of arterial events and/or a high-risk aPL profile (which is associated with a high risk of arterial thrombosis2) are at a higher CVR2 3 9 10 31 32 versus those without. Risk classes based on APSevents were defined according to the presence of arterial versus non-arterial events. Following the EULAR recommendations,2 4 aPL-stratified classes were defined according to the number and titre of aPL. The aGAPSSCVD risk classes were defined based on available cut-offs10 24 suggesting that the presence of triple aPL positivity classifies patients at high-risk even in the absence of concomitant ASCVR factors included in this risk prediction model.

    Risk assessment modalities are reported in detail in the online supplemental data.

    Assessment of BP and lipid profile

    Hypertension was defined as systolic BP (SBP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or use of antihypertensives.15 Hyperlipidaemia was defined as non-target non-HDL-cholesterol levels (tailored to SCORE or mSCORE classification and calculated according to the ESC guidelines16) and/or use of hypolipidaemics. Non-HDL-cholesterol targets were used because current evidence suggests they may better reflect ASCVR16 33 34 and their use has been proposed for diseases with a comparable ASCVR to APS,8 23 such as DM.16 18 Based on the ESC guidelines,15 16 patients not undergoing BP-lowering or lipid-lowering treatment were stratified into treatment-naïve categories, while those receiving antihypertensives or hypolipidaemics were assigned to ‘adequate treatment’ or ‘inadequate treatment’ subgroups, according to BP and lipid targets (see also online supplemental data).

    Eligibility for BP and lipidaemia treatment initiation according to CVR classification

    The EULAR recommendations for CVR management in APS4 stated that CVR assessment should include both disease-related and traditional CVR factors, using general population guidelines for BP and lipid modification therapy. According to the ESC,14 16 ASCVR factors not included in the SCORE equation and/or VUS-detected atherosclerosis can be used as CVR enhancers in patients stratified at low or moderate risk by the clinical prediction tools.

    Considering both sets of recommendations, and following a previously applied stepwise approach to assess CVR in SLE using both traditional and disease-related CVR factors in addition to VUS,35 eligibility for initiation of BP and lipid treatment was assessed by testing the following risk assessment modalities:

    1. Actual risk classification after applying the relevant ESC recommendations.14 16 Actual very-high risk was defined by the presence of plaques on VUS examination; actual high risk by the presence of a ≥1 ASCVR factor not included in SCORE and the absence of plaques on VUS; and actual low-moderate risk when neither of the very-high/high risk conditions were present (see also online supplemental data). The actual risk classes were then used as the reference categories to determine eligibility, against which all the other risk assessment modalities were compared.

    2. Predicted risk classification by traditional ASCVR factors, that is, SCORE, mSCORE or DIME alone.

    3. Predicted risk classification by traditional ASCVR plus disease-related risk factors, that is, SCORE, mSCORE or DIME with the addition of APSevents or aPLprofile to each of the three ASCVR tools, as well as the aGAPSSCVD.

    Risk assessment and eligibility are summarised in figure 1.

    Figure 1
    Figure 1

    Overview of risk classification and eligibility for BP or lipid modification treatment in patients with APS. *As defined by vascular ultrasound of the carotid and/or femoral arteries. †As defined by initial SCORE estimates in the absence of very-high or high-risk features. aGAPSSCVD, adjusted Global APS Score for cardiovascular disease; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; APSevents, risk related to the type of APS thrombotic event; BP, blood pressure; CVE, cardiovascular events; DIME, diabetes mellitus-equivalent atherosclerotic cardiovascular risk; DM, diabetes mellitus; mSCORE, modified SCORE; SCORE, Systematic Coronary Risk Evaluation.

    Statistical analysis

    χ2 test or Fisher’s exact test were used to assess qualitative data. Quantitative variables were assessed with Student’s t-test or Mann-Whitney test. Results are reported as relative frequencies and mean±SD or median with IQR for categorical and continuous data, respectively.

    Classification ability of the different risk assessment modalities was tested with Matthews’ correlation coefficient (MCC) using the actual risk classes as reference classifiers. Cohen’s kappa was used to examine agreement of eligibility between the predicted risk assessment approaches and eligibility as determined by the actual risk classes as a reference.

    Patients with SLE-APS may be at a higher CVR compared with PAPS cases due to the additional impact of SLE-related CVR factors, including high disease activity and glucocorticoid exposure, or due to lack of the protective effect of hydroxychloroquine in non-hydroxychloroquine users.4 8 Thus, in the subgroup of patients with BP-lowering or lipid-lowering treatment-naïve SLE-APS, a logistic regression analysis was performed to assess whether SLE-related variables are associated with very-high actual CVR, including high disease activity (defined as SLE Disease Activity Index−2000 (SLEDAI-2K)≥6), measures of glucocorticoid exposure (mean daily dose; daily dose ≥10 mg; cumulative dose) and the absence of hydroxychloroquine use.

    A p value<0.05 was used to set statistical significance. Statistical analyses were performed with the Stata V.13.0 software tool (StataCorp, College Station, Texas, USA).

    Results

    Baseline characteristics of study participants

    One hundred and eleven patients with APS (mean age 45.2±11.7 years; 68.5% women) were included in the study. Baseline clinical and laboratory characteristics are shown in online supplemental table S1. PAPS was present in 64% of cases and one-third of all patients had experienced at least one major cardiovascular event. High-titre aPL were present in 58.6% of patients and triple aPL positivity in 42.3%. Mean SBP was 124±13 mm Hg, mean non-HDL-cholesterol 131±37 mg/dL, while hypertension and hyperlipidaemia were observed in 35% and 46% of cases, respectively.

    Patients’ CVR assessment is shown in online supplemental figures S2 and S3. As displayed, atherosclerotic plaques at carotid, femoral or both arterial sites were documented in 12.6%, 9.9% and 12.6% of patients, respectively. Among examined CVR assessment tools, DIME and APSevents assigned a statistically significant higher proportion of patients with plaques at very-high risk (p=0.002 and 0.004, respectively). Participants without atherosclerotic plaques were more likely to be classified at low-moderate risk by both SCORE equations. BP and lipid profile analysis showed that patients with normotension or normolipidaemia were less likely to have VUS-detected plaques.

    BP and hyperlipidaemia management in treatment-naïve patients

    CVR factor profile

    The traditional and disease-related CVR factors in patients (with and without plaques) at low-moderate SCORE risk, not undergoing BP-lowering or lipid-lowering treatment, are shown in table 1.

    View this table:
    Table 1

    Traditional and disease-related risk factors in patients with APS at low or moderate SCORE-predicted risk not receiving antihypertensives or hypolipidaemics (N=95)

    Atherosclerotic plaques at carotid, femoral and both carotid and femoral arteries were detected in 44%, 22% and 33% of patients, respectively. Patients with plaques were more likely to be middle-aged (p<0.001), have untreated hypertension (p=0.007) and hyperlipidaemia (p=0.025) and atherogenic dyslipidaemia (p=0.013) versus those without plaques.

    Among the examined potential risk classifiers (figure 2), ASCVR factors characteristic of DM were significantly more prevalent (p=0.019) in patients at very-high actual risk (ie, those with plaques on VUS); the same group of patients was less likely to have a history of non-arterial thrombotic events (p=0.006).

    Figure 2
    Figure 2

    Distribution of potential clinical risk classifiers among 111 patients with APS with and without subclinical atherosclerosis. aCL, anti-cardiolipin antibodies; aPLprofile, risk related to the antiphospholipid antibody profile; APS, antiphospholipid syndrome; APSevents, risk related to the type of APS thrombotic events; anti-β2GPI, anti-beta-2 glycoprotein I antibodies; DIME, diabetes mellitus-equivalent atherosclerotic cardiovascular risk; LA, lupus anticoagulant; Plq, presence (+) or absence (−) of plaques on vascular ultrasound.

    Assessment of risk classification modalities

    The actual and predicted risk of patients with APS is shown in figure 3. Patients not undergoing BP-lowering or lipid-lowering treatment at actual low-moderate, high and very-high risk amounted for 7.4%, 8.4% and 10.5%, and 38.9%, 16.8% and 17.9% of the total population, respectively. In antihypertensive-naïve patients, DIME plus APSevents and DIME plus aPLprofile missed all patients at actual low-moderate risk, while no lipid-lowering treatment-naïve cases were stratified at low-moderate risk by mSCORE plus aPLprofile and DIME plus aPLprofile. mSCORE alone did not classify any patients at very-high risk in both groups of treatment-naïve patients.

    Figure 3
    Figure 3

    Predicted and actual risk in patients with APS at low-moderate baseline SCORE risk (*) not undergoing BP-lowering or lipid-lowering therapy. Percentages refer to the proportion of cases per treatment eligibility group per total population of treatment-naïve patients. aGAPSSCVD, adjusted Global APS Score for cardiovascular disease; aPLprofile, risk related to the antiphospholipid antibody profile; APS, antiphospholipid syndrome; APSevents, risk related to the type of APS thrombotic events; BP, blood pressure; DIME, diabetes mellitus-equivalent atherosclerotic cardiovascular risk; mSCORE, modified SCORE; SCORE, Systematic Coronary Risk Evaluation.

    Classification ability of the different CVR assessment modalities is shown in table 2.

    View this table:
    Table 2

    Classification ability of risk assessment modalities to inform blood pressure and lipid management in patients with APS at low or moderate SCORE-predicted baseline ASCVR not receiving antihypertnesives or hypolipidaemics (N=95)

    Among ASCVR classifiers, DIME performed better than mSCORE to identify BP treatment-naïve patients at low-moderate and very-high risk. Classification ability of DIME and mSCORE was comparable for high-risk patients (MCC=0.16 and 0.20, respectively). MCC values for very-high risk patients were 0.32, 0.14, 0.13, 0.27, 0.10 and 0.20 for DIME, APSevents plus SCORE or mSCORE, DIME plus APSevents, aPLprofile plus SCORE or mSCORE, DIME plus aPLprofile and aGAPSSCVD, respectively.

    In lipid-lowering treatment-naïve patients, better risk classification of low-moderate risk patients was performed with SCORE and mSCORE, alone or in combination with assessment by APSevents. In the high-risk subgroup, DIME alone and DIME plus APSevents or aPLprofile had the best classification ability (MCC=0.43, 0.43 and 0.50, respectively) among all examined modalities. Among very-high risk patients, APSevents plus SCORE, mSCORE or DIME had similar classification ability, while DIME alone or in addition to aPLprofile showed lower MCC values compared with the APSevents plus SCORE, mSCORE or DIME modalities (0.30–0.32 vs 0.26 and 0.29, respectively).

    In the subgroup of patients with SLE-APS at low-moderate SCORE-predicted risk who were not receiving antihypertensives or hypolipidaemics, no association of high disease activity, glucocorticoid exposure, or non-use of hydroxychloroquine and very-high actual CVR was found (online supplemental table S2).

    Assessment of eligibility for BP and lipid-lowering therapy in treatment-naïve patients

    Antihypertensive treatment. In patients at high and very-high actual risk, eligibility for initiation of BP-lowering therapy was 4.2% and 10.5%, respectively (table 3). In high-risk patients, eligibility based on predicted risk was 1%, 7.4%, 6.3%, 10.5% and 5.3% using mSCORE alone or APSevents plus either of the SCORE equations, DIME, DIME plus APSevents or aPLprofile, SCORE (or mSCORE) plus aPLprofile and aGAPSSCVD, respectively. In the same subgroup, agreement between eligibility determined by actual and predicted risk classification was higher for DIME plus APSevents or aPLprofile (kappa=0.51), while there was slight disagreement in the assessment by mSCORE alone and APSevents plus any of the SCORE equations (kappa=−0.07 with all three modalities). For patients at very-high risk, eligibility for BP-lowering treatment according to predicted risk classes would comprise 0%–13.7% of cases. Most of the examined risk assessment modalities showed negligible agreement to moderate disagreement with actual eligibility (kappa range from 0 to 0.14 and −0.25, respectively), except in the case of DIME (kappa=0.31).

    View this table:
    Table 3

    Risk-stratified eligibility for BP and lipid lowering treatment in patients with APS at low or moderate baseline SCORE-predicted risk not receiving antihypertensives or hypolipidaemics (N=95)

    Lipid-lowering treatment. As shown in table 3, actual eligibility for lipid-lowering therapy based on the reference risk qualifiers would be 5.3% for patients at low-moderate risk, 12.6% for those at high risk and 16.8% for very-high risk cases. In the low-moderate risk subgroup, SCORE (or mSCORE) plus APSevents would deem eligible 12.6% of patients and showed the highest agreement (kappa=0.41), followed by SCORE alone (eligibility: 22.1%; kappa=0.31). Eligibility for high-risk patients based on predicted risk ranged from 1% to 18.9%, with the highest agreement observed for cases assessed with DIME alone or along with APSevents or aPLprofile (kappa=0.41, 0.43 and 0.50, respectively). All risk classification modalities, except for mSCORE, deemed as eligible for initiation of hypolipidaemics a higher percentage of very-high predicted risk patients (18%–34%) compared with the other risk classes and agreement with actual eligibility was better when using SCORE (or mSCORE) plus APSevents (kappa=0.30).

    Discussion

    Our study showed for the first time that disease-related risk factors, as well as cardiometabolic features associated with established high-CVR disorders such as DM, contribute to refinement of CVR assessment to guide hypertension and hyperlipidaemia management in APS.

    Uncontrolled BP and lipid levels significantly impact cardiovascular prognosis in APS.7–10 13 Owing to evidence limitations, EULAR recommendations for CVR management in RMDs4 proposed to control BP and hyperlipidaemia in APS according to general population guidelines such as those of the ESC.15 16 ESC guidelines suggest the use of SCORE, with or without the addition of other risk qualifiers such as VUS, to guide treatment initiation in the general population targeting optimal BP and lipid levels.15 16 Studies on the performance of ASCVR prediction models in APS are currently lacking,4 8 but evidence from other RMDs such as SLE4 36 suggests that SCORE alone would underestimate actual risk. In order to improve CVR management, EULAR recommended that both traditional and disease-related risk factors should thoroughly be considered in CVR assessment in APS.4

    In our study, SCORE misclassified as low-moderate risk approximately three-fourths of BP treatment-naïve and half of patients not receiving hypolipidaemics, indicating that using this tool alone to assess patients’ risk could hamper CVD prevention in APS. SCORE has been found to underestimate actual CVR in hypertensive individuals.37 This finding is of particular importance for patients with APS because uncontrolled BP is a major CVR factor for stroke,15 the most common cardiovascular event in this RMD.3 Our results also revealed poor agreement between mSCORE-guided and actual eligibility across all examined subgroups and risk classes, arguing against the use of mSCORE to manage BP and hyperlipidaemia in APS. Application of multipliers to risk calculated with ASCVR equations to optimise CVR assessment in RMDs has been proposed,4 14 17 but is currently under debate.4 8 35 36

    Risk classifiers included in DIME were based on the CVR traits introduced by the ESC to inform ASCVR assessment in DM.14 18 DIME identified actual high-risk and very-high-risk patients more precisely compared with SCORE and mSCORE in both eligibility groups. Importantly, DIME-stratified eligibility for antihypertensive treatment was the only instance of fair agreement with actual eligibility in very-high risk patients. A number of features included in DIME define the metabolic syndrome (MetS), a constellation of conditions increasing the risk of cardiovascular events and incident DM.38 Evidence indicates that components of the MetS are associated with arterial events and subclinical atherosclerosis (a very-high risk classifier14 16) in patients with APS.8 19 Thus, our findings about DIME suggest that ASCVR features associated with DM and not included in SCORE may help to better delineate high-risk cardiometabolic profiles in APS amenable to stricter risk factor monitoring.

    The addition of APSevents to SCORE and mSCORE improved eligibility in very-high risk cases in both BP and lipid management groups and in low-moderate risk hypolipidaemic-naïve patients. Mixed findings were observed with use of DIME plus APSevents compared with DIME alone, including decreased agreement to actual eligibility in very-high risk patients eligible for BP modification therapy. Incongruous results were also noted with use of aPLprofile plus SCORE, mSCORE or DIME versus sole use of each of the ASCVR classifiers. Nevertheless, employment of APS features collectively enhanced eligibility rates in most clinical scenarios, indicating that consideration of disease-specific characteristics in addition to ASCVR factors, as advocated by EULAR,4 is likely to benefit cardiovascular prevention in APS.

    Risk-stratified eligibility for BP and lipid modification therapy according to SCORE, mSCORE or DIME plus aPLprofile would require analysing and integrating multiple types of information. Use of a risk assessment model that incorporates all necessary variables to calculate CVR, such as the aGAPSSCVD, could obviate this need. Regrettably, this risk classifier yielded acceptable agreement to actual eligibility only for high-risk BP treatment-naïve cases. aGAPSSCVD includes ASCVR factors similar to those of SCORE and DIME10 24; however, it uses slightly different measures for BP and lipids compared with SCORE and DIME, and does not incorporate the interaction of age and gender. The relative underperformance of the aGAPSSCVD could also pertain to the fact that aPL positivity is heavily weighted in comparison to ASCVR factors. Considering the aforementioned differences, risk classification with this disease-related model should not be considered equivalent to risk assessment with the modalities using aPLprofile to interpret the results about aGAPSSCVD. Nevertheless, examining future recalibrations based on CVR classifiers as those proposed by the ESC14 18 and EULAR2 4 for ASCVR factors and aPL profile, respectively, along with validation in larger populations, could help to better clarify its role in CVR assessment in APS.

    In patients with APS, the concomitant presence of SLE could further compromise cardiovascular health because of the impact of disease activity and treatment-related CVR factors such as glucocorticoid use.4 8 35 In this study, we did not identify any significant associations between high SLE activity, treatment with glucocorticoids, or hydroxychloroquine non-use and a very-high actual ASCVR. This finding may be due to the small sample of patients with SLE-APS, the low disease activity (mean SLEDAI-2k 2.4) or daily and/or cumulative doses of glucocorticoids in our SLE-APS subpopulation, which are considerably lower compared with those associated with cardiovascular damage in SLE,4 35 or both.

    Discordance between eligibility informed by composite risk assessment modalities and ASCVR classifiers may be grounded to the complex and reciprocal interactions between traditional CVR factors and aPL. Indeed, hypertension and hyperlipidaemia increase the risk of thrombotic events in aPL-positive patients without prior atherosclerotic CVD, while aPL positivity is linked to atherogenesis in normotensive, normolipidaemic individuals.7 8 10 24 These observations highlight the multifaceted nature of CVR in APS, and possibly argue for a reappraisal of the distinction between ‘traditional’ (ie, predominantly driving atherosclerosis) and ‘disease-specific’ (ie, representative of autoimmune cardiovascular damage) risk factors to manage cardiovascular health in this RMD. Future studies that address this intricate issue, not least the potential clinical implications thereof, would be welcomed.

    Previous studies in APS highlighted that different types of thrombotic manifestations including cardiovascular events may be associated with disease-related features such as the aPL profile, but also with particular clusters of ASCVR factors and comorbid conditions.2 8 9 24 31 32 39 However, disease features commonly examined as predictors of vascular damage in other RMDs4 35 such as disease activity and the impact of angioprotective treatment on various components of CVR (eg, possible modifications of ASCVR by use of antiplatelets or hydroxychloroquine) have yet to be thoroughly investigated in APS. The need for more research on these topics, which would allow to outline clinical CVR phenotypes to optimise personalised preventive efforts in APS, as also underlined by EULAR recommendations for CVR management,4 cannot be overemphasised.

    The main strengths of our study are the multidisciplinary approach involving different medical specialties; the multimodal CVR assessment by examining risk factors associated with both immune-mediated and atherogenic cardiovascular damage, as recommended by EULAR for patients with APS2 4; and the identification of actual and predicted risk to determine eligibility to initiate BP-lowering and lipid-lowering treatment according to ESC guidelines.14–17 We evaluated standard14 17 and novel10 18 CVR qualifiers by stratifying risk classes based on current evidence about the impact of traditional and disease-related CVR features in APS applied to a comprehensive BP and lipid profiling. Accounting for the rarity of the disease,20 our study included a rather large sample of patients with APS, considering also the exclusion criteria and the high percentage of patients with APS followed in our department who accepted to participate in VUS studies.

    A possible limitation of this study is the inclusion of patient with both PAPS and SLE-APS groups. However, SLE-specific variables were not found to act as additional very-high risk classifiers in the group of SLE-APS cases. Thus, in the context of multimodal CVR assessment, the examined traditional, cardiometabolic and APS-specific CVR features common to both PAPS and SLE-APS can apply as risk classifiers to all APS cases. Nevertheless, large-population, multicentre studies to appraise and/or validate our findings, allowing to stratify results in various clinical scenarios (eg, SLE-APS vs PAPS, or the impact of ‘non-criteria’ features on CVR), are warranted. In addition, generalisation of our results is precluded by the inclusion of only white Europeans from a geographical area not included among high-ASCVR countries.14

    To conclude, our study tested the SCORE equations in the context of risk-stratified management of BP and lipid levels and found that use of these risk classifiers alone would compromise optimal risk factor modification. The addition of disease-related features based on clinical and laboratory APS phenotypes, as well as considering measures of ASCVR previously identified for DM, may improve CVR factor management. Future research further assessing our observations about the use of composite risk classification modalities including disease-specific traits, high-ASCVR cardiometabolic features or APS-specific risk models to inform CVR management in APS is needed.

    Data availability statement

    Data are available upon reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study was approved by the Laiko General Hospital Scientific Board (SB number: 1790). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We would like to thank all patients for their participation and Dr S Liatis, MD, for his helpful comments.

    References

    1. ↵
      1. Miyakis S,
      2. Lockshin MD,
      3. Atsumi T, et al
      . International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. doi:10.1111/j.1538-7836.2006.01753.x
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Tektonidou MG,
      2. Andreoli L,
      3. Limper M, et al
      . EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296–304. doi:10.1136/annrheumdis-2019-215213
      OpenUrlCrossRefPubMed
    3. ↵
      1. Cervera R,
      2. Serrano R,
      3. Pons-Estel GJ, et al
      . Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015;74:1011–8. doi:10.1136/annrheumdis-2013-204838
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Drosos GC,
      2. Vedder D,
      3. Houben E, et al
      . EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis 2022;81:768–79. doi:10.1136/annrheumdis-2021-221733
      OpenUrlAbstract/FREE Full Text
    5. ↵
      1. Sciascia S,
      2. Cuadrado MJ,
      3. Sanna G, et al
      . Thrombotic risk assessment in systemic lupus erythematosus: validation of the global antiphospholipid syndrome score in a prospective cohort. Arthritis Care Res (Hoboken) 2014;66:1915–20. doi:10.1002/acr.22388
      OpenUrl
    6. ↵
      1. Sciascia S,
      2. Sanna G,
      3. Murru V, et al
      . The global anti-phospholipid syndrome score in primary APS. Rheumatology (Oxford) 2015;54:134–8. doi:10.1093/rheumatology/keu307
      OpenUrlCrossRefPubMed
    7. ↵
      1. Radin M,
      2. Sciascia S,
      3. Erkan D, et al
      . The adjusted global antiphospholipid syndrome score (aGAPSS) and the risk of recurrent thrombosis: results from the APS ACTION cohort. Semin Arthritis Rheum 2019;49:464–8. doi:10.1016/j.semarthrit.2019.04.009
      OpenUrlCrossRefPubMed
    8. ↵
      1. Tektonidou MG
      . Cardiovascular disease risk in antiphospholipid syndrome: thrombo-inflammation and atherothrombosis. J Autoimmun 2022;128:102813. doi:10.1016/j.jaut.2022.102813
      OpenUrl
    9. ↵
      1. Moreno-Torres V,
      2. Royuela A,
      3. Tarín C, et al
      . Impact of cardiovascular risk factors in antiphospholipid syndrome: an observational study from the Spanish national registry. Clin Exp Rheumatol 2022;40:2161–6. doi:10.55563/clinexprheumatol/h2tkx3
      OpenUrl
    10. ↵
      1. Di Minno MND,
      2. Scalera A,
      3. Tufano A, et al
      . The association of adjusted global AntiPhospholipid Syndrome Score (aGAPSS) with cardiovascular disease in subjects with Antiphospholipid antibodies. Atherosclerosis 2018;278:60–5. doi:10.1016/j.atherosclerosis.2018.09.010
      OpenUrlPubMed
    11. ↵
      1. Bolla E,
      2. Tentolouris N,
      3. Sfikakis PP, et al
      . Cardiovascular risk management in antiphospholipid syndrome: trends over time and comparison with rheumatoid arthritis and diabetes mellitus. Lupus Sci Med 2021;8:e000579. doi:10.1136/lupus-2021-000579
    12. ↵
      1. Yelnik CM,
      2. Martin C,
      3. Ledoult E, et al
      . Dyslipidemia is insufficiently treated in antiphospholipid syndrome patients. Lupus 2022;31:1379–84. doi:10.1177/09612033221114275
      OpenUrl
    13. ↵
      1. Panopoulos S,
      2. Thomas K,
      3. Georgiopoulos G, et al
      . Comparable or higher prevalence of comorbidities in antiphospholipid syndrome vs rheumatoid arthritis: a multicenter, case-control study. Rheumatology (Oxford) 2021;60:170–8. doi:10.1093/rheumatology/keaa321
      OpenUrlCrossRefPubMed
    14. ↵
      1. Piepoli MF,
      2. Hoes AW,
      3. Agewall S, et al
      . European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–81. doi:10.1093/eurheartj/ehw106
      OpenUrlCrossRefPubMed
    15. ↵
      1. Williams B,
      2. Mancia G,
      3. Spiering W, et al
      . ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104. doi:10.1093/eurheartj/ehy339
      OpenUrlCrossRefPubMed
    16. ↵
      1. Mach F,
      2. Baigent C,
      3. Catapano AL, et al
      . ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019;41:111–88.
      OpenUrlCrossRef
    17. ↵
      1. Rossello X,
      2. Dorresteijn JA,
      3. Janssen A, et al
      . Risk prediction tools in cardiovascular disease prevention: a report from the ESC prevention of CVD programme led by the European Association of Preventive Cardiology (EAPC). Eur J Prev Cardiol 2019;26:1534–44.
      OpenUrlPubMed
    18. ↵
      1. Cosentino F,
      2. Grant PJ,
      3. Aboyans V, et al
      . ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2019;41:255–323.
      OpenUrl
    19. ↵
      1. Bolla E,
      2. Tentolouris N,
      3. Sfikakis PP, et al
      . Metabolic syndrome in antiphospholipid syndrome versus rheumatoid arthritis and diabetes mellitus: association with arterial thrombosis, cardiovascular risk biomarkers, physical activity, and coronary atherosclerotic plaques. Front Immunol 2022;13:1077166. doi:10.3389/fimmu.2022.1077166
    20. ↵
      1. Ambrosino P,
      2. Lupoli R,
      3. Di Minno A, et al
      . Markers of cardiovascular risk in patients with antiphospholipid syndrome: a meta-analysis of literature studies. Ann Med 2014;46:693–702. doi:10.3109/07853890.2014.959559
      OpenUrlCrossRefPubMed
    21. ↵
      1. Karakasis P,
      2. Lefkou E,
      3. Pamporis K, et al
      . Risk of subclinical atherosclerosis in patients with antiphospholipid syndrome and subjects with antiphospholipid antibody positivity: a systematic review and meta-analysis. Curr Probl Cardiol 2023;48:101672. doi:10.1016/j.cpcardiol.2023.101672
    22. ↵
      1. Kravvariti E,
      2. Konstantonis G,
      3. Tentolouris N, et al
      . Carotid and femoral atherosclerosis in antiphospholipid syndrome: equivalent risk with diabetes mellitus in a case-control study. Semin Arthritis Rheum 2018;47:883–9. doi:10.1016/j.semarthrit.2017.10.015
      OpenUrl
    23. ↵
      1. Evangelatos G,
      2. Kravvariti E,
      3. Konstantonis G, et al
      . Atherosclerosis progression in antiphospholipid syndrome is comparable to diabetes mellitus: a 3 year prospective study. Rheumatology (Oxford) 2022;61:3408–13. doi:10.1093/rheumatology/keab882
      OpenUrl
    24. ↵
      1. Calcaterra I,
      2. Tufano A,
      3. Lupoli R, et al
      . Cardiovascular disease and antiphospholipid syndrome: how to predict and how to treat Pol Arch Intern Med 2021;131:161–70. doi:10.20452/pamw.15415
      OpenUrl
    25. ↵
      1. Petri M,
      2. Orbai A-M,
      3. Alarcón GS, et al
      . Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86. doi:10.1002/art.34473
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Grundy SM
      . Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1–4. doi:10.1161/01.cir.95.1.1
      OpenUrlFREE Full Text
    27. ↵
      1. Chapman MJ,
      2. Ginsberg HN,
      3. Amarenco P, et al
      . Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345–61. doi:10.1093/eurheartj/ehr112
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Touboul P-J,
      2. Hennerici MG,
      3. Meairs S, et al
      . Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 2012;34:290–6. doi:10.1159/000343145
      OpenUrlCrossRefPubMed
    29. ↵
      1. Urowitz MB,
      2. Ibañez D,
      3. Su J, et al
      . Modified Framingham risk factor score for systemic lupus erythematosus. J Rheumatol 2016;43:875–9. doi:10.3899/jrheum.150983
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Hippisley-Cox J,
      2. Coupland C,
      3. Brindle P
      . Development and validation of QRISK3 risk prediction Algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ 2017;357:j2099. doi:10.1136/bmj.j2099
    31. ↵
      1. Matyja-Bednarczyk A,
      2. Swadźba J,
      3. Iwaniec T, et al
      . Risk factors for arterial thrombosis in antiphospholipid syndrome. Thromb Res 2014;133:173–6. doi:10.1016/j.thromres.2013.11.012
      OpenUrl
    32. ↵
      1. Sevim E,
      2. Zisa D,
      3. Andrade D, et al
      . Characteristics of patients with antiphospholipid antibody positivity in the APS ACTION International clinical database and repository. Arthritis Care Res (Hoboken) 2022;74:324–35. doi:10.1002/acr.24468
      OpenUrl
    33. ↵
      1. Abdullah SM,
      2. Defina LF,
      3. Leonard D, et al
      . Long-term association of low-density lipoprotein cholesterol with cardiovascular mortality in individuals at low 10-year risk of atherosclerotic cardiovascular disease. Circulation 2018;138:2315–25. doi:10.1161/CIRCULATIONAHA.118.034273
      OpenUrlCrossRefPubMed
    34. ↵
      1. Brunner FJ,
      2. Waldeyer C,
      3. Ojeda F, et al
      . Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium. Lancet 2019;394:2173–83. doi:10.1016/S0140-6736(19)32519-X
      OpenUrlPubMed
    35. ↵
      1. Drosos GC,
      2. Konstantonis G,
      3. Sfikakis PP, et al
      . Lipid management in systemic lupus erythematosus according to risk classifiers suggested by the European Society of Cardiology and disease-related risk factors reported by the EULAR recommendations. RMD Open 2023;9:e002767. doi:10.1136/rmdopen-2022-002767
    36. ↵
      1. Drosos GC,
      2. Konstantonis G,
      3. Sfikakis PP, et al
      . Underperformance of clinical risk scores in identifying vascular ultrasound-based high cardiovascular risk in systemic lupus erythematosus. Eur J Prev Cardiol 2021;28:346–52. doi:10.1093/eurjpc/zwaa256
      OpenUrlPubMed
    37. ↵
      1. Courand P-Y,
      2. Lenoir J,
      3. Grandjean A, et al
      . SCORE underestimates cardiovascular mortality in hypertension: insight from the OLD-HTA and NEW-HTA Lyon cohorts. Eur J Prev Cardiol 2022;29:136–43. doi:10.1093/eurjpc/zwaa163
      OpenUrl
    38. ↵
      1. Wilson PWF,
      2. D’Agostino RB,
      3. Parise H, et al
      . Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112:3066–72. doi:10.1161/CIRCULATIONAHA.105.539528
      OpenUrlAbstract/FREE Full Text
    39. ↵
      1. Danowski A,
      2. de Azevedo MNL,
      3. de Souza Papi JA, et al
      . Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J Rheumatol 2009;36:1195–9. doi:10.3899/jrheum.081194
      OpenUrlAbstract/FREE Full Text

    Supplementary materials

    Footnotes

    • Twitter @MariaTektonidou

    • Contributors GCD: conceptualisation, methodology, investigation, resources, data curation, writing—original draft, writing—review and editing and visualisation. GK: investigation, data curation and formal analysis. PPS: investigation and resources. MGT: conceptualisation, methodology, investigation, resources, writing—review and editing, supervision and project administration; guarantor. All authors contributed to data interpretation and gave final approval of the manuscript.

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

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.