Modern therapy of patients with lupus erythematosus must include appropriate management of their heightened rates of atherosclerotic cardiovascular events: a literature update

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains the biggest killer of patients with lupus erythematosus (LE) and the general non-autoimmune population. In this literature update on LE and ASCVD, we focused on published work since our earlier review article, meaning from 2021 to the present, with an emphasis on cutaneous LE. Several themes emerged. First, new work shows that patients with lupus still exhibit a high burden of conventional risk factors for ASCVD events. Second, recent studies continue to implicate possible effects of lupus disease activity to worsen rates of ASCVD events beyond predictions from conventional risk factors. Third, new work on estimating the risk of future ASCVD events in patients with lupus supports arterial-wall imaging, inclusion of lupus-specific factors, estimators of ASCVD event risk that take lupus status into account and considering lupus as a diabetes equivalent or even as a diabetes-plus-smoking equivalent in this context. Technologies for arterial-wall imaging continue to improve and will likely play an increasing role in ASCVD assessment and management. Fourth, purported cardiovascular benefits from certain disease-modifying antirheumatic drugs such as antimalarials have become less clear. Fifth, earlier treatment of atherosclerosis, which is a lifelong disease, can be accomplished with diet, exercise, smoking cessation and new classes of safe and effective medications for lipid-lowering and blood pressure control. Benefits on subclinical arterial disease by imaging and on ASCVD events have been reported, supporting the concept that ASCVD is eminently manageable in this autoimmune condition. Sixth, despite the heightened risk for ASCVD events in patients with lupus, available therapeutic approaches remain unused or underused and, accordingly, event rates remain high.

Raising awareness among patients and healthcare providers about ASCVD assessment and management in patients with LE is essential. Greater vigilance is needed to prevent ASCVD events in patients with lupus by addressing dyslipidaemias, hypertension, smoking, obesity and physical inactivity.

Correspondence to Dr Victoria P Werth; [email protected] ; Dr Kevin Jon Williams; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Atherosclerotic cardiovascular disease (ASCVD) remains the biggest killer of patients with lupus erythematosus (LE) and the general non-autoimmune population.

• Recent data continue to indicate that patients with cutaneous LE (CLE) often display elevated levels of conventional risk factors for ASCVD events.

WHAT THIS STUDY ADDS

• The high prevalence and severe impact of ASCVD among patients with lupus underscore the urgent need for improved management strategies.

• Atherosclerosis is a lifelong disease, and several authors have argued for earlier interventions, especially as arterial-wall imaging improves, thereby facilitating the detection of subclinical atherosclerosis.

• Rheumatologists and dermatologists should increase their efforts to screen patients with lupus for plasma levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a) and triglycerides; blood pressure and tobacco smoking; as well as the presence of image-evident arterial plaques.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• This information should provoke prompt referral of these patients to preventive cardiology and to smoking cessation specialists.

• Future research should focus on enhancing risk estimation models, developing comprehensive guidelines tailored for patients with SLE and CLE and improving implementation to better address their cardiovascular health.

1. Introduction

It is a sign of therapeutic success that patients with lupus erythematosus (LE) only rarely die early from their disease or its complications anymore.^{1 2} But this success means that atherosclerotic cardiovascular disease (ASCVD), always an important source of morbidity and mortality in LE, has become even more prominent as patients with LE live longer.^2–5 Thus, modern comprehensive management of patients with LE must include prevention and treatment of ASCVD to avoid its clinical manifestations—called ‘events’—chiefly heart attacks, strokes and new-onset symptomatic peripheral artery disease.^5–7

To address the burden of ASCVD in LE, we reviewed published literature several years ago, concluding that most studies in this area show that patients with LE are at a heightened risk of ASCVD events.⁵ Accordingly, we also proposed guidelines for assessing patients with systemic LE (SLE) and cutaneous LE (CLE) using four defined categories of ASCVD event risk, with corresponding guidance for clinical management in each ASCVD event risk category with lifestyle modifications and modern medications (table 1).⁵ We explicitly modelled our proposed guidelines after risk categories and therapeutic goals that had been established for diabetes mellitus, a well-studied condition that also shows a heightened risk for ASCVD events and has been incorporated into standard clinical guidelines for the management of ASCVD event risk. Recently published longitudinal data from us⁸ and others,⁹ reviewed in more detail in several of the sections below, provide quantitative support for the use of guidelines that treat lupus as a diabetes equivalent, or even as a diabetes-plus-smoking equivalent, in the context of management of ASCVD event risk.^{8 9}

Table 1

Categories of ASCVD event risk for patients with lupus erythematosus, with recommended targets for lipoprotein cholesterol and apolipoprotein B (Reproduced with permission from Keyes et al⁵)

Risk category	Risk factors	Target serum levels (mg/dL)
		LDLc	Non-HDLc	ApoB
Recent recurrent ASCVD events	Any patient with clinically evident ASCVD* who experiences two atherosclerotic vascular events within 2 years despite taking maximally tolerated statin therapy, regardless of other medical conditions	<40	No explicit recommendations	No explicit recommendations
Extreme risk	Patients with LE and clinically evident ASCVD	<55	<80	<70
Very high risk	Patients with LE with ≥1 conventional risk factor for ASCVD events†, or evidence of subclinical atherosclerosis on imaging‡, or the presence of certain SLE-specific factors§	<70	<100	<80
High risk	Patients with LE without conventional risk factors for ASCVD events†, evidence of subclinical atherosclerosis on imaging‡ or other comorbidities	<100	<130	<90

Non-HDLc pertains to a convenient parameter that includes the cholesterol carried by all harmful plasma lipoproteins and is calculated as the total plasma cholesterol concentration minus HDLc.

*Clinically evident ASCVD: angina, prior myocardial infarction, atherosclerotic stroke or transient cerebrovascular ischaemic attack, and/or symptomatic peripheral artery disease.

†Conventional risk factors for ASCVD events: major risk factors are age (men aged >45 years, women aged >55 years), high LDLc (>160 mg/dL), high non-HDLc (≥190 mg/dL), high plasma apoB (>110 mg/dL), cigarette smoking, hypertension (blood pressure ≥130/80), low HDLc (≤40 mg/dL in men, ≤50 mg/dL in women), family history of premature ASCVD events (age <55 years in first-degree male relative, <65 years in first-degree female relative), stage 3 or 4 chronic kidney disease, diabetes mellitus. Additional risk factors are abdominal obesity, polycystic ovarian syndrome and/or high plasma Lp(a). A calculated 10-year ASCVD event risk of ≥7.5% by the Framingham Risk Score×2 or QRisk3 (if SLE is present) calculator could also be used to reclassify a patient with LE from high to very high risk.

‡Evidence of subclinical atherosclerosis on imaging can include a non-zero coronary artery calcium score, carotid or femoral plaque on ultrasound, or image-evident plaque on coronary CT angiography.

§In LE, certain disease-specific factors, particularly high disease activity, long duration, high cumulative damage, a history of corticosteroid use, the presence of serum antiphospholipid antibodies and lupus nephritis, can also be used to reclassify a patient from high to very high risk.

ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; LE, lupus erythematosus; Lp(a), lipoprotein(a).

For a literature update, we searched PubMed for published work since our earlier review article,⁵ that is, from 2021 to the present, using the terms ‘lupus’ and ‘atherosclerosis’ (265 hits), and then a title review to eliminate case reports, basic science articles and references not related to both search terms, thereby limiting ourselves to relevant published clinical studies (69 hits). Our update emphasises CLE, meaning CLE without (CLE-only) or with (CLE+SLE) systemic LE. Here, we present a short overview of the field (section 2) and then our updates in specific areas (sections 3–8), each beginning with a brief background and then a summary focusing on the newly published work. Recent data continue to indicate that patients with CLE often display elevated levels of conventional risk factors for ASCVD events (section 3). In addition, there is some evidence that LE disease activity worsens ASCVD and its manifestations beyond predictions from conventional risk factors (section 4). Patients with LE experience a greater accumulation of atherosclerotic plaques (section 5) and have higher age and sex-adjusted rates of ASCVD and arterial thrombotic events compared with the general population (section 6).^{5 8} New data also address how to clinically assess the heightened risk of ASCVD events in individual patients with lupus (section 7) and how to manage their heightened risk (section 8). We end with Conclusions and future directions (section 9). Section headings generally follow our earlier review article.⁵

2. Overview of the field: the pathogenesis of atherosclerosis, how end-stage plaques cause ASCVD events, the role of conventional risk factors in assessment and management, and likely effects in patients with lupus that accelerate atherogenesis and then ASCVD events

2.1. Pathogenesis of atherosclerosis: the response-to-retention model

Atherosclerosis begins early in life, often during childhood,^{10 11} and has become a widespread epidemic.^12–14 The key initiating event in atherosclerosis is the retention, or trapping, of low-density lipoprotein (LDL) and related cholesterol-rich lipoproteins, such as lipoprotein(a) (Lp(a)) and cholesterol and triglyceride-rich lipoproteins (C-TRLs), within the subendothelial region of the arterial wall (figure 1).^{5 15–18} Examples of C-TRLs include very-low-density lipoprotein, intermediate-density lipoproteins and chylomicron remnants.¹⁹ All of these lipoproteins are atherogenic, and the major protein of these particles, including LDL, is a large hydrophobic molecule called apolipoprotein B (apoB). Each atherogenic lipoprotein particle contains exactly one molecule of apoB, and so plasma levels of apoB have emerged as a strong factor in estimating the risk of future ASCVD events, performing better than any measurement of plasma or lipoprotein lipids, including cholesterol.²⁰ Because of the high atherogenicity of Lp(a),^{20 21} its plasma levels should be measured separately. These apoB lipoproteins become trapped within the arterial wall, modified by local enzymes and other factors, and the modified material triggers a series of strikingly maladaptive responses that lead to plaque development and growth (figure 1).^{5 15–18}

Figure 1. The response-to-retention model for the pathogenesis of atherosclerosis. Arrows are colour coded to indicate crucial mechanisms in retention and modification. The key initiating step in atherogenesis is the retention and aggregation of cholesterol-rich atherogenic apolipoprotein B lipoproteins within the arterial wall (yellow). Then, maladaptive local responses to the retained and modified lipoproteins lead to plaque growth and progression (red). Processes to the left of the vertical dashed line are characteristic of early atherosclerotic plaques and hence remain entirely or nearly entirely reversible, while processes to the right of the vertical dashed line are characteristic of advanced, end-stage plaques and hence appear to be only partially reversible. Foam cell pertains to a macrophage or smooth muscle cell that has accumulated intracellular droplets of lipid. C-TRL, cholesterol and triglyceride-rich lipoprotein; IDL, intermediate-density lipoprotein; IEL, internal elastic lamina; IFN, interferon; IL, interleukin; LDL, low-density lipoprotein; LP, lipoprotein; Lp(a), lipoprotein(a); LpL, lipoprotein lipase; MMPs, matrix metalloproteinases; PGs, proteoglycans; SMase, the secretory acid sphingomyelinase; SMC, smooth muscle cell; TF, tissue factor; UC, unesterified cholesterol. Reproduced with permission from Williams, 18 which was adapted from Williams and Tabas. 16

One of these maladaptive responses is the recruitment of macrophages that abnormally linger within the developing lesion and release several harmful products. Their harmful products include lipoprotein lipase, a protein that acts synergistically with the secretory acid sphingomyelinase within the arterial wall to vastly accelerate the entrapment and aggregation of additional cholesterol-rich apoB lipoproteins; proteases that weaken the fibrous cap overlying the plaque, thereby predisposing to its rupture or erosion; and tissue factor that ensures robust clot formation on plaque rupture or erosion (figure 1).^{5 15–18 22}

2.2. Rupture and erosion of end-stage plaques cause ASCVD events

After many decades, advanced plaques reach an end stage characterised by rupture or erosion. Typically, it is the resulting clot that forms at the site of rupture or erosion, in combination with the plaque itself, that acutely obstructs the arterial lumen to cause an ischaemic event downstream.^{23 24} Most atherosclerotic heart attacks are caused by ruptured or eroded plaques that were less than 50% occlusive shortly before the event, primarily because these smaller plaques are so numerous.^{24 25}

2.3. The role of conventional risk factors for ASCVD events in the assessment and management of non-autoimmune patients and patients with LE

Crucial to the clinical management of atherosclerosis and prevention of ASCVD events is the concept of risk factors. Risk factors are readily assessed parameters, such as plasma concentrations of LDL cholesterol (LDLc), Lp(a) and apoB; blood pressure; smoking status; and male sex, that long-term population studies have associated with an increased chance of having a future ASCVD event. Risk factors originated as epidemiological concepts, with no implications about causality. Based on the response-to-retention model of the pathogenesis of atherosclerosis, we recently reclassified epidemiological risk factors into causative agents (LDL and other apoB lipoproteins that are <70 nm in diameter to allow their entry into the arterial wall); exacerbating factors that worsen the disease but only in the context of abundant apoB lipoproteins (eg, hypertension, smoking, diabetes, LE, male sex); and mere bystanders that are associated with future ASCVD events but do not directly affect disease progression (eg, elevated plasma homocysteine levels, elevated levels of C reactive protein per se, low plasma concentrations of high-density lipoprotein cholesterol (HDLc)).^{17 18} Causative and exacerbating factors that can be modified are targets for therapy; bystanders are not.^{17 18}

Conventional assessments of the risk of a future ASCVD event in the general non-autoimmune population rely on these conventional risk factors but also make a large distinction based on the absence or presence of clinically evident ASCVD.^{5 6 26 27} Clinically evident ASCVD includes prior myocardial infarction (MI), angina, atherosclerotic stroke, transient cerebrovascular ischaemic attacks and symptomatic peripheral artery disease—but not venous thromboembolic events, which are not atherosclerotic. In at least one guideline, unequivocally documented atherosclerosis on imaging known to be predictive of future ASCVD events, such as significant arterial plaque on coronary angiography or CT scan, was considered equivalent to clinically evident ASCVD in terms of assessment and management of event risk,²⁷ and more recent data support this conclusion.²⁸

Risk assessment and management in patients without clinically evident ASCVD is called primary prevention and relies on open-access online risk assessment tools tailored specifically for this purpose, such as the American College of Cardiology (ACC) ASCVD Risk Estimator Plus^{26 29} and the newer PREVENT equations^{30 31} from the USA, as well as the Systematic COronary Risk Evaluation version 2 (SCORE2), which was developed for use across four risk regions within Europe.^{32 33} The clinician enters each primary prevention patient’s values for a list of conventional risk factors into the online forms, and the tool calculates an estimate of the risk for an event in the next 10 years (‘10-year ASCVD event risk’). This estimated 10-year ASCVD event risk is a major component of guideline-based care to direct the intensity of therapy.^{26 27} Many risk assessment tools now also provide an estimate of residual lifetime risk for an ASCVD event, meaning beyond just 10 years, to assist longer term management.

Since our guidelines were published,⁵ the European League Against Rheumatism (EULAR) updated their guidelines for cardiovascular risk management in systemic LE.⁶ The EULAR guidelines include advice on the use of these ‘generic’ risk calculators, which were not developed specifically for patients with LE. The EULAR guidelines agree that patients with lupus have higher atherosclerotic event risk than predicted by these conventional calculators. Two principal authors of the EULAR guidelines emphasised this point in a more recent article presenting evidence of a mismatch in patients with SLE between the risk predicted by the SCORE2 and the risk revealed through the detection of subclinical atherosclerotic plaques using carotid and/or femoral arterial ultrasonography,⁷ a non-invasive imaging technique recommended by the European Society of Cardiology (ESC) to enhance risk classification and guide lipid-lowering therapy in the general population of primary prevention patients.²⁷

In contrast, management of patients with clinically evident ASCVD or its equivalent is called secondary prevention, and the online risk estimators do not apply. In secondary prevention, the measures are more aggressive, owing to the patients’ heightened risk of recurrent events. These individuals should receive comprehensive follow-up subspecialty care, including cardiology, endocrinology and nephrology.⁵ Figure 2 summarises this approach for assessment and management of clinically evident ASCVD in the context of patients with LE.

Figure 2. Flow chart of management, both primary and secondary prevention, in the context of lupus erythematosus (LE). ACEi, ACE inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease. Updated with permission from Keyes et al. 5

2.4. Likely effects in patients with lupus that accelerate atherogenesis and then ASCVD events

In our earlier review,⁵ we summarised the likely effects of lupus on four specific steps in atherogenesis and then ASCVD events—namely plaque initiation, plaque growth, destabilisation-rupture and the formation of an occlusive arterial thrombus (table 2).⁵ Sections 3 and 4 cover these topics in greater detail.

Table 2

Specific processes in LE that may accelerate atherosclerosis and hence ASCVD event risk (Reproduced with permission from Keyes et al⁵)

Pathogenetic step	Explanation	References
Plaque initiation	Worsening of causative agents (dyslipoproteinaemia: elevated plasma triglycerides, with low levels of high-density lipoprotein cholesterol) and exacerbators (hypertension, renal disease), associated with LE and LE therapies, particularly glucocorticoids. Possible effects beyond conventional factors: increased LDL retention through effects on arterial matrix and susceptibility of LDL to aggregate owing to changes in its lipidome specific to LE. Endothelial dysfunction, a known feature of LE, might include increased permeability to the entry of LDL and other apolipoprotein B lipoproteins.	87 102–107
Plaque growth	Worsening of causative agents (dyslipoproteinaemia) and exacerbators (hypertension, renal disease). Increased immune cell responses to retained lipoproteins, a finding in mouse models of LE after they are made hypercholesterolaemic. Endothelial dysfunction in this context might include increased expression of chemoattractants and cell adhesion molecules. Increased induction and intra-arterial secretion of local proaggregation enzymes (lipoprotein lipase and the secretory acid sphingomyelinase) released from activated endothelium and local persistent immune cells.	108–113
Plaque destabilisation	Decreased collagen synthesis; increased protease production.	114 115
Formation of occlusive thrombus	Systemic procoagulant state and hyperresponsive platelets that increase the likelihood of the formation of an occlusive thrombus after plaque rupture or erosion. Procoagulant microvesicles have been implicated, particularly tissue factor-positive microvesicles. Endothelial dysfunction in this context might include impairment of the anticoagulant luminal surface and impaired vasodilation, thereby facilitating occlusion.	116

ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; LE, lupus erythematosus.

3. Why does LE exacerbate atherosclerosis, arterial thrombosis and ASCVD events? Increased prevalence of conventional and novel risk factors for ASCVD events in patients with LE

3.1. Background

As noted in the Introduction section and ref ⁵, prior literature indicates that patients with LE often display elevated levels of risk factors for ASCVD events. These include abnormal lipoprotein profiles, called dyslipoproteinaemia (usually characterised by elevated plasma triglyceride concentrations and low levels of HDLc), as well as high blood pressure (reviewed in this section). Moreover, patients with CLE exhibit a higher prevalence of conventional risk factors compared with the healthy population and with patients with SLE.^{8 34} They tend to smoke more than the general population, and this increased smoking rate, along with high rates of psychiatric comorbidities and low serum vitamin D levels (suggesting an indoor lifestyle), may exacerbate the risk of ASCVD events in patients with CLE.^34–36 Despite its status as a powerful anti-inflammatory agent, glucocorticoids used to treat LE can worsen known cardiovascular risk factors such as obesity, metabolic syndrome, pre-diabetes and type 2 diabetes.^{5 37 38}

3.2. Recent findings

Recent studies with patients with LE continue to document the high prevalence of conventional risk factors for ASCVD events in these patients.³⁹ Additionally, elevated levels of apolipoprotein C-III (APOC3), currently an investigational target for lipoprotein and ASCVD management in non-autoimmune populations,^40–42 were recently associated with disease activity in patients with SLE,⁴³ suggesting that APOC3 could be a potential target in these autoimmune patients as well.

In 2023, Zhao et al from our group reported data on risk factors for ASCVD events, current management of those risk factors and actual ASCVD event rates in a longitudinal single-centre cohort of patients with CLE, split nearly evenly between CLE-only and CLE+SLE.⁸ Both subgroups had high rates of untreated or undertreated conventional risk factors for ASCVD events and, accordingly, high 10-year ASCVD event rates (section 6.2).⁸

Farina et al⁴⁴ (in a single-centre study from the UK) and Bolla et al³⁹ (in an international multiethnic survey) reported similar findings in SLE—namely a high prevalence yet undermanagement of conventional risk factors for ASCVD events. The problem is especially prominent in middle-income countries and among those with antiphospholipid antibody syndrome.³⁹ Both of these studies highlight the need for improving cardiovascular health through appropriate management of conventional cardiovascular risk factors in patients with SLE internationally.^{39 44}

For several reasons, circulating levels of APOC3 have become a novel and potentially modifiable risk factor of interest, particularly in the context of lupus. First, the APOC3 protein inhibits the clearance of atherogenic C-TRLs. Thus, plasma levels of APOC3 associate with higher concentrations of C-TRLs and apoB and an increased risk of future ASCVD events, including in Mendelian randomisation studies.⁴⁵ Second, circulating APOC3 levels are now an investigational therapeutic target in non-autoimmune cohorts (table 3).^40–42 Third, a recent report showed that among patients with SLE, autoimmune disease activity, severity and disease damage are independently associated with higher serum APOC3 levels.⁴³

Table 3

Approved agents and agents in development to lower plasma concentrations of apoB lipoproteins and thereby reduce ASCVD events (Updated with permission from Keyes et al⁵)

Class	Specific drugs	Effects/indications	References
Therapies approved by the FDA to lower plasma LDLc levels and/or ASCVD event risk
Statins	Lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin	Reduce plasma LDLc levels and ASCVD events; FDA approved for both.
Anti-PCSK9 inhibitory monoclonal antibodies	Evolocumab, alirocumab	Lower plasma levels of LDLc to approximately 30 mg/dL and reduce ASCVD event risk. FDA approved for both effects.	80 81
Cholesterol absorption inhibitor	Ezetimibe	Approved for lowering LDLc; also shown to decrease ASCVD events in two key clinical trials (IMPROVE-IT and EWTOPIA 75), but not FDA approved for this indication.	82 83
Omega-3 fatty acid derivatives	Icosapent ethyl	Lowers plasma levels of triglycerides and apolipoprotein B; FDA approved for ASCVD event reduction in patients at a high ASCVD event risk with plasma triglyceride levels of ≥150 mg/dL.	117
Bile acid sequestrants	Cholestyramine, colestipol, colesevelam	Lower plasma LDLc concentrations and ASCVD event risk; but can have significant gastrointestinal side effects and can raise plasma concentrations of triglycerides.	118
ATP citrate lyase inhibitor	Bempedoic acid	FDA approved for LDLc lowering in heterozygous familial hypercholesterolaemia or established ASCVD. CLEAR Outcomes trial demonstrated decreased ASCVD events in statin-intolerant patients. Appears to have no effects in muscles. Available alone and in a fixed combination with ezetimibe.	40 119
siRNA against PCSK9 mRNA	Inclisiran	FDA approved for LDL lowering in heterozygous familial hypercholesterolaemia or established ASCVD; after two loading doses it is administered only twice per year, which may improve convenience and adherence.	120–122
Candidate therapies under investigation in dyslipoproteinaemias and ASCVD events
Antisense oligonucleotide against APOC3 mRNA	Volanesorsen	Approved in Europe for familial chylomicronaemia syndrome, which is a rare condition of extremely high plasma triglycerides. Approval was declined in the USA based on its risk–benefit ratio.	40–42
Antisense oligonucleotide targeting APOC3 mRNA: olezarsen	Olezarsen	Results of the phase II trial were published. Significant reductions in TG, apolipoprotein C-III, very-low-density lipoprotein cholesterol and non-HDLc were also seen, while LDLc levels changed minimally or increased with some doses. Phase III studies are currently ongoing with olezarsen in patients with familial chylomicronaemia syndrome or severe hypertriglyceridaemia.	42 123
siRNA inhibiting APOC3 mRNA	AROAPOC3	Reduced TG up to 90% in phase I trials; GalNAc-linked siRNA; phase III trials are ongoing.	124
Humanised monoclonal antibody against ANGPTL3	Evinacumab	FDA approved for homozygous familial hypercholesterolaemia, a rare syndrome of extremely high LDL levels; also under evaluation in more common circumstances.	125
Antisense oligonucleotide against LPA mRNA	Pelacarsen	Lowers Lp(a) levels in a dose-dependent manner in patients with elevated Lp(a) and clinically evident cardiovascular disease.	126–128
siRNAs against LPA mRNA	Olpasiran, lepodisiran, zerlasiran	Lower Lp(a) levels in a dose-dependent manner in patients with elevated Lp(a) and clinically evident cardiovascular disease.	126–130
Orally administered agent to block Lp(a) formation	Muvalaplin	Lowered plasma Lp(a) concentrations, as assessed by an intact lipoprotein(a) assay and by an apolipoprotein(a) assay.	131
Antisense oligonucleotide against sulfatase-2 mRNA	Unnamed	Restores normal postprandial clearance of C-TRLs via hepatic syndecan-1 in obese type 2 diabetic animals.	132

ASCVD, atherosclerotic cardiovascular disease; C-TRL, cholesterol and triglyceride-rich lipoprotein; FDA, US Food and Drug Administration; HDLc, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDLc, LDL cholesterol; Lp(a), lipoprotein(a); TG, triglyceride.

4. Why does LE exacerbate atherosclerosis, arterial thrombosis and ASCVD events? Possible effects of LE disease activity on ASCVD events beyond predictions from conventional risk factors

4.1. Background

Regarding potential contributions from lupus disease activity to ASCVD that are beyond predictions from conventional risk factors, prior literature had linked some lupus therapies with possible cardiovascular benefits.⁵ Recent reports have added to this literature by comparing ASCVD event rates in patients with systemic versus skin-only lupus⁸ and by examining ASCVD or ASCVD markers during the use of older and newer LE therapies, including hydroxychloroquine, tofacitinib, belimumab, anifrolumab and colchicine. The reported effects of these therapeutic agents rely on correlations from cohort studies, not primary outcomes from large-scale randomised clinical trials of cardiovascular benefit in patients with LE, and many of the effects remain controversial. For example, a recent meta-analysis suggested that studies reporting benefits of antimalarial therapy on ASCVD biomarkers in patients with SLE relied on low-quality to very-low-quality evidence.⁴⁶

4.2. Recent findings

As noted in section 3.2, Zhao et al studied patients with CLE-only or CLE+SLE in a longitudinal cohort.⁸ In particular, patients with CLE-only had statistically significantly worse conventional risk factor profiles than did patients with CLE+SLE. The difference was driven in part by higher rates of untreated hypertension and, consistent with prior reports, higher rates of tobacco smoking in the CLE-only subgroup.⁸ Nevertheless, the 10-year ASCVD event rates were strikingly similar at 13.2% and 13.7%, respectively, as were the prevalences of clinically evident ASCVD between the two subgroups. Thus, patients with CLE-only have a greater burden of conventional ASCVD risk factors, meaning causative agents and non-autoimmune exacerbators, whereas patients with CLE+SLE have a greater burden of LE that apparently exacerbated their ASCVD event rate. As discussed in more detail in section 6.2, these 10-year ASCVD event rates also indicate that both subgroups are at heightened risk.⁸

Recent work has shown an association between the use of hydroxychloroquine, a first-line medication for lupus, and lower rates of major adverse cardiovascular events (MACE) in patients with SLE, but not CLE, in a large nationwide cohort study from Denmark, suggesting cardiovascular benefits from treating their autoimmune disease with this agent.^{5 47} In another study of patients with SLE, however, the use of hydroxychloroquine, cyclophosphamide or rituximab was not associated with either the absence or presence of adverse ASCVD outcomes.⁴⁸ Regarding arterial disease, non-use of hydroxychloroquine was associated with plaque progression over 5 years in adult women with SLE⁴⁹ and with an increased risk of MACE in patients with SLE, but not necessarily patients with CLE.⁴⁷ Use of azathioprine has also been associated with lower odds of atherosclerosis by carotid ultrasonography in patients with SLE.⁵⁰ Other work did not detect a protective effect of hydroxychloroquine on the progression of subclinical atherosclerosis, and the authors proposed possible explanations for this finding compared with prior literature.⁵¹ As noted above, a recent meta-analysis suggested that the reported benefits of antimalarial therapy on ASCVD biomarkers in patients with SLE relied on low-quality to very-low-quality evidence.⁴⁶ In particular, structural assessments, such as carotid intima-media thickness (cIMT), ultrasound for carotid plaque and coronary artery calcification, showed no associations with use or non-use of antimalarial therapy, and for functional markers, such as endothelial and arterial stiffness, benefit was also unclear.⁴⁶

A very recent study examined patients with SLE treated with belimumab (Benlysta), which is an inhibitory antibody against B-cell activating factor, also known as B-lymphocyte stimulator, that is approved for use in this disease. Treatment of patients with SLE with this medication was reported to produce improvements in HDL function and in the HDL lipidomic signature.⁵² Nevertheless, all treatments to date to increase plasma HDL concentrations or even to improve HDL function in non-autoimmune patients have failed to produce any cardiovascular benefits, most recently in the unsuccessful AEGIS-II trial of an HDL-like preparation, raising serious doubts about the role of HDL in human ASCVD.^{17 18 53} Mendelian randomisation studies in human populations have given the same message: genetically elevated or reduced levels of HDLc in plasma do not affect rates of ASCVD events, arguing against HDLc as a therapeutic target.^{5 17 18 54}

In a recent study of anifrolumab, a monoclonal blocking antibody against the type I interferon receptor that is approved for the treatment of SLE, effects in these patients on the formation of neutrophil extracellular traps (NETs) and two unconventional cardiometabolic disease markers were assessed compared with a placebo.⁵⁵ The cardiometabolic disease markers examined were cholesterol-efflux capacity (CEC), which is related to HDL function hence of unclear value, and glycoprotein acetylation (GlycA), which is a nuclear magnetic resonance signal found on acute-phase response proteins. Both markers were significantly dysregulated in patients with SLE compared with healthy controls (p<0.001). Administration of anifrolumab led to a significant reduction in NET complexes and GlycA levels and an improvement in CEC from baseline (p<0.05) in the patients with SLE, while the placebo produced no such improvements.⁵⁵

Recent data have been mixed or negative regarding possible cardiovascular benefits of tofacitinib,^{56 57} a Janus kinase inhibitor that is currently approved for the treatment of rheumatoid arthritis and severe ulcerative colitis, and colchicine,^58–61 a microtubule inhibitor with anti-inflammatory and antiplatelet properties.

5. Increased burden and progression of arterial disease in patients with LE

5.1. Background

As noted in the Introduction section and ref ⁵, prior literature indicates an increased burden of atherosclerosis among patients with LE compared with the general non-autoimmune population.

5.2. Recent findings

In the context of lupus, arterial-wall imaging has been informative in measuring plaque burden, and analyses of pulse waves have been used to assess arterial stiffness. Recent imaging studies involving patients with lupus, however, often include a relatively small sample size, typically fewer than 100 participants, which suggests potential limitations in statistical power. In addition, recent imaging studies have focused on SLE, not CLE, and will be covered only briefly here. Nevertheless, important new imaging data support the management of conventional risk factors for ASCVD events in slowing the progression of arterial disease in LE.

Papazoglou et al reported that patients with SLE had four times the rate of developing new plaques than did healthy controls during 7 years of follow-up. Importantly, regarding management, multivariate regression analyses indicated an ~50% decrease in plaque progression in patients with SLE who achieved the ESC targets for five conventional modifiable cardiovascular risk factors: blood pressure, smoking status, body weight, lipids and physical activity (OR 0.56, 95% CI 0.34, 0.93, p=0.026).⁵¹ In a separate study, Lertratanakul et al found that increased waist circumference and higher fasting glucose levels were linked to plaque progression over 5 years in adult women with SLE.⁴⁹ Overall, these longitudinal arterial-wall imaging results highlight the importance of controlling key conventional risk factors for ASCVD events in the specific context of lupus.

Evangelatos et al found that patients with antiphospholipid syndrome (APS) had three times the rate of atherosclerosis progression compared with healthy controls and double the rate compared with patients with diabetes during 7 years of follow-up.⁹ The comparison with diabetes lends further support for treating SLE with APS as a diabetes-plus-smoking equivalent in the context of management of ASCVD event risk.⁸ Of note, these authors also found that sustained achievement of target LDLc levels was associated with a striking two-thirds reduction in the risk of plaque progression (OR 0.34, p=0.021), supporting the concept that atherosclerotic arterial disease is eminently manageable even in autoimmune conditions.^{5 8 18}

The use of glucocorticoids is another factor that has been associated with accelerated atherosclerosis and ASCVD events in patients with lupus.^{5 62} Croca et al recently reported that the total plaque area (measured by ultrasonography of both carotid and both femoral artery bifurcations) was larger in patients with lupus taking prednisolone than in those who were not.⁶² Moreover, while most plaques were echolucent, increased echogenicity was linked to both lupus disease activity and prednisolone use.⁶² Explanations for these findings could include direct effects of glucocorticoids to worsen plaques and indirect effects through worsening lipoprotein profiles, blood pressure, glycaemic control and body weight.

6. Increased age and sex-adjusted rates of ASCVD events in patients with LE, especially CLE

6.1. Background

As noted in the Introduction section and ref ⁵, prior literature indicates that patients with LE face a higher risk of ASCVD events than the general population.

6.2. Recent findings

New studies, including real-world data, in addition to clinical trials, continue to highlight the increased risk of ASCVD events in patients with SLE and CLE compared with the general population.^{8 63 64} Factors in patients with SLE such as higher hypertension rates were associated with worse cardiovascular outcomes, regardless of treatment with hydroxychloroquine or other medications.^{8 26 48 64}

As briefly noted above, Zhao et al presented real-world data on 10-year ASCVD event rates in a longitudinal cohort of patients with CLE-only or CLE+SLE.⁸ The 10-year ASCVD event rates of 13.2% and 13.7% (average 13.5%) were particularly striking, given the preponderance of women (82.4%) and the patients’ relative youth at enrolment (47 years of age on average). These event rates are well above the key cut-off of 7.5% estimated 10-year ASCVD event risk from the ACC/American Heart Association (AHA) guidelines for primary prevention of ASCVD events in the general population.²⁶ In those guidelines, estimates of 10-year ASCVD event risk ≥7.5% come with substantially more aggressive recommendations for management compared with the recommendations for patients with estimates of 10-year ASCVD event risk <7.5%.²⁶ For comparison, a conventional online tool for use in the general non-autoimmune population, the ACC ASCVD Risk Estimator Plus,^{26 29} gives an estimate of 10-year ASCVD event risk of 13.5% for a 47-year-old woman if she has a combination of diabetes, current smoking, treated hypertension, an HDLc of 40 mg/dL (1.0 mmol/L) and a non-HDLc of 196 mg/dL (5.1 mmol/L) if Caucasian and a non-HDLc of 131 mg/dL (3.4 mmol/L) if African-American.⁸ These results support the use of guidelines, such as the ones proposed by Keyes et al,⁵ that treat lupus as a diabetes equivalent, or even as a diabetes-plus-smoking equivalent, in the context of management of ASCVD event risk.⁸

Another study of patients with CLE was performed using a nationwide cohort from Denmark, which included 2062 patients with CLE and 8248 individuals without CLE who were matched for age, sex and comorbidities.⁶³ The median age of the population studied was 50 years (25th–75th percentiles: 37–62 years). The 10-year cumulative incidence of MI was 3.05% (95% CI 2.18% to 4.15%) for patients with CLE versus 1.59% (95% CI 1.29% to 1.93%) for the matched non-CLE population (p<0.0001). In the same study, the cumulative incidence of ischaemic stroke in patients with CLE was 3.25% (95% CI 2.38% to 4.32%) vs 2.50% (95% CI 2.13% to 2.93%) in the matched non-CLE population (p<0.02). These results highlight the greater risk of adverse ASCVD events in patients with CLE compared with the general population.⁶³

In 2023, Olbrich et al reported the results of their large-scale, propensity-matched global retrospective cohort study, in which they used an international network of electronic medical records to assess rates of a broad range of cardiovascular diseases, identified by the International Classification of Diseases 10th Revision codes, in patients with CLE compared with controls.⁶⁴ Matching included conventional risk factors for ASCVD events, such as age, sex, disorders of lipoprotein metabolism, essential hypertension, nicotine dependence, overweight or obesity and diabetes mellitus. Patients with SLE were excluded. Consistent with prior literature, their work showed that CLE is associated with significantly increased risks of developing peripheral vascular disease, chronic ischaemic heart disease and heart failure, among others.⁶⁴ The number of patients was sufficient to separately examine the two major subtypes of CLE—namely chronic discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Interestingly, the associations with increased rates of many cardiovascular diseases were apparent in cases of DLE but much less so, or not at all, in SCLE. These findings bolster the concept that not all inflammatory conditions have the same exacerbating effects on atherosclerosis.^{5 61} The study also highlighted an increased risk of 5-year all-cause mortality and three-point MACE in CLE.⁶⁴

Regarding patients with SLE, several recent cohort and case–control studies showed higher rates of young ischaemic stroke (defined as an event occurring in patients under 50 years of age),⁶⁵ clinically evident premature coronary artery disease (defined as occurring in men <45 years old or in women <50 years old)⁶⁶ and MACE (defined as MI and ischaemic stroke)⁶⁷ compared with rates in non-autoimmune controls. Importantly, in patients with SLE, symptomatic cardiovascular disease frequently preceded a first-time MI, which should prompt more aggressive management before the MI.⁶⁸

7. Clinical assessment of the heightened risk of ASCVD events in individual lupus patients with CLE and/or SLE

7.1. Background

In 2021, Keyes et al⁵ proposed guidelines for assessing and managing ASCVD risk in SLE and CLE, delineating four distinct categories of ASCVD event risk.⁵ The lowest two categories were for patients with LE in primary prevention, and the highest two were for patients with LE in secondary prevention. The approach was modelled after established guidelines for conditions such as diabetes mellitus.^{26 27} The approach also took into account specific disease factors in LE, such as high disease activity, prolonged disease duration, cumulative damage, a history of glucocorticoid use, presence of serum antiphospholipid antibodies, lupus nephritis and stage 3 or 4 chronic kidney disease from any cause.⁵

7.2. Recent findings

The 2022 EULAR guidelines stated, “Direct comparison of the performance of most commonly used generic risk assessment tools in SLE is currently lacking.”⁶ Several studies since our previous review⁵ have now addressed this issue. The overall conclusion from this new work supports arterial-wall imaging, inclusion of lupus-specific factors, estimators of ASCVD event risk that take SLE status into account (eg, QRisk3^{69 70}) and treating lupus as at least a diabetes equivalent when estimating the risk of future ASCVD events.^{8 9} Recent data indicate that these approaches improve cardiovascular risk assessment and hence management for patients with LE.

In a longitudinal cohort of patients with CLE-only and CLE+SLE published in 2023, Zhao et al⁸ compared three systems for assessment of ASCVD event risk in primary prevention—namely the primary prevention categories of Keyes et al⁵ and two commonly used online risk calculators designed for application to the general population: the QRisk3^{69 70} and the ACC ASCVD Risk Estimator Plus.^{26 29} The categories of Keyes et al and the QRisk3 take lupus status into account and generally lead to higher risk categorisation, hence implications for more intensive management than does the ACC ASCVD Risk Estimator Plus, which does not consider lupus status. Zhao et al found that these three systems for estimating the risk of a future ASCVD event were concordant for only 39.2% of primary prevention patients with LE, that is, discordance for almost two-thirds of patients with LE that could affect their clinical management.⁸ Further analysis of their published data indicates that the two systems that take lupus status into account—Keyes et al’s categories and the QRisk3—were concordant for 61.9% of these patients, whereas Keyes et al and the ACC ASCVD Risk Estimator Plus were concordant for only 39.9%. Zhao et al concluded that it is currently unclear how to accurately assess these patients’ future ASCVD event risk. To clarify the situation, Zhao et al also documented the actual 10-year ASCVD event rates in their longitudinal lupus cohort, indicating that these patients’ risk is substantial (section 6.2).⁸

Regarding systemic LE, Choi et al recently developed an SLE-specific cardiovascular risk prediction tool (SLECRISK) that emphasises lupus-specific factors.⁷¹ Using SLECRISK, the sensitivity for detecting moderate/high-risk MACE was 0.74, which was better than the sensitivity of the ACC/AHA model. Also, the performance of the SLECRISK model was similar to the Framingham Risk Score (FRS) and to the modified FRS.⁷¹

For patients with lupus, the presence of image-evident atherosclerotic plaque is strongly associated with higher rates of future ASCVD events, and conversely, the absence of arterial disease by imaging is associated with lower event rates, similar to long-standing data in non-autoimmune cohorts.⁷² Several recent studies have attempted to distinguish patients with lupus with plaques versus without plaques through the use of non-imaging parameters to enhance assessments of ASCVD event risk. For example, Liang and colleagues developed a predictive model, based on non-imaging parameters, for distinguishing patients with SLE without early-onset versus with early-onset atherosclerosis identified by carotid ultrasonography.⁵⁰ The authors chose five non-imaging clinical parameters to incorporate into their tool (nomogram): two conventional risk factors (patient age and hypertension) and three lupus-specific factors (APS, duration of glucocorticoid therapy and use of azathioprine). The last of these, use of azathioprine, was the only one associated with lower odds of atherosclerosis (section 4.2). Nevertheless, the group did not compare their newly developed tool against previous risk estimators, nor does their tool take into account plasma lipid values.⁵⁰ Importantly, several modern imaging technologies, including carotid ultrasonography, are not difficult tests and may be worth performing directly rather than relying on indirect assessments.

Along similar lines, Quevedo-Abeledo et al⁷³ compared the original version of the SCORE⁷⁴ with its updated version, SCORE2,^{32 33} for their abilities to discriminate for the presence of subclinical carotid plaque by ultrasonography in 235 patients with SLE ≥40 years of age. Surprisingly, SCORE did not significantly discriminate for the presence of carotid plaque (area under the curve (AUC)=0.521), whereas SCORE2 did (AUC=0.720, p<0.001 for the difference between the two calculators). Given the predictive power of carotid atherosclerosis for future ASCVD events in patients with SLE,⁷⁵ these results suggest significant superiority of SCORE2 over SCORE in this context.⁷³ Of note, neither SCORE nor SCORE2 takes lupus status into account.⁷³ The same group⁷⁶ performed a similar study of the QRisk3 calculator,^{69 70} an assessment tool that takes into account glucocorticoid use and SLE (but not CLE), in addition to conventional risk factors for ASCVD events. QRisk3 showed a statistically significant superior capacity compared with SCORE to discriminate the presence of carotid plaque on ultrasonography; C-statistics were 0.765 (95% CI 0.711, 0.820) vs 0.561 (95% CI 0.494, 0.629), p<0.001.⁷⁶ To our knowledge, the QRisk3 calculator has not been compared directly with the new SCORE2 in patients with lupus.

Panopoulos and colleagues demonstrated that using SLE-specific tools, such as QRisk3, instead of generic risk scores, was more effective in predicting the progression of subclinical atherosclerosis in patients with SLE, as detected by carotid and femoral ultrasonography at baseline and then after 3 years of follow-up.⁷⁷ Thus, implementing SLE-adapted risk scores, calculating SCORE2, closely monitoring disease-specific factors such as glucocorticoid use and the presence of antiphospholipid antibodies, and especially the use of arterial-wall imaging may enhance the evaluation and treatment of ASCVD in patients with lupus.

8. Management of the heightened risk of ASCVD events in patients with lupus

8.1. Background

As reviewed in ref ^{5 18} and elsewhere, management of ASCVD event risk begins with lifestyle. This strategy should include a healthy diet, weight loss when indicated, regular physical activity and support for quitting smoking. All these lifestyle changes are associated with a reduced risk of future ASCVD events.^{78 79} In addition, pharmacological management of lipid and lipoprotein levels is crucial to minimising plaque burden and lowering the frequency of ASCVD events. Medications such as statins, PCSK9 inhibitors, ezetimibe and bempedoic acid are available and safe, effectively reducing plasma concentrations of LDLc, non-HDLc and apoB (table 3). Moreover, in non-autoimmune populations, they have been shown in prospective randomised controlled clinical trials to decrease ASCVD events.^{18 40 80–83} In patients with lupus, statins are the primary choice for treating hypercholesterolaemia owing to their well-established safety, efficacy at LDL lowering, reduction of ASCVD events in non-autoimmune cohorts and even evidence of benefit on arterial disease, morbidity and mortality in LE cohorts.^{5 84 85} All of these classes of lipid-lowering medications are reliable options for patients with SLE.⁵

For blood pressure management, the target should be <130/<80 mm Hg, which is now the standard for the general population⁸⁶ and has been associated with reduced rates of atherosclerotic cardiovascular events, including in patients with SLE.^{72 87} Regular assessments and management of glycated haemoglobin (HbA1c) and plasma triglyceride levels are also recommended.^{5 72 79}

8.2. Recent findings

New work continues to substantiate the benefits in patients with lupus of early management of conventional risk factors for ASCVD events. Nevertheless, the implementation of these interventions remains suboptimal in lupus, just as it is for the general population and even in other high-risk conditions worldwide.^{8 87–92} Also, purported cardiovascular benefits from certain disease-modifying antirheumatic drugs such as antimalarials have become less clear (ref ^{46 48 51} and section 4.2).

Regarding lifestyle in patients with lupus, Pocovi-Gerardino et al recently reported a cross-sectional study showing that following a Mediterranean diet correlated with positive effects on autoimmune disease activity and risk factors for ASCVD events in patients with SLE.⁹³ An inverse relationship between the Mediterranean Diet Score (a 14-item questionnaire on food consumption frequency and habits) and the Systemic Lupus Erythematosus Disease Activity Index was seen in the study (p≤0.001).⁹³ A recent meta-analysis of studies on diet and nutrition of patients with lupus also supports low fat intake and a Mediterranean diet for reducing the risk of ASCVD events.⁹⁴ Large interventional studies of lifestyle modifications in patients with LE, however, are not available.⁹⁴ Regarding exercise, a recent systematic review concluded that aerobic exercise improves cardiovascular risk factors, while resistance training improves physical function in patients with lupus.⁹⁵

Regarding implementation of lifestyle and medications, Zhao et al examined the management of ASCVD event risk in patients with CLE in a real-world clinical setting.⁸ Zhao et al found that over two-thirds of patients with CLE in primary prevention for ASCVD events had plasma LDLc concentrations above the recommended ranges (211/316, 66.8%). For patients with CLE in secondary prevention, 70.4% had above-goal LDLc levels (38/54). Alarmingly, a supermajority of all patients with CLE with LDLc levels above the recommended ranges were not receiving any documented LDL-lowering medications (159/249, 63.9%), indicating significant untreated or undertreated hypercholesterolaemia among patients with CLE. In the same cohort, 266 patients with CLE (71.9%) had hypertension, and 198 out of these 266 (74.4%) received no treatment or were undertreated for blood pressure. This last percentage is nearly identical to 73.7% (471/639) of untreated or undertreated hypertensive patients with SLE in a Canadian cohort using the same updated blood pressure criteria.⁸⁷ Regarding smoking status, Zhao et al reported that 76 out of 95 (80.0%) patients with CLE who were former or current smokers had no documentation of smoking cessation counselling or referrals in their charts. This recent study⁸ highlights the discrepancy between guideline-based assessment and management of ASCVD event risk versus real-world clinical care of these patients, consistent with substantial prior literature in other high-risk conditions.⁹¹

9. Conclusions and future directions

ASCVD events remain a major source of morbidity and mortality among patients with lupus and in the general population. Patients with lupus face a disproportionately high burden of atherosclerosis and ASCVD events, necessitating heightened clinical attention and proactive management. The high prevalence and severe impact of ASCVD among patients with lupus underscore the urgent need for improved management strategies. Atherosclerosis is a lifelong disease, and several authors have argued for earlier interventions, especially as arterial-wall imaging improves, thereby facilitating the detection of subclinical atherosclerosis.^{18 96}

The current uncertainties in accurately predicting and managing future ASCVD risk in patients with lupus call for refined assessment tools and strategies, but these problems should not dissuade the clinician from implementing what is already known. Rheumatologists and dermatologists should increase their efforts to screen patients with lupus for plasma levels of apoB, non-HDLc, Lp(a) and triglycerides; blood pressure and tobacco smoking; as well as the presence of image-evident arterial plaques. This information should provoke prompt referral of these patients to preventive cardiology and to smoking cessation specialists. Future research should focus on enhancing risk estimation models, developing comprehensive guidelines tailored for patients with SLE and CLE and improving implementation to better address their cardiovascular health. A promising avenue is the use of arterial- wall imaging to motivate patients and clinicians by demonstrating a lump, plaque or growth in the vessel wall.^{18 97} Currently, the best method appears to be photon-counting detector CT angiography, which produces accurate, reproducible, high-resolution images of plaques in the arterial wall with detailed assessments of plaque characteristics.^98–101 ‘You have a lump in your coronaries/carotids!’ can be a powerful motivation for patients and clinicians.^{18 97}

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.

Footnote

Contributors LLAG conceptualised and designed the study, collected and analysed the data, drafted the initial manuscript and reviewed and revised the manuscript. DFF contributed to data collection and analysis, provided critical revisions and reviewed the final manuscript. LX, SC and CS assisted in data interpretation and reviewed and revised the manuscript. VPW and KJW supervised the study, critically reviewed the manuscript for important intellectual content, approved the final version for submission and are the guarantors.

Funding This manuscript was funded by the National Institutes of Health USA (NIH-USA) grants R01AR071653 (to VPW) and the US Department of Veterans Affairs Merit Review BX005921-01 (Veterans Health Administration, Office of Research and Development and Biomedical Laboratory Research and Development, to VPW).

Competing interests VPW has grants from Celgene, Janssen, Pfizer, Biogen, Gilead, Corbus Pharmaceuticals, Genentech, AstraZeneca, Viela, Syntimmune, Amgen, Regeneron, Argenx, CSL Behring, Ventus, q32 Bio, BMS and Horizon and has consulted for Celgene, Genentech, Janssen, Lilly, Pfizer, Biogen, BMS, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Sorona, CSL Behring, Principia, Crisalis, Viela Bio, Argenx, Kwoya Kirin, Regeneron, Principia, AstraZeneca, AbbVie, Octapharma, GSK, AstraZeneca, Cugene, UCB, Corcept, Beacon Bioscience, Rome Pharmaceuticals, Horizon, Gilead, Merck, Kezar, Sanofi, Bayer, Akari, Calyx and Cabaletta Bio. The University of Pennsylvania owns the copyright for the CLASI.

Provenance and peer review Commissioned; externally peer reviewed.

References

¹ Taylor T, Anastasiou C, Ja C, et al. Causes of Death Among Individuals With Systemic Lupus Erythematosus by Race and Ethnicity: A Population-Based Study. Arthritis Care Res (Hoboken) 2023; 75: 61–8. doi:10.1002/acr.24988

² Bello N, Meyers KJ, Workman J, et al. Cardiovascular events and risk in patients with systemic lupus erythematosus: Systematic literature review and meta-analysis. Lupus (Los Angel) 2023; 32: 325–41. doi:10.1177/09612033221147471

³ Lai C-H, Hsieh C-Y, Barnado A, et al. Outcomes of acute cardiovascular events in rheumatoid arthritis and systemic lupus erythematosus: a population-based study. Rheumatology (Sunnyvale) 2020; 59: 1355–63. doi:10.1093/rheumatology/kez456

⁴ Appleton BD, Major AS. The latest in systemic lupus erythematosus-accelerated atherosclerosis: related mechanisms inform assessment and therapy. Curr Opin Rheumatol 2021; 33: 211–8. doi:10.1097/BOR.0000000000000773

⁵ Keyes E, Grinnell M, Jacoby D, et al. Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis. Int J Womens Dermatol 2021; 7: 560–75. doi:10.1016/j.ijwd.2021.08.015

⁶ Drosos GC, Vedder D, 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

⁷ Drosos GC, Konstantonis G, 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: 1–10. doi:10.1136/rmdopen-2022-002767

⁸ Zhao M, Feng R, Werth VP, et al. State of current management of the heightened risk for atherosclerotic cardiovascular events in an established cohort of patients with lupus erythematosus. Lupus Sci Med 2023; 10: 1–15. doi:10.1136/lupus-2023-000908

⁹ Evangelatos G, Tentolouris N, Sfikakis PP, et al. Seven-year follow-up atherosclerotic plaque progression in patients with antiphospholipid syndrome versus diabetes mellitus and healthy controls. Rheumatology (Sunnyvale) 2024; 0: 1–6. doi:10.1093/rheumatology/keae097

¹⁰ McGill HC, McMahan CA, Herderick EE, et al. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr 2000; 72: 1307s–15s. doi:10.1093/ajcn/72.5.1307s

¹¹ Raitakari O, Pahkala K, Magnussen CG. Prevention of atherosclerosis from childhood. Nat Rev Cardiol 2022; 19: 543–54. doi:10.1038/s41569-021-00647-9

¹² Schipper HS, de Ferranti S. Cardiovascular Risk Assessment and Management for Pediatricians. Pediatrics 2022; 150: 1–12. doi:10.1542/peds.2022-057957

¹³ Ramezankhani A, Mehrabi Y, Azizi F, et al. Cumulative burden and trajectories of body mass index and blood pressure from childhood and carotid intima-media thickness in young adulthood. Prev Med 2023; 177: 107747. doi:10.1016/j.ypmed.2023.107747

¹⁴ Martin SS, Aday AW, Allen NB, et al. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2025; 151: e41–660. doi:10.1161/CIR.0000000000001303

¹⁵ Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 1995; 15: 551–61. doi:10.1161/01.atv.15.5.551

¹⁶ Williams KJ, Tabas I. Lipoprotein Retention—and Clues for Atheroma Regression. Arterioscler Thromb Vasc Biol 2005; 25: 1536–40. doi:10.1161/01.ATV.0000174795.62387.d3

¹⁷ Borén J, Williams KJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol 2016; 27: 473–83. doi:10.1097/MOL.0000000000000330

¹⁸ Williams KJ. Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late. Arterioscler Thromb Vasc Biol 2024; 44: 48–64. doi:10.1161/ATVBAHA.123.320065

¹⁹ Lütjohann D, Klör HU, Stellaard F. Measurement of Serum Low Density Lipoprotein Cholesterol and Triglyceride-Rich Remnant Cholesterol as Independent Predictors of Atherosclerotic Cardiovascular Disease: Possibilities and Limitations. Nutrients 2023; 15: 1–12. doi:10.3390/nu15092202

²⁰ Glavinovic T, Thanassoulis G, de Graaf J, et al. Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk. J Am Heart Assoc 2022; 11: e025858. doi:10.1161/JAHA.122.025858

²¹ Björnson E, Adiels M, Taskinen M-R, et al. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. J Am Coll Cardiol 2024; 83: 385–95. doi:10.1016/j.jacc.2023.10.039

²² Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; 41: 2313–30. doi:10.1093/eurheartj/ehz962

²³ Friedman M, Van den Bovenkamp GJ. The pathogenesis of a coronary thrombus. Am J Pathol 1966; 48: 19–44.

²⁴ Davies MJ. Anatomic features in victims of sudden coronary death. Coronary artery pathology. Circulation 1992; 85: I19–24.

²⁵ Mann JM, Davies MJ. Vulnerable plaque. Relation of characteristics to degree of stenosis in human coronary arteries. Circulation 1996; 94: 928–31. doi:10.1161/01.cir.94.5.928

²⁶ Arnett DK, Blumenthal RS, Albert MA, 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. Circulation 2019; 140: e596–646. doi:10.1161/CIR.0000000000000678

²⁷ Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41: 111–88. doi:10.1093/eurheartj/ehz455

²⁸ Budoff MJ, Kinninger A, Gransar H, et al. When Does a Calcium Score Equate to Secondary Prevention?: Insights From the Multinational CONFIRM Registry. JACC Cardiovasc Imaging 2023; 16: 1181–9. doi:10.1016/j.jcmg.2023.03.008

²⁹ American College of Cardiology. ACC ASCVD Risk Estimator Plus. 2018. Available: https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/ [Accessed 6 Nov 2024 ].

³⁰ American Heart Association. American Heart Association PREVENT™ online calculator. 2024. Available: https://professional.heart.org/en/guidelines-and-statements/prevent-calculator [Accessed 6 Nov 2024 ].

³¹ Khan SS, Matsushita K, Sang Y, et al. Development and Validation of the American Heart Association’s PREVENT Equations. Circulation 2024; 149: 430–49. doi:10.1161/CIRCULATIONAHA.123.067626

³² SCORE2. Available: https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-Risk-Charts [Accessed 24 Sep 2024 ].

³³ SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J 2021; 42: 2439–54. doi:10.1093/eurheartj/ehab309

³⁴ Guo LN, Nambudiri VE. Cutaneous lupus erythematosus and cardiovascular disease: current knowledge and insights into pathogenesis. Clin Rheumatol 2021; 40: 491–9. doi:10.1007/s10067-020-05257-3

³⁵ Miot HA, Bartoli Miot LD, Haddad GR. Association between discoid lupus erythematosus and cigarette smoking. Dermatology 2005; 211: 118–22. doi:10.1159/000086440

³⁶ Böckle BC, Sepp NT. Smoking is highly associated with discoid lupus erythematosus and lupus erythematosus tumidus: analysis of 405 patients. Lupus (Los Angel) 2015; 24: 669–74. doi:10.1177/0961203314559630

³⁷ Akarsu S, Ozbagcivan O, Semiz F, et al. High Prevalence of Metabolic Syndrome in Patients with Discoid Lupus Erythematosus: A Cross-Sectional, Case-Control Study. J Immunol Res 2017; 2017: 3972706. doi:10.1155/2017/3972706

³⁸ Medeiros MM das C, Xavier de Oliveira ÍM, Ribeiro ÁTM. Prevalence of metabolic syndrome in a cohort of systemic lupus erythematosus patients from Northeastern Brazil: association with disease activity, nephritis, smoking, and age. Rheumatol Int 2016; 36: 117–24. doi:10.1007/s00296-015-3316-z

³⁹ Bolla E, Semb AG, Kerola AM, et al. Prevalence and target attainment of traditional cardiovascular risk factors in patients with systemic lupus erythematosus: a cross-sectional study including 3401 individuals from 24 countries. Lancet Rheumatol 2024; 6: e447–59. doi:10.1016/S2665-9913(24)00090-0

⁴⁰ Ruscica M, Ferri N, Santos RD, et al. Lipid Lowering Drugs: Present Status and Future Developments. Curr Atheroscler Rep 2021; 23: 1–13. doi:10.1007/s11883-021-00918-3/Published

⁴¹ Tardif J-C, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J 2022; 43: 1401–12. doi:10.1093/eurheartj/ehab820

⁴² Gouni-Berthold I, Schwarz J, Berthold HK. Updates in Drug Treatment of Severe Hypertriglyceridemia. Curr Atheroscler Rep 2023; 25: 701–9. doi:10.1007/s11883-023-01140-z

⁴³ Martín-González C, Ferrer-Moure C, Quevedo-Abeledo JC, et al. Apolipoprotein C-III in patients with systemic lupus erythematosus. Arthritis Res Ther 2022; 24: 104. doi:10.1186/s13075-022-02793-y

⁴⁴ Farina N, Webster J, Luo W, et al. Factors associated with cardiovascular events in systemic lupus erythematosus in a monocentric cohort with up to 40 years of follow-up. Semin Arthritis Rheum 2023; 61: 152226. doi:10.1016/j.semarthrit.2023.152226

⁴⁵ Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014; 371: 32–41. doi:10.1056/NEJMoa1308027

⁴⁶ Munguía-Realpozo P, Mendoza-Pinto C, García-Carrasco M, 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. Autoimmun Rev 2021; 20: 102887. doi:10.1016/j.autrev.2021.102887

⁴⁷ Haugaard JH, Dreyer L, Ottosen MB, et al. Use of hydroxychloroquine and risk of major adverse cardiovascular events in patients with lupus erythematosus: A Danish nationwide cohort study. J Am Acad Dermatol 2021; 84: 930–7. doi:10.1016/j.jaad.2020.12.013

⁴⁸ Ajeganova S, Hafström I, Frostegård J. Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years. Lupus Sci Med 2021; 8: 1–11. doi:10.1136/lupus-2020-000454

⁴⁹ Lertratanakul A, Sun J, Wu PW, et al. Risk factors for changes in carotid intima media thickness and plaque over 5 years in women with systemic lupus erythematosus. Lupus Sci Med 2021; 8: e000548. doi:10.1136/lupus-2021-000548

⁵⁰ Liang R, Xu H, Yao R, et al. A predictive model for premature atherosclerosis in systemic lupus erythematosus based on clinical characteristics. Clin Rheumatol 2024; 43: 1541–50. doi:10.1007/s10067-024-06934-3

⁵¹ Papazoglou N, Kravvariti E, Konstantonis G, et al. The impact of traditional cardiovascular risk factor control on 7-year follow-up atherosclerosis progression in systemic lupus erythematosus. Rheumatology (Sunnyvale) 2024; 63: 50–7. doi:10.1093/rheumatology/kead184

⁵² Dedemadi A-G, Gkolfinopoulou C, Nikoleri D, et al. Improvement of high-density lipoprotein atheroprotective properties in patients with systemic lupus erythematosus after belimumab treatment. Rheumatology (Sunnyvale) 2025; 64: 648–57. doi:10.1093/rheumatology/keae192

⁵³ Povsic TJ, Korjian S, Bahit MC, et al. Effect of Reconstituted Human Apolipoprotein A-I on Recurrent Ischemic Events in Survivors of Acute MI. J Am Coll Cardiol 2024; 83: 2163–74. doi:10.1016/j.jacc.2024.03.396

⁵⁴ Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. The Lancet 2012; 380: 572–80. doi:10.1016/S0140-6736(12)60312-2

⁵⁵ Casey KA, Smith MA, Sinibaldi D, et al. Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus. Arthritis Rheumatol 2021; 73: 459–71. doi:10.1002/art.41518

⁵⁶ Hasni SA, Gupta S, Davis M, et al. Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat Commun 2021; 12: 3391. doi:10.1038/s41467-021-23361-z

⁵⁷ Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022; 386: 316–26. doi:10.1056/NEJMoa2109927

⁵⁸ Jolly SS, d’Entremont M-A, Lee SF, et al. Colchicine in Acute Myocardial Infarction. N Engl J Med 2025; 392: 633–42. doi:10.1056/NEJMoa2405922

⁵⁹ Kelly P, Lemmens R, Weimar C, et al. Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial. The Lancet 2024; 404: 125–33. doi:10.1016/S0140-6736(24)00968-1

⁶⁰ Li J, Meng X, Shi F-D, et al. Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial. BMJ 2024; 385: e079061. doi:10.1136/bmj-2023-079061

⁶¹ Williams KJ. Inflammation in atherosclerosis: a Big Idea that has underperformed so far. Curr Opin Lipidol 2025; 36: 78–87. doi:10.1097/MOL.0000000000000973

⁶² Croca SC, Griffin M, Farinha F, et al. Total plaque area and plaque echogenicity are novel measures of subclinical atherosclerosis in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2021; 60: 4185–98. doi:10.1093/rheumatology/keaa905

⁶³ Shams-Eldin AN, Yafasova A, Faurschou M, et al. Long-term risk of adverse cardiovascular outcomes associated with cutaneous lupus erythematosus: a nationwide cohort study. Clin Rheumatol 2022; 41: 3525–36. doi:10.1007/s10067-022-06302-z

⁶⁴ Olbrich H, Kridin K, Zirpel H, et al. Cutaneous lupus erythematosus is associated with an increased risk of cardiac and vascular diseases: a large-scale, propensity-matched global retrospective cohort study. EBioMedicine 2023; 93: 104639. doi:10.1016/j.ebiom.2023.104639

⁶⁵ Huang Y-C, Lai E-C, Liao T-C, et al. Evaluating the risk of ischemic stroke at a young age in patients with autoimmune inflammatory rheumatic diseases: a population-based cohort study in Taiwan. Front Immunol 2024; 15: 1272557. doi:10.3389/fimmu.2024.1272557

⁶⁶ Lai E-C, Huang Y-C, Liao T-C, et al. Premature coronary artery disease in patients with immune-mediated inflammatory disease: a population-based study. RMD Open 2022; 8: 1–8. doi:10.1136/rmdopen-2021-001993

⁶⁷ Han J-Y, Cho S-K, Kim H, et al. Increased cardiovascular risk in Korean patients with systemic lupus erythematosus: a population-based cohort study. Sci Rep 2024; 14: 1082. doi:10.1038/s41598-024-51546-1

⁶⁸ Samuelsson I, Parodis I, Gunnarsson I, et al. Myocardial infarctions, subtypes and coronary atherosclerosis in SLE: a case-control study. Lupus Sci Med 2021; 8: 1–9. doi:10.1136/lupus-2021-000515

⁶⁹ QRISK®3-2018 risk calculator. 2017. Available: https://qrisk.org [Accessed 9 Dec 2024 ].

⁷⁰ Hippisley-Cox J, Coupland C, 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

⁷¹ Choi MY, Guan H, Yoshida K, et al. Personalizing cardiovascular risk prediction for patients with systemic lupus erythematosus. Semin Arthritis Rheum 2024; 67: 152468. doi:10.1016/j.semarthrit.2024.152468

⁷² Tselios K, Sheane BJ, Gladman DD, et al. Optimal Monitoring For Coronary Heart Disease Risk in Patients with Systemic Lupus Erythematosus: A Systematic Review. J Rheumatol 2016; 43: 54–65. doi:10.3899/jrheum.150460

⁷³ Quevedo-Abeledo JC, González-Gay MÁ, Ferraz-Amaro I. SCORE2 versus SCORE in patients with systemic lupus erythematosus. Ther Adv Musculoskelet Dis 2022; 14: 1759720X221092373. doi:10.1177/1759720X221092373

⁷⁴ Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: 987–1003. doi:10.1016/s0195-668x(03)00114-3

⁷⁵ Kao AH, Lertratanakul A, Elliott JR, et al. Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol 2013; 112: 1025–32. doi:10.1016/j.amjcard.2013.05.040

⁷⁶ Quevedo-Abeledo JC, Caceres L, Palazuelos C, et al. QRISK3 relation to carotid plaque is higer than that of SCORE in patients with systemic lupus erythematosus. Rheumatology (Sunnyvale) 2022; 61: 1408–16. doi:10.1093/rheumatology/keab531

⁷⁷ Panopoulos S, Drosos GC, Konstantonis G, et al. Generic and disease-adapted cardiovascular risk scores as predictors of atherosclerosis progression in SLE. Lupus Sci Med 2023; 10: e000864. doi:10.1136/lupus-2022-000864

⁷⁸ Booth JN, Colantonio LD, Howard G, et al. Healthy lifestyle factors and incident heart disease and mortality in candidates for primary prevention with statin therapy. Int J Cardiol 2016; 207: 196–202. doi:10.1016/j.ijcard.2016.01.001

⁷⁹ Al Rifai M, Greenland P, Blaha MJ, et al. Factors of health in the protection against death and cardiovascular disease among adults with subclinical atherosclerosis. Am Heart J 2018; 198: 180–8. doi:10.1016/j.ahj.2017.10.026

⁸⁰ Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376: 1713–22. doi:10.1056/NEJMoa1615664

⁸¹ Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018; 379: 2097–107. doi:10.1056/NEJMoa1801174

⁸² Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387–97. doi:10.1056/NEJMoa1410489

⁸³ Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial. Circulation 2019; 140: 992–1003. doi:10.1161/CIRCULATIONAHA.118.039415

⁸⁴ Mok CC, Wong CK, To CH, et al. Effects of rosuvastatin on vascular biomarkers and carotid atherosclerosis in lupus: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken) 2011; 63: 875–83. doi:10.1002/acr.20440

⁸⁵ Yu H-H, Chen P-C, Yang Y-H, et al. Statin reduces mortality and morbidity in systemic lupus erythematosus patients with hyperlipidemia: A nationwide population-based cohort study. Atherosclerosis 2015; 243: 11–8. doi:10.1016/j.atherosclerosis.2015.08.030

⁸⁶ Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018; 138: e426–83. doi:10.1161/CIR.0000000000000597

⁸⁷ Tselios K, Gladman DD, Su J, et al. Impact of the new American College of Cardiology/American Heart Association definition of hypertension on atherosclerotic vascular events in systemic lupus erythematosus. Ann Rheum Dis 2020; 79: 612–7. doi:10.1136/annrheumdis-2019-216764

⁸⁸ Aref-Eshghi E, Leung J, Godwin M, et al. Low density lipoprotein cholesterol control status among Canadians at risk for cardiovascular disease: findings from the Canadian Primary Care Sentinel Surveillance Network Database. Lipids Health Dis 2015; 14: 60. doi:10.1186/s12944-015-0056-8

⁸⁹ Masson W, Rossi E, Mora-Crespo LM, et al. Cardiovascular risk stratification and appropriate use of statins in patients with systemic lupus erythematosus according to different strategies. Clin Rheumatol 2020; 39: 455–62. doi:10.1007/s10067-019-04856-z

⁹⁰ Cannon CP, de Lemos JA, Rosenson RS, et al. Use of Lipid-Lowering Therapies Over 2 Years in GOULD, a Registry of Patients With Atherosclerotic Cardiovascular Disease in the US. JAMA Cardiol 2021; 6: 1060. doi:10.1001/jamacardio.2021.1810

⁹¹ Nelson AJ, O’Brien EC, Kaltenbach LA, et al. Use of Lipid-, Blood Pressure-, and Glucose-Lowering Pharmacotherapy in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. JAMA Netw Open 2022; 5: e2148030. doi:10.1001/jamanetworkopen.2021.48030

⁹² Taboun Z, Naik N, Brown V, et al. Awareness Among Primary Care Physicians in Canada of Guideline Recommendations for Lowering LDL-Cholesterol in High-Risk Patients. CJC Open 2023; 5: 357–63. doi:10.1016/j.cjco.2023.02.002

⁹³ Pocovi-Gerardino G, Correa-Rodríguez M, Callejas-Rubio J-L, et al. Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: a cross-sectional study. Rheumatology (Sunnyvale) 2021; 60: 160–9. doi:10.1093/rheumatology/keaa210

⁹⁴ Tsoi A, Gomez A, Boström C, et al. Efficacy of lifestyle interventions in the management of systemic lupus erythematosus: a systematic review of the literature. Rheumatol Int 2024; 44: 765–78. doi:10.1007/s00296-024-05548-x

⁹⁵ Blaess J, Goepfert T, Geneton S, et al. Benefits & risks of physical activity in patients with Systemic Lupus Erythematosus: a systematic review of the literature. Semin Arthritis Rheum 2023; 58: 152128. doi:10.1016/j.semarthrit.2022.152128

⁹⁶ Robinson JG, Williams KJ, Gidding S, et al. Eradicating the Burden of Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B Lipoproteins Earlier in Life. J Am Heart Assoc 2018; 7: e009778. doi:10.1161/JAHA.118.009778

⁹⁷ Näslund U, Ng N, Lundgren A, et al. Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA): a pragmatic, open-label, randomised controlled trial. The Lancet 2019; 393: 133–42. doi:10.1016/S0140-6736(18)32818-6

⁹⁸ Si-Mohamed SA, Boccalini S, Lacombe H, et al. Coronary CT Angiography with Photon-counting CT: First-In-Human Results. Radiology 2022; 303: 303–13. doi:10.1148/radiol.211780

⁹⁹ Sandfort V, Bluemke DA. Overcoming a Technological Hurdle: Coronary CT Angiography with Photon-counting CT. Radiology 2022; 303: 314–6. doi:10.1148/radiol.212943

¹⁰⁰ van der Bie J, van Straten M, Booij R, et al. Photon-counting CT: Review of initial clinical results. Eur J Radiol 2023; 163: 110829. doi:10.1016/j.ejrad.2023.110829

¹⁰¹ Halfmann MC, Bockius S, Emrich T, et al. Ultrahigh-Spatial-Resolution Photon-counting Detector CT Angiography of Coronary Artery Disease for Stenosis Assessment. Radiology 2024; 310: e231956. doi:10.1148/radiol.231956

¹⁰² Borba EF, Bonfá E. Dyslipoproteinemias in systemic lupus erythematosus: Influence of disease, activity, and anticardiolipin antibodies. Lupus (Los Angel) 1997; 6: 533–9. doi:10.1177/096120339700600610

¹⁰³ Amaya-Amaya J, Montoya-Sánchez L, Rojas-Villarraga A. Cardiovascular involvement in autoimmune diseases. Biomed Res Int 2014; 1–31. doi:10.1155/2014/367359

¹⁰⁴ Vincze M, Dér H, Kerekes G, et al. Decreased flow-mediated dilatation with increased arterial stiffness and thickness as early signs of atherosclerosis in polymyositis and dermatomyositis patients. Clin Rheumatol 2014; 33: 1635–41. doi:10.1007/s10067-014-2561-y

¹⁰⁵ Szabó MZ, Szodoray P, Kiss E. Dyslipidemia in systemic lupus erythematosus. Immunol Res 2017; 65: 543–50. doi:10.1007/s12026-016-8892-9

¹⁰⁶ Ruuth M, Nguyen SD, Vihervaara T, et al. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur Heart J 2018; 39: 2562–73. doi:10.1093/eurheartj/ehy387

¹⁰⁷ Ferreira HB, Pereira AM, Melo T, et al. Lipidomics in autoimmune diseases with main focus on systemic lupus erythematosus. J Pharm Biomed Anal 2019; 174: 386–95. doi:10.1016/j.jpba.2019.06.005

¹⁰⁸ Qiao JH, Castellani LW, Fishbein MC, et al. Immune-complex-mediated vasculitis increases coronary artery lipid accumulation in autoimmune-prone MRL mice. Arterioscler Thromb 1993; 13: 932–43. doi:10.1161/01.ATV.13.6.932

¹⁰⁹ George J, Afek A, Gilburd B, et al. Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies. Lupus (Los Angel) 1997; 6: 723–9. doi:10.1177/096120339700600908

¹¹⁰ Marathe S, Schissel SL, Yellin MJ, et al. Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling. J Biol Chem 1998; 273: 4081–8. doi:10.1074/jbc.273.7.4081

¹¹¹ Gu L, Johnson MW, Lusis AJ. Quantitative trait locus analysis of plasma lipoprotein levels in an autoimmune mouse model: interactions between lipoprotein metabolism, autoimmune disease, and atherogenesis. Arterioscler Thromb Vasc Biol 1999; 19: 442–53. doi:10.1161/01.atv.19.2.442

¹¹² Stanic AK, Stein CM, Morgan AC, et al. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Proc Natl Acad Sci USA 2006; 103: 7018–23. doi:10.1073/pnas.0602311103

¹¹³ Ma Z, Choudhury A, Kang S-A, et al. Accelerated atherosclerosis in ApoE deficient lupus mouse models. Clin Immunol 2008; 127: 168–75. doi:10.1016/j.clim.2008.01.002

¹¹⁴ Zhang CY, Qu B, Ye P, et al. Vulnerability of atherosclerotic plaques is associated with type I interferon in a murine model of lupus and atherosclerosis. Genet Mol Res 2015; 14: 14871–81. doi:10.4238/2015.November.18.52

¹¹⁵ Santiago-Raber M-L, Montecucco F, Vuilleumier N, et al. Atherosclerotic plaque vulnerability is increased in mouse model of lupus. Sci Rep 2020; 10: 18324. doi:10.1038/s41598-020-74579-8

¹¹⁶ Liu ML, Williams KJ, Werth VP. Microvesicles in Autoimmune Diseases. Adv Clin Chem 2016; 77: 125–75. doi:10.1016/bs.acc.2016.06.005

¹¹⁷ Kastelein JJP, Stroes ESG. FISHing for the Miracle of Eicosapentaenoic Acid. N Engl J Med 2019; 380: 89–90. doi:10.1056/NEJMe1814004

¹¹⁸ Hegele RA, Gidding SS, Ginsberg HN, et al. Nonstatin Low-Density Lipoprotein-Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 2015; 35: 2269–80. doi:10.1161/ATVBAHA.115.306442

¹¹⁹ Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med 2023; 388: 1353–64. doi:10.1056/NEJMoa2215024

¹²⁰ Khvorova A. Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering Drugs. N Engl J Med 2017; 376: 4–7. doi:10.1056/NEJMp1614154

¹²¹ Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med 2020; 382: 1507–19. doi:10.1056/NEJMoa1912387

¹²² Ray KK, Haq I, Bilitou A, et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet Reg Health Eur 2023; 29: 100624. doi:10.1016/j.lanepe.2023.100624

¹²³ Bergmark BA, Marston NA, Prohaska TA, et al. Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med 2024; 390: 1770–80. doi:10.1056/NEJMoa2402309

¹²⁴ Gaudet D, Clifton P, Sullivan D, et al. RNA Interference therapy targeting apolipoprotein C-III in hypertriglyceridemia. NEJM Evid 2023; 2: EVIDoa2200325. doi:10.1056/EVIDoa2200325

¹²⁵ Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med 2020; 383: 711–20. doi:10.1056/NEJMoa2004215

¹²⁶ Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med 2020; 382: 244–55. doi:10.1056/NEJMoa1905239

¹²⁷ Yeang C, Karwatowska-Prokopczuk E, Su F. Cholesterol and Corrected Low-Density Lipoprotein Cholesterol. J Am Coll Cardiol 2022; 79: 1035–46. doi:10.1016/j.jacc.2021.12.032

¹²⁸ Paragh G, Zilahi P, Kolozsvári LR, et al. Novel Therapeutic Approaches for the Management of Elevated Lipoprotein(a): From Traditional Agents to Future Treatment Options. Life (Basel) 2024; 14: 1–14. doi:10.3390/life14030374

¹²⁹ Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA 2023; 330: 2075–83. doi:10.1001/jama.2023.21835

¹³⁰ Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA 2024; 332: 1992–2002. doi:10.1001/jama.2024.21957

¹³¹ Nicholls SJ, Ni W, Rhodes GM, et al. Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. JAMA 2025; 333: 222–31. doi:10.1001/jama.2024.24017

¹³² Hassing HC, Mooij H, Guo S, et al. Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia. Hepatology 2012; 55: 1746–53. doi:10.1002/hep.25580