Under Crossfire

Thromboembolic Risk in Systemic Lupus Erythematosus

Giuseppe A. Ramirez; Maria Efthymiou; David A. Isenberg; Hannah Cohen


Rheumatology. 2019;58(6):940-952. 

In This Article

Clinical Implications

Tools for Ischaemic Risk Assessment in SLE

The Framingham risk equations are widely used to estimate the 10 year risk for coronary artery disease, stroke and cardiovascular disease in the general population. With respect to the general cardiovascular outcome, age, gender, history of smoking or diabetes, systolic blood pressure and antihypertensive treatments, total cholesterol and high-density lipoprotein levels constitute relevant predictive variables.[124] However, cardiovascular risk estimates according to traditional factors fail to capture the whole population of patients with SLE that will eventually develop a cardiovascular event.[125] Accordingly, attempts have been made to integrate SLE-specific clinical parameters of potential relevance for thromboembolic diseases into the Framingham core of risk factors. A score combining antiphospholipid-related with conventional cardiovascular risk factors has been developed in APS and validated in small cohorts of patients with SLE and APS. In particular, the Global APS score takes into consideration the presence of arterial hypertension, hyperlipidaemia and positive serology for aCL, anti-β2GPI, LA and/or anti-PS/PT.[126] Similar algorithms, which also consider disease activity markers, have been developed retrospectively in large SLE cohorts, but only partially validated.[127,128] Recently Urowitz et al.[129] reported that assigning double values to each Framingham item consistently predicts the development of coronary artery disease in patients with SLE. Currently there is no SLE-specific score for assessing the risk of venous thromboembolism.[130] Genetic determinants of increased thrombotic risk seem to independently affect the risk of venous events,[131] while acquired factors such as cancer, renal failure or aPLs (especially LA) might play a synergistic role in SLE, suggesting that patients with those comorbidities should be assigned to a high-risk category.[21,130,132]

Current Status and Perspectives for Therapeutic Interventions

Taken together, the data so far presented confirm that heterogeneity is a hallmark of the pathogenic events that underlie the development of SLE and in particular of its cardiovascular complications. There is a notable lack of prospective trials aimed at assessing the potential benefit of specific interventions for preventing the development of ischemic complications in SLE. A trial on the role of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, in vascular prevention in SLE is ongoing (NCT02338999). More consistent evidence has been acquired on the role of anticoagulants in patients with APS. In particular, according to the available data, patients with thrombotic APS generally require lifelong anticoagulation.[133–135] Warfarin has long been the mainstay of treatment in this setting. However, the recent Rivaroxaban for Antiphospholipid Antibody Syndrome (RAPS) trial reported that in APS patients with venous thromboembolism and a target international normalized ratio range of 2.0–3.0, rivaroxaban, a direct oral anticoagulant, might offer the potential to be an effective, safe and convenient alternative to warfarin.[136] However, since the RAPS study employed a surrogate laboratory marker of pharmacological efficacy and did not met the primary endpoint (<20% inferiority in reduction of the endogenous thrombin potential compared with warfarin), further clinical trials with clinical endpoints would aid in defining the role of direct oral anticoagulants in APS. Despite the advances in the setting of APS, there is still a significant area of uncertainty with respect to the treatment of both criteria as well as non-criteria APS manifestations such as aseptic endocarditis.[133] In addition, little is known about the optimal strategies to combat the most severe manifestations of APS, such as CAPS and thrombotic microangiopathy.[46,137] In the acute phase of CAPS, removal or neutralization of pathogenic autoantibodies can be achieved by plasma exchange or IVIGs in addition to glucocorticoids and alternatively to conventional immunosuppressants.[137] Rituximab could play a role in maintaining remission and improving survival in the long term.[138] Similar strategies can be employed for refractory thrombotic APS.[134] IVIGs, or the anti-C5 antibody eculizumab, can be useful in complement-driven conditions such as thrombotic microangiopathy. Novel therapies, including decoy β2GPI domains, have also been proposed.[50,134] According to a recent meta-analysis, aspirin has a clinically relevant prophylactic role in patients with SLE who are asymptomatic carriers of aPLs.[139]

Antimalarials such as HCQ constitute the backbone treatment for patients with connective tissue diseases and have a robustly established role in SLE to increase overall survival and prevent disease flare. In addition, anti-malarials might reduce low-density lipoprotein levels[140] and (especially in combination with low-dose aspirin[141]) have a protective effect against thrombosis in SLE and APS, although the evidence in this regard is, at least in part, conflicting.[142,143]

Given the increased prevalence of traditional cardiovascular risk factors in SLE, aggressive control of hypertension, lipid profile, diabetes, smoking and other lifestyle habits might be rewarding. Preliminary data from large inception cohorts apparently confirm this idea.[17] Statins constitute the mainstay of treatment in dyslipidaemic patients at increased risk of atherosclerosis. Furthermore, statins might also exert non-metabolic, immunoregulatory effects such as enhanced T-regulatory function or reduced oxidative stress in monocytes, besides protection from atherosclerosis.[144–147] Statins may also behave in synergy with anti-malarials to dampen IFN-α-related responses.[148] Similar pleiotropic effects have also been observed with metformin, a widely used antidiabetic drug.[149]

However, these agents probably have a limited effect on the main pathogenic drivers of the disease,[150] which also probably comprise a constellation of possible concurring events. The presence of pathogenically distinct subsets of patients in the clinical landscape of SLE[28] highlights the need for individualized treatment approaches.