Systemic lupus erythematosus complicated with cardiovascular disease

As a common rheumatic immune disease, systemic lupus erythematosus (SLE) is a chronic autoimmune disease that usually affects women in their reproductive years. Its clinical manifestations are complex and variable; it can involve the production of a large number of autoantibodies and can affect important organs, such as the cardiovascular system, the nervous system, the kidneys, and the lungs,1 which can even be life-threatening. In recent years, cohort studies of SLE patients in low- and middle-income have found neuropsychiatric lupus, infection, and disease activity as the main causes of death in 1 to 3 year survival,2 and renal failure, pulmonary hypertension, and cardiovascular disease (CVD) as the main causes of late death. In high-income countries, the main causes of death in SLE are infections, cardiovascular events due to atherosclerosis, tumors, and organ failure.3 After the recent coronavirus disease 2019 (COVID-19) pandemic, some studies reported that patients with SLE and CVD were worse after having COVID-19.4 Cardiovascular disease has become an important factor affecting the long-term survival and quality of life of SLE patients, and the discovery of risk factors and predictors for its occurrence and early identification, and interventions to prevent the development of CVD have become two of the goals of late treatment of SLE. Age, SLE Disease Activity Index 2000 (SLEDAI-2K), hyperuricemia, and glucocorticoid use and dose were found to be risk factors for the development of coronary artery disease in patients with SLE,5 therefore early CVD screening is recommended for SLE patients with risk factors. Current studies have found that immune disorders in SLE patients also accelerate the formation of atherosclerosis, and Wilhelm et al found in animal experiments that CD4+ T cells transferred successively from SLE-susceptible mice could induce lupus-associated atherosclerosis formation in mice.6 There is a correlation between T helper type 17 (Th17)/regulatory T (Treg) cell imbalance and SLE combined with atherosclerosis, and the number of Treg cells, suppressor function and transcription factor Foxp3 expression are significantly lower in patients with early-onset atherosclerosis in SLE than in other SLE patients and normal controls, probably because the decrease in Treg cells and reduced function have a reduced suppressive effect on the inflammatory response, and the body is more prone to a pathological immune response, which leads to inflammatory activation, plaque instability, and the development of atherosclerosis.7 Hence, during disease treatment, there is a need to restore T-cell homeostasis and mitigate disease activity, as well as reduce vital organ involvement. B-cell depletion therapy has shown good results in SLE treatment, whereas anti-B-cell-activating factor belonging to the tumor necrosis factor family (anti-BAFF) treatment attenuates atherosclerotic lesions in mouse models.8 However, the inhibitory effect of anti-BAFF treatment in SLE-associated CVD is dependent on lipid content. In low-lipid conditions, anti-BAFF protects against atherosclerosis, whereas in a high-lipid environment, anti-BAFF leads to atherosclerosis due to macrophage antagonism.9 Further search for the pathogenesis of SLE to solve the therapeutic confusion in clinical treatment is also one of the main goals in SLE research. Regulatory B (Breg) cells have been found to exert a negative immunosuppressive function and to reverse the Th17/Treg cell imbalance in SLE. An animal study found that Breg cells were reduced in mice with lupus complicated by atherosclerosis; the Th17/Treg cell imbalance was significant, and the two were negatively correlated. Breg cells also had a negative correlation with the atherosclerosis risk factors total cholesterol, triglycerides, and low-density lipoprotein, suggesting a regulatory effect of Breg cells on Th17/Treg cell balance.10 In addition, folic acid increased interleukin-10-positive Breg cells,11 providing thoughts and possible therapeutic targets for further optimization of clinical treatment. Carotid intima-media thickness, presence of carotid plaque, and coronary artery calcium score can be used as markers to assess the development of atherosclerosis in patients with SLE when managing them, as recommended in the 2019 guidance update from the European Alliance of Associations for Rheumatology. Recently, Thai investigators found that the Adjusted Global Antiphospholipid Syndrome Score could be used as an indicator of the risk of atherothrombosis in SLE patients,12 and although it needs to be validated in other SLE cohorts, it also provides a new target for CVD prevention in SLE patients. Glucocorticoids are routinely used in SLE but have a negative impact on the cardiovascular system.13 In clinical treatment, there is a need to explore the use of appropriate doses to alleviate SLE disease activity while minimizing the adverse effects, especially cardiovascular effects. One study found that the efficacy of low-dose prednisolone was similar to conventional high-dose treatment of lupus nephritis, with no significant differences between them, and that the incidence of prednisolone-dose-related adverse events was lower in the low-dose prednisolone group,14 which provides some reference for the clinical use of prednisolone doses. Similarly, hydroxychloroquine, a conventional treatment for SLE, was found to have a cardioprotective effect while alleviating SLE disease activity—reducing carotid plaque incidence and vascular stiffness by antagonizing platelet action.15 A recently completed large-scale study of pioglitazone in the treatment of SLE, evaluating cardiovascular risk markers, found a positive effect of pioglitazone on cardiometabolic parameters,16 and a therapeutic effect of pioglitazone by reducing CD4+ T-cell activation and proliferation, enhancing Treg cell function and proliferation, and decreasing interferon-γ (IFN-γ) synthesis.17 The IFN-γ receptor-targeting drug anifrolumab and the Janus kinase inhibitor tofacitinib reduced cardiovascular risk in SLE patients by inhibiting the IFN-γ pathway and improving the severity of the disease and its associated vascular damage.18-20 The immune and inflammatory features of SLE drive the development of CVD, and we need to explore the pathogenesis of SLE in more detail, mitigate the damage to the organs and systems of the body from its pathology, and continuously improve cardiovascular risk screening and monitoring capabilities to prevent the development of CVD in SLE patients. All authors conceived and designed this manuscript together, which was written jointly by K-QL and Z-ZZ, and have a co-contribution to this manuscript. We would like to thank our laboratory teachers for their support and help during the performance of the experiment. This work was supported by funding from the National Natural Science Foundation of China (Grant number 81760298), Guangxi Natural Science Foundation (Grant number 2021GXNSFAA220006), and the 139 Program for the High-Level Medical Talents in Guangxi Province. Huasong Zeng is an Editorial Board member of the International Journal of Rheumatic Diseases and a co-author of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication. The data that support the findings of this study are available from the corresponding author upon reasonable request.