Various studies indicate that early and appropriate treatment of immune dysregulation in SLE could be key to hampering CVD development and progression in SLE. Patients treated with lower doses of cyclophosphamide, azathioprine or corticosteroids had greater progression of CVD than those treated with higher doses [5
]. Further, aortic atherosclerosis risk is lower in SLE patients who have undergone treatment with cyclophosphamide when compared to SLE patients who have not received this medication [9
]. The role of corticosteroid treatment is complex and poorly understood, with potentially dual effects on CVD risk that may depend on dose and time of exposure [8
While no studies have shown a reduced incidence of CVD in patients taking antimalarials, these drugs have positive effects on glucose tolerance, lipid profiles, and thrombosis potential [86
]. Studies using surrogate markers for CVD have provided mixed results. Antimalarials were significantly associated with decreased presence of carotid plaque in patients with SLE [87
]. A correlation between lack of antimalarial use and increased vascular stiffness in SLE patients has been demonstrated, but no association between their use and coronary calcification was found [88
]. A cohort study suggested a clear survival benefit in SLE patients taking antimalarials, but the mechanisms for this effect remain to be determined [90
]. Because antimalarials can weakly inhibit IFN-α production through inhibition of IC formation and toll-like receptor-7 and -9 signaling [91
], modulation of IFN-α levels with a potential improvement in endothelial function and vascular repair may contribute to the survival benefit. More research into the vascular effects of antimalarials is needed to understand their benefits and whether they have an impact on atherosclerotic development.
Mycophenolate mofetil (MMF), an immunosuppressive medication commonly used in SLE, may be potentially beneficial in atherosclerosis. MMF has a protective effect on the development of both transplant and diet-mediated atherosclerosis in animals and is also beneficial in preventing coronary pathology in cardiac transplant patients [92
]. MMF decreases atherosclerotic plaque inflammation in patients treated for 2 weeks prior to carotid endarterectomy [93
]. Whether this drug has a CVD benefit in SLE patients remains to be determined, and future studies will hopefully address this question.
The role of novel biologics in CVD prevention in SLE remains unknown. Currently, studies targeting type I IFNs, IL-17 and the various anti-B cell therapies are underway in SLE and other diseases. Long-term follow-up to assess atherosclerosis progression in these groups would be important to identify if favorable effects are identified. Given the recent observation that impairment in IL-1 pathways in SLE may mediate abnormal vascular repair in this disease [32
], a note of caution is added with regards to the use of anakinra and other anti-IL-1 therapies, particularly in SLE, but also in other diseases where aberrant vasculogenesis is observed.
Other non-disease modifying medications may also have a benefit in SLE-related CVD. SLE patients have a higher incidence of metabolic syndrome and insulin resistance, and this correlates with increases in homocysteine and high sensitivity CRP [94
]. Treatment of insulin-resistant states may improve CVD profiles in SLE. Our group reported that treatment of SLE-prone mice with the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone, which is used to treat type II diabetes in humans, resulted in improved insulin sensitivity, improved endothelial function and restored EPC differentiation [94
]. Additionally, rosiglitazone, another PPAR-γ agonist, decreased aortic atherosclerosis in lupus- and atherosclerosis-prone Gld.apoeE-/- mice [54
]. How this class of medications would benefit CVD in SLE patients warrants additional studies.
Guidelines for CVD prevention in SLE remain nebulous. The latest European League Against Rheumatism (EULAR) recommendations suggest yearly monitoring of traditional and/or non-lupus-specific CVD risk factors, including smoking, activity level, oral contraceptive use, hormonal therapies and family history of CVD. Monitoring of blood pressure, lipids and glucose is also recommended [95
]. One group has proposed treating SLE as a coronary heart disease equivalent, targeting recommendations as suggested by the Adult Treatment Panel guidelines (ATPIII) [96
]. However, whether these guidelines will be sufficient to abrogate CVD risk in SLE remains to be determined. The use of statins in SLE has not been systematically or extensively studied, but they have been shown to improve endothelium-dependent flow-mediated dilation and possibly slow progression of carotid IMT in adult lupus as well as increase EPC numbers in other conditions, including diabetes mellitus [97
]. While trending toward a protective effect for carotid IMT thickness in pediatric SLE, prophylactic statin use in children did not show a statistically significant difference compared to placebo [100
]. A murine lupus/atherosclerosis model displayed decreased atherosclerosis and amelioration of renal disease when treated with simvastatin [101
]. Statins can also block IFN-α production in peripheral blood from healthy controls in response to exposure to SLE patients' serum. Th is blockade occurs through inhibition of the Rho kinase, likely in plasmacytoid DCs [102
]. Future research will hopefully clarify the role of statin use in SLE patients.
Finally, diet may be an important modifiable risk factor that can alter predisposition to atherosclerotic lesions. LDL receptor-deficient mice that underwent bone marrow transplant with SLE-prone cells had increased sensitivity to dietary fat. A Western-style diet containing 21% fat increased atherosclerotic lesions, pathogenic antibody formation and severity of renal disease when compared to mice fed a regular diet [55
]. A different model of lupus-prone mice fed high-fat chow or administered leptin had accelerated and increased proteinuria, suggesting an interplay between diet and lupus [68
]. Certainly, some murine lupus models have decreased life spans when fed a high-fat diet [103
]. Thus, further understanding of the role of diet on immune modulation and CVD risk in SLE may be key in vascular damage prevention.