Sizing up stability: combination therapy with Apo-AI peptide mimetics and statins in systemic lupus erythematosus-mediated atherosclerosis

In a study published recently in Arthritis Research & Therapy, Woo and colleagues investigated the effects of pravastatin in combination with an apolipoprotein-AI (Apo-AI) mimetic peptide in a mouse model of lupus-accelerated atherosclerosis. Combination treatment resulted in a significant decrease in systemic inflammation but increased aortic root lesion size. However, this treatment changed the phenotype of the lesion to a more stable plaque. Because plaque stability is also important for protection against the deadly manifestations of atherosclerosis, combination therapies using Apo-AI mimetics and statin might offer a good additional therapy to treat autoimmunity and cardiovascular disease in patients with lupus.

Systemic lupus erythematosus (SLE) (lupus) is a chronic autoimmune disease characterized by the production of autoantibody against several self-antigens such as double-stranded DNA (dsDNA), phospholipids, and apolipoproteins. Individuals suff ering from lupus usually develop a myriad of comorbidities, including hemolytic anemia, neuropathies, glomerulonephritis, and cardiovas cular disease (CVD). In the mid-1970s, Urowitz and colleagues [1] demonstrated a bimodal mortality in which individuals who died soon after diagnosis usually succumbed to either kidney disease or infection (due to extensive immunosuppressive therapy) whereas those who survived longer past diagnosis most likely developed CVD. In 1997, a seminal paper by Manzi and colleagues [2] reported for the fi rst time that the risk for developing CVD and myocardial infarction is signifi cantly increased in premenopausal women. Since that time, numerous studies have described the existence of premature subclinical and accelerated atherosclerosis in patients with lupus (reviewed in [3]). To make matters worse, many patients with lupus do not exhibit the traditional risk factors for atherosclerosis, namely increased lowdensity lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. Instead, most patients develop dyslipidemia characterized by increased triglyceride and slight decreases in HDL but no signifi cant increase in LDL cholesterol. Th erefore, it is possible that the traditional LDL-lowering therapies that have been so successful in treating CVD and atherosclerosis in the general population may not have the same eff ect in patients with lupus.
By now, it is commonly accepted that HDL and apolipoprotein-AI (Apo-AI) are cardio-protective in both humans and mouse models of atherosclerosis. However, it was recently demonstrated that individuals suff ering from active SLE can develop a dysfunctional HDL defi ned as infl ammatory HDL [4]. Th is modifi ed lipoprotein is characterized by reduced concentrations of Apo-AI and paraoxonase, molecules important for mobilizing cholesterol from cells and protecting LDL from oxidative modifi cations, respectively. Th erefore, patients with SLE have a particular disadvantage in both levels and phenotype of protective HDL.
Owing to the cardio-protective nature of Apo-AI, research has been focused on developing eff ective Apo-AI-based therapies for CVD. One approach shown to be eff ective in reducing atherosclerosis and systemic infl ammation in mice is the use of synthetic peptides that mimic Apo-AI in both structure and function [5,6]. Th ese mimetics, termed D-4F and L-4F, can increase the ability of HDL cholesterol to protect LDL from oxidation, increase HDL levels, and increase cholesterol effl ux from cells [7]. Th erefore, it is a logical extension that these peptides should be tested for their abilities to increase

Abstract
In a study published recently in Arthritis Research & Therapy, Woo and colleagues investigated the eff ects of pravastatin in combination with an apolipoprotein-AI (Apo-AI) mimetic peptide in a mouse model of lupus-accelerated atherosclerosis. Combination treatment resulted in a signifi cant decrease in systemic infl ammation but increased aortic root lesion size. However, this treatment changed the phenotype of the lesion to a more stable plaque. Because plaque stability is also important for protection against the deadly manifestations of atherosclerosis, combination therapies using Apo-AI mimetics and statin might off er a good additional therapy to treat autoimmunity and cardiovascular disease in patients with lupus. not only the quantity but also the quality of HDL in SLE as a possible mechanism of protection from accelerated atherosclerosis.
Undoubtedly, one of the most popular, and successful, therapies for the management of CVD and lipids in the general population has been the use of statins. Given that statins have had positive clinical eff ects in patients with rheumatoid arthritis, it is logical to expect that individuals with SLE would likewise benefi t from this therapy [8]. Unfortunately, the clinical studies testing statin use in patients with SLE have not been very promising [9]. In a study published recently in Arthritis Research & Th erapy, Woo and colleagues [10] investigated whether statin therapy might have positive eff ects in a mouse model of lupus-mediated accelerated atherosclerosis and osteoporosis.
In that study, Woo and colleagues [10] tested the hypothesis that treatment of apoE-defi cient (apoE −/− ) mice lacking Fas (hereafter referred to as apoE −/− Fas −/− ), with a high-dose statin, pravastatin (5 mg/kg), either alone or in combination with the Apo-AI mimetic, L-4F, could decrease the progression of atherosclerosis and have positive eff ects on osteoporosis. Th e authors observed, in agreement with the anti-infl ammatory properties of Apo-AI, a decrease in autoantibody titers to dsDNA and oxidized phospholipid as well as a reduction in glomerulus tuft size, proteinuria, and lymphocyte infi ltration in mice treated with L-4F or L-4F plus pravastatin compared with the vehicle-treated group. Surprisingly, the anti-infl ammatory eff ect of this treatment was accompanied by an increase in aortic root atherosclerotic lesion area in apoE −/− Fas −/− mice that received L-4F, pravastatin, or combination therapy, despite reduced interleukin-10 and chemokine levels and decreased VCAM-1 (vascular cell adhesion molecule-1) expression on endothelial cells. Th is eff ect was independent of circulating lipoprotein levels. Interestingly, combination therapy, but not L-4F or pravastatin therapy alone, resulted in decreased macrophage infi ltration and plaque remodeling, suggestive of a more stable plaque. Furthermore, L-4F therapy resulted in the improvement of bone density in these mice. Because plaque stability and not just plaque size is important for protection against the deadly manifestations of atherosclerosis (a view that is commonly accepted), combination therapies using Apo-AI mimetics and statin might off er a good additional therapy to treat autoimmunity and associated CVD and osteoporosis in patients with SLE.
Collectively, the fi ndings of Woo and colleagues [10] represent a glimmer of hope for a group of patients who have not had a major breakthrough in treatment in the past 30 years. Patients with SLE are subject to a large number of comorbidities; two of the more severe comorbidities are accelerated atherosclerosis and increased risk of myocardial infarction. Although L-4F and other Apo-AI mimetics may have positive eff ects on SLE symptoms and plaque stability, the increase in total lesion area obviously represents a signifi cant hurdle for the practical use of these molecules in the clinic.