The role of statins in inflammatory vasculitides

Abstract

While the statins are best known for their cholesterol lowering capabilities, they also appear to have anti-inflammatory, anti-oxidant and endothelial-repairing properties that have raised the question as to whether this class of drugs can be of benefit in non-atherosclerotic, acute and chronic vasculitides. These effects, independent of the lipid-lowering effects, make the statins a class of drugs that are primed for repurposing and being used in disease states where innate and adaptive immunity and endothelial damage play a key role. Thus far, statins have been used in Behcet’s, rheumatoid arthritis and Kawasaki disease with some promising results. Further study is needed to better understand the innate and adaptive immunological response to statins in cardiovascular diseases as well as the full potential of statins in acute and chronic inflammatory vasculitides.

• Atorvastatin
• Behcet’s
• Kawasaki disease
• rheumatoid arthritis
• repurposing

Introduction

The success of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, in reducing cardiovascular morbidity and mortality independent of lowering cholesterol has raised the question about the anti-inflammatory and antioxidant role of statins. Several clinical trials of statins in atherosclerosis have demonstrated that reduction in inflammatory markers, such as C-reactive protein (CRP) and high sensitivity (hs-) CRP, are closely tied to study outcome [1–4]. A trial of pravastatin in patients with a history of myocardial infarction and average cholesterol levels [The Cholesterol and Recurrent Events (CARE) trial] found that in patients with normal cholesterol levels and a history of myocardial infarction, relative risk for recurrent infarction was associated with higher levels of systemic inflammation and subjects randomized to receive placebo rather than pravastatin [3]. In the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, both the absolute risk and the absolute risk reduction for cardiovascular disease with rosuvastatin therapy were related to the level of high sensitivity (hs)CRP independent of the low density lipoprotein (LDL), which is known to correlate with cardiovascular illness [2]. Other prospective cohort studies have also shown that the highest reduction in recurrent myocardial infarctions is associated with a greater decrease in hs-CRP [1,4,5]. Thus, the effects of statins seem to be in some instances independent of their lipid lowering capabilities.

In a recent article entitled “Mining for therapeutic gold”, Director of the National Institutes of Health, Dr. Francis Collins, stated that “drug repurposing” should be a strategy “to translate research into clinically useful products” [6]. Given the potential effects of statins independent of their lipid lowering abilities, statins are great candidates for repurposing. Studies to explore these non-cholesterol associated effects have shown that statins inhibit cytokine-inducible expression of the co-stimulatory molecules necessary for T-cell activation, increase the number and suppressive function of regulatory T-cells and reduce disruption of the endothelial cell junction [7–9]. Statins have also been shown to reduce epithelial to mesenchymal transition, to inhibit the secretion of matrix metalloproteinases (MMPs) by myofibroblasts, and to increase the number of circulating endothelial progenitor cells [10–13]. As for vascular oxidative stress, statins increase plasma levels of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, decrease the NADPH-oxidase activity (a major source of free radical oxygen in human coronary arteries) and increase endothelial nitric oxide species production [14–18].

Statins in chronic inflammatory disorders: Behçet’s and rheumatoid arthritis

These anti-inflammatory, anti-oxidant and endothelial-repairing properties of statins have raised the question as to whether this class of drugs can be of benefit in non-atherosclerotic, small to large vessel vasculitides. Behçet syndrome, a chronic systemic vasculitis of unknown etiology characterized by recurrent mucocutaneous manifestations and chronic relapsing uveitis, can also cause vascular aneurysms along any part of the arterial tree and thrombophlebitis of the superficial or deep veins of the legs [19]. In a prospective, randomized, double-blinded, placebo-controlled study, 92 subjects with Behçet’s were randomized to receive either atorvastatin, lisinopril (an angiotensin-converting enzyme inhibitor) or placebo [20]. Subjects treated with a 3-month course of either atorvastatin or lisinopril had a larger improvement in their endothelial function, as measured by brachial artery flow-mediated dilatation, compared to placebo. Measures of acute phase reactants, including hs-CRP, erythrocyte sedimentation rate and fibrinogen, were not significantly different between the three groups. The immunomodulatory effects of statins on the chronic inflammatory disorder of rheumatoid arthritis have also been evaluated. The initial clinical data that supported an anti-inflammatory effects of statins in rheumatoid arthritis was the Trial of Atorvastatin in Rheumatoid Arthritis (TARA) study in 2004 that demonstrated that after 6 months subjects treated with atorvastatin had a more rapid decline in the CRP and ESR and that the number of swollen joints also fell more significantly as compared to subjects on placebo [21]. An in vitro experiment in which peripheral blood mononuclear cells from patients with rheumatoid arthritis were treated with simvastatin demonstrated significant reduction in the proinflammatory cytokines IL-17 A, IL-6 and IFNγ in a dose dependent manner [22]. A similar in vitro study demonstrated that IFN-gamma expressing CD4+ T cells and the IFN-gamma cytokine concentrations in culture supernatants were significantly reduced in the atorvastatin-treated T cell cultures from RA patients [23]. Culture of fibroblast-like synoviocytes with simvastatin decreased the expression of IL-6 and IL-8, which are proinflammatory cytokines induced by TNFa [24]. Regulatory T cell number and suppressive function have also been shown to be higher in atorvastatin-treated RA patients as compared to those treated without atorvastatin [25,26]. A recent meta-analysis of 15 studies with a total of 992 rheumatoid arthritis patients, 487 of whom were allocated to statin therapy, revealed that subjects taking statins had a more significant decrease in erythrocyte sedimentation rate (ESR), CRP and swollen joint count [27].

Statins in acute vasculiltis: Kawasaki disease

The statins have also been considered for use in Kawasaki disease (KD), a self-limited vasculitis of unknown etiology that is the most common cause of acquired heart disease in children [28,29]. The coronary artery abnormalities (CAA) in KD result from immune activation, oxidative stress and vessel wall infiltration by myofibroblasts, neutrophils and T-cells with secretion of pro-inflammatory cytokines, elastases and matrix metalloproteinases (MMPs) [30–34]. The major sequelae of CAAs include thrombosis, late coronary artery stenosis, myocardial ischemia, myocardial infarction and death [35–37]. Currently, there is no recommended therapy to halt the progression of arterial wall damage and prevent CAA formation. Thus the anti-inflammatory, anti-oxidant and endothelial-healing properties of statins may be beneficial in blocking CAA progression KD. Genetic studies have shown an impact of genetic variation in matrix metalloproteinases (MMP) genes, which form proteases that degrade extracellular matrix and are thought to be involved in CAA formation in KD, on both KD susceptibility and aneurysm formation [31]. Immunohistochemistry studies have demonstrated increased secretion of MMP-9 in the inflamed arterial wall from KD autopsy tissue [38,39]. A murine model of KD has also highlighted the importance of MMP-9 in the inflamed arterial wall [40]. Atorvastatin attenuates MMP-9 gene expression and activity in vitro [11,41,42]. In a mouse model of KD, atorvastatin was shown to decrease the release of tumor necrosis factor (TNF)-α and to reduce secretion of MMP-9, a potent collagenase that contributes to aneurysm formation [43].

Statins have been shown to increase the number of circulating regulatory T-cells (Treg; CD25+ high/FoxP3 +) [44,45]. Circulating Treg has been characterized in the peripheral blood of acute KD subjects [30]. Further characterization of Treg in acute KD has provided strong evidence that intravenous immunoglobulin (IVIG), the standard of care treatment for KD, acts by expanding IL10 secreting tolerogenic dendritic cells (DC) and a specific Treg population that recognizes the heavy constant region of IgG [46,47]. Based on these data, it can be postulated that recovery from inflammation in KD is mediated by Treg.

Statins inhibit cytokine-inducible expression of MHC class II molecules and co-stimulatory molecules by antigen-presenting cells and prevent antigen presentation to CD4+ T-cells [48]. As for the role of myofibroblasts, genetic studies have underscored the importance of the TGFβ signaling pathway in the pathogenesis of CAA [49]. Immunohistochemistry studies of the coronary arteries from autopsy cases demonstrated α-smooth muscle actin+/smoothelin− infiltrating cells that have a myofibroblast phenotype and secrete both IL-17 and MMP-9 [34], which could potentially be inhibited by statins [10,50–53].

Pitavasatin was recently used for 2 years in a 40-year-old male with a history of KD and a giant left coronary artery aneurysm and noted to have a reduction in coronary artery inflammation by ¹⁸fluorodexoyglucose positron emission tomography [54]. Another study treated 13 children ages 2–10 years with medium-to-giant coronary aneurysms at least 1 year after KD onset with pravastatin (5 mg/day for children <5; 10 mg/day for children ≥5 years) to determine the effects of this statin on endothelial function and acute inflammation, as measured by hs-CRP [55]. After 6 months of treatment, endothelial function as measured by flow-mediated dilation had improved significantly compared to baseline as had the hs-CRP, though the number of circulating endothelial progenitor cells had not increased.

Safety of statins in children

As for the safety of statins in children, they have been shown to be safe and well-tolerated in children with hypercholesterolemia as well as those with diabetes [56,57]. In the pravastatin study previously described, the treatment was well-tolerated [55]. In a study of 20 children with KD (median age 9.3 years [range 0.7–14.3]) and medium- and giant-sized aneurysms treated with 5 or 10 mg atorvastatin for a median of 2.5 years (range 0.5–6.8), atorvastatin was well-tolerated over a median of 2.3 years (range 0.3–8.9) of use. As atorvastatin is FDA-approved for children 10 and older with hypercholesterolemia in the US (approved for 6 years and older in Europe), is well-tolerated in children, and data support its anti-inflammatory role in pathways critical to CAA formation in KD, it is currently under study in a Phase I/IIa dose-escalation study of atorvastatin in children ≥2 years old with acute KD and CAA (NCT01431105) as well as in children at least 10 years of age with giant aneurysms (NCT02114099) [9,41,42,56,58–60]. Further studies such as these will help determine the role of atorvastatin in acute KD as well as late into the course of illness in attenuating CAA damage.

Declaration of interest

The author reports no conflicts of interest. The authors alone are responsible for the content and writing of this article.