Statin use and ocular inflammatory disease risk

Uveitis refers to inflammation of the uveal tract. Uveitis is a frequent cause of ocular complications with subsequent visual impairment [1]. Two studies of patient populations in the west coast of the USA have estimated that the incidence of uveitis ranges from 25.6 to 52 cases per 100,000 person-years and the prevalence ranges from 69 to 115 cases per 100,00 persons [2, 3]. Interestingly, the lower estimate of incidence and prevalence above are obtained from a study of Veterans Affairs (VA) patients in the Pacific Northwest, pertinent to the current study's patient population. As uveitis accounts for up to 10% of blindness in the USA and up to 15% worldwide [4], it is a disproportionate cause of visual disability in light of its frequency. Scleritis is inflammation of the sclera, and similar to uveitis, it is primarily due to autoimmune disease [5–8]. Collectively, uveitis and scleritis may be referred to as ocular inflammatory diseases (OID). Treatment for autoimmune OID consists of suppression of inflammation with corticosteroids or immunomodulatory/steroid-sparing medications. Antimetabolite medications are the most commonly used after corticosteroids [9] and are effective in up to approximately two-thirds of patients [10–12]. Alkylating agents are more effective, but may carry with them greater risks as well [9, 13]. Newer agents such as biologic response modifiers hold great promise for the treatment of OID, but may also have increased risks [9].

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (the so-called ‘statins’) has been shown to be beneficial in reducing cardiovascular morbidity and mortality [14]. In addition to reducing serum cholesterol levels, statins are also believed to modify atherosclerosis via anti-inflammatory pathways [15]. Multiple studies have suggested that these modulatory effects of statins may be therapeutic in systemic autoimmune disorders [16]. Various studies have examined the possible impact of statins in ophthalmic conditions, including age-related macular degeneration [17–23], glaucoma [24], and diabetic retinopathy [25–27]. Although the role of statins in ocular disease is not fully understood, given the numerous mechanisms by which statins may modify the inflammatory response, we sought to investigate the potential impact of statin use on OID.

There are several mechanisms by which statins might exhibit anti-inflammatory effects in the eye [28]. Statins are known to inhibit the activation of Rho guanosine triphosphatase (GTPase), a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration [29–31]. Statins thus inhibit interactions between leukocytes and endothelial cells, preventing leukocyte transmigration from the vasculature, across the blood-retinal barrier [29, 32–34]. Endothelial cell nitric oxide synthase expression is up-regulated in the presence of statins, leading to higher levels of nitric oxide, which has protective effects on endothelial cells [35]. Statins also inhibit the formation of oxygen free radicals by endothelial cells [36, 37]. Thus, statins may act to stabilize the blood-ocular and blood-retinal barrier, transgression across which enables inflammatory mediators and immune activator cells to enter the anterior chamber, vitreous cavity, and retinal tissues. In addition, statins reduce a number of key inflammatory cytokines, including IL-6, IL-8, and TNF [38, 39]. Finally, statins decrease T cell activation by inhibition of GTPase activity [40–43].

The effect of statins in animal models of uveitis has been examined. In a mouse model using B10.RIII mice, a strain that is highly susceptible to experimental autoimmune uveitis (EAU) and typically manifests severe disease, Thomas and colleagues [44] found that atorvastatin administered orally did not have a significant effect on measured levels of inflammatory cytokines, although they did observe a mildly reduced level of histological inflammation in the group receiving high-dose (10 mg/kg/day) treatment. Similarly, Gegg and colleagues [45] reported that neither atorvastatin nor lovastatin administered orally demonstrated a significant therapeutic effect. However, parenteral lovastatin (20 mg/kg/day) suppressed clinical ocular pathology, retinal vascular leakage, and leukocyte infiltration into the retina. In a rat model of uveitis induced with S-antigen, Kohno and coworkers [46] demonstrated a therapeutic effect for both atorvastatin (10 mg/kg/day) administered orally and lovastatin (2 mg/kg/day) administered intraperitoneally. These studies suggest that the effect of statins varies by route of administration, dosage, as well as across different models of EAU. This data indicates that the potential beneficial effects of statins in EAU may require doses greater than those used in the routine treatment of hyperlipidemia in humans. For example, the highest recommended dose of atorvastatin in humans is 80 mg/day, which for a 70-kg male adult is 1.14 mg/kg/day, ninefold lower than the effective dose used by Kohno and colleagues [46]. In the current study, it is likely that the majority of filled statin prescriptions were for simvastatin, as this was the first line medication on the BVAMC formulary for hyperlipidemia during the study period. The BVAMC data set did not include medication dosage information, so we are unable to comment on an association between dosage and OID protection.

Strengths of this study include its nested case–control design, which allowed for the identification of statin use before the diagnosis of OID. Additionally, an electronic prescription record was utilized, obviating the need to rely on self-reported medication use which may be historically inaccurate.

In summary, the data presented demonstrate a possible reduction in the risk of the development of OID in patients using statins, a reduction that becomes more pronounced with increasing duration of use. This effect did not reach statistical significance, with a p value of 0.13 for any use of statins. It is important not to overemphasize this finding given the non-signifcance, but it is important not to reject an effect out of hand in an underpowered study. A twofold reduction in risk, with a p value trending toward significance, may be statistically insignificant, but still clinically relevant. To fully address the question of the effect of statin use on OID risk, evaluation of larger databases with longer follow-up periods, such as insurance company claim files where both disease and pharmacy data are maintained, could provide a definitive answer. A randomized clinical trial would be necessary to establish whether statins would be a useful addition to the therapeutic arsenal against OID.

RWR is a Research to Prevent Blindness physician scientist.