Statins: a revised appraisal for potential additional future treatment indications

Vandebriel and colleagues [1] report that the statins atorvastatin and pravastatin orally administered before disease induction in collagen-induced arthritis (CIA) in male DBA/lOlaHsd mice led to accelerated onset and higher disease incidence compared to controls. In addition, atorvastatin applied after induction of CIA resulted in earlier disease onset than administration before induction of CIA. Atorvastatin, but not pravastatin, administration also resulted in increased production of anti-collagen autoantibodies. In line with these novel findings in CIA, the same group recently demonstrated in a retrospective analysis of patients with rheumatoid arthritis (RA) that statins increase the risk for development of RA [2]. Statins are one of the most prescribed drugs in clinical medicine at present. Their main mechanism of action is selective, competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Statins are indicated in patients with significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia for reduction of mortality from coronary heart disease, non-fatal myocardial infarction and stroke and reduction of coronary and non-coronary revascularization procedures. Furthermore, statins are indicated in patients with various forms of hyper lipidemia. While statins have a clear and well established positive effect in the disease conditions named above, emerging data for additional indications is rather weak and side effects should be taken into consideration. In addition to the inhibition of HMG-CoA reductase, a multitude of additional drug-related and off-target effects with possible therapeutic value have been described. Importantly, it has also been demonstrated that statins have immunomodulatory properties. Most prominently, atorvastatin application in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, leads to reduced disease severity due to effects on antigen presentation and T-cell activation and phenotype [3]. Unexpectedly, clinical studies in multiple sclerosis patients could not confirm the beneficial effects of statins observed in experimental autoimmune encephalomyelitis [4]. Statins that pass the blood-brain barrier should also be used with caution for other reasons, since some experi mental data indicate that statins inhibit remyeli nation [5]. Statins have been evaluated as a treatment of Alzheimer’s disease. There are positive trends, but the data are conflicting and further studies in patients with mild Alzheimer’s disease will possibly clarify the assumed therapeutic value [6]. The findings of Vandebriel and colleagues are in contrast to previously published reports in which atorvastatin, pravastatin, simvastatin and rosuvastatin given by various routes after CIA induction in mice have been reported to reduce disease or to have no effect (summarized in [1]). The reasons for the discrepancy could be differences in disease induction, route of dosing and dose, used substrains of mice and the animal housing Abstract