Six disease modifying drugs (DMD) have been approved for the treatment of MS, including interferon-beta-(IFN-?)-1a (Avonex®, Rebif®), IFN-?-1b (Betaseron/Betaferon®), glatiramer-acetate (GA; Copaxone®), mitoxantrone (Novantrone®), and natalizumab (Tysabri®). The approval of two new oral drugs – fingolimod (Gilenia®) and cladribine (Leustatin®) and the introduction of several monoclonal antibodies and other DMD will soon increase the arsenal of treatment options for MS. Nevertheless, these therapies are only partially effective, and potential serious adverse events limit the use of some of them. More effective therapies are needed, using either new drugs and treatment strategies, or combination of drugs with complementary mechanisms of action that target several elements in the immunological and neurodegenerative cascades leading to inflammation, demyelination and axonal loss in MS.
Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase. Their recently elucidated immunomodulatory, anti-inflammatory and neuroprotective properties, combined with their convenient once-daily oral administration, favorable safety profile and relatively low price make them attractive candidates for the treatment of MS either as monotherapy or in combination with other MS drugs. However, pro-inflammatory actions of statins have also been demonstrated that may be deleterious in MS and antagonize the effects of IFN?; statins increase the production of interferon-gamma and interleukin (IL)-12, decrease the production of the anti- inflammatory cytokine IL-10 and enhance the activity of matrix metalloproteinase (MMP) 2 and 9. The combination of IFN?-1b and atorvastatin increases the levels of IL12p70, the bioactive heterodimer form of IL-12. Moreover, in contrast to studies demonstrating neuroprotective and regenerative properties of statin, other studies showed inhibition and impairment of remyelination in the central nervous system induced by simvastatin.
Initial open-label clinical trials confirmed the safety and efficacy of statins as monotherapy on short- term clinical and magnetic resonance imaging (MRI) measures in MS. However, a recent double- blind placebo-controlled trial evaluating atorvastatin 80 mg/d for 12 months in 81 patients with clinically isolated syndromes (StayCIS) failed to demonstrate effect on progression to clinically- definite MS or prevention of the development of >3 new MRI T2 lesion, although significantly more patients in the atorvastatin group remained T2-lesion free compared with the placebo group.
Several in-vitro and animal studies demonstrated synergistic effects of statins combined with IFN-?, GA, rolipram or minocycline on immune responses, histological and clinical outcomes in experimental autoimmune encephalomyelitis (EAE). However, animal data cannot predict what will happen in human patients and should not be considered as having therapeutic implications. Although several small, mainly non-randomized open-label clinical studies in MS suggested that the combination of IFN-? and statins is safe and probably beneficial, other recent randomized studies failed to confirm these preliminary results, and one study even found increased MRI and clinical disease activity with the combination. In this small but well-designed randomized placebo-controlled study, Birnbaum et al. randomized 26 stable MS patients treated with subcutaneous IFN?-1a to add- on treatment with 40 mg or 80 mg atorvastatin or placebo for 9 months. Ten of the 17 subjects on atorvastatin had either new or enhancing T2 lesions on MRI or clinical relapses, compared with one of the nine subjects on placebo (p=0.019). Some relapses occurred after years of stable disease, and baseline differences did not influence the risk of disease activity. Possible explanations for this antagonistic effect may include blocking of the STAT1 phosphorylation signaling pathway of interferon by statins and increased activity of MMP 2 and 9 that cleave IFN? and increase inflammation. In a post-hoc analysis of the SENTINEL trial which determined the effects of natalizumab and intramuscular IFN?-1a, 40 MS patients who received statins to treat their hyperlipidemia in addition to IFN?-1a were compared to 542 patients who were treated with IFN?-1a only. There were no differences between groups in annualized relapse rate, disease progression, number of MRI enhancing lesions or number of new or enlarging T2 hyperintense lesions after 2 years. Two other large randomized controlled combination clinical trials with statins yielded negative results: In the recently completed SIMCOMBIN trial, 380 treatment-naïve RRMS patients were randomized to intramuscular IFN?-1a 30 mcg weekly plus either daily simvastatin 40 mg or placebo