Combining statins with interferon β in multiple sclerosis: think twice, it might not be all right.

672 www.thelancet.com/neurology Vol 10 August 2011 Since the fi nding that cholesterol-lowering statins could induce T-cell-mediated immune modulation and reverse paralysis in mice with experimental autoimmune encephalomyelitis (EAE), there has been substantial interest in whether this class of drugs is benefi cial in multiple sclerosis. One question that has not been answered is whether a statin used alone is benefi cial; more energy has been devoted to establishing whether statins can provide added benefi t when combined with interferon beta, the most commonly prescribed class of drug in multiple sclerosis. Results from trials have been mixed. Although one study showed that the combination of a statin with interferon beta was antagonistic, other small studies have suggested that there could be a benefi t. In this issue of The Lancet Neurology, Per Soelberg Sorensen and colleagues tested whether oral simvastatin could augment the benefi t of intramuscular interferon beta-1a. 307 treatment-naive patients with relapsing-remitting multiple sclerosis were enrolled in the SIMCOMBIN trial, the largest study to date evaluating the combination of a statin with interferon beta in multiple sclerosis. After a 3-month run-in period with weekly intramuscular interferon beta-1a, patients were randomly assigned to receive simvastatin 80 mg (n=151) or placebo (n=156) in addition to interferon beta, then followed up for clinical exacerbations and development of demyelinating lesions on brain MRI for 1–3 years. Although the combination of simvastatin and interferon beta was tolerated, no signifi cant diff erence was reported at 12 months in annualised relapse rate (the primary endpoint) or in development of new or enlarging T2 brain MRI lesions. Not only was there a lack of benefi t, but the non-signifi cant suggestion of better results in the placebo group again raised concern that there could be antagonism when a statin and interferon beta are combined in multiple sclerosis treatment. Interferon beta binds to the type 1 interferon receptor, which is expressed on nearly all cells; this binding leads to activation of the signal transducers and activators of transcription (STAT) 1 and STAT2, the initial steps in the biochemical cascade leading to immune activation and regulation by type 1 interferons (fi gure). By inhibiting HMG CoA reductase, statins inhibit synthesis of molecular intermediates and so can block the activation of STAT1. Thus, opposing eff ects on STAT1 represent one point for potential antagonism. Although the combination of an interferon beta and a statin was not studied in vivo before testing in clinical trials, when tested in EAE, statins have increased the activity of other agents. For example, atorvastatin increased the activity of glatiramer acetate, providing support for testing of this combination in multiple sclerosis. Interestingly, glatiramer acetate, like statins, inhibits STAT1 activation in myeloid cells. Clinical studies in multiple sclerosis have now tested diff erent statins and preparations of interferon beta in combination. Just as individual interferon beta preparations diff er in pharmacological characteristics, statins vary in their capability to reduce cholesterol and might diff er in their potential immune modulatory Combining statins with interferon beta in multiple sclerosis: think twice, it might not be all right