Are "statins" beneficial or harmful in multiple sclerosis?
Christopher Lock, MBBS, PhD
In this issue of Neurology®, Dr. Birnbaum and co-authorsstudy whether cholesterol medications called statins are helpfulor harmful when combined with common multiple sclerosis (MS)treatments called interferons in patients who have MS.1 Interferonsare drugs often used for treating MS, and they include interferonbeta-1b (Betaseron) and interferon beta-1a (Rebif, Avonex).Statins are drugs given by doctors to lower cholesterol. Statinsdo more than lower cholesterol (figure). They also affect thebody’s immune system (the system that helps the body fightinfection and sickness) and decrease inflammation. The anti-inflammatoryeffects may partly explain why these medications protect patientsagainst heart attacks and strokes. Some studies have suggestedthat these effects of statins might help patients with MS. Animalswith a disease similar to MS did better when a statin was combinedwith MS therapy.2 Small studies in patients with MS or at riskfor developing MS suggested a possible benefit of statins.3Could a benefit of statins when added to interferons be confirmed?
Dr. Birnbaum and co-authors asked whether a high dose of a statin—atorvastatin—canbe given safely to MS patients taking an interferon. Twenty-sixpatients with relapsing-remitting MS who were taking interferonbeta-1a three times a week entered the study. All patients hadto have stable disease activity for 6 months before the studybegan. The MS patients stayed on interferon, and then startedon atorvastatin (40 or 80 mg) or placebo (a "sugar pill") for6 months. Patients were examined and had pictures of the brain(magnetic resonance images or MRIs) done at 0, 3, and 6 months,and after stopping the statin at 9 months. Patients were monitoredfor signs of increased disease activity on examination or MRI.The study was blinded which means that neither the investigatorsnor the patients knew which treatment was being given. Bloodtests were watched carefully. One patient had abnormal livertests that may have been related to the interferon or to atorvastatin.There were no other side effects apart from the expected loweringof cholesterol levels in the patients taking atorvastatin.
Surprisingly, MS patients treated with atorvastatin seemed toget worse. Ten of the 17 patients who received either 40 mgor 80 mg of atorvastatin had either a relapse or a new lesionon MRI. Only 1 of 9 patients taking placebo had a relapse withactive lesions on MRI. In the end, the authors decided thatthe 40 mg or 80 mg of atorvastatin, taken with interferon, worsenedthe MS.
The study is important for several reasons. Treatments for MSare not completely effective, and combining drugs that workin different ways may improve results. Drugs that can be givenby mouth rather than by injection are preferred. Statins havea good safety record, and laboratory studies with animals predictthat statins may be helpful to people suffering from MS. However,studies in humans sometimes do not follow the same pattern,or there may be unexpected drug interactions.
Today, there is not enough information about the effects ofstatins on MS to know for certain whether they help or harm.Statins are widely used to treat high cholesterol and are consideredsafe. Four other studies of statins used with interferons werepresented at a European MS meeting last year, and none of thesepreliminary studies showed a bad effect of taking a statin onMS. Some patients with MS may need to be on a statin to preventheart disease or stroke. Dr. Birnbaum and co-authors recommendthat MS patients taking the combination of a high-dose interferonwith a statin should be watched closely, or should take a differentstatin.
Studies using more patients will be needed to know for certainwhether there is a harmful interaction between interferons andstatins in MS. In small studies like this, there may be randomvariations between groups, which tend to skew the results. Thestudy did not find that disease activity was worse in MS subjectstaking a higher dose (80 mg per day) of atorvastatin vs a lowerdose (40 mg per day), which might be expected if taking interferonplus atorvastatin was causing worsened disease. Atorvastatincould possibly get in the way of the good effects of interferon,and lower doses of atorvastatin or other statins might not interfere,but this is not known. We hope to have the answer in the nextfew years.
Multiple sclerosis (MS) is a condition that affects the whitematter of the central nervous system (CNS), which includes thebrain, spinal cord, and optic nerves. It can be relapsing-remittingor progressive. The white matter of the CNS consists of projectionsof nerve cells or axons covered with a fatty substance termedmyelin. Myelin is like the insulation on a wire and the axonis like the core. MS is thought to be an "autoimmune" conditionin which the immune system attacks myelin by mistake. Whilemyelin is the main target, MS may affect axons or affect thegray matter of the brain. "Multiple" refers to the involvementof different areas of the CNS at different times, and "sclerosis"refers to the scarring that occurs where the myelin is injured.The damage to myelin can cause slowing or block conduction inthe nerve, disturbing the flow of information to and from thebrain and spinal cord.
WHAT ARE THE SYMPTOMS OF MS?
The symptoms of MS vary from person to person depending on wheremyelin injury occurs. Symptoms may include changes in vision,numbness, weakness, dizziness, imbalance, difficulty walking,fatigue, and changes in sexual function, bladder and bowel function,and cognition. The course and severity of MS is unpredictableand covers a broad range. Most people with MS have a normalor near-normal life expectancy.
WHO IS LIKELY TO SUFFER FROM MS?
About 400,000 people in the United States and 2 million aroundthe world have MS. Most MS begins between 20 and 30 years ofage, but MS may affect children or begin in later life. Womenare affected about two to three times as often as men are. MSis more frequent in countries further from the equator. MS isnot a genetic disease, but having an affected relative increasesthe risk of developing MS. These observations point to bothenvironmental and genetic factors.
HOW IS MS DIAGNOSED?
MS is diagnosed by medical history, neurologic examination,MRI of the brain and spinal cord, and analysis of spinal fluid.Blood tests are used to rule out other conditions that can mimicMS. There is no single laboratory test for MS. To make a diagnosis,there must be evidence of injury to at least two separate areasof the CNS, occurring at different points in time, and otherconditions must be ruled out.
WHAT TREATMENTS ARE AVAILABLE FOR MS?
There are now six FDA-approved drugs to help MS: beta interferons(Avonex, Betaseron, and Rebif), glatiramer acetate (Copaxone),mitoxantrone (Novantrone), and natalizumab (Tysabri). High-dosecorticosteroids are often used to treat flare-ups. Other medicationsare available to manage symptoms. Physical therapy and rehabilitationcan help improve and maintain function.
WHAT ARE THE CURRENT AREAS OF INTEREST IN MS?
Among the many areas of investigation, several stand out:
Clinically, MS is classified into relapsing-remitting, secondaryprogressive, and primary progressive subtypes. Different MStypes may have different causes, and in the future it may bepossible that MS will be further divided into different subtypesbased on other tests.
Biomarkers (blood tests, MRI techniques,or other biomarkers)could help to predict the course of MSand response to treatment.
Advances in the understanding ofthe immunology of MS has broughtattention recently to new partsof the immune system that mayplay an important role in thedisease and that may be targetsfor therapy.
There are probablya large number of genes involved in determiningwhether someonecould have MS, and recent family studies haveidentified severalnew candidates.
Many new drugs are being studied, includingseveral that canbe taken by mouth. Combination therapies arebeing tested. Aswell as stopping the injury to myelin by dampingdown the misdirectedimmune response, a large effort is beingmade to repair nerves,which holds great promise for the future.
Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008;71:1390–1395.[Abstract/Free Full Text]
Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest 2006;116:1037–1044.[Medline]
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363:1607–1608.[Medline]
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