Drug Treatment:

Corticosteroids

Corticosteroids (commonly called steroids) are mainstay treatments for acute relapses patients with relapse-remitting MS. High-dose methylprednisolone given intravenously (IVMP) is typically administered for major relapse, often followed by oral prednisone for a few days. Steroids reduce inflammation in the central nervous system and may help suppress the immune system's attack on myelin and even improve electrical conduction.

Steroids, in general, do not improve the long-term course of the disease and can lose effectiveness if overused. They are not generally used for maintenance therapy. Some research shows a potential benefit with the use of pulsed administration of intravenous methylprednisolone. Such an approach typically administers the steroid daily for 5 days every 4 months for 3 years, then every 6 months for 2 years. More evidence is needed before it can be recommended. Steroids can also have considerable adverse effects when used over time.

Side Effects. Side effects of long-term use of steroids include weight gain and facial fullness, hypertension, diabetes, osteoporosis, cataracts, intestinal bleeding, and increased susceptibility to infections. In addition, side effects of steroids on the central nervous system (sleeplessness, memory loss, anxiety, and depression) can be particular problems for patients. It is extremely important to taper withdrawal very carefully after continuously taking steroids for a prolonged period of time. This gives the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.

Interferons

Interferons (so-called because they “interfere” with viral replication) both suppress important inflammatory factors in the immune system and have anti-viral properties. Interferons specifically block immune factors known as class II MHC molecules, which are associated with the attack on myelin and the breach in the blood-brain barrier that allows the destructive T cells to pass through.

Specific Interferons Used for MS. Interferon drugs used for MS are IFN1b (Betaseron) and IFN1a (Avonex, Rebif). They are now the treatments of choice for relapsing-remitting MS. Expert organizations urge that these medications be used early in the course of the disease and continued indefinitely, unless they produce no benefits or have severe side effects.

Successes and Drawbacks. Interferons can reduce flare-ups overall by 30% and have an even greater effect on reducing major relapses. Disease activity, as measured by MRI scanning, is reduced by over 80%. They appear to be about equal in delaying disability. To date, only Avonex has demonstrated slowing progression of mental impairment. It also appears to be better tolerated than other interferons. Studies on their effects on quality of life are limited. None of the interferons are a cure, in any case, and when the drug is discontinued, disease activity may increase. All of these drugs need to be injected. (Oral forms are under investigation.)

Side Effects and Complications. Side effects include:

• Pain at the injection site. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Experts recommend taking acetaminophen (Tylenol) before the injection and then every 6 hours after each injection for 24 hours during the first 6 months of treatment.
• Skin injury at the injection site. Black dead tissue may form around the site, and many patients taking Betaseron have reported severe skin eruptions. These skin injuries heal after the drug is withdrawn, but scarring can occur. This side effect is least severe with Avonex, followed by Rebif.
• Other physical side effects. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, and dizziness. Such side effects usually fade after 2 - 3 months.
• Depression. Early studies associated taking interferon with a higher risk for depression during the first 2 - 6 months following initial therapy. More recent studies, however, have reported no greater risk for depression in patients taking any of these drugs. MS itself, in any case, is highly associated with depression.
• Thyroid abnormalities. Interferon has been associated with autoimmune thyroiditis, a cause of hypothyroidism. Some experts recommend monitoring for thyroid function, particularly in the first year and in those with a history of thyroid problems. If there is no evidence of the condition during that period, the risk for its occurrence appears to be very low.
• Liver damage. Interferon may cause liver damage and, in rare cases, liver failure. Patients should avoid alcohol and have regular liver function tests while taking this drug

Neutralizing Antibodies That Reduce Effectiveness. Over time, people taking interferons develop antibodies to the drugs, some of which can neutralize their effects. The risk for neutralizing antibodies (NAbs) increases with higher doses and greater frequency of use. Interferons injected under the skin (Betaseron, Rebif) are more likely to produce neutralizing antibodies than Avonex, which is injected into a muscle. Patients who have this, however, often can be treated with an alternative interferon or with glatiramer, which has an extremely low risk, for NAbs. Often after switching drugs, NAb levels decline, and the patient may be able to return to the original interferon.

Glatiramer Acetate

Glatiramer acetate (Copaxone) is a synthetic molecule that resembles a basic protein found in myelin. It is used as a decoy to trick white blood cells into attacking it instead of myelin. It is approved to help reduce the frequency of relapses in patients with relapse-remitting MS. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement. Benefits have lasted for years. Glatiramer acetate can also help reduce the number of new brain lesions.

Glatiramer acetate has also been studied for treatment of patients with primary progressive MS. To date, trials have not demonstrated any effectiveness for treating this type of multiple sclerosis.

Side Effects. About 15% of patients have side effects, usually right after the injection. They include pain at the injection site, chest pain, rapid heartbeat, flushing, anxiety, and shortness of breath.

Natalizumab and Other Monoclonal Antibodies

Monoclonal antibodies (MAbs) are drugs that target specific antibodies involved with the immune response. In 2004, natalizumab (Tysabri) became the only MAb approved for treatment of MS. Shortly afterwards, reports emerged of progressive multifocal leukoencephalopathy (PML) occurring among patients who took natalizumab for more than 2 years. PML is a rare neurological disease that can affect people with compromised immune systems. Based on these reports, the FDA suspended marketing of natalizumab in February 2005 and recommended that patients discontinue its use.

In June 2006, the FDA allowed natalizumab to return to the market with certain safety restrictions. Doctors can prescribe the drug only to patients who have failed to respond to or who cannot tolerate other MS treatments. Natalizumab can only be taken alone, not in combination with other immune-modifying drugs. Patients who take natalizumab must enroll in a special program called TOUCH, which is run by the drug’s manufacturer. Patients need to get magnetic resonance imaging (MRI) brain scans before they begin taking the drug, and they are evaluated regularly during drug treatment to make sure they are not at risk of developing PML. In the year after these restrictions were implemented, no new cases of PML were reported.

In 2008, a warning about potential liver damage was added to natalizumab’s prescribing label. Cases of liver injury have been reported within a week after a first dose of natalizumab, as well as after multiple doses. Signs of liver injury include yellowing of skin and eyes (jaundice), sudden darkening of urine, fatigue, and nausea and vomiting. Patients should immediately contact their doctors if any of these symptoms develop. If blood tests confirm liver injury, natalizumab should be discontinued.

Clinical trials indicate that natalizumab’s benefits may outweigh its risks. In general, risks of significant complications from short-term use are low.

Other MAbs under investigation for MS include daclizumab (Zenapax), alemtuzumab (Campath), and rituximab (Rituxan). Most of these drugs are in phase 2 trials for MS treatment. While they have shown some benefit, their long-term safety in the treatment of multiple sclerosis has not yet been proven.

Intravenous Immunoglobulin

Intravenous immunoglobulin treatments are monthly infusions of natural antibodies. They appear to have some modest benefits for relapsing-remitting MS. Studies suggests that intravenous immunoglobulin reduces relapse rates and occurrences of new lesions and slows disease progression in relapsing-remitting MS. It does not appear to reduce disability. It is extremely expensive and appears to have very little or no benefit for patients with primary and secondary progressive MS.

Immunosuppressants for Chronic Progressive MS

Many drugs being investigated for chronic progressive multiple sclerosis are immunosuppressants, which block certain factors in the immune system that contribute to the inflammatory process. Each of these drugs can cause serious side effects, including susceptibility to infection. Evidence on benefits is uncertain, mainly because of high toxicity or study limitations. Still, some immunosuppressants may help certain patients with severe MS. Among immunosuppressant drugs or procedures that have been investigated with little or no obvious benefits or unacceptably high side effects are total lymphoid irradiation, sulfasalazine, cyclosporine, acyclovir, and oral bovine myelin.

Mitoxantrone. Mitoxantrone (Novantrone) was the first drug approved specifically for secondary progressive MS. Studies suggest that it may help reduce progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, so the drug is only used for a limited period. Mitoxantrone is also being studied in combination with glatiramer acetate. In one preliminary study, initial treatment with mitoxantrone, followed by maintenance treatment with glatirimer acetate, helped reduce relapses for up to 5 years.

Methotrexate. In some patients, low doses of the immunosuppressant methotrexate may slow the course of chronic-progressive MS, particularly in those with secondary progressive MS. A clear benefit has not yet been proven however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS, generally producing minimal side effects.

Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and suppresses the immune system. Some studies have reported benefits for patients with chronic-progressive MS who are rapidly getting worse. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities, and should be used for patients only in select situations.

Azathioprine. Azathioprine (Imuran) is designed to suppress the immune system and reduce the number of cells attacking the CNS myelin. It is used with or without steroids and is sometimes used as an alternative to patients with relapsing-remitting MS who do not respond to either interferon beta or glatiramer acetate. One study reported that 40% of patients had not experienced a relapse after taking the drug for 3 years, although others report only modest benefits. The drug has no effect on progression of disability. Because of the risk of cancer, cumulative doses of 600 g should not be exceeded.

Cladribine. Cladribine (Leustatin) may be effective in delaying progression in patients with chronic progressive MS. It has no significant effect on relapsing-remitting MS.

Experimental Drugs and Treatments

Treatments are under investigation that may prove to be helpful for multiple sclerosis. Below are only some of them.

Immune-Modulating Drugs. Most MS drugs are injected, but researchers are developing several new drugs that can be taken by mouth. Four of the most promising candidates are fingolimod (FTY720), teriflunomide, laquinimod, and a fumarate drug called BG00012. In late-stage clinical trials, these drugs have shown some positive results in the treatment of relapse-remitting MS.

Sex Hormones. Women with MS have a reduced risk of experiencing relapses during pregnancy, probably because of their high levels of the female sex hormones estrogen and progesterone. Because of this association, researchers have investigated whether oral estrogen therapy (estriol) can help prevent relapses. Some small studies have indicated that estriol treatment may help reduce lesions and disease activity, but the overall evidence is still inconclusive. The male sex hormone testosterone is also being studied as a treatment for men with relapse-remitting MS. Small studies have suggested that it may help improve cognitive function, slow brain degeneration, and increase muscle mass.

Cannabinoids. Cannabinoids are compounds in marijuana (cannabis), which may have properties that protect nerve cells. Cannabis has been found to improve pain, mobility, tremor, mood, appetite, fatigue, vision, sexual and urinary function, and memory. Not all patients respond. The drug may also worsen balance and posture in patients with spasticity. Synthetic versions are being investigated that allow rapid delivery without the unwanted side effects of natural cannabis.

Potassium Channel Blockers. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small preliminary trials, use of some of these drugs has been associated with mild-to-marked improvement in vision, strength, and coordination. Beneficial effects, however, lasted only a few hours. Further studies are necessary.

Statins. Statins are currently the most important drugs for lowering cholesterol. They are also showing additional possible benefits, including anti-inflammatory and nerve protecting properties, which may help patients with neurologic conditions, including multiple sclerosis. Small case reports have claimed benefit. Larger trials are needed.

Plasmapheresis. Plasmapheresis with plasma exchange is a procedure in which blood is removed from the body. Blood cells are separated from plasma (the liquid portion of blood) and mixed with replacement plasma, which is then returned to the body. The replacement plasma is thought to dilute antibodies and other immunologically active substances that may trigger MS. Small randomized controlled trials have shown no consistent benefit. Side effects include risk of infection and blood clotting problems.

Stem Cell Transplantation. Investigators are studying the benefits of stem cell transplantation procedures. Stem cells are produced in the bone marrow and are the early forms for all blood cells in the body (including red, white, and immune cells). Early studies indicate that stem cell transplantation may slow MS progression. Larger randomized controlled trials are currently under way.