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Multiple sclerosis

Description

An in-depth report on the causes, diagnosis, and treatment of MS.


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, however, is reporting benefits from 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. Some research suggests that this approach might reduce destruction in central nervous system, although more evidence is needed before it can be recommended. They 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 they 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 reducing 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 is 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:

Neutralizing Antibodies That Reduce Effectiveness . Over time, people taking the 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 experience this, however, often can be effectively treated with an alternative interferon or with glatiramer, which has an extremely low risk, for NAbs. In many cases, after switching drugs, NAb levels decline and the patient may be able to return to the original interferon.

Glatiramer Acetate

Glatiramer acetate (Copaxone) formerly called Cop-1 or copolymer-1, is a synthetic molecule created to resemble a basic protein found in myelin. It is being used as a decoy to trick white blood cells into attacking it instead of myelin. Studies indicate that this drug may be superior to others in reducing relapse rates, with a 2003 comparison study reporting relapse free rates of 83% during a 16-month period. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement. Benefits have persisted for years.

Side Effects. Side effects occur in about 15% of patients, 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 be evaluated regularly during drug treatment to make sure they are not at risk of developing PML.

Clinical trials indicate that natalizumab’s benefits may outweigh its risks. Several studies published in 2006 in the New England Journal of Medicine showed that natalizumab, alone or in combination with IFN1a (Avonex) can help prevent disability in patients with multiple sclerosis. Another study suggested that the risk of PML is very low if patients use natalizumab for less than 18 months.

Other MAbs under investigation for MS include daclizumab and alemtuzumab. Results from a 2005 phase II trial for alemtuzumab (Campath) indicated that the drug helped prevent relapse but also caused serious side effects. Patients who took the drug had a high risk for developing a serious bleeding disorder caused by a low blood platelet count.

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 does not appear to have any benefits for patients with 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 produce serious side effects, including susceptibility to infection. Evidence on benefits is uncertain, mainly because of high toxicity or study limitations. Still, some may help some 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. Two studies suggested that it may be of some help in reducing progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, so the drug is only used for a limited period.

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. To date, studies have found beneficial effects only on the upper body, however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS and so side effects are generally minimal.

Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and also suppresses the immune system. Some studies, but not all, have reported benefits for patients with chronic progressive MS. Small studies suggest that monthly intravenous administration or a combination with interferon-beta may help some patients with rapidly deteriorating MS. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities, and should be used for patients who do not respond to methotrexate.

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.

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

A number of treatments are under investigation that may prove to be helpful for multiple sclerosis. Those discussed below are only some of them.

Aminopyridines. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small, preliminary trials, 4–aminopyridine, or AP, has been associated with mild to marked improvement in vision, strength, and coordination and was well tolerated. Beneficial effects, however, lasted only a few hours. A related compound, 3,4–diaminopyridine, or DAP, has also produced temporary improvements in nerve conduction without harmful side effects, even when taken for several weeks. One study comparing the two drugs, however, found that AP was superior in improving walking, fatigue, and overall function. Side effects of AP are more apt to include dizziness and confusion. DAP may cause abdominal pain, numbness, or tingling. Overdose can occur at relatively low doses in both drugs and may cause epileptic seizures.

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. In a 2003 study, patients reported less pain and improved mobility (although spasticity itself did not improve). 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.

Estrogen. Although estrogen is commonly associated with heightened immune factors, some autoimmune diseases, including multiple sclerosis, improve during pregnancy when levels of estriol, a form of estrogen, are high. (Estriol levels are low at other times.) In one small study, estriol treatment was associated with significantly fewer lesions and less disease activity in patients with relapsing-remitting MS. Long-term use may have adverse effects, however, and further research is needed.

T-Cell Modulators . Teriflunomide is being investigated for treating multiple sclerosis with relapse. Although many multiple sclerosis drugs are injected, teriflunomide is taken by mouth. In 2006, a phase II trial of teriflunomide showed promising results in preventing relapses and reducing the number of brain lesions (damaged tissue). Teriflunomide appears to affect the response of the immune system’s T cells.

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 investigative studies suggest this procedure may have significant benefits for some patients with severe MS, particularly if they are younger and have an early response to this treatment. Side effects include risk of infection and blood clotting problems.

Oligodendrocyte Implants. A newly developed, minimally invasive method to transplant modified oligodendrocyte cells directly into the brain is under investigation. Such cells stimulate nerve and axon growth. If feasible, this approach might be helpful in patients whose MS is not caused by an autoimmune response (where the new cells would be attacked, just as the patient's own cells were).

Stem Cell Transplantation. Some 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 it may slow progression, although at this point it is not a cure.

Statins. Statins (medically referred to as HMG-CoA reductase inhibitors) are currently the most important drugs for lowering cholesterol. They are also showing possible benefits, including anti-inflammatory and nerve protecting properties, which may help patients with neurologic conditions, including multiple sclerosis. In one 2002 study, the statin atorvastatin (Lipitor) improved MS symptoms in mice. Other statins include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), and fluvastatin (Lescol).


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