William Stuart, MD; MS Center of Atlanta, GA
There are approximately 350,000 people in the United States and 2.5 million people worldwide living with multiple sclerosis (MS), a disease that can affect any area of the nervous system, and cause a wide variety of symptoms such as visual problems, weakness, or numbness, that may come and go over time.
Though there is no cure for MS, there are a number of effective treatments available that can slow the progression of the disease. Some of the medications most widely used to slow MS progression, such as Betaseron, Avonex, and Rebif, are called interferons. These drugs have proven to be some of the most effective medications for relapsing MS.
However, some people taking an interferon medication may produce antibodies against the drug itself, potentially derailing its effectiveness overtime. Antibodies are specific proteins that are normally produced by the body to fight foreign substances such as bacteria or viruses.
But, many drugs being used and developed today, such as interferons and monoclonal antibodies, are engineered proteins, and when these agents are introduced into the body they are perceived as foreign and the body mounts an immune attack. This can result in the production of "neutralizing antibodies" against the very drug that is intended to treat the disease. These neutralizing antibodies can develop in people with multiple sclerosis receiving interferon; and they have also been seen in people receiving interferon to treat hepatitis C virus, in people with hemophilia receiving factor VIII, in people receiving epoeitin, to treat anemia as well as in people receiving monoclonal antibody therapy for a variety of diseases. The growing debate in the medical community concerns the role, if any, these neutralizing antibodies may play in disease progression or relapse. And many physicians are monitoring the development of neutralizing antibodies in their patients receiving engineered proteins in an effort to keep patients on course with their treatment to control their disease.
The importance of neutralizing antibodies was underscored this year on November 12, when the Food and Drug Administration (FDA) approved new labeling for Avonex, one of the interferon preparations used to treat multiple sclerosis, to reflect a lower occurrence of neutralizing antibodies in people treated with the drug for at least a year.
Below, Dr. Bill Stuart, Medical Director of the MS Center in Atlanta, discusses the role of neutralizing antibodies in multiple sclerosis and how they may affect treatment decisions.
What are antibodies?
WILLIAM STUART, MD: Antibodies are protein substances that the body develops in response to some offending antigen (a different substance), whether it's outside the body or inside the body. The antigen provokes the body's response to develop an antibody, which then protects the body. What is the concern about the interferon medications creating antibodies? The concern is that these neutralizing antibodies will render the drugs ineffective in controlling the disease.
The medications we use to treat MS -- with the exception of Copaxone - are interferons, which produce antibodies. The body recognizes the drugs as foreign substances that it doesn't want there. And the drugs that we have available -- Betaseron, Avonex and Rebif, all of which are interferons - have varying degrees of antibody production. These range from about 40-45% in Betaseron to 25% in Rebif and 2-5% in Avonex.
How do these antibodies develop?
The injection of a substance, such as an interferon, into the body, can stimulate the body to produce antibodies by other cells in the body. It is like coming into contact with a virus, which stimulates the immune system to react and create antibodies. Once those antibodies are there, the capacity for them to be there -- even though they may change in levels from time-to-time -- is permanent.
How long does is take MS patients to have clinically significant levels of antibodies?
Between a year and two years is when you generally start to see some problem with antibody formation. We're seeing, though, in some of our long-term treatment patients, that the antibodies may develop seven or eight years into treatment. At least, that's when they are recognized. The patients begin to fail the benefits of treatment and you check the antibodies and they're positive.
Do we know for sure whether antibodies decrease the effectiveness of MS treatments?
Yes, I think it is known for sure that the presence of antibodies has an impact on the effectiveness of the drugs. It isn't known for sure what the extent of their effect is, but I think the data about antibodies that has come from the existing phase III trials is enough to raise concern.
How do antibodies affect your decisions about treating patients?
You want to pick a drug that you can use for an extended period of time. I look for the drug that is going to provoke the least amount of problems so that the patient's compliance in taking it long-term will be good. I think it is very important to consider the production of antibodies in determining which drug to use, particularly if there is any truth to the issue that the presence of the antibodies to one drug may counteract the effectiveness of another drug.
We talk to our patients about the potential development of antibodies, and we describe it as one of the issues involved in long-term treatment. It's important that they understand it, and it factors into their treatment decisions.
How does this information affect your patients?
MS is a very difficult disease to monitor. We expect progression, even under the best of circumstances. We know that none of the drugs are completely effective. If the patient is progressing, then it's hard to know whether it's driven by neutralization from the antibodies or if the drug that they're taking just isn't quite effective enough. So you have to send off a specimen for antibody testing to find out. This isn't always easy to get reimbursed for, and it's a fairly expensive test, so you can't do this every week or every month.
Do you think that all patients should be tested for the presence of
I'm increasingly coming to the conclusion that we should test it more frequently and if we could get coverage for the test, we probably would do it maybe twice a year as a routine on patients who are taking interferons, because the incidence is relatively high.
Do you recommend that your patients switch medications if they have high levels of neutralizing antibodies?
Yes, I do. My opinion is that there is high probability that neutralizing antibodies are rendering the drug, if not totally, at least partially ineffective. What I switch them to depends a lot on what they were on. There is some evidence that you can go from one of the interferons to another one -- particularly if the latter drug is less capable of producing antibodies. For example, in switching from Betaseron to Avonex, there is some indication that the antibody levels will fall and may fall to a range that is not meaningful. But to go from a less antigenic drug (producing less antibodies) to a more antigenic drug (producing more antibodies) is tough.
What's the bottom line for MS patients?
Patients need to know about neutralizing antibodies. It is an issue
under significant discussion and needs further investigation. And they
need to know that antibodies may be one of the reasons that their medication
isn't working effectively. It has to be factored into the long-term, 10-,
20-, 30-year decision-making regarding their treatment.
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