DAVID MARKS, MD: Hi and welcome to our webcast. I'm Dr. David Marks. Today we're talking about multiple sclerosis. One of the hallmarks of the disease, unfortunately, is often progression or relapse. We're going to talk to an expert today on how to deal with that.

With me is Dr. James Miller. He is the Director of the MS Center at Columbia Presbyterian Medical Center here in New York City. Thank you for being here.

JAMES MILLER, MD: Thank you for having me.

DAVID MARKS, MD: Now one of the best ways to talk about this is going through a case. So I want to give you a case and you can tell me how you deal with it.

JAMES MILLER, MD: All right.

DAVID MARKS, MD: Let's say you were dealing with a 35-year-old man who was diagnosed about five years ago. He had an EDSS of 3, began interferon treatment at the time of diagnosis, and was doing well on interferon, but developed neutralizing antibodies about three years after treatment. His titer was low, about 1-10.

He has had some periodic relapses, about one a year, but the disease hasn't really progressed until now. What do you do now?

JAMES MILLER, MD: This is an interesting problem. The problem, first off, is when you test people for antibodies to the interferons and find a low level, what's considered a low level commonly now, is how do you handle this? One of the problems, and the reason this is an issue, is that nobody knows how much biological activity you're taking away by a low level of antibody.

But be that as it may, with a patient like that, I think most people would generally keep them on the drug, because in fact, these are usually reported as negative in the common reporting system.

But we've gotten to the point where the treatment is no longer holding in the sense of the patient progressing. We know this is going to be an issue for a fair number of people on interferons. We know that interferons are really only partially effective in the treatment of multiple sclerosis. They are, unfortunately, not a cure for the disease. They don't stop it dead in its tracks, because we know from all the studies that have been done with interferons, inflammation continues, although much abated.

But when you get to the point of progressive changes in the neurologic examination, as opposed to accrual of deficits from attacks, you're getting to an issue that's now being thought about very carefully. What does progression mean?

There is some information that suggests that progression may not be the effects of acute attacks going on at the time that someone becomes progressive, but actually the end result in terms of axon or neuron loss during the times of previous acute episodes.

We know from studies of the interferons that they will continue to damp down active inflammation in the progressive phase, but they seem to have less effect on progression of the disease in terms of general neurologic worsening at this time.

This may be partly the fact that the studies haven't shown much benefit when you do study people with progressive disease. We're just not studying them for long enough to see the effect of what damping down the current inflammation will have on progression later on.

That having been said, you have to figure out what to do to help this person.

DAVID MARKS, MD: Right. And what are your first steps?

JAMES MILLER, MD: Well, my steps would certainly be to repeat the neutralization titer if the patient was still taking the interferon, as he seems to be, and see if that becomes an issue. If not, then depending on how much change has occurred over the MRI scan and what the patient's perceptions are, I probably would offer either additional treatment to the interferon or a change in treatment to some more potent immunosuppressive treatment.

DAVID MARKS, MD: But you're saying you would follow up with an MRI scan?

JAMES MILLER, MD: I would follow up both with an MRI scan and the neutralizing antibody studies.

DAVID MARKS, MD: Okay. Let's say you get the MRI results, and it shows that the person has a large lesion burden. There are a lot of active lesions present.

JAMES MILLER, MD: Well then, I would probably opt for a switch in medications to a more potent immunosuppression treatment. Right now, the one I usually use is mitoxantrone, which seems to be very effective in shutting down active lesions.

DAVID MARKS, MD: Is this a typical course?

JAMES MILLER, MD: It's not typical because it seems to be a little bit more aggressive than most people's courses. But in fact, over time, many people who have relapsing-remitting disease do start to get progressive elements in their examination and qualify for having secondary progressive multiple sclerosis.

DAVID MARKS, MD: How do you know if someone is failing treatment? What kind of test results are you looking at? What kind of physical signs are you looking for?

JAMES MILLER, MD: The definition of failing treatment is a very difficult one in MS, mainly because we know the medicines are only partially effective. My definition of failing treatment is when the patient and/or I feel that the treatment isn't doing what they wanted it to do and we look for reasons why that might be. Of course, the question of the development of neutralizing antibodies comes to mind as the most important issue. If those antibodies haven't become elevated, then it probably is a matter of the patient's disease just becoming more active and the effects of the interferons can no longer contain it.

DAVID MARKS, MD: So then what do you do?

JAMES MILLER, MD: Well, as I said, what I usually do is either opt -- if it's a modest worsening, I opt for an add-on treatment. Often methotrexate is tried, although we don't have good evidence on yet how effective it is. We do have some fairly good evidence that at least it's reasonably safe to use. It's becoming common.

It's becoming very common in MS now to think about combination treatments, along with the interferons, as a way of handling this kind of problem. And perhaps even starting sooner, as we get more confident that these things might be helpful.

But if it's really, as I say, a more rapidly progressive course or sudden C-change, then I would opt for something like mitoxantrone. Some people use cyclophosphamide or Cytoxan instead of mitoxantrone, but either one would be acceptable, I think.

DAVID MARKS, MD: You mentioned combination treatments. What medicines are you combining to use for the best efficacy that you can actually obtain?

JAMES MILLER, MD: Well we don't know, as I say, much about efficacy because most of the studies are too preliminary. One of the problems with the medicines that we're choosing as add-on medicines is that they are generic medicines. So companies are not jumping in to support large-scale studies that will show efficacy because the power of these studies would probably require very large numbers of patients to really prove something.

There are some exceptions, and some studies are getting started. But methotrexate comes to mind as a medicine. There are studies that we're trying to start with Copaxone and interferon as a combination therapy. Again, there is good information that safety is okay using these together, although initially there was some question about that. But there is still no definite evidence of efficacy.

In Europe, things like azathioprine have been used in combination.

DAVID MARKS, MD: What's the long-term prognosis for a patient like this one?

JAMES MILLER, MD: Well, in the fact that he's tilted over fairly soon, it worries me that he's going to have a fair amount of difficulty. But I have seen patients, on the other hand, who have a brief period of very active disease who then level off. I'm particularly hopeful that using things like mitoxantrone may get people through a particularly active phase without too much trouble, and then maybe return to the interferons for treatment again.

DAVID MARKS, MD: But there is no way to predict?

JAMES MILLER, MD: There is no way really to predict for an individual patient what's going to happen. That has obviously its good points and its bad points.

DAVID MARKS, MD: Well if you can't predict, then I'm sure that none of us can either.

Thank you for joining us. I appreciate it.

JAMES MILLER, MD: Pleasure.

DAVID MARKS, MD: And thank you for joining our webcast. I'm Dr. David Marks. Goodbye.