FREDERICK MUNSCHAUER, MD: Good evening, everyone. My name is Frederick Munschauer and I'll be your for this evening's MS Conversations, a conversation about secondarily progressive MS - what we know about it and what we can do about it, brought to you - hosted by healthology.

We're very fortunate tonight to have an expert in the field of MS and MS therapeutics, Dr. Michael Kaufman, from the Carolinas Medical Center. Dr. Kaufman has been integrally involved in therapeutics and multiple sclerosis and runs the largest MS center in the State of North Carolina. So Michael, we're glad to have you here to try to sort out this difficult diagnostic and therapeutic challenge. The portion of MS we refer to is secondarily progressive MS. Good evening, Michael.

MICHAEL KAUFMAN, MD: Good evening, Rick. It's nice to be here.

FREDERICK MUNSCHAUER, MD: Michael, what is secondarily progressive MS and how do we really classify patterns of MS.

MICHAEL KAUFMAN, MD: Well, I think that the classical patterning of multiple sclerosis is divided into four different types of multiple sclerosis. But the distinctions between those four types is less clear in day-to-day management of patients than it is in textbooks, I'm afraid. But about 85% of patients start with relapsing remitting multiple sclerosis, meaning that a patient may have sometimes dramatic, sometimes less than dramatic subacute onset of a new neurologic finding or recurrence of an old neurologic finding that lasts anywhere from more than 48 hours to sometimes a matter of months, but on an average, one to two to three weeks. And then in between these attacks, the patient is relatively stable. That's relapsing remitting disease.

Secondarily progressive disease is said to be that phase of disease that starts with relapsing remitting disease but then the patient has a slowly worsening course, often predominantly motor weakness in the legs, but it can be other findings as well. That in between any overt dramatic or somewhat dramatic event has a slow deterioration so that maybe over six months to a year that patient is not able to perform the kinds of things that he could functionally prior to that.

Now in - sometimes that point of transition between relapsing remitting multiple sclerosis and secondarily progressive multiple sclerosis is not clear, as you can imagine. And sometimes it's only realized in retrospect about when that occurred. This is further complicated by the fact that some patients with relapsing remitting disease have a slow rate of progressive between relapses that can't be detected in six months or a year but maybe can be detected over four or five years. And some patients with secondarily progressive disease, particularly in early secondarily progressive disease has relapses - somewhat of a tongue-in-cheek answer but in one of the trials that I was associated with, one of the investigators said that that distinction is often dependent upon whether he's admitting patients into secondarily progressive trials or relapsing remitting trials. So it can be quite indistinct.

Primary progressive disease is the third type that is generally separated and those patients have a slow progressive onset from the initial exacer - from the initial time that the disease is recognized. And again, that often will present with motor weakness in the legs or fatigability of leg strength.

Primary progressive patients often have a somewhat later onset than relapsing remitting patients and, in fact, one of the curiosities about that particular type of classification is that patients with primary progressive disease have their onset roughly the same time that patients with secondarily progressive disease have notable - have noticeable secondarily progressive disease.

FREDERICK MUNSCHAUER, MD: This raises a number of very interesting points. Do you think that relapsing remitting disease and secondarily progressive diseases, as you said the word "phase" - two phases of the same illness, sort of like - well, I can imagine going from adolescence into adulthood? Or do you feel that they represent two biologically different processes?

MICHAEL KAUFMAN, MD: Well, I think they are two phases of the same illness, but I'm not sure that that excludes the biologic change. There are some obvious differences in the immunology of patients with relapsing remitting disease. There are obvious differences in the response to treatment. So the pathophysiology of the disease may actually change somewhat with time.

I think that the - an interesting offshoot of that question and one that I think is even more controversial is whether primary progressive disease is a different disease or is it the same biology that where the patient is just sort of skipped the relapsing remitting phase. And I think that is more controversial because in addition to those things that I mentioned primary progressive disease generally has a different looking MRI scan, whereas the MRI scan from relapsing remitting flows into secondarily progressive obviously.

FREDERICK MUNSCHAUER, MD: Well, I will ask you some more questions about that in just a few minutes because as a clinician that's a very interesting fact. If I have a patient in front of me with relapsing multiple sclerosis early on in the course of the disease and that patient asks me, "Doctor, am I going to go on to secondarily progressive MS?" What would be your answer? Do all patients with relapsing disease evolve into secondarily progressive MS?

MICHAEL KAUFMAN, MD: Even without treatment the answer is no. And it depends on whose figures you use, but somewhere between 5 and 15% of patients with relapsing remitting disease never progress to secondarily progressive disease. That group sometimes is referred to as benign multiple sclerosis. But they stay relapsing remitting disease for the entire duration of their illness, have minimal difficulties and minimal disability.

With treatment, I guess we are all - all of us who are very invested in multiple sclerosis are very eager to find out whether treating patients early in the course of the disease may increase that number above the 5-15%. Some of us with long history of treating patients, at least intuitively feel that that's going to be the case. But we cannot - we can't definitely say that we can do better than that at this time.

FREDERICK MUNSCHAUER, MD: What kind of questions should a physician ask a patient or a patient ask the physician to determine whether or not they had made the transition from relapsing disease to secondarily progressive disease? What do you ask your patients to help you reach that understanding?

MICHAEL KAUFMAN, MD: Well, I think the obvious one is to tell me about your most recent relapses and how long it's been since a relapse. As you make a transition from relapsing remitting disease to secondarily progressive disease, the relapses change character a little bit. They don't start as suddenly. They tend to continue longer and their resolution seems to be less satisfactory. There is not such a good response to - well, we conventionally use high-dose methylprednisolone.

The second area that I ask about is in the patient's walking and ambulation. I think that when patients make that transition from an EDSS of 4 where they can walk 500 meters or more without stopping to the higher EDSS scores up to 6.5 when they're walking less than 500 meters without stopping or where they require a cane or a walker. As they make that transition where they can no longer walk 500 meters, then it - it often becomes a little more apparent between visits that they're not doing as well as they were let's say six months or a year ago.

FREDERICK MUNSCHAUER, MD: In a slow fashion.

MICHAEL KAUFMAN, MD: In a slow fashion.

FREDERICK MUNSCHAUER, MD: I'd like to take this opportunity to ask our listeners to e-mail or telephone in any questions they have for Dr. Kaufman as we proceed. We'd like to get to your questions to address those areas, the management of secondarily progressive MS that you might find important.

Mike, moving on a bit. Do you think that when we see a patient and who is in a wheelchair or needing a walker that we might automatically assume they were in secondarily progressive form of disease and do you think that's a problem with how we diagnose it?

MICHAEL KAUFMAN, MD: I think there is some biases in that direction. Certainly, I think it's very safe to say that the majority of patients that require walkers and wheelchairs are in secondarily progressive disease. It's not always the case and I have a few patients who have had - I'm thinking of a young woman who had a severe brain stem attack of multiple sclerosis so was - is currently dependent on a cane. You might think that she because of that has secondarily progressive disease. But yet she's relatively early in the course of the disease and is still have exacerbations of the disease. And I wouldn't classify her solely on the use of an appliance or solely on being in a wheelchair, although the majority of the patients will have secondarily progressive disease in that status.

FREDERICK MUNSCHAUER, MD: You had mentioned before that you thought that although secondarily progressive disease may represent a continuum from relapsing disease, but there might be some differences in the underlying biology of the disease. Could you expand on that a little bit? What do we know about the differences between relapsing forms of MS and the more progressive form?

MICHAEL KAUFMAN, MD: I know the clinical biology better than the immunology, although the group at Brigham - Brigham and Women's have found differences in the way T cells respond to signals. They often turn them off so that what are called cytotoxic lymphocytes are less responsive to the types of signals that will often reduce their activity in secondarily progressive disease. There are also differences in the cytokine production of cells with patients with secondarily progressive disease. So they tend to be more activated, more independent of external controls, if you will.

FREDERICK MUNSCHAUER, MD: And do you see that on imaging?

MICHAEL KAUFMAN, MD: Now on imaging I was going to say that the clinical aspects such as imaging are also different and the number of new T2 lesions or gadolinium-enhancing lesions goes down with secondarily progressive disease. Sometimes the lesion burden actually goes down with secondarily progressive disease. As the ventricles expand and atrophy becomes more apparent, sometimes the amount of white matter, bright signal on the T2 lesion will actually decrease in secondarily progressive disease. So you see fewer new lesions. Retraction or scarring down of some of the old lesions and to fill the void you see more brain atrophy in secondarily progressive disease.

FREDERICK MUNSCHAUER, MD: So in secondarily progressive disease, fewer gadolinium-enhancing, fewer new T2 lesions and maybe more rapidly progressive atrophy as witnessed by expanding of the lateral ventricles.

MICHAEL KAUFMAN, MD: I think the latter point, now that I've said that is less apparent. I know that Rick Rudick's study on using brain parenchymal fractions suggests that the atrophy maybe just as dramatic early in the course of the disease. But it certainly is more obvious that patients have when you just look at the scans without a computerized program, it becomes much more obvious that there is atrophy in secondarily progressive disease. But if you actually measure it, I'm not sure that that's substantiated.

FREDERICK MUNSCHAUER, MD: Well, let's turn the focus of our conversation now to treatment. And once again, I'd ask the listeners if they had any questions to e-mail them or phone them in. We'd be glad to get them.

From my understanding of it, Mike, the treatment of secondarily progressive MS is a thorny issue. Do you want to comment a little bit about what we know about treating that form of the disease?

MICHAEL KAUFMAN, MD: Well, I can tell you that there have been four studies with interferons that are large studies getting - they're well validated, well run studies. Three of them did not show - did not meet their primary endpoint. The very first one did.

The first study was a European study using interferon beta 1b or Betaseron and that study showed about a 22% reduction and confirmed change in the EDSS which in that case was one point worsening in the EDSS. Unfortunately, that experience was not -- with an EDSS change - was not shared by the other three studies.

One was the North American trial using Betaseron. One was a European trial using Rebif and one was a European-U.S. trial using Avonex. The Avonex trial was interesting in that it used a more sensitive, perhaps, outcome measure called the "Multiple Sclerosis Functional Composite" that was developed by Gary Cutter (?) and a board of neurologists at the recommendation of the National Multiple Sclerosis Society and that is a composite that measures ambulatory function, coordination of the arms and cognitive function. And the IMPACT study using Avonex did show a significant - about 40% reduction of the worsening on the Multiple Sclerosis Functional Composite with the majority of the change being seen in the test of arm coordination which is the 9-hole pegboard test.

The next strong trend was seen in the cognitive function or the PASAT, Pace, Auditory, Serial Addition Test and no real difference seen in the test of leg function which is the 25-foot or the timed 25-foot walk. The interesting coordination with that is that the EDSS, of course, measures leg function and how far you could walk. What our treatments may do is they - our optimistic view of the treatments anyway would be that they may not effect the long motor fibers going down to the legs, or down to the spinal cord segments that innervate the legs, but that we may be able with our treatments to do some sparing of cognitive function and some sparing of upper arm function in patients, at least with early MS - early secondarily progressive MS.

In fact, when the cohorts were analyzed in the European study, it appeared that those patients were more like late relapsing remitting patients - or more early in their secondarily progressive disease than the other cohorts.

FREDERICK MUNSCHAUER, MD: If I understand you then, the failure of the North American Betaseron study in secondarily progressive MS and the Rebif European study called SPECTRUMS is really driven by the fact that the EDSS itself may be so dependent - primary outcome measure for those two studies was this EDSS scale, which I - which is so dependent on your ability to ambulate. And is it safe to say that the Avonex trial showed efficacy when it began to measure more carefully upper extremity function and cognitive function.

MICHAEL KAUFMAN, MD: That's exactly what I think it says. Of course, it's the only trial that's - now that in secondarily progressive disease that's utilized the MS Functional Composite so it's just one trial. But the other studies didn't and one could at least tentatively make that assumption.

FREDERICK MUNSCHAUER, MD: What about the MR data in all of the secondarily progressive trials? Was there a trend towards either slowing down the progression of MR measured burden of disease?

MICHAEL KAUFMAN, MD: Actually, of great interest was that it was more than a trend, there was a statistically significant difference and I believe that it was - [STUTTERS] statistically significant for all of the trials and that the number of new MRI lesions was less in the treated group and the number of relapses in fact, remember that some patient with secondarily progressive disease still have relapses were also in the same range that one saw for relapsing remitting disease. So there was about a 30% or so reduction in relapses in all of these trials, too.

Very consistent effect on MRI and relapses suggests that there may be a so-called degenerative aspect to secondarily progressive disease that is not inflammatory and doesn't respond as well to some of our inflammatory treatments.

FREDERICK MUNSCHAUER, MD: Would you say in interpreting the data as a whole from all of these studies that the beneficial affect you just mentioned on MRI is at least suggestive evidence that there is a role for interferons in the treatment of secondarily progressive MS?

MICHAEL KAUFMAN, MD: I think so. And again, particularly in early secondarily progressive disease I think that I personally even though this is off-label for early secondarily progressive disease, I will treat patients. It gets hard when somebody has late disease. I'm not sure how much we can help people with late disease. But I think we still need to at least investigate that and see if over a longer period of time whether we preserve cognitive function or some other functions in that group as well.

FREDERICK MUNSCHAUER, MD: And if you're looking at the slowing of upper extremity function and cognitive function in the Avonex IMPACT trial, is that a clinically meaningful therapeutic effect in your opinion? When you read that study do you think you've made a difference in those patients quality of life?

MICHAEL KAUFMAN, MD: Well, I think I'd be reaching further then I'm really qualified to say, but my opinions - I can give you my opinion as opposed to any real hard recommendation. And my opinion is that cognitive function is very important. If you look at it, it's often the reason why patients are disabled. And I think if you can - that you improve social interaction, you improve quality of life greatly if you can preserve cognitive function. So even though the FDA has not given their blessing on this, I feel justified in treating patients again with good cognitive function, relatively early secondarily progressive disease with interferons provided we can get it covered by their providers.

FREDERICK MUNSCHAUER, MD: We've mentioned the interferons. Is there any information about Copaxone in secondarily progressive MS?

MICHAEL KAUFMAN, MD: Copaxone doesn't - there's no formal study in secondarily progressive multiple sclerosis. There is a study in primary progressive multiple sclerosis and unfortunately that data isn't available. But we know that it too failed its primary outcome measure which was a change in the EDSS. And we do have information on that study about the Multiple Sclerosis Functional Composite. That information was gathered, but I don't know what it shows. And none of the investigators of that trial, to my knowledge, knows what it shows at this time.

FREDERICK MUNSCHAUER, MD: Then turning back to the interferons. Is there any wisdom you can give us in choosing between the interferons in secondarily progressive MS? If it's your impression that we should treat, particularly people early on in this secondarily progressive phase of the disease, what would be your suggestions?

MICHAEL KAUFMAN, MD: Well, I think that we don't have any head-to-head trials in secondarily progressive disease and we don't have any long-term trials in relapsing remitting disease. So a lot of my recommendations are going to be based on beliefs in that data and I think you have to look back at the data in relapsing remitting disease and you have to look back at the original trials and you have to make a choice based on that.

None of these treatments I think is as effective as we would like them to be. I think we clearly need to have some - we have to find out more about this degenerative problem that seems to be part of the secondarily progressive disease pathophysiology - whether it has to do with some kind of growth factors supplied by oligodendroglial cells or some other function is open to question. But I think that I would present the data the same way that I present to patients with relapsing remitting disease. I talk about neutralizing antibodies. I talk about brain parenchymal fraction data. I talk about head-to-head studies. I talk about convenience. I talk about side effects and then we make a choice based on that. I have used all of these drugs in relapsing remitting disease. I tend often to prescribe Avonex. I often tend in patients, however, who don't like intermuscular injections and they're more convinced by some - let's say the European trial because it's the only one that showed efficacy of Betaseron, so I don't have a firm recommendation.

FREDERICK MUNSCHAUER, MD: I think probably getting people on interferon therapy is the overriding concern at least in early secondarily progressive and hopefully, starting interferons early in relapsing forms of the disease will make this less of a problem.

In our last two minutes, I'm going to ask you to just really sort of look into the future, if you could, and look into the agents that you know of in phase III clinical trials and those that may be considered for phase II or phase III clinical trials. Where do you think the future of MS therapeutics and secondarily progressive MS is going to be two years from now and ten years from now?

MICHAEL KAUFMAN, MD: Well, in two years from now, we've got a number of exciting treatments for relapsing remitting disease. They're probably going to be tried in secondarily progressive disease and my guess is that they're going to have even more of an effect on relapses and MRI changes and possibly be more protective for cognitive function and may be combining them with the current treatments. I know you're well aware that Antegren and alpha IV beta-1 monoclonal antibody has made a lot of press lately because it was reported in The New England Journal of Medicine. I think we'll probably down the road see a secondarily progressive trial with that medicine.

I think, however, ten years down the road, we're going to have to understand oligodendroglial cell biology and how it supports axons and what the interaction is between oligodendroglial cells and axons. We already know that there are receptors for neurotransmitters and oligodendroglial cells that may direct them and make them grow. We may be treating secondarily progressive disease with a combination of neurotransmitters and growth factor, maybe ten, maybe fifteen years from now. So I think there is a lot of work that needs to be done. It's exciting, but I think it's going to be slow going.

FREDERICK MUNSCHAUER, MD: Oh, it is indeed. But there is a lot of hope for the future in trying to deal with secondarily progressive MS.

And I think with that I will close. I want to thank Dr. Kaufman for a very erudite discussion of this challenging form of multiple sclerosis, the secondarily progressive patient. And as all of us take care of patients with MS, this is a form of the disease that we deal with on a daily basis. Your insights, Mike, and your evaluation of therapeutic options was greatly appreciated.

With that I'd like to thank the listeners for this version of MS Conversations, a look at secondarily progressive disease, hosted by healthology. Good night and we hope to see you at a future MS Conversations meeting. Thank you, Mike.

MICHAEL KAUFMAN, MD: Thank you, Rick.