Use of Surrogate Markers in Monitoring Disease Modifying Therapy In Multiple Sclerosis

J. THEODORE PHILLIPS, MD, PhD: Hello. I'm your host, Dr. Ted Phillips, from the Multiple Sclerosis Center at Texas Neurology in Dallas. Today, we're going to discuss the use of surrogate markers in monitoring disease-modifying therapy in multiple sclerosis.

I'm pleased today to be joined by Dr. Mariko Kita, director of the Virginia Mason Multiple Sclerosis Center in Seattle, and Dr. Norm Kachuck, associate professor of clinical neurology from the Keck School of Medicine at the University of Southern California.

Because of the protracted and unpredictable clinical course of MS, biological surrogate markers are much-needed to make the assessment of disease-modifying treatments more efficient. MRI outcome measures such as gadolinium-enhancement, T1 and T2 abnormalities and axonal loss are now widely used to monitor treatment outcome in MS and may be considered as surrogate markers for disease activity. Today, we'll provide an opportunity for neurologists to understand the use of these surrogate markers in the monitoring of disease-modifying therapy.

Mariko, I'd like to get started with you. MRI, obviously, we use to diagnose MS on a regular basis and at least there is some discussion, some people feel that MRI has a use, not universally agreed-upon certainly, but a use in monitoring people after the diagnosis has been made, whether they are on therapy or still off therapy. Where do you see MRI being used, if at all, after diagnosis?

MARIKO KITA, MD: Well, I'm a huge believer that the MRI scan is one of the best surrogate markers of this disease. I mean, I think it is the disease. It tells us what the disease is doing. So I think there's a big role for its use during the monitoring. If a person is not on treatment, that might be an individual who would, in my practice, require more frequent monitoring by MRI scan.

J. THEODORE PHILLIPS, MD, PhD: Well, when you say "more frequent," what do you mean "more frequent"? How frequent?

MARIKO KITA, MD: So, right after diagnosis, I would say every three to six months or at least the first three- to six-month interval.

J. THEODORE PHILLIPS, MD, PhD: Okay.

MARIKO KITA, MD: And then the behavior of the disease in that period of time might dictate the future interval. And when a person's first started on treatment, I tend to like to get an MRI scan at one year to see what's happened in that year. The earlier they are in their disease, the less we know about how their disease is going to behave. So once we get a sense of how their disease is going to behave, then I might pull off in terms of the frequency, so maybe two years, etc.

J. THEODORE PHILLIPS, MD, PhD: Okay. Norm, how do you use MRI or do you use MRI in the context of following patients after diagnosis?

NORM KACHUCK, MD: I do use it, but it's in the context of a couple of important realizations that happen when a patient comes in. We're diagnosing them with a chronic disease and we're going to decide how this alliance between them and me is going to work. They're going to be reporting certain things to me and I'm going to be assessing certain things in them and, somewhere, we meet together.

I mean, certainly, everybody that treats MS realizes that these folks have good days and bad days, good weeks and bad weeks. There are going to be times when our exam shows nothing and they changed and they're going to say, "You know doc? No matter what your exam looks like, I feel worse." Or you examine them and you feel like, you know, they're a little weaker and they're saying, "You know, I'm exercising and it hurts a little more now but the therapist is helping me move around and so, you know, I'm a little worn-out, but I really feel better." And you have to take the preponderance of the evidence.

MRI, in its place, is going to help them and I discuss and establish what our benchmarks are for the progress of their disease. Unfortunately, even though MRI is good, as Mariko has opined I can't say that I think MRI is showing me the disease. It's showing me some hallmarks of a disease process, mostly when we use conventional MR metrics inflammation and the consequences of inflammation.

To the extent that we may have new software technology in the not-too-distant future that will help us establish better metrics of volume and tissue loss, the actual changes that are in a lesion that we now describe as a hyperintensity lesion on T2, what is in a hypointensity T1 hole lesion, what constitutes a neuronal network deficiency or a defect in that, the loss of some of the markers of integrity of the axon. All of those will make an enormous difference in my ability to use MR as a direct measure of what MS is doing to them.

In the meantime, I can't say that I disagree with Mariko's idea that we need to use at least MRI in the first couple years to help us define how the person's going to do. We have pretty good criteria in terms of a bad-acting disease, based on the first year. If they have a lot of relapses, if there are a lot of MRI lesions, if they've got a lot of disability that accrues on exam in that first little bit, that's going to tell us a lot about the bad-acting disease. It may not tell us, though, if, in the absence of those, that it's going to be a bad disease. So you kind of mix and match what you've got.

J. THEODORE PHILLIPS, MD, PhD: You know, in general practice, the MRI report comes back with -- well, honestly, probably not all of the information that, as people interested in MS, that we would optimally hope for. But, pretty reliably, it's going to come back with at least some semi-quantitative comment on T2 abnormalities, gadolinium-enhancement or not and maybe, if there is an old film to compare to, any changes that have occurred in the interim.

Of those most commonly reported MR abnormalities (that is, gadolinium and T2), in what context do you use those abnormalities not only to monitor patients but maybe to alter your therapeutic plans for the patient? Well, Mariko, for instance, if there's no new gadolinium activity at that snapshot time that the MRI is obtained, but there are new T2 foci, does that mean to you that their current therapy is a failure?

MARIKO KITA, MD: Right. Well, that's not an uncommon situation.

J. THEODORE PHILLIPS, MD, PhD: Yes.

MARIKO KITA, MD: And I think what we find that the MRI scan, as you were alluding to, was just one piece of what we need to assess. So whatever objective measures you can use, that certainly would be one of them, but another would be "How is their clinical behavior? Is their exam changing? Is their relapse rate any different?" And then I think a really important component, too, is what does the patient think and how do they feel? And so it's in that context that we do evaluate that.

So all things equal or let's say all things positive, so people feel well and their exam hasn't changed and they have two new relatively small lesions, I'm not sure that would be enough, but it does tell us that they do have persistent, active disease despite treatment. I don't know if that's the make-or-break or if a certain number would be a make-or-break, but I think it's the whole picture together.

J. THEODORE PHILLIPS, MD, PhD: And so what I think I'm hearing you say is that you refuse to have a standard algorithm that is equally applied to each and every patient that you see.

MARIKO KITA, MD: Right, I can't do that.

J. THEODORE PHILLIPS, MD, PhD: It's a very individual thing. Would you agree or disagree with that, Norm?

NORM KACHUCK, MD: I think because of the inadequacy in the standardization of our use of MRI, we have to be in place. And I think, if I could digress, a couple points should be made about the use of MRI. You noted that we may see a couple of new spots. Well, that predicates that we have a previous scan to examine, that the scans were done in generally the same way. That the technique used to acquire that MRI didn't differ substantially from one time to another. That the slices are contiguous, that they are of a reasonable thinness so that we don't lose too much, so 3 mm to 5 mm. That the head position was generally the same, so that when we look at a particular axial, sagittal or coronal cut and we see something, that we can be assured, when we look back on the previous scan, that we're looking in the same volume of tissue.

And, with all that said, who is reading the scan will make a difference, especially if you have a radiologist who's skilled in doing what we think we need in MS, which is counting the lesions, looking carefully at their size, telling us whether there is a rim of enhancement or a T2 hyperintensity or a T1 hypointensity and noting those as separate criteria, that makes a big difference compared to if you don't have that help. Or if you feel confident as a neurologist that you can read it as well or better than your local radiologist and you're looking for that, then make sure that you've documented those things.

We certainly know from literature that the person with a certain number of lesions is much more likely to have MS, the nine lesions that Fred Barkhof and his group have established as at high risk. But, after that, we don't know anything more about the quantitation of severity, the quantitation of volume lost that's going to be associated specifically with a clinical state. So the neurologists have to be reading into it for clinical relevance anyway.

J. THEODORE PHILLIPS, MD, PhD: Well, your discussion brings up an interesting point. You know, in busy medical practices you order an MRI, you get back a report. In MS in particular, do you feel that it is important to go beyond merely the report, no matter who it's coming from? Do you feel the need to look at those films yourself?

MARIKO KITA, MD: You've got to look at the scans, I think. And in cases where I don't look at the scan, that's when I dictate that. I say, "I was unable to view the films," because, more often than not, unfortunately, we have a different opinion.

At least at my institution now, it becomes very easy for me to pick up the phone and say, "Listen, can we look at this film together?" And we'll say, "Sequence 5, image 3, did you see that? Did that look the same to you as what was on the former image?" etc. And I think it's really important for us to feel confident in looking at the films.

NORM KACHUCK, MD: Especially if you're going to have to show it to the patient. Some people like to look at it and some people don't.

J. THEODORE PHILLIPS, MD, PhD: Yes.

NORM KACHUCK, MD: And purely on a venal level, my high level of complexity, neurologic exam charges are based on what I actually do. And if I look at the MRI and I document that I've looked at it, that goes into the level of complexity that I can bill for.

J. THEODORE PHILLIPS, MD, PhD: Yes. Well, to switch gears a little bit, and I admit this is a rapidly-evolving area. What are we looking at on MRI? I mean, we've talked about gadolinium, we've talked about gadolinium-enhancing foci, we've talked about T2 hyperintense foci, we've talked about T1, "black holes." What is the current thinking on what each of those three abnormal findings actually represents and the relevance to the evolution of the disease as itself? Norm?

NORM KACHUCK, MD: I think it's fairly established that there is a now sequence of events that can occur, documented radiologically by MR, that starts you at the point where inflammation seems to be beginning. Let's say magnetization transfer may be the earliest way that semi-conventional MR may pick up a lesion occurring and that, after that abnormality, you may see changes in the T2 hyperintensity side with gadolinium happening somewhere in between the magnetization transfer and the T2. The gadolinium should last no more than some weeks, though there are people who will have persisting gadolinium-positive lesions on a T1 accession.

J. THEODORE PHILLIPS, MD, PhD: And gadolinium positivity represents?

NORM KACHUCK, MD: The passage of the molecule of the gadolinium is a size that we have established. If it crosses the blood-brain barrier, it's associated with a permeability change and inflammation which is associated with it, with the diapedesis of cells and materials from the blood into the parenchyma.

So with gadolinium positive into the T2 hyperintensity, you've now evolved a lesion and that lesion can either resolve and disappear which, rarely, I imagine can happen. Or it can become a persistent T2 hyperintensity and it may change in size over time and it can get smaller and it can get larger. Or it may become and evolve into a T1 hypointensity, which would be a persistent hole where the clearing, the astrocytosis, the various inflammatory activities have come to a point where there is no more -- or there's a paucity -- of tissue left, very little there left. And you will see something that is either at least less bright than conventional tissue would be. It may not be dark or black. It may not be CSF, it may be some intermediate, but it's going to be less.

Now, we know what that is. That's a loss of tissue. We know that gadolinium is inflammation, but the T2 lesion is nonspecific. It doesn't tell you whether there's ongoing inflammatory change, cellular activity from the immune standpoint, macrophage, microglial activity, even a set of immune cells that may be migrating in and out of the lesion and the lesion may be evolving, though we may not know that because the T2 lesion does not change with many of those activities.

So, to the extent that it may demonstrate, when you do functional imaging, actually a normal-looking axonal transmission through that area and actually that can be documented ex vivo in the models of inflammation, that you can have a normal axon in the midst of a big T2 lesion that can function normally. That may be happening and you can go all the way to a point where there is very little except gliosis, astrocytosis, the sort of thing one expects from a lesion with very little function likely to be left.

J. THEODORE PHILLIPS, MD, PhD: So it's fair to say that it -- a T2 hyperintense area in MS is -- is a heterogenous mix of a lot of different process, processes including damage, but maybe also some repair processes can have the appearance of a T2-hyperintense area and yet one would not have the T2 hyperintense area unless there was damage in the first place.

NORM KACHUCK, MD: Right.

J. THEODORE PHILLIPS, MD, PhD: It's kind of a footprint of the disease in a sense.

NORM KACHUCK, MD: But you pointed out an area where we know very little and that is that we have a regenerative and repair process ongoing in the brain, including in the MS brain, that we have not got good metrics for. And the inability of the MS brain to repair is actually a set of issues which we are now facing, I think, as an MS research community. To ask the right question, experimentally now, will become very interesting and MRI will play a part in that, I'm sure.

J. THEODORE PHILLIPS, MD, PhD: Yes. Mariko, regarding T1 hypointensities or so-called "black holes" -- or, actually, for that matter, regarding all three of the more commonly noted lesions, gadolinium-enhancing foci, T2 hyperintense and T1 hypointense, how well do any of these by themselves or in aggregate actually correspond to what's evolving clinically in the patient do you think?

MARIKO KITA, MD: Well, I think that there are data out there, certainly, that would suggest that there is a relatively decent correlation, actually, with certain, some of those metrics. I mean, it's a little controversial, because certain studies show poor correlation, other studies show relatively good correlation. But I think most of us can agree that the data suggests T1 hypointensity or at least, let's say, brain volume correlates well with disability.

But, in clinical practice, it's a little bit harder to apply and I think all of those things, we use all of those measures together. We look at the T2, we absolutely look at the gadolinium-enhancement, which suggests kind of the more active disease. But then the T1 hypointensity is really important for that long-term sense of "Gee, how much tissue are we losing?"

NORM KACHUCK, MD: And the localization of the lesion. If it's in a critical place, it may make a difference, too. When you're looking at something happening in the brainstem or in a very rich functional area for that person, it may make a difference.

And certainly we know that the volume of T1 hypointensity can associate with cognitive losses. If there is one measure of MR lesion formation that will go directly to, at this point, something that may happen in the life of the person, it may be that that is the best metric. But we don't really have a good way, in practice, to look at an MRI and say, "Well, no, that's enough T1 hypointensity to be a big problem for you. We better get neuropsychological evaluation." It's just not going to work that way.

J. THEODORE PHILLIPS, MD, PhD: But, you know, Norm, you bring up a good point that I thinks worth emphasizing that not all 6 mm gadolinium-enhancing or T2 hyperintensities are necessarily created equal. A 6 mm new lesion lost in the frontal white matter is maybe not going to have the same clinical impact as that same size 6 mm lesion in the spinal cord.

NORM KACHUCK, MD: Or, as Bruce Trapp has pointed out, in the cortex. We have missed the phenomenon of the cortical MS lesion in our haste to define, first, this as a demyelinating disease. So we forgot that it was an axonal disease, too. In the rush to use MRI, which, in it's earlier versions was not very good at all at picking up cortical gray matter lesions in MS, but now that we have more sophisticated software, that we've got bigger magnets, if everybody can get a three Tesla, be the first hospital on your block to get it, you may be able to see some lesions which are probably impacting a great deal more dramatically on the neurologic state of people because it's involving that very thin line of neurons and the palisades of the gray matter of the cortex.

MARIKO KITA, MD: I would say that I think the way we see activity in the form of the T2-enlarging lesion or the gad-enhancing lesion, that's disease activity that I feel, as a clinician, we can try to impact. But once we start to see those other measures, cortical involution, sometimes we can actually see the thinning occurring over a period of time, that's difficult to know how to respond to. It's difficult to know how to treat, so it's that other phase of that disease that, you know, we really haven't scratched the surface of, really.

J. THEODORE PHILLIPS, MD, PhD: Norm, a few moments ago, you mentioned magnetization transfer. And, of course, that opens up an area for discussion of we have been talking about the so-called conventional measures on MRI, but there's a whole host of other measures that start getting into investigational, experimental measures. What do you think, among those investigational measures -- what do both of you all think -- may be among the measures that show the most promise for the future?

NORM KACHUCK, MD: I think I need to preface my remark on this in saying that it's okay to be confused now and I feel okay because I've had to deal with uncertainty my whole professional life, especially in MS, you've got to deal with uncertainty. A lot of what we know now is that we don't know. We don't know how extensive MS is, a disease of the whole central nervous system using conventional MRI measures now.

What we know, from a variety of research, experimental design, and findings ranging from histology and biopsy through measures like MRI spectroscopy and mag transfer, is that this is not a disease of the plaques. This is a disease of the whole central nervous system and that you can find -- using sophisticated magnetization transfer and spectroscopy techniques -- that you can see disease even in what's called normal white matter and certainly now we're saying normal gray matter, too. And that, to the extent that it's all sort of tip of the iceberg, that we're seeing up here and that there's a whole lot more iceberg down below, we're probably missing a lot of it.

I would say what we will hope to use in the next decade would be measures of this whole-brain, whole-central nervous system affectation, the inflammatory and, as I'm sure we'll bring up, the noninflammatory side of this disease's effects on the central nervous system.

I'm clear that magnetization transfer is something that nearly all radiologists and their technicians can handle now. I mean, it's a pulse that is supposed to help us differentiate the water that is relatively free from that which is colloidally-based. And, to that extent, it may even be a very nice next-step measure in order to see, a little more early in the evolution, the MS lesion as it occurs.

Spectroscopy is a software technique. It doesn't require any new kind of magnet. Whether we can use it to establish new benchmarks for normalcy and abnormalcy is something that needs some time.

But the N-acetyl aspartate to creatinine ratio is an excellent way of establishing at least integrity of the axon. Choline should be a measure of inflammation. Glutamate should be a very good measure of excitotoxicity. These are not the kinds of measures that are impossible for the community neurology, community neuroradiologist's facility to start utilizing, when they get the right way of interpreting the software's findings and getting it done standard.

So I don't think that those are impossible to foresee. Actually, I say a decade; it's probably within years, don't you think? Three to five years?

MARIKO KITA, MD: I think it's easy to see it happening, but how it will help us to manage our patients, I think is a different question.

NORM KACHUCK, MD: Yes.

MARIKO KITA, MD: I mean, I think right now these techniques are really exciting and they're exciting because they can help us to understand what's happening with the tissue and, hopefully, we can take it a step further to say, "Well, what's happening immunologically in that tissue?" But, right now, we're really still fighting about what's the best way to do it.

NORM KACHUCK, MD: Well, we don't even use flare as a primary outcome now. But I can tell you, any time I get a flare, I look at that even before the T2.

MARIKO KITA, MD: Yes.

NORM KACHUCK, MD: But we're not standardized in our outcomes on using the flare, which actually makes the CSF nice and dark compared to my periventricular lesions. And it's something that now probably we should start using as an outcome measures in some trials, too, but we don't.

J. THEODORE PHILLIPS, MD, PhD: Well, Mariko, you've done a lot of work over the years with mag transfer. As maybe a technology that could be conceived to be the next new one to become available, do you think that mag transfer is that close to prime time. What do you think about mag transfer?

MARIKO KITA, MD: Well, I'm actually glad you're asking me about mag transfer, because I haven't done a lot of work. I've done enough work to, I think, have an understanding of it, which is appropriate for advising people in a similar situation.

So I think that mag transfers, one can easily acquire that , but I've seen it happen in clinical practice right now and it's been confusing to practitioners. When you get a mag transfer image, it looks like a contrast-enhanced sequence and it's very difficult to compare those sequences with the T1 contrast. And so while it's easily done and it's acquired, how we're going to interpret that is different, so we're not getting histograms of the brain, we're not getting specific ROIs, we're getting pictures.

NORM KACHUCK, MD: Regions of interest.

J. THEODORE PHILLIPS, MD, PhD: Yes.

MARIKO KITA, MD: Regions of interest, thank you. So we're getting pictures and to apply those pictures to what we're doing, I think, is not helpful right now. But if we can get it down to trying to understand that region of interest or if the researchers who are doing this right now can say, "Listen, we should use whole-brain or we should use this slab, then we can take that and say, 'Gosh, okay, now I understand what that means." But the actual pictures themselves, I mean, I don't know how helpful they are right now.

J. THEODORE PHILLIPS, MD, PhD: Well, bringing this back to the underlying pathophysiology of the disease, though, from an investigational standpoint, even though it may not, in fact, be ready for prime time yet. From an investigational standpoint, mag transfer, in your opinion, has done what, if anything, to increase our understanding of the underlying basic pathophysiology of the disease?

MARIKO KITA, MD: Oh, no, I think it's definitely taken us a big step forward to begin to understand what's happening in the tissue. So all those things that you were talking about, what's happening in that T2 lesion, mag transfer has been able to help us understand -- is it on the way to healing or not? How much healing? Back to baseline or not quite. So I think it's helping us to characterize what's in that lesion.

NORM KACHUCK, MD: It's helping because it's so sensitive to what we think is inflammation. I think that the earlier mag transfer abnormality connotes an inflammatory change, which is prior to the actual sensitivity of gadolinium to pick up this change.

J. THEODORE PHILLIPS, MD, PhD: And , indeed sometimes, even weeks before, if not months before, in some instances, you see a mag transfer change.

NORM KACHUCK, MD: Yes, and maybe we'll see that in practice, but I think what you're pointing to and I think we can talk about, is the fact that there's a whole lot going on in the MS brain that is not, at this point, clearly associated with inflammation per se. And that there's cell injury, cell death, dysfunction in areas that are not going to show up as abnormal on our conventional measures and may, at this point, not even show up as abnormal on mag transfer. And those are areas which we are completely unable to establish abnormality, unless we have some other ways of taking that axonal loss and that degenerative loss that is in those areas that are not amenable to MR investigation, conventionally.

J. THEODORE PHILLIPS, MD, PhD: Well, so kind of going along that pathway, if the disease itself in most people, starts off relapsing-remitting, the most dramatic evidence of early relapsing-remitting MS are the inflammatory events that show up as gadolinium-enhancing, new gadolinium-enhancing foci. And then, yet, in so many other of our patients, as time goes on, there is this insidious progression that happens.

Two things I'd like to talk about are, one, whether you think that the progression is an obvious and completely expected outcome of the inflammation or is it something separate. And, two, we've talked a lot about how MRI kind of identifies, fairly sensitively, the inflammatory component of the disease. Do we have anything with MRI that serves to identify the progressive part of the disease? So first, maybe, Mariko, is progression just another aspect of inflammation or do you think it's a second process?

MARIKO KITA, MD: I don't know.

J. THEODORE PHILLIPS, MD, PhD: Do you think it's reasonable to wonder whether there's two processes going on?

MARIKO KITA, MD: Oh, no, I think there probably are two processes going on but I don't think we understand much about that degenerative phase yet. And the way that I try to make sense of it is that they have to be somewhat related because one leads into another and the health of the brain at the end of that inflammatory phase, I think, can help us to predict how they might do in that degenerative phase. But I do think that there are underlying, primarily degenerative processes that are underneath that initial inflammation that we haven't seen yet.

So I do think there are two processes, but I'm not sure that we know exactly how to tease it apart.

J. THEODORE PHILLIPS, MD, PhD: Do you think MRI, at this point, is necessarily helping us tease it apart or what aspect of MRI?

MARIKO KITA, MD: I don't think conventional MRI is helping us tease it apart.

J. THEODORE PHILLIPS, MD, PhD: Norm, what's your take on this?

NORM KACHUCK, MD: There's a heterogeneity in the MS population, just in terms of immunopathology and not even talking about their response to therapy, which we haven't gotten to yet. But it's essential that we recognize that the field is moving towards subtypes of MS that are going to differ in the type and quality and quantity of inflammation and type, quality and quantity of something else which may be an oligodendrogliopathy, it may be an axonopathy. Whether or not a process that results in cell loss starts as inflammation as we understand it or the loss is because of some intracellular defect, metabolic, or a viral infection and it results in death of that cell or injury that actually promotes the identification of that area as a subject for the immune system to recognize and do something with is something that's probably different from group to group in these subtypes of MS and also maybe in individual patients at different parts of their disease history, varying.

J. THEODORE PHILLIPS, MD, PhD: So we're talking about subtypes of MS or you're talking about subtypes of MS that are not the same as the conventional relapsing-remitting, secondary progressive, primary progressive, progressive-relapsing. You're talking about a different subtyping.

NORM KACHUCK, MD: Yes, I think that nosology is obsolete. I don't think that's going to help us, because as far as I'm concerned, I think that the data that shows that we get a lot of amyloid precursor elevation, that shows axonal damage right at the beginning of the disease and then it kind of tapers off, people look like the relapsing-remitting because they have such a good reparative and functional recovery potential in a brain that can compensate. And it's only over time that we kind of exceed the ability of that brain to compensate for its injury that you end up with what appears to be a super-threshold disability that doesn't show up as clearly as relapses and remission any more.

Also, as Mariko has pointed out, relapses usually happen early in the disease, so there is something more fulminant, but it's going to be a much more complex process to measure and MRI, as she points out, has not gotten us to the point where we can look at that and say, "Well, this is inflammation, this is post-inflammation degeneration, this is noninflammatory degenerative axonopathy, oligodendrogliopathy." Those are subtleties lost on us.

J. THEODORE PHILLIPS, MD, PhD: Along these lines and getting on to talking a bit about currently available disease-modifying therapies, when you look at the group of available disease-modifying therapies as a whole, one is sort of struck, in many cases, that the impact of these treatments on the inflammatory aspect of the disease seems to exceed the impact on the later progressive part of the disease. Is this trying to tell us something about the disease process again or is it rather trying to tell us something about the relative inefficiencies of the currently available therapies?

NORM KACHUCK, MD: Is that a leading question?

J. THEODORE PHILLIPS, MD, PhD: Well, let's talk about disease-modifying therapies.

NORM KACHUCK, MD: You know, I wish we had that kind of information clear. You've set a set of wonderful goals for us to achieve. It would be important to know how much we can associate relapses with disability progression. To know whether we can say that we reduce relapse rate and that is a marker for what the person's going to look like thirty, forty years down the road. I mean, the main disjuncture is short-term benefits or short-term outcomes that we can measure and the long-term look of the disease.

And I don't know about you, but I can't tell, except if a relapse results in disability, what's going to happen down the road in terms of degenerative process and result of that. It's just that that's an area of blindness for me.

J. THEODORE PHILLIPS, MD, PhD: Mariko, what are your thoughts on this?

MARIKO KITA, MD: I mean, I think that the treatments, and maybe you're trying to get to this point, but I think what we know that some of the treatments can have a fairly decent antiinflammatory effect, and so we are measuring it that way and we're putting it in the box of that's what it does. And maybe that's what you're getting at, that we expect that of the drugs and so we look for that in the drug, but we don't expect it to do much more than, in time, have an anti-inflammatory effect. So what can it do in that less inflammatory progressive phase?

J. THEODORE PHILLIPS, MD, PhD: Yes, you know actually, not meaning to get overly philosophical, but I would submit that we really didn't know what to expect until we were faced with the data of what we got. You know, at the beginning that these therapies and their trials would have not only a prominent effect on the inflammatory relapsing-remitting part, but would also similarly affect, slow down, prevent disease, long-term sustained disease progression. And yet what we got and what we have to deal with are, as you say, the treatments that are certainly better than placebo at preventing inflammatory events, but yet leave something still to be desired when it comes to really slowing down or stopping progression.

My personal belief is that all of the currently FDA-approved therapies do have a beneficial impact on disease progression and relapses and inflammatory aspects of the disease but there's still, in my mind, this disconnect between the effect on the inflammation part of the disease and the effect later on that is the somewhat not so inflammatory part of the disease.

I mean, in your mind, does this mean that we're maybe going in an incomplete or not quite right direction in terms of therapies for trying to impact the progression part? I mean, should we be looking at neuroprotective possibilities?

NORM KACHUCK, MD: Well, Ted, we're trying. We're trying, man. There's a lot of work being done and MS is only one of many areas in which we would like to prevent tissue loss and loss of function. The groups that are looking at Alzheimer's disease and various other dementing illnesses, those that are looking at even the sequelae of stroke and ischemic disease, those that are working in other degenerative diseases that are looking at final common pathway of cell injury are all interested in this, quote-unquote, "protective" process. And it would be wonderful to know how the brain repairs itself. Don't know yet. You're going to just have to wait.

J. THEODORE PHILLIPS, MD, PhD: Alas.

NORM KACHUCK, MD: It's tough and it's all -- for all of us you know -- you take your vitamins and hope for the best.

J. THEODORE PHILLIPS, MD, PhD: Yes.

NORM KACHUCK, MD: I think that it's very important for us to have a certain degree of humility in this, and I mean we get a wonderful, sometimes serendipitous, insight into a disease process and when we realized that there was a immune part of the MS process that we can ameliorate and we looked at T-cells and we thought that the T-cells, if we changed them, would be a wonderful way to measure a benefit and it turned out we can move from animals to humans. And when we got our interferons, we got glatiramer, we had a wonderful new world to deal with in MS therapeutics. It doesn't mean that we knew what we were doing back then with those, per se. And we've learned a lot more about them as we've gone along.

I think that it's quite possible that these medicines are, quite-unquote, "protective." I think that there have been enough studies to show that the reduction of pathologic immune attack on the central nervous system results in protection by reducing the amount of brain matter loss, various ways that you can demonstrate if you have less inflammation, that you have less disease activity, whatever that's going to be, and that the people do better. Though the doing better is hard to do when you have open-label trials and registries that have a lot of dropout. You can't be sure.

But I think we're making a difference. And that natural history is something that we'll, in the fullness of time, realize. And I think one of the most important things is that we know that, if we can keep people in a relatively low state of disability, before they hit this EDSS, the disability status scale number 4, that we can keep them from getting into what seems to be sort of an unstoppable, nearly standardized transition from a modest amount of disability to a severe disability, in which a person, at least in terms of ambulation, requires assistive devices with both hands. And we know that that happens from Confavreux's data in a relatively set amount of time, regardless of how long them it took them to get from normal to where that transition starts. If we can show that -- and we have shown that -- we keep people longer in that pre-transition time with the available medicines, then we have made a difference.

J. THEODORE PHILLIPS, MD, PhD: Yes. And, just for clarification, that EDSS of 4.0 is at the time where the person is starting to have difficulty walking and are limited in how far they can walk, although they're not requiring any sorts of aids to do that.

NORM KACHUCK, MD: Right. But it is a point where you've got to make a decision about whether you've got the right -- or you've got the right combination -- and you may be making treatment decisions with the person, somewhere where you're starting to worry about that transition coming on.

J. THEODORE PHILLIPS, MD, PhD: So, in the last few minutes that we have, we've spent a lot of time talking about MRI and the details of MRI and the correlations or not. Just in the remaining one or two minutes here, I'd like to hear just briefly from each of you, where you see the future going in terms of potential new surrogate markers that are not imaging in nature. Mariko, where do you see this going? I mean, if we're not looking at a scan. If we're not looking at the picture worth a thousand words, what is around the corner that may also help us either determine who might respond best to a given therapy or track people, in addition to the MRIs that we undoubtedly will still be getting?

MARIKO KITA, MD: Well, I think it's in the immunology and I think it's bringing that immunology to those of us practicing medicine. So, will there be ways that we can tell a patient, when they come in and we've made a diagnosis that they have MS, "You know what? This type of treatment's going to be better for you." And that would be the first step in really becoming more successful in treating this disease.

And then there are other markers of "When can we tell that a patient is no longer going to be responsive? When have they exhausted that window?" And I think it's going to be in the immunology.

J. THEODORE PHILLIPS, MD, PhD: Norm?

NORM KACHUCK, MD: Surrogates, by definition, may not be the disease state. It's going to be something that identifies or parallels the course of the disease state and we've got a lot of measures that may be candidates for that. A lot of what is happening in genomics and proteomics will allow us to take measures of how you can challenge the person's lymphocytes, their system perhaps, and see in that response a way to create a surrogate marker for their ability to use a medicine successfully.

And, certainly, when we look at microarray with all of its complexity, now we're very confused about the profundity of the just sheer volume of data that we get from it and we don't know how to interpret it. I'm imagining that we'll narrow our focus down to some candidate gene and gene expression profiles and we'll use those just like we used the MS panel on spinal fluid for all these years and we'll get an aggregate and we'll say, "These sets of findings will predict, in this person, a responsiveness to this kind of medicine," or at least we can start there and then, using those same measures along the way, take a snapshot of them and see how they do. And I don't think that that's too far away.

J. THEODORE PHILLIPS, MD, PhD: Great. I mean, I foresee that in the not-too-distant future as well.

So we are out of time for this program. I want to thank my friends and colleagues, Dr. Mariko Kita -

MARIKO KITA, MD: Thank you, Ted.

J. THEODORE PHILLIPS, MD, PhD: -- and Dr. Norm Kachuck for joining us. We've tried to give an idea of the current status of MRI in the monitoring of this disease and also some insights into maybe the pathophysiology of the disease and as well as the activities of various disease-modifying therapies in this disease.

I'd like to thank the audience online for staying with us throughout this discussion. I'm Dr. Ted Phillips.

Case Study

J. THEODORE PHILLIPS, MD, PhD: Hello. I'm your host, Dr. Ted Phillips, from the Multiple Sclerosis Center at Texas Neurology in Dallas. Welcome to the case study portion of our program on the use of surrogate markers in monitoring disease-modifying therapy in multiple sclerosis.

I'm pleased to be joined by Dr. Mariko Kita, director of the Virginia Mason Multiple Sclerosis Center in Seattle, and Dr. Norm Kachuck, associate professor, clinical neurology from the Keck School of Medicine at the University of Southern California. Thank you both for joining us.

Mariko can you please start us off with your case study.

MARIKO KITA, MD: Well, thanks for letting me share this with you. This is a 28-year-old woman whose first neurologic symptoms started in the year 2001 and, at that time, she experienced a bout of transverse myelitis with numbness and tingling up to her waist. Her symptoms lasted about two weeks and then they spontaneously resolved and then she was well for two years until February of 2003 when she had recurrence of tingling in her feet.

So it was at that time that she had a workup done. An MRI scan of the brain showed five areas of abnormal signal intensity in the brain, consistent with MS. And a spine MRI that showed a lesion at T9, so thoracic level 9. A spinal tap showed presence of oligoclonal bands and, at the time, her neurologic exam was completely normal.

So she was started on intramuscular weekly interferon beta 1a in June of 2003. And she does well, until March of 2004 when she checks in with you just to tell you that everything's going well, she's tolerating the medication well and not having any relapses. At that time, her exam again remains normal. And then we had anticipated seeing her just a few months after that for her one-year checkup with an MRI scan, but she missed it because she was just doing too well.

It wasn't until January of 2005, so another six months after that, where she is feeling just a significant amount of stress at work; she's got a full-time job, she's taking twelve credits at school, so she's also basically a full-time student. And she develops numbness of her right hand, then numbness of the left torso.

About a month after that, she's starting to feel incoordination of the right arm and leg, difficulty writing, she's dragging that right leg a little bit and, by March 2005, she doesn't have any treatment and the right-sided symptoms have completely resolved. She has a little bit of numbness left in her torso and she comes in, April 2005, you do an MRI scan of the brain and it shows maybe two or three new small punctate areas of abnormality in the brain, they don't enhance and then the spine MRI shows a lesion at T9, which was the old lesion, no change, but there's a new lesion in the cervical spine at C3-C4.

No contrast was given for the spine images, so we don't know if those were enhancing, but that's the situation with this 28-year-old woman.

J. THEODORE PHILLIPS, MD, PhD: Okay, so let me see if I've got this right. After disease-modifying therapy was started after the second, if you will, defining attack and workup to rule out mimickers and so forth. And then after disease-modifying therapy was started, she went how long before a first defined attack?

MARIKO KITA, MD: Eighteen months.

J. THEODORE PHILLIPS, MD, PhD: So, at least in my opinion, not an unreasonable length of time to go. I mean, recognizing that none of the available treatments are cures and people do have attacks on these agents, although, hopefully, fewer attacks than they would have had. She goes eighteen months, has an attack that resolves and was not treated. And then goes how long again? Did she have, was there a fourth attack.

MARIKO KITA, MD: No.

J. THEODORE PHILLIPS, MD, PhD: Okay. Okay. So, I guess maybe a first kind of discussion point would be -- and I realize, at the outset, that there is no absolute answer to this -- but would you view this a treatment failure? Okay, you start somebody on disease-modifying therapy, they go eighteen months, not just relapse-free, but it sounds like doing great. And then they have an attack, eighteen months into it, I mean, does that mean that they are failing their disease-modifying therapy? Norm, what do you think?

NORM KACHUCK, MD: Suboptimal response to a treatment that is not a cure is hard to define and I don't think our community has decided, as MS researchers and MS clinicians, what that threshold is. And, as you said, a person who has had a relapse in eighteen months after starting an interferon is not having, at least statistically, a suboptimal response, if you go by the percentages in the trials. If you consider the average MS patient, just from an epidemiologic standpoint, having relapses, your average MS patient may have one every fifteen to eighteen months, maybe a little more in some places, a little less in others.

But the nice thing about when you are pitching the choices of these medicines to people is that you can say, "Well, the population had an X percent reduction in relapse rate, so we're hoping that, given your history, you're going to have a reduced response rate, but since we don't really know what's going to happen with you individually, you could be either having no relapses or you could be having some relapses and we're really going to need time to see how you respond."

Now, we're given this patient's problem as a sort of -- she's taking the medicines and she's doing great and then she has a relapse. In the real world, compliance is a big issue. Mariko didn't tell us all the times this lady had to call up and complain about this and that and handling the symptoms and getting her insurance to pay for the drug, to get it delivered and various other things that get in the way of people doing what they're supposed to, at least what we think is immunologically and therapeutically appropriate with these medicines. And that's an uphill battle in a lot of people's lives when they're getting used to an injectable therapy.

Once you've licked that and you think you've got a person who has been compliant and they come in with this kind of problem that's not even requiring steroid therapy for an acute relapse, I think you're really on the horns of a dilemma. Everybody has to decide what their threshold is. Are you going to have a zero tolerance for anything at that point or are you going to say, "Well, let's see how it goes"? And from what Mariko was saying, they decided to see how it goes and it went okay, for a little bit longer.

J. THEODORE PHILLIPS, MD, PhD: Well, go ahead, Mariko.

MARIKO KITA, MD: Her repeat MRI was just last week. So we haven't come up with an entire plan yet, but does it bother you more that her relapse resulted in a lesion on the spine?

J. THEODORE PHILLIPS, MD, PhD: It would bother me more, because a relapse is a relapse and a new gadolinium-enhancing lesion or a new T2 lesion is a marker of disease activity. But, a similarly sized lesion within the confines of the relatively small spinal cord may have substantially more clinical ramifications than one lost within the hemispheres that may actually be clinically, at least, asymptomatic.

That, coupled, with the fact that there is some evidence from the literature that areas that have been hit previously by inflammatory activity are, perhaps, somewhat more likely to be hit again and, for all the obvious reasons, the spinal cord can be a disastrous place to have any activity or certainly too much activity.

Would this be an issue in trying to decide whether you have a treatment failure? Is MRI going to play a role here in helping you to decide whether this is just an incomplete therapy and people are going to have attacks from time to time versus "No, for whatever reason, whether it's neutralizing antibodies or lack of compliance or whatever, no, this the tip of an iceberg and, yes, she's had an attack and, indeed, this illness is progressing without us even fully realizing it"? Is MRI going to be useful here, in general?

NORM KACHUCK, MD: I think this is a critical juncture that all of us face as neurologists with MS patients. Sooner or later, we're going to have to decide whether a single-agent therapy in this milieu is going to work in the future for them.

This person has active disease, no doubt about it, and the MRI is a wonderful way of establishing if there's new lesion activity, that this is not quiescent. So you're at a point where you can say there are now reasons to think that you're in trouble. And certainly we know, from looking at the placebo groups of our big phase III trials, that when you have a relapse, it's very likely you'll end up with disability after that. Relapses are not good for you. And to the extent that we now have that, plus the MRI lesions, means that this lady could be in trouble.

But, for me to decide what you should do for that person is not evidence-based. And I think, for everybody, we are at that point, stuck with knowing that we need to do something, but we don't have a way of really establishing risk-benefit ratio.

And I want to just caution us that "treatment failure" in a treatment regime that is not a cure is not, probably appropriate terminology. I think your use of "suboptimal response" is better. Because we can only expect so much and I think realistic expectations are a very important part of what we have to bring to the table with someone and say that, you know, "You've gone for this nine months, you're sick and tired of this drug, let's just switch to another." That's not a great way. That's not reasonable goal-orienting. But, in this case, maybe we have a reason to want a change.

J. THEODORE PHILLIPS, MD, PhD: So, Mariko, you had said that you hadn't come up with a firm plan yet for this person. Do you have any leanings, though, at this point in time, of what you're thinking you might do?

MARIKO KITA, MD: Well, I think it's interesting, because I was much more bothered by what had transpired than the patient was. So I was much more bothered that she had a new spinal cord lesion, despite what she says is very good compliance, and did feel the need to respond to that, that there is disease activity that we're seeing here that we could try to better treat.

But the reason why I said we hadn't finalized a plan yet is that -- exactly as you said -- it's not really clear the best way to go. So we talked about enrollment in two different clinical trials, one which would require an add-on treatment to her current, the other would be potentially changing therapies. And the other choices were to not participate in a clinical trial, but do one of those options in practice and then the last choice was to, I suppose, not do anything.

And she was really leaning towards not doing anything, insisting that this was a very unusual set of circumstances. Starting in January, she was under just a huge amount of stress, much more than usual and not really wanting to make any changes.

So I'm at the point right now where I'm trying to figure out how strongly I feel about encouraging a change versus waiting, say a shorter period of time, a three-month period of time or a six-month period of time to take another look at an MRI scan.

J. THEODORE PHILLIPS, MD, PhD: Yes. I mean, it's always in my experience, the balance between what you, the physician feel is appropriate to do based on your experience, not only with the individual patient at hand but your larger clinical experience, and balancing that against what the individual patient wants to do, because for all the obvious reasons, if the patient isn't fully on board with what they're doing, they surely will not be compliant to it.

And I take that what your patient was more kind of tending towards was just kind of staying the course and basically seeing what happens. And certainly that is an option. Did I gather from you, though, that if that is what ends up being the case, that you would feel the importance of more frequent or more vigilant clinical exams or MR imaging in her case, if that's the direction you go?

MARIKO KITA, MD: If that's the direction I go. I think we do owe her some more vigilant monitoring, perhaps to help her understand her disease better, too. I think if she were to see subclinical change on her MRI scan of the brain, let's say, that might be something that would sway her more towards changing something about her regimen.

J. THEODORE PHILLIPS, MD, PhD: Yes, right. Yeah, I think that's a great approach if that turns out to be the plan offered. Any parting comments from you, Norm?

NORM KACHUCK, MD: There are going to be people in our MS-treating community that would say, "Zero tolerance. This is something which is unacceptable and, even though our therapies are a two-edged sword with, hopefully, the cutting edge, the therapeutic edge being a little more sharp than the side effect edge and toxicity edge, but that in this kind of situation, we want to grab this disease at this point before it reaches some threshold of activity and disability, at which time we have very little to offer." And there are going to be people who say that this is a person who need either a change in a monotherapy or an add-on therapy in order to arrest this process. And I could make an argument for that here. And, even if she doesn't like it, it has to be set out as the physician talks to the patient about their expertise -- they don't have to force it on them, but I think you have to make it clear.

And just because she's under stress doesn't mean that it's just the stress. The Academy of Neurology's committee on assessing the impact of stress on MS established that you can definitely have an association, at least in history, showing a person with physical or mental stress and MS activity. It's not a clear connection, but it's one we have to take into account.

J. THEODORE PHILLIPS, MD, PhD: Well, thank you both very much for your thoughts and insights into this. Thank you to Mariko Kita for sharing with us this case, we certainly wish her and you the best in figuring out what is next going to be best for her. Thanks, Norm, as always, for your insightful comments.

NORM KACHUCK, MD: My pleasure.

J. THEODORE PHILLIPS, MD, PhD: And thanks to the listening audience for joining us as well. I'm Dr. Ted Phillips.