SYED RIZVI, MD: Breakthrough disease in multiple sclerosis is difficult to define. But if you want to make a definition, basically you’re describing a patient who has worsened from their original, stable condition. So, breakthrough disease would be something which has worsened, either from a clinical point of view: the patient is not doing as well as they were doing previously, they’re having more relapses, or they’re getting more disabled, so they’re having more progression, as we define it.

You can also look at the MRI, and basically, if somebody has been stable on an MRI and the MRI hasn’t changed for years, and now you’re getting an MRI which is showing increasing lesions and increasing enhancement, that’s also not a good thing.

Similarly, subjectively, patients may come in saying that, you know, they’re not feeling the same. They’re getting more tired. They’re not able to walk as much as they could. So, when we look at patients who we think have breakthrough disease, we look at the MRI, we look at the clinical situation and we look at subjective complaints, and basically it is a comparison to a previous state of stability. There’s no clear definition. You can’t clearly look at one thing and define breakthrough disease. It’s basically a combination of things.

ANDREW GOODMAN, MD: There is no standard definition of suboptimal response or breakthrough disease. That being said, many clinicians consider somebody who has been on one of the disease modifying therapies—that is one of the interferon treatments or glatiramer, for a year or so who have had more than one relapse, a severe relapse, new MRI activity, particularly with enhancing activity and, most importantly, significant progressive worsening of the MS. Those are the factors that I think we weigh together in different proportions among different experts. But those are the factors that I think we weigh together to decide whether or not somebody is not responding as well as we would hope.

KHURRAM BASHIR, MD, MPH: In my opinion, suboptimal response should be defined in a patient who has been on immunomodulatory agents for at least six months of therapy. Early on in disease, based on our clinical trials, it is difficult to determine if the patients would respond clinically. MRI response can be seen sooner than clinical response, but, in my opinion, clinical response takes at least six months of therapy.

Factors Used To Define Breakthrough Disease or Sub-optimal Response: Clinical Status

KHURRAM BASHIR, MD, MPH: Considering relapses to define suboptimal response, we really should look at the quality as well as the number of relapses. Not all relapses, in my opinion, are equal. A mild sensory relapse probably does not carry the same weight as a severe relapse. And so when I evaluate patients for relapses, I generally will evaluate them based on their frequency of relapses as well as severity of relapses, the symptoms that are involved, whether they're motor or cerebellar symptoms, localization of relapses and also whether they respond to steroid therapy or not.

Another important factor to consider when evaluating relapses is the degree of recovery from a relapse, whether there is complete recovery or partial resolution with residual deficits.

SYED RIZVI, MD: If somebody had, for example, three or four relapses in the previous year, and they had one in the year after, that’s a relative success. So that wouldn’t be considered. So you really have to go by a previous baseline type of thing. But, for most purposes, I think if somebody’s having more than two or two relapses, I think it’s a little too much. And regardless of whether you’ve done better than your previous relapse rate, I think two relapses probably is not a good thing and is resulting in a significant amount of damage.

ANDREW GOODMAN, MD: Some doctors have been of the opinion over the years that all pathways or parts of the nervous system are not created equal in terms of their impact on MS. I haven't been persuaded by this, at least in the sense that sensory pathways are somehow less meaningful or less severe prognosticators of worsening.

I have been persuaded that patients who have cerebellar problems may carry a worse prognosis, particularly people with cerebellar and cognitive problems that seem sometimes to track together. They are people that I'm more concerned about because I think that may be a subcategory or subgroup of patients who are more severe.

That being said, to me physiologically, a lesion is a lesion. If you're getting them in the sensory pathway or in a motor pathway, it really doesn't matter. It tells us that the disease is not under control and that we have to be concerned about the effectiveness of our treatment.

Brain stem and spinal lesions may be "more eloquent," meaning that they may have more obvious symptoms to the patient and be easier to measure on the part of the doctor. They also, particularly spinal cord symptoms, may perhaps leave more residual deficits and, therefore, in that sense may be somewhat more of a concern. Nonetheless, I believe that if one is getting relapses, be they on MRI or clinically, then that should be of concern.

KHURRAM BASHIR, MD, MPH: Involvement of multiple pathways is important because natural history studies reveal that patients who have poly-lesion relapses involving multiple systems at the same time tend to have worse prognosis in the long run, compared to patients who have monosymptomatic or relapses that involve a single system and that should be taken into account when determining whether patients are going to develop disability or not.

Motor and cerebellar relapses and symptoms are more significant than purely sensory or purely visual relapses, primarily because of involvement of the brainstem, cerebellar region and involvement of the spinal cord.

SYED RIZVI, MD: Motor and cerebellar symptoms both tend to have a worse outcome. Most people who have a motor weakness, for example, inability to walk, that’s considered a worse relapse. You know, you just can’t walk. You’re more disabled. The recovery may be prolonged, and the ultimate resultant residual damage may be significant down the line, while if somebody has a minor sensory relapse, it’s a little bit of tingling and numbness and comes and goes and it doesn’t really lead to a whole lot of disability.

ANDREW GOODMAN, MD: Incomplete recovery from a relapse is concerning because there are natural history studies that seem to indicate that that is a prognosticator of a worse outcome over time. So those are worrisome when people are not recovering from a severe relapse to a near baseline level. Therefore, we may be more concerned that the MS is, if you will, upping the ante at a more rapid rate. And therefore, we may need to have a lower threshold for being more aggressive out of concern that this person, this patient may be worsening more rapidly.

KHURRAM BASHIR, MD, MPH: Expanded Disability Status Scale (EDSS) has been the gold standard in clinical trials and is the one that most neurologists are familiar with and it's the most commonly used. Despite its limitations, it gives a good idea of the disability of a patient. It is heavily weighted towards walking, which is a major factor in disability of MS patients. It is an objective score that has been well-validated and it gives you an idea of how extensive the disability of a given patient is.

The advantage of EDSS is that it is based on neurological examination and can easily be performed by any neurologist who does a complete examination and, in my opinion, it should be performed in all patients on immunomodulatory therapy at least every six months to actually determine whether they have any progressive disability. In patients who continue to show disease activity, it should be performed probably every three months.

SYED RIZVI, MD: Most of the time, if you have a relapse, and it’s a sensory relapse, patients can continue to function and go to school, go to work, and they are emotionally not that badly affected, versus if you have a relapse in which you just can’t function and you are limited to the house or use a cane and a wheelchair, that’s obviously both emotionally and physically not a good thing and would affect the patient in a worse way.

ANDREW GOODMAN, MD: EDSS can certainly change in the face of an acute relapse. However, it's known that EDSS scores may actually improve over a period of weeks and months if a patient recovers from the relapse. So the most meaningful evaluations of relapse by EDSS's impact on disability is measuring EDSS over time. That means a change for the worse in EDSS over three months, six months, one year or more has more meaning and is more concerning if it's worse than in the near-term.

The MSFC is the Multiple Sclerosis Functional Composite Score. This looks at three dimensions of MS; an upper extremity dimension, measured by the testing of putting pegs in a pegboard, a lower extremity dimension, measured by speed of walking, and the third dimension is a cognitive dimension, measured by the ability to do mental arithmetic under duress of timing.

The point of this was to get a new method for evaluating disability that would hopefully have better measurement properties and be more sensitive to change and to therapy than the existing method, which is change in EDSS.

In my opinion, the MSFC is more sensitive than EDSS to change, and therefore, has the potential for being a useful outcome.

I have, in trials that I have helped design, recommended using the MSFC, so this is my personal bias.

SYED RIZVI, MD: There’s really no measure which is used commonly to look at fatigue. There are certain fatigue scales which are around, but, you know, most people don’t use them on a regular basis. Similarly, cognition can be followed by neuropsych testing, but may not be practical in a clinic situation, in an office situation.

Factors Used To Define Breakthrough Disease or Sub-optimal Response:
Subjective Impressions

ANDREW GOODMAN, MD: Although we like to be as objective as possible with MRI and counting relapses and so on, I think as clinicians we also have to respect what our patients are feeling and what they're telling us they're feeling. So I'm persuaded, and I think other doctors are as well, when somebody is complaining of a great deal of fatigue or cognitive problems, even though I can't measure them easily, I do feel that those may be important indicators that the disease is not well controlled and is progressing, despite the fact that the things that we like to measure may not be changing appreciably.

KHURRAM BASHIR, MD, MPH: I think patient perceptions are important in determining whether the therapy is working or not, but, most of the time, it should be supported by objective evidence, on an objective examination and assessment by an experienced clinician.

Patients' perceptions in terms of fatigue, cognitive impairment, depression, side effects of medication are very important, because we do not factor them in in our objective assessments as much. In terms of their physical disability, I think an objective measure is more important because, in that setting, patient perceptions tend to change from day to day depending on their level of activity or fatigue, exposure to heat, underlying infection and becomes less objective at that point. And a treatment decision based on subjective perceptions alone is probably not going to be appropriate.

SYED RIZVI, MD: You’re doing an assessment to see if there’s any progression, and you’re taking the patient’s account, as well. But obviously, the bottom line is, obviously, you will go with the patient, as well, but you do need to have hard evidence of a worsening exam and worsening MRI. Because when you’re talking about treatment of MS, you know, there are not many choices. You can’t just make treatment changes all the time and get back to where you were.

KHURRAM BASHIR, MD, MPH: Physician's assessment, if done in an objective manner, measuring relapses and progression of disease, is important in determining disability because physicians can then relate this or compare it to what has been shown in clinical trials, what has been shown in natural history studies of MS, and that's where an objective assessment is very helpful, because those studies and those natural history progression of disease has been based on objective assessments.

SYED RIZVI, MD: When you’re talking about patients who have had disease for years and have been in treatment or, you know, are not doing as well, probably the most common complaint they will have is the ability to ambulate, which may go down over the years. They may have sudden worsening of ability to walk, they may be in the middle of a relapse as well.

Cognitive difficulties become prominent as time goes and as people start entering secondary progressive disease, or if their disease is worsening for whatever reason. Similarly, fatigue is a big issue, and bladder symptoms and increased frequency of many of the symptoms in the form of relapse or just chronic symptoms will all point towards the worsening of the disease.

KHURRAM BASHIR, MD, MPH: I think all neurological symptoms are important in MS and MS is such a variable disease from patient to patient that it is difficult to label just one symptom as the most important. Being the nature of disease is as unpredictable as we see, and it's as variable in individual patients as it is. I think it depends, the constellation of symptoms dictates in each individual patient as to which is most important.

From an objective standpoint, I think visual, motor and cerebellar symptoms are probably the most important.

SYED RIZVI, MD: You do want to make sure that they may not have a pseudo-progression or a pseudo-relapse which could occur from, for example, a urinary tract infection or any other infections. The worsening can occur as part of increasing spasticity, for example, which is not actually worsening of disease, but worsening of a symptom which may actually worsen everything and may appear as a generalized worsening.

KHURRAM BASHIR, MD, MPH: The first thing that a physician or a clinician should decide, when a patient complains of inability to do their day-to-day activities, is try to determine what the underlying reason is. It could be related to MS, it could be related to other things like depression or fatigue or other symptoms that may be related to MS, but are not a direct effect.

SYED RIZVI, MD: Depression is present in almost 50 percent of patients with MS at some point and something we look for all the time, because these depressed patients feel more tired, they may not function the same, and it can affect their cognition adversely. So it’s extremely important that you monitor for depression, look for depression, and if you feel that there is some underlying depression, have a lower threshold of treating them with antidepressants. It can make a whole lot of the difference in their whole overall management.

Another problem with depression is most people, most patients when they’re depressed tend to respond poorly to treatment. And, you know, these treatments are long-term treatments. They have side effects. If somebody’s depressed, it may be an issue. And interferons, for example, can sometimes cause a little bit of depression, although it’s not that common and can easily be treated.

All the treatment options, the neuromodulating agents, or the disease-modifying agents as we call them, tend to have some side

effects, and interferon especially sometimes can cause increase in spasticity and produce flulike symptoms which may produce fatigue and cause a little bit of an increase in complaints.

So therefore, most treatments we use for MS, apart from the disease-modifying agents, are symptomatic treatment, drugs used for symptomatic treatment or targeted symptomatic. All these drugs may at some point produce worsening if you don’t really monitor them carefully.

Factors Used To Define Breakthrough Disease or Sub-optimal Response:
MRI Indicators

KHURRAM BASHIR, MD, MPH: MRI is a very sensitive and effective tool in management of MS. MRI has shown disease activity that is not seen clinically and would be missed if this tool was not available. However, because of the clinical imaging paradox, where we have all seen patients who have a lot of disease activity but relatively few MRI lesions or a lot of MRI lesions but very little to show on examination. It is not the absolutely perfect surrogate marker for disease activity.

In our clinical practice, we use [MRI] for diagnostic purposes. We also use it for following disease activity for patients who are on treatment.

There is a lot of debate currently among MS experts as to how frequently the MRI should be performed, whether they should be performed routinely, annually, every two years or every three years, but a spot MRI is not very useful and should not be used to determine clinical effectiveness of the drug. Generally, what I would do is repeat an MRI after somebody has been started on treatment about a year after they have been on therapy. Following that, the frequency of MRI is variable depending on the clinical response of the patient.

And I think that debate is going to evolve over time, but, in my practice, I use MRI features in addition to the clinical determination of disease activity to decide whether the treatment is effective or if the patient is experiencing suboptimal response.

SYED RIZVI, MD: The more we do MRIs, the more we realize that maybe MRI is not a good test for monitoring. It’s very, very helpful, and it’s actually incorporated in the McDonald criteria for diagnosis, and it’s essential for diagnosis. But as far as monitoring, it’s a little difficult to evaluate the data which comes out of it. And so, you know, we start off doing MRIs every year or so, but more recently, you know, in my practice I’ve cut down the use of MRIs more frequently, and so I would probably recommend doing an MRI if I’m changing treatment so that I have a new baseline. I would also recommend if the patient is doing unexpectedly worse, in which case I just want to see, and increasing lesions would obviously hint me towards worsening or progressive or breakthrough disease.

ANDREW GOODMAN, MD: No new lesions is certainly a worthy goal for current MS therapies, but of course, MRI lesions are in the eye of the beholder. Basically, it means what technique or technology or protocol are you using to measure MRI. For example, you may not see an enhancing lesion with a standard dose of gadolinium that's not looked at with the appropriate delay after infusion. So, no new enhancing lesions doesn't necessarily mean the same thing in different settings. That's just one example of how we can be fooled. But in general, we would like to see no new lesions. We'd like to see no worsening of atrophy, and we'd like to see improvement of existing lesions if that were possible.

SYED RIZVI, MD: All these treatments are partial treatments, and so when you have partial treatments, you have to expect a certain degree of disease activity. So, if you have a couple of lesions on a follow-up MRI, most people would not really respond to it, because you know these drugs are going to work 30 to 50 percent, whatever, depending on what trials you’re looking at.

Similarly, having a relapse does not necessarily mean that you’re not responding to treatment, because, again, it doesn’t really reduce relapse by 100 percent. It does so by, in the range of 30 percent. So you can expect a certain degree of disease activity. And again, that’s why it’s important to compare it to a baseline.

Now, if you’re starting treatment on a new patient, then you need to monitor them going forward. If they continue to have relapses, then, you know, you might want to consider more aggressive treatment.

KHURRAM BASHIR, MD, MPH: Multiple sclerosis lesions in the brainstem, and I would also say in the spinal cord, are important because of the location. Lesions in the posterior fossa and in the spinal cord are more likely to result in disability, are more likely to result in more significant relapses and also, if there is accumulation of disability in these locations, there is a higher probability of patients accumulating physical disability. Lesions in the supratentorial region, although associated with physical disability and inflammatory damage to the brain are proportionately less significant.

ANDREW GOODMAN, MD: T2 lesions are, in the short-term and in the acute phase, a combination of edema, demyelination and perhaps glial scar. In the long-run, the accumulation of permanent T2 lesions, at least in the early phases of MS, seems to be a reasonable measure of damage accrued from the MS, as opposed to T1 enhancing lesions, which are a measure of blood-brain barrier integrity.

Now there is a type of T1 lesion that's a so-called black hole or a dark spot in the brain that basically evolves after an acute lesion in roughly one-half of the acute lesions. Those, we think, represent actually a more severe type of brain damage that may be irreversible.

KHURRAM BASHIR, MD, MPH: In my understanding of the literature and MRI, all of these measures, T2 burden of disease, T1 black hole volume, gadolinium enhancement, atrophy, MR spectroscopy are important, and they tell us different facets of the disease process. T2 burden of disease appears to be correlated with all clinical features of disease but more so with cognitive impairment. T1 black hole volumes seem to correlate more with physical disability as they are associated with axonal loss. And these measures are all important, but, if you are looking at physical disability, I'm usually more concerned about T1 black hole development that are chronic and development of atrophy.

Factors Used To Define Breakthrough Disease or Sub-optimal Response:
Weighing the Three Factors

KHURRAM BASHIR, MD, MPH: In assessment of patients with suboptimal response, using relapses, progression of disease and MRI changes over time and I think all three are important. I think, in terms of looking at long-term disability, anyone would agree that progression of disease is probably the most important predictor. But continued relapse activity, which is a marker, a surrogate marker for clinical disease activity, changes on MRI, which we know are predictive of future development of new lesions and disability, all of them have to be taken together, in my assessment, to determine if a patient is responding to the treatment or not.

SYED RIZVI, MD: You don’t really require deterioration in each one of the three. You may have a patient who has a normal-looking MRI or, when I say normal, unchanged MRI to a previous MRI, but they may be complaining that, you know, they can’t really walk that far. And on examination, you may find significant increasing weakness.

So the MRI is not a good test to look for neurodegeneration, in general. A normal or conventional MRI is really not a good test to look for atrophy and the neurodegenerative type of worsening. There are newer techniques which may be coming out, MTR spectroscopy, which actually may help us a lot, because they may correlate better with neurodegeneration.

So, if you have somebody who is complaining of worsening from a clinical point of view and if you have a normal-looking MRI, I think the MRI at that point would become irrelevant. You really have to treat the patient, not the MRI.

Treatment Approaches for the Breakthrough Patient: Interferons, Immunomodulators, Steroids

ANDREW GOODMAN, MD: When a neurologist is concerned that one of their MS patients is not responding or failing therapy with one of the FDA-approved treatments, there are a number of approaches. One is, let's say a person is on interferon. Let's say it's the once-a-week interferon, Avonex. There are some doctors who are persuaded that more frequent dosing may boost the efficacy of interferon and therefore, will switch to one of the more frequent subcutaneous interferon forms.

SYED RIZVI, MD: When you talk about switching therapies, if you are on one interferon, it’s usually not a big thing to switch from one interferon to another. But the effects of the interferon are pretty much the same. If you are, obviously, on a lower dose, then you can try to go up on the higher dose. But if you’re on higher dose interferon, then it doesn’t make sense to switch from one interferon to another.

ANDREW GOODMAN, MD: However, the tradeoff in doing that, in my estimation, is the issue of neutralizing antibodies, and those more frequent interferons are associated with a higher frequency of neutralizing antibodies, which of course may abrogate the effect of treatment all together.

Another approach is switching classes, so that if somebody is not responding to interferon, in whichever formulation, some doctors will switch to glatiramer or Copaxone. Vice versa, this is also true, so that somebody who is not responding adequately to Copaxone may be switched to one of the interferon forms.

KHURRAM BASHIR, MD, MPH: Switching from interferon to Copaxone or Copaxone to interferon makes sense on the basis that they have different mechanisms of action.

The use of high-dose pulse steroids in MS has been an attractive and effective therapy for a long time in treating acute relapses. Pulsed methylprednisolone therapy has been used in at least one clinical trial that was very well-designed in Europe and showed that it prevented relapses, new MRI lesions and disability after use of pulse steroids for five years in a very well designed placebo-controlled trial.

It is a practice that is becoming more frequently used in clinical practice in a variety of centers at this time. It has its set of limitations because of potential adverse effects of steroids, but it is an effective therapy in patients who show continued disease activity and recurrent relapses after each treatment with steroids.

Treatment Approaches for the Breakthrough Patient: Chemotherapeutic Agents and Immunosuppressants

ANDREW GOODMAN, MD: In a broad sense, medicines like azathioprine, and certainly methotrexate, are types of chemotherapy, in a, if you will, low dose oral form. There is a treatment approved specifically for worsening MS, and for secondary progressive MS. That is a chemotherapeutic agent used as an immunosuppressant. That treatment is mitoxantrone, also known as Novantrone.

KHURRAM BASHIR, MD, MPH: Mitoxantrone is an anthracenedione derivative, a chemotherapeutic agent that has very broad immunosuppressive effects. And it has been approved for use in patients with mostly relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis subtypes.

It is a very effective agent which is effective in patients who continue to show disease activity despite therapy with primary immunomodulator agents. It has its own set of limitations but, in terms of effectiveness on secondary progressive disease, this agent is the only one that has been approved by the FDA and clearly been shown to delay progression of disability.

ANDREW GOODMAN, MD: This is often a difficult decision to make because the baggage, so to speak, that the term chemotherapy carries with it is a scary one for most patients. There are known complications of this treatment which are, in fact, very concerning.

The first is cardiac failure. It's known that mitoxantrone is toxic to myocardium. This seems to be a dose-dependent effect, so that given enough time and enough mitoxantrone, essentially everybody will get a weakened myocardium and have congestive heart failure.

The FDA has recommended that no more than 140 mg/m2 lifetime dose should be used. They have also recommended recently that cardiac scanning needs to be done prior to the first dose and each dose to monitor for worsening ejection fraction, meaning worsening cardiac function because of the concern about congestive heart failure.

The other serious complication of this treatment is drug-induced leukemia. This is, fortunately, a rare event. In studies in France, it was less than 1 percent of patients. There is some indication that doctors using the non-FDA-approved approach to induction, meaning monthly treatments at first with mitoxantrone may be at increased risk for leukemia, compared to using the FDA-approved regimen, which is once every three months.

KHURRAM BASHIR, MD, MPH: Azathioprine is an immunosuppressant that was an effective therapy as monotherapy before we have our currently available immunomodulators. It is a therapy that is used as an add-on treatment in patients with suboptimal response at the present time. There are a number of anecdotal and small case series studies that have shown that, when added on to primary immunomodulators, in a small number of patients, it would be an effective combination therapy.

Methotrexate is an immunosuppressant that has been used and shown to decrease worsening of disability of MS patients as a monotherapy, but the effect of methotrexate is fairly limited by itself. As an add-on therapy, it has been shown in a number of anecdotal reports and case series that have been published to add to the effect of immunomodulators when used as a combination therapy.

Cyclophosphamide is an old drug that has been used very effectively in multiple sclerosis as monotherapy. It's role has become more limited since mitoxantrone became available, but it is an effective drug, especially in patients with rapidly progressive multiple sclerosis, in preventing disability and stabilizing disease activity.

ANDREW GOODMAN, MD: In some centers they have tried mycophenolate. I should point out that none of these oral immunosuppressants are specifically approved for the use of MS, so patients certainly need to be informed of their potential risk and the fact that these are not proven therapies for MS, either as standalone treatments or in combination with one of the FDA-approved therapies.

Treatment Approaches for the Breakthrough Patient: Combination Approaches

ANDREW GOODMAN, MD: As far as when somebody is dramatically worse or we've basically run out of options, one needs to consider more aggressive treatments for suppressing the immune system. One approach is to use a platform treatment that would be one of the interferon treatments, and add in or add on top of that an immunosuppressant. These are generally oral forms of immunosuppressant. Examples of treatments that have been tried have been azathioprine or Imuran and methotrexate.

SYED RIZVI, MD: A lot of times what I do is consider a combination treatment. I think a lot of physicians consider combination treatment as probably the best option available, because you may address the disease issue in various ways.

So combination treatment would include treatment with very aggressive drugs such as Novantrone or mitoxantrone, which is an FDA-approved drug, versus Cytoxan or cyclophosphamide or a semi-aggressive approach with the use of oral immunosuppressive agents such as methotrexate, CellCept and Imuran or possibly pulse steroids, monthly steroids, which we use sometimes as combination agents.

KHURRAM BASHIR, MD, MPH: Looking at combination therapy for multiple sclerosis is a very attractive option for patients with suboptimal response. This is based on the hypothesis that multiple sclerosis is a complicated immunological disease. And, if you look at other complex chronic diseases, combination therapies have been effective.

We have to be careful, though, because combining therapies is not always synergistic. There may be antagonistic and unexpected effects of these therapies as well. Taking caution, though, it is a good approach for patients with suboptimal response, especially if you think that the original immunomodulatory agent was at least partially effective and adding another agent on top would be more effective than the monotherapy used initially.

There are a number of approaches that are used in terms of combination therapy at this time. Our options include combining interferons with glatiramer acetate, combining interferons or glatiramer acetate to one of the chemotherapeutic agents like mitoxantrone or using one of the immunosuppressants like azathioprine or methotrexate or CellCept in addition to an immunomodulator.

Conclusion: Multiple Sclerosis: The Course of the Disease

KHURRAM BASHIR, MD, MPH: Multiple sclerosis is a variable disease and the hallmark of this disease is variability and unpredictability. In majority of the patients, it would start out as relapsing-remitting MS, where patients will have periods of neurologic dysfunction defined as relapses, followed by recovery and periods of inactive clinical disease which are called remissions.

Most of these patients who start out with relapsing-remitting disease will change to what is defined as secondary progressive multiple sclerosis, where, instead of experiencing inflammatory episodes and relapses, patients will gradually start to show progressively increasing disability in a gradual manner. Majority of patients without treatment will enter secondary progressive phase, usually within ten to fifteen years after the onset of their symptoms.

About 15 percent of patients will start out with progressive disease from the onset. Two-thirds of these patients would continue to have progressive disease without any superimposed relapses clinically, and these patients are termed as primary progressive MS patients. A third of the patients who start out with progressive disease without any preceding inflammatory relapses would develop relapses superimposed on the disease course and these patients are termed progressive-relapsing MS patients.

These categories of MS are based on clinical assessment of patients and may have different pathological underlying disease.

ANDREW GOODMAN, MD: MS clinical trials are difficult, time-consuming and expensive to do. It's disappointing, but not surprising given those concerns, that we don't have more clinical trial information, really clinical data, scientifically rigorous data, that helps inform us as to what to do in these situations.

But I should point out that we are still in the early stages—infancy some people have said—in treating MS. It's really only been 10 years or so that we've been having any success with treating MS in the sense of modifying the disease course. Nonetheless, I think clinical trials are the way forward to try and get to the answers that we all want, which is, "What do we do when things aren't working? How can we do better?"