Clyde E. Markowitz, MD

To round this out, Bob, what are your words of wisdom to community practitioners, whether they are neurologists or other health care providers who may be involved in the care of our patients with MS [multiple sclerosis]? What are things you would say to them?

I would say 3 things. The first is that MS is a treatable condition. We have good treatments, and we have spent a lot of time here today reviewing how to consider therapies, how to monitor therapies, and how to change therapies. Secondly, there are a lot of symptoms that can be left after the active inflammation has been stopped. Pat touched on that briefly here: there are many symptoms that can be improved. In fact, there are few symptoms that result from MS for which we are unable to do anything, so there is a lot of symptom management that we can do.

There are a lot of lifestyle changes as well. Pat was alluding to many of them, and I have had patients say to me, “Doctor, what diet should I follow with MS?” I will say, “There is some evidence about that. I am glad that you are asking about it, but what is more important is that you stop smoking because that is what is going to have a really negative impact on your MS.” Lifestyle changes can include smoking cessation, exercising, and healthy eating. The Mediterranean diet is the best diet as far as we can tell, but combining that with lifestyle management for a patient’s MS is also important.

Clyde, the same question: what do you relay to the community health care practitioners or a primary care doctor who may be cotreating or trying to help a common patient?

There are a couple pieces to this. First, for a community neurologist who may not be specializing in MS, it is important to let them know that the field has changed since they were in training because I still see people who are thinking about the disease-modifying therapies as the injectable therapies that you go to, and then you see how they do. That needs to shift in the field. Most of us who are practicing in big MS programs understand that issue. We have been doing studies for years now, so we understand where that is, but we have to get that out to most community neurologists so that they understand that we think of the disease differently now. There are more risks, there is more monitoring, and if they are not comfortable with that to start with, they need to refer the patient, and we will be able to take care of that and make the recommendations about how to monitor somebody on these therapies. That is important, and it is a shift in the way of thinking and the way we train people. All our residents these days are aware of that shift, and we have been able to impart that, but there are a lot of community neurologists out there who are still not in that game. We have to get that out there. Hopefully they will watch this program.

This is critical because that window of opportunity is there, and you do not want to miss that window. I am frustrated when patients come to us years later and are already using an assist device, or they are wheelchair bound. It is not that you cannot help that individual because you can work on their symptomatic care and their rehabilitation needs, but from a disease-modifying therapy perspective, the horse is already out of the barn in that situation, at least with our current therapeutics.

What about you, Pat? What are your words of wisdom to the community? What are your top 2 or 3, even if they are similar to what was said?

Looking at all the developments in MS, it is impossible for somebody to keep up with them unless they have a vested interest in MS and see a large number of patients. We are setting a high bar. I am now telling patients that our expectation is that they are going to be able to lead a normal life. We cannot allow them to be cheated, so there is a responsibility for those who are not experts to partner with an MS center or an individual who is more knowledgeable of MS. Use them to help guide the initial early stages of diagnosis and initiation of the original disease-modifying therapy. Those are probably 2 of the most important things that are going to happen that can set the individual on the right pathway. You must partner with those with MS expertise. You owe that to your patients for them to do as well as possible, so I would emphasize that very strongly.

I totally agree, and this is where the workforce of the future is so critical in training new people to get out there because we know that the majority of MS is outside of the big centers. That is where it is being treated, so we need to populate more regions of not just the United States but abroad as well.

This has been fantastic. I love doing webinars with colleagues, and I love poking fun at some of you guys. It is all in fun as you know, except for Clyde. Thank you.

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Advice to community physicians and neurologists who play a role in caring for patients with multiple sclerosis in community practices on optimizing therapy with high-efficacy and newer treatment options.


Managing Multiple Sclerosis in the Community Setting 

Pat, why don’t you tell us about the future for treating patients? Talk about the symptomatic care and the healthy lifestyle choices because we always talk about the disease-modifying therapies [DMTs] and what the MRI scan shows, how much reduction in relapses in this study. Until recently, there has not been a lot of focus on wellness, and there are definitely studies out there that are showing the impact of healthy lifestyle and wellness.

I will start by saying that we need to decrease our misdiagnosis rate as we try to make the diagnosis as early as possible. To me, that argues for a thorough work-up. Secondly, we need to get treatments for neurodegeneration, and we need CNS [central nervous system] repair. Those are gaps; those are lax. We need to develop them. Thirdly, you are speaking about things that boost CNS resiliency and the ability to repair, and this makes wellness important. It makes healthy lifestyle choices important, such as not smoking and maintaining an optimum body weight. Stimulation mentally, socially, and physically becomes important. It is interesting, we come back to this aging phenomenon. We know that, as the brain ages, it becomes less able to contract, and we are beginning to see people talk about the development of treatments that might rejuvenate the brain. That is an exciting possibility in MS [multiple sclerosis].

If you look at the person in totality, quality of life matters. Quality of life can have a negative impact, and the key to quality of life is optimum management of symptoms. We do not talk about it that much, but we recognize symptoms in MS. Some of them can clearly be injurious to the central nervous system, such as depression, which is a comorbid condition as well. Developing better symptomatic strategies is a key important component. I will also add that we have heard about developments in better following patients, parameters to follow. Looking at activity outside of the brief time in the outpatient department and tracking activities at home is going to be a promising frontier for us in the future.

 I agree. There are studies looking at actigraphy, which watches how much activity someone does. There might be something here. People are studying this, and that may help us care for people in a greater way such that, when the patient comes in and says, “I am exercising. I am getting my 10,000 steps,” I have the data that show they are or are not. They may be sitting on their couch like I will be this weekend.

We have to treat the person as a whole. As was mentioned previously, it is not just about the DMTs. The DMTs are not necessarily going to improve the quality of life that the person has today. We have to focus on treating the whole person, and that involves symptomatic interventions in care, exercise, and all the things that go into it.

Gaps in care that neurologists experience when treating patients with relapsing-remitting multiple sclerosis and considerations for recommending lifestyle modifications to help manage symptoms.

Relapsing-Remitting MS: Current Treatment Gaps 

Looking ahead in the world of MS [multiple sclerosis], as has been alluded to, there are different biomarkers being studied. Maybe we can add these new biomarkers into that category of NEDA [no evidence of disease activity], MIDA [minimal evidence of disease activity], or whatever acronym you want to use for no evidence of disease activity or minimal activity. Bob, tell us about some of the exciting biomarkers that may be used in clinics over the next 5 or so years.

Ideally, what we want is to be able to look at a patient, look at an MRI, look at a blood test to say,” Based on this, this is the therapy that will work best for you.” At this point, we do not have that. We have markers that predict what [medications] will have problematic safety issues. If the patient has a positive JC [John Cunningham] virus serology, we say stay away from natalizumab. If a patient has a heart arrhythmia, we stay away from the S1P [sphingosine-1-phosphate] modulators. We can use the safety aspects to guide us as to what therapies to stay away from, but we do not know how to be guided toward the more effective therapy for an individual patient. 

Once we have chosen a drug and the patient starts it, MRI is the key biomarker right now; it goes along with our clinical assessment of whether the patient is having relapses. What goes along with that is the MRI, and it is usually just the brain MRI because the spinal cord is such an eloquent pathway that, when patients develop lesions in the spinal cord, they can usually tell us about it because they have new symptoms. We get spinal cord imaging now and then for specific reasons, but as a surveillance tool, it is usually relegated to just the brain MRI to identify new lesions.

In terms of blood measures, there are a couple of measures that are looking potentially promising: serum neurofilament light chain [NfL] is probably our most well-developed marker at this point. There are some other markers like serum GFAP [glial fibrillary acidic protein], contactin, and other things that also look promising. Serum neurofilament light chain is the most developed, but at this point, we do not know if that is any better than the MRI. There are some studies that suggest that the serum neurofilament is not as sensitive as the brain MRI in identifying new areas of ongoing inflammation. Although serum neurofilament light chain is widely available, I do not think we yet know how to use it to monitor the disease; what are the cutoffs to say, “That is too much. We need to move on to another therapy.” There is a lot of work being done, and hopefully over the next several years, we will have a better way of being able to detect ongoing inflammation despite our current therapies.

I am glad you brought up some of the unknowns about NfL because some of the things I am worried about due to the lack of data are these questions: what is the impact of comorbidities and what is the impact of age on NfL? We do not have a lot of data, especially within the MS population. There is more to come.

The one message that I will usually say to trainees is that, if we have serum neurofilament light chain available, do not just take it at 1 time point. This is something that you are going to have to take at multiple points just like we do with the MRI, and just like we do in the clinic when we see people over time. It is an evolving story.

Clyde, what do you think? Are there any other cool things out there? I know at the NIH [National Institutes of Health], they are doing a lot of interesting imaging work. You mentioned central vein sign a couple of times. What do you think?

To add to the neurofilament light chain conversation, we might be able to use it as a cross-sectional idea where, if you are evaluating somebody from the beginning and get a neurofilament light chain level, then that may give you some information that is going to tell you this is a high-risk individual you are going to have to worry about going forward. We also know that, on many of the clinical trials, the investigators have been using this biomarker for the idea of response to therapy. If somebody has a good response, where you follow them longitudinally and their levels came down, you might feel more comfortable that this is a good responder. In reality, we will probably incorporate it into our world. I do not think it will be able to replace things, but it could be an additional piece of data that will help us with all the other metrics.

OCT [optical coherence tomography] is another thing that is interesting, where we have been looking at that for probably 15, 20 years by now. We think that the back of the eye, being purely neuronal, could be a marker of what is happening in the central nervous system, particularly within the brain. There are now some data to suggest that it correlates fairly well with MRI. It may even correlate to some degree with EDSS [Expanded Disability Status Scale] scores. We are now starting to see some data that suggest good correlation with progression of the disease. It could be worth considering following these people longitudinally with the OCT biomarker.

Looking at MRIs, the newer techniques being implemented, such as central vein sign, become interesting ideas for us to use to figure out whether the lesion is an MS lesion, because as our population ages, there are going to be lesions that show up from hypertension, aging, diabetes, and migraines. Not every white spot on an MRI scan is going to be because of a lack of therapy or an ineffective therapy for MS, because they still have all the other problems that might show up with white matter lesions. Being able to distinguish a white matter lesion that is MS vs a white matter lesion from hypertension can be helpful in terms of trying to figure out a decent response to whatever therapy you are going to consider.

There is a lot going on with high field magnets and being able to look at cortical lesions. The whole arena of these assessments is just starting to scratch the surface now where we may be able to say that we have abnormalities on imaging studies related to thalamic volumes or gray matter volumes: things that are going to give us good windows into the parts of MS that we do not adequately assess currently. How is somebody functioning in their day-to-day world in their job? Do they have complaints of fatigue or do they have the brain fog that they all complain about? We are not capturing that in most of our clinical trials, but some of the research studies are pointing us in the direction of how we can get at that and be able to follow that over time. Higher field strength magnets looking at spinal cord imaging is going to be better than what we currently have. The field going forward is starting to get into this biomarker arena that is evolving, and we will be able to care for our patients even better over the next 5 to 10 years.

Exciting strategies and biomarkers being investigated to improve the evaluation and treatment of patients with relapsing-remitting multiple sclerosis.

Exciting Developments in Relapsing-Remitting MS 

Pat, what about you? I have read a couple of your papers, and one sticks out in my mind where you nicely laid out what the definition is for a subtherapeutic response. I know a lot of this is from consensus, guidance, and guidelines, but what are some of the things that maybe the rest of us have not mentioned that you take into consideration?

The AAN [American Academy of Neurology] 2018 practice guidelines had a good statement about unacceptable breakthrough activity, and that was a year on treatment. They tried to exclude that most of the DMTs [disease-modifying therapies] are going to take about 2 and a half months to be operational. If the patient had 1 or more clinical attacks, or had developed disability on the examination, or had 2 or more lesions, then that should trigger a switch discussion. That is a good idea. They drew the line, saying that 1 new lesion is not sufficient, and of course we do not know when that occurs. A new lesion on the new baseline imaging would probably have me repeat a brain MRI scan 6 months from then, rather than to let it go the full year. Those are pretty good guiding principles to follow.

This is the advantage of having multiple options. We try to optimize the first disease-modifying therapy choice, of course, but we then follow the patient closely and make sure that we have good communication. If it turns out that was maybe not the best treatment for them, and we talked about breakthrough activity. We heard Clyde talk about other issues such as poor quality of life, unacceptable adverse effects, needle fatigue, pregnancy concerns, change in the risk/benefit ratio, which is particularly pertinent to PML [progressive multifocal leukoencephalopathy], and an unacceptable laboratory abnormality that is not going away. That would have to be unacceptable. These are reasons to switch, and we have multiple options. That is the good news. We probably want to do stuff early. It seems to be early after the disease has announced itself. For the next few years, that sets the course for late disability. That is an important window of opportunity to pay attention to in our therapeutic approach to MS [multiple sclerosis].

 I like that window of opportunity quote because I feel that, in relapsing onset MS, that window is probably within the first couple years, maybe 5 years. We could argue back and forth what that window is, but there is clear evidence way back in the CIS [clinically isolated syndrome] trials that those who started treatment early did much better long term. Even when those who were on placebo started the active treatment, they never caught up. There are studies that have shown that again and again even as of recent days, so it is important.

There was that interesting big MS database study in which treatment in the first 6 months was the only treatment that significantly lessened late disability, not treating later. That is probably too rigid, but it echoes findings in rheumatoid arthritis. Early on, there is something critical happening after that patient has approached that is probably key. We try to get them on treatment and treat them well.

 Bob, I do not know if you have any words of wisdom to round this out before we move on?

I agree. We do not have the clear cutoffs, although we have some guidance as Pat was alluding to. The longer the patient is on the drug, the less tolerant we are, but occasionally 1 lesion sneaks by. Do we throw out the current therapy that the patient is tolerating well and seemingly doing well on for just 1 lesion over 3, 4, or 5 years? Probably not, but as they start stacking up over time, we “say uncle” at some point and move on.

 For the person you mentioned, after a few years, you have 1 new T2 lesion, and maybe it is in a noneloquent area. In my practice [Johns Hopkins Multiple Sclerosis and Transverse Myelitis Center], I would say that, instead of repeating the MRI in a year, I would do it in 3 to 6 months. You become more vigilant to find more disease activity. For some of those patients, I will invite them back to the clinic in 6 months vs a year to make sure we stay on top of it.

I have also found it helpful with some patients to describe controlling MS like this: it is not like cancer where any growth to the tumor is bad, and we need to change things because any growth is bad. Rather, it is more like controlling blood pressure where we want that 120 over 80 mm Hg or better, and if they are 180 over 110 mm Hg, then that is bad, and that is not good control. What if they are 124 over 82 mm Hg? That is a bit off, but do we change everything for that? If patients approach controlling their MS more like blood pressure, where we want good blood pressure control, but if it is a bit over that goal, we might be OK and ride it for a while and see how that goes. If they are way over what our target is we, may say, “No, we have to move on right now.”

Although I will say, Bob, that those numbers seem to be getting lower, lower, and lower for blood pressure control.

It may get to the point that we may have to be dealing with that in the MS world as the 1 lesion conversation, let’s say.

Drs Patricia K. Coyle and Robert Fox comment on approaching multiple sclerosis relapses as early as possible with high-efficacy therapy.  

Clyde E. Markowitz, MD

Articles

Managing Multiple Sclerosis in the Community Setting

Relapsing-Remitting MS: Current Treatment Gaps

Exciting Developments in Relapsing-Remitting MS

Best Strategies for Controlling Relapsing-Remitting MS