Future Direction of MS Treatment


Key opinion leaders in neurology, Lawrence Steinman, MD and Enrique Alvarez, MD, PhD, reflect on future developments in the management of multiple sclerosis and share key advice for community physicians.

Enrique Alvarez, MD, PhD: As we look at all these treatment options, how do we start to identify patients who are not doing well on that treatment at an earlier stage before they’re in a progressive disease state? What helps us predict that they will continue to do well? It’s interesting, because we’ve gotten really fancy with some of our biomarkers recently. We’re starting to talk about the use of neurofilament light [NfL]. Earlier, I had some work in my fellowship looking at intrathecal synthesis of CXCL13 as a biomarker for inflammation that gives us some information about developing inflammatory disease activity and predicting whether you’re going to respond to treatment. The simple stuff that we sometimes don’t think about as much is important. Age is a huge 1. The number of attacks is really high earlier on in disease course, as well. Using age and time with MS [multiple sclerosis] is often overlooked as a biomarker. Having a clinical sense of that, along with the effect of race, becomes important. With MRI, patients who have a lot of disease activity or a higher number of contrast-enhancing lesions will go on to have more disease activity. Putting all these things together is important.

For new biomarkers, we’re still trying to figure out how to use neurofilament light in clinic. It’s not fully available, but there are starting to be places where you can send for it. There’s an effect to NfL levels at baseline based on age. There’s an effect on it based on weight. Bigger people have lower levels of neurofilament light, probably because we dilute out neurofilament light compared with skinnier people. How to use these levels becomes important. One of the easiest ways, and where we’ll probably start to see it, is looking for changes if you’re doing repeat monitoring of patients. We still need to better understand how neurofilament light levels change over time. How high do they go when you have an attack? Do they go up equally as high if you have a spinal cord attack vs a brain attack? We still need to learn how to use these a little better.

With MRI for relapsing disease, the number of lesions is important. That’s not really helpful with progressive disease. It’s helpful to evaluate for progression vs worsening, because if somebody is getting worse, you want to make sure they don’t have those new lesions that would go with relapsing MS. It starts to get into these difficult questions to answer. A common 1 for patients is, “Why am I getting worse if my MRI is stable?” Understanding what to look for in patients’ MRIs is important. Atrophy becomes important. There’s been a lot of effort to try to measure atrophy in clinic, but it’s important to recognize that there’s another progressive disease that happens in all of us. We all get older and all our brains shrink after the age of 30 or 35. That amount is really small: maybe 0.25% per year. Our brains shrink and grow easily that much within a day if you’re hydrated vs dehydrated. We had a study a few years back. Our research MRI scanner was switched and everybody’s brain grew 2.5% on average. It would have taken us 10 years to see that change of 0.25% and overcompensate for the differences in MRI scanners. You need to have a similar MRI that has to be looked at in the same protocols.

In brain atrophy, it becomes an important marker, but I’m not sure it’s ready for clinical use yet. We’ll have to look at other things. Here, age becomes important. You’re much more likely develop progressive disease the older you get. The higher the level of disability, the much higher the chance of becoming progressive or having progressive disease. There are some early trials suggesting that by the time somebody needed to have a cane, they were undoubtedly in a progressive phase and would continue to progress at a very specific rate. I’m not sure that we’re seeing that. I have a lot of patients who are on canes and not progressive, but a lot of my patients who I have using a cane are in that progressive phase. It’s important to look out for that and ask patients about that. Understanding if you’re looking for relapsing or progressive disease and then what markers can go with that is important.

Right now, we’re in a great place as far as managing MS. We can look at a patient and tell them, “We’ve got you covered from a relapsing perspective.” If we can catch these patients early and start them on good therapies, it’s especially great to be able to tell them, “We can stop your disease.” They’re not quite cures, but close to it. That’s a great place to be. We’re starting to see treatments that can slow progression. The data from the ORATORIO studies with ocrelizumab really give us some comfort in being able to look at these patients and say, “We can slow down this rate of progression.” That’s important. We still need a little help in repair. Hopefully we’ll see some therapies getting approved in the next 5 to 10 years. There’s definitely a lot of research happening in this area.

If I have any advice after today’s discussion, 1 would be recognizing in the disease course the differences between progression and worsening. It’s important to understand the rates of progression. Start thinking about PML [progressive multifocal leukoencephalopathy] when there’s progression that happens a little faster than what you might expect in that progressive phase, which is really slow. Start to think about worsening. There might be some relapses. Getting MRIs to rule these things out becomes important.

It’s important to understand that there are a lot of different drugs and drug classes available for MS. We may not need to have all the information for every drug. With as many drugs as we have, I definitely have not kept up with some of the drugs I don’t use as often. We have a lot of different options for patients. Don’t feel stuck, because there are even drugs that aren’t approved that we often can use in MS. You want to feel comfortable treating patients with MS. If you don’t feel comfortable or you’re starting to have questions, you can refer to specialists. You can often comanage with the specialist. That’s something we do here in Colorado with a wide geographic area. This is a model that we often use and feel quite comfortable doing. It’s a great time to be treating patients with MS with all the treatment options we have.

Lawrence Steinman, MD: Stay well educated. Make sure the patient comes away feeling that they’ve received the best advice.

Success has been enormous. Someday, we’re going to have more effective treatments in the progressive aspects of multiple sclerosis. Then there are other aspects of the pathophysiology that need to be addressed. When people have considerable damage, can we regenerate or heal those damaged areas of the brain? Those are the frontiers.

Transcript Edited for Clarity

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