How Thinking on Relapse and Progression in MS Is Changing: Fred Lublin, MD

Multiple sclerosis (MS) care has undergone transformation over the past decade—not just in the therapies available to patients but in how clinicians conceptualize the disease itself. The traditional boundaries between relapsing and progressive disease have blurred, high-efficacy treatments have moved earlier in the treatment algorithm, and forms of neurological decline that evade conventional clinical detection have come into view.

Fred D. Lublin, MD, the Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, a leading authority on MS disease classification and treatment, spoke with The American Journal of Managed Care^® (AJMC^®) about how thinking on relapse and progression has matured, the promise and limits of high-efficacy therapies, and what outcome measures the field must prioritize to truly capture the patient experience.

This interview was lightly edited for clarity.

AJMC: How has our understanding of relapse, progression, and treatment response evolved over the past decade?

Lublin: The essence of MS as a disease is one that presents as both relapses and, as progression. And even as we are now thinking about altering the terminology of how we describe the clinical courses—away from the more classical descriptions—those 2 concepts will always remain, because they're the essence of MS. It's what distinguishes MS from other neurodegenerative diseases: the relapse. We think that relapse and progression are driven by different immunopathogenesis, but there are also some relations there. Over the past 30-plus years, we've developed really good strategies for treating relapses, and we're very good at it—not perfect, but very good. Progression has been a more difficult target.

More recently, we've come to understand that relapse and progression can be coexistent, and progression could start very early in some patients and may be difficult to recognize, especially separating it out from the effects of relapse. There are only 2 ways you get worse in MS: one is from a relapse, where you don't fully recover, and that happens about 50% of the time, but it depends on how hard you look. And the other, of course, is this progression that's independent of the relapse activity, which is progressive disease. Again, they can be difficult to sort out. It doesn't really matter to the patient how it's happening. They just know if they're getting worse, we need to do something about it.

AJMC: How has the shift toward earlier use of high-efficacy therapies changed the long-term outlook for patients with relapsing MS?

Lublin: The high-efficacy therapies have been a major boon for us. They're highly effective at turning off relapses and shutting down MRI activity, and so there's been a shift in the community to start high-efficacy therapy earlier in the course of disease. But the data to support starting everybody out with high-efficacy therapy, for example, rather than doing escalation therapy or sorting out some people who don't need high-efficacy therapy, are not there yet. There are a lot of anecdotes. There are a couple of studies underway to try to answer that question, and hopefully they will. It's a difficult one to answer, but high-efficacy therapies have been a major breakthrough.

There's another side to that, and that is, for example, with the anti-CD20 therapies that are highly effective, but there are growing concerns over their long-term use because of risks of hypogammaglobulinemia and infections and things like that. Even though serious infections are not common, they can be very serious. One of the things that we have to think about for the future is, should we have transition strategies so that people may need to have one level of control of their disease at the onset, but maybe several years down the road, they don't need that level of control and the disease could be controlled with less aggressive therapies and maybe less toxic therapies? There's even a study underway now to see whether one can actually stop the anti-CD20s and get a prolonged effect while being off therapy, but still having your immune system modulated such that it's not active.

AJMC: Relapse has traditionally been a central marker of disease activity. How should clinicians think about relapse today in the context of “silent” progression and MRI-based disease activity?

Lublin: We tend to equate MRI activity and relapses. They're both activity, and it's just a matter of whether it hits the clinical threshold or not, but we think it's a sign that disease is active. We treat that, and it ought to be treated with medications that would suppress the relapse. I don't like the term “silent progression”—it's unrecognized progression. It wasn't silent to the patient, but it's unrecognized. That's a matter of our developing more sensitivity to picking up subtle changes outside of the usual markers we use. Clinically, we can miss things. The MRI, in fact, is much more sensitive than we are—and even patients are—clinically. You pick up 10 to 20 lesions on the MRI for every 1 that shows up clinically, so that's highly sensitive. We tend to try to suppress the MRI activity because we think we're suppressing relapses that way. The underlying progression is still something we need to work on.

AJMC: What are the risks of under-treating early disease activity, even in patients who appear clinically stable?

Lublin: If you under-treat, then you run the risk of residual impairment. Every relapse, as I mentioned earlier, has a risk of not recovering completely and leaving what's called relapse-associated worsening, and that can build up over time and cause impairment. And of course, relapse itself has its own things. We have patients who are impaired; there's time away from work, time away from family, and such. But just as important is the fact that they may or may not fully recover, and we're not very good at predicting that, and only some of the medications have an effect on reducing the amount of impairment that may occur with any given relapse. So, we can't ignore relapses.

AJMC: How do you see real-world evidence complementing clinical trial data in shaping MS treatment strategies, particularly for high-efficacy therapies?

Lublin: The best evidence comes from well-controlled studies. Real-world studies can add value by looking at populations that weren't studied in the clinical trial. In the clinical trial, you try to get as homogeneous a population as you can so that the difference between your, let’s say, 2 arms is due to the therapy you're employing, rather than some other bias. In the real world, you don't have that kind of control, and there are all sorts of confounds and things you can't account for. One has to be careful about real-world data, because it is very liable to biases and confounds—but it does expand on what you have. If you already have an approved agent, but you haven't tested it, for example, in an older population or in a population with comorbidities, that's where real-world data can add to that. And of course, the real-world data are very useful for picking up safety signals.

AJMC: What end points beyond relapse rates—such as brain atrophy, cognition, or disability progression—do you believe should carry weight in treatment decisions?

Lublin: We need to look broader at outcome metrics—certainly beyond those. This is one of the issues of picking up the progression that we may not always be aware of. That's looking at cognition—I think that's a very important one—and looking at finer measures of motor function, sensory function, and even visual function. If you do, you find that, in fact, there can be progressive changes. The broader and harder you look, the better we'll do. And this gets us into things like getting more long-term data, like using digital instruments to measure how long people are walking in a week or a month, what their mobility is, their speed, or their dexterity. These are all things that we should be working on for the future.