Let's Hit the Brakes on the Escalation-vs-Induction Debate in MS

Stephen Krieger, MD


April 26, 2019

This transcript has been edited for clarity.

Hi. I'm Dr Stephen Krieger from Mount Sinai in New York, here for Medscape with an opinion commentary on multiple sclerosis (MS) treatment strategy.

There has been a long-standing debate in the field of MS over induction versus escalation. We even debate what those terms mean when it comes to MS treatment. But in principle, the debate rages around whether we should be using high-efficacy medicines early or in a stepwise approach when disease breakthrough declares itself.

In recent years, a lot of emphasis has been placed on the concept of "no evidence of disease activity" (NEDA) and whether we can reach that goal for all of our patients. Even more recently, the debate has shifted further to ask whether NEDA is even enough. That is, when a patient is stable on a treatment with no new relapses, T2 lesions, or signs of new progression on neurologic exam, should we be treating even more aggressively to try to shut down disease activity that we can't measure and can't even see?

Now, to be sure, things like brain volume loss and gray matter lesions matter, but we can't measure them well with our conventional imaging. It's awfully hard to treat a patient preventively when we can't even see what we're trying to prevent. How can we treat to target when we are effectively shooting in the dark?

High Efficacy at What Cost?

In a sense, I think we've gotten ahead of ourselves. We should take a step back with the array of medicines that we have and think about how we can best use them for individual patients. I realize that this is an era where bigger, newer, and stronger is better. In a sense, I'm making a potentially unpopular argument here, and I don't want to risk sounding too conservative. I'm certainly not arguing that our highly efficacious agents for MS aren't indeed highly effective; they are. All of the head-to-head trials that we've conducted that have been positive show that some of these newer medicines are more efficacious than the older agents to which they've been compared. That's inarguable.

Rather, I'm pointing out that there's a real risk-benefit calculation and decision to be made here for each patient. For every number needed to treat, there's also a number needed to harm. It's not enough to prove the high efficacy of a medicine or even of a treatment strategy. We have to consider high efficacy at what cost. I don't mean financial cost, although that's also a consideration, but at what cost in terms of the risks and outcomes to an individual patient with MS and to the MS population at large.

We think of MS as a lifelong chronic disease, and one that we don't always adequately predict in the individual patient. The safety of these strategies hasn't been fully or properly factored into how we consider the usefulness of early aggressive treatment, even when it comes to hematopoietic stem cell transplant or bone marrow transplant. These are immune ablative strategies and, of course, they prevent lesions and relapses. It's not clear that they prevent progression itself. But what matters is entirely the safety profile, that balance of efficacy to safety.

Wrestling With Two Divergent Approaches

More broadly, I think that we risk being disingenuous in our field by saying two things simultaneously. On the one hand, many people are saying that high-efficacy agents must be used first-line, upfront in all patients with MS. At the same time, we're saying that we need biomarkers and better predictive tests so that we can have personalized or precision medicine approaches to MS. That was the theme of the recent Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2019 forum: "Precision Medicine Approaches for MS: Scientific Principles to Clinical Application."

And I think that's truly the point, whether you focus on emerging imaging biomarkers like thalamic atrophy, lab tests like neurofilament light, or the importance of lesion localization, as in my topographical model of MS.[1] All of these things are ways of trying to predict and personalize the disease course for an individual patient.

We recognize in our field that MS is a heterogeneous disease, that no two patients are alike. And yet those advocating for early high-potency treatment strategies for everyone are effectively trying to treat MS with a one-size-fits-all approach. I think MS treatment will never be that way.

We need to wait for the data from the ongoing trials comparing early high-efficacy treatment strategies with the more traditional stepwise approach, such as the DELIVER-MS and TREAT-MS trials. I think the results of those studies will be very important in helping us to understand where to use early high-efficacy therapy and where we can safely and effectively use a stepwise incremental treatment strategy.

I'm also not arguing that these highly efficacious agents are uniformly dangerous—not at all. But I think it can be dangerous assuming that we know more than we already do about how to treat our patients. We can't seek precision medicine and biomarkers while arguing for a one-size-fits-all uniform treatment strategy first. We need to go where the data take us. Even then, we need to apply these data in practice, to customize them to our patients' needs, preferences, comorbidities, and individual risk tolerance. MS care providers will still need to be clinicians. Call me old-fashioned.

With this opinion commentary for Medscape, I'm Stephen Krieger.

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