Using New Tools to Assess Relapses, Progression in MS

Ludwig Kappos, MD, professor and chair of neurology, University Hospital, Basel, Switzerland, called relapses “essential to the very definition” of multiple sclerosis (MS), but also suggested that the current concept of the term may need to be abandoned.

The conundrum over what constitutes a relapse in MS—how to define it, how to measure it, and how new tools of measurement can predict future disability—was the theme of a joint session on the final day of ECTRIMS 2019, the 35th Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis, taking place in Stockholm, Sweden.

These new concepts are “the overarching topic of this congress,” said Giancarlo Comi, MD, of the Institute of Experimental Neurology, Scientific Institute San Raffaele, in Milan, Italy, as he opened the session held in partnership with the European Academy of Neurology.

When progression begins is “the most difficult question to answer,” Comi said, as rethinking the starting point of when MS starts—the preclinical phase—is constrained by current definitions of phenotypes and prescribing guidelines. Progression also been difficult to assess due to inadequate measuring tools.

All this is changing, Comi said, because of modern magnetic resonance imaging (MRI) techniques, which are exploring how changes in the brain relate to physical symptoms and disability, and because of expanded knowledge of how biomarkers, such as the neurofilament light (NfL) chain, can serve as predictors of future disease activity and disability.

“Progression is defined by what we measure,” Comi said, and that is important, because this can guide how aggressively patients are treated. He noted that the various steps in the Expanded Disability Status Scale (EDSS) “are quite bit in terms of functional changes—there are a lot of components that are not so clearly included,” and elements like “fatigue,” or “cognition,” can be difficult to measure.

Then, Comi said, there is the challenge of asynchronous progression, in which different aspects of the disease do not progress at the same rate. Progression may be seen in the distal parts of the body before the upper limbs, but a therapy may be effective in the upper limbs and still be necessary and effective.

Why not use a composite measure, taking all elements in to account? This creates a different set of problems, Comi said.

What is essential to acknowledge is the evidence that shows the effect that relapses have on disability 10 to 20 years in the future, and this impact can be seen at the MRI level. For patients with relapsing MS, “The amount of lesions in the first period of follow-up [is] having a major role in determining the risk of evolution to progressive MS,” he said.

New research also shows that it’s not just the relapses themselves that lead to physical decline; there is “accumulation of disability that is independent of relapses.” For this reason, patients need a frequent MRI to track this activity, he said.

Comi also discussed the question whether there was a point of no return in MS, where it is impossible to reverse disability. Having a bone marrow transplant appears to be a predictor of stopping progression, especially if it is done relatively early.

However, he said, “We need to complement these observation with many types of approaches. We many other ways to examine progression.”

Kappos then discussed the emerging role of biomarkers, including NfL chain, which received lots of attention during ECTRIMS 2019. He mentioned the BENEFIT 15 study presented the day prior, which found that age, being female, and the annualized relapse rate (ARR) up to year 5 are the most important predictors for relapse activity over 15 years. Lower EDSS in the first 6 months of treatment, baseline brain volume, and changes in brain volume in years 1-2 and year 5, meanwhile, were better predictors of disability.¹

What researchers are learning, Kappos said, is that in the later phases of MS, brain lesions tell us less about what will happen in the future, as “there is a loss of correlation to pace of disability.”

With less connection to the clinical assessment of relapse, “even if we continue with the classical MRI, that is still not deep enough to understand the pathological process,” he said.

Kappos discussed axonal data and NfL, and how the use of the SIMOA assay has made it possible to glean more information from NfL chain data. More evidence is showing a clear correlation with the number of lesions and raises questions about the connection of NfL as a marker of inflammation.

He cited a paper by a Swedish group that took serum NfL from US military personnel that later predicted future neurological disorders, “5 or 6 years before the first event.” Later, a member of the audience asked if this was enough to justify treatment, and Kappos said he did not yet have enough evidence, but the issue clearly merits more study, as NfL is showing up as marker in other disorders, such as Alzheimer disease.

But it all points to this fact: “We need to complement or even replace our current clinical classification [with] a more granular description” of key pathogenic processes, he said, “using sensitive clinical imaging and body fluid markers.”

Mara Rocca, MD, of the Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale San Raffaele, Milan, Italy, concluded the session with a discussion of modern MRI techniques, which she said can shed light on the related phenomena of neuroinflammation and neurodegeneration.

It starts with the fact that the majority of MS lesions form around a central vein; when lesions form in other patterns, that indicates other conditions. Rocca also discussed:

• Chronic active lesions are seen in patients with longer active disease duration.
• Researchers are paying more attention to active involvement of gray matter.
• The amount of lesions a patient has on the first scan may be an important indicator of future clinical disability.
• “Black holes” on the scan correspond to tissue loss, which Rocca called the most destructive aspect of the disease.
• As important as black holes and brain atrophy are, they provide “only a partial assessment of the pathological processes.”

Reference

1. Kappos L, Freedman MS, Edan G, et al. Baseline and on-study variables that predict 15-year disease activity in patients with CIS treated with interferon beta-1B in the BENEFIT trial. Presented at: 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 11-13, 2019; Stockholm, Sweden. Abstract P1016.