Panel Calls for New Way to Classify MS Based on Underlying Biology

An international panel is calling for new methods to classify multiple sclerosis (MS) that reflect the disease’s underlying biology, rather than differences in clinical presentation.

The approach would fundamentally change how patients, clinicians, and other stakeholders understand and describe the disease, but would enable the development of biologically based treatment approaches that are better tailored to an individual’s disease course.

The International Advisory Committee on Clinical Trials in MS published its recommendations in The Lancet Neurology, in a personal view study, “Multiple sclerosis progression: time for a new mechanism-driven framework.”

“Describing MS based on underlying biology, rather than how it appears clinically, will require a better understanding of the mechanisms that drive disease worsening,” Tanja Kuhlmann, MD, lead author of the study, and associate professor at Münster University Hospital in Germany, said in a press release from the European Committee for Treatment and Research in Multiple Sclerosis.

“This paper reviews ongoing research to uncover and detect the underlying biological mechanisms active in individuals with MS and identifies knowledge gaps,” Kuhlmann added.

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MS has typically been classified into three main types

Multiple sclerosis has traditionally been classified into three main types, based on how the disease presents. Most people are initially diagnosed with relapsing-remitting MS (RRMS), which is marked by bouts of sudden symptom worsening — relapses — that are interspersed by periods of remission where symptoms ease or disappear entirely.

Many RRMS patients will eventually develop secondary progressive MS, which is defined by symptoms gradually worsening independent of relapse activity. A minority of MS patients will initially develop primary progressive MS, which is marked by gradual symptom worsening from disease onset.

However, these different categories are not absolute: some patients classified as having RRMS may experience worsening symptoms without relapse, and many people with progressive types of MS also experience some relapse activity.

Nonetheless, the type of MS a person is diagnosed with can have very concrete consequences. For example, while more than a dozen medications are currently approved to treat relapsing types of MS, far fewer options are available for non-relapsing progressive forms of the disease.

Describing MS based on underlying biology, rather than how it appears clinically, will require a better understanding of the mechanisms that drive disease worsening

Clinical course of MS is better considered as a continuum, committee says

In this paper, the committee suggests moving away from this system that recognizes discrete subtypes of the disease, and instead moving toward a system that reflects that “the clinical course of multiple sclerosis is better considered as a continuum, with contributions from concurrent [disease-causing] processes that vary across individuals and over time.”

In other words, the goal is to describe MS based on the biological processes that underlie the disease, rather than the clinical outcomes.

“We envision a future in which clinical benefit accrues directly from biomarker-based, biologically informed treatment decisions,” the committee wrote.

MS is caused by inflammation in the central nervous system (the brain and spinal cord), which damages nerve fibers and interferes with their ability to send electrical signals, ultimately leading to disease symptoms.

Some of this damage arises as a direct consequence of inflammation, while other damage accumulates due to gradual nerve cell dysfunction (neurodegeneration) and metabolic abnormalities that prevent cells from getting enough energy.

As these disease-driving processes occur, repair systems are activated to help fix the damage, all while the brain is constantly rewiring itself in response to new information and changing over time as a natural consequence of aging.

The panel proposes understanding MS as a disease that is influenced and driven by ongoing processes: periods of acute inflammation may give rise to a relapse, while gradual neurodegeneration can cause disease progression without relapse activity, which may be influenced by differences in repair activity and changes in the aging brain.

“Multiple sclerosis researchers must develop methods to identify and quantify these mechanisms on the patient level, and incorporate the relevant measures into both clinical trials and clinical practice,” the committee wrote.

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The team noted that developing a new system will require substantial work and refinement as the biological understanding of MS continues to evolve. It will also be important to find ways to smoothly transition away from the current system, particularly in areas like medication approvals that are currently type-specific.

“Focused efforts will then be needed to integrate the new framework into clinical trials and practice, and to transition away from the legacy framework used by regulatory agencies and health authorities for drug approvals,” the team wrote.

Ultimately, moving toward a new system promises to help improve care for people with MS, the researchers said.

“This proposal is among many initiatives that the Committee has supported over the years as part of its overarching aim to constantly improve, update and enhance clinical trial design and inform clinical care delivery for people living with MS and their healthcare teams,” said Ruth Ann Marrie, MD, PhD, chair of the committee.