An important article published this month in Nature Reviews Neurology outlines the transition roadmap to new MS course descriptors. In this Spotlight, we go behind the scenes to explore the steps that led to this paper and the challenges that still await.
It is time to revisit the clinical descriptors for multiple sclerosis (MS). Patient care and research have historically relied on clear-cut categories: relapsing-remitting, secondary progressive, and primary progressive [1.] Yet, these labels may fall short of characterising the underlying biology of MS [1.] Do these distinctions still adequately reflect our current understanding?
“Well, no,” Professor Alan Thompson of the University College London (UCL) tells us. “We know that MS is a single, continuous condition, and both relapsing and progressive processes are probably going on simultaneously. Somehow, we need to try to capture this.”
The Meeting in Dublin of the IACCTMS
Last year, about fifty experts were gathered in Dublin for a meeting of the International Advisory Committee on Clinical Trials in MS – co-sponsored by the National MS Society and ECTRIMS – to discuss a new way to describe the clinical course of MS.
“The level of engagement was incredible,” Professor Thompson recalls. “The dynamic was quite unusual. People were so fired up by the discussion that they could not wait to break into smaller groups and debate their ideas. It was a fascinating, albeit challenging, meeting to manage. Trying to synthesise such a rich range of perspectives was no easy task, but that energy truly underscored how crucial this area of research has become.”
The experts travelled from across the globe to tackle an important challenge. For 30 years, current descriptors have been fundamental to MS clinical care and research. Embedded in health systems around the world, they have long served as a guide for communication between clinicians and individuals living with MS [2.] Furthermore, these terms are pivotal in clinical trials: they help recruit patients, ensure results are applied to the appropriate populations, and are integral to the regulatory procedures for treatment approvals [2.]
“We had fruitful and productive discussions,” Professor Jiwon Oh of the University of Toronto notes. “For decades, current course descriptors have been helpful and necessary; they described what we observed clinically. However, nowadays, due to advances in therapeutics, imaging, and fluid biomarkers, it is becoming clear that the existing descriptors are no longer sufficient. One very clear conclusion that was drawn from the meeting is the need for a new framework. The challenge lies in determining exactly what that framework should be. That is where we’re at. There is a crucial, shared recognition: change is necessary. Naturally, changes never happen overnight. But the meeting was very important for experts from around the world to get together and say: ‘Yes, this is where we are; we recognize that we need a new framework. We don’t know exactly what that’s going to look like, but let’s discuss our ideas.’”
Ensuring a Smooth Transition
In the article published this month in Nature Reviews Neurology, the experts convened by the International Advisory Committee on Clinical Trials in MS highlight the key hurdles: elaborating a new framework and facilitating a smooth transition toward its future implementation [3.] Moving towards a biologically informed, unified, and patient-centred model will require thorough preparation and validation [3.]
“We are not there yet,” Professor Fred Lublin from the Icahn School of Medicine at Mount Sinai, New York, explains. “There are certain aspects we still need to consider. The existing descriptors, established in 1996 and then modified in 2013, were clinically based; they described exactly what a clinician would see when sitting in a consultation suite with a patient. The clinician would describe the clinical course with one of those labels. In 2013, we tried to make them a little more dynamic by adding subtyping for activity and progression over time [4.] The descriptors were framed within a temporal context. And that’s where we are now. The next step is to make these descriptors more biologically relevant.
But what do we need to do? We need to consider the unique feature of MS: a disease characterised by relapses and by progression, which are interlinked to a degree. However, not every patient has relapses, and certainly not every patient progresses. So, what we’re trying to do is see if we can get better at describing dynamically the clinical reality of each patient, using multimetric analyses (which include multiple clinical and biological measures) and expanding the tools at our disposal. The aim is to better characterise how the individual looks at any given time. And, in the meantime, we must continue the underlying research to deepen our biological understanding.”
What are the current gaps in our understanding? Prof. Lublin tells us, “To date, we have a pretty good understanding of the biology of relapsing disease, which involves the adaptive immune system and the infiltration of cells into the central nervous system (CNS). We’re also gaining a clearer picture of progressive disease in terms of the compartmentalised inflammation within the CNS. But we don’t have as good a handle on the neurodegenerative aspect of the disease and the role the immune system plays in driving that neurodegeneration.”
Limitations of Current Descriptors
Continuing the conversation, we ask Prof. Lublin: Could you give an example of where current descriptors fail? “Take, for instance, the definition of secondary progressive MS. Once you characterise someone as having progressive MS, you can’t take it back. And that’s a bit of a problem, because not all progressive disease progresses. In some cases, progression stops. So, we are instead starting to think in terms of phases or states. Someone may be in a relapsing phase or a progressive phase or a stable phase.
Furthermore, the concept of PIRA (progression independent of relapse activity) has taught us that we should look for the onset of progression much earlier. This leads to the idea of using multimetric analyses, which help better characterise what’s going on so we can identify who is at risk of progression. Hopefully, we will also develop better treatments for progression. So, we aim at looking at things more dynamically, recognising phases or states someone is in at a given time. However, this can be a little complicated, because it is often easier to determine when a phase begins than when it ends. This also raises the question: how do we adjust the therapy for each individual’s state or phase? Questions like these remain, and they need to be discussed.”
A Broader View of the Individual Experience
“There is a point that patients often make,” Prof. Thompson says. “Current course descriptors do not capture what they feel. They know when numbness is getting worse, they know when balance is deteriorating. Yet, we still define their disease course in the same way. We say they are not active. Well, of course they are active. We need a multimodal description: what is happening biologically, what they are feeling, how that is changing. This would be far more relevant to people living with MS. We need a more comprehensive view of the person sitting in front of us. And then, as we learn more about the condition, the mechanisms will become increasingly central, while the clinical descriptors will play a lesser role. We must go through these steps – it is a transition roadmap.”
Written by Stefania de Vito
Special thanks to Prof. Fred Lublin (Icahn School of Medicine at Mount Sinai, New York), to Prof. Jiwon Oh (University of Toronto, Canada), and to Prof. Alan Thompson (University College London – UCL) for their insights.
References
[1] Kuhlmann T et al. The Lancet Neurology 2023; 22(1): 78-88.
[2] Lublin FD et al. Neurology 2020; 94(24): 1088-1092.
[3] Thompson AJ et al. Nature Reviews Neurology 2026; 1-9.
[4] Lublin FD et al. Neurology 2014; 83(3): 278-286.