Broad rim lesions in multiple sclerosis: A novel biomarker of rapid disease progression?

Dr Joost Smolders discusses the biology of broad rim lesions, their association with faster disability accumulation and how they could help inform future prognostication and treatment strategies in multiple sclerosis.

Emerging biomarkers capable of identifying patients at risk of rapid disability progression could help transform the management of multiple sclerosis (MS), particularly as progression-targeted therapies continue to emerge.

At the European Academy of Neurology (EAN) Congress 2026, Dr Joost Smolders, MD, PhD, Associate Professor and Consultant Neurologist at Erasmus MC Rotterdam, discusses new research into broad rim lesions, a novel pathologic biomarker associated with more rapid disease progression, and explores their potential role in improving prognostication, patient monitoring and future treatment decision-making.

Dr Joost Smolders, MD, PhD, is Associate Professor and Consultant Neurologist at Erasmus MC Rotterdam, where he heads the ErasMS MS Center. His work spans the Departments of Neurology and Immunology at Erasmus MC, alongside the Neuroimmunology Research Group at the Netherlands Institute for Neuroscience in Amsterdam. His research focuses on the clinical, radiologic and immunologic mechanisms underlying MS, with a particular interest in disease progression within the central nervous system.

Could you briefly explain what broad rim lesions are and why they are attracting attention as a potential biomarker of rapid disease progression in MS?

We think broad rim lesions are a subtype of mixed active-inactive white matter lesions, or chronic active white matter lesions, as people often refer to them. Histologically, chronic active white matter lesions are characterized by a hypocellular demyelinated core surrounded by a hypocellular rim of activated myeloid cells.

When we compared this lesion type between Netherlands Brain Bank donors with either a very rapidly or a very slowly progressive disease course, Prof. Tanja Kuhlmann (Medizinische Fakultät Münster, Münster, Germany) noticed a phenotypic difference between these chronic active white matter lesions. She observed that more than half of the donors with a severe disease course had these broad hypocellular rims surrounding the lesions, often exceeding 1 mm in width. You could even see these with the naked eye when looking at the tissue sections, and that’s why we termed them broad rim lesions.

We showed through histologic and molecular profiling that these rims are essentially different in many respects from the biology we normally see in classical chronic active lesions.

The interesting part of the story is that this is a histologic biomarker identified at autopsy that correlates with disease severity during life. But of course, what you really want to know is whether people have these broad rim lesions during life.

That’s why we were really happy to collaborate with Dr Laura Airas’ group in Finland. She has extensive expertise in imaging white matter lesions using TSPO-PET and had previously shown that having TSPO-PET-positive lesions is also associated with a more severe disease course in MS. Her group was able to measure the width of these inflammatory rims surrounding MS lesions and showed that broader TSPO-PET-positive rims also predicted faster disability accumulation.

So this really suggests that having broader rims surrounding your MS lesions may be a biomarker of faster disability accumulation, at least in a subset of people with multiple sclerosis.

How do you see these broad rim lesions comparing with other established MRI biomarkers of disease activity and progression, and what additional information might they provide in clinical practice?

That’s an excellent question because we currently have several MRI biomarkers that we think reflect this compartmentalized, chronic CNS biology in MS, such as paramagnetic rim lesions and slowly expanding lesions.

From the imaging data Laura Airas has collected so far, we know that the TSPO-PET-positive broad rim lesions do not overlap with paramagnetic rim lesions. So we think these biomarkers capture complementary characteristics of MS lesions rather than the same biological process.

How these relate to slowly expanding lesions we don’t know yet. But we think these are all different characteristics of chronic lesions that can help us learn different things about progressive MS biology. Therefore, I really think they should be viewed in a complementary way.

From the research you presented, what was the rationale behind the study, and what do the findings tell us about the relationship between broad rim lesions and future disability accumulation or disease progression?

The study was really designed around something we all recognize in our outpatient clinics. Every neurologist knows patients who have lived with multiple sclerosis for decades and remain independent, with very limited disability. At the same time, we also have patients whom we treat with highly effective therapies but who still relentlessly progress over time.

The study was really designed to compare the pathology between these two groups and learn more about the factors that distinguish them.

I think the main finding was that the width of this hypocellular rim surrounding chronic white matter lesions appears to be a biologically relevant variable that helps us understand the variation in the rate of disability accumulation, at least in a subset of people with multiple sclerosis.

Now, I think the next frontier is figuring out how we can identify these lesions more easily during life and, at the same time, better understand the underlying biology that drives the formation of these broader lesions.

If these findings are validated, how might broad rim lesions influence patient monitoring, prognostication and treatment decision-making in the future?

I think this is very timely because this week the EMA also approved market authorization for tolabrutinib, for example. So we’re entering an era where we have therapies targeting progressive disease rather than inflammation alone. With the further development of therapies that selectively target progression in MS, it becomes really important to distinguish, in the individual patient, between relapse-driven biology and progression-driven biology.

If we could translate broad rim lesions into routine imaging modalities, I think we could really begin to understand more about the progressive biology taking place in individual patients, much as has already been suggested for paramagnetic rim lesions.

I think, in the long run, this could really help us estimate the benefit of specific therapeutic strategies for individual patients and also assist with treatment allocation.

Closing remarks

I think we’ve really only scratched the surface of what the variable width of these hypocellular rims actually represents.

There are still so many questions we want to answer. Is this an intermediate lesion type? Is this something that remains present throughout life? And what are the factors that really make someone susceptible to developing these broad rim lesions?

One of the interesting things we learned from the Netherlands Brain Bank donors is that this really seems to be a donor trait. Either a donor has no broad rim lesions, or we see multiple broad rim lesions in that individual.

If we can really pinpoint what makes someone susceptible to developing these lesions, it could provide important clues about whether we can also use this knowledge for more targeted treatment strategies.

I think that’s really the exciting part of making a novel observation like this. It gives us the opportunity to better understand a part of MS biology that we really didn’t know before, and hopefully learn whether that knowledge can ultimately help guide future treatment strategies.