The concept of silent progression in MS has long been underestimated, despite being reported by many people living with MS. Even when no relapses occur and MRI scans appear stable, the disease can continue to progress quietly. This is exactly what I discuss in this podcast episode with Prof. Dr. Heinz Wiendl, one of the leading experts in neuroimmunology.
He explains why this silent form of progression has gained increasing attention in recent years, which biological processes are involved, and how both clinicians and patients can become more aware of subtle changes at an earlier stage. We talk about invisible symptoms, the limitations of traditional assessment tools, emerging research approaches, and why the coming years offer real hope for the treatment of multiple sclerosis.
This article was supported by Sanofi S.A. and is an English translation of the original German interview.
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Further information 'Table of Contents
Introduction & Personal Background
Professor Wiendl, could you please briefly introduce yourself? Who are you, and how did you come to work in multiple sclerosis research?
Prof. Dr. Heinz Wiendl:
Of course. My name is Heinz Wiendl, I am a Professor of Neurology, and my area of expertise is neuroimmunology, with a particular focus on multiple sclerosis. My professional career has included positions in Würzburg and Münster, and for the past year I have been the Medical Director of the Department of Neurology at the University Medical Center Freiburg.
I am strongly committed to translating insights from research into clinical care. One example of this is my involvement in the disease-specific German Competence Network for Multiple Sclerosis (KKNMS), where I serve as spokesperson. Our work there focuses on quality assurance and on ensuring that scientific findings are effectively integrated into everyday clinical practice.
What does “silent progression” mean?
For a long time, the assumption was: if a person has no relapses and no new lesions, their MS is under control. What has challenged this view?
Prof. Dr. Heinz Wiendl:
For many years, relapses were indeed considered the main driver of the disease. With today’s highly effective therapies, we are now able to stop relapses completely in many patients. And yet, we still see people whose condition continues to worsen slowly over time.
Three key developments have changed this understanding:
Clinical observation: In some patients, disability continues to progress even without relapses. We refer to this as progression independent of relapse activity (PIRA).
Pathology: When examined under the microscope, certain lesions remain persistently active. These are known as smoldering lesions.
Imaging: There are diffuse changes in the brain that are not related to the classic, clearly defined focal lesions.
Together, these insights show that relapses are only one part of the disease.
How common is silent progression – and does it affect everyone or only certain patients?
Prof. Dr. Heinz Wiendl:
It does not affect everyone. The current discussion can sometimes give that impression, but in reality, it affects approximately 20–30% of patients, even when relapses are well controlled.
Silent progression can occur in different ways:
early in the disease course,
later on, when the nervous system’s capacity for regeneration declines,
or as a mixed pattern, occurring alongside relapses.
The real challenge is to identify early on who is affected. Many patients remain stable under therapy and do not experience these processes.
Endophenotypes – what’s behind this concept?
You have conducted research on endophenotypes. How can they help us better understand silent progression, and what exactly are endophenotypes?
Prof. Dr. Heinz Wiendl:
Endophenotypes are immunological patterns in the blood that can be measured early after diagnosis.
We were able to identify three distinct types:
one that is more strongly driven by inflammation,
one that shows less inflammation but a reduced capacity for recovery,
and an intermediate type.
At this point, we do not yet know for certain whether a specific endophenotype is more strongly associated with silent progression — this is currently being investigated. However, endophenotypes may help us better understand treatment response and prognosis in individual patients.
Ways to recognize silent progression
Why does silent progression often remain unnoticed for such a long time?
Prof. Dr. Heinz Wiendl:
One reason is that established assessment scales, such as the EDSS, mainly capture walking ability.
Another reason is that invisible symptoms are often not adequately considered, including:
memory and concentration,
fatigue,
bladder function,
spasticity.
Any change in one of these dimensions can be a sign of silent progression. What is important to me is this: it’s not only about motor function — multiple sclerosis is a whole-brain disease.
What role does MRI play – and where are its limitations?
Prof. Dr. Heinz Wiendl:
MRI can provide important signals, such as:
increasing brain atrophy,
signs of smoldering lesions.
However, it is not sufficient to focus only on new lesions. MRI does not capture everything that is clinically relevant. That is why we need to combine multiple levels of assessment — symptoms, patient self-reports, neurological examination, and imaging.
Digital tools are increasingly being added, but there is still no single standard that everyone can reliably rely on.
What can patients do themselves?
Prof. Dr. Heinz Wiendl:
Patients can contribute a great deal themselves, for example by:
using standardized self-monitoring tools,
documenting changes regularly,
and not relying solely on the annual neurology appointment.
At the same time, it is important to keep in mind that multiple sclerosis is not driven by day-to-day fluctuations. Continuous 24-hour monitoring is therefore not helpful. What really matters is observing long-term changes over months.
Collaboration between research and clinical practice
Which insights on silent inflammation are currently being integrated into clinical care?
Prof. Dr. Heinz Wiendl:
First of all, it is important to say that silent progression is real. Pathological, imaging, and immunological studies clearly demonstrate this.
What is still missing are reliable biomarkers. Ideally, we would like to have simple blood or cerebrospinal fluid markers, similar to blood glucose measurements in diabetes. Unfortunately, such markers do not yet exist.
Current research is therefore focused on:
understanding the underlying biological mechanisms,
making these mechanisms measurable in living patients,
and linking these measurements to clinically meaningful changes.
This takes time, because these three levels — biology, measurability, and clinical impact — are often difficult to align.
Where do you see gaps in diagnostics?
Prof. Dr. Heinz Wiendl:
The biggest gap is the lack of clear and reliable markers. We would like to have a test that tells us, “This is silent progression.” But such a test does not yet exist.
However, we are making progress. I am confident that within the next two to three years, we will have a much better understanding of what is happening biologically and how these processes can be measured.
BTK inhibitors – what makes this approach special?
BTK inhibitors are close to regulatory approval. What makes this approach special, and which patient groups might benefit most?
Prof. Dr. Heinz Wiendl:
BTK inhibitors are currently generating a great deal of interest because they represent a class of drugs that targets mechanisms we have not been able to address therapeutically so far. They inhibit a specific enzyme — Bruton’s tyrosine kinase (BTK) — which is required by both B cells and microglia.
We are very familiar with B cells from MS therapy, as they play a central role in disease development. Microglia, however — the immune cells of the central nervous system — have increasingly come into focus when we talk about silent progression. Until now, we have not had a therapy that specifically targets microglia. BTK inhibitors could change that.
Another important aspect is that these drugs are small molecules capable of penetrating the central nervous system. This is crucial, because the processes that likely contribute to silent progression occur precisely there. The fact that these substances can reach “where they are needed” represents a key difference compared with previous therapies.
In addition, they are oral medications, taken as tablets.
One example of such a compound is tolebrutinib. It is currently being investigated in a large clinical trial program:
in relapsing multiple sclerosis,
in non-relapsing secondary progressive multiple sclerosis,
and in an additional program for primary progressive multiple sclerosis, for which data are still pending. (Update: The Phase 3 PERSEUS study did not meet its primary endpoint, and Sanofi has stated it will not pursue regulatory approval for PPMS.)
Why are these results considered so significant?
Prof. Dr. Heinz Wiendl:
Because they show, for the first time, that a medication can influence disability progression — and not merely as a consequence of reducing inflammation, but beyond that.
In other words, this approach achieves something that previous therapies have not. For people who no longer experience relapses but continue to worsen, this could represent a meaningful step forward.
What does the future hold?
Prof. Dr. Heinz Wiendl:
This is where an aspect comes into play that I consider particularly important. If a drug such as tolebrutinib shows efficacy in this area for the first time, it is not only a success for that specific medication, but a gateway for the entire field.
We have seen this in other areas of MS therapy as well: once a therapeutic principle has been clearly shown to work,
scientific interest increases,
additional compounds are developed,
and momentum builds across the entire therapeutic concept.
For this reason, I hope that BTK inhibitors will, over the long term, gain importance not merely as a single product, but as a therapeutic class — with several further-developed medications that may be even more effective, safer, or more specific.
This would allow us to reach a group of patients for whom we have had very limited options so far: people whose disease progresses silently, despite the absence of classical disease activity.
Learn more about the BTK inhibitor treatment approach:
- Episode 146 with Dr. Klarissa Stürner
- Episode 150 with Dr. Boris Kallmann
Looking ahead
With all these new insights, what developments would you like to see in the field of MS over the next five years?
Prof. Dr. Heinz Wiendl:
First and foremost, I would like to see a consistent shift toward the understanding that MS is best treated when the diagnosis is made as early as possible and when highly effective therapy is initiated as early as possible. Early and optimal disease control should become the new standard.
Second, I hope that over the coming years we will have therapies that can better influence silent progression. Current developments give me confidence that we will see meaningful progress in this area.
And third, I would like us to be able to describe much more precisely which stage of the disease a patient is in.
Not just counting relapses, not just relying on a neurological exam with a reflex hammer, but truly understanding:
Is the disease active?
Is silent progression present?
Or has a stage of stability been reached?
To achieve this, we need biological and data-driven markers that tell us how well the brain is holding up and which processes are taking place beneath the surface.
Closing message
Is there anything you would like to share with our listeners as a final message?
Prof. Dr. Heinz Wiendl:
I believe my most important message is this: we can be hopeful.
The developments of recent years show that we are far from reaching the end of the road. On the contrary, we have learned that progress continues — new therapies are being developed, and our understanding of the disease is steadily improving.
At the same time, there are still cases that are frustrating, because patients are not treated early or effectively enough, or because the disease course is particularly challenging.
That is precisely why we must continue to do research, continue to improve, and continue to refine our approaches.
My hope is that in five years’ time, we will be able to say: now everyone truly benefits from these advances.
And I hope this sends a positive signal — one of courage and optimism for the future.
I would like to thank Prof. Heinz Wiendl for this insightful interview and for his encouraging outlook on current developments and future perspectives.
See you soon and try to make the best out of your life,
Nele
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