The chronic smoldering inflammatory process in MS explains many things that have long seemed like a blind spot: Why do some people with MS experience a decline in functionality even though they no longer have relapses and their MRI scans appear normal? In this episode, I talk to Dr. Klarissa Hanja Stürner, senior physician and neuroimmunologist at UKSH Kiel, Germany.
She explains clearly what happens in the brain “behind the blood-brain barrier,” how acute relapses differ from smoldering inflammation, what role microglia and macrophages play, why MRI has its limitations—and why new therapies such as BTK inhibitors offer hope for better influencing the progression of the disease.
The episode is a translation of the original German interview and was supported by Sanofi S.A..
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1. Who is Dr. Klarissa Hanja Stürner?
Could you please introduce yourself briefly?
Dr. Klarissa Stürner:
My name is Klarissa Stürner, I am a neurologist and have been working as a doctor for almost 20 years. Early on in my studies, I became fascinated by the combination of the immune system and the nervous system, which is why I went into neuroimmunology relatively directly. This paved the way for MS research and clinical work with people with MS.
For me, it’s an ideal niche: I can indulge my scientific curiosity and care for people in the clinic at the same time. The approach of shared decision making—i.e., making therapy decisions together, transparently, and on an equal footing—is particularly important to me. I deliberately learned this from my former mentor in Hamburg, Prof. Christoph Heesen, and it has been my approach ever since.
I enjoy discussing things, even controversially at times, and I am comfortable with patients consciously choosing something different from what I would personally choose. The main thing is that decisions are informed, well thought out, and fit the individual’s life.
2. Why is MS a chronic inflammatory disease?
Dr. Klarissa Stürner:
To understand this, it helps to take a look at history: our understanding of MS has changed significantly over the last few decades. Today, we see relatively clearly that MS has two main components:
- An inflammatory component, which is primarily visible in acute relapses.
- A progressive component, marked by gradual, often insidious worsening.
The inflammation is what those affected typically experience as a flare-up: new symptoms suddenly appear—for example, visual disturbances, sensory disturbances, or paralysis. This acute inflammation can usually be treated effectively with cortisone or subsides on its own without treatment – sometimes, however, with lasting residual symptoms.
Thanks to modern MS therapies, we now have much better control over relapse activity. And it is precisely this that has made it really apparent that there is something “underneath” or ‘beside’ it: people who no longer have relapses and appear stable on MRI, but are nevertheless slowly getting worse. We call this slow detoriation “progression” – and an important driver of it is the smoldering inflammation we are discussing today.
3. Relapse vs. smoldering inflammation
What distinguishes a relapse from smoldering inflammation?
Dr. Klarissa Stürner: In the case of an acute relapse, we assume that immune cells from the blood—especially T cells—migrate into the central nervous system through the blood-brain barrier.
The blood-brain barrier is a kind of “biological wall,” a protective system between the blood and the brain. It ensures that not every substance and not every bacterium can simply enter the brain. This is extremely important for the brain—but this system can be disrupted in MS.
When T cells and other immune cells migrate into the brain, they primarily attack the myelin layer – the “insulation” of the nerve fibers, similar to the plastic coating of a cable. If this insulation is damaged, nerves conduct signals less effectively or not at all. This is the basis of a relapse: a “functional cable break” occurs, which can sometimes be repaired, but sometimes leaves permanent damage. Cortisone can dampen this acute inflammatory reaction and thus alleviate the symptoms of a relapse.
The smoldering inflammation, on the other hand, proceeds quite differently:
- It takes place behind the blood-brain barrier, i.e., in an area that is, in a sense, disconnected from the rest of the immune system.
- Microglia and macrophages are particularly active here. Microglia are the brain’s permanent immune cells – they migrate into the brain during the embryonic period and remain there for life. Macrophages are part of the innate immune system and can clean up tissue, but they can also fuel inflammation.
The idea is that microglia and macrophages are permanently “switched on” in certain areas and form a kind of self-perpetuating inflammation: it simmers constantly at a low to medium level and damages nerve cells and their fine extensions over years and decades. This is not as spectacular as an acute flare-up – but it can lead to a constant, slow loss of function.
4. Progression, aging, and lifestyle
What role do aging and lifestyle play?
Dr. Klarissa Stürner: When we talk about progression, we can’t pretend that there is only one mechanism. We have to distinguish between several levels:
- Smoldering inflammation behind the blood-brain barrier.
- Normal biological aging, which we all go through.
- Lifestyle factors that can accelerate or slow down biological aging—e.g., exercise, smoking, nutrition.
- Previous damage caused by untreated or late-treated inflammatory activity, which reduces the reserve capacity of the nervous system.
In neurology, you can see very clearly how differently people age. There are 80-year-olds who biologically appear more like 60-year-olds – and 60-year-olds who actually give the impression of being 80. This is strongly related to lifestyle, previous illnesses, and rehabilitation opportunities.
In people with MS, there is the additional factor that a nervous system that has suffered repeated inflammatory damage over many years may have less reserve capacity. This can cause normal aging processes to become more rapid and more noticeable. This can also contribute to progression – in addition to the smoldering inflammation.
5. Why is smoldering inflammation so difficult to see (on MRI)?
Dr. Klarissa Stürner: That is indeed one of the major challenges. We have evidence that certain types of lesions are associated with smoldering inflammation, but we are still unable to visualize them comprehensively and easily on MRI.
An important clue was the presence of iron deposits in certain MS lesions. It has long been known that iron deposits form in the brains of some MS patients, but the exact reason for this was not understood. Today, we know that these iron deposits are associated with the activation of microglia and macrophages.
In MRI, these foci can be visualized as paramagnetic rim lesions—lesions with a “paramagnetic rim” that indicates iron and thus active inflammatory cells. There are even more technically sophisticated methods that can be used to quantify these rims.
However:
- Such special sequences are usually only available in university hospitals and in the context of studies.
- Every MRI machine is slightly different in technical terms – transferring a sequence “via USB stick” does not work so easily in practice because it has to be fine-tuned for each device.
- And not every smoldering lesion is associated with iron deposits – so even with perfect technology, we would only see part of the processes.
That’s why we’re still a long way from someone being able to walk into the nearest radiology department and say, “Please measure my smoldering inflammation.” But that would be a major goal: an easy-to-use MRI sequence that would allow us to see microglia and macrophage activation in the brain per person – and thus estimate how severe the smoldering process is.
6. Symptoms & Red Flags
What clinical warning signs do you see?
Dr. Klarissa Stürner: Yes, there are clinical red flags that immediately set off alarm bells for me. Particularly important is:
- Rapid deterioration in walking distance within about 6 to 12 months,
- without relapses and without any other plausible explanation.
When someone tells me:
“Six months ago, I could walk 500 meters at a stretch, but today I can only manage 100 meters”
– I immediately think of rapid progression, which could very well be explained by smoldering inflammation. The same applies to:
- noticeably poorer cognition (e.g., less resilience during mental work),
- significantly increasing fatigue,
- rapid deterioration in hand function.
It is always important to
rule out other causes, such as injury, a fall, or orthopedic problems. However, if nothing else fits and the deterioration continues steadily over months, this is a strong signal to rethink the course of the disease and possible treatment options.
I encourage those affected to describe such developments clearly and specifically—for example:
- “It now takes me twice as long to get to work.”
- “I can only manage half the spreadsheets in the office.”
These everyday details are very helpful in assessing progression.
7. What does PIRA mean?
Dr. Klarissa Stürner: PIRA describes exactly the phenomenon we are talking about:
- a worsening of the disease that
- cannot be explained by relapses
- and not only by new, classic inflammatory lesions on MRI.
In the past, we focused heavily on relapse rates: fewer relapses = success. Then MRI came along: fewer new lesions = another success parameter.
PIRA makes it clear that
even if no relapses occur and no new lesions are visible on MRI, the disease can still progress—for example, in the form of a shorter walking distance, increasing fatigue, or poorer cognition. This is a separate progression pathway that can be measured independently of acute inflammatory activity.
In practice, this means:
- Studies define new outcome parameters, e.g., deterioration in walking distance in meters or seconds, cognitive tests, standardized questionnaires.
- Doctors and patients must look beyond relapse rates and MRI images.
- Therapy goals are changing: not only preventing relapses, but also slowing down the gradual deterioration.
PIRA is thus an expression of a mature understanding of MS – made possible by the advances of the last 10–15 years.
PIRA stands for Progression Independent of Relapse Activity.
8. Mechanisms in the brain
What happens at the cellular level?
Dr. Klarissa Stürner: As already mentioned, microglia and macrophages play a central role.
- Microglia are the brain’s “household and court immune soldiers” – they are there from the very beginning.
- Macrophages originate from the innate immune system and can migrate into tissue, where they clean up, but also maintain aggressive inflammatory states.
In tissue examinations of people with MS, very characteristic lesions can be seen in some patients:
- Old lesions surrounded by a thick layer of activated inflammatory cells – essentially a “ring” of microglia and macrophages.
- The thickness of this ring correlates with the speed of clinical deterioration: the thicker the ring, the faster the affected individuals lose important functions, such as the ability to walk or core motor functions.
This fits very well with the concept of smoldering inflammation:
- these are not new, large acute lesions,
- but existing lesions with persistent inflammatory activity at their edges,
- which continue to damage the surrounding area and nerve fibers over a long period of time.
These tissue findings are a strong argument that we are not dealing here with pure “wear and tear,” but with an independent inflammatory process that uses different cells and signaling pathways than the classic relapse.
9. BTK inhibitors
Why are BTK inhibitors so exciting?
Dr. Klarissa Stürner: BTK inhibitors inhibit Bruton’s tyrosine kinase (BTK). Tyrosine kinases are switching points on cells—they are used to switch signaling pathways on and off.
BTK is found primarily in B cells (which we already know from other MS therapies), but also in macrophages and microglia. This is the exciting point:
- BTK inhibitors are small molecules,
- they can cross the blood-brain barrier into the brain,
- and there they can precisely influence the cells involved in the smoldering inflammation.
So the idea is this:
We have drugs that not only work in the bloodstream, but also intervene directly where the smoldering inflammation occurs—in the central nervous system.
However:
- Not all BTK inhibitors are the same. They differ chemically, and what looks promising in the Petri dish does not automatically work in clinical trials.
- Some substances in this class have not made it to positive approval.
A study on a BTK inhibitor in secondary progressive MS was very exciting:
- The relapse rate was not further reduced by the drug compared to an active control – here it was “only” no worse.
- However, progression – i.e., progression without relapses – was reduced by about 30% compared to placebo.
30% is not a “miracle pill,” but for a first substance in a completely new treatment approach, this is a remarkable effect. Especially since it occurs precisely in the area that has been of great concern to us so far: smoldering inflammation and PIRA.
It is also important to note that
- this substance is not a typical “first-line relapse medication.”
- It is particularly interesting for people
- who no longer have relapses,
- no new MRI lesions,
- but who notice a clear deterioration in a short period of time.
Another point: BTK inhibitors are taken orally and metabolized in the liver. Therefore, regular blood tests are necessary to detect possible changes in liver values at an early stage. This is not an exotic effect, but rather something we are familiar with from many other diseases. This class of drugs is not suitable for people with pre-existing severe liver disease; for others, it can be used effectively under supervision.
You can find out more about the therapeutic concept of BTK inhibitors here:
- Episode 148 with Prof. Dr. Wiendl
- Episode 150 with Dr. Boris Kallmann
10. Wishes for the next five years
What are your wishes for MS research over the next five years?
Dr. Klarissa Stürner: If I could wish for anything, it would be several things:
- That BTK inhibitors really find their place—just like earlier MS drugs that have changed the field forever. Ideally, they will help us control progression much better.
- An MRI sequence that allows us to reliably and comprehensively measure microglia and macrophage activation – not only in study centers, but also in everyday clinical practice.
- And, as before, a vaccine against the Epstein-Barr virus (EBV). The data on the role of EBV in the development of MS is so strong that it would be incredibly appealing to have something preventive at our disposal.
An EBV vaccine would not only be exciting for people with MS, but especially for future generations. Theoretically, it is even possible that the field of work for MS specialists could one day change dramatically or become unnecessary if we could effectively prevent MS.
11. Message to those affected
What would you like to say to people with MS?
Dr. Klarissa Stürner: We live in exciting times. That can be unsettling—but it also presents an enormous opportunity.
I hope that we will not let ourselves be frightened by this, but instead face what lies ahead with optimism and a desire to shape the future. The world is changing – and it can clearly change for the better.
We see this particularly in the field of MS research and MS therapy: in just a few decades, we have gone from “we can only watch” to “we can significantly reduce relapses and tackle progression in a more targeted manner.” And this path continues.
We can hold on to that – not only in relation to MS, but also in other areas of life.
Many thanks to Dr. Stürner for the insightful interview and this positive outlook on the present and the future.
See you soon and try to make the best out of your life,
Nele
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