Tomas Kalincik is Professor of Neurology and Applied Statistics at the University of Melbourne and the Royal Melbourne Hospital in Australia and is concerned with treatment sequences in order to choose the strategy that offers the best long-term prognosis for MS patients. In the interview, he explains how complex and difficult this is and why it nevertheless usually makes sense to opt for a highly effective treatment. He also provides many positive arguments for looking to the future, as the understanding of multiple sclerosis is improving rapidly, enabling ever better therapeutic success.
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Table of Contents
[00:00:00] Nele Handwerker: Hello, Thomas. It’s such a pleasure to have you on the show today. And I send a hello to Australia, to Melbourne.
[00:00:07] Prof. Tomas Kalinicik: Hi, Nele. Hello from Australia. And thank you for inviting me to join you on this conversation.
[00:00:13] Nele Handwerker: Yes. And before we actually start with the interview, it would be lovely if you could introduce yourself to the audience, so they know who is with me on the podcast today.
Introduction – Who is Prof. Tomas Kalincik?
[00:00:23] Prof. Tomas Kalinicik: With pleasure. Dear Ladies and gentlemen, my name is Thomas Kalincik. I’m a neurologist in Australia, in Melbourne. I’m the Director of the Neuroimmunology Centre at the Royal Melbourne Hospital, which is a dedicated neuroimmunology centre, which looks after people with MS, but also with other neuroimmunological conditions. And also, I am the Head of Clinical Outcomes Research Unit, also known as CORE at the University of Melbourne, whose focus is on analysis of observational data and translating data into evidence.
[00:00:59] Nele Handwerker: Yes, and that’s very important. And how did you end up there?
Personal motivation for your career choice?
[00:01:10] Prof. Tomas Kalinicik: I always wanted to work with the brain and clinically work with the brain, but I was looking for a research challenge and I have tried a few different research areas. What attracted me to neuroimmunology, especially to MS, is the fact that it is a big problem affecting many people. And I have seen, I have joined the field at the time when I have seen emerging success. That was around the time when Natalizumab was becoming available. It was a very exciting time. And seeing an area in neurology where progress was being made so fast and so dramatically, was a very appetizing perspective. So, we saw at that time registries emerging, large data sets emerging, and I was realizing that there is a lot of signal that is buried in lots of noise that comes from everyday real life, real treatment of real people with MS. And with my propensity towards statistics. I always wanted to use these advanced methods to separate the true signal from the background noise. And that’s how I ended up working there.
[00:02:29] Nele Handwerker: Sounds good. And before we go into the deeper understanding of everything, I would like to start with some basic knowledge.
Understanding MS Progression and Treatment Effectiveness
What is the natural course of progression in multiple sclerosis, and what factors contribute to disease advancement?
[00:02:53] Prof. Tomas Kalinicik: So that is a very complex question. If we think about it, traditionally we have thought about MS or the causes beyond MS, there’s two camps. The risk factors for so-called disease susceptibility. So, in other words, what makes someone develop the disease and someone else not develop the disease.
And then the other camp are factors that lead to progression of the disease, worsening, accumulation of symptoms and new damage to the brain and the spinal cord. So, we know about, we have learned traditionally about the former group of risk factors, which interestingly, it’s important to remember that we typically speak about associations because defining causation in risk factors for MS susceptibility is very difficult. But what we have learned is that there are factors that are very strongly associated with the risk of MS, such as geography, latitude, in which people live.
And I tend to view that as a label that stands for something else. Why certain latitudes or higher latitudes make people more at risk of developing MS remains a mystery. And there could be sunshine. It can be sun exposure. UVB radiation exposure, to be precise, or there could be pathogenic composition of the viruses and bacteria in certain locations around the globe. Or it could be the genetic composition of the populations living in those areas. So that leads me naturally to these other risk factors, such as vitamin D levels, for example, which are closely associated with UVB radiation that comes to us from the sun. We noticed that most people at the time of diagnosis had very low vitamin D levels.
And therefore, the risk factors of worsening of MS, there are some that are intertwined with the so-called susceptibility, such as high BMI, people who have larger body mass are at high risk of developing MS. And there were beautiful studies done in Norway that showed to us that people in the 1960s and 70s who were screened as part of a TB screening program with x-rays and had their BMI documented, so body mass index documented at that time. Those who had higher body mass index, especially children, were at higher risk of developing MS further down in their life. And smoking.
Smokers are definitely at a higher risk in general of inflammatory and autoimmune diseases. And these two factors also propagate into the higher risk of a more severe course of the disease. From clinical practice, and there are always scars that are available, I noticed that certain ethnicities tend to suffer from more severe causes of MS. I see this a lot in people from Middle Eastern areas or from Sub-Saharan African areas. And of course, there must be a strong involvement of diet in the risk of more severe or possibly option of less severe disease.
However, this is a very mysterious area because it’s very hard to disentangle diet from everything else that a human does in their life. And we can see that while we are able to say with confidence that diet is implicated in the severity of MS, we can’t say which diet is the right diet. And you will see that when you go through the list of diets that different people recommend, which vary from pescetarian or vegan diets all the way to the opposite end of the spectrum, the paleo diets, which are mutually exclusive. So, there is an area that requires a lot of research and very difficult research to carry out. So that is my long-winded answer to a very complicated question.
[00:07:06] Nele Handweker: Sorry for starting off with that. And by the way, there is a lovely interview with Claudia Marck on smoking and how to stop smoking. She is in Australia as well. So just for the listeners, maybe you want to listen to that interview. It’s at the beginning. I don’t know the number right now. But it’s very important and I can’t give good advice because I never smoked, luckily. But okay, let’s come to the next question.
Which aspects of MS can be effectively managed with current treatments, and at what stage is treatment most effective in addressing inflammatory processes and preventing disease progression?
[00:07:48] Prof. Tomas Kalinicik: I like how you phrase the question, Nele, because I think at this day and age, what is a sign of time the last two years is as a movement away from this slicing and dicing of the disease into these very discrete categories, such as relapse and remitting MS, secondary progressive MS, primary progressive MS, which still holds some value, but we have learned that it’s very difficult to draw boundaries between these different disease types.
And from that, last year, there was a communication in Lancet Neurology that was already pointing us in the direction rather than categorizing the disease, we should be classifying the different processes underpinning the disease, and trying to quantify those processes and recognize that some processes are better responsive to some types of therapies, and other processes to other types of therapeutic approaches.
So far, our therapeutic approaches have focused on managing the disease that is propelled by this episodic localized inflammation, that’s the hallmark of relapsing, so-called relapsing-remitting MS. This is a disease that presents with relapses, so episodes of symptoms, new symptoms or worsening of old symptoms that last for a certain period of time and gradually over time improve, in some people more quickly, in some people at a slower rate. And there are some treatments that can facilitate the quick improvement that help shut down the blood-brain barrier and shut down the inflammation further rapidly, such as infusions of corticosteroids.
And these therapies in general have been really the focus of the development of drugs for the first 15 or 20 years of research in MS. And this is, I’m talking about the spectrum of so-called disease-modifying therapies ranging from interferon-beta and glatirameracetate to the most contemporary therapies such as natalizumab, ocrelizumab, ofatumumab, alemtuzumab, which are monoclonal antibodies, highly sophisticated molecules that specifically attack, specifically focus on a certain antigen on the surface of cells and thereby modulate how our immune system works.
So, we have become quite efficient in preventing episodes, these episodes of focal localized inflammation to the point that we are able to prevent that with the most important therapies, about 60 to 75% of these events that otherwise would have happened. That is very nicely illustrated by the trends that we see in large registries, whether national registries or the international registry, where 15 years ago, the average number of relapses that a patient would experience in a year with MS would be around 0.6 or 0.8 relapses per year. Whereas nowadays, the baseline relapse rate ranges from 0.2 to 0.3 relapses per year. And that only speaks to the proactive approach and the effectiveness of managing or preventing these issues.
However, the second part of the story is the story of more insidious, slow worsening that happens in the background. And I like to think of it as a continuum. Some of that we can see, and we can measure with disability scales, such as EDSS, or with specialized tests that allow testing of fine motor skills of the hand, or walking speed, or cognitive function, which is a function of memory and higher processing functions. And some of these changes we can see on, for example, MRI of the brain in the form of fragile, slow loss of brain tissue, but faster than what one would expect for a general population.
These processes that are not visibly driven by this episodic focal inflammation are very hard for us to control with the current medication, which so far has really focused on controlling that episodic and focal inflammation. And the whole scientific and clinical community is now really energized to invest a lot of focus, attention, and research activity in that area of understanding what fuels these slowly progressive processes, and where we could break the chain, where we could potentially, where we need to hit those processes to abolish them in an individual.
The problem in that research is again complex. It is a process that we do not fully understand, but I’m very excited that over the last two years we have made very significant advances through understanding of things such as viral involvement in some of those processes. EB virus, Epstein-Barr virus, which is a virus that causes infectious mononucleosis, is now thought to be strongly involved in the susceptibility to MS, so the risk of one developing MS, but also potentially we are exploring whether it can be still implicated in the progression of MS.
And, the roles of cells, immune cells, that infiltrate the brain in the life with MS, and they settle there, and they become what we call resident immune cells. Could these be cells that fuel that slow process, in which case, if the process is inflammatory, these cells make themselves a home behind sealed blood-brain barrier, which is a very tight barrier and doesn’t allow larger molecules and cells to come from outside the brain to inside the brain, which would make therapies such as our highly sophisticated monoclonal antibodies ineffective. And we need to think about ways to get the therapies where we need them and where they still affect the cells that sit inside the brain.
So, it’s a very exciting time. I think I’m anticipating that in the next two or three years, we will learn a lot more about these processes, we will start seeing more therapies that are specifically acting on the inflammation that’s hidden inside the brain and potentially fueling these changes. And what we are also passionate about here at the Neuroimmunology Centre at the Royal Melbourne Hospital is exploring the hidden part of this slow process.
I spoke so far about that visible part which presents with changing disability, slow accumulation of new symptoms or visible changes on brain MRIs. But I believe that there is a hidden element that oftentimes we do not see. And I do reflect on that in conversations with people with MS when they sit in the room with me and they say, “Hey doc, there’s something not 100%, something’s happening, I can’t quite tell you what’s going on”. And I try hard, we do all the assessments, we look at MRIs, we can’t find evidence of deterioration. I’m not dismissive of that statement.
I say, “I believe you, there’s something going wrong. I’m not able to see it. But you know about it”. And then oftentimes we look back five years down the track at that moment in time and realize, okay, remember that time I told you there was something going on? Now we can clearly see that over the last five years this has resulted in deterioration in my clinical status. So, what we want to learn is how to quantify, see, and measure that very subtle change before it becomes clinically apparent. Because if we can measure it, then we can answer the question whether the treatments that we are using are targeting that slow, subclinical, or latent, if you wish, process before it becomes clinically overt. So that is one strong area of focus in our research at the present time.
[00:16:20] Nele Handwerker: Very good. And I try to use certain words a bit more often, so people get used to it. And I use the word “neurodegeneration”. I always have problems with pronouncing it correctly as a German. Yes, that’s a very complex thing. And I think it was quite obvious at ECTRIMS. Some people pointed out very clearly that people at the beginning thought, “Hey, if we can control relapse activity, fantastic, we will be done”. I think it was even Stephen Hauser at his talk and then we could control relapse activity quite well. And unfortunately, there was still that hidden neurodegeneration or deterioration. Another important aspect is that our immune system changes with age.
How does the immune system change with age, and what implications does this have for MS progression and treatment considering the change in effectiveness and risk of side effects of disease-modifying therapies?
[00:17:26] Prof. Tomas Kalinicik: So, you’re probably alluding to the whole spectrum of very active immune system in the childhood, all the way to the other end of the lifespan, and that is the immune senescence, so-called immune senescence, so the decrease or decline in the activity of the immune system. That is a very interesting phenomenon to understand and drive. In simple terms, quantitative processes as I described, children have highly active immune systems and older people have less active immune systems. We do see that very clearly when we look at data in large databases from people across the spectrum of their lives and study the risk of relapses, we see that in people around age 18 or younger, the frequency of relapses is very high.
In people after age 60, 65, the frequency of relapses becomes much lower. And also, interestingly, we see a difference in the frequency of relapses between men and women. So, while the curve is a decline over the lifetime, also, there is a separation of sexes. And the separation becomes most apparent around the time of puberty. And interestingly, around the time of menopause, that separation starts to disappear again. So, we think that there is a hormonal involvement in this of some sort. And this has been a hypothesis for some time, that so-called low estrogen state, such as a state that a woman experiences through large proportion of her fertile life, is conducive of pro-inflammatory state, whereas high estrogen state, such a state that a woman experiences during pregnancy, would be more immunoprotective or protective from autoimmune processes, anti-inflammatory, so to speak, which is a hypothesis that has been tested in animal models and there is possibility of exploiting this in clinical trials.
That’s the quantitative perspective, the amount of inflammation. I can’t speak to the qualitative changes. There are people who are much better placed to do that, and I’ll be fascinated to learn more about how qualitatively the responses will change. So, for example, is the inflammation in children more driven by the adaptive immune system, the immune system that rests on antigen presenting cells such as dendritic cells that collect the antigens from circulation and present it to T and B cells, which are lymphocytes that are part of this adaptive system that learns about the environment and interaction of the human body with the environment.
And where on the other hand, possibly, in elderly people, it’s more the innate immune system that takes over that is more important. These are cells that are naturally present in the body with immune properties. One of them is very aptly called natural killer cell. And it is a cell that really, his job is to identify the target and destroy it. I’m not sure, as I said, I’m not able to speak to how qualitatively different these processes are at the different stages of life, but if they are different, are these different qualities of the processes also responsible for the different types of presentation, as in frequent relapses versus less frequent relapses, but more pronounced progression of disability at various different stages of life.
What further clouds that view is the fact that children and young people have more brains to spare than in inverted commas. There was a bit of a tongue-in-cheek statement, but you see what I mean? There’s more reserve capacity in the human central nervous system when we are young and a hitch to the brain can be absorbed by the brain or the spinal cord he is more easily at that time when there are other neurons around that can relearn the function of the damaged neurons, and also where the neurons are used to relearning the so-called plasticity, because plasticity is something that is very prominent in children’s development.
Whereas once the imprint of the brain is cast in later life, in later adult life, then the neurons are much less willing to relearn their function, they kind of sit and they follow the set pattern. So that regenerative capacity or the capacity to take over a function of other damaged parts of the nervous system becomes much less prominent. That’s probably why an older brain is more vulnerable to inflammatory damage than a younger brain. And of course, there is other cumulative damage, of course, that comes into play.
And there’s damage that we accumulate throughout our life, either through self-exposure to smoking or through things such as other conditions, metabolic conditions, medical conditions, stroke, all sorts of other influences. So, I’m really curious to see what the research of the qualitative changes in the ways of immune response will teach us about how we should treat MS at different stages in life and perhaps whether there are different therapies that should be predominantly used in children versus other therapies that should be predominantly used in elderly people.
[00:23:27] Nele Handwerker: I had just for the German podcast a very good interview with Barbara Kornek from Austria, who is an expert in pediatric MS. There will be an episode on pediatric MS in English as well. But just to make that clear, it’s really important to treat these children. Even so, they can repair better. But if it’s not treated, they end up earlier in progressive status. And that, of course, is something we want to, as best as possible, prevent. And with the older people, as you just explained, just for a summary, I think it’s important that as inflammatory activity is not as high to make a good choice whether it makes sense to use disease-modifying therapies or concentrate on the relapse activity versus maybe hopefully soon to come medications who will concentrate on the other aspects of disease progression.
What methods are currently available to predict who will experience high disease activity versus mild MS symptoms?
Nele Handwerker: For example, I have a really mild MS course. I’m in the disease for 20 years. I’m pregnant right now, so I’m not taking medication because I have a mild course. But yes, there are some things where you say, “okay, looks like this will be an aggressive one or a mild one”, because you must make these decisions at the beginning, I guess, best possible.
[00:25:17] Prof. Tomas Kalinicik: I guess different aspects of the disease are differently amenable to prediction. For example, we have constructed a model that brings together lots of different signals, namely 52 different variables are pooled into these large predictive models. And what we have tried to predict was things such as the rate at which one accumulates disability, or the probability of experiencing a relapse, or probability of developing a more progressive form of the disease. So, one thing that we have learned is that MS is very hard to predict. And I like to say based on one particular study in which we looked in the past and in the future from certain disability milestones, which corresponds to the time when people start using a walking cane to walk at least 100 meters. What we have learned from that is that the tempo of visibility worsening before that time point, and after that time point are completely unrelated.
[00:26:30] Nele Handwerker: Okay.
[00:26:33] Prof. Tomas Kalinicik: So, I guess the negative view, the glass half empty view of that is that we are very bad at predicting what’s going to happen in the future. The glass half full view is if you’ve had a bad MS course so far, you’re not doomed. This can still change in the future. And what we have seen in that particular analysis is when we tried to analyze what defines how quickly one will continue to accumulate disability after the time point that I mentioned, the use of the walking stick, the most important determinant was the use of highly effective therapies. So that’s a great message.
That means that we can still reverse or significantly modulate the cause of MS even if your experience so far has been very bad with lots of disability accumulation in a short period of time. So, from that, we have assumed the position that MS is an amnesic disease. It tends to forget about its past to a certain extent, probably not completely. For example, one hypothesis, one that you alluded to in your previous comment, Nele, that we tested was that the amount of inflammation that one experiences in the earliest years of life with clinically over MS, will determine how quickly they will accumulate disability much later in life once the MS is labeled as secondary progressive. And we found no association between the early relapses and the rate of disability worsening at the late stages. To my disappointment, it was my hypothesis that the rate of worsening in secondary progressive MS is determined by early inflammation and therefore preventable by a very proactive approach to treatment in very early stages of the disease.
But as science goes, every scientist should be prepared to refute their favorite hypothesis in the face of data. That’s exactly what I did. And again, we expanded that analysis to look at what then modulates that accumulation of visibility, and again, it was the same signal that use of highly effective therapies during the later stages when once the disease is progressive is the best way to prevent further disabilities from evolving. This is not equally valid across everyone with MS and there is a so-called treatable target if person experiences progressive disease with a predominantly progressive disease, but with superseded episodic inflammatory activity that is presenting in the form of either relapses or lesions, then they will benefit from highly effective therapy more.
Whereas in people who only experience the slow progressive course of a disease, even highly effective therapy is currently available with the current mechanisms of action, we’re not able to mitigate the rate of disability accumulation at those later stages of MS. So, that is answering a question of prediction through looking at the so-called phenomenology of the disease, so how it behaves differently, again, relating to the previous question, different stages of life with MS and how one compartment, so to speak, of the disease feeds into another compartment of the disease.
If we explore purely the predictive models that I mentioned earlier, not only ours, but many other teams have also built their own predictive models. CEMCAT in Barcelona has done excellent work in developing predictive models for prediction of outcomes early after disease onset. So, what we see is that we are reasonably good at predicting how frequently someone will relapse, which has a limit, it has a horizon. We are not able to predict that indefinitely. Probably, I would say up to four years, we are reasonably okay at predicting the frequency of relapses. But of course, these are only predicted on certain assumptions under certain conditions, such as that the patient stays on the therapy that they are taking at the time of prediction. But of course, one of the reasons why we do the prediction is to change the treatment in the future.
[00:31:19] Nele Handwerker: All right.
[00:31:20] Prof. Tomas Kalinicik: So that we prevent bad things from happening. And that only tells us whether a statistician would relate to this. Basically what it means is that we think Bayesian statistics is a statistics that doesn’t only look at the distribution of data and from the data, in a very contorted way, the probability that a hypothesis, if we run 100 experiments and the hypothesis is true, what proportion of those experiments would show the results similar to the results that we are seeing in this present experiment. So, you can see the explanation is quite complicated in frequency statistics. But this is not how we think. We think Bayesian. We think about so-called posterior probability.
If I say, if I’m a patient with MS, what is my individual probability of having a relapse in the next year? Is it 20% or is it 5%? That’s a Bayesian statement. And the Bayesian statements actually have the advantage of bringing together individual data with all our previous experience and all our previous predictive models. That’s how we think and that’s actually what a clinician does in their room. They see the patient, they think about what’s happened to this patient last time and what do I know about this disease, what does the evidence tell me, and then synthesize all the information together and then make a prediction about what’s going to happen over the next one year and how they should therefore modulate the treatment to prevent things from happening. And this is really the way in which we are heading now with the predictive models, to try to integrate this information while respecting the boundaries of predictability or unpredictability of some components of MS, but trying to shed some light on these probabilities, give people a probabilistic estimation of what is the risk of having a relapse, having a worsening of disability in the future, or experiencing a disease that becomes more prominently progressive.
And then the second step after that, which is something that we’re currently working on, is to predict these conditional futures, depending on treatment decisions. So, it’s like creating parallel universes for every person. And we say in this universe, you’re trading, you’re taking glutathione acetate, and in this other universe, you’re taking dimethyl fumarate, and in this other universe, you’re taking natalizumab. And let’s now compare what your future will look like over the next year or two in terms of relapse frequency and likelihood of accumulating disability or developing a progressive disease, given that you make the decision A, B, or C. And that’s where we are heading towards more granular prediction, the prediction of individual treatment responses, which is the instrument that a clinician needs presently in the absence of clear evidence of what is a prediction. We currently do not have individual predictors of individual treatment response. So, this is something that we need to establish to go out to treatments more accurately.
[00:34:36] Nele Handwerker: Yes, and this is something my neurologist is working as well quite a lot with his digital twin, Prof. Tjalf Ziemssen. And my husband is a physicist. So, kind of it’s getting into parallel universes and parallel realities. Very interesting. I love that. Even so I am coming from marketing, but I love that because that helps us as patients. You’ve made a fantastic movement to the next questions, where I want to talk a little bit more about now treatment approaches and strategies.
Treatment Approaches and Strategies
What are the key inflammatory processes targeted by disease-modifying therapies, and how do they influence MS progression?
Nele Handwerker: I want to have a repetition on that, so people actually realize, okay, something is coming from the periphery versus staying in the central nervous system.
[00:35:35] Prof. Tomas Kalinicik: Yeah, I guess I built my answer on a piece of information that I provided a few answers earlier and that was about the innate immune system and the adaptive immune system. So, these are two important components of the immune system, each of them functions on different principles. So, the innate immune system is quick to respond, is there, attacks at will, but is not learning from the previous experience, whether the adaptive immune system is the immune system that we develop in our lifetime. And that’s actually a probably very important part of the pathogenesis of MS, because one of the cells that is Essential, that is critical, central in the adaptive responses, as we have learned from Roald Martin’s work five or six years ago, is B-cell.
Before we thought about B-cell as a cell that is an antibody factory. And we knew from people who were treated with therapies that eliminate B-cells, like rituximab, and from Stephen Howes‘ work also, more contemporary molecules such as eculizumab, and more recently, Ofatumumab, that these molecules actually control MS very effectively. How is that possible if the only role of B cell is making antibodies and MS is not an antibody driven disease? And that’s where Roland Martin’s discovery of B cells orchestrating the response of the other cells around being an antigen presenting cell and really talking to the T cells about how to basically prepare the strategy of a tag on the brain. How the B cell is a really important central element and then eliminating that element is in the periphery in the circulation. It’s a very important step to sort of mitigate that preparation of the attack that is happening outside of the borders of the brain. It’s like armies that are gathering in the blood, getting ready to attack the brain and the spinal cord.
So, this is disrupting the process before the armies actually invade the territory of the brain and the spinal cord by eliminating the B-cell. And interestingly, B-cell is a target of a virus that I’ve already mentioned, the Epstein-Barr virus. It’s a virus that causes glandular fever, and then settles and rests in the B cells. And we don’t quite know… it’s a bit of a we know; we know a fair bit about how the virus sits in there. And, but we don’t quite know the details of what it does there, and how it influences the B cell. But it’s a very tantalizing, tempting prospect, thinking that the way that these cells are modulated, may result in some sort of immune damage further down the track. And actually, a very recent work from Austria, from Vienna, showed, which is a collaboration between virologists and neurologists, with Thomas Berger being involved, showed that failure to eliminate B cells that are infected by certain strains of EB virus, and they are targeted against molecules inside the human brain and spinal cord, may lead to MS. And this failure to eliminate these cells is more common in people with certain genetic composition.
Now, also, B cells have a receptor, sorry, the EB virus has a molecule on its surface that is quite similar to one of the molecules inside the human brain. And also, it has a receptor for antigen or molecule that is quite similar to vitamin D receptor. And now you can see that this just reminds me of my favorite writer Hermann Hesse and his “The Pearl Game book”, where you start linking the doors and these pieces, bits and pieces of evidence are starting to come together. I think these are really exciting times where these jointed pieces that I presented to you in response to the risk factors, the question about risk factors of MS, are now actually starting to centralize themselves around a certain part of the immune response that is all orchestrated in the periphery with a B-cell in the center of that, that cell being infected by a virus that potentially modulates how it works in people who have genetic predisposition to an insufficient elimination of the modified B-cells from their circulation.
Interestingly, in people without MS, these cells also appear, they get infected by EB virus, and they also are targeted towards molecules inside the brain and spinal cord, but they do get eliminated very quickly by natural killer cells. So, this is where the other component that I mentioned comes into play, natural killer cells as part of the innate immune system, and also other elements in the innate immune system that are probably more the responsive arm, the doer of the immune system. So, think of the adaptive immune system as the coordination center of that attack, and the innate immune system are the armies. These are the forces.
Over simplifying it, of course, the adaptive immune system also plays some role in the execution of the immune response. But if you think about it, then the adaptive immune system, once it finds a place and creates a center, a new logistic central somewhere in the brain, either around a vessel, and we are learning that these cells, B and T cells do settle inside the brain, particularly in later stages of the disease and become tissue resident. And then they are surrounded by these more peripheral standing armies of the innate immune system that slowly expands the existing lesions. These are the recently plentifully discussed slowly expanding lesions or the paramagnetic ream lesions that we see on brain MRIs.
This could be a very clear link between those two systems and also the breach from the periphery, from the circulating immunity to the brain and what happens behind the blood-brain barrier. And you can see that with time, with enough time, if there are enough cells from this adaptive immune system that make it to the brain and keep directing the innate immune system inside the brain, there would be a critical volume of infiltration of the brain to be causing slow, gradual destruction of tissue in the form of slow expansion of lesions or loss of, subtle loss of tissue volume at many places around the brain at the same time, which was, you can imagine how that would lead to gradual accumulation of disability and therefore what we call the progressive form of MS.
[00:43:01] Nele Handwerker: Yes, very good. And I like your “making it easy with the metaphorics” because for most patients, I mean, I’m studying now since one and a half years multiple sclerosis management with all these neurologists, but I think for the normal MS patient, it helps a lot if you do these easy to understand pictures, if you draw them. And of course, I can always learn quite a lot when I have interview guests like you.
How feasible is it today to offer personalized MS treatment based on evidence-based medicine and available biomarkers?
[00:43:45] Prof. Tomas Kalinicik: The polite answer would be this is the era of unmet need. It’s really something that I’m really passionate about, I really like to focus on. We are currently kicking off a project where we will be recruiting a large number of people and studying their disease forms in depth with a number of different instruments that are contemporary and complementary. And that is in response to the fact that currently, well, we do not have a silver bullet, and I don’t think we will ever have. What I mean by that is, there is not a single marker that will predict the disease, or that will predict the response.
There are a number of times that we believe that we already have it, like brain MRI lesions, like brain atrophy, like serum neurofilament chain. But we know that there are predictors of certain phenomena in certain people, and they’re pretty better in some subsets of populations rather than other subsets of populations. And this is what we’re learning. And by saying subsets, that means that these markers can be taken as predictors on their own, they need to interact with something else. So, what I see as the next step is we learn to substratify this pool of people with MS.
Let’s say people with a certain genotype, so-called HLA genotype, or people look at separately sexist, female, and male. And let these markers interact with the stratifiers and look at in which subpopulations these markers are more accurate and in which other subpopulations we need to look into other markers. And then that also leads us to another level of interaction and there’s interaction between different predictive markers. You would have heard about GFAP, for example, as another predictive marker that is soluble in, that can be found in blood and cerebrospinal fluid.
So, learning how the volumes at the levels of NFL neurofilmanent light chain in blood are interpreted in the context of different levels of GFAP in blood is also an important factor. Maybe higher levels of both have a different predictive meaning to a level of just one of them. And whether this ultimately, this complex interaction of the network of interaction between different markers of cell destruction, and where I believe is a lot of potential is interactions among different elements of the immune system. And Heinz Wiendl is doing fantastic work in that area. Understanding this actual involvement of different cells and different molecules that drive the immune response, tells us which therapy that individual in the room with me is likely to respond to. Just to give you a very concrete example, if we are able to identify the range type of a B cell or abnormal natural killer response to the range type of a B cell, then I would expect that an individual with this immunological profile would most benefit from a therapy that eliminates their B cells, like rituximab or eculizumab.
If we, for example, see another individual where the B cells are being eliminated appropriately by natural killer cells, but they do lack T regulatory cells, which is a cell that modifies the activity of other immune cells. And it’s kind of this is the peacemaker of your armies, and this is the cell that walks around and says “Okay, hey guys, calm down. There is no reason to attack”. And let’s say there is a person in an individual who does not have the T regulatory cells. Then in that person, you would want to have to develop a tolerogenic approach. So, you would like to develop a way to teach the immune system to tolerate certain molecules. And you can either program, or you can either make T-regulatory cells and infuse them into this patient with a specific message, this is the antigen you should be protecting, not attacking.
Or you could modulate antigen-presenting cells, like dendritic cells, and teach them, this molecule is a friend, leave it alone, where currently… there is no such message in the person’s immune system, that message is lacking. So, you can see how…and these are, I’m talking about two…the thing, what this trickles down to is the patient, the first patient that I described, that example would be treated by infusion of monoclonal antibodies that eliminate B cells. So, the second patient would be given an infusion of cells derived from their own immune system, that teach other cells to be calmer and tolerant of certain molecules in their body. So, this is where I think the future lies. There’s a lot of work that needs to be done. But we are again, living at very exciting times where I can see the foundations for these approaches to treatment already being laid.
[00:49:10] Nele Handwerker: Yes. And that’s always something when patients with a new diagnosis are asking me… I always try to explain to them, “You know, it’s best to have the diagnosis as late as possible because research is moving on and moving on and becoming faster and faster”. And let’s say it’s the luck of late birth or late onset of MS, because if you had the diagnosis in the 70s, 1970s, there was not much you could do against it. And nowadays, more and more approaches are coming.
Can you explain the concept of "flipping the pyramid" in MS treatment, where high-efficacy therapies are initiated early and de-escalated later in life?
[00:50:00] Prof. Tomas Kalinicik: Yes, that is a concept that responds really to that epidemiology of inflammatory type of MS that I described earlier. The fact that children and younger people with MS tend to relapse much more frequently. So, they have this very prominent episodic focal localized type of inflammation. And the therapies that we use are primarily targeted against this type of immune processes. So, it makes sense that in this population, we use more potent therapies, we trigger a potent response, that is not yet what we would call an induction therapy.
So that is the, as you may know, this is the base of the pyramid that sits on top. Induction is basically starting with high efficacy therapy, with a protracted long-term effect, such as Alemtuzumab, which leads to a decade or maybe two decades of immune modulation or maybe permanent change of the immune system. Another immune reconstitution therapy is cladribine that leads to long-term changes. And we are yet to learn about what long-term changes are triggered by consistent depletion of B cells with B cell depletion therapy, such as the ones that I mentioned, Rituximab, Etoricoxib, and ofatumumab over the long term, do these therapies, are these therapies same as therapies that only act while people take them, or do they also lead to some sort of permanent reprogramming of the immune responses?
So this is the basis for the flipping of the pyramid for the induction of treatment and assuming that this leads to some permanent changes that are long-standing and on the basis then on the background of this treatment then later we introduce therapies that are more short-lived in terms of their effect on the immune system then only add some additional degree of modulation of the immune system after the immune system has been changed more substantially by this more important therapy in the past. I think there is a good rationale for this approach. There are also good reservations, valid reservations for why we need to be cautious. These therapies, therapies such as Alemtuzumab that I mentioned, or stem cell therapy, which is a bit of a misnomer. It’s really a heavy chemotherapy followed by a stem cell salvage, which permanently reprograms the immune system. They are associated with significant side effects. There are potentially toxic therapies.
So, it’s hard for us to drive ourselves, to motivate ourselves to use these therapies in children or very young people, where we have a chance of controlling the disease with approaches that are potentially less toxic. And using something like natalizumab, which is a therapy that acts on the periphery and stops the transition of the immune response from the circulation into the brain is a very tempting prospect because we’re actually not suppressing the immune system, we’re just closing the door, we’re sealing the borders. But otherwise, we’re not interfering with the immune system that much.
So, it is a dilemma, it is a therapeutic dilemma. Cladribine is probably a slightly more acceptable approach to this, but also a milder approach. It’s not as profoundly immune reprogramming therapy. It’s an immune reconstitution therapy that leads to initially transient decrease in both T and B cells and a few other cell types and then repopulation of cells over the long term. And probably with some permanent qualitative changes to immune responses, but not as profound as chemotherapy with stem cell transplant or as Alemtuzumab.
And therefore, we don’t quite know how sustained these changes will be in 10 or 20 years down the track from treatment with plantar beans but could be a potential candidate for this type of approach in a slightly milder spectrum of the and less toxic spectrum of therapies. I think in the end, again, we will be reverting to that concept that we have discussed in response to your previous question. We will identify people in whom we will need to reprogram our immune system more substantially, and where the benefit of using Substantial therapies, such as chemotherapy with sepsis therapy, Alemtuzumab, outweighs the risks. And we’ll be going early with these therapies where the immunological patterns that we can measure and describe in these people tell us that this is the best strategy and that we potentially either do not need to treat further or we only treat with mild therapies as a maintenance.
And there probably will be a very large population of people who will not require this approach. And we will be able to, we currently are not, but hopefully in the future, we will be able with the help of immune knowledge to identify these people and make the decision that in these people, we don’t need to go for the most robust approaches, but we can choose an immune modulation of a milder caliber used over the long term.
[00:55:37] Nele Handwerker: I loved watching Star Trek, and there was a doctor who had a scanner and kind of used all these biomarkers and then knew what he should do. And of course, one basic guideline I think of medicine is as much as needed, but as low as possible, and this is always very important. And I don’t want to see people like me be treated with aggressive medication because I’m on, I don’t know, EDSS 1.5 after 20 years. So, it would be horrible if somebody would have treated me with highly effective medication. I would have had more disadvantages from it.
Sources for Evidence-Based Medicine
What role do clinical trials play in shaping evidence-based medicine for MS treatments? How do they contribute to treatment guidelines? And where are their limitations when it comes to long-term outcomes?
[00:56:45] Prof. Tomas Kalinicik: Clinical trials are an essential part of our discovery process. They tell us about the treatment efficacy, which in translation means, does the treatment work? So, we find a population that is most likely to respond to that therapy. That’s why you see trials, you see fairly strict exclusions that can be only people of a certain age or certain volume of previous disease activity of certain maximum disability or the greater disability where we believe things can still be modulated. And then they are randomized to the target therapy and in the past, typically placebo, which is a substitution for no therapy.
I think the times of placebo-controlled trials in MS are gone, and we really now need and are implementing different strategies, such as trials with active comparator arms. And as we have recently learned from a negative trial of a BTK inhibitor, also about a different comparator, different strategies to choosing comparator therapies, in these trials and different designs, such as non-inferiority trials, which will become a necessity in the space that is really saturated with very potent therapies. So, this piece of evidence tells us if something works, that is essential information, but it’s just a foundation step. Knowing that something works does not mean that it will work for everyone to what extent it works, and how an individual interacts with that treatment decision and how previous treatment decisions interact with a treatment decision.
And that’s where we need the so-called real life. I don’t like that term, because I think everything is real life, including randomness. There’s just a section of it. So that’s why we need observational data, where people…where we have large volumes of information from people from different walks of life, who make different decisions at different time points. And we can study the interactions about these different factors and where, for example, a certain new therapy fits in comparison to other therapies in the context of previous treatment exposures, in the context of the inherent disease activity.
How does real-world data complement evidence from clinical trials in understanding the effectiveness and safety of MS treatments in broader patient populations and what are their pros and cons?
[00:59:41] Prof. Tomas Kalinicik: Yeah, the real-world data as opposed to the chocolate world data. I did expand on my previous answer. Probably the reason why I spoke about both in response to your previous question is that they belong together. They’re part of the same process and each of them or each group of studies answers a different process. It would be naive to think that observational data can allow us to fully, without a bias, quantify the magnitude of the effect of a certain therapy. And we need to work really, really hard to suppress the bias, something that we call treatment indication bias is most prominent.
It basically means that a neurologist and the patient choose the therapy for a reason. They will be more likely to choose more potent therapy in someone who has…in whom they predict that the disease will become more severe. And I think your example is centered around your own story. It is a very good example that someone in your instance made that prediction a long time ago that your disease is going to be fairly mild and that you will not require more potent and potentially more toxic therapy. So that leads to treatment indication bias, which we need to eliminate. And fortunately, we are able to mitigate it substantially with fairly sophisticated statistical methods, given that we have access to large volumes of data.
But it will be also equally naive to think that we can solve all the questions in MS from randomized trials. It is naive to believe that in a randomised trial, you run a randomised trial, then you know exactly where the treatment fits and how it performs in comparison to all the other therapies, and that’s all we need to know. So, these two really complement each other, and both types of studies come with their own caveats. Randomised contract trials are not broadly generalizable. They can only be applied in the populations that are very narrowly selected for the randomized control trials.
They are very expensive, which limits their duration. So, we can observe only the efficacy of the treatments for a limited period of time, typically two or three years. And that applies, while they are rigorous in collecting safety information, they do that also only within these limited timeframes. And in therapies such as B-cell depletion therapies, of course, the big question that we are facing now is, while B-cell depletion is reasonably safe in the two to three year horizon, and as we are learning from extension of the trials, which is typically one trial finishes, people who participate in a trial go in a registry that is followed over time looking for adverse events of therapies.
However, that extension is no longer randomized, of course. We have the answer that we’re trying to get for the B cell depleting therapies is what happens after 10-20 years of consistent depletion of B cells and what long term downstream effects this can have on a human organism, there’s very little that we know about that. And we are very transparent about it. One of the questions, for example, that will stem from that knowledge or that can be explored in parallel to that knowledge is, is there a point at which we can choose to stop depleting B cells? Has the immune system been modulated enough and permanently that we do not need to worry about the direct B cell anymore?
They are all in line now, and the effect of certain duration of B cell depletion, two or three years, will now last into the coming decades. So those are the main limitations of the randomized controlled trials. I mentioned the limitation of observational studies, the interim form of bias, the treatment indication bias, which we mitigate with statistical approaches. And I guess the advantage of observational studies is that they tend to be slightly more generalizable because these are, depending on the nature and the way that these data sets that are serving the purpose of the analyses are collected, defines how generalizable the new evidence is. If you have a large national population-based registry, such as Swedish registry or the Danish registry, or Canada has excellent access to healthcare data, then you can derive, or make, conclusions that are potentially applicable to the entire population that are really unbiased, where the underlying pool of data leading to this analysis is unbiased, is representative of the population.
And then you have other approaches, such as MS-BASE, which is more selective. That’s a kind of self-selective approach to databasing. So, the disadvantage is that it’s not a population-based registry. The advantage is that it does operate across multiple regions. So, you get this very nice, broad variability in the nature of conditions, contingent on ethnicity, the genetic background by proxy, the geography. So, this type of resource allows people to study the behavior of the disease and the effectiveness of therapies in all sorts of different contexts, not just a very specific narrow context in which a randomized clinical trial will be run.
Shared Decision Making and Patient Understanding
How does patient understanding of multiple sclerosis and its disease course impact treatment decision, therapy adherence and overall disease management?
[01:05:49] Prof. Tomas Kalinicik: It’s an absolutely essential, absolutely crucial part of the entire process. Hopefully we have put those times where the very patronizing relationships between healthcare providers and patients behind. I certainly was raised in a very different model of healthcare, and I can see that the whole model is evolving in a positive direction further. So, my conversations with people who come to our neurology center are always open conversations and patient led conversations where our role is to provide guidance, information, and evidence. And some people of course do not want to process all the volume of information.
So, they entrust us with the decision, which is very entirely appropriate. In the end, that’s what we go to school for. But it’s important, of course, the person who implements or who enacts that recommendation is the patient, is the person living with MS. So, it’s absolutely essential to understand what the person is willing and is not willing to do, to give them enough information to be able to make an informed decision in an unbiased way, to understand the perspectives and the roles, places of different pieces of evidence in that very large puzzle. And also, to understand the uncertainty around evidence and the possibility of error.
A very good example, I mentioned the diet, for example, it’s something that people tend to be very religious about. Even though the evidence for a particular diet is weak, or if there is any. And so, if people understand, if we help people, people understand that coming to my previous statement, diet must play an important role in MS, but I can’t tell you what is the right approach because we just don’t know. That hopefully helps the person make up their own mind about what they want to do. They know that they probably can try something. They shouldn’t hang everything on that decision and should be working, should be bringing other elements into their care. That means also adhere to potent therapy as appropriate for their disease severity, avoid risk factors such as smoking, and try to control their BMI.
But it is in the end, the person sitting in front of me who’s integrating all those decisions into one place. The other aspect is the motivation. And, and I’m not a psychologist, I will really leave this to a motivation psychologist, which is a big area to explore. And I’m really an amateur in this area. But some people do not need motivation, for some people, the motivation is staying healthy, being active, being able to embrace their passions and pursue their life. Some people need a little bit more external stimuli, it gets complicated by other concomitant diseases, which are more prevalent than this and may be actually biologically grounded, such as depression, for example.
And in these instances, we do have medical ways of helping. And also, there are lifestyle changes that can help in those instances. So, these are the compounding factors that add to the motivation problem. And then there are, of course, this very complex area of the social backgrounds and people from different social backgrounds and cultural backgrounds have different levels of motivations, dynamism within families and how the cultural groups usually work together or do not work together to deal with these problems are also very important. I know I’m giving you a very vague answer but there is no guideline for how to navigate it. But I think if there was one central element, it is I do whatever I can to empower the person with MS, to get them to realize that they are in charge. I’m here to hold them, but they are the ones making the decisions.
Quickfire Q&A Session
Complete the sentence: "For me, multiple sclerosis is...."
[01:10:59] Prof. Tomas Kalinicik: An autoimmune disease of the central nervous system.
What development would you like to see in the field of multiple sclerosis in the next 5 years?
[01:11:07] Prof. Tomas Kalinicik: I would like to see personalization of neuroimmunology to drive therapy.
Farewell
Finally, what message of hope or encouragement would you like to share with the listeners?
[01:11:34] Prof. Tomas Kalinicik: That we are very close. It’s exciting times, as I mentioned several times during this interview, and hopefully I have justified those claims with some mentions of research that has recently been completed, literally in the last two or three years, where we are becoming much more apt in understanding the pathogenesis of MS and how that understanding feeds into the development of new therapies or use of the currently available therapies. So, stay tuned.
How and where can interested people follow your research activities?
[01:12:13] Prof. Tomas Kalinicik: We have a website, the Core Clinical Outcomes Research Unit at the University of Melbourne. We have a website where we highlight publications that come from the team. The Neuroimmunology Centre at the Royal Melbourne Hospital also has its own website where we sometimes feature research and we also communicate through channels such as MS Translate, the ECTRIMS platform and MS Australia.
[01:12:40] Nele Handwerker: Fantastic. Thomas, thank you very much. You answered a lot of questions. I feel a little bit bad now for squeezing you so much, but it was very interesting and yeah, exciting times. I think so too. Thank you very much. And I’m looking forward to listening to another of your presentations, probably not live at ECTRIMS 2024 because my little one will be half a year old by then, but maybe by 2025. Thank you very much.
[01:13:12] Prof. Tomas Kalinicik: It was a pleasure, Nele, and all the best for your little one. I’m sure it will be a lovely time.
[01:13:17] Nele Handwerker: Thank you.
[01:13:18] Prof. Tomas Kalinicik: Bye-bye. Bye-bye.
See you soon and try to make the best out of your life,
Nele
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