Today’s interview on immunotherapy for MS marks the start of the series on disease-modifying therapies. It is also episode 250 for the German podcast and I translated it into English. I have once again invited Prof. Dr. Tjalf Ziemssen, who is one of the most committed MS experts and, among other things, initiated the Multiple Sclerosis Management Master’s program in German and English, which I myself have been attending since August 2022. Thanks to this very well-founded study program, I have gained enough expertise to be able to pass on my knowledge of the therapies to you.
Prof. Ziemssen answers important questions about the procedure, the selection and why it is so important to appreciate it when you see nothing in MS, when you manage to achieve disease remission. We also talk about why it is sometimes more important to move quickly into preventative therapy rather than focusing on rehabilitation and relapse treatment first. A brief detour leads to generics and biosimilars, which are increasingly playing a role in the drug landscape. We talk about how important it is to prevent MS activities as early as possible, what is involved in good monitoring and how patients are becoming more actively involved in all processes, as it is ultimately about our quality of life.
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Table of Contents
Introduction – Who is Prof. Tjalf Ziemssen?
Dr. Tjalf Ziemssen is Professor of Clinical Neuroscience and Head of the MS Center Dresden at the University Hospital Carl Gustav Carus. He also initiated and directed the German and international Master’s Program for Multiple Sclerosis Management. He is a health visionary, digital health expert, pioneer of the digital twin and keynote speaker.
[00:00:00] Nele Handwerker: Hello Tjalf, I’m delighted that you’re here today as my podcast guest once again.
[00:00:07] Prof. Dr. Tjalf Ziemssen:Yes, hello Nele, this is my privilege. First of all, congratulations from my side too. Who would have predicted that you would survive 50 and now 250, amazing.
[00:00:33] Nele Handwerker: I wouldn’t have thought at the beginning that it would happen relatively quickly. You also got a particularly nice episode today, because I know that you know a lot about the topic of immunotherapy for MS. And we’ll start with the basics and how to come to a decision.
Basics and decision-making
To what extent do the results of clinical trials influence the use of immunotherapies in MS patients and how much flexibility do neurologists have beyond this?
[00:01:02] Prof. Dr. Tjalf Ziemssen: Yes, first of all the clinical trials are the most important entry ticket, because that is our main instrument, that is also what has proven itself in recent years. If a drug shows safety and efficacy, then this is done in the gold standard studies, in the phase 3 studies. These are large studies that include sufficient time and patient numbers. And I think that can be described as the necessary ticket to prove that I am safe and effective. Of course, that doesn’t mean it’s the best individual therapy for me. But it does mean that we have to discuss this therapy in the first place. And we’ve already dealt with many outsider therapies, you’ve also dealt with them in the podcast, that haven’t gone through the whole process. And where it may well be that the safety profile is not right.
Or that the efficacy is more likely to be, yes, just a placebo effect or the belief in it. And that’s why I think it’s very, very important and also a pillar of conventional medicine to carry out very good, high-quality studies that are also acceptable to the regulatory authorities in order to discuss these drugs with patients in the first place. This means that what is really on the table, what can be discussed, has really undergone a check, which is really essential. It still doesn’t mean that it is the best individual therapy in each case.
How are immunotherapies for MS categorized into different efficacy categories, and what significance does this categorization have for therapy selection?
[00:03:06] Prof. Dr. Tjalf Ziemssen: Yes, the category was done as part of the German guidelines. They tried to categorize based on the reductions in relapse rates that were seen. Of course, what we are mainly looking for is not just a reduction in relapse rates, but also a positive influence on disability progression, which is much more difficult. As I said, I find this division into three categories relatively difficult, because it is very difficult to compare therapies with each other, as we can only compare things that have actually been compared with each other in a clinical trial. And then we can compare them for the patient collectives that have been examined. And many of the more than 20 therapies that we have available have of course not been tested against each other.
And then we also have the problem that the testing did not take place at the same time. This means, for example, that the first therapies to be investigated, the interferons, were tested in the 1990s. And drugs such as ublituximab, our latest B-cell-depleting antibody, were tested in the last three or four years. And that’s also problematic, of course, because you can’t compare the patients you treated in clinical trials in the 1990s with those now. And that’s why I’m generally more in favor of the Australian model. They see all therapies as a choice for the patient, they don’t somehow make a graduation according to certain aspects and then also allow relatively flexible use of these drugs.
This situation is unthinkable in Germany and also in Europe, because in addition to the guidelines we have this threefold category, we have a technical information, which is practically the document that is defined by the European regulatory authority and there is a clear indication in it and that is ultimately also the indication that I have to adhere to. So the thing is, guidelines are relatively long-lasting, I can say that this is a special case, as I always say, and that’s why I don’t have to stick to the guideline here, because I have these and these arguments and the guidelines often give me the freedom to do it this way. But the prescribing information is relatively binding, it’s the decisive document and if it says, for example, that this is now a drug that is only approved for active relapsing-remitting MS and active means that they must have had a relapse or have had MRI activity and I now have a patient in front of me who doesn’t have that, then it’s classically off-label and then the whole problem starts because it’s not actually approved there.
So categories should tell us that we have different drugs. I think it’s pretty unidimensional if you only sort by relapse rate. I always like it when, for example, you also sort by form of application, when you look at how long the medication effect lasts, how much do I commit to the next therapies? Does this mean that I can only start the next therapy in a year’s time, or can I change relatively quickly, like a dress that is easy to change? What does this mean immunologically? What does this have to do with pregnancy? Especially with predominantly female patients. I think I would rather derive such complex ones, which are of course more difficult, into a nice three-category graphic. That’s why people take note of it. But I don’t think it’s that helpful for the treatment decision.
Especially as it has to be said that the very active and immunologically very specific drugs are actually in category 3, which I think is a bit unfair. Because in my understanding this always means that I only take them at the end of the line, but that has to be interpreted differently. So you can also discuss with the patient that I take a category 3 as a starting therapy.
[00:08:03] Nele Handwerker: Yes. This is happening more and more worldwide. That was also clearly discussed at ECTRIMS.
What criteria does a doctor use to advise on the right treatment strategy for an MS patient?
[00:08:19] Prof. Dr. Tjalf Ziemssen: Yes, I always like to work with the process of elimination. You have to find a decision and it’s very important for the patient to make the decision themselves. I’m just the consultant, I share the decision, as they say. Of course it’s very difficult, because as a patient I don’t have the knowledge and I’m dependent on the doctor to advise me. So it’s difficult and I’m not convinced that Christoph Heesen can’t hear me now, but I don’t believe that even with the best booklet I can always make decision-making easier and always make it 100 percent watertight.
I think it’s also our job and our experience to find out from the patient typology whether this or that therapy is suitable. And I think it’s just a piece of paper that tries to explain how big the effects are in individual cases, which is very difficult for the patient. But I think it’s important to first rule out which therapies don’t work. For example, if I want to get pregnant relatively quickly as a patient or if I have an allergy to self-injections as a patient, you can cut back relatively quickly. And I think that’s always very helpful, because if you cross out, you already have a smaller group and can then sort yourself into this smaller group.
And you really have to discuss this smaller group with the patient and tell them what the concept behind it is. And of course you start primarily with the type of multiple sclerosis, where we stand, how active it is, what are the prognosis factors, what has happened so far, what previous therapies have been used. You practically always start with the patient’s individual disease characteristics. Then, of course, there are the patient’s concomitant diseases, which we didn’t exclude right at the beginning, such as pregnancy. Then there’s also diabetes, a tumor, another autoimmune disease, where you might have to kill two birds with one stone. Comorbidity is a very important thing, co-medication, what other medication does he have, are there things there that are not so optimal?
We all know, for example, that the group of S1P antagonists, such as fingolimod, ponesimod, siponimod, ozanimod, can have cardiac effects, for example, on the heart and lungs. In this respect, patients with significant illnesses, arrhythmias, for example, are not so suitable. That is one example. And then you get to a point, and then it’s often a bit about the therapy concept, what you want to do. As a patient, are you more likely to be someone who really wants to start with a basic therapy, in other words a therapy that has been tried and tested for a very, very long time, as you know, and then trusts that you will respond to it? You can see that it can work very well. But you have to look very closely and see the signs of the times if you want to escalate. So you really have to have very good neurological care, very good MRIs, so that you can build on that.
Or the other thing is to say, yes, there are some risk markers, I’m going to step up now. But then, of course, the question is always how long can I start? I think this is actually quite good for the patients who are now being treated, because you can often reference what happens to the study patients. So even if I get involved in B-cell depletion today, I now have patients who already received B-cell depletion ten years ago. This means that I always have a significant group of experience to guide me. It’s always very good when you have a drug and when you know patients at the center where you are being treated who have been treated with the therapy principle for a long time, because then you know what comes out of it. And then it becomes a bit richer in nuances.
In the end, it’s more about the unimportant things – should the syringe be pink, should the syringe be blue, for example. That you can adapt it and the patient really understands that I’m not a salesman with different commissions, like a bank advisor trying to talk me into something, but it’s simply very important to me that the patient has a treatment that suits them and that they follow through with it, rather than me favoring a particular treatment. So, like a good dating app, I try to use experience and feelings and scientific evidence to find the ideal dating partner with whom you can hopefully spend the rest of your illness and where we hope that we have made a good choice that will bring the patient a positive outcome.
[00:14:17] Nele Handwerker: Exactly, so that there are as many people as possible who are just as well off as I am, who are basically more annoyed about, I don’t know, sinusitis or something like that and not about MS.
[00:14:28] Prof. Dr. Tjalf Ziemssen: Exactly, but it’s more the offspring that’s responsible for that, the so-called daycare killer germs that then come.
[00:14:37] Nele Handwerker: The daycare killer germs, right.
Why is it important to switch between different therapies as little as possible, and what risks can frequent switching entail?
[00:14:57] Prof. Dr. Tjalf Ziemssen: Yes, you have to say that this is a phenomenon that we see for every therapy. If I’m talking about efficacy alone, it’s the case that every therapy is less effective if it is given in a later sequence line. Fingolimod, for example, is much more effective in the first line than in the second and third. So it goes further back. And there is no drug for which this does not apply. Whenever it slips one line back in the sequence, it is less effective. This is probably related to immunological factors, pre-therapy factors and, of course, patient selection. From this phenomenon alone, one would refuse to say, please jump from therapy to therapy, because ultimately every change of therapy means that the therapeutic agent I use is less effective.
Secondly, in addition to this efficacy phenomenon, the other problem is that there is of course more and more immunological interference. With one therapy, I switch off one part of the immune system, but have another… For example, with B-cell depletive therapies, I switch off the B-cells and the T-cells are still there. But if, for example, I then have a therapy that is very T-cell directed and I still have the overlap from the B-cell depletive therapies, then of course I have completely different situations, because I don’t go in normally with the next therapy that I start, as I did in the clinical trials, for example, but I go in with depleting B cells.
If I touch the T cells functionally through the therapy, it is of course completely different whether the B cells are still functional or not. And if there’s nothing left in the immune system, it’s no longer fun. This takes me into areas that we don’t actually know in the field of MS, that we really know immunocompromised patients with really relevant infectious diseases. Of course, we also know that certain therapies or in certain patients, frequent infections can occur. But as a rule, we have to say that we are lucky that most of our therapies don’t cause us any problems. But of course, if we really go in and influence different lines at the same time, then this can happen much more easily.
[00:17:40] Nele Handwerker: Exactly, thank you for explaining that so clearly again. I think that’s really important. That was also a topic in my studies when it came to vaccinations. This is now a short hop to the side, but the fact that with B-cell-depleting therapies you can still clearly see that the T-cell response…
[00:18:02] Prof. Dr. Tjalf Ziemssen: Exactly, we were able to show wonderfully, if you even vaccinated directly after the B-cell depletion, that also worked, then you had super T-cell responses that a person without MS would have dreamed of. But you can see that the immune system can compensate. Only if you restrict this compensation even further by messing around with different pathways can it become really problematic. And if you keep T and B cells in check in the long term, this is a problem for the immune system.
Management of relapses
How do you deal with MS patients who suffer many relapses in a short period of time and thus suffer considerable impairments? What are the main treatment options?
[00:19:04] Prof. Dr. Tjalf Ziemssen: That’s where we often see the problem. Every now and then, patients are diagnosed with severe relapses in an inpatient setting, not always in our outpatient setting. And in the inpatient setting, for example, it is then said that we will send the patient to rehab first. Yes, and in many cases we have overlooked the fact that we do have some patients who need to start treatment relatively quickly, which gets to the root of the problem. And it has to be said that the cortisone therapy or blood washing that we do acutely in relapse therapy is good at putting out the fire, in other words putting out the fire for the episode, but that nothing is done about the root cause.
So if we think, for example, that a defective fuse box repeatedly leads to fires in the brain, then of course the acute fire is extinguished by relapse therapy. But the fuse box, which sparks again and again and can spread everywhere, with its inflammatory inflammation, is not. And in some patients you see that once the cortisone effect is gone, it quickly comes back. Many then come back from rehab as a complaint, with the next relapse. That’s why you have to ask yourself, also in the overall concept, how quickly do I have to get patients onto a therapy? Of course, we also have therapies that take a relatively long time to take full effect. Then we have therapies that block migration behavior via an antibody mechanism, such as Natalizumab, which of course works very quickly. Therapies that deplete also work more quickly, although there are of course differences from depletion to depletion. But you can also create a setting.
For some patients, I would say that they don’t go to rehab now, we first have to clarify the therapy, set it on the path that depletion, which is usually used if you want to treat very effectively. Or just Natalizumab, that I already carry out the loading. And only think about rehab in the second instance. Because you don’t enjoy life if the inflammatory activity comes up again during rehab and the rehab has to be discontinued, that’s not good for anyone involved.
[00:21:46] Nele Handwerker: Yes, exactly.
[00:21:48] Prof. Dr. Tjalf Ziemssen: That’s why it’s always important that when I have a relapse, it’s just the acute thought, but every relapse, if it’s part of the initial diagnosis, must of course lead to a therapy concept, when, what, immediately. Every relapse, if it occurs during an existing therapy, must lead me to question myself: am I still on the right path? And then I have to take another look at the whole case. In other words, I should ideally also look at the MRI again, because if the MRI is congruent, especially in patients who are on therapy, I have now had a relapse, I have now seen new lesions that have been added, then this literally calls for a change of therapy and escalation.
Generics and their influence on therapy
Why are generic MS drugs being developed and what are the potential benefits to the healthcare system?
[00:22:51] Prof. Dr. Tjalf Ziemssen: Exactly, so basically we are a system that needs innovation. And innovation is expensive, so it’s a good thing that pharmaceutical companies are paid for drug development. I believe that it is certainly better that a pharmaceutical company does it than the state. As we can see, I’m not convinced by state-run drug development. It’s better in free competition. But of course you always have to ask yourself, how much is a drug worth? We have developed very difficult mechanisms in Germany. Every drug has this early benefit assessment. Is that all right? Well, it certainly makes drugs cheaper.
On the other hand, the drugs only have a certain patent term and after this time other manufacturers will also produce them if they can prove that their formulation is suitable. This can lead to significant financial reductions, that very expensive drugs become cheaper, they don’t become inexpensive, they don’t become super cheap, but they level out. It is of course a competitive situation, which is always good. You have to differentiate, so I don’t see a big problem for various preparations if generic preparations are created. But of course we have also had experience in neurology with which preparations this is more difficult.
For example, with drugs that we use for epilepsy, which may contain the same active ingredient, but the release of the active ingredient is different, then I would just stick with one preparation. That is also what I recommend in MS. We have clearly communicated that generics are important, also in order to continue to ensure a very good supply. We can’t always spend the money on original preparations because we need the money for the development of new preparations or we have to spend it elsewhere… And of course we are happy to do this where costs can be saved without compromising on quality.
But I don’t imagine that, for example, if I have now opted for a generic preparation of active substance A, that the next time I get another one, or another one again. But what we would like to see, and as a patient you should also make sure that if you now, for example, what are the names of well-known companies? Hexal, Ratiopharm, Viatris. If I am on the corresponding preparation, I should stay on it the next time and not keep switching back and forth. Then there are the other, biologically produced drugs, such as antibodies, which are called biosimilars. Because they can’t be produced identically.
For example, all the small molecules such as teriflunomide and fingolimod can be produced relatively well and identically. I could even manage that, even as a non-pharmacist. But of course it’s completely different with an antibody. And that’s why with a biosimilar, such as natalizumab, for example, a proper approval study has been carried out. The classic generics have to prove that their properties are the same, but it is enough to prove what the blood concentrations look like, what they show. But with antibodies it’s not enough, there really has to be a separate approval study for the drug to prove that the antibody is just as effective as the original.
Monitoring and adjustment of therapy
How important is the regular monitoring of MS patients in order to adjust the treatment strategy if necessary? What role do imaging techniques and clinical assessments play in this?
Prof. Dr. Tjalf Ziemssen: If we have a patient on a therapy, then it is very important to continue to observe this patient and to carry out the so-called monitoring. We have to distinguish between two components and sometimes this is not so clear to the patient. We have a monitoring component, which is general MS monitoring. We would do this regardless of whether the patient is taking medication or not, they cannot escape our monitoring. These are simply the things that are necessary to provide optimal MS care and a description of MS. And we do this even if the patient is not receiving therapy or if the patient is undergoing his or her outpatient procedures, simply to monitor this.
Then there is always a component that is caused by individual things in the patient that are related to the therapy. And then there are things that specifically come together with comorbidities or co-medications. For example, if I have a patient who has confirmed hepatitis B, I have to look more at the liver with a drug that affects the immune system than I would if the patient didn’t have hepatitis B or tuberculosis or something like that. I would also look at more things in diabetes because we know that there are more things interacting. And there needs to be a monitoring plan.
But I think it’s helpful if you always differentiate and say: this is MS monitoring, this is due to the therapy, this is the monitoring that we need due to other comorbidities, due to other illnesses that you have. Or this is now, for example, monitoring that we need because you are receiving symptomatic therapy that also needs to be observed and controlled so that this can be seen. And the whole thing then merges into a monitoring pathway, but ultimately this is made up of different components. Of course, when we look at the main MS monitoring pathway, disease activity control plays a very important role.
We can see very clearly that with our therapies we can best suppress focal inflammation, that is, the classic inflammatory lesions that arise when the immune system penetrates the brain from the outside and forms inflammatory lesions there. That’s why we have to see whether we are successful with the patient, with the main instruments we have. And we know that MS is an iceberg disease, as you have often described in the podcasts, and that only 10 percent of the iceberg is really on the surface. In other words, if we only do clinical monitoring, well, how are you, you’ve had a relapse, everything’s fine, then the main iceberg is not perceived, only the 10 percent above the surface of the water. And the 90 percent below, we can only visualize that if we really look at the MRI regularly, with high quality, with the same technology and ideally nowadays already AI-based. And check the imaging to see whether new lesions have appeared.
And now in Germany, hopefully from the middle of the year, also with biomarkers, with markers from the blood, the neurofilaments, which will really become available for broad-based care. [Note: There will be differences between countries and if the health care system pays for it or not.] That can show whether nerve cells are dying due to inflammatory changes in the brain. This is why imaging and hopefully soon these biomarkers will be of particular importance. Of course, it may also be that imaging is not only there to detect and investigate disease activity, but that we need imaging to detect a potential side effect that occurs during a therapy.
That’s why, for example, we normally do an MRI once a year as MS monitoring, but with certain therapies, such as natalizumab, if I have an increased risk of developing PML, for example, due to the whole constellation, this viral infection that can occur during natalizumab therapy. I am then required to have an MRI once every six months. So you can see that it’s not just the efficacy that’s relevant for imaging, but that it’s also a safety-relevant point.
Nele Handwerker: Exactly. That also came out nicely in our module during our studies. To you out there, you also benefit from my studies. And it was very nice to see that the topic of PML in particular has lost a lot of its fear, because MS experts have simply learned a lot and are doing good therapy monitoring.
Prof. Dr. Tjalf Ziemssen: I think it’s important anyway to be able to deal with things where you know what the evidence is and what the possibilities are. Of course, there’s still a lot we don’t know. But that’s also important for us, because we need to do more research. And I think you can already see that as clinicians and researchers we try to find certain lines and laws that we can use as a guide. The mere fact that you have a certain overview of certain side effects that can occur makes them more manageable, because you know what the side effects look like.
The worst thing is something so diffuse. You can sense the enemy in the undergrowth, but you don’t know what it is. We experienced this with daclizumab, a drug that was around for a short time and then because of these side effects, which could be clarified through diligent and very precise examinations. Yes, that’s the worst thing, when you have the feeling that something isn’t right and you haven’t figured out the pattern yet and don’t have a plan in which direction it’s going. So it’s very important to get a feel for it, because then half the horror of a side effect is already taken away when I have this information.
Patient recommendations and quality of life
How should MS patients deal with the risks and side effects of their treatment, and why is it important to take them seriously and discuss them with their doctor?
Prof. Dr. Tjalf Ziemssen: I think it’s fundamentally important to talk about it because the doctor is not a prophet. And the doctor can’t think for you either. Especially when it comes to safety issues, which are handled very individually and differently. I know patients who say that safety isn’t relevant for me, it’s an issue that I’ll look into if it’s there, but I’m not going to let it drive me crazy. It’s the same when you get into a car these days, you can say, okay, the car is a safe means of transportation, I’ll just do it, I don’t think much about it when I get into the car. And then there are those who panic when they get into a car because they think it’s a certain death sentence, that you’re going to have a fatal accident. Yes, and that’s the spectrum you have. That’s why it’s very important for the patient to give a signal, or that’s our primary task – it’s not really the patient who has to take action, but the good doctor who has to find out where the patient stands and what the patient is worried about.
The difficult thing is that it’s not just the side effect, but we have different things that we can’t mix up. For example, we have the daily hassles, the everyday pitfalls that come with therapy. You know yourself, sometimes you wish you didn’t have to inject and then the regular thing and it gets on your nerves and now this again. That’s not a serious side effect. It also depends on the type, but there are patients who can’t cope with regular injections or swallowing tablets, for whom it’s a huge problem. It’s not the life-threatening illness, the side effect that comes. But these are sometimes more important issues that cause patients to stop taking medication than the really serious side effect. And that is very important. As doctors, we have to be aware of that.
Or the young woman who injects and wants to have her bikini figure. And if nodules form in the skin, as a doctor I have to be understanding. We should be happy if the MS is slowed down and everything else is subordinate. No, of course it’s the personal lifestyle that comes into it. Or how side effects are perceived, that’s not always the objective measure, it’s very different how I interpret it myself as a patient. And it’s not my role to say you have to go through this, but if the patient says it’s not possible, then it’s not possible. Or it’s important and that’s the component that plays a role, then it won’t work.
So it’s a very individual thing, but you have to differentiate between those annoying things that are associated with the medication and really serious side effects. Fortunately, these are very rare and tend to be erratic and statistical. With some side effects, we have to tell the patient that it’s more likely that they’ll be run over than that they’ll have these side effects. And you have to say that, and I always say that to those who don’t take therapy these days for safety reasons, that’s a huge problem when I look at their safety due to severe MS. So it’s not that we’re doing something for cosmetic reasons or that we’re doing a lifestyle drug, but we’re dealing with MS, a disease that will be with you for another 40 or 50 years when I’m 20.
Yes, and of course sometimes we have to say that’s not possible. Our problem is, of course, that you always have to be careful not to go to extremes. So, of course, I could probably get every patient into therapy with the right points or arguments that I give the patient or with incorrect arguments. For example, if I tell him, you patient, if you don’t take the therapy now, you’ll be in a wheelchair in a year. Then I’ll probably get a lot of patients on the medication. Or what is an even greater danger is that we tend to tell patients too positively about the medication. So if you go on the medication now, then the MS is cured and in many cases we don’t say that, in many cases it’s something that the patient listens to because they want to hear it.
That’s where things come together. The doctor is perhaps so positive because he doesn’t always want to come across as a gruel. If I then say to you, yes Nele, it’s good with you, but it will probably get extremely bad at some point. So if I said that every time, you would say that Ziemssen is getting worse and worse. It’s just like when you sign a contract, you can communicate that, or you can overemphasize the problematic parts that are in the contract. And there are patients who only see certain parts, that is, they only see the good things, the others are ignored or they only see the others. And that’s what makes it so difficult.
But in the end, if you say they have no side effects and the MS is cured, these are also huge problems. Because in the first year of treatment, side effects or those daily hassles, the annoyances, play a role in why I stop the medication. But from year two onwards, it’s no longer the side effect that leads to this, but disappointed therapy expectations. That I realize, oh, I still have a relapse, I still have this. And of course that also has to do with how I use it. Of course… I put my hope into it and of course I want that too. But as I said, curing MS is difficult. So addressing the topic for everyone is very individual. That’s why you can only discuss these things individually with the patient. You can’t present it as a group effect because everyone is so individual. That’s also the beauty, I think anyway, that it’s not statistics, but that it’s really individual treatment and individual decisions and not a recipe that goes on like this for the next 1,000 dishes, unchanged.
Nele Handwerker: Exactly. To put you in a good light again, in case anyone misunderstood. You’ve always said that if something should happen at some point, we’ll talk about it and make a new decision about therapy.
Prof. Dr. Tjalf Ziemssen: Exactly. And the good thing is always that there are treatment alternatives. That’s what I actually always say, what are possible exit strategies. Because if the patient has the feeling that I’m going into treatment now and Mr. Ziemssen doesn’t have an exit strategy or an alternative, then you really have the feeling that your back is against the wall. That’s why it’s important to talk to patients about alternatives, including stem cell transplantation, although I don’t believe that stem cell transplantation will be necessary. But it is an option that we would consider if certain constellations were to present themselves. It gives the patient personal certainty. On the other hand, I’m not a neurologist who says I have to save everything until the end. There are some who say, okay, don’t take the treatment option now because I want to save it. I also think that’s complete nonsense. If I need a therapy, then I’ll take it and I wouldn’t say I’m happy if I still have a lot of therapies up my sleeve. I can’t understand that argument.
Nele Handwerker: Yes, exactly, you had a nice image in our lecture that you only take out the good wine when it…
Prof. Dr. Tjalf Ziemssen: Exactly. I bring out the good wine when the party makes it necessary, when the guests make it necessary. And I don’t always start with the Tetra Pak wine and only switch when the guests are completely pissed off.
Nele Handwerker: Exactly. And to you out there, address this, I was very well informed at the time, I also had this long overcoming, I also did podcast episodes about the side effects, but luckily, what we discussed at the beginning has been the right therapy for me so far, I’m still on it. So I haven’t had to make any changes. But it was also due to the good information I received that I was able to hold out for the first time, when I really had to deal with the unpleasant but not terrible side effects.
Prof. Dr. Tjalf Ziemssen: Yes. On the other hand, I can only say that it’s important to address this. So I say to every patient who initially comes to me, I don’t need Hollywood. With me, they don’t have to have the Oscar for brave behavior, but I’m there for that and we’re just wasting time if I have a mask. Instead, I want to quickly find out exactly how the patient is really feeling and how they are coping so that we can discuss it. And it doesn’t do anyone any good, neither the doctor nor the patient, if you fool yourself. You have to play with open cards and of course that also applies if you have problems with a medication or mentally. There are some patients who can’t cope with being given a medication that could potentially cause PML. In that case, it doesn’t make sense to say I’ll go through with it anyway. Instead, if you say I have a non-rationally recognizable aversion to it, then you have to accept that. Or you have to say, yes, unfortunately we have no other alternative, that’s the only thing. After all, if you don’t want to try again, we would like to give you professional help so that this can be discussed again. But it’s important to talk about it openly.
Nele Handwerker: Exactly. My mom immediately comes to mind. If you told my mom to go to therapy where she goes into a room full of spiders every day, you’d be out.
Prof. Dr. Tjalf Ziemssen: Exactly.
Nele Handwerker: Would she tell you in an worst-case scenario, I do that and she would never go into that room.
Prof. Dr. Tjalf Ziemssen: Exactly. And that would be the problem with the frequent injections, for example. You have to address that and find a way to do it.
How can the quality of life of MS patients be improved through individualized therapy, and what role do patient-specific factors such as age, lifestyle and comorbidities play in this?
Prof. Dr. Tjalf Ziemssen: Yes, of course our main goal is the patient’s quality of life. For me, this always means that the patient is not constantly thinking about the disease, but can live their life. So for an MS patient, quality of life means that MS is not the focus of their life, but that they can live or achieve what they want, like someone without MS, that they can have a family, a job, travel as they wish. I believe this is very important and ultimately our quality of life, to have this freedom. And I think the better our dating app is with the medication, the more suitable, the better. It’s like having the wrong life partner, I don’t think that’s any fun either. And that also reduces your quality of life and usually means that it doesn’t last long, that you’re no longer adherent and that you leave it. I think it’s an overall constellation that has to be found.
The patient-specific things, the therapy has to suit me and the concept behind the therapy. If these things are guaranteed, then it works very well. There are of course a few things, you mentioned influencing factors, age, gender and so on. However, I don’t believe that these things, which are defined as patient characteristics, play such a big role. I think it’s more about the individual. So I would say that if I have highly active MS with a 20-year-old patient or a 70-year-old patient, the actual reasoning will not differ greatly. It’s then a question of how I tick, how I approach such a therapy. Do I want more information? Do I want to say, yes, that’s enough for me, I don’t need to know everything in detail about what the therapy does? I think that plays a much bigger role than the question of whether I’m a man or a woman or whether I’m old or young. I think the individual decision has to do with what makes the individual patient tick.
Nele Handwerker: Exactly, I just had the same thing with the pregnancy, all the checks. They didn’t look so much at whether Nele is healthy, but Nele is 43, so she’s simply a high-risk patient.
Prof. Dr. Tjalf Ziemssen: Yes, of course. I mean, that’s also the case with us, of course. You can do some things however you want, but if you have 40 lesions in your head and if you have a lot of spinal lesions, then you’re in a risk category and that plays a completely different role than other things, you know. So it’s true that there are things that are leading. In our case, for example, the vascular risk profile, which plays a huge role in pregnancy, and when you’re older you’re simply because a placenta is not a simple structure and is always on the verge of insufficiency. And the older you get, the more inadequate it becomes, the more difficult it is for the body to build it up. Of course, that plays a much bigger role, but fortunately that’s not the case for us, for us it’s more other things that play a role. Not so much the vascular side as disability and the ability to compensate, which can vary. But these are things that need to be clarified and discussed individually with the patient.
How are advances in research and development of new immunotherapies contributing to a better long-term prognosis for MS patients?
Prof. Dr. Tjalf Ziemssen: Well, we have to distinguish between two steps. The first step, which we already have, is that we have more and more therapies available, which is very good. Secondly, this availability of more and more therapies makes it difficult, of course, because it means that the choice of therapy is more complex. And that doctors are overwhelmed by this and that you have to be careful that doctors don’t say, okay, if it gets more complex now, then I’ll show regression. That’s how it is sometimes in adulthood, I become like a child again and start with the simple things because the difficult therapies overwhelm me. That shouldn’t mean that I’m left behind, but that I really put everything into it. The patient has a right to that.
And thirdly, I must have a therapist who can and does use any weapon. And not somehow only have small caliber and say with large caliber it’s not for me, it’s too bloody for me, I won’t do it. I’m working on using personalized therapies. That’s what we’re doing with the digital twin and with all data collection, that we’re phenotyping MS. At the same time, we document what therapies I have and then I know, for example, with the next Nele disease characteristics, that I can make very good progress with this and that therapeutic approach. I think that’s the challenge at the moment, where we have to work very hard. We need a great deal of data for this, and the pivotal studies mentioned at the beginning don’t help us, because the patient cohorts we have there are too few, too short and too small. We need longer data and we really need to be able to predict things in order to be able to make truly personalized treatment decisions.
Finally, what recommendations would you give to MS patients who are about to decide on a specific immunotherapy?
Prof. Dr. Tjalf Ziemssen: I think we should always say that the main opponent is MS and that the therapies are tools to protect us against it. And it is of course important, especially when making a decision, that I realize how my opponent, whom I actually want to keep at bay, has positioned himself. It makes no sense to be naive and say, oh yes, I’m fine, I have no restrictions. These are not the things we judge, but we have to make decisions for MS situations that will arise in 20 or 30 years‘ time. It’s not about how I’m going to feel next week. It’s not like in oncology, where I make treatment decisions as to whether I will still be alive next year or not.
I make decisions so that I can still walk in 20 years‘ time and have no restrictions, so that I can still ski and do sport. For me, it’s not about what will happen in a year’s time, but we tend to underestimate things in the long term. We have to pay attention to that and I think it’s very criminally negligent not to make use of these treatment options nowadays with the really, really good therapies that are available and if the situation is such that I have disease activity, that the MS is not completely silent. I can only say that in other countries, they would be very grateful if they had the same situation as in Germany. You also do a lot in the English podcast, where you see that in America it’s all about either having the necessary money or being insured to have it. We are already blessed with great therapy. But I think it’s bitter not to take advantage of it.
It’s also very bitter for the patients, I think, who didn’t have the opportunity 20 or 30 years ago. It’s also difficult for us when you see the patient getting worse. And we are now in the situation with MS, we do the therapy so that deficits don’t arise or fewer deficits arise. And once the deficit has developed, there is nothing more we can do. In our experience, it is sometimes the case that patients only decide to undergo therapy after a severe relapse or a significant increase in progression. And then I have to realize that the therapy is no longer as effective and that’s just the stupid thing. We know that there is a time factor, that the therapy works better the earlier it is given. Our therapies are most effective in the CIS group, in clinically isolated syndrome, in patients with the first relapse. The problem is that I don’t yet know how aggressive my disease is, of course, but if I already have prognostic factors that are negative, I should take immediate action and start a very effective therapy right away.
Nele Handwerker: Exactly, and to talk briefly about my family again, my parents are both now over 70, my daughter is five, sometimes complains, grandma and grandpa are always on the go. But the nice thing is that you can lead a totally fulfilling life even at 70, which for me is another 25 years, then I’ve had MS for 45 years, that’s my personal goal and that’s why I always think about using therapy and of course all the other factors that you have lifestyle-wise. Because I think that’s very nice and my grandparents on my mother’s side both lived to a very old age. My grandma is about to turn 98 as we speak. There’s still a lot of life ahead of me that I want to make good use of.
Prof. Dr. Tjalf Ziemssen: Yes, of course. And I’ve been looking after patients for a long time now. And when you see that patients that I had at the beginning are now retired and can still enjoy it and really benefit from it. That’s our goal and that has to be our goal, and of course there’s always the problem that if I don’t take advantage of certain opportunities, it’s just a shame. Yes, we have the opportunity and when you see that a lot of pseudo-arguments are put forward against this, it’s a real pity.
Nele Handwerker: Exactly. I’ve already had a few luminaries here on the podcast. They’ve experienced the times when you couldn’t do much and they’re all grateful for what you can do now.
Prof. Dr. Tjalf Ziemssen: Sure. The rule is, if I do something early, I see it first and that’s the point. So the later I go in, the more critical it becomes and that’s why, if you have the opportunity, you should consider going in early, because the more time goes by, the more difficult it becomes.
Farewell
Where can people find you and your scientific work on the Internet?
Nele Handwerker: Exactly. Dear Tjalf, it’s been a pleasure as always. For those who haven’t listened to the other podcast episodes, where can they find you and all your output? You also generate a lot of output on the internet.
Prof. Dr. Tjalf Ziemssen: Yes, the German video podcasts are on our YouTube page. Otherwise, our German podcasts take place on the first Tuesday of every month. And we hope to have you with us this year. We’re not as productive as you are, because I have to do other things from time to time.
Nele Handwerker: Looking after patients.
Prof. Dr. Tjalf Ziemssen: Looking after patients, yes. But this August we’re celebrating our 50th podcast, our 50th monthly podcast, which is really good in the hospital landscape. You know how it is with doctors‘ podcasts: sometimes you do one, then sometimes not. Then it’s quiet for a year or now, after Covid, many have disappeared. We’re proud of the fact that, as our head of communications at the university hospital says, we’ve been merciless. You know, it’s a lot, now of course with 250 German podcasts and over 50 English ones, it’s a lot of spirit that you have to have and you also have to overcome your weaker self, because of course it always comes at times when you don’t actually have the time, but where you simply have to stay in the rhythm, because when you say A, I think it’s just difficult, right? So you have to make sure that you stay true to this concept, I think, yes? Otherwise you’re missing something yourself. But that’s not easy.
So now, in August, the 50th anniversary. And, yes, we still have a few things planned. We want to improve further training, you know, we want to work together to tackle specific topics in a different way. I think there’s a lot to do because we’re seeing how important it is for me as a patient to be informed and involved. And that’s why, I think, even as a patient, you can’t hear enough about the disease, new things if possible. Not just rehashing textbook knowledge from 30 years ago, but it’s really about, as you did, now, last year, this year it will be a bit more difficult, but with the ECTRIMS, where you report on it, that you really hear the fresh things, that you also hear what the science is about, what’s on our minds at the moment.
And I think it’s good if we no longer do this alone, in the closed sect of neurologists, but if we do it together with the patients, if we also consider study designs, how we can proceed. I believe that it will be much more important in the future to proceed with a division of labor and participation. And I believe that we will then also see greater commitment and willingness on the part of patients if we really address valid points that are also important to patients.
Nele Handwerker: Exactly. On our side, therapy adherence, if it’s the right one that effectively stops MS. And on your side, of course, just like me, podcast adherence.
Prof. Dr. Tjalf Ziemssen: Absolutely. But I think that’s well on the way. And I mean, if treating patients was so complicated until you’ve built up a solid base of podcast listeners, you have to have a lot more patience, because these are mechanisms that you don’t understand. I’m, let’s say, an older generation that didn’t grow up with swiping. And it’s always shocking for me when I see that I have very good content, like yours, and yet the cat video beats Nele Handwerker. These are things that don’t really fit in, but that’s life. That the cute cat video or something is preferred to that, that’s life. Nevertheless, you can’t be discouraged and we have to get through it together and have the necessary persistence. Because there are patients who need this and for whom the information is worth its weight in gold.
Nele Handwerker: Exactly. On that note, I’m already looking forward to episode 50 with you. And thank you so much for being here.
Prof. Dr. Tjalf Ziemssen: Yeah, first of all, all the best to you.
Nele Handwerker: My second child will be already born when the show airs.
Prof. Dr. Tjalf Ziemssen: Yes, let’s see. Let’s be surprised.
Good, thank you.
Okay, take care. Bye.
See you soon and try to make the best out of your life,
Nele
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