 Hello, and welcome to this NeurologyLive® Peer Exchange titled, “Global Approaches to the Management of Relapsing Multiple Sclerosis.” I’m Dr Fred Lublin from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai Medical Center in New York. Joining me today in this virtual discussion are my colleagues: Dr Wallace Brownlee, from the National Hospital for Neurology and Neurosurgery in London; Dr Patricia K. Coyle, from Stony Brook Neurosciences Institute in Stony Brook, New York; and Dr Sven Meuth from the University of Münster, Germany. Today, we’re going to discuss a number of topics pertaining to the diagnosis and treatment of multiple sclerosis [MS], offering a global perspective. Let’s get started on our first topic. 

The diagnosis of multiple sclerosis has, for the last almost 20 years, been dependent on something called the McDonald Criteria. This is a set of guidelines that were first published in 2001, named after the chairman of the group that first put these out, Ian McDonald, who came from Dr Brownlee’s Institution of the National Hospital for Neurology and Neurosurgery. After coming out in 2001, they were modified in 2005, in 2010, and then the last time, in 2017. Each time, they’ve become more and more evidence-based, and each time, they have improved upon the accuracy and produced some simplicity in terms of acquiring these criteria. Wallace, why don’t you start out and talk to us about the 2017 revisions? 

: Thanks, Fred. Some of the key changes that came in the 2017 revisions to the McDonald Criteria were changes in the requirements for dissemination in space, and some new sites were added for dissemination in space, including the inclusion of cortical lesions. And more importantly and what has had a bigger impact on my practice is the inclusion of symptomatic lesions in dissemination in space. In patients with transverse myelitis, we can now count spinal cord lesions on MRI, in our MRI criteria for making the diagnosis of MS. The other key change for me was the addition of oligoclonal bands. If patients have unmatched IgG [immunoglobulin G] oligoclonal bands present intrathecally in the CSF [cerebrospinal fluid], this can be used as a substitute for either clinical or MRI evidence of dissemination in time within the diagnostic criteria. 

: Patricia, you’re rather critical of the 2001 criteria. As they’ve evolved, have you become happier with them? 

: I am now a fan, Fred. The 2017 diagnostic criteria are very crisp, very clear. We should be promoting their use on a regular basis. That’s not really being done in the United States. I like that they clarified that these are supposed to be applied to very crisp neurologic syndromes, not foggy brain, not pins and needles, not joint pain, muscle pain, but the optic neuritis, the transverse myelitis, the isolated brainstem syndrome. They clarified that periventricular lesions should abut the ventricles because people were calling things periventricular lesions that were not, and juxtacortical lesions should abut the cortex. And I like that they pushed imaging the spinal cord. We at Stony Brook Neurosciences Institute do the entire spinal cord routinely. They also enhanced the value of spinal fluid. We routinely do CSF on everybody. So I am a big fan of these revised diagnostic criteria. 

: May I add something for Germany? You all might know that we have a history when it comes to spinal tapping. We’ve liked it forever, so we are very happy that it is now included in this new criteria, but I learned that in the United States, you are not doing it on a regular basis. Is this correct? 

: It’s rather variable. For example, as Dr Coyle said, she’s long been a proponent of spinal fluid analysis in the diagnosis of multiple sclerosis. Other centers, not so much, including ours at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai Medical Center, but I must say that, since the 2017 criteria came out, we’re doing more spinal taps. It’s been a useful addition to the criteria, even though it breaks the concept of dissemination in time, which has been around so long that I miss it in terms of the uniqueness of multiple sclerosis, but it’s been an important change. I did want to highlight something Patricia said, and say it again: the criteria are really for the typical first episodes, first clinically isolated syndromes of partial myelitis, brain stem cerebellum inflammatory lesions, and optic neuritis. That’s what they were tested in for their accuracy. Other vaguer neurologic symptoms don’t necessarily hold up. Another important point I want to make that I’d like you to comment on is that that the McDonald Criteria are for diagnosing multiple sclerosis, not differentially diagnosing multiple sclerosis. 

P: That’s absolutely right, Fred, and the application of these criteria, how they perform in clinical settings, is entirely dependent on what the pretest probability of MS is. If you’re evaluating someone with nonspecific neurologic symptoms like Patricia described, then these criteria shouldn’t be applied. There’s still a key role for the clinical neurologists in taking a history, undertaking a neurological examination, and confirming that the person has symptoms that are suggestive of MS, and at the same time, being vigilant for other conditions that may mimic multiple sclerosis. 

: Fred, that’s really a key point, that everything rides on having ruled out other possibilities for the syndrome: creating the differential diagnosis, evaluating the patient, and that’s why we would argue for a very robust laboratory work-up. 

Diagnosis of Multiple Sclerosis: The McDonald Criteria

: After the 2005 criteria came out, and each of these criteria have always had the caveat that there be no better diagnosis—every diagnostic criteria for multiple sclerosis [MS] going back, I don’t know how far now, has always had that caveat because dissemination in time, dissemination in space is characteristic of multiple sclerosis, but not unique to multiple sclerosis. And so after 2005, there was from the community a cry saying, well enough of this caveat, give us some guidelines, and that led to a 2008 paper. The lead author was David Miller, MBChB, FRACP, from your institution, Wallace, National Hospital for Neurology and Neurosurgery. Among other things, it provided some very useful differential diagnosis information in the form of charts that had high probability, median probability, low probability of red flags, of things to be watched for that, if you see those, then you ought to rethink your diagnosis of multiple sclerosis independent of whether someone fulfilled these criteria. That was published in the Multiple Sclerosis Journal in December 2008, but it had interesting things like a red flag if you have a persistently enhancing lesion, one ought to think of something else. If you have joint disease concurrently or skin rashes or things of that sort, that one ought to think of something else. That was already 12 years ago. Do you think you see a need to update those? 

: I do think there might be a real value to readdress that. For example, we are pretty routinely now in first attack checking for IgG [immunoglobulin G] to aquaporin-4 and IgG to MOG [myelin oligodendrocyte glycoprotein], particularly in the optic neuritis, transverse myelitis. But if we’re trying to define the MOG-antibody associated syndrome, then it’s reasonable to do that, although we might have a debate about that. There would be some help in a re-analysis of what might be recommended evaluations and work-ups for ruling out other conditions. 

: I agree entirely with what Patricia said, but I’d also highlight how, in recent years, it’s become clear that the conditions that are most likely to be mistaken for multiple sclerosis, and multiple sclerosis is likely misdiagnosed, are actually other quite common conditions. For example, migraine, functional neurological disorders, nonspecific white matter lesions on MRI that you might see in people with vascular disease, for example. While it is helpful to emphasize the rare or the less common conditions that can mimic multiple sclerosis, all neurologists should be vigilant to the fact that common neurological disorders can also be included in the differential diagnosis of MS. 

: This has become something that developed more concern about it, and when we were doing the 2017 criteria, we spent a reasonable amount of time talking about this concern of a misdiagnosis. And there have been a number of good papers on this over the last several years, highlighting what you said, Wallace: that there were common things, migraine and vascular disease, and psychiatric disease, and such like that. One of the big drivers of the error was misapplying the MRI criteria. They’ve been laid out, for example, that a periventricular lesion ought to touch the ventricle and the juxtacortical lesions should touch the cortex if not include it entirely, and things like that. Not because MS can’t produce lesions that don’t do that, but because the basis of the criteria was on lesions that did do that. 

: They also reemphasize the size: 3 mm or greater. 

: Misdiagnosis was an issue, and then almost shockingly, when one looked at how the misdiagnosed patients were treated, they were treated quite aggressively with disease modifying therapies, which we’re all happy to use in patients with MS, but not so happy to see them used in patients who don’t have MS. 

: Since we have the new definition of the criteria with all these items you already mentioned, do you still think that we have a high percentage of misdiagnosed patients? 

: I suspect we do. I haven’t seen it updated in the last year, but part of the problem is that when you write these criteria, we’ve made them easier and easier to do. The downside of easier criteria are that they can be more easily misapplied. The statistics on the positive predictive value, the negative predictive value, and the accuracy all come from highly qualified MS centers. But our intention for the criteria is that they be used by all clinicians who are going to be diagnosing multiple sclerosis, and that’s where the problem comes in. Even more than clinically, I think the MRI misinterpretation is most troublesome.  

Differential Diagnosis of Multiple Sclerosis

: The other point that Patricia raised that has become a part of standard practice is looking at antibodies aquaporin-4 IgG [immunoglobulin G] and anti-MOG [myelin oligodendrocyte glycoprotein]. When the aquaporin-4 IgG assay came out, I think it was around 2006 or thereabouts, we did find people who had been carriers of MS [multiple sclerosis] who actually had NMO [neuromyelitis optica]. And it was the cusp of the NMO spectrum, so they weren’t the classical Devic disease that was pretty much a disastrous disorder. Well, we learned that the NMO spectrum could be considerably milder and had some overlap with MS. I don’t see that happening so much anymore. That syndrome is much more clearly recognizable now that we’ve expanded things, looking at the lower brainstem lesions, the longitudinally extensive spinal lesions.  

The patients with MOG are a little more concerning because I’m not entirely clear which are a syndrome and which are resulting from having inflammation in the central nervous system. MOG sits right in between NMO and MS and overlaps with both, and this one is causing us some more concern. 

: Based on the pathophysiology, one would assume that entire MOG disorders are directed against oligodendrocytes, so it should be more in the spectrum of multiple sclerosis, in my opinion, compared to aquaporin, which is obviously expressed on astrocytes. 

: That’s a very good point. I never thought to distinguish them, and trying to figure out when it’s pathogenic and when it’s not. 

: The first thing we need to do is assign what populations are MOG positive, what syndromes are MOG positive. Some of them are transient, very common in post-infectious encephalomyelitis, ADEM [acute disseminated encephalomyelitis]. A good proportion of them fade away and disappear. But if the MOG antibodies persist, then that patient with ADEM is at increased risk for later optic neuritis. 

: This might also be the reason why we have 20% of MOG-positive children where it’s, from the very beginning, not so easy to distinguish between relapsing inflammation, so MS, or monophasic disorder. 

: I do think, though, that the syndromes associated with MOG spectrum or MOG-IgG are becoming clearer, just like it took some time for the full spectrum of NMO SD [spectrum disorder] associated with aquaporin-4 antibodies to become clear. We are getting better at recognizing the sorts of patients who are likely to have MOG antibodies. For example, people with unilateral or bilateral optic neuritis in which there is prominent optic disc swelling or prominent pain, or the patient with transverse myelitis where there is a long lesion involving the conus. These are some clinical situations where the suspicion for MOG-IgG is high. 

MOG-IgG in Multiple Sclerosis

: Coming back to 2017, has it made much difference in how you’re figuring out who to treat? 

: In Germany, we had an ongoing discussion when we still worked with the concept of clinically isolated syndrome [CIS] and early relapsing-remitting MS [multiple sclerosis], and since we have the new criteria, my idea is that the group of patients with clinically isolated syndrome is now much smaller. This is also why we don’t have to discuss any more that some of the platform therapies are only approved for relapsing-remitting MS, but not for clinically isolated syndrome. This whole discussion stopped with the new criteria because we now have a chance to, early on, diagnose relapsing-remitting MS and to start treatment immediately. For us, it was quite helpful. 

: That’s an important difference in the United States where for CIS high risk, we’re able to treat that patient. Granted, greater than 50% of first attack patients will meet the 2017 criteria. But if you have a first attack and you fit for high risk for MS, and you’ve ruled out other things, you basically have relapsing MS. That’s your first attack, whether you met the criteria or not. We can treat those patients in the United States. 

: Clinically isolated syndrome, we’ve been treating it in the United States without difficulty even before there was labeling here for a clinically isolated syndrome. Now, all are labeled for clinically isolated syndrome except for a couple of the more aggressive ones. You wouldn’t feel there is much difference between the first attack and the subsequent attack, but I know that regulatory authorities have had some issues with that.   

: As for insights, I think that, in Europe, the updated McDonald Criteria have been helpful, and they allow an earlier diagnosis of multiple sclerosis than previously and do open up new therapeutic opportunities for patients with relapsing MS.  

: After the 2010 change, which had a big change in dissemination in time by allowing a single MRI to do that, the clinically isolated syndromes dropped by about 50%, because they then met criteria for MS. I don’t know what’s happened with 2017, whether that’s made a difference. 

: Some very early data that have come out of the Netherlands have shown that perhaps up to 70% of patients can now be diagnosed confidently with MS at the time of the first clinical attack that is highly suggestive of relapsing MS, like optic neuritis or partial myelitis. 

Clinically Isolated Syndrome Versus Multiple Sclerosis

: Let’s move on to our next segment. Our next segment is first-line therapies for relapsing MS [multiple sclerosis]. Patricia, why don’t you start out with the concept of first-line therapies and whether that’s a reasonable concept to continue? 

: I don’t like the concept of first line, second line, third line. We should be able to use any agent that we feel is the best choice in our patient initially. Now, that having been said, what are first-line treatments? Well, obviously the injectables, the varieties of glatiramer acetate and interferon-beta. With regard to the orals, I consider every oral but cladribine to be a first-line agent. That’s the natural spot to use an oral. Why is cladribine not listed? Well, in the label that cladribine got in the United States, they did not recommend using it in a patient with a first attack. I think it could be, but that’s bending the curve a little. Then when we go to the infusibles, monoclonal antibodies. I think they’re all first line with the exception of mitoxantrone, which we basically never use in the United States, and alemtuzumab, which has been recommended in the US label as a third-line agent. I feel very comfortable using the orals, using several of the monoclonals and infusibles, and certainly the injectables as “first-line agents.” 

: I cannot agree more. I would like to support your concept that we should be free as physicians to decide which agent we are using in a given patient. However, I have to say as an MS center, as a university hospital, we at the University of Münster are a little bit free to have a certain concept. However, when it comes to reimbursement, the office-based neurologists are not allowed to go on these treatments, and this is why we are a little bit limited, based on this reimbursement situation. From the pathophysiology behind it, I cannot agree more. If we have a given patient with a highly active disease, we should not play around with something like platform therapies, but we should be able to start with a monoclonal, for instance. 

: When you say they’re limited, the clinicians out in the community, what can they start with? 

: If it’s really a highly active patient demonstrating more than 9 T2 lesions in the MRI, and more than 2 relapses with an EDSS [Expanded Disability Status Scale] progression, they are allowed to start right away with a highly active agent. We have 1 difference here in Europe compared to the United States, and this is the approval of fingolimod, which is, in our country, approved as an agent only for highly active patients, while it’s in your spectrum of regular, or of first-line therapies, if I recall correctly. This is a difference, and this brings me to the approval of new sphingosine 1-phosphate modulators. But in the majority of patients, we have to start with platform therapy or first-line therapy, and then we can have this escalation concept, and this is, in my opinion, not the way to go. 

: Are any of the orals in your first lines? 

: Yes, dimethyl fumarate and teriflunomide are among the first-line therapies. 

: Tell me again, what was the definition of highly active? 

: Highly active should be if the patient is treatment naïve, then we are asking for 2 relapses leading to EDSS progression and a significant T2 load, normally defined as 9 or more lesions. And I think you will agree that this is far too late to quantify these patients as highly active. 

: Yes, in practice in the United Kingdom, British neurologists are increasingly using early intensive therapy in patients with newly diagnosed relapsing MS. Until alemtuzumab was suspended by the European Medicines Agency last year and investigated in detail, we were using quite a lot of alemtuzumab first line at our center, the National Hospital for Neurology and Neurosurgery. Increasingly in the last year, that has been replaced by either using ocrelizumab, or in some patients, perhaps more like the ones that Sven described, cladribine also. We also have access to all of the oral medications first line with the exception of fingolimod. 

: Fingolimod, like in Germany, is reserved for patients who are second line or very highly active, and that’s really on the basis of concerns around the time it was licensed over cardiac safety. While I must say with long-term clinical experience with this drug, that has become less of an issue, and it’s become clear that really that is a problem only with the first dose. 

: What’s happened in Europe with alemtuzumab? Where you using that as first line? 

: We were using it first line, and we’ve still got the option of using it first line in people whose MS is taking a very aggressive course. Although, generally these days, we are mainly using it as a second- or later-line therapy in people who’ve continued to experience relapses and/or MRI activity on a first-line treatment. 

First-Line Therapies for Relapsing Multiple Sclerosis

: Let’s take a look at the individual lesion. We’ll start with interferon since that was our first agent. Sven, tell us a little bit about the use of interferon, both historically and where it plays a role now. 

: It was heavily used 20 years ago when it was coming to the market, and the majority of patients in Germany were treated with the different interferon-beta preparations over years. However, since the approval of the oral agents, EMF [electromagnetic fields], and teriflunomide, we don’t find too many patients starting with interferons anymore. There’s a significant decrease in the usage of interferons. However, especially patients being stable over years on interferons, they like to continue therapy with these injectables, and so, never change a winning team. Interferon patients who are stable on treatment continue this treatment. However, for newly diagnosed patients, they are looking, at least in our country, more for the oral agents, so there is a development in this injectable market, I have to say. 

: Any thoughts on the mechanism of action? 

: This is quite a good question, and I think we can spend the next 30 minutes talking about the mechanism of agents. For our patients we try to keep it simple, and we are talking about a shift from TH1 [type 1 helper T cells] responses toward TH2 [type 2 helper T cells] responses, but I think we all know that there are many effects contributing to the mechanism of action of interferons. If we have the pathophysiology of MS [multiple sclerosis] in mind, we can nearly say that each and every step in this whole cascade is somehow impacted by interferon. It alters the cellular recognition by a modulation of MHC2 [major histocompatibility complex class 2] and the T-cell receptor. It reduces, thereby, lymphocyte activation and proliferation, but it has also an impact on the transmigration over the blood-brain barrier from the periphery to the central nervous system [CNS]. There are some data published that also in the CNS, this leads to a downregulation of pro-inflammatory cytokines, and it shifts somehow the differentiation also in the CNS toward the TH2 answer, so a very broad mechanism of action. 

: It’s not entirely clear which one is the primary player, if there is a primary mechanism involved. Wallace, use of interferon in the United Kingdom? 

: Like in other countries, our use of interferon as a first-line or first DMT [disease-modifying therapy] for people with MS is definitely on the downward slope. One new thing in the last year would be the change in the label for pregnancy in Europe. We now have the option of treating women who are wanting to fall pregnant, or during pregnancy and breastfeeding, and that is on the basis of observational studies suggesting this approach is safe. There is also still a role for interferons and other injectable therapies in patients with certain comorbidities that make other treatments difficult. I recently saw a patient who’d had a renal transplant, so they were immunosuppressed on 2 immunosuppressive medications and low dose steroids, and they developed relapsing-remitting multiple sclerosis on top of that. One of the injectable agents, the patient in this case went for interferon, is a good option because you don’t need to worry about drug interactions or immunosuppressive effects. 

: With regard to interferon-beta, usage is absolutely dropping in the United States, but I agree with Sven: for patients who are on it, who are doing very well, who are very happy with it, not having any significant adverse effects, there would certainly be no reason to change that. 

: We’ve had the same experience. I haven’t started many patients with interferon, but I have individuals who I’ve been treating since November of 1993 when we first got interferon beta-1b, and they’ve done spectacularly well. As we know with all of these agents, there are some people who have responded to all of them, and I think we don’t change a winning team was much the logic. They may say, “Well, I’m not that happy about these injections, but I don’t want to change because I’ve done so well over the years.” I must say, going back to 1993, that was one of the most exciting periods of my professional life, when we had our first therapy come along for a disease, so it was really a very exciting time. 

The other issue with interferon right here and now is when I’ve gotten phone calls from patients, as we all have, saying, “What about this COVID-19?” The ones who are calling on interferon, I say, “You’re in a great position because, not only doesn’t it immunosuppress you, but interferon is probably the main immune response that helps you to fight off viral infections, so we’re happy to have you on interferon.” There will continue to be a use for it in individuals, and then we’ll come back to the comorbidity issue after we have a discussion about glatiramer acetate. 

The Use of Interferon in Multiple Sclerosis

: Patricia, why don’t you tell us a little bit about glatiramer acetate [GA]? 

: Glatiramer acetate consists of random polymers of 4 amino acids. It is a biophysical analogue of myelin basic protein. It was discovered at the Weizmann Institute of Science where they were looking at peptides that induced an animal model of MS [multiple sclerosis] called EAE [experimental autoimmune encephalomyelitis], and glatiramer acetate paradoxically protected against it, so they began to study it in MS. Glatiramer acetate has 2 major claims to fame. Number 1, it’s the only disease-modifying therapy [DMT] that requires no laboratory monitoring whatsoever. That’s a stamp of approval with regard to great safety and tolerability. As pointed out, it is not immunosuppressive. It’s an immune modulator as are the interferon-betas.  

Secondly, it has the widest human pregnancy exposure. Thousands of cases, absolutely no signal, at least hundreds of women with MS treated during pregnancy. You don’t need a washout; you could use it during pregnancy, and you can use it with breastfeeding. Those are 2 dramatic statements that promote it. Very safe, no monitoring, the best documented DMT for pregnancy. The mechanism of action is not known for sure, but it creates regulatory T cells that appear to be helpful. It shifts to a T helper 2 type profile, so there’s a cytokine switch. It has a potent effect on antigen presenting cells, so there is an innate immune component to glatiramer acetate, and you see increase in neurotrophic factors like BDNF [brain-derived neurotrophic factor]. All of those have been postulated to perhaps be mechanisms of action, although, precisely, we’ve been using it for years, we really don’t know. 

: Like the interferons, there is still a role for this injectable therapy, but the role is diminishing. It can be a particularly attractive treatment option for women who are planning pregnancy, and again, for patients with comorbidities. 

: There’s not much left to add. I can only support Wallace and Patricia. This is the same reason why we are still using glatiramer acetate in Germany, especially for patients starting family planning and based on the safety profile of this drug. 

: This one has been interesting in the terms of the population that comes in. There is a population of patients who come in to see us, and when we start to talk about disease-modifying therapies, they’ll say, “How long has that drug been around?” As soon as they ask that question, I know where the conversation is going to go because then they’re going to say, “Well, I worry about what I put in my body. What’s the safest thing you have?” Now, we know there are some people who come in and say, “What’s the best thing you have?” But there’s a significant percentage who come in and say, “What’s the safest thing you have,” because they worry about it. They worry about adverse effects and things of that sort. That’s the group that I start and still start on glatiramer acetate for just that reason. 

The other is, as was brought up, people who are thinking about planning a family sometime soon. It’s a very good agent to deal with in that regard. Of course, like interferon, because GA came out in 1997, we also have a large cohort of individuals who were taking their injection, most of them switched to 3 times weekly from daily, who also said, “I don’t like these injections, but I don’t want to switch because I don’t want to mess with success,” and that holds for GA as well. The other thing, as you brought up, Sven, I can think of 1 patient who was being treated with chemotherapeutic agents and also needed to have their MS treated, and it was a good addition in that situation. 

The Use of Glatiramer Acetate in Multiple Sclerosis

: Let’s move on to cladribine. Cladribine is an older drug that’s a new drug. Wallace, why don’t you take us through cladribine? 

: Cladribine, as you say, is a medicine that has been around for a little while, and the previous formulation has been used in the treatment of hairy cell leukemia. It was studied in MS [multiple sclerosis] over a decade ago in 2 large phase 3 trials: the CLARITY study, which included patients who had relapsing/remitting multiple sclerosis and the ORACLE study, which took patients with CIS [clinically isolated syndrome]. Although many of them would be classified as MS with the updated diagnostic criteria that we’ve discussed. Cladribine is a prodrug. When it comes into the body, it is phosphorylated into the active metabolite, and the level of phosphorylation that occurs depends on the tissue type, so it is primarily taken up by lymphocytes where phosphorylation occurs and lymphocyte depletion occurs, possibly followed by an immune reconstitution effect. The immune system may be different after a course of cladribine. Of the available MS therapies, it is probably the most convenient in that it is given as short courses of treatment, with up to 20 days of oral treatment over 2 years. Generally, 5 days in months 1, 2, 13, and 14, and with those 20 days of treatment, what was seen in the CLARITY study was that patients can remain free of relapses and new MRI activity in the absence of ongoing therapy. 

: How has that experience been using it? 

: We at the National Hospital for Neurology and Neurosurgery 

have found this a very straightforward medication to use. Firstly, the medicine seems to be extremely well tolerated by patients. The main concern is lymphopenia. In the CLARITY study, the rates of grade 4 lymphopenia, this is a lymphocyte count below 200, were around 0.7%, so quite a rare event. Patients generally tolerate the course of treatment extremely well. Occasionally, patients will report problems with headache, tiredness, or sore throat during the treatment, but generally, it tends to produce very little in the way of adverse effects. 

The other very attractive quality is the monitoring burden associated with it is very low. Compared with a number of other oral agents and monoclonal antibodies, there is very little monitoring required: just a couple of follow-up blood tests over the first 6 months of treatment, and then you need to ensure the lymphocyte count is above 800 to proceed with treatment in the second year. 

: I have to say, when the drug was approved, there was some uncertainty in Germany because, first of all, the study was so long ago, and cladribine was tested as a platform or as a first-line therapy. In the CLARITY trial, over 70% of patients included were treatment naïve, and when it came to the market, it was all of a sudden approved for highly active patients. We all recognized the convenience of cladribine; however, it was difficult to get an idea about the real potential when it comes to efficacy. Now using it for more than 2 years, I can support Wallace’s opinion that it is very well tolerated, and I have to say the majority of patients are quite stable on this therapy. For me as an immunologist, it’s also very intriguing to have this concept of a pulse therapy so that you treat in years 1 and 2, and you have this treatment-free interval while the patients remain stable in years 3 and 4.  

This is a bit of a different history compared to the United Kingdom, where this concept of pulse therapy was already introduced with alemtuzumab. And alemtuzumab was largely used in the United Kingdom, while in Germany, it was always a discussion, if you want to have a continuous treatment because you can interrupt this treatment and you can get rid of the treatment effects compared to pulse therapy, which is convenient. However, it is not so easy to stop therapy while you are on your way, and this is why cladribine was not introduced or it did not explode into the market. Now, numbers of patients are constantly increasing because the combination of efficacy and convenience for the patients is quite good. 

: You bring up an interesting point about this drug, which is different than any other, and that was in the extension study, after 2 years on therapy, patients who were untreated did as well as those who went onto another course, suggesting a very long-acting effect over time. How do you figure out when to re-dose after the first 2 years? 

: This is the discussion that we have right now because so far it’s only approved for 2 courses, and this is also comparable to the situation when alemtuzumab entered the market. There, we were all surprised. What do we do after 2 courses? If there is still relapse activity, are we then allowed to go for a third course, or do we necessarily have to switch therapy to a new drug? However, the patients we have had for the longest time on cladribine are now entering year 3, so we can still discuss this question 1 and a half years in addition, but then we have to come up with an idea about how to continue. My personal note on this is that, if the patient is stable in years 1 and 2 and remains stable in years 3 and 4, this is a full responder, in my opinion. In these cases, I would recommend to continue cladribine because obviously the mechanism of action is working in this particular patient. 

However, if we have a situation that the patient is stable in years 1 and 2 but starts relapsing already in year 3, this might be an indication that this mechanism of action in this given patient is not working very well, and then we think we should maybe change to a monoclonal antibody. But right now there are no data available, there are only opinions that we can discuss. 

: I think that’s right, Sven, and there is a lot of uncertainty about what to do beyond year 4. I must say with our initial clinical experience in the United Kingdom, and I’d be interested to hear your experience from Germany, we found this a very effective medication. When we looked at the first 100 patients that we treated at the National Hospital for Neurology and Neurosurgery at Queen Square, we found that the overwhelming number, over 85%, were relapse-free in the first year of treatment. Our initial clinical impression supports the subgroup findings from the CLARITY study: this seems to be quite an effective medication, particularly in patients with high levels of disease activity. 

Clinical Trials for Cladribine in Multiple Sclerosis

: Does this not provide us an opportunity to think about de-escalation when you’re thinking about what to go to next and the individuals who have done very well? 

: That’s right, Fred. There are a couple of groups of patients who are particularly attractive to treat with cladribine. One is perhaps the patients who are more treatment experienced, older, or have a higher EDSS [Expanded Disability Status Scale] score. This medicine may be a nice exit strategy from disease-modifying treatment [DMT] without the concerns that you have with other agents about inducing rebound or severe disease reactivation when medication is stopped. Another particularly attractive group of patients to treat is young women, as we’ve heard already. We have an increasing number of treatment options that facilitate family planning, but this is a particularly good option in that women are able to fall pregnant 18 months after starting the therapy if they complete both courses of treatment and then wait 6 months. Then they’re free to start trying for a baby. 

: Patricia, the Europeans were ahead of us on this one and have more experience, but I’d love to hear your thoughts about cladribine. 

: It’s very interesting. We’re looking in the United States at what exactly is the role for cladribine. It has a fairly high efficacy agent, higher than the other orals, maybe a step below the monoclonal antibodies, and it is an induction immune reconstitution agent. As noted, it is very appealing to work pregnancy around that, very appealing to people who like the idea of taking short courses and having a prolonged drug-free period. There were some very respected MS [multiple sclerosis] neurologists who used parenteral cladribine off-label over the years. They would re-dose periodically, and they felt that this was very successful. To me, the most unsteady, disconcerting thing is this, “Treat for the specific 2 courses, and then don’t treat again.” We have to come to some resolution, so I’m hoping that we get valuable data from Europe to guide us since they’re about a year and a half ahead of us. 

: We all feel comfortable though, Patricia, in patients treated with alemtuzumab just to monitor patients because we know from the long-term follow-up of the CARE-MS I, CARE-MS II study, this treatment paradigm of giving short-course pulse immune reconstitution therapy can bring about a lasting remission for a good proportion of people, at least for alemtuzumab, and perhaps for cladribine also. 

: Absolutely. You have some data for alemtuzumab, but do you have that data for cladribine? 

: No, and that’s what we need to collect. 

: You’re using cladribine in the first line in Europe? 

: Yes, that’s right. At our center, the National Hospital for Neurology and Neurosurgery, it’s roughly half of patients we treat. It’s patients who are first line, generally those with more active MS as described earlier: 2 relapses in the previous 12 months. And then the other half of patients are people who’ve had ongoing disease activity on a previous treatment. It’s interesting to note that, in the United Kingdom now, cladribine is the number 1 medicine for first switches, so people switching from their first DMT to another therapy, cladribine is now the front-runner in that particular race. 

: Interesting. In the United States, there was a relabeling of the drugs that occurred after the siponimod approval, where all the disease-modifying therapies for relapsing disease were re-labeled to include clinically isolated syndrome [CIS], relapsing-remitting MS, and secondary progressive MS with activity. We can come back to the issues with that labeling characterization, of which there are quite a few, later. But cladribine, which had a study in clinically isolated syndrome, which many of the others did not, was excluded from including clinically isolated syndrome in their label, as was alemtuzumab. Any thoughts on that, Patricia? 

: It doesn’t make sense that cladribine, which had what looked like a very positive CIS trial, was excluded. It was excluded strictly because they’re saying we’re concerned about malignancy issues, but it got approved in the United States because they weren’t so concerned about malignancy issues. This was on scheduled to be the first approved oral agent, and it wasn’t. It wound up ultimately getting approved because it didn’t overtly cause major cancer concerns, so it is quite puzzling to me. It doesn’t make sense. 

: On that safety concern, have any safety concerns arisen in Europe over the time you’ve been using it? Anything new? 

: We have some patients, around 10%, reporting fatigue while they are taking the medication, which is a transient phenomenon, and we have some higher rates of herpes infections compared to the CLARITY trial, but this is basically it. There was 1 herpes encephalitis reported as maybe a major adverse effect, but this could also be treated with IV [intravenous] acyclovir treatment. So far, it is quite safe, I have to say.  

Treating With Cladribine in Multiple Sclerosis

: Another new drug: siponimod. Wallace, why don’t you take us through siponimod? 

: Siponimod is a recently approved medicine from the same family as fingolimod: it’s a sphingosine 1-phosphate [S1P] modulator. Siponimod is exciting for a couple of reasons, particularly because this is a medicine that has been shown to have a positive phase 3 trial in secondary progressive multiple sclerosis [MS]: this was the EXPAND study. In subgroup analyses, it looked like the benefits of siponimod on reducing the risk of confirmed disability worsening were mainly driven by patients who had so-called active secondary progressive multiple sclerosis, so patients who had ongoing relapses or MRI evidence of disease activity. That is the label the medicine has received in Europe for that subgroup of patients with secondary progressive MS. Although I understand that, in the United States, you’ve got a much broader label, even though formal studies in patients with CIS [clinically isolated syndrome] or relapsing-remitting MS haven’t been undertaken. 

: Right. Did you want to say a little bit about how siponimod differs from fingolimod? 

: There are a number of S1P receptors in the body, and siponimod is more selective than fingolimod. In theory, that may influence both efficacy and potentially [adverse] effect profile. Bradyarrhythmias and bradycardia, which are a concern with fingolimod, seem to be less common in patients treated with siponimod, partly because of a dose titration used to mitigate this first dose effect. 

: Siponimod is selective for S1P1 and S1P5 receptors. Fingolimod hits S1P1, S1P3, S1P4, and S1P5 receptors. That may explain some of the differences there, but you bring up one important point, which is that with the dose escalation, there is no first dose observation with siponimod. Patricia, use of siponimod? 

: Siponimod is a second-generation S1P receptor modulator. It’s beginning to get a crowded field. It was very impressive that they had a phase 3 trial positive in pretty significant secondary progressive MS. You have to give credit: they met the primary outcome. It was critiqued as not being a stunning success in the primary outcome. Nevertheless, it was, and this is a small molecule that penetrates into the CNS [central nervous system], and therefore, it is at least possible—and there are S1P receptors inside the CNS&mdash;that it could be having a direct effect on neurodegeneration to have an impact on secondary progressive MS. It was terribly disappointing when that was not recognized by the FDA. However, if you look at the S1P receptor modulators as a class, you might make the argument that siponimod, if it’s effective in relapsing&mdash;which is clearly true, you have a phase 2 trial, and look at the other S1P receptors&mdash;plus it has a neurodegenerative effect, you could potentially say is that my preferred, go-to S1P receptor modulator? That’s an intriguing question to think about. 

: I can add that I’m most impressed by the EXPAND trial because of the patient recruitment. If we compare all the different trials in patients with secondary progressive MS [SPMS], I had the impression that the majority of trials tried to also involve patients with late-stage relapsing-remitting MS with a lot of inflammatory activity. This may also be the reason why the beta-interferon trial in SPMS in Europe was positive, while it was negative in the United States. In the European trial, there have been 70% of patients with a relapse while being in the study, and if we compare this to the recruitment strategy of the EXPAND trial where we had over 50% of patients already having an EDSS [Expanded Disability Status Scale] score of 6 or 6.5, this is the first trial recruiting a pure SPMS cohort. This is why I support Patricia’s take on the study.  

We saw something in this really progressive cohort, and this is much more meaningful as reflected by the approval of siponimod. In Europe, it is only approved for secondary progressive MS with activity, and this activity has to be shown by clinical relapses or by MRI activity. So far in Europe, we have 2 approved S1P modulators. However, we cannot use them as a first-line therapy because we have fingolimod for active patients and siponimod for active SPMS patients and this is, for me, hard to understand. 

: I don’t have any further comments. We don’t have access to siponimod yet in the United Kingdom, so I haven’t used the drug myself. 

: You highlighted some of the paradoxes with this drug. This was a good study. They set out to get a group of patients for secondary progressive MS, and they succeeded. It’s a population like no other study that’s been done, so I give them a lot of credit for doing that. They had a high EDSS, they had long duration of disease, and it was a good study. As Patricia said, it was a modest effect, but it was an effect that clearly occurred, and now the confusion is in the labeling, both in the expanse of the labeling, which was a leap because of the way this drug was done. For me, more troubling is the lack of understanding of the regulators of what the term “activity” means.  

Wallace and I have had this discussion when I visited out in their place at the National Hospital for Neurology and Neurosurgery a year and a half ago, and that is activity must be framed in time. Neither regulatory group on either side of the Atlantic recognized that this must be framed in time. What that does is, if you say secondary progressive with activity, that is every secondary progressive patient because, by definition, they had to have activity at some point. Then the regulators split on how they defined activity. 

In the United States, where the regulators don’t accord a lot of respect to MRI, they only talked about clinical activity. The European regulators talk about clinical and MRI activity, but again, neither one specifies the timeframe. One could have done that, but even then, you were looking at a subset analysis of a clinical trial. As scientists, we’re always cautious about what we do with subsets and how we interpret them. This is an interesting situation. We have a paper in press right now in Neurology trying to clarify these issues for the community, so at least they will understand what the concepts are around having activity and not having activity, and most importantly, this issue of timeframe.  

Role of Siponimod in Multiple Sclerosis

: Let’s move on to ocrelizumab, and Patricia, you lead us off on that. 

: Well, I’d like to talk about ORATORIO, which was the phase 3 primary progressive trial because ocrelizumab is the first DMT [disease-modifying therapy] approved for primary progressive MS [multiple sclerosis]. This trial entered about 732 primary progressive patients. They were randomized 2 to 1 to receive IV [intravenous] ocrelizumab 600 mg every 6 months or placebo. The primary outcome was confirmed disability progression at 12 weeks, and that was met 33% versus 39% in favor of siponimod over placebo. In addition, confirmed disability progression for 24 weeks was met; T2 lesion volume decreased in the ocrelizumab group compared to increasing in the placebo group. You had a positive effect in slowing brain volume loss in favor of ocrelizumab. It was a positive study.  

Now, it was interesting: less than 0.1% of this monoclonal penetrates into the CNS [central nervous system]. If you looked at the curves for the primary outcome, they were separating by 6 months. To me, that has to be an anti-inflammatory extraneural impact, which is pretty amazing. We were able to impact progression in primary progressive MS [PPMS] by manipulating the external immune system, and that’s telling us something very important. Now, this phase 3 trial was informed by a negative phase 2 trial with rituximab in primary progressive MS, where in an analysis, for younger PPMS patients who had enhancement of focal inflammatory component, they had a positive treatment effect of the rituximab.  

ORATORIO capped the age at 55. They had to be ambulatory. They had to have abnormal spinal fluid as an inflammatory marker. They couldn’t have PPMS longer than 15 years, and indeed, they had about 26% going into the study who had enhancement, and the group that had enhancement had a better response with regard to progression. The question is how much that can be applied to other cohorts. I’ll mention one other very bothersome thing. The FDA asked for an analysis based on sex, and there was no progression effect in women with primary progressive MS. It made the men’s response look better. This is puzzling. I don’t think it’s real, but it is being addressed in post-marketing studies with ocrelizumab. 

: Your initial experience with it? Not so much initial anymore; it’s been around for 3 years. 

: This is a humanized anti-CD20. You have to have reasonable expectations. It’s also approved for relapsing MS, where it’s a stellar treatment. It’s not saying it’s going to stop progression. It slows it compared to placebo or compared to no treatment. The patients need to have accurate concepts of expectations of what it’s going to do. As you get to older groups, nonambulatory groups, or individuals who have a lot of comorbid conditions, if you’re concerned about immunosenescence, it does raise concerns about risk-benefit ratio with this agent.  

Ocrelizumab for the Treatment of Multiple Sclerosis

: In Europe, England and Germany, is this approved for primary progressive MS [multiple sclerosis]? 

: Yes, it is approved, and based on the experiences in Europe with the ocrelizumab, especially from Sweden, it entered the market, and there was already a very positive feeling when an approved B-cell depleting agent entered the field. This is why it’s also quite frequently used, but I agree. It’s more used in patients with relapsing-remitting MS where it has a significant impact on the disease course. However, we are now starting to treat more patients with PPMS [primary progressive MS] because there is a lack of alternatives, and the hypothesis behind to interfere with the B-cell compartment and maybe to get, sooner or later, more B cells out of the brain is intriguing, in my opinion. However, we have a bit of a problem. We are wondering, when do we stop ocrelizumab in a PPMS patient, because as already mentioned before, we are not claiming that progression is fully stopped. It is somehow slowed, but when do we see a point in time to say, “In this given patient, the efficacy is not as expected?” This is, for me in the clinics, quite difficult to define, and I would be happy to learn your strategy of when to start ocrelizumab, but also when you think about cessation. 

: We use ocrelizumab method for primary progressive MS in the United Kingdom. We’ve also had discussions about this issue around time and activity, and in the United Kingdom, active has to have been in the last 3 years. To initiate on ocrelizumab, patients need to have had either a Gad-enhancing lesion or new T2 lesions appearing on their scan in the last 3 years, and be ambulatory, and be in the early stages of primary progressive MS to try to recapitulate the clinical features that seemed to be associated with greatest benefit in the trials.  

Like Sven, a big dilemma in treating both relapsing and primary progressive MS with ocrelizumab is when do you stop treatment? Because over time, we’re seeing increasing reports of low immunoglobulin levels in patients who had been treated with B-cell depleting agents for a prolonged period, and we are aware that the pharmacodynamic effect on B cells lasts much longer than the licensed dosing interval of 6 months. Whether there is an opportunity for an adaptive dosing or personalized dosing based on, for example, CD19 counts, these are all areas of uncertainty with this drug. 

: How did they come up with the 3-year definition? 

: The 3-year definition of activity was taken as a line in the sand, and I think 3 years is not unreasonable. We know the activity is less common in people with primary progressive MS than it is in, say, early relapsing MS. There are different risks to this treatment, and you want to try to identify patients who are likely to benefit on the basis of recent inflammatory activity. Three years is not an unreasonable line in the sand. 

: I’m intrigued and often puzzled about how regulators come up with these numbers because they don’t necessarily comport with the clinical data that are available. My experience with this is, one little paradox, and that is when I’m evaluating a primary progressive patient, and I tell them I want them to go out and get an MRI, they look at me a little funny when I say, “I hope I see a Gad-enhancing lesion,” because normally, you don’t want to see them, certainly not in our relapsing-remitting population. As Patricia alluded to, there was a hint. It wasn’t statistically significant, but there was a hint that if you had activity on your MRI, that you would do better. This was the whole business with siponimod, which we talked about, but it is a little paradoxical. I want to see something change. I’d feel a little more comfortable.  

My experience is that I have some people who do very well on it, and then some people who don’t. The ones who continue to progress, those are the ones I take off: I stop it. If someone’s doing OK, I continue it. I think from a pharmacobiology point of view, we still have a lot to learn about these self-depleters, just as you folks alluded to, in terms of the durability of the effect and even trying to get a better understanding on the nature of the B cells that return, initially, as they’re returning and whether they may be a more protective population. That will more rationally guide our re-dosing, which right now is not done terribly rationally, but there is a lot more to learn with that. 

: Maybe that’s something that COVID-19 is going to teach us, Fred, in that we have large numbers of patients around the world who are deferring further courses of B-cell depleting agents because of fears that immunosuppression might be associated with a higher risk of developing COVID-19 infection or a higher risk of more severe infection. Maybe we’re going to start getting some of these data from real-world practice in 2020. 

: That’s a very interesting thought because that’s exactly what we’re doing. We are delaying, and we’re delaying not only because of the concern of immunosuppression but also because of the capacity of our infusion centers to distance people. The number of patients they can deal with has gone down. And we’re trying to limit trips to the hospital and to the infusion center. We should hopefully learn something good from that. 

Role of Ocrelizumab in Europe for Multiple Sclerosis

: Let’s move on to the diroximel fumarate, Patricia. 

: It’s a prodrug that has monomethyl fumarate, which is the active agent of dimethyl fumarate. It’s packaged differently. This was studied in EVOLVE-MS-2, which was a trial that entered about 506 patients with relapsing MS [multiple sclerosis]. It was only a 5-week trial. The patients were randomized to dimethyl fumarate 240 mg PO [by mouth] twice a day, or diroximel fumarate 462 mg twice a day, so that’s 2 capsules twice a day versus the 1 capsule twice a day. The primary outcome was gastrointestinal [GI] symptoms rated on a daily scale. They were significantly less with diroximel fumarate compared to dimethyl fumarate. The dropout rate due to [adverse] effects of GI was much less with diroximel fumarate. In other words, this is a differently packaged DMF [dimethylformamide] that significantly decreases the GI [adverse] effects of DMF, and you don’t need to take it with food. This has now been approved. It’s on the market here. Right now it’s being suggested that, if there was somebody who you would want to start on DMF but they had GI issues, you could consider using diroximel fumarate, or if somebody starts DMF and they have GI issues, you could switch them. It’s interesting. 

: It’s not approved at the moment in the United Kingdom, but at least in my practice [at the National Hospital for Neurology and Neurosurgery], gastrointestinal disturbance is one of the main reasons that people discontinue dimethyl fumarate, at least in the first couple months of treatment. I see this as potentially being an attractive treatment option in patients who, as Patricia says, don’t tolerate dimethyl fumarate, or those who have irritable bowel syndrome or other gastrointestinal comorbidity, you may want to start this in preference to dimethyl fumarate. 

: We also haven’t gotten approval yet, but it’s a very valuable option. I also don’t know why we continue on Tecfidera [dimethyl fumarate] if we can have it without the [adverse] effects. 

: It’s hard to understand, but patients starting on Tecfidera without [adverse] effects are very happy with this drug. We do see a certain percentage of patients starting the drug, but they have to stop because of [adverse] effects. If we can now significantly reduce these [adverse] effects, that would be fantastic. 

Role of Diroximel Fumarate in Multiple Sclerosis

: Let’s move on to the last agent we’re going to discuss with you, Sven: that’s ozanimod. 

: Ozanimod. Now it’s getting difficult to get a differentiation between the different sphingosine 1-phosphate [S1P] modulators because ozanimod is also claiming to be very specific on S1P1 and S1P5 receptors, and therefore, the profile looks quite comparable to siponimod, which we discussed a minute ago. However, there have been several trials, phase 2, phase 3…. In the phase 2 study, RADIANCE, it could be shown that ozanimod reduces the activity on MRI compared to placebo, and this was then the reason to continue with the phase 3 trial, the SUNBEAM trial, a multicenter randomized trial. There, they compared ozanimod versus interferon beta-1a, and they could show that, if patients are treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate compared to interferon beta-1a. 

The safety profile seems to be as expected for this class of agents, and the study was further supported by a second phase 3 trial, the RADIANCE Part B trial, where the patients were randomized and treated over 24 months. For Europe, the approval makes a difference. As mentioned before, we have this specific approval for fingolimod and siponimod, so ozanimod would be the first S1P modulator entering the market in our hands for first-line therapy. The study was significant when it comes to MRI and annualized relapse rate. However, the effect on disease progression was not significant, and this started a whole discussion. My opinion on this is that, even in the interferon beta-1a group, there was not much of a progression, so concerning the secondary endpoint of the study, the study might be underpowered. 

: Has it been approved in Europe as well as in the United States? 

: Not yet, but you’re hopeful that it will be approved for relapsing-remitting MS [RRMS]? 

: You think it’ll be treated differently than the fingolimod because it won’t have a first-dose observation? 

: Yes, because maybe the safety profile is a bit in favor of ozanimod because we don’t have the first-line observation, and the study is clearly targeting a cohort of early MS [multiple sclerosis] patients. It’s recruiting-relapsing remitting patients aged between 18 and 55, and they are starting with a EDSS [Expanded Disability Status Scale score] between 0 and 5, so this is, in my opinion, an early RRMS cohort. But you are right, maybe they have the idea that it should be approved comparable to fingolimod or siponimod. This is not necessarily, as discussed before, based on the available data, so I’d be surprised. 

: There are some nice MRI data that have come out from the phase 3 trial program of ozanimod. One of the things that’s concerned us has been that it didn’t appear to be a reduction in disability progression, and that’s probably because this is a tough end point to make in patients with very early MS when you’ve got an active comparator. What was impressive were some of the MRI data that came out of the phase 3 trial program where they looked at some pretty advanced MRI, in particular, not just whole brain atrophy but gray matter atrophy, which may be better correlated with later physical disability and particularly cognition. They showed an 80%-plus reduction in grey matter atrophy in the ozanimod treated patients. This is potentially exciting, and in Europe if this has a first-line license, it’ll be a particularly useful addition. 

: Patricia, how are we going to decide which S1P to use? 

: It’s interesting. Ozanimod breaks down to 2 major metabolites that make up 88% of the active drug. Their half-life is 11 days, so this needs a washout at 3 months. It’s a longer washout than fingolimod, and way longer than siponimod. And if you think about the S1P receptor modulators as a whole cohort and you’re going to choose 1, I’d choose the 1 that had an effect on your degeneration plus the relapsing form of MS. You’d have to give me a good argument to not choose that 1. 

Role of Ozanimod in Multiple Sclerosis

: Let’s move into our next segment, which is sequencing therapies. Wallace, I’m going to start with you with this question: How do you monitor response to treatment and disease worsening? 

: We routinely monitor both clinically and with MRI. The clinical measures that we’re most interested in are relapse rates and disability. There are different ways of measuring disability. The way that is most established is to measure the EDSS [Expanded Disability Status Scale] score, which is largely derived from the results of the neurological examination and walking the patient. Although increasingly, we’re integrating into our clinical practice other measures of disability, including the timed walk test for lower limb function, 9-hole peg test for upper limb function and dexterity, and measures of cognitive impairment like the SDMT [Symbol Digit Modalities Test], which is fairly easy to integrate into clinical practice. 

In terms of MRI monitoring, at our center, [the National Hospital for Neurology and Neurosurgery], we undertake at least annual MRI follow-up. We focus on following the brain MRI. We tend to use less and less gadolinium in our center, mainly because we’ve sorted out MRI protocols, and patients are now all receiving a 3D flare scan, which facilitates new lesion detection very easily without the use of gadolinium. After arranging a re-baseline MRI, say 3 to 6 months after starting on a therapy, we’ll then do regular MRI scans to measure response in terms of looking for new T2 lesions. 

: Sven, taking into consideration what we can measure, which Wallace has nicely outlined, how do you make a determination as to when we need to switch? 

: This is always based on an individual decision. Following this concept of patient empowerment, we normally try to discuss all the decisions together with the patients, and we try to make a joint decision. My opinion is that the decision is largely focused on the efficacy of a drug. The treatment effect concerning the efficacy is normally driven by relapses because these are easy to count and are along the guidelines. I think it is supported by EDSS progression and maybe by new lesions; however, all of the additional measures are, in my opinion, very useful. Wallace mentioned the SDMT, which is important concerning cognition atrophy scores, and the MRI might be important.  

However, the treatment decisions are still based mainly on relapse activity and new lesions, and there is also an interesting note. This was also reported in a paper that the patients are much more engaged earlier in treatment decisions, but if it is then not working, the physician is more and more taking over because he or she feels more informed compared to the patient. We start with a joint decision, but sooner or later, the physician takes over in a way. 

: There are various reasons why you might switch therapy. Breakthrough disease activity in the AAN [American Academy of Neurology] 2018 guidelines said, a year on treatment, if there are 1 or more clinical attacks, worsening on the examination, or 2 or more MRI lesions, it should trigger a discussion about switching. 

Adverse events, intolerable adverse events; with multiple options, a patient should not be forced to stay on a treatment that they’re miserable on and hate. A treatment that led to a laboratory disturbing abnormality in liver enzymes, or white blood cell count, or lymphopenia would be a fair reason. Neutralizing antibodies that were persistent in the case of natalizumab would indicate it should be switched, and a changed risk-benefit ratio that was now unacceptable to the patient and the physician would also be a reason to talk about switching. There are multiple reasons that one might switch. 

: I agree with all of those comments. One area of uncertainty is what to do with patients who are progressing on a therapy. So in people who are taking a medication and they’re not experiencing relapses, and their MRI is stable, but their EDSS is worsening. We’re lacking evidence about how best to treat those patients, and that’s something that does need to be addressed going forward. 

: You highlight an important issue, and that is the near absence of decent evidence on defining inadequate treatment response. Adverse effect profile is easy, but inadequate treatment approach is something we haven’t done yet, so it becomes, as Sven started out saying, a very individual thing. It is a conversation with you and the patient. It’s interesting what Sven points out, that patients become engrossed or embedded in their own therapy and become a little more resistant over time to switching than they would be earlier on. That’s an interesting observation, but we need data. Unfortunately, it looks like the data are going to be agent specific because what little data we have that came out of the Barcelona group suggested that the indicators of an inadequate response to interferon didn’t necessarily hold up to be inadequate responses for glatiramer acetate. It’s certainly an area that we need to explore and develop better guidelines for because our patients need it, and our economics need it, and we need to figure out how to do that. 

Switching Therapies in Multiple Sclerosis

: Let’s move along and talk a little bit about engaging patients because shared decision-making is something that gets a lot of lip service, but in this disease, it is extremely important. Patricia, why don’t you say a little bit about that? 

: Shared decision-making is very important. Knowledge is power. It’s the patient’s disease; they have to live with the treatment, so you want to engage them. You want them to be a partner, you want to instruct them, and you want them to understand realistic expectations from the therapy, how they need to follow-up, and what we would be looking for so that they buy into the treatment. Shared decision-making does not mean you ask the patient, “What do you want to go on?” Shared decision-making does not mean the doctor decides, “This is what you’re going to go on.” Shared decision-making means we communicate. We elicit what is important to the patient. We tell them what we feel is in their best interest based on our acute assessment of their disease, their particular desires, and the drug properties, and we make a strong recommendation, but we’re choosing as a partner, and that gets adherence. That gets buy-in from the patient. 

: We have to work as partners with our patients as Patricia said, and you can bet your bottom dollar that, if you put a patient on a treatment they do not want to be on, they’re not going to take it. 

: If we want to have a relationship over time with our patients, we have to go for shared decision-making because if we decide something and it is not working, we will lose the patient, maybe forever, and we will not have a second chance. If we explain our rationale, if we give a strong recommendation, and as mentioned before, if we convince the patients that the decision is in their best interest, then it’s a shared decision. If then something is not working, we have quite a good chance that the patient returns to us for a second guess and a second shot. 

: There is an important clinical skill involved in this, and that is reading what the patient wants from you. We’ve seen criticism of both ends, of people saying, “The doctor didn’t pay any attention to what I wanted to do with my body,” to the other side, people saying, “I went to this physician for them to tell me what I needed to do for my disease, and they kept asking me what I wanted to do.” There is a certain skill in there to figuring out how to best meet the patients’ needs and incorporate that into the decision-making. 

Decision-Making Process for Treating Multiple Sclerosis

: The last segment we’re going to discuss is looking ahead to the future. First, Sven, talk a little bit about the potential for biomarkers.

: There are a number of new biomarkers published and evaluated in clinical trials. Some of them are quite interesting. Maybe we can discuss a bit concerning NfL [neurofilament light] because there was a huge body of evidence. NfL is interesting because it is a protein, a neurofilament light chain. It is a protein expressed in axons, so it indicates how much tissue is at risk or already degenerating. All of the data presented so far indicate that it is also an inflammation driven biomarker. This is a problem that lies in the disease because, if we have inflammation triggering neurodegeneration, maybe it will not be possible to identify a marker indicating pure degeneration. This is why we have the correlations with NfL and Gad-enhancing lesions or also number of relapses. If we have a stable patient with the clinical readouts, like relapse activity and MRI, this can give us an additional hint if this patient is stable as indicated by the classical readouts or if they have to be treated in a different direction. 

These new biomarkers might also help to develop new study designs; for instance, the INFORMS trial where fingolimod was tested in patients with primary progressive MS [multiple sclerosis]. There have been some effects that could not be detected due to the readout parameters because how much progression do we need in such a clinical trial over 2 or 3 years to make a difference with a disease-modifying therapy? However, if we would enter the field with such a study that might be biomarker driven, the responders may be indicated by a reduced amount of NfL, even in this cohort. Then, maybe we can continue a study for a longer period. There might be a reason why these biomarkers could really help in clinical practice and for study design. A second biomarker I’m interested in is OCT [optical coherence tomography] because this is available. It’s a fast measure, and it might also help to depict near degenerative aspects in our patients. This is why I picked NfL and OCT, but if you have additional markers, I’m happy to hear about them.

: Yes, those are good ones. Patricia, what are you seeing changing in terms of managing the disease for the future?

: I would mention 3 areas. Number 1, there is a major focus on the neurodegenerative component of MS, progressive MS, and CNS [central nervous system] repairs. We need strategies for progressive MS, neurodegeneration, and we need strategies for CNS. Secondly, artificial intelligence, machine learning applied to neuroimaging. What we’re finding, unfortunately, is that the computer is better at reading and analysis than the human being, and we’re going to see some major breakthroughs as we apply machine learning, artificial intelligence to analyze MS. Finally, wearable devices at home that can look at activity that are picking up transition to secondary progressive MS before the patient realizes it, at-home computer type devices. COVID-19 [coronavirus disease 2019] has pushed us into telehealth: all of us. We’ll see a burgeoning and selective use of that, more computerized ways to treat MS, and more home devices to monitor this disease and get a better handle on it.

: Excellent. Wallace, what advice do we have for our colleagues out in the community?

: Fred, one of the biggest challenges facing all neurologists treating MS at the moment is this dizzying array of treatment options that we have available. Increasingly, as we’ve heard already in this panel discussion, this concept of first, second, third line is maybe not the right way to be going. We have to try and tailor our therapies to the patient, depending on the disease profile, the number of relapses, what their MRI is looking like, what the level of disability is, their comorbidities, and desire for family planning. One unresolved question in the MS field is this: Are we better to take an escalation approach to therapy, or should we be hitting patients hard with more effective medicines early in the course of the illness?

Now, increasingly over the last couple of years, we’ve had more and more observational data. For example, from the MS base suggesting that earlier use of highly effective medications is associated with a more favorable prognosis and lower risk of developing SPMS [secondary progressive multiple sclerosis] in the future. Hopefully we’re going to get some more definitive answers to this question from the ongoing phase 3 studies DELIVER-MS and TREAT-MS with patients being randomized to either an escalation or early intensive treatment approach in a rather pragmatic way that should be quite generalizable to everyday practice.

: Well, thanks, all of you, for this rich informative discussion, Dr Brownlee, Dr Coyle, and Dr Meuth, and thank you again to our viewing audience. We hope you found this NeurologyLive® Peer Exchange discussion to be useful and informative.

Global Approaches to the Management of Relapsing Multiple Sclerosis