Staff neurologist, Unity Health Toronto–St Michael's Hospital; assistant professor, University of Toronto

Kristen Krysko, MD

My last question is going to be to Joe and Fred, again in the context of looking ahead. What advice would you give to community-based neurologists who are treating patients with progressive MS [multiple sclerosis] and may not have access to the multidisciplinary teams that specialist centers have at their disposal? A lot of people live in rural areas and have a harder time accessing the MS centers that are typically in major metropolises. How do you advise the community-based practitioner?

Managing MS is complex. It’s multifaceted and time-consuming. One of the things that I always recommend is: Don’t be afraid to reach out. I practiced in a state that was predominantly rural. There were fewer neurologists for the entire state than we have in the city of Philadelphia. It was very often that I’d see patients who had MS maybe once or twice a year and then co-managed these cases with their community physicians. There was no way that they were able to get into Lexington, Kentucky, with the frequency that they would have had I been practicing closer.

The most important bit of advice is: Don’t be afraid to reach out to people who have skills in managing MS, because it’s become much more difficult these days. There was a time when we really didn’t have any therapies for multiple sclerosis. It wasn’t all that long ago. It was certainly while Fred and I were practicing. With the new drugs as they’ve come onto the market and the new ways of monitoring patients and their symptoms, it’s sometimes best to have an individual who has experience with doing so weigh in periodically. Don’t be afraid to co-treat patients. Even if it’s a phone call, it’s often worthwhile. 

 I agree with what Joe just said. It requires comprehensive care. We had that conversation already. It’s obviously not available in the community. But what we do is we partner with the guys out in the community. I have great respect for the guys doing general neurology because they have to know a lot about what I know and a lot about epilepsy, migraines, and Parkinson disease. All these areas have become more complicated as well.	

We’ll partner. We’ll see their patients about once a year, and they’ll work with them in the interim. That way they have the advantage of our comprehensive care staff, but they still could be far away, not have to travel as far, and have a local neurologist as well. Now with telehealth, we’ve expanded the range of people we can see comfortably, where they don’t have to travel into the city as often. 

That’s great. One of the teachings from the pandemic is that we are able to help patients remotely. All of us have developed a set of telehealth skills that we never had before as a consequence of not seeing patients in person and asking people not to travel. This has added to our skill set. 

This has been a fantastic discussion. I want to thank Dr Krysko, Dr Lublin, Dr Fox, and Dr Berger for their participation in today’s program. Thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Videos

Joseph R. Berger, MD, and Fred D. Lublin, MD, offer advice to community physicians and neurologists in managing patients with multiple sclerosis. 

Advice for Managing MS 

 In our last section for discussion, I want to turn our attention to looking ahead and what we think the future is going to look like for managing MS [multiple sclerosis]. I’m going to ask Kristen and Bob to comment on this. Where do we go from here? What do we do next?

We focus on progressive MS, which we’ve been talking about. As we highlighted, we need to focus on having better ways to identify progressive MS, to diagnose it early at a time where they may be more treatable, ways to monitor and capture progression, not only for clinical practice, but also to study medications and their effect on progression. We need to look at developing better tools, be they MRI measures, biosensors, laboratory measures, that can help us monitor and diagnose progression. There’s a lot of work going on in this area. In the future, we’ll have better ways to monitor that. 

As we’ve talked about, we have medications that target inflammation very well and seem to target the active part of progression if someone’s also having relapses or inflammatory activity. Developing strategies to target that progressive aspect of the disease and having a way to get that into the clinic would be a big step in the right direction.

We also need to improve access to multidisciplinary care. A lot of these symptoms we’ve talked about—the fatigue, exercise, nutrition—can all be helped by having a multidisciplinary team in the MS clinics where patients can meet with all many different health care disciplines to optimize their function, even if we’re not able to stop or slow the progression as much as we would like. 

I agree. Progressive MS is the big nut that is waiting to be cracked, to figure that out. A key aspect of progressive MS that is an unmet need is: What is it? What is the pathophysiology of progressive MS? What is driving that slow, insidious decline? If we knew that, we could better direct and design treatment trials to test new therapies.

We also need to better understand the 2 ends of the relapsing MS management spectrum. Early on, what is the ideal treatment? Are there biomarkers that can point us to which therapy patients will respond to better? There’s that age-old question: Do we start low and gradually escalate, or do we start with very aggressive therapy? There are 2 ongoing trials that are looking to address that. It’s an important question. Do we come out of the gate guns blazing with a highly effective therapy, or do we escalate? Is that an acceptable approach?

At the other end of the relapsing spectrum are the older patients who probably don’t need MS therapy. Can we stop the therapies? How do we stop them? What are the risks and benefits of stopping them? There are a couple of ongoing trials, from which we should get answers over the next few years. It’s an important question. We have our patient doing well, but does the patient still need therapy now that they’re 20 or 30 years into their MS?

Discontinuation of treatment is a very interesting and highly controversial topic that we’re going to have to wrestle with more and more as our patients age out of the inflammatory phase of the disease.

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Kristen Krysko, MD, and Robert Fox, MD, look to the future of multiple sclerosis management. 

Future of MS Management  

 We’ve touched upon nutrition and cognition. What about exercise? Joe, can you comment about exercise in MS [multiple sclerosis]?

 Sure. I recommend exercise for all of my patients, regardless of whether they have MS. It’s important. I do think that exercise in patients with MS is valuable for multiple reasons. These patients often become deconditioned. They also often have problems with their strength and balance. Various forms of exercise, particularly aerobic exercise, can be helpful in that regard.

There’s hardly a patient I see who, when I ask them to do a tandem gait, doesn’t tell me, “I’m better today at it than I was last time I was in the office because I’ve been practicing it.” That’s true of anything we do. If you practice it, you get better at it. In terms of strength and balance, exercise is important.

Another important factor with respect to exercise is maintaining or reducing your weight. As I believe Bob mentioned earlier, one of the things that’s important is to not be obese. Don’t smoke, take your vitamin D, and don’t be obese. Exercise also helps in maintaining the appropriate weight.

A third benefit of exercise is less fatigue. When people exercise, we find that levels of fatigue are improved. Their sleep is also improved. There are many benefits to exercise, and it should be strongly encouraged.

Is there a particular form of exercise that people should engage in? I think it’s a bit like diets. We don’t really have any evidence that there’s a particular form of exercise that is beneficial. It’s important to just get off the chair and get on the exercise bike, treadmill, do Pilates, or whatever you can. That’s what I tell my patients.

 You didn’t mention squash or racquetball, Joe. 

That’s true, I didn’t and I don’t. It’s usually a little too vigorous. 

I would also add that mood is known to improve with exercise.

With depression being as common as it is in patients who have MS, there is evidence and some trials now underway to evaluate the direct impact of routine exercise on mood. 

I tell my patients that the best exercise for MS is the one they like to do. Because that’s the one they’re more likely to do. If you tell Joe to do yoga, he’ll laugh at you. But if you tell Joe to go play racquetball or squash, he’ll be on the court this afternoon. The most important thing is the exercise that the patient likes to do. Aligning your recommendations with their preference is key. 

Exercise is important. Fred, what do you do with your patients who are combating fatigue? How do you evaluate fatigue, and then what do you do about it? 

First, try to determine whether it’s the true fatigue of MS, fatigue from being depressed, or fatigue because they’re not sleeping well enough. That’s not all that difficult to sort through. The one that’s probably the easiest to deal with first is sleep. We do a sleep hygiene assessment to try to sort that out. Then we do simple things. We ask people specifically about whether they’re having spasms at night that are waking them up. They don’t have to be painful. They could just be spasms that wake you up. So you work on sleep hygiene. 

Mood is an important one. We deal with that. If that all works, then you get a good description of fatigue, which is different from what ordinary people think of fatigue. Sometimes the patients can’t describe it, but you hear it enough from them when they say it’s different, or it’s not like when they have the flu or any of that sort of thing. 

Then we try to treat it. If it’s depression, you treat their mood. If it’s sleep, you deal with sleep problems. The problem with trying to treat fatigue pharmacologically is that the data are so bad. The TRIUMPHANT-MS study was just published, which said, “We don’t think any of these work, except for maybe sleep issues.” But when we discussed this during our ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis] course, most of the clinicians said, “We saw that data, but it wasn’t a responder analysis,” which is an important critique. 

I try these various agents, modafinil or amantadine, because as with any of the symptom management medications, you can determine pretty quickly whether you’re doing anything. You could try it for a couple of weeks. If it helps, there’s not much cost to it because they’re pretty well-tolerated. I do avoid stimulants because I don’t like to get into those. But I will try things like modafinil or amantadine.

Considerations regarding the role of exercise and combatting  fatigue when treating patients with multiple sclerosis.  

Exercise and MS Fatigue 

 I want to discuss other aspects now. Bob, do you use nutrition in MS [multiple sclerosis]? If so, is there a particular diet you endorse? What’s your approach to this aspect of lifestyle management in MS?

 It’s very common for patients to ask, particularly at the time of diagnosis when we start talking about therapies, “What else can I do to help with my MS? What else can I do besides those drugs?” They may be antidrug or on board with a drug, but they want to do more. Diet is one of the things that patients most commonly think of initially. At this point, we don’t know the best diet for MS. There are a number of ongoing studies. There have been diets purported to help MS for many decades, going back to the 1990s with the Swank diet and a number of others.

The best evidence right now is for a heart-healthy diet, the so-called Mediterranean diet. There have been some fairly good epidemiologic studies, including by the group I help direct, the NARCOMS [North American Research Committee on Multiple Sclerosis] MS patient registry, that has found that patients with MS who follow a heart-healthy diet, the Mediterranean diet, appear to do better over the longer term than patients who don’t.

In general, I recommend the heart-healthy Mediterranean diet, along with controlling other medical conditions like diabetes and hypertension. They are known to have an adverse effect on MS, along with smoking. I’ve had many patients ask, “What diet should I follow for my MS?” I’ll say, “We don’t really know. Heart-healthy. But stopping smoking is the most important thing you can do to help your MS.” Smoking cessation, a heart-healthy diet, and controlling common conditions like hypertension and diabetes are the things I focus on when patients ask about complementary and natural therapies for MS.

Thanks, Bob. Kristen, I want to ask you about 2 topics. First, I’d like to get your opinion on the concept of neurological and cognitive reserve and how it applies to MS. Also, I’d like you to comment on cognitive impairment and what strategies you might use to manage cognitive impairment in MS. You spoke earlier about monitoring patients with the Symbol Digit Modalities Test and other measures of cognition. But once a patient has developed cognitive impairment, how do you help those patients?

 Sure. Cognitive reserve is a concept in other areas as well, like Alzheimer disease. It relates to the resilience of the brain to damage before resulting in impaired cognition. This seems to be affected by a number of factors: level of education, IQ, occupation, certain lifestyle factors like exercise, cognitive leisure activities like reading, writing, being involved in the arts, and playing structured games like cards. These can all improve cognitive reserve. This would explain why 2 people who may have similar-appearing MRIs, a similar amount of atrophy, and a similar number of lesions, may have different cognitive function. Some MS studies have demonstrated that those with measures of higher cognitive reserve may have less impact from their lesion burden on cognition. That’s the concept. 

In terms of patients who have cognitive impairment, prevention is best. If we’re able to treat someone with an effective disease-modifying therapy earlier in the disease to prevent cognitive dysfunction, that’s the best thing we have. Once someone’s developed it, we have difficulty treating that. I don’t think we have any good treatments to improve cognition once the damage has been done. 

I tend to refer to our neuropsychiatrist, Anthony Feinstein MBBCh, PhD, who’s in Toronto. He’s done a number of studies and work in this area. He has cognitive testing performed and a multidisciplinary team that then does cognitive and physical rehabilitation. That helps, and helps engage some of the patients who may be having higher levels of disability. I’ve heard positive reviews from patients. 

Evaluating for potential reversible causes of cognitive dysfunction is important. If we identify that a patient is also deficient in vitamin B12 or has thyroid abnormalities, those can be addressed. The same goes for sleep disorders. If someone has sleep apnea resulting in fatigue and impaired cognition, that can be treated. Addressing those other potential contributors can be helpful.

Patients with progressive MS may be on a number of symptomatic therapies that could also affect cognition. If someone’s on a number of neuropathic pain medications, antispasticity medications, or medications for overactive bladder, those could also potentially contribute to cognitive symptoms. Considering that and optimizing their medications can be helpful.

Dr Feinstein has also done a number of studies with cannabis and cognition. Cannabis does seem to impair cognition, even when one’s not actively using it, so addressing that if they’re using cannabis is potentially helpful.

I don’t think we have a lot of treatment that benefits cognition. There have been studies of stimulants and antifatigue medications like modafinil, and there are conflicting findings. Some studies have shown benefit, whereas others have not. Then importantly, memantine was shown to worsen some symptoms of MS, including fatigue and cognition, despite it being used in other neurodegenerative diseases. Avoiding that is also helpful.

 Thanks, Kristen. That’s a superb review of cognitive dysfunction, and what we can and perhaps can’t do at this point.

The importance of proper nutrition as a therapy for symptom control in multiple sclerosis and some strategies to manage cognitive impairment. 

MS: Nutrition and Managing Cognitive Impairment  

 I want to come back to a topic that Joe and Fred had touched on earlier: shared decision-making. It sounds like Joe is willing to try things and be a bit more aggressive in terms of therapeutic management. Joe, how do you have these discussions with your patients? What is your approach to shared decision-making when you don’t have overwhelmingly compelling data to make a therapeutic decision?

It’s laying out the facts as we understand them, explaining to the patient what the likelihood of benefit is going to be, and explaining what the risks are likely to be. Patients are your partners. If they’re not willing to take a medicine, it doesn’t make any sense in prescribing it. In my opinion, if they’re very keen on being treated, even when the evidence is soft, they should be given the benefit of the doubt and treated. 

Of course, it depends on the patients’ risk tolerance, what their treatment preferences are, whether they prefer infusions or oral therapy, and whether they have comorbidities that may preclude the use of a particular drug. All those things have to be discussed with them. 

We’re very fortunate in our institution to have 3 pharmacists who work in the MS [multiple sclerosis] clinic. In addition to hearing from me about these drugs, they invariably sit down with the pharmacist and spend another half hour to an hour going over the nature of the drugs, the benefits, adverse effects, and the monitoring required with the drugs. They make a decision after hearing that. It’s very much an integrated event, the nature of treatment that people get started on. 

This takes us right into a very important element of today’s discussion. We’ve spoken a lot about medical management of disease-modifying therapies in the context of appropriate and accurate diagnosis and considerations of things such as disease activity and patient age. But there’s so much more that goes on in terms of what we do to help patients.	

I want to turn our attention to what might be considered complementary approaches to medical management. This has to do with natural therapies and symptom control in MS. For some of our patients, we’re going to be reticent to start high-potency disease-modifying therapies. These may be patients who are older than those who had been studied in clinical trials or have worse disability, such as being wheelchair-bound. There are no data to support use of these potent immunotherapies in these patients. There could be very serious consequences for the patients’ overall well-being from the use of powerful immunosuppressants.

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Joseph R. Berger, MD, elaborates on the importance of shared decision making in the treatment of multiple sclerosis and how it relates to complementary and natural therapies for symptom control. 

Shared Decision-Making and Complementary Therapies in Progressive MS

I’m going to come back to this point, because I think it’s an important one. A lot of our patients who are on these platform therapies don’t have evidence of disease activity. The platform therapies, even teriflunomide, are very effective at suppressing MRI lesions, so you may not see a new lesion. But the patients can still progress. 

Let’s say you’ve got a younger patient, somewhere between the ages of 50 and 55, and they’re worsening despite treatment with the platform. What do you do then? It sounds like you’re a bit more conservative with those patients, Bob. Are there other opinions out there?

Firstly, if I see disease activity, regardless of whether the patient has progressive disease or not, I’m going to switch their medication. That’s another story altogether. 

The real question is: if the patient is progressing in the absence of any disease activity that’s apparent clinically other than their progression, or radiographically, what do you do with them? I have switched them. I don’t know whether it’s the right thing to do, because as Bob mentioned, we don’t have the data to support that. But I would give them the opportunity that wouldn’t exist if you didn’t switch them to a medication in which there has been some positive data generated that there’s an effect on progression. I will switch them to one of the drugs that has been demonstrated to have some effect on progression. I usually switch them to an anti-CD20, but I would switch them.

 I sort of agree. I would try either one, especially in someone who wasn’t old. That’s the group where I’m most likely to get a benefit. I’ll give them a year. I like to monitor for people for a year on one of these. At the end of the year, I can get an idea of whether we’re having an effect on their progression, of course, understanding that progression can settle down on its own. 

The big concern in people who are on any of the therapies and doing well, but are slowly progressing, is: if you took away that therapy, would they progress more? That’s also one of the things we think about as part of the conversation, saying, “You’re no longer doing them any good. Stop the therapy altogether.” But there are a number of unknowns in doing that. Sometimes we’ll do it, especially in an older group. I have a much lower threshold for stopping therapy with older age groups. There is some work out of the Mayo Clinic that suggested that if you’re not progressing after the age of 75, you’re never going to progress.

 It’s a rather curious thing I find in our conversation today, Fred and I are talking about 75- and 80-year-olds while Bruce and Bob are talking about 50- and 55-year-olds. To me, old is like they’ve got to be older than I am.

 It’s all relative. There is something that is going on with age and MS [multiple sclerosis]. There’s clearly an interaction there. We know that contrast enhancement and lesions—we see these macroscopic lesions present on MRI—occur early on in the course of the disease and taper off gradually over time. We know that phenomena is an age-dependent process that we don’t exactly understand. Does it have to do with immunosenescence? Does it have to do with compensatory responses? Does it have to do with exhaustion of target tissue and loss of myelin? There are lots of possible explanations that we just don’t have a good handle on.

Nonetheless, there is this waning effect in terms of age: withering away relapsing activity, relapses decrease in frequency with age, and withering away inflammatory disease activity measured by these macroscopic lesions present on MRI. Age being a major driver for progressive disease and worsening disability is almost as if the MS brain is aging in an accelerating way. 

Immunosenescence is just plain offensive. Joe will agree with that. In fact, earlier today, Benjamin Segal, MD, gave a keynote address at the ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis] Forum. He talked about some of the changes occurring in aging. Immunosenescence is probably an incorrect concept. There are changes, and some of those changes are actually making immune function worse and more toxic in certain ways. This is something that future research will help us with. There are changes with age, obviously, mostly for the better. Nevertheless, there are changes toward a more toxic environment. 

In the very young patients, I will be completely flipped. In the patient who’s in their 20s or 30s with progressive MS, I will take the approach of knowing their risks of complications from these therapies are much lower, and they can’t afford to have another lesion inflicted on their spinal cord. I want to be even more aggressive with my anti-inflammatory therapies to prevent new lesions because they were already struggling at a very young age, and the risks are probably going to be a fair bit lower. I will flip my argument on its head in the very young patients and become more aggressive, even in the absence of evidence of active inflammation. 

Kristen, do you have any comments on this very controversial topic about what to do with patients who don’t have active disease? What do you do with these nonactive progressive patients?

Yes, I have a similar approach. Age is a big factor, as well as level of disability. I’ve seen some bad outcomes in patients who were wheelchair-bound being treated with strong immunosuppressive agents. I tend to steer away from that more. But if someone’s younger, in their 50s, and actively worsening, those are the patients I would tend to treat even without inflammatory activity. 

In Canada, we’re a bit limited sometimes because SPMS [secondary progressive multiple sclerosis] with activity is the only indication for siponimod. We cannot give it if there’s no documented activity. Sometimes the regulatory rules and coverage do impact that. Similarly, we can’t get ocrelizumab covered if we label someone as having secondary progressive MS. We would have to call them relapsing MS. For instance, having a relapse within the last 2 years is required. 

 It’s interesting how these things all shake out in different health care environments.

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Considerations regarding age in treatment decisions in patients with nonactive multiple sclerosis progression. 

Age Considerations: Patients With Nonactive MS Progression  

I want to turn our attention to a topic that was alluded to in our last group discussion, which has to do with monitoring response to treatment and some of the uncertainties there. 

Kristen, how do you monitor whether a particular drug you’re using is working in a patient with progressive MS [multiple sclerosis]? What are the outcomes you look at? Do you use imaging, spinal fluid, or just clinical outcomes? How do you determine whether a particular product is helping your patient?

 Yes, this alludes to what we talked about: these drugs have been shown to potentially slow disability progression, which is a hard thing to monitor in clinical practice. It’s pretty difficult to determine if someone’s trajectory of worsening disability has decreased in terms of the rate of decline. Patients sometimes have a hard time making that determination.

On the clinical examination, it’s also hard to determine. In clinical practice, we tend to use a standard neurological exam and EDSS [Expanded Disability Status Scale] scores, which may be insensitive to detect change. They are problematic, especially because they rely on measuring ambulatory function, whereas they may not capture if someone’s upper limb function, for instance, slowed in decline. It can be difficult. 

In clinic, I tend to add on the timed 25-foot walk because that’s pretty easy to do and is something that we can monitor as well. If they’re not continuing to worsen on that measure, that’s a good thing. But at the same time, we don’t expect improvement, which is sometimes difficult to convey to the patient. 

Ideally, we would also be monitoring cognition and upper limb function. I know some clinics are able to incorporate a CMT [Charcot-Marie-Tooth disease test] or the 9-hole peg test. Sometimes there’s not enough time to do all of this in the clinical evaluation. But if that’s translated into some sort of app or monitoring they can perform during the waiting room time, then that would be beneficial. 

In terms of imaging, I still tend to order an MRI at the new baseline, about 6 months after starting disease-modifying therapy in these patients. I tend to monitor MRI annually, although we’re often not seeing inflammatory activity, and we don’t really have a good measure to determine whether progression is affected. In clinical practice, we don’t tend to use measures of atrophy at this point, but in the future, spinal cord atrophy or other whole-brain atrophy measures may be helpful to monitor that, as would biomarkers such as sensors and monitoring step count. Potentially other laboratory biomarkers could be helpful in the future, but we’re not really using that in clinical practice yet. 

Thanks, Kristen. That’s terrific. One of the considerations when we’re looking at some of our patients as they transition from relapsing MS to secondary progressive MS is about what to do in terms of switching treatment. 

I want to have an opportunity to review that with everybody. I’m going to ask Bob to start that discussion. Let’s say you have a patient on a platform therapy, one of our ABCR [Avonex, Betaseron, Copaxone, and Rebif] drugs, or even teriflunomide. At what point do you decide to transition a patient who you think has secondary progressive MS? Is there a particular go-to drug once you’ve decided that it is appropriate to move a patient onto a progressive therapy?

Robert Fox, MD: What’s important to recognize is we have no clinical trial data to guide our decisions here. I’m not aware of any clinical trials that enrolled patients who had progression on an MS therapy and randomized them to a number of different treatment options. We just don’t know how to best treat patients. 

I follow a first principle approach. If there’s evidence of active inflammation, either clinical relapses or new lesions or active lesions on MRI, along with their secondary progression, then I will shift them to a different anti-inflammatory therapy, whether it be an S1P [sphingosine-1-phosphate], an anti-CD20, or natalizumab. 

If they have solely gradually progressive myelopathy from progressive MS and no evidence of active inflammation, particularly if they’re older—which to me is roughly in the mid-50s and older—then those are patients who I generally don’t move to another MS therapy. I have many colleagues who do. Again, we don’t have clinical trial data to guide us as to what is the right thing to do. But if there’s active inflammation, I will change to another anti-inflammatory therapy. If there’s not active inflammation, particularly in the older patients, then those are patients I will either take off of therapy entirely or leave on their current therapy and instead optimize their symptom management.

Experts discuss how they monitor response to multiple sclerosis therapies and disease progression.  

Monitoring Response in Progressive MS

Bob, I’m going to ask you to summarize the ibudilast study that you were the principal investigator on, and comment on neuroprotection. I want you to define what neuroprotection is. Tell us whether you think ibudilast is a neuroprotective drug and whether we’ll ever see application of this in progressive forms of MS [multiple sclerosis].

 Sure. What we’ve been getting at throughout this program is that progressive MS can have active inflammation, relapses, and new lesions on MRI, but a lot, if not the majority, of the progressive aspects of progressive MS are not that. It is something else. It is this gradually insidious pathophysiology that’s leading to a gradual decline in our patient’s function. The therapies we’ve talked about today have been certainly able to target the inflammation. It’s a little less clear whether they target that other aspect. 

Ibudilast is a therapy that tried to target that other aspect. It is an orally absorbed medication. It’s approved in many countries in Asia to treat asthma and post-stroke symptoms. The mechanism of action is a little unclear in the central nervous system, but it does have an inhibitory effect on several cyclic nucleotide phosphodiesterases. Also, macrophage migration inhibitory factor and toll-like receptor 4. These are different cellular pathways that may be related to neurodegenerative processes that may be going on in progressive MS. 

SPRINT-MS was a placebo-controlled trial that randomized patients to up to 100 mg a day of ibudilast compared to placebo. It followed patients over 2 years. The primary outcome was progression of whole-brain atrophy with secondary outcomes, including cortical atrophy, advanced MRI measures such as MTR [magnetization transfer ratio] and diffusion tensor imaging, and retinal nerve fiber layer thickness, as measured by OCT [optical coherence tomography].

The primary outcome was met, in that ibudilast-treated patients had about a 50% slowing in progression of whole-brain atrophy. There was also a slowing in progression of cortical atrophy and a decline in magnetization transfer ratio. There were trends seen in OCT and diffusion tensor imaging consistent with a protective effect, although not statistically significant.

Importantly, there was no reduction in the few relapses seen in these progressive patients, and there was no reduction in the new T2 lesions seen on MRI. This is one of the few therapies that were targeting that other aspect. Even though it did not slow the number of new lesions or disease activity, it did reduce or slow the evidence of neurodegeneration, as measured by things like atrophy and MTR. 

As for its next steps, that was a phase 2 trial. You can’t get regulatory approval based on just MRI outcomes. It is waiting to go into a phase 3 trial. I have not heard any further updates regarding the company that has the IP [investigational product] interest in ibudilast in terms of moving forward into a phase 3 trial. We’re still waiting for that next step: the definitive phase 3 trial for that drug.

Experts in progressive multiple sclerosis summarize the phase 2 SPRINT-MS trial and the rationale for treating patients with ibudilast.

Ibudilast for Progressive Treatment 

 Fred, what do you do with your patients who have nonactive progressive forms of multiple sclerosis [MS]? Do you offer these patients treatment based on the results of these trials, or do you just offer symptom management in that setting?

Following up on what Dr Fox just said, it depends on their age. If it’s a young person who’s progressing, I will try one of these. In an older individual, I actually take the paradoxical view that I do MRIs on them and hope we see some activity, which is of course the opposite of what you want for the younger relapsing population. If I at least see some activity on the MRI, it makes me think I could maybe do something for these people.

When you look at all these studies, including some that failed, like the INFoRm study, if you have activity, you’re more likely to do better. The problem here, which Joe partially addressed, is that even in these studies, we’re treating inflammatory activity, so we have this paradox of how much of what we see in progressive disease is from the underlying inflammation. We know from the pathologist that there’s inflammation there all along the course of MS. We’re not sure how much is underlying inflammation vs neurodegeneration that we’re probably not touching. 

These studies were designed where you couldn’t separate it enough to be sure. People have either shown that they were negative, like the INFoRm study—so even there because the amount of inflammation was sufficiently low. Even though when you dig into it, you can see a therapeutic effect on the inflammation, it didn’t affect the underlying progressive metric in that population.

In the ocrelizumab studies and the siponimod studies, there was enough turning off of inflammatory activity to say, “Maybe that’s what’s going on in here.” But you don’t know for sure because, with ocrelizumab, when you did the subset analysis, there wasn’t enough power to answer the question of whether people had activity or not. 

I’ll raise one other issue: it really depends on how you want to look at activity. Do you want to look at what the activity was when people came into the study, going back a year or 2 years, which is what was done in the unfortunate subset analysis done in siponimod? Or do you want to look at the activity on study, which has been looked at in EXPAND? Nevertheless, that’s actually the population that’s telling you something that’s different between those who do and those who don’t. 

 There’s another component to this: what the patient wants. It’s sometimes very hard to talk patients out of some form of treatment. They come in and have read about these drugs. They know they’re available and they say, “I would like you to treat me with something.” Very often, I feel compelled to do so. It’s hard to talk them out of being treated, even when you describe the risk-benefit analysis.

Joe, I’m not sure our job is to talk patients in or out of a therapy. Our job is to explain the potential benefits and the potential risks before they help choose. I have a lot of patients who make what I think is an incorrect decision, either starting a therapy or not starting a therapy, but it’s a decision that’s in their purview to make. Our job is to give them the data and the information. As long as we’ve given them the proper information, then I think it’s OK for them to say, “I hear you. That drug may not help me much and has some risk, but by jove, I’m going to jump in and try it,” and I say, “OK.” 

 Yes. Well, that’s precisely what I was meaning.

 Shared decision-making is of course what we do in clinical practice today. That’s I have to say entirely different from when I was a first-year medical student and things were done in a very different style. But I think this is a much better way of practicing medicine today.

A discussion of how experts treat nonactive multiple sclerosis in terms of trial results or symptom management and how decisions are based on patient age.

Nonactive MS: Treatment Therapies

 I’m now going to ask the panel a question about the selection of patients. Bob and Kristen provided excellent summaries of the clinical trials. They’ve highlighted a couple of features, which I believe are commonly shared for both studies. Younger patients who have evidence of disease activity, ie, either gadolinium-enhancing lesions at baseline for both studies, or a recent history of relapses for the secondary progressive MS [multiple sclerosis] clinical trial, meaning relapses within 2 years prior to entry into the study, tended to do quite well on these therapies.

I’ll open this up to panel discussion, but I’m going to ask Joe first. How do you select these treatments for your patients with SPMS [secondary progressive multiple sclerosis] and PPMS [primary progressive multiple sclerosis], knowing that some of them have disease activity and others simply don’t?

 It’s an extremely difficult question to answer. I tend to default in my patients with primary progressive MS, particularly those who are younger. We certainly see people in their late 70s and 80s when they first present, and I’m not sure about the wisdom of starting them on any medication. 

But with younger patients, I generally default to ocrelizumab because the data were generated for PPMS with ocrelizumab. As I mentioned earlier, I can’t say that I’m bowled over by the effects of the drug. Sometimes it’s extremely difficult to determine what effect you’re having on the course of the illness because every patient is so unique.

Since we are able to use anti-CD20 antibodies, at least in the United States, and the mechanism of action is similar in the patients with PPMS as in the SPMS group, I often, not invariably, default to an anti-CD20 with patients who have SPMS. I’ll occasionally use an S1P [sphingosine-1-phosphate modulator], depending on what the patient is interested in. There are a fair number of patients who simply don’t get treated. They get treated symptomatically, and I don’t feel as if there’s a particular therapy that’s going to be particularly helpful for them. 

That’s generally what I do, but I depend as much on the patient preferences, which we’ll talk about a little later. There are some patients who come in and insist on being treated. In some instances, I’ve tried both drugs sequentially. When one doesn’t appear to be working, I try another. 

Bob, I’m going to pick on you to follow up on this idea that Joe just mentioned about sequential therapy. Do you do sequential therapy between these products? If so, how do you select which one to begin with? What kind of patient do you begin it in?

There are 2 main things that I’m now wrestling with in the middle of a pandemic, and hopefully we will be in a post-pandemic period soon. We know that older patients have a decreased benefit from these therapies and may have an increased risk of complications. Keep in mind that the siponimod secondary progressive trial enrolled no one over than the age of 50, and the ocrelizumab primary progressive trial enrolled no one over the age of 55. 

We don’t know what the risk-benefit trade-off is in patients who are older than those ages. We have lots of patients, as Joe alluded to, who are over age 60 with primary and secondary progressive MS, and we don’t have trial data to guide us. I am worried that the risk-benefit trade-off may not be positive for patients who don’t have evidence of active inflammation and do have risks of complications from these rather strong immune-modulating therapies. Adding to that, we know the response to vaccines is decreased in patients treated with anti-CD20s, and with S1P modulators. 

We would expect that the response to, for example, a COVID-19 vaccine will be diminished. We know that the complications of COVID-19 in anti-CD20–treated patients are higher than the complications of COVID-19 in the patients not treated with anti-CD20 antibodies. 

We’re now getting a better sense of balancing the risks and benefits, and realizing that there are some risks, risks of other complications and of insufficient response to a vaccine. That has made me quite cautious before I put a patient, particularly those aged over the mid-50s to 60, without evidence of active inflammation, on these drugs. 

In terms of sequential therapy, it’s a little tricky. I’m more comfortable going from an S1P, which washes out quickly, to an anti-CD20. It’s a little bit hard to know when the anti-CD20 is no longer effective, and I don’t have the potential additive complication risk of an anti-CD20 plus an S1P modulator. That makes it much more complicated to go from an anti-CD20 to S1P than the reverse. 

You touched upon an excellent point, which has to do with safety considerations with the potential for sequential therapy use.

Experts in the field of multiple sclerosis discuss patient selection for drugs based on disease activity.