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Smoldering and Spiking: Mapping MS and Modern DMTs
Released: March 13, 2026
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Smoldering and Spiking: Mapping MS and Modern DMTs
Introduction
Disclosures
My name is Patricia Coyle. I'm a Distinguished Professor of Neurology, Vice Chair for Academic Affairs and Head of the MS Comprehensive Care Center at Stony Brook University on Long Island in New York. I'm delighted to be here with you.
Setting the Stage: Progression and Treatment Landscape
So let's set the stage for the treatment of MS. We want to interrupt the damage cascade in MS, the pathophysiologic processes that are damaging precious central nervous system tissue. We want to be up to speed on the latest in the development of clinical trial data to support the treatment of MS with our best options. And then we'll make some conclusion summary statements key points at the end.
New View of MS Spectrum Disorder
We're viewing MS in a new light. One of the key features of MS, in addition to being a disease that affects young people with a female predominance, is that it's so variable. No two patients are alike. There's no cookie cutter pattern of how MS occurs in individuals. Everyone is very unique, and that's an interesting and unique feature to this major neurologic disease, but it is currently considered to be likely homogeneous, meaning the two components of MS, the relapsing and the progressive component, are believed to be present in virtually all MS patients, but may dominate at different times. And this would suggest that progression is an identical product in progressive from onset, so‑called primary progressive MS, and secondary progressive MS, patients that really had been relapsing for a period of time and then went into a progressive stage, that this may be a single process.
And this has repercussions. It would mean that if you showed a benefit in slowing progression in one form, primary progressive or secondary progressive, it should hold for the other form. And you could actually do models of treating progressive disease where you enter both primary progressive and secondary progressive.
We know that we don't know what causes MS exactly, but there's genetic input, risk susceptibility and disease severity genes, environmental factors, and then an attack on the precious central nervous system, the brain, the spinal cord and the optic nerve. So there's variability at all points because people are born with different degrees of central nervous system surveillance, central nervous system reserve. People are born or or develop co‑ diagnoses, but somebody might have no co‑diagnosis at all. So people are going to be very different and obviously that's playing a factor into the variability of this disease.
Neuropathology of MS
Now, as I mentioned, we currently think that there's two underlying neuropathologies, one for relapsing MS with clinical attacks, the other for progressive MS with smoldering inflammation and neurodegenerative injury, and we believe that those two forms of inflammatory conditions are present in virtually all MS individuals. So first there's acute focal inflammation where blood lymphocytes penetrate across the blood‑brain barrier around small veins to cause a contrast enhancing lesion and then a macroscopic T2 FLAIR lesion and a possible clinical attack in a minority of individuals. That's acute focal inflammation that is believed to underlie relapsing MS, causing different attacks, optic neuritis, transverse myelitis, etc., and there's an age relationship. That acute focal inflammation involving the systemic adaptive acquired immune system is most pronounced in young MS individuals and decreases over time. So it would be most prominent in pediatric onset MS and then fall over time and may, in a number of individuals with MS, ultimately burn out so that if somebody gets to a certain age and they have not moved into a progressive stage, it may be that they no longer have an active focal inflammatory relapsing phase and could potentially come off treatment for relapsing MS, really further work is needed.
The second type of neuropathology is really smoldering within the central nervous system, more innate immune involving glial cells as well. This seems to underlie neurodegenerative MS, with damage to axons, neurons, and synapses that underlies progressive MS. There's an age relationship here also, where clinically progression of MS tends to occur at midlife, age 45 to 55. And the current interpretation of that is that there's – there's neurodegenerative damage from the earliest time point, but there's such good CNS reserve, you don't see the clinical impact of that, the gradual worsening, until you reach midlife, where you've lost enough CNS reserve to see that. So there's also an age relationship in this second type of MS neuropathology.
Mechanisms Driving Progression
You'd want to know what are the damage mechanisms in progressive MS. Because, quite frankly, we have lots of disease modifying therapies for relapsing MS, but very limited options for progressive MS. And so that's a major focus at this point in time.
So, the the damage mechanisms that appear to be driving smoldering CNS inflammation within the CNS involve activated microglia and astrocytes. In fact, glial toxicity is one of the damage mechanisms, we believe, in progressive MS. There's certainly a lot of neurodegeneration. This is the synapse axon neuron damage. There are age‑related changes that are promoting this progressive course. There's oxidative stress and injury. There's progressive mitochondrial cell dysfunction and energetics failure. There's glutamate excitotoxicity, iron deposition that’s driving oxidative injury. Ion channel and axonal transport disruption. Negative secretory products, including certain cytokines and chemokines and loss of myelin trophic support and loss of the ability to repair well with age. These all probably contribute to the progressive neurodegenerative smoldering inflammation damage. We don't know what percent or what are the most significant, but obviously this would be very important to design the best treatment strategies for progressive MS.
Questions About Progression
So there are two major ways that an MS individual can worsen. They can have relapse associated worsening, RAW, where you don't make a complete recovery from an attack. Or they can have PIRA, progression independent of relapse activity, worsening due to neurodegeneration and smoldering inflammation. And the current studies have suggested that PIRA seems to be a dominant way to explain worsening in most individuals, not just progressive MS, but even in relapsing MS.
Now, one of the problems with PIRA, which has been a big study point and is reported in a lot of articles, is that there is no uniformly used diagnosis for PIRA. The strictest PIRA would be excluding clinical relapse activity, a clinical attack, but would also use MRI data to say there are no contrast lesions, there are no new lesions on the MRI scan. And that actually is not always done. It may be simply clinically defined. And if you're very strict and say, I require no MRI activity, no macroscopic MRI activity, then your rate of PIRA drops significantly. And a recent study showed a strong PIRA association with concurrent MRI activity that would say that really shouldn't be considered PIRA, they – that may have an element of RAW, and they even found a relatively high rate of improvement that seemed to be independent of relapse activity.
So PIRA and RAW are interesting concepts, but we still haven't got our act together in clinically really defining them and using that consistently.
Current DMTs and Approach
Now we have multiple disease modifying therapy options in our current approach, should really be focused on a personalized and ultimately, we're not there yet, precision medicine approach. Well, we're certainly using a personalized approach on the individual MS patient and precision medicine should come in the future, we hope. But think of treatment as multi‑pronged. It's not just optimizing what DMT to use, but it's optimized management of symptoms and relapses and positive features to promote CNS reserve and optimized aging. Aging seems to be an element of damage in MS, and we really want people to age well. That means it's important that they follow a wellness program. It's important that comorbidities be identified and optimally managed. It's important that they not smoke, drink, or be obese, that they really want good lifestyle choices. And then when we look at the DMTs, a good way to divide them up would be immunomodulators, immunosuppressives and the high efficacy monoclonals. And that explains these groups.
Injectable DMTs
So the injectable DMTs go back to the 1990s. We rarely start them at this point in time. We rarely start them.
Oral DMTs
We have the oral DMTs that include the S1P‑receptor modulators, the fumarates, teriflunomide, and cladribine, which is an induction agent. You treat for ten days in year one, ten days in year two, and then theoretically do not need to treat in years three and four. So these are more convenient. They're not needle injected. So that's a positive feature. You're taking them by mouth. Their efficacy is as good or better than the injectables that we just discussed. But none of these would be considered truly high efficacy. Cladribine would be the closest to that.
Monoclonal Antibodies
And then we have the monoclonal antibodies. These are the high efficacy agents. The first two monoclonals, natalizumab carries risk of progressive multifocal leukoencephalopathy, or PML, and alemtuzumab is an agent that carries great risk for associated immune‑mediated diseases, and patients need to be followed for a number of years after they are treated. These are both black box warning agents and require a REMS program.
The monoclonal antibody evaluation was expanded with the anti‑CD20s. These are high efficacy monoclonals that do not have black box warnings and do not require any special REMS program. And we have three approved anti‑CD20s, ocrelizumab, ofatumumab and ublituximab, first approved in 2017, in 2020, and 2022. And these are high efficacy agents that people feel pretty comfortable about using in MS at the current time.
Current DMTs and Approach
So we're seeing increasing use of the high efficacy monoclonals, the anti‑CD20s. These are B‑cell lytic agents. They give excellent control of relapsing MS. And ocrelizumab is the only formally approved DMT for primary progressive MS.
However, we're beginning to hear concerns from various centers about use of the anti‑CD20s with regard to occasional patients after a period of time having real problems with infection rate. And so one of the answers that we don't have is how long can you safely treat with an anti‑CD20? We also see the need to get more treatments for progressive MS, and we have absolutely no treatment available for CNS repair at this point in time with MS. So these are great needs, great needs in the development of disease modifying therapies for MS at the current time.
Current DMT Issues
So what are some current DMT issues? We have no practical treatment biomarkers, maybe neurofilament light protein in blood, maybe glial fibrillary acidic protein in blood will will take over here. We have no guidance on the optimal duration of time treatment. Most of our options are moderate efficacy. There's an age related factor in the patient not responding as well as they get older, the response rate may diminish. Co‑morbid conditions can really make MS more severe. So does the person have comorbid conditions or they don't? Those are going to be very different populations. MS treatment requires an ongoing risk ‑benefit analysis of course and sometimes adverse events can limit use of a given agent. And I think we're becoming more aware of do we have a CNS penetrating agent that may be needed to get better treatments for progressive MS, and what exactly is the immune targets of the treatments that we're talking about.
Clinical Trial Data
With regard to clinical trial data, I think we're doing trials now to try to improve trial design, to clarify the best use of our current DMTs and to test potential new DMTs, particularly for progressive MS and CNS repair strategies.
OCTOPUS Trial Design
And this is the OCTOPUS trial design, a multi‑arm, multi‑stage, MAMS design. It's being used in the United Kingdom and it's being focused on progressive MS. It allows the treatment of multiple therapies at the same time. They first focus on does this seem to be effective on an MRI basis. And if you get a yes, then they will go on to a clinical basis. And you can have multiple arms and you can be x’ed out if you fail to have an MRI response for example. So this is a way to – it's been used in other diseases, this is the first time it's being used in, in MS. It, it it, it allows very rapid treatment to put in a new study or end – end a study if it's not working. Screening with MRI scanning and then going on to clinical evaluation in multiple arms at the same time.
Clarify Best Use of Current DMTs
Clarifying best use of our current DMTs are trials that are designed to generate long term safety and efficacy data. To clarify a vaccine impact with a given DMT, for example, to evaluate alternative delivery routes. So you had natalizumab subcutaneous tested where natalizumab had been given IV, you had ocrelizumab that was given IV and then you had subcutaneous tested. You're also evaluating the best dose, a higher dose was tested in ocrelizumab but didn't give any additional benefit. And you're looking at using various DMTs in pediatric onset MS and conserving – and – and confirming that they work well. So these have clarified best use of our current DMTs.
Novel Potential DMTs
And then we have potential new DMTs. And I think it's very good to see this is a vigorous area, even though we already have a lot of DMTs, particularly for relapsing MS. The oral BTK inhibitors are a big area of interest that may be treatment for progressive MS. Intravenous frexalimab and anti‑CD40 ligand monoclonal antibody is being studied in both relapsing and progressive MS. CAR T‑cell therapy, where you personalize T‑cells to go after a targeted antigen target. This is not just for malignancy, we're seeing CAR T approaches being used in MS. And intranasal human anti‑CD3, anti‑T‑cell monoclonal antibody is in preliminary testing Vidofludimus, which is a Nurr1 activation and a DHODH enzyme inhibitor, a second generation teriflunomide, but with that newer one, which may be a neuroprotective activities being studied, and multiple CNS repair studies. Thank you very much.