Episode 481: It's Time to Update the Way We Describe MS with Dr. Peter Calabresi

0:18 It's November 10th, and we have a lot to talk about. This week, we're wrapping up our coverage of MS Toronto 2026 with my conversation with Dr. Peter Calabresi. Dr. Calabresi chaired an important session focused on biological disease course descriptors at MS Toronto 2026. This is a topic we've discussed on this podcast before, and it's a topic we'll continue to highlight because it reflects a huge step forward in MS research and in MS care. If you're late to this conversation, some background is in order, along with an explanation of why adopting biologically-driven course descriptors is a very good thing for people living with MS.

1:02 First, what do we mean by course descriptors? Well, those are the words we use to describe MS. And since 1996, we've used the well-known terms relapsing-remitting, secondary-progressive, and primary-progressive. These terms describe the clinical presentation of MS, and given what researchers and clinicians understood about MS in 1996, that made perfect sense. And while our experts' understanding of MS has continued to evolve over the past 30 years, the language we use to describe MS hasn't. When someone is diagnosed with multiple sclerosis, they walk out of the clinic carrying one of those three labels that were standardized back in 1996.

1:48 On paper, those terms were created to bring order to clinical trials and give clinicians a standard shared vocabulary. But for that person sitting nervously in the exam room, those words do something entirely different. They don't just describe a medical category. They become an identity. They shape how you see yourself, how your loved ones understand what you're dealing with, and what you imagine your future is going to look like. Words matter. And the hard truth is, given what we know today, our current course descriptors are often far too vague for a disease as complex and heterogeneous as MS.

2:29 Take relapsing-remitting MS. Two people can share that exact same label. One might have a single, mild sensory flare every few years and remain fully functional for decades. People may never even know that person is living with MS. Meanwhile, another person might experience frequent aggressive disease activity accompanied by steady, silent disability accumulation. How do these two individuals get lumped into the same diagnostic bucket? It's a recipe for uncertainty. I've said it before. Uncertainty may be the single most frightening and difficult aspect of living with MS.

3:11 And when medicine leaves us with an informational vacuum, our imaginations rush to fill it, often by turning to social media and adopting worst-case anecdotes as a personal prognosis. Even worse is the disconnect that occurs in routine neurological appointments every single day. A person living with MS sits down with their neurologist, their doctor reviews the latest MRI, smiles and says, good news, no new lesions, your MS is stable. Yet that person is sitting there thinking, wait a minute, I know I've lost a step in my stride. My balance is worse than it was six months ago.

3:53 My fatigue is heavier, my thinking feels cloudy, and I'm struggling with depression. They know these symptoms are part of their MS and they know they're worsening, yet the expert charged with helping them manage their disease just told them they're stable, and their chart still reads, relapsing remitting. That reality gap breeds self-doubt, anxiety, and a feeling that maybe even their own health care team doesn't truly grasp what's happening to them. Well, it's what science now recognizes as progression independent of relapse activity. Yet our everyday terminology hasn't caught up to that.

4:35 We see the exact same friction in the so-called transition from relapsing-remitting to secondary-progressive MS. That boundary is never clear. I saw this firsthand when my wife received her initial diagnosis, and she was told she had secondary progressive MS. Now, if you look up secondary progressive MS, the clinical definition tells you that it's a stage of MS that follows an initial relapsing-remitting phase. The neurologist noted the lesions on my wife's MRI had clearly been there for a very long time. But my wife was certain she had never experienced that initial phase. Her medical history was remarkably benign.

5:17 So how could that be? It took time, but eventually she was able to identify three separate health events, each one characterized by a different symptom, each occurring about six or seven years apart. She had never connected what, in hindsight, were likely three mild relapses. But until those dots were connected years later, she was left to wrestle with a label that didn't feel like it fit. And when a diagnosis only serves to create confusion, that confusion breeds fear. That's why we have to do better. Imagine what happens when we replace 30-year-old clinical buckets with descriptors that actually reflect an individual's underlying biology, incorporating biomarkers, cellular inflammation, and objective measures of neurodegeneration.

6:11 Biologically driven course descriptors wouldn't just be an academic exercise, they would be transformative for people affected by MS. Instead of being left in the dark to guess, people living with MS would understand the true biological state of their disease and be in a position to make proactive life plans with realistic expectations. And when a patient and their neurologist share precise language that acknowledges subclinical progression, clinical appointments move away from dismissive stability checks and move toward meaningful disease management. Accurate course descriptors would provide caregivers at home with a concrete framework to anticipate care needs and advocate effectively alongside their loved ones.

6:59 And we're just focusing here on the benefits in MS care. The benefits in future MS research are even more significant. Far beyond their clinical definitions, the words used to describe MS become the words someone uses to describe their life. It's our responsibility to choose those words with precision, empathy, and scientific honesty. That's why today's conversation is so critical. Dr. Calabresi is one of the world's leading neuroimmunologists, and he's been at the forefront of the movement among experts to modernize how we classify and treat MS, moving us away from outdated clinical silos and toward biologically defined descriptors.

7:44 But before we get to my conversation with Dr. Calabresi, there are a few other things that you should know about. We just touched on this a moment ago, but if you're living with non-active secondary progressive MS, then you're already familiar with the frustration. Your relapses have stopped. Your routine MRIs look stable with no new gadolinium-enhancing lesions. But walking gets a little harder. Fatigue digs a little deeper. And disability seems to be inching forward. We call that progression independent of relapse activity, or because science loves an acronym, PIRA.

8:28 And right now, there are virtually no disease-modifying therapies specifically approved to stop that process. That's why we've been watching an investigational therapy from Tiziana Life Sciences called Foralumab. And last week, Tiziana reported top-line results from their Phase 2a INFORM-MS clinical trial. Let's look at what they discovered and what it means for people living with secondary progressive MS. To understand this trial, we have to look under the hood at progressive MS. In relapsing MS, damage is largely driven by peripheral immune cells breaking across the blood-brain barrier during acute flare-ups.

9:11 But in non-active secondary progressive MS, things change and the pathology shifts indoors. It turns into what researchers describe as slow, compartmentalized inflammation driven by microglia. Those are the resident immune cells in the central nervous system. When chronically activated, microglia stop doing their job of repairing damage and start causing ongoing neurodegeneration. And this is where this investigational therapy, Furalumab, comes in. Feralumab is a fully human anti-CD3 monoclonal antibody, but instead of an IV infusion or a standard injection, it's formulated as a nasal spray.

9:58 And the biology here is pretty interesting. By dosing through the nasal passage, forallumab interacts with the nasal mucosal immune system to stimulate regulatory T-cells. Those regulatory cells travel into the brain and spinal cord and act like a breaking system to quiet down those overactive microglia. This Phase IIa clinical trial was a randomized, double-blind, placebo-controlled study involving 48 participants with non-active secondary progressive MS across eight sites in the United States. Trial participants were split into three groups for 12 weeks.

10:41 One group received a 50-microgram nasal dose of forallumab. One group received a 100-microgram dose of forallumab. And one group received an inactive placebo nasal spray. The primary goals of the trial were straightforward. It was designed to test the safety and tolerability of feralumab and to measure changes in microglial activation using a specialized brain scan called TSPO-PET. And here's what the top-line data showed. In participants who received the 50-microgram dose, researchers saw a statistically significant reduction in microglial activation compared to placebo.

11:26 That confirmed that the drug reached its target and dampened that inflammatory activity taking place inside the brain. Now, interestingly, the 100-microgram group did not show a statistically significant difference compared to placebo, and that could be the result of a very small sample size of just 11 participants. In terms of safety and tolerability, all 48 participants completed the 12-week study. There were no treatment-related serious adverse events, no deaths, and no dropouts due to side effects. The most common adverse events were mild, things like nasal congestion, runny nose, and headaches.

12:11 Ironically, the overall reported side effects were numerically lower among people actually receiving forallumab than those participants who are receiving a placebo. And while biomarkers on a PET scan are great, the real question every patient asks is, will this make me feel or function better? Well, because this was a small 12-week Phase 2a study, it was not powered or long enough to show changes in physical disability on the EDSS scale. And EDSS scores remained unchanged, exactly as expected in this short 90-day window.

12:53 However, the secondary endpoint, which focused on fatigue, is worth talking about. Using the Modified Fatigue Impact Scale, participants on both doses reported meaningful drops in fatigue, a 6.17-point reduction from baseline in the 50-microgram group and a 7.18-point reduction in the 100-microgram group. Now, as a comparison, the clinical benchmark for a meaningful change on that scale is 4 points. So, seeing this meaningful improvement in fatigue when brain inflammation gets tamped down is not only encouraging, it's something worthy of further exploration.

13:39 Tiziana Life Sciences plans to present the complete dataset at an upcoming scientific congress, and they'll be sitting down with the FDA to map out the next stage of clinical development for this drug. Meanwhile, we're left with a caveat alongside some encouraging results. We want to keep in mind that this is early phase data, and a 12-week trial of 48 people may not really prove a lot. But for a patient population that has had almost nothing in the pipeline addressing the root driver of non-active secondary progressive disease, this chronic compartmentalized neuroinflammation, Seeing proof that this therapy was successful in engaging its biological target in a convenient and well-tolerated nasal spray gives us genuine reason for cautious optimism.

14:32 We'll be watching those upcoming regulatory conversations closely. It's no secret that every day, AI chatbots like ChatGPT, Gemini, and Claude field millions of questions from people looking for medical information and advice. And when it comes to translating lab results, decoding medical jargon, or creating a list of questions to bring to your next doctor's visit, these tools can be a great sounding board. But where does being an informational sounding board end and the practice of medicine begin? And what happens when an AI chatbot actively steers a patient away from real-world medical care?

15:19 That fundamental question is at the heart of a major wrongful death lawsuit filed in San Francisco County Superior Court against OpenAI and its CEO, Sam Altman. The lawsuit was brought by the parents of 31-year-old Bowen Wan, a Seattle woman living with epilepsy. Bowen was unhappy with the side effects created by her anti-seizure prescription medication. In February, Bowen died in her apartment, and the medical examiner confirmed the cause of death as sudden unexpected death in epilepsy. According to her family's lawsuit, Bowen's death was a direct result of a detailed plan generated by ChatGPT to completely taper off her anti-seizure medication. Thank you.

16:08 Now, anyone managing a chronic condition knows that abruptly stopping or rapidly tapering some maintenance medications, especially anticonvulsants, well, that can trigger severe life-threatening complications. I'll also mention here that, yes, abruptly stopping certain MS medications can have severe health consequences. In this poor woman's case, she was described an anticonvulsive medication at 400 mg daily. According to the complaint, ChatGPT didn't just give her general information. It generated a specific schedule, dropping her dose from 400 mg down to zero over roughly 25 days, all without the knowledge or approval of her physician.

16:58 Even worse, the lawsuit cites a message where ChatGPT instructed Bowen not to mention this medication reduction plan to her doctor. And when Bowen refused a routine blood test that could have alerted her care team to the drastically lowered drug levels in her system, the complaint alleges that ChatGPT praised her decision. In clinical terms, this isn't just an error. In AI engineering, it reflects a dangerous failure of alignment. ChatGPT mirrored and reinforced this individual's harmful impulses rather than applying a hard stop.

17:38 And this isn't an isolated lawsuit. There are other pending suits filed by individuals or their surviving family members alleging that ChatGPT provided dangerous or deadly medical advice. In fairness, OpenAI has repeatedly noted that ChatGPT is explicitly not designed to be a substitute for professional health care. But how much do disclaimers that are routinely buried in fine print really matter when a conversational interface mimics human empathy, builds trust, and then issues step-by-step prescription adjustments? I'll be the first to say I use ChatGPT, Claude, and Gemini as research partners.

18:24 These tools are great at summarizing research, helping to draft emails, and explaining complex terms. But please remember, they possess no clinical judgment. If you or someone you care about is living with MS, never adjust, taper, or stop a prescribed medication based on output from an algorithm. Algorithms don't live with the consequences of their medical advice. Patients do. While we're talking about consequences, while not nearly as dire, the decision to use vague, outdated language to describe someone's MS diagnosis also carries consequences.

19:06 Consequences like confusion, fear, misunderstanding, and a complete lack of empowerment. We have to do better. And in a moment, Dr. Peter Calabresi joins me to explain the how and the why behind adopting course descriptors that better reflect the pathology that's actually taking place in your central nervous system. Dr. Peter Calabresi is an internationally recognized expert and neuroscientist specializing in multiple sclerosis. Dr. Calabrese is also the chair of the Department of Neurological Sciences at the University of Vermont, Larner College of Medicine.

19:49 And one of the things you're doing at MS Toronto 2026 is co-chairing a session on biologically driven course descriptors. Now, for decades, MS has been separated into categorical clinical buckets, relapsing remitting, secondary progressive and primary progressive, With accumulating evidence showing that compartmentalized inflammation, neuroaxonal loss, and progression independent of relapse activity occur from the earliest stages of clinical activity, how will moving toward biologically driven descriptors fundamentally reshape how we classify multiple sclerosis? Hi, Jon. Great to see you again. Excellent question.

20:32 And just the complexity of the question speaks to how challenging this problem is, right? Because we've moved into an era where our understanding of MS biologically and, as you said, mechanistically has grown so dramatically that we're... Struggling to keep up with how to communicate that and define it in the clinic. And so one of the challenges has to do with all these different biomarkers that we use. But I'm optimistic that we're actually already moving the needle. So if you go back to the Lublin paper in 2013, that paper was pivotal in that it broke out secondary progressive MS into two types, right? The people with active MRIs and not active MRIs.

21:14 And that was a very simple, but I think very useful way of thinking about it because we know that the therapies that we have today are predominantly immune modulating. And if you have an active MRI, they're pretty effective at shutting that down. And so we use that in the clinic. The question is moving forward is how do we incorporate some of the more subtle features like the Bayes rim lesions where there's iron or spinal cord imaging, how do we get at the degenerative progressive phase, define that in a way that we can communicate to people living with MS. And I think the discussions that we're having at this meeting and moving forward are really helpful. And these problems are not easy or straightforward, but we're getting there.

21:57 How would new biologically driven course descriptors benefit someone who's living with MS? I think in several ways. First of all, we're entering into an era where there are therapeutics that are designed specifically to target the biology-underlying progressive MS. And by that, I mean the inflammation that exists inside the brain, not just the peripheral immune cells that we already know how to target. And as drugs become available, maybe it'll be the BTK inhibitors, other classes are being tested as well. It will be really useful to know if you have that biological process and whether you should go on that drug, because that's what I encounter when I see people living with MS is they want to know, should I try this new drug?

22:40 And the answer is, well, it depends on what's going on with your MS. And so we want to fine tune as much as possible the treatment for what's happening inside that person's brain or spinal cord. Secondly, and this is really important, having these tools will allow us to quantify what's going on in clinical trials. And so this will pave the path forward to showing that the drugs really do impact that aspect of the disease. And of course, having biomarkers that predict progression is really critical because we can't do clinical trials for five or 10 years, even though five or 10-year outcomes are really, really important. We need to get an answer in 12 or 24 months in a more feasible manner.

23:25 Shifting from purely descriptive, retrospective phenotypes to biological characterization requires robust, accessible biomarkers, as you just alluded to a couple moments ago. So which paraclinical tools, such as serum neurofilament light chain, GFAP, paramagnetic rim lesions, or advanced atrophy measures, which of those are realistically ready for individualized clinical decision-making and which are still considered research endpoints? As always, Jon, you hit the nail on the head. So in my opinion, I think serum neurofilament light, what we call NFL, and the phase rim lesions with iron around them are clinically available now and ones that we could incorporate into our treatment decision and staging.

24:18 There's some important caveats, though. It's important to understand that NFL is not specific. Other disease processes can cause elevations of NFL. It needs to be interpreted in the context of age and comorbid disease processes. But if you use a patient's value as their baseline and then look at changes over time, and I like to have repeated measures. I'm not going to act on one elevated neurofilament. A lot of things can happen. You can bump your head. You can have a seizure that can cause elevation. But if the neurofilm is chronically elevated in a reproducible manner, I think that is important. And it's telling us something about the biology of the disease. The phased rim lesions, as we heard from Danny Reich this morning, obviously very important for perhaps segregating people as to where they are, whether they are reactive to treatment.

25:08 I'm less convinced that they're going to be useful for estimating a treatment outcome. But at least it did appear to have some value in the tolibrinib trial in terms of defining people who might benefit or not from the drug. Redefining disease course descriptors has immediate, tangible consequences for the people who are living with MS, for whom labels like relapsing, progressive, well, they carry real emotional and practical weight. How can clinicians adopt a biological framework at the bedside in a way that empowers patients, clarifies their prognosis, and improves collaborative treatment planning without causing unnecessary fear and confusion?

25:52 Yeah. So the open communication is where it all starts. And I think including people living with MS in the conversations right from the beginning, asking them whether what we come up with, does it seem like something that you would feel comfortable with? Is this something that you feel captures all the domains of your MS? And so we do that. The National MSI has been great about incorporating people living with MS into the discussion groups. I think it needs to be simple enough that people can understand and physicians need to get to know their patients. So I know some of my patients are worried about everything. And so you have to understand who you're talking to.

26:34 And then other people tend to be, you know, less worried and just want to go and live their life. And sometimes you have to make them understand, you know, this is serious. You need to pay attention to this. So I think it's always about a conversation and good communication. Everyone is so anchored in the course descriptors that we've all used for the past 30 plus years. And there are so many stakeholders, including the regulatory agencies like the FDA in the United States, clinicians, pharmaceutical companies, insurance companies, and of course, patients and caregivers. How does a transition of this magnitude occur? Slowly. I think these things take time.

27:15 When you have been working with one paradigm for 30 years, it's not going to change overnight. And as many of my colleagues feel, the terms relapsing and progressive are not useful anymore. It's just too much to make them go away overnight. They're too embedded in the third-party payers' language, as well as the regulatory agency. So I think what we need to do is set up parallel descriptors, as we did in the 2013 Lublin paper, to say, OK, you're secondary progressive, but you have an active MRI or not, and start to incorporate these biologies into the more familiar terms so that people can slowly transition and get it.

27:57 Oh, okay, I have axons that are being transected. It's causing my neurofilament to go up, even though everything else looks stable or not. Or this might be one more piece of information that we factor into a compilation of different outcomes. And so I think MS is probably going to be hard to capture with just one measurement. So it might be a variety of things. And if you think about it, we do this in cancer already. It's not just that you have breast cancer, but it's, you know, what are the receptors in the cells and is it's been spread yet? And so there are a variety of factors with MS that we need to incorporate into our description. Well, Dr. Peter Calabresi, I want to thank you for all you do and all of your leadership in the field. Thanks so much for talking with me today.

28:44 Pleasure talking to you, Jon. That's going to wrap up this episode of Real Talk MS. Real Talk MS is powered by the National MS Society, and you can share this episode of the podcast by letting your friends or family members know all they have to do is point their web browser at realtalkms.com slash, 481. You'll find that link in today's show notes, so you can easily copy and paste it right into an email or a text. I also want to invite you to download the free Real Talk MS app for your iOS or Android smartphone or tablet. It's the best way for us to stay connected.

29:24 The app will automatically download the latest episode of Real Talk MS. You'll be able to download and listen to past episodes. You'll be able to save your favorite episodes. And what I'm particularly excited about is that I'll be able to share all kinds of bonus content with you. And that content will only be available on the app. So I hope you'll take a minute to visit the Apple App Store or the Google Play Store and download the free Real Talk MS app. And you'll find those links in today's show notes or at realtalkms.com. Next week, you'll meet Chuck Edward, a recently retired human resources executive at Microsoft who lives with MS and who learned firsthand how employee resource groups, or ERGs, can support people with disabilities in the workplace in ways that go beyond what a human resource department can deliver.

30:20 Whether you work at a large company like Microsoft or you're part of a smaller business, you'll come away from my conversation with Chuck with some new ideas when it comes to taking your MS to work. I'm Jon Strum. Thanks for listening. Stay safe and make healthy choices.