#095: Hidden Challenges – Exploring Smoldering MS with Prof. Gavin Giovannoni

Introduction – Who is Prof. Gavin Giovannoni?

Nele von Horsten: Hello Gavin, it’s a pleasure to have you on the podcast today. Before we begin, could you please introduce yourself for those who may not be familiar with you?

Prof. Gavin Giovannoni: Thank you, Nele. I am a neurologist at the Royal London Hospital and a professor at Queen Mary University in London. Originally from South Africa, I focus on research and treatment innovations in multiple sclerosis (MS), aiming to improve patient outcomes.

Understanding Smoldering MS

Let’s talk about Smoldering MS. What is it, and how does it change our understanding of the disease?

Prof. Gavin Giovannoni: I mean, smoldering MS is a term, it’s evolved over the last six to eight years, but it’s a concept to try and capture the part of multiple sclerosis that we’re not measuring using clinical outcomes and MRI. So most people think about multiple sclerosis as having relapses or attacks, and we measure those clinically. And on MRI, we get these new lesions that come and go.

We call that MRI activity. And those two components of multiple sclerosis are what we call the inflammatory component. And we now know that when we actually put people with multiple sclerosis on therapy and we stop them having relapses and stop them having MRI activity, a significant number of them will still get worse. And that’s called PIRA, progression independence of relapse activity, which is what we measure in trials every three months by doing disability scores or whatever. But in addition to that, there’s also evidence of smoldering MS that’s not picked up by our outcome measures in clinical trials. And so the smoldering MS umbrella is to try and capture all the components of worsening MS that’s not detected using our standard outcome measures. And most people with multiple sclerosis are aware of this. You know, they often go to see the neurologists before their sixth or annual follow-up appointments, and they’re told, you know, you’re relapse-free, your MRI is stable, therefore your disease is under control, go away. And most people don’t feel satisfied with that because they know that things may be getting worse. And that’s what we’re trying to capture, that worsening that we’re not measuring with our standard outcome measures. And there’s a whole lot of different processes that are underlying smoldering MS.

What are the underlying mechanisms of Smoldering MS, and why is it so challenging to diagnose?

Prof. Gavin Giovannoni: Yeah so what we think there are quite a few mechanisms. So one of the things is that the inflammation that’s driving MS becomes compartmentalized. It it’s actually happening within the brain and spinal cord and that’s driven by a group of cells called the microglia. They actually derive from white blood cells that go into the brain when the brain’s developing and they produce inflammatory mediators and chemicals that damage you know nerve fibers so that’s what we call the hot microglial component and there are treatments now to try and switch off these microglia. Also with inside the brain and spinal cord of people with ms there are these cells called B-cells and plasma cells these are the cells of the immune system that make antibodies. And we think those antibodies are actually part of what’s driving smoldering MS. They attack the nerve cells and the myelin causing ongoing damage and our current treatments don’t really get into the central nervous system to kill these. So we now have to develop a new class of therapy, or therapies, I should say, that go into the brain to try and scrub the brain clean of these B-cells and plasma cells.

And there is a biomarker when we do lumbar punctures and take the spinal fluid out, and we find these things called oligoclonal bands. These are immunoglobulin bands, and that’s actually a marker of these B-cells and plasma cells making these antibodies. So in the future, we may want to scrub the brain clean and clear the spinal fluid of these oligoclonal bands.

Then there’s persistent demyelination. So we know that MS causes the myelin, the insulation of nerve fibers, to be stripped off. And although some of those nerve fibers can remyelinate, in some people, remyelination doesn’t progress. And so persistent demyelination is another mechanism. So therefore there’s this rationale to create remyelination therapies.

Another component is what we call energy deficit. So when you’re actually conducting down a demyelinated nerve fiber, it takes much more energy to stick the electrical signal down the nerve fiber. And in addition to that, the mitochondria, the little component of the cell that makes energy, is actually not working as well in people that have got inflammation in the brain and spinal cord. And so there’s an energy deficit. So there are potential mechanisms to try and enhance energetics in the brain. And that’s where oxygen therapy and things try and promote mitochondrial function are in. And then there’s also premature aging. We know that what protects us from aging is what we call brain health, how much reserve capacity our brains and spinal cord has. And we know that multiple sclerosis reduces that by causing death of nerve fibers and the axons, your reserve is reduced. So as you get older, you start seeing aging happening earlier. So aging mechanisms come in. And we don’t really have anti-aging treatments at the moment. You know, we have a clue that brain health is important for anti-aging mechanisms, exercise in particular, but there’s things around diet and sleep, preventing what we call comorbidities, people getting high blood pressure, diabetes, all those things that are poor for brain health also play out in people with MS. So this is one of the reasons why it’s very important for people with MS, not only to just focus on MS, but also to focus on general health, because general health is important for the brain and spinal cord. So there’s different components that we think are driving smoldering MS.

What percentage of MS patients are thought to have Smoldering MS, and how can early detection benefit long-term outcomes?

Prof. Gavin Giovannoni: I think it’s important not everybody does have smoldering MS because we do know that some people come to post-mortem, they die in old age, and they’ve got MS on their brains and spinal cord, but they’ve never developed MS in life, never been diagnosed. So whatever’s causing multiple sclerosis, that person’s immune system must clear it. And then there’s some people that end up old age with no disability. So they’ve had MS their whole life, and they don’t get worse.

In retrospect, we call that benign MS, but we don’t like that term because it’s very difficult to predict who’s going to have benign disease. Sothe proportion of people that end up with benign MS was very low in the past because most people ended up with disability. But I think now that we’ve got effective treatments, we begin to see the proportion of people ending up in old age with less disability is increasing. So I do think our treatments are working by preventing relapses and MRI activity, but they’re also having an impact on smoldering disease. And I would be giving you an incorrect figure by giving you a definitive figure. But I would estimate in people with established MS, about 30% to 40% of them now will get to old age without disability. And in the future, we want that to be 80% to 90%. And this is why detecting smoldering MS is important, because there’s going to be a new class of therapies coming out, people will be potentially eligible for that would target smoldering mechanisms. So we’re anticipating in the next 12 months a new class of therapy to come out that will work much better on smoldering MS than the current therapies. So there is an incentive going forward to detect this.

They want to know about this because they’re experiencing it and then they ask the question what can I do about it and so obviously using a disease modifying therapy is one strand but also focusing on all the other things. Being aware of what else you can do to tackle smoldering MS is also an important part of MS management. Rather than put your head in the sand and ignore it, I think it’s much better to confront it and understand what’s going on. Maybe you disagree with me. I know there are some people who don’t want to know about this, but that’s a personal choice. If they don’t want to know they’ve got smoldering MS, then they shouldn’t be told.

Nele von Horsten: Yeah, of course. And it’s everybody’s choice. But my motivation to do that podcast is get people informed so they can do whatever is possible to stay as healthy as possible. And of course, people can decide not to listen to the podcast or other things like going to the dentist, getting your vaccinations, being sporty, living a healthy lifestyle. There are so many little components we can do. And I prefer to choose all the little modules to end up in the 30% to 40% range without disabilities in old age. And I would love to see it happen, that 80% to 90% get old without disabilities in the future. That would be so lovely.

Prof. Gavin Giovannoni: So another thing that people tend to just live with is infections. So we know that people with multiple sclerosis get bladder problems, and they’re much more likely to get recurrent bladder infections. And some of them may get recurrent chest infections because of swallowing problems. And some of them may have inflammation in their gums. We call that periodontal disease. And some people get recurrent sinusitis. But there is also evidence now showing that if you get recurrent systemic infections, that causes smoldering MS to speed up. And, you know, rather than live with your bladder infections, because some people just seem to say, I’ll get a bladder infection every six to eight weeks and I’ll just get antibiotics and that’s fine. Well, I don’t think that is acceptable. You know, there are really good strategies now to prevent people getting urea tract infections and also to prevent themselves getting severe chest infections. So, it’s also engaging with other health care providers to stop infections. It’s another component of treating smoldering or preventing smoldering MS. And I’m always shocked when I get new patients to hear from them how many of them just accept recurrent infections. And I say – you don’t have to live with recurrent infections. There’s a lot we can do. That’s another message to get across.

Why are terms like RRMS, SPMS, and PPMS becoming outdated?

Prof. Gavin Giovannoni: The concept here is how do we define diseases. So when you define diseases in the medical field i’m not talking about psychiatry they do a little bit differently to us because psychiatrists tend to talk about symptoms phenomenology rather than, in medicine we talk about a clinical pathological corridor. So when you usually what we call medical philosophy framework MS is one disease it’s got a clinical phenotype what you see clinically, and it’s got a pathology that goes with that, what you see under the microscope. And when you do the clinical pathological correlate, there isn’t any difference between the different types of MS. They kind of fall into the same spectrum. But what happened was to get drugs licensed for a disease or to help incentivize the pharmaceutical industry, various governments created these things called the Orphan Drug Act. So this is to try and encourage drug companies to develop drugs for diseases that affect small numbers of the population. And the Americans were the first to do this. The FDA, the Food and Drug Administration, put forward an Orphan Drug Act that goes back to I think the late 70s, early 80s.

The Orphan Drug Act defined an orphan disease as a disease that only affected 200,000 or less Americans. Andwhen you actually look at MS, there were more than 200,000 people with MS in America at that time. So what they decided to do, and this is just a business political decision, they decided to actually slice up MS initially into three diseases, relapsing remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and then each grouping would have less than 200,000. The reason for doing that is to get interferon licensed with one trial. And that’s how interferon beta got licensed on one trial, because MS was an orphan disease. So it was essentially a fudge. It wasn’t based on biology. It wasn’t based on pathology. And then they added a fourth group called clinically isolated syndrome (CIS) to that. And I think when the diagnostic criteria change, they’ll take asymptomatic MS, radiologically isolated syndrome (RIS), and create another category. So you’ve got these little pigeonholes to define what the disease looks like. And they’re not really different diseases. And the reason why I say this is because you can actually push people from one type to another type. I’ll just give you an example.

Somebody may have relapse-remitting MS, and you put them on a very effective disease-modifying treatment, and you stop them having relapses, and they’re getting worse because of smoldering MS. That’s progressive MS. That’s what we see, worsening independent of relapse activity. And similarly, you can take somebody who’s got primary progressive disease, and if you give them a certain type of immune stimulant, you can actually cause them to have relapses. So you can push people along the spectrum. So I think my interpretation of what we see clinically is you’ve got MS, and the real disease is a smoldering disease. And then what you see from a clinical perspective is the inflammation that occurs from the systemic inflammatory response to the disease, whether you can have relapses on MRI activity. And this analogy doesn’t only apply to MS. It happens in many other diseases. We see this, what we call a clinical phenotype, a spectrum, based on how the immune system responds to what’s causing the disease.

And I think actuallya large proportion of the MS community, research community, are now beginning to accept that MS is one disease, and that putting people into these little pigeonholes is artificial. You know, the reason why this is important is because it has implications for treatments. People think that treatments don’t work in progressive disease. Well, I think that’s wrong. They do work. They just don’t work as well because people with progressive disease are much older and further and more advanced. So you don’t see the treatment effect being that prominent compared to early MS. It’s just a matter of where you are on the course of the disease.

Treatment and Management Approaches

Why should we move beyond the terms RRMS, SPMS, and PPMS when pursuing personalized treatments?

Prof. Gavin Giovannoni: I think what will happen is you’re going to be labeled or people are going to get given a diagnostic label as having multiple sclerosis. And then on top of that, they’re going to ask, do you have any evidence of inflammation, focal inflammation? Are you having relapses or new lesions? And then you’ll have to have that treated with a particular class of disease model, an anti-inflammatory. And then if you’ve got evidence of smoldering disease, you’re going to have therapies that target those smoldering processes. That’s going to open up this new therapeutic era where we’re going to be using combination therapies not just one treatment at the moment. You know treatments are monotherapy you can only take one therapy at a time but I think going forward we’re going to be doing combination therapies to tackle both processes.

What current treatment options are available for Smoldering MS, and how effective are they?

Prof. Gavin Giovannoni: We don’t have any therapies that are licensed specifically for add-on, smoldering MS. There’s a new class of drugs called bruton tyrosine kinase, BTK inhibitors. The first one was only tested in relapsing-remitting disease, and it wasn’t shown to be better thanteriflunomide, a licensed therapy, so it never went forward. But tolibrutinib, which is the second trial, there were three trials to report out, shows that the drug actually works above and goes beyond focal inflammation and actually slows down a smoldering component. So that’s potentially going to get licensed. So somebody who’s on an existing DMT and is getting worse would potentially be eligible for tolibrutinib. But I’m not 100% sure what the European Medicine Agency (EMA) will do. You know, the agencies may have different opinions.

But I see the American FDA has fast-tracked the approval process for tolibrutinib so they probably will get it in the United States earlier than the European community. That will be an option in the next 12 to 18 months and then they areother BTK inhibitors. After that there are two big trials happen. There’s one called fenibrutinib and then there’s one called remibrutinib and there’s one after that as well so that’s that and then in additionthere are other therapies been tested. So there are drugs that are being repurposed from an oncology field that go into the brain. There’s proteasome inhibitors that hopefully will kill the B cells and the plasma cells that make the antibodies.

Cladribine is one of the therapies that are licensed for treating relapsing MS. We have evidence that because it’s a small molecule it does go into the brain, and it does kill B cells and it does reducethe amount of antibody in the brain. So that’s actually a drug that possibly has an effect on small ring component in addition to the inflammatory component in the periphery. So clearly this is new in the field, but there’s going to be treatments where we will target smoldering MS. And then at the same time, people with multiple sclerosis have to engage with the non-MS targets. Like I mentioned to you, and, you know, certain thingsare reallyimportant. I don’t know how aware your audience is of social determinants of health so these are the things that affect you socially that impact on brain health so things like social isolation and loneliness.

These things are really important and there’s preliminary evidence suggesting that people that have got socially isolated or lonely in other words they don’t have enough social interactions their social capital do worse, it’s very well known that, these social determinants have an impact in mental health, particularly, but they also look like they have an impact in MS. So part of our responsibility as healthcare professionals is to try and identify people that have what I would call modifiable social determinants and then use different types of treatments. There’s a thing called social prescribing. Now, I don’t know, in Germany, is social prescribing a big thing or not?

Nele von Horsten: I’m not sure. I mean, I had Anthony Feinstein on the podcast talking about the COGEX study where they found out how important the social component is. But I’m not sure what social description means.

Prof. Gavin Giovannoni: So the example would be if somebody is socially isolated, you could actually see what they like and then you can give them subscriptions to art classes, music lessons. They can join gardening classes, walking clubs. But the important thing about these activities is not so much the activity. It’s the fact that they go and do it as a group and they have interactions with other people and they form friendships and they regrow their social networks. So it’s more about reconnecting people that have become disconnected from their communities. The church, you know, religion is very important. I’m not saying I’m going to promote religion yet, but one of the things about religious groups is they tend to maintain social capital. Because by participating in a religious group, by going to church and involved in religious activities, you are keeping that component of your social determinants healthy. It’s what I call social health. And we can’t underestimate social health. You know, I see it all the time, when people lose motivation, then it impacts on mental health and all those things make things get worse much more quickly.

This why I have this philosophy of marginal gains, trying to fix all the little things adds up to big changes. And that also