What Role Does Age Play in Multiple Sclerosis?


The director of the Multiple Sclerosis Program at Cleveland Clinic Lou Ruvo Center for Brain Health discussed the correlation between age and disease duration in MS, as well as what was learned from a subanalysis of the EXPAND study of siponimod.

Dr Le Hua

Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health

Le Hua, MD

Multiple sclerosis (MS) is a difficult disease for physicians to treat, even with the relatively vast arsenal of therapeutics available as treatment options.

Additionally, a wide variety of factors, from the patient’s age at diagnosis to the duration of the disease, can influence the physician’s decisions in managing its progression. Currently, the disease-modifying therapies (DMTs) for MS treatment target the early phase of the disease course—characterized by lesion activity and inflammation—while treatments for progressive disease have required a modified approach.

To find out more about the questions MS specialists are facing and the relationship between age, disease duration, and treatment in patients, as well as what can be gleaned from the age-based subanalysis of the EXPAND clinical trial, NeurologyLive sat with Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health.

NeurologyLive: How much do we know about the correlation between disease duration and age in MS?

Le Hua, MD: Disease duration and age go hand-in-hand, right? The older you are, the longer you're likely to have the disease, as the pretty general rule. However, there are some nuances, like late-onset MS. Patients who have onset when they're a kid will have longer disease duration even though they're younger, rather than someone who has the first manifestation in their late 30s. But, in general, age will correlate with disease duration.

When we take a different look at the natural history of the disease overall, early on we see a lot of peripheral inflammation, a lot of relapse, there's a lot of MRI activity. A lot of the studies have shown that the older you get, the fewer relapses there are, the less MRI changes, the less disease activity, and it's been brought up a couple of times at ACTRIMS and in different analyses—we don't have a really good idea if we should be treating older patients differently, and if what's actually underlying the disease is different. For instance, early on patients have a lot of disease activity, a lot of peripheral inflammation—drugs are targeting that. As they get older and their relapse is decreased and MRI changes decrease, do the drugs still treat the current pathophysiology of the disease? We believe that the older patients, when they start having more of the progression and the neurodegeneration, that it's more smoldering inflammation and compartmentalized inflammation and then loss in metabolic pathways that really aren't reliant on the peripheral immune system anymore. Our drugs aren't really targeting that either. As patients get older, they also have different risks. They have greater infection risk. We don't really understand what the role of our medication is in that age group. We understand that the disease reduces, but we're not quite sure if our medications still treat what we want to treat in the older age group. That's kind of what's the most lacking at this time.

How has age entered the discussion around treatment decisions in MS?

The first MS DMT was approved in 1993, so we're really talking about a short amount of time, and because our main focus for this time is really the need to get therapies out there—we need to get stronger therapies—we haven't really thought of age as a factor to consider, until now. We're seeing that because we're doing so much better at earlier diagnosis and at treating, the prevalence of MS is shifting. It used to be younger, but now the average age of an MS patient is getting older. That's because we're doing much better job at treating and taking care of them, so they're living longer, they're able to survive, and then we've had them on treatments for a long time. Now, we're actually starting to think about age in a way that we never had before.

The data is actually fairly lacking because it's just kind of a recent phenomenon that we're looking at. For me, how I kind about age is: what's actually happening in their disease? If they're a new diagnosis of MS, is it because they had a new enhancing lesion or a new change or new relapse? Or did they finally just come in, they've had symptoms for 30 years but they finally just started coming to a doctor? Those are 2 different patients—1 has most likely had the disease, they've just never seen anyone, and with the other there's something new going on. I treat them kind of differently, in that anyone with any new disease activity, new inflammation, there's still evidence of peripheral inflammation—we treat them just like a brand-new diagnosis. If more likely they've had the disease for a while and there's really no new evidence, then I'm treating them as I would a progressive patient, in that what are their comorbidities, what are their risk factors, is there any real benefit of instituting a medication now versus can we watch it and wait? If I don't think that they have active disease, I'll watch them, I'll check MRIs and then we'll monitor for disease activity. If they do have active disease, then we treat just like a presenting patient who has new disease activity.

Overall, in both cases, we're also looking at comorbidities, we're looking at symptom management, do they have spasticity or leg weakness, would they benefit from physical therapy exercise, do I counsel them on nutrition? Older patients will likely have more comorbidities, so what is their risk of heart disease, risk of cancer? And then their social networks—are they able to kind of do some of the interventions that I talked about? Can they come to clinic and drive, are there social barriers that would affect that? That kind of also seems to correlate with age as well.

How does the subanalysis data from the EXPAND study fit into this discussion of age in MS?

The subanalysis is very unique and I think it's great because it really does get into that question of can we dichotomize our patients? We know that there's a younger group and there's an older group. We really wanted to then look at if there is a difference in the drug working on 1 group or the other. Siponimod is an S1P1 selective, P1P5 selective modulator, so we know it has a peripheral effect. It definitely will reduce peripheral lymphocytes, it should have an effect on inflammation and attacks, which then would make us think that if younger patients have more inflammation, they would also have more effect. But an older patient group which has less peripheral information, is there still an effect?

Now the original siponimod study was looking at secondary progressive MS patients and looking for their primary outcome of 3-month confirmed disability followed by 6-month confirmed disability progression, and in the overall trial, there was a benefit when you looked at the overall group on both of those endpoints. Then we split it because siponimod was approved for active secondary progressive MS, we then defined the subgroup in looking at just active secondary progressive MS patients—they were defined as active if they had either a clinical relapse or a new GD enhancing lesion within the last 2 years. In that subgroup, we then split them into younger than 45 years and older than and including 45 years, and in both groups, it actually looked fairly similar in their efficacy on both of those 2 end points. So, it didn't seem that age mattered, the drug worked in both age groups on at least disability end points.

The other part of that was then if there were any safety signals that were different between the 2 groups, and they looked fairly similar there as well. The decreasing lymphocytes, lymphopenia, liver abnormalities, and infection risks were similar younger than 45 as well as greater than and including 45. That's kind of reassuring that this drug works in both a younger population and older population, and safety seems to be about the same. We still kind of need a tease out if 45 is really the age we should be splitting patients into, but the reason why 45 was picked is that it gave us well-balanced numbers to actually be able to make a comparison. If you have way too many patients in 1 group and the other 1, then you're introducing other biases that might not be as appropriate.

Transcript edited for clarity.


1. Bar-Or A, Cohan SL, Coyle PK, Lublin FD, Meng X, Su W, Cree BA. Analysis of the effects of disease duration on the efficacy and safety of siponimod in patients with active SPMS from the Expand study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P030.

2. Hua L, Bar-Or A, Lublin FD, Meng X, Su W, Cree BA, Fox R. Analyses Of The Effect Of Baseline Age On The Efficacy And Safety Of Siponimod In Patients With Active SPMS From The Expand Study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P029.

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