Dr John Corboy: Why Disease-Modifying Therapy Efficacy Varies With Age

October 9, 2020

Older individuals need medications that focus on effects inside the nervous system, explained John Corboy, MD, of University of Colorado Denver, School of Medicine, and Rocky Mountain MS Center at Anschutz Medical Campus.

Immunopathology changes with age, so older individuals with multiple sclerosis need medications that focus on effects inside the nervous system, explained John Corboy, MD, professor of neurology, University of Colorado Denver, School of Medicine, and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus.

Transcript

Why are disease-modifying therapies for multiple sclerosis (MS) more effective in younger patients?

That’s an outstanding question for which there’s not a simple answer. I think, partly, I believe it’s because the pathology changes as people age. We know that MS is an inflammatory or autoimmune disorder, as well as a neurodegenerative disorder. But the pathology of a 25-year-old, the neuropathology of 25-year-old is not the same as that of a 65-year-old.

When people are younger, they tend to have these highly inflammatory lesions, which are associated with flooding of white blood cells, lymphocytes, macrophages into the nervous system, creating what we think of as these acute plaques, especially in white matter, also in the gray matter of the brain and spine. But they’re highly inflammatory, and we see that as manifested clinically with these relapses—acute sudden changes in disease activity followed by remissions—but also associated with changes that we see on MRI scans with damage to the so-called blood-brain barrier, which allows the entrance of all these white blood cells from the periphery, from the blood, from the lymph nodes, emptying into the blood, going into the nervous system, and causing these acute changes.

As people age, there is much less in the way of these types of changes and there’s more of what’s felt to be inflammatory processes that are more segregated inside the nervous system, as well as in the lining of the brain, the meninges, where you can see significant changes that are not seen typically in younger patients.

So the immunopathology changes as people age, and the medicines that are presently available are just simply more effective in those individuals who have the types of changes immunologically when they are younger. So that’s not to say that there’s not an immunological approach that might be useful in people as they age, but it’s probably going to have to be a different approach, one focused more on immunological changes and/or degenerative changes that are perhaps separate from acute inflammation, but it’s centered inside the nervous system.

Many of the medicines going forward, we’re going to have to be certain that these medicines, for example, can cross the blood-brain barrier and actually have impact inside the nervous system proper in order to be effective, whereas that’s not really necessarily the case. Tysabri is perhaps the best example. Tysabri (natalizumab) has its impact by literally blocking cells entering the nervous system, so its effect is deliberately outside of the nervous system.

Going forward, I think it’s more likely that we’re going to have to see medications that are focused on presence inside the nervous system and effects inside the nervous system, if we’re to have an impact in individuals who are older, especially those individuals who have progressive MS that is slow progression of symptoms, especially with gait disturbance and cognitive impairment that is either independent of relapses or has perhaps relapses superimposed upon it. But it’s certainly a significant amount of progression independent of relapses.

So, I think that’s the best answer, but I think the real answer is also no one’s exactly sure.