Fred D. Lublin, MD, leads a discussion about the different classifications of secondary progressive multiple sclerosis, including the relationship between disease activity and progression of disease.
Bruce Cree, MD: Before we talk about medications, I want to dig a little bit deeper into SPMS [secondary progressive multiple sclerosis] and some of the work that’s being done in terms of further characterizing it. I’m going to ask Fred to comment on this because this is some of his seminal work in trying to understand the relationship between disease activity and progression, and the utility of providing further classifications. Fred, do you want to take this one?
Fred D. Lublin, MD: Let’s look at the disease courses that Joe outlined earlier, which we published in I believe 1996. We looked at them again in 2012 or 2013 to see if they needed to be updated. We decided that the courses had served us well in the clinic, in clinical trials, and the regulators had used them and used them well. But we thought there were some changes that we needed to make.
One was that we wanted to have a way of assessing, in a dynamic way, where someone was at any given point. To do that, we added 2 subclasses, modifiers, on the courses. One was whether they were active or not active; because once you diagnose someone as having MS [multiple sclerosis], they have it for the rest of their lives until somebody takes the diagnosis away.
When you say someone has relapsing-remitting MS, they have it unless something changes. But over the years, especially with treated patients, you want to know how they’re doing. This is important for figuring out what you’re going to do with them—maintain a therapy, stop a therapy, or change a therapy.
We said, “Let’s characterize them as whether they’re active or not active.” In doing that, we said active meant having had either a relapse or new MRI activity. One of the important points that perhaps we didn’t stress enough because it’s caused considerable confusion, especially among regulators, is that that determination had to be framed in time. We said that you could pick whatever timeframe you want when you see your patient and characterize their activity, but that it should be annually at a minimum. That meant that you should have it assessed annually, whether there had been a relapse or a change in the MRI in the last year.
The second characterization was for progressive patients—primary progressive or secondary progressive—whether they were progressing or not progressing, and again, framed in time. We all know that there are patients with progressive disease who go long periods without changing as we’re measuring them. We said that you should assess progression at least annually on a clinical basis. We could not come to agreement as to any MRI requirement for progressive patients to assess progression because there is no MRI equivalent for progression. So that, too, had to be framed in time.
You end up having 4 possible characterizations for someone with progressive disease, which is what we’re talking about today. They could be active and progressing. They could be active, meaning they’ve had a relapse or a new MRI lesion, and not progressing. They could be progressing and not active. That’s a group that we’ll spend some more time discussing because that’s the one that’s probably of greatest interest to us. It certainly meets our most pressing therapeutic need. Then there are people who are not active and not progressing, meaning they are stable.
After you get done doing these things, there are all sorts of consequences, intended and unintended, that you think about after the fact. One of them was that by defining activity as either a clinical event or an MRI event, we equated those. Biologically, I think that makes sense. Because if you have an MRI that causes a lesion but it doesn’t hit clinical threshold, is that biologically less important than one that does? That may be more a matter of the stochastic choice of where the lesion occurred. We also codify the idea that there should be at least an annual MRI in patients who have a relapsing form of MS. That was useful for clinicians for dealing with insurance companies.
Bruce Cree, MD: Fred, I’m going to follow up with that. You very nicely described the subclassifications of progressive MS in terms of active and not active, with and without progression. Would you say the same set of criteria apply regardless of whether a particular patient is classified as having secondary progressive or primary progressive MS?
Fred D. Lublin, MD: Yes. They’re both important in somewhat different ways. There’s some older literature that had suggested that once you hit a progressive phase, it doesn’t matter whether you have any relapses. More recent literature suggested that’s not right; that for example, secondary progressive patients who are having relapses develop disability milestones faster than those who are not.
It turns out that there’s more activity going on in primary progressive disease than we would have thought a decade or more ago. They also have activity. How much that is contributing to their underlying cause is not as clear-cut because there’s less activity there, but it still occurs.
Bruce Cree, MD: Bob, what criteria do you use to diagnose primary progressive MS [PPMS]? It seems like the distinction between PP [primary progressive] and SP [secondary progressive] might have to do with an event that occurred in the distant past that may or may not have been adequately characterized medically. What criteria do you use for PPMS?
Robert Fox, MD: To me, PPMS looks exactly like SPMS. There’s a gradually progressive decline in neurologic function, most often manifested as a walking difficulty. So there’s a progressive myelopathy in walking function, but sometimes an arm function instead, or in addition. The MRI findings are typical of demyelination, but the absence of a clinical episode. As we mentioned, that clinical episode may be a little bit fuzzy, and so sometimes we’re left unsure as to whether the patient has primary or secondary progressive MS.
At the end of the day, the neurologist has to decide. Do they think there is a history consistent with the demyelinating clinical event? If the answer is no, then primary progressive MS is the diagnosis that one is left with. The bottom line is that it looks exactly like secondary progressive MS, except that a neurologist, in the best judgment of his or her experience and clinical judgment, says, “No, there’s no history of a clinical relapse.”
Bruce Cree, MD: Is MS just 1 disease, or is it all these different subgroups? This is a question for everybody. Should we be thinking of MS as just MS, or should we be thinking about it in these different ways?
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Transcript Edited for Clarity