Risk of MS Disease Progression and Complementary Diagnostic Tools

EP: 1.Disease-Modifying Therapies (DMTs) in Multiple Sclerosis (MS)

EP: 2.Approaching Treatment for MS Management

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EP: 3.Risk of MS Disease Progression and Complementary Diagnostic Tools

EP: 4.DMT Adherence and Routes of Administration in MS

EP: 5.Efficacy and Safety of Oral Therapies in MS

EP: 6.Use of Cladribine in MS Treatment

EP: 7.Sequencing of Therapies in MS

EP: 8.Role of Oral BTKi in MS Management

EP: 9.Emerging Therapies and Unmet Needs in MS

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: If you have this idea that this is somebody who has a more aggressive type of disease, I’m worried about them. They’ve had an attack, and now their exam a couple of months later is not normal. I think that’s a very important finding because as you know, when patients present with MS [multiple sclerosis], their first symptoms are not the first episode of MS.

Ahmed Zayed Obeidat, MD, PhD: That’s right. They’ve probably had the disease for a while.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: They do the MRI and they’ve got all sorts of stuff. They’ve harbored the disease for a while, and at some point, it builds to suddenly having symptoms. Whatever mechanisms are at play that kept the disease silent have decompensated, and now the patient has symptoms. I think already that’s a telltale sign that they’re going to have more.

Ahmed Zayed Obeidat, MD, PhD: They can progressively decline, quickly sometimes.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: If you just watch these patients, they’re going to have more events, and they’re often going to have them soon. So you have this decompensated patient, if they’ve recovered completely, there’s no residual disease, they are good repairers. Maybe they don’t need aggressive therapy. We have imaging that helps us to delineate how much silent disease is occurring, whether there are certain locations that we know are more apt to produce long-term worsening in patients, the worst being the cerebellar type things.So, brainstem, cerebellar, the myelopathies that leave people dragging their feet and having bladder issues. If you have too many lesions in those areas, those are people you’re more worried about. It’s not black and white, but you put it all together with the story, and maybe these are individuals who are at a higher risk.

Now we even have some biomarkers. We’re using neurofilament light [NfL] chain to measure in most patients at baseline and we follow them. We’ve shown that the baseline level of neurofilament outside of an attack, if it’s elevated, those individuals are quite at risk of early progression.

Ahmed Zayed Obeidat, MD, PhD: Let’s touch base on this since we are talking about biomarkers. In your clinic, you mentioned you’re using MRIs, you’re using a clinical examination of course, and then you’re using also NfL.Is any GFAP [glial fibrillary acidic protein] used?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: We can’t get that yet routinely, but you’re bringing in the notion that there are other biomarkers. So NfL is a marker of axonal breakage. It’s not specific to MS. You break an axon anywhere in the body, peripheral or central, and you’re going to get a rise in NfL. But if there’s no other explanation for it, it’s probably the MS. GFAP on the other hand, glial fibrillary acidic protein, it’s the glia, it’s the astrocyte. Why would an astrocyte be dumping its GFAP into the serum? This is a marker of scarring.

Ahmed Zayed Obeidat, MD, PhD: Scarring, yes.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: When does that occur? That occurs later in the disease. What we’ve seen now is that if you measure the GFAP, it might be more apropos to do it in patients you’re worried about who are progressing. Whereas the NfL aligns itself with the inflammation. It’s kind of giving you the same information as the MRI is, but it’s a lot easier to get a blood test.

Ahmed Zayed Obeidat, MD, PhD: And maybe you were missing things on the MRI.Conventional MRIs don’t show much of the lesions sometimes.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: All the disabling stuff is from here to here; most people don’t get MRIs.

Ahmed Zayed Obeidat, MD, PhD: Even when getting the spine, it’s harder to interpret sometimes with the motion of breathing, and artifacts, and things like this.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Trying to find a new lesion when you’re talking about tiny things.

Ahmed Zayed Obeidat, MD, PhD: Yes, thoracic cords.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: It’s very difficult. I think the NfL is a complementary test to the MRI imaging. If you had no change on the head MRI, but the NfL went up 10-fold….

Ahmed Zayed Obeidat, MD, PhD: There might be something.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: There might be something cooking somewhere else. That’s a good reason to bring the patient in and re-examine them. Maybe you now find upgoing toes, there’s an indication that the spinal cord is involved. You could maybe make a change in therapy before things happen.

Ahmed Zayed Obeidat, MD, PhD: In assessments in the clinic, are you using any cognitive assessments? Are you using anything complementary to the neurological exam? Are you collecting EDSS [Expanded Disability Status Scale data] routinely, for example?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Oh, yes.

Ahmed Zayed Obeidat, MD, PhD: You are, that’s nice.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: We do the EDSS, but you’ve touched on a very important point with regard to cognition. We’re not doing a great job of that. Most clinics don’t have time.

Ahmed Zayed Obeidat, MD, PhD: To do the assessments?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: To do it. We finally got these iPads for patients. They were implemented the last couple years, but with COVID-19 protocols, you couldn’t use them. We have these iPads where the patients do their SDMT [Symbol Digit Modalities Test] in the waiting room.

Ahmed Zayed Obeidat, MD, PhD: Nice.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: We are on Epic [software system] for an EMR [electronic medical record]. So the number that is generated from the SDMT automatically goes into it.

Ahmed Zayed Obeidat, MD, PhD: It goes directly to the record? Wow, that’s nice.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: That’s starting, but SDMT is just one little facet.

Ahmed Zayed Obeidat, MD, PhD: Measuring the processing speed….

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: At least we’re trying.

Ahmed Zayed Obeidat, MD, PhD: But that’s moving in a good direction. How about patient-reported symptoms and outcomes, and things like this? Are you incorporating those routinely in practice? We always talk to patients and get their history and understand what their concerns are.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Of course.

Ahmed Zayed Obeidat, MD, PhD: Sometimes we use this as guidance and even for therapy change. Do you routinely implement those in the clinic?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Probably not in a systematic way. What you’re saying though is you have to listen to the patient, and we’ve heard repeatedly at various conferences that the detection of progression is subtle in a lot of folks. It might not be as obvious as, “I can’t climb the stairs anymore.” The patient may tell you, “I’m having difficulty at work. Something that took me 10 minutes now is taking me a half an hour, and I’m getting too fatigued with doing almost nothing. I go for walking my dog and have to stop and rest halfway.” That information is giving you a sense that they are progressing. Even though physically, they haven’t changed on the neurological exam, but something is going on in those individuals that may be underlying disease progression.

Ahmed Zayed Obeidat, MD, PhD: Now we’re referring to the term smoldering disease in the pathology. But it’s more like a progression, right?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: I think that’s an MRI term.

Ahmed Zayed Obeidat, MD, PhD: It’s an MRI term.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: These are wonderful pieces of information that we’ve gleaned from clinical trials. But to measure things like pearls and smoldering lesions requires sequential scans that are done in a sophisticated way. And when you send your patients for a scan, they’re slapped in there, and however quickly they can get the scan, you get the results. They’re not aligned so that when you take the 2 sets of images and compare them, often they don’t overlap.

Ahmed Zayed Obeidat, MD, PhD: The angle is different and things like this.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: So now you’re guessing. The finite information that’s coming out of the clinical trials due to, I’m going to say, critical positioning of the patient, that never happens in real life.

Ahmed Zayed Obeidat, MD, PhD: That’s the difference between real-world and clinical trial-types of data.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Absolutely.

Ahmed Zayed Obeidat, MD, PhD: Which we will touch on a bit also.

Transcript edited for clarity