Darin Okuda, MD, FAAN, FANA, on Early Detection of RIS and Significance of ARISE Study Findings

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Darin Okuda, MD, FAAN, FANA

Since the 1980s, preclinical multiple sclerosis (MS) has been identified as brain MRI findings consistent with an incidental finding of central nervous system demyelination among asymptomatic individuals. In 2009, Darin Okuda, MD, FAAN, FANA, and colleagues previously defined this entity as radiologically isolated syndrome (RIS). RIS does not mean that a patient will always be diagnosed with MS, but there is a strong association between the conditions and treating RIS early affects her potential risk of developing MS. Some researchers believe it is possible.

Okuda, director of the Neuroinnovation and Multiple Sclerosis & Neuroimmunology Imaging Program at UT Southwestern Medical Center, is the principal investigator of the ARISE study (NCT02739542), a double-blind trial evaluating dimethyl fumarate (Tecfidera; Biogen) in patients with RIS. was. This study of his 87 patients who met his RIS criteria in 2009 was considered successful. As survey results showed a significant reduction of 82% Risk of first clinical demyelination event during 96-week treatment period (hazard ratio, 0.18; 95% CI, 0.05-0.63; P. = .007). Overall, this is the first time a disease-modifying effect has been demonstrated in this patient population.1

Additional findings showed new and/or newly enlarged T2-weighted hyperintense lesions in 31% of the placebo group and 26% of the dimethyl fumarate-treated group at the end of the study period. Of the patients with MRI progression, 6 of 8 in the placebo group and 1 of 7 in the dimethyl fumarate group converted to first clinical presentation. As part of a new iteration of NeuroVoices, Okuda discussed next steps for interpreting these findings, including identifying subgroups of responders. Additionally, he provided perspective on the need to improve his awareness of RIS and whether abolishing the clinical phase would help better manage the condition.

neurology live®: Can we identify subgroups of patients who, albeit early, may respond better to treatment?

Darin Okuda, MD, FAAN, FANA: That’s a great question, but it’s a little early for that. Naturally, we want to identify the best individual for treatment. It is also important to emphasize that there is always a risk of overtreating individuals, whether they have clinically isolated syndromes, relapsing-remitting MS, or primary progressive MS. I understand your concern because I realize that standards may be different if you’re using RIS. I think future research aimed at finding out who are the most ideal candidates should be noted. We know that those with subtentorial changes within the stem (brain stem, cerebellum), along with other findings regardless, may be more ideal people to treat. than others. But we don’t have those data yet.

However, ARISE has a few things to offer. One is the recognition that RIS is an early stage of multiple sclerosis. I think that’s really important. And if we intervene early, individuals will respond to treatment. This is great. The effect that dimethyl fumarate had is also evidence of the existence of this early stage of MS. That’s because those who didn’t receive treatment actually evolved differently than they did if they were exposed to a particular disease-modifying therapy.

I think there are still many challenges that we have to deal with. One is how do we know these people are at risk? We now rely on MRIs by chance. We challenge the risk of misclassifying people with MRI-sensitive, non-specific white matter alterations as having features consistent with CNS (central nervous system) demyelination. There are many other challenges here, but I think the big plus here is what this ultimately means for our field. The greater recognition of the segregation during the biological onset of the disease that RIS truly represents is due to the structural abnormalities seen that strongly suggest misidentification of the brain and spinal cord optic nerves by the immune system.

I don’t know how people would have lived if change had been suppressed. We know that multiple sclerosis has very pronounced changes punctuated by these bright, large, white T2 hyperintense lesions in the brain and spinal cord. However, there are also potential changes below the resolution of MRI. What if the cure for actually dealing with changes to old code worked? Would a particular individual be more likely to do something physically or academically or academically? It’s clear and exciting to think about.

What improvements have been made in detecting RIS? Where are the clinical gaps?

The general perception of entities is massive. This sets the criteria to different levels. Moving forward science focuses on shifting that curve further to the left. How cool would it be if we could recognize people with abnormal immune systems and intervene before the first brain lesions occur? That would be exciting. Currently, the definition of the biological onset of the condition is still contested because anything happens within the immune system, whether it is virally based or caused environmentally by certain substances. It is and can be different for different individuals.

Overall, this allows us to look at the multiple sclerosis spectrum in a different way. It’s a challenge for anyone to start thinking of better ways to identify disease early. We can also create strategies that work for people with existing multiple sclerosis. The ability to identify blood-based markers of nerve damage could also apply to established people with a confirmed diagnosis. Overall, raising awareness alone is very important. So how should we parse these other strategies for how we will classify multiple sclerosis in the future?

Overall, what is the significance of these results?

I think the real chance here is for RIS to be recognized as a therapeutic indication even by the FDA. Of course, having proper guardrails and such, but that means a lot to everyone in the field. While this means a lot to our colleagues around the world, healthcare systems are very different and have different access. Recognizing and formally defining whether you want to call it a subtype or a phase within the MS spectrum will be very important moving forward.

But I think it’s the early aspects of the disease that scientists will invest in in the future, and look at the impact of early treatment in similar groups by race and ethnicity. ? There is also a big opportunity. I pursued the field of neuroimmunology because I felt like I was at a foundational level of something very exciting, regardless of when someone entered the field, and who is entering the field now. Even so, I felt that I could open up great things. Meaning to field. I still feel it today. There are people in training who are interested in multiple sclerosis, and I think that’s what makes our field so exciting when compared to other subspecialties that exist in neurology.

Edited transcript for clarity. Learn more about NeuroVoice here.

1. Okuda DT, Kantarci O, Lebrun-Frenay C, et al. Dimethyl fumarate delays radiologically isolated syndromes of multiple sclerosis. Anne Nellore. Published online November 18, 2022. doi:10.1002/ana.26555

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