What’s New in MS Research – May 2023

Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD

Multiple sclerosis (MS) clinicians and research were well represented when neurologists from across the country and around the world gathered in Boston in April for the 75th Annual Meeting of the American Academy of Neurology (AAN). Indeed, findings from more than 270 studies on various aspects of MS were presented at the meeting.

The 14 studies summarized below reflect the breadth of that research. They include Phase III, double-blind, placebo-controlled trials and analyses of large insurance-claims databases, studies conducted both in the United States and abroad, and topics ranging from the efficacy and safety of investigational and FDA-approved treatments to simple strategies for helping people with MS avoid overheating during exercise.

Several of the findings reported are quite encouraging, including study results detailing how various dietary approaches can favorably affect cognition, fatigue, and sleep in MS. Perhaps the most encouraging news of all, however, is just how many talented and committed researchers and clinicians are pursuing so many different avenues of inquiry into MS, all with the aim of improving diagnosis, treatment, outcomes, and quality of life.

Studies suggest that changes in diet may help to preserve cognition and improve energy levels and sleep in MS

The old adage, “Let food be thy medicine,” received new support from three studies presented last month at the 75th Annual Meeting of the American Academy of Neurology (AAN).

In the first study, researchers reported that greater adherence to a Mediterranean diet was associated with higher scores on measures of cognition among 563 people with MS.¹ A Mediterranean-style diet emphasizes vegetables, fruits, lentils, nuts, whole grains, and extra virgin olive oil, along with moderate amounts of fish and little or no red meat or processed foods. Prior research has documented cardiovascular and other benefits from this approach to eating, and researchers also have demonstrated that the diet has a favorable effect in terms of reduced disability in MS.

This latest study found that after adjusting for factors such as age, sex, body mass index, and the presence of other health conditions, a higher degree of following a Mediterranean diet predicted a 20% lower risk for cognitive impairment relative to the risk seen in people with MS with lesser or no adherence to the dietary approach. The researchers also found that the link between diet and cognition was more evident in people with progressive forms of MS than in those with relapsing MS. “The strength of the relationship in progressive disease suggests the possibility of a neuroprotective mechanism,” the investigators wrote, adding that “longitudinal studies and interventional clinical trials are needed” to further explore this issue.

Meanwhile, a team from Oregon Health & Science University presented research at the AAN meeting showing that a low-fat diet reduced fatigue in people with MS.² The researchers recruited 39 people for their study. The study participants had an average age of 50 years and mean BMI of 31 kg/m², which is considered obese. Twenty of those people received four weeks of nutritional counseling and then followed a low-fat diet for another 12 weeks. The other 19 study participants served as a control group. At the end of the 16-week study, the people in the low-fat group saw the percentage of calories from fat in their diets decreased by almost 11% compared to the control group, and their scores on two validated measures of fatigue were significantly lower (indicating reduced fatigue) compared to the controls.

Finally, another group of researchers examined the impact of a ketogenic diet on sleep in people with relapsing MS.³ Unlike the Mediterranean diet or low-fat diets described above, a ketogenic diet emphasizes fats, and typically includes foods like butter, cheese, eggs, meat, nuts, oils, seafood, and seeds. The diet is also marked by moderate amounts of protein and scant carbohydrates. The Atkins^® Plan is one of the best-known examples of a ketogenic diet.

This six-month study enrolled 45 adults with relapsing MS. Thirty-nine of those people completed the study, following a modified Atkins ketogenic diet for half a year. While 15.4% of them had reported excessive daytime sleepiness before beginning the diet, only half that proportion (7.7%) said they experienced the problem at the end of the study. Study participants also showed improvement in measures of insomnia, sleep apnea, and other sleep disorders.

These three studies are the latest contributions to a growing body of evidence documenting the links between diet and MS. While the studies assessed markedly different diets and their impact on varied aspects of multiple sclerosis, that diversity of tactics and targets speaks to clinicians’ increasing ability to tailor nutritional advice to the individual patient and his or her main concerns.

Examining the impact of body mass index on anti-CD20 therapies

Higher body mass index (BMI) is associated with faster repopulation of B cells – immune cells that play a role in MS relapses and disease progression – in people who receive disease-modifying therapies (DMTs) that work by driving down B cell counts, two Stanford researchers reported.⁴

DMTs such as Ocrevus^® (ocrelizumab) and Kesimpta^® (ofatumumab) reduce the number of B cells in a person’s immune system by targeting a protein on the surface of those cells known as CD20. The Stanford researchers analyzed data on 157 people with MS who had received an anti-CD20 therapy. The study subjects had an average age of 51.8 years; 63% were women.

The researchers divided the study participants into those with a BMI of 18.5 to 25 kg/m², which is considered normal, and those with a BMI of 25 kg/m²or greater, which is considered overweight or – at higher levels – obese. They then analyzed the people’s bloodwork to look for a particular immune cell that has been validated as a marker of B cell repopulation. They found that while B cell repopulation did not differ by participants’ age or sex, it was greater in the group with higher BMI.

Research has shown that excess weight increases the risk for cancer, heart disease, and diabetes in all people. Studies also have documented a heightened risk for developing MS and for experiencing greater MS-related morbidity. Now, these findings show that being overweight also affects the impact of therapies administered to treat the disease.

Many women are slow to resume MS therapy after a hiatus during pregnancy

Most women with MS who take a disease-modifying therapy (DMT) prior to pregnancy discontinue that treatment once they conceive, and many are slow to resume treatment once they deliver.

That finding emerged from an analysis of insurance claims data for 944 women with MS.⁵ Researchers found that while 36.3% of the women had received a DMT in the six months prior to becoming pregnant, that proportion dropped to 17.9% in the first trimester and declined to just over 5% in the second and third trimesters. The analysis, which looked at insurance claims from January 2016 through April 2021, found that 20.4% of the women were taking a DMT within three months after delivery, but that this rate had climbed to only 24.4% at four to six months’ postpartum, just two-thirds the level of pre-pregnancy DMT use.

One reason women may be reluctant to resume a DMT after delivery is concern about whether the medication might affect their baby if they are breastfeeding. Two researchers from the University of Colorado recently provided reassuring findings on that score in terms of medications such as Ocrevus^® (ocrelizumab) and Kesimpta^® (ofatumumab), which target a protein found on the surface of B cells. These immune cells play an important role in protecting overall health by producing antibodies that bind to and neutralize viruses and other foreign substances, but they also have been implicated in the MS disease process.⁶

The researchers examined bloodwork values on seven breastfed infants whose mothers had taken anti-CD20 medications following delivery. They found that all the babies had normal cell counts and no indication of B-cell abnormalities in the weeks after their mothers received an infusion or injection of an anti-CD-20 therapy.

Noting that their study involved a small number of people, the researchers said that they plan to examine data on more mothers with MS and their children. Their results to date, however, constitute welcome findings for mothers striving to protect both their own health and that of their infants.

Study examines if faster thinking may predict slower disease progression in MS

Better performance on tests of cognitive processing speed (CPS) was associated with a lower risk of increased disability over two years or longer in a study involving 624 people with relapsing-remitting, secondary-progressive, or primary-progressive MS.⁷

The study participants completed the Symbol Digit Modalities Test (SDMT), a measure of cognitive processing speed, on at least two occasions two years or more apart. At baseline, the study subjects had an average score of 1.7 on the Expanded Disability Status Scale (EDSS), which assesses degree of disability in people with MS. The EDSS runs from 0 to 10 in half-point increments, with 0 representing a normal neurological examination and no MS-related disability and 10 representing death due to complications of MS.

After adjusting for participants’ age, sex, and baseline EDSS scores, researchers found that a 10-point increase in SDMT score (measuring cognitive processing speed) from baseline to follow-up test was associated with a 25% lower risk of progression to EDSS 3.0, a 19% lower risk of progressing to EDSS 4.0, and a 33% lower risk of reaching EDSS 7.0 during the two-year period.

The researchers concluded that, based on their findings, cognitive processing speed “could be used by clinicians as a prognostic tool to inform earlier therapeutic intervention, which in turn may delay long-term disability accrual.”

When DMT initiation doesn’t follow a diagnosis of MS

Roughly one-third of people included in a recent analysis did not start a disease-modifying therapy (DMT) within 12 months of an insurance claim indicating they had been diagnosed with multiple sclerosis.⁸

The study drew on a large commercial insurance database to extract information from 2016 through 2021. It identified 2,024 people with claims coding that indicated a new diagnosis of MS. It then looked for other claims showing that those people had been prescribed a DMT. The analysis found that 17% of people began a DMT within 30 days of their first MS diagnosis code, while another 16% started treatment within 31 to 60 days of a diagnosis. Others initiated a DMT in later months, but 12 months after a claim with an initial MS diagnosis code was filed, 34% of people did not have a subsequent claim for a DMT.

Insurance claims analyses have inherent limitations, just as every type of study does. Drawing on a database has the advantage of allowing researchers to look at large numbers of cases to identify trends, but has the disadvantage of not being able to capture exactly what occurred in the clinical setting, including circumstances and nuances that may be very significant. Nonetheless, the finding that one-third of people apparently did not start a DMT within a year of learning they had MS is very concerning, particularly given the growing evidence of the benefits to be derived from early intervention in the MS disease process. This study underscores the need to identify and address causes of delay in treatment.

Study assesses Briumvi^® benefit in people with highly active MS

The disease-modifying therapy Briumvi^® (ublituximab-xiiy) achieved a greater reduction in annualized relapse rate (ARR) in people with highly active MS than Aubagio^® (teriflunomide), researchers report.⁹

In December 2022, the Food and Drug Administration approved Briumvi for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting MS, and secondary-progressive MS. Briumvi won FDA approval largely on the strength of two Phase III studies, ULTIMATE I and ULTIMATE II, which compared Briumvi — which was administered intravenously every 24 weeks – with Aubagio, an oral medication, taken once daily for 96 weeks. The ULTIMATE I and II studies enrolled a broad population of people with relapsing forms of MS. In the subpopulation analysis reported here, investigators focused on people in those studies who had highly active MS, which was defined as two or more relapses in the prior year and one or more gadolinium-enhancing lesions on T1 magnetic resonance imaging (MRI) at baseline. The analysis included 88 people with highly active disease who received Briumvi and 80 who received Aubagio.

Study participants receiving Briumvi had an unadjusted ARR of 0.145, compared with an unadjusted ARR of 0.496 for people taking Aubagio. The difference between the two rates of relapse was statistically significant. People in the Briumvi group also had a lower number of gadolinium-enhancing lesions on T1 imaging and fewer new or enlarging T2 lesions per scan than those receiving Aubagio. Looking at Weeks 24 to 96 in the ULTIMATE I and II studies, 77.9% of people in the Briumvi group had no evidence of disease activity, as compared to 16.4% of people in the Aubagio group, with the difference being statistically significant.

Highly active MS long has posed a challenge to people affected by frequent relapses and to their clinicians. The results of this analysis suggest that clinicians and patients now have another option they can draw upon in responding to that challenge.

Does Aubagio^® efficacy differ between treatment-naïve patients and those who switch from another therapy?

As more and more disease-modifying therapies (DMTs) become available, people with MS are facing a new, but welcome, question: If I’m not experiencing significant side effects on my current DMT, but I’m also not fully satisfied with that therapy, is it worth switching to another medication?

One of the keys to answering that question, of course, is determining whether the new medication offers people already exposed to a DMT the same benefits that it provides to people who take the medication as their very first disease-modifying therapy.

A team of Spanish investigators recently explored that issue as it pertains to Aubagio^® (teriflunomide), an oral DMT, in people with relapsing-remitting multiple sclerosis (RRMS).¹⁰ The researchers analyzed data from TERICARE, a prospective study of Aubagio conducted at multiple centers throughout Spain. Of the 325 patients included in the study, 117 were treatment-naïve, meaning that Aubagio was the first DMT they took after being diagnosed with MS, and 208 had switched to Aubagio from another therapy. Compared to the patients who switched, people in the treatment-naïve group were, on average, younger (40.9 vs. 44.4 years), had a shorter duration of disease (3.1 vs. 9.5 years), had experienced a higher number of relapses in the past two years (1.3 vs. 0.6), and had a higher annualized relapse rate (0.63 vs. 0.31), with all those differences being statistically significant.

The researchers found that the annualized relapse rate (ARR) was significantly reduced in both groups after 12 months on Aubagio (0.24 ARR in the treatment-naïve group and 0.21 in the “switch” group), as well as at 24 months (0.19 and 0.16, respectively), with the treatment-naïve group having a greater reduction in ARR at both time points. Higher percentages of treatment-naïve people had disability worsening at 12 months (20% vs. 13.2%) and at 24 months (24.2% vs. 17.6%), but the differences between groups was not statistically significant. People in the treatment-naïve group had greater improvement in a measure of psychological status at 24 months, with the difference in degree of improvement being statistically significant.

The researchers concluded that Aubagio “shows effectiveness in both DMT-naive and switch RRMS patients with a trend towards better relapse and quality of life outcomes in DMT-naive.”

Encouraging long-term data on evobrutinib

The investigational medication evobrutinib demonstrated efficacy and tolerability over 3.5 years of treatment in people with relapsing forms of multiple sclerosis (MS), according to an international team of researchers.¹¹

Evobrutinib belongs to a class of medications known as Bruton’s tyrosine kinase inhibitors (BTKIs). These medications inhibit the activity of a signaling molecule involved in the maturation, migration, and activation of B cells and microglia, which are immune cells that play a role in MS. Earlier studies have shown that evobrutinib can cross the blood-brain barrier and, as a result, exercise its effects in the brain.

People with relapsing MS who had participated in a 48-week Phase II study of evobrutinib were given an opportunity to continue into an extended study conducted to assess the longer-term impact of the medication. In the initial study, those people had been assigned at random to receive one of the following regimens:

• placebo, with a switch at Week 24 to 25 mg of evobrutinib once daily
• 25 mg of evobrutinib once daily
• 75 mg of evobrutinib once daily
• 75 mg of evobrutinib twice daily
• dimethyl fumarate, a disease-modifying therapy marketed generically and under the brand name Tecfidera^®

At Week 48, all study participants were able to receive evobrutinib, first at a dose of 75 mg once daily, with the dose then increased to 75 mg twice a day. Of the 267 people who participated in the 48-week trial, 213 entered the open-label extension study. Of those, 158 completed 228 weeks or more of treatment.

Researchers found that the annualized relapse rate (ARR) declined from 0.18 to 0.10 when people in the extension study switched from once-daily to twice-daily evobrutinib 75 mg. Over 228 weeks of treatment, the ARR was 0.13, meaning that if 1,000 people with relapsing MS took evobrutinib for one year, there would be 13 relapses in the entire group during that 12-month period. Twenty-eight percent of study participants reported treatment-related adverse events during the extension study, with seven people reporting serious treatment-related adverse events. Eleven people had severe and/or opportunistic infections. (Opportunistic infections are those that occur more often and/or are more severe in people with weakened immune systems.)

The researchers concluded that over 3.5 years of observation, evobrutinib showed continued benefit and tolerability, with no new safety concerns emerging.

Cool news: A potential new way for people with MS to avoiding overheating when exercising

It’s a conundrum: Exercise has been shown to provide many benefits to people with MS, but exertion can trigger the overheating that is a common feature of the disease.

Faced with the potential for experiencing immediate problems in the pursuit of long-term gain, many people opt to play it safe and not lace up those sneakers. Now, however, researchers from Columbia University Medical Center and other Columbia institutions may have identified a simple strategy for obtaining the benefits of exercising while reducing the risk for overheating on the treadmill or at the weight machine.¹²

The researchers conducted a Phase III, double-blind, placebo-controlled trial of administering aspirin to people with MS before those study subjects exercised. The trial involved 60 people with relapsing-remitting MS who reported heat sensitivity. At each of three study visits, participants received either 650 mg of aspirin, acetaminophen (a medicine available generically and under brand names including Tylenol^®), or placebo. After waiting an hour, they then pedaled on a stationery cycling machine, seeking to reach their maximum exercise level. One of the study’s two primary outcome measures was change in body temperature from pre-test level to immediately after the test. Thirty-seven of the 60 people initially enrolled completed at least one study visit and were included in the analysis.

Temperature increased during exercise in all groups, but people who took an aspirin saw their temperature go up by only about one-fifth the amount (approximately 20%) compared to those who received placebo. People who took acetaminophen before exercising saw their temperature increase to a level only about 40% that of people in the placebo group.

The researchers concluded, “Aspirin and acetaminophen are effective, accessible, relatively safe, and affordable cooling treatments to permit many [people with MS] to benefit from exercise. Wide recognition, recommendation, and uptake of this simple treatment is the next challenge.” Of course, use of aspirin or acetaminophen involves both benefits and risks, with the exact nature and degree of those consequences highly dependent on an individual’s overall health, lifestyle, and any other medications he or she is taking. Be sure to check with your MS clinician or other healthcare provider before taking aspirin or acetaminophen prior to exercising.

In addition to these new findings on aspirin and acetaminophen and their potential for reducing the risk of overheating while exercising, the medical community as well as many members of the MS community have long been aware of the benefits of cooling technology to help avoid overheating – whether caused by exercise or simply by being exposed to an overly warm environment. This method of gradually cooling the body through various types of apparel – such as cooling vests, wrist bands, and neck wraps – has been proven through clinical trials to be very effective in avoiding overheating and the temporary but often severe symptoms it can cause. Anyone interested in learning more about MSAA’s Cooling Distribution Program may visit this section of our website.

New insights on when unexpected MRI findings may signal future MS

People with no obvious symptoms of MS sometimes are found to have indicators of the disease when they undergo magnetic resonance imaging (MRI) for an unrelated reason, such as to look for possible traumatic brain injury following a car accident.

When this occurs, the person is said to have radiologically isolated syndrome, or RIS. The finding naturally is very concerning to the person involved, and prompts questions about the likelihood that he or she eventually will be found to have clinically definite MS. As scientists seek answers to that question, they have investigated which MRI findings are most strongly associated with the subsequent emergence of multiple sclerosis.

A team of Canadian and American researchers recently explored this issue by studying 36 people with RIS.¹³ The study subjects had a median age of 43 years, and 70% were women. Over a median 6.3 years of follow-up, nine of the people – or 25% of the total – developed clinical MS. Six had relapsing-remitting MS, while the other three had primary-progressive MS.

Several MRI findings differentiated the people who developed MS during the follow-up period from those who did not. The study subjects who went on to clinically definite MS had a median number of 11 paramagnetic rim lesions (PRLs) at baseline, compared to a median number of one such lesion for their counterparts, with the difference being statistically significant. These lesions are areas of chronic inflammatory demyelination in the brain. They have a central core that shows clear demyelination surrounded by a border or “rim” of immune cells full of iron. The iron is believed to accumulate as a byproduct of disease activity, and researchers are investigating the role of PRLs as a marker of MS progression and severity.

The study subjects who went on to have MS during the follow-up period also were found to have more spinal cord lesions and more white matter lesions positive for what is known as the central vein sign – meaning that imaging shows a vein running through the lesion – than the other study subjects. After performing sophisticated statistical analyses, the researchers found that the difference in paramagnetic rim lesions at time of RIS diagnosis was the variable most predictive of the later emergence of MS.

While the investigators note that their findings require validation in larger studies, these results could help inform approaches to monitoring people with RIS and facilitate earlier identification and treatment of MS in this population.

How much are neurologists-in-training learning about MS?

The demand for MS clinicians is expected to exceed the number of available providers by 2035. After offering that attention-grabbing statistic for context, four researchers from the University of Connecticut and University of Utah provided interim results of their web-based survey of the MS-specific training included in neurology residency programs across the country.¹⁴

Of 27 residency programs surveyed:

• 85% are associated with a comprehensive MS center
• 74% have three or more faculty members with training in MS
• 66% offer MS fellowships
• 56% require an MS/neuroimmunology rotation
• 44% report that over the past five years, they have had three to four graduates pursue a subspecialty in MS, while 11% said they had five or more residents in that period who decided to subspecialize in MS.

Further, 85% of residency program directors responding said MS should be a required rotation for neurology residents.

Noting that their preliminary data showed variability in neurology residents’ training in MS, the authors said that their final study results should serve to “quantify the gaps in exposure and training of future neurologists in MS and neuroimmunology.”

References

1. Katz Sand I, Fitzgerald K, Sumowski J. Mediterranean Diet is associated with cognition in multiple sclerosis. S46.010. AAN 2023.
2. Chen V, Chase E, Lane M, et al. A randomized, controlled trial of low-fat diet for fatigue in multiple sclerosis. P6.008. AAN 2023.
3. Perlman J, Lehner-Gulotta D, Wetmore E, et al. Ketogenic diet intervention improves sleep in patients with relapsing multiple sclerosis. P8.009. AAN 2023.
4. Loeffler J, Han M. Influence of body mass index on B lymphocyte repopulation in multiple sclerosis patients treated with anti-CD20 therapy. P7.016. AAN 2023.
5. Shah A, Bove R, Applebee A, et al. Patterns of disease modifying therapy utilization in women with multiple sclerosis before, during, and after pregnancy. P9.016. AAN 2023.
6. Shah A, Alvarez E. Evaluation of B-cell abnormalities in infants of breastfeeding mothers on anti-CD20 therapies for multiple sclerosis. S31.001. AAN 2023.
7. Howard D, Lokhande H, Healy B, et al. Cognitive processing speed predicts disability milestones in multiple sclerosis. P5.014. AAN 2023.
8. Jordan K, Hua H, Ghoreyshi A, Edgeworth M. Disease modifying therapy in newly diagnosed people with multiple sclerosis – a real-world administrative claims study. P3.017. AAN 2023.
9. Alvarez E, Steinman L, Hartung H-P, et al. Disease outcomes with ublituximab in participants with highly active disease: subpopulation analyses of the Phase 3 ULTIMATE I and II studies in participants with relapsing multiple sclerosis. P6.002. American Academy of Neurology (AAN) 2023.
10. Meca Lallana J, Prieto JM, Caminero AB, et al. Comparison of 2-year teriflunomide outcomes between DMT-naive and switch patients with relapsing MS: subanalysis of the real-world TERICARE study. P6.003. AAN 2023.
11. Montalban X, Wolinsky JS, Arnold DL, et al. Efficacy and safety of the Bruton’s Tyrosine Kinase inhibitor evobrutinib for relapsing multiple sclerosis over 3.5 years of treatment: an ongoing Phase II open-label extension. S16.008. AAN 2023.
12. Leavitt V, Nelson K, Boehme A, et al. Aspirin precooling improves exercise performance in multiple sclerosis: results of a double-blind randomized controlled trial. P8.008. AAN 2023.
13. Oh J, Lim T, Suthiphosuwan S, et al. Paramagnetic rim lesions predict the development of clinical MS in radiologically isolated syndrome: results from a prospective cohort study. S27.003. AAN 2023.
14. Dimaandal I, Cabrera Pulla J, Germaine S, Imitola J. Educational research: multiple sclerosis (MS) and neuroimmunology education in neurology residency training in the United States. P3.016. AAN 2023.

For More Information

For general information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.

Written by Tom Garry, Medical Writer
Reviewed by Dr. Barry Hendin, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer