What’s New in MS Research – May 2022

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

Advances in understanding and managing multiple sclerosis (MS) were front and center when the nation’s neurologists convened in Seattle in April to share their latest research at the 2022 Annual Meeting of the American Academy of Neurology (AAN). Almost 300 of the 2,400+ abstracts presented at the gathering focused on MS.

The brief reports presented below provide a sense of the wide variety of topics researchers are examining as they explore the causes of MS, its course in specific patient populations, the safety and effectiveness of approved and investigational medications, and the steps people can take to reduce the burden of MS and its symptoms.

Two studies highlight the beneficial role of diet in managing MS

Two studies presented at the AAN meeting add to the growing body of evidence indicating that diet can have a significant, positive impact on the course of MS.

The first study involved 500 people with MS, 70% of whom are women. Those study participants completed the Mediterranean Diet Adherence Screener (MEDAS), which measures the extent to which people follow a diet consisting predominantly of plant-based foods, with fish, poultry, and dairy eaten in moderation, and red meat and sweets eaten only occasionally. Those people also completed the Multiple Sclerosis Functional Composite (MSFC) instrument, which evaluates cognition, upper extremity coordination, and gait speed. Finally, they had magnetic resonance imaging (MRI) studies that measure third ventricle width (TVW) in the brain, which helps neurologists estimate the degree of cerebral atrophy.1

Researchers found that greater adherence to a Mediterranean diet was associated with better functioning as measured on the MSFC and less cerebral atrophy on MRI. Study authors said that their findings suggest the possibility of a neuroprotective mechanism with the Mediterranean diet, but added that long-term studies and interventional clinical trials are needed to further explore that possibility.

The second study assessed the safety and tolerability of a ketogenic diet (KD) in 65 people with relapsing MS, and also evaluated how the diet affected several measures of clinical status.2

A ketogenic diet is a low-carbohydrate, high-fat diet similar in some ways to the Atkins diet. Research has shown that the diet mimics the fasting state and plays a role in immune system regulation. Study participants were asked to follow this eating plan for six months. At the start of the study, researchers made baseline assessments of the people’s levels of fatigue and depression, quality of life, and MS-related clinical measures.

Eighty-three percent of the study subjects adhered to the ketogenic diet for the full six months. At the end of that period, they showed – on average – less fatigue and depression, improved physical and mental quality of life, reduced fat mass, an ability to walk further over the course of six minutes, and reduced MS-related disability as measured by the Expanded Disability Status Scale (EDSS). Laboratory tests conducted as part of the study found that the diet also reduced pro-inflammatory peptides in the body while increasing levels of anti-inflammatory peptides.

Danish study identifies how gender affects disease course in relapsing MS

Women with relapsing-onset multiple sclerosis tend to have more inflammatory disease activity than men with relapsing MS, while men frequently experience more neurodegeneration and a shorter time from diagnosis to serious disability.3

Those were the main findings to emerge from a study that included more than 8,900 Danish citizens who have received disease-modifying therapies (DMTs) since 1996. The study, which examined data on 6,142 women and 2,780 men, found that the annual rate of breakthrough relapses was 0.225 for women and 0.186 for men. The difference between those two rates was statistically significant and provided the basis for the authors to conclude that women had more inflammatory disease activity than men. The researchers added that the difference was particularly pronounced in women of younger age.

Meanwhile, men were 1.49 times more likely than women to reach an Expanded Disability Status Scale (EDSS) score of 6 – which signifies the need to use a walking aid, such as a cane, to walk about 100 meters, or 109 yards. This finding, which also was statistically significant, supported the researchers’ conclusion that men tended to have greater neurodegeneration and experience serious disability earlier than women.

With more than twenty DMTs now available and other interventions such as physical therapy increasingly used to manage MS, these findings can help clinicians and people with MS factor gender into their choice of medications and development of an individualized treatment plan.

Can intravaginal estrogen help improve bladder dysfunction symptoms?

A small study suggests that intravaginal application of estriol, a form of estrogen, can significantly reduce the symptoms of bladder dysfunction experienced by most people with multiple sclerosis (RRMS).4

The pilot study involved 12 women with relapsing-remitting MS. All of the women had reached menopause or had undergone hysterectomy. None had a history of breast, uterine, or ovarian cancer. The women were prescribed 1 mg of estriol applied intravaginally by an applicator. They used the estriol in addition to any other medications they might be taking to improve their symptoms, such as prescription medicines to reduce urinary frequency.

The women completed questionnaires about their urinary tract symptoms and their MS-related quality of life at the start of the study, as well as after six months and nine months of using intravaginal estriol. Participant scores on those questionnaires showed statistically significant improvements at both six and nine months, including gains in mental and physical aspects of quality of life, and improvements related to urinary urgency, urinary frequency, and how often they developed urinary tract infections.

While this treatment approach will need to be evaluated in a larger group of individuals, these findings suggest that clinicians and women with RRMS may have a new option for dealing with these urinary issues that can greatly impact one’s quality of life. Researchers estimate that bladder dysfunction affects up to 80% of people with MS.

A neurologist-patient gap in perceptions of cognitive impairment presence and severity

Concerning problems with memory, concentration, and information processing, people with MS tend to think they have cognitive impairment (CI) far more often than what their neurologists find with regard to CI in those individuals.5

That discordance between patient and clinician identification of cognitive impairment was documented in a study involving almost 4,300 people with MS living in the United States, the United Kingdom, France, Germany, Italy, and Spain. Researchers matched each person’s reports of symptoms of cognitive impairment with his or her neurologist’s assessment of the individual’s condition.

Sixty-two percent of study subjects reported that they had some degree of cognitive impairment. By contrast, their neurologists thought that only 27% of those individuals had CI, meaning that in more than half of all cases, an individual thought that he or she had cognitive impairment but his or her neurologist did not agree.

There was a similar discordance in terms of the perceived degree of CI. For example, while 6.1% of individuals reported having extreme problems concentrating in the past two weeks, neurologists identified just 0.3% of these people as having experienced such severe difficulties.

Researchers said the difference in patients’ and neurologists’ views about the presence and severity of cognitive impairment “clearly indicates an unmet need.” One step in addressing that need is making a point of discussing any concerns about memory, concentration, or information-processing speed at your next clinic visit, and perhaps requesting cognitive testing to obtain an objective assessment.

Study: Ocrevus® stabilizes or improves cognitive function in people with progressive MS

After one year of treatment, the disease-modifying therapy Ocrevus® (ocrelizumab) stabilized or improved cognitive function in most individuals with progressive forms of multiple sclerosis, according to an international team of researchers.6

Those researchers recently provided an interim analysis from the Phase IIIb CONSONANCE study, sharing findings on 629 people with MS, 304 of whom have primary-progressive MS (PPMS) and 325 of whom have secondary-progressive MS (SPMS).

Study participants completed cognitive assessments including the Symbol Digit Modalities Test (SDMT), and the Brief Visuospatial Memory Test-Revised (BVMT-R). The impact of Ocrevus was evaluated by measuring mean percentage change from baseline and a change in the SDMT of 4 or more points.

Before treatment with Ocrevus, which is administered by infusion every 24 weeks, study participants had a mean BVMT-R score of 18.8. At one year, that score had increased by 14.9%, indicating improvement. Similarly, participants’ mean baseline SDMT score of 42.3 had improved by 10.7% after one year. Meanwhile, 34.4% of these individuals had a clinically meaningful improvement of 4 points or more in their SDMT score, although 30% had clinically meaningful worsening of 4 or more points on the SDMT.

The investigators, who noted that the participants’ baseline scores indicated moderate-to-severe cognitive dysfunction, reported that results were similar between people with primary-progressive MS and secondary-progressive MS.

The CONSONANCE study is designed to enroll 900 people and follow them over a four-year period.7 If longer-term results align with those of the two-year interim analysis, the findings will represent very encouraging news in the effort to address one of the most dreaded effects of progressive MS.

Examining how various MS medications affect post-vaccination risk of COVID-19

British researchers report that the risk for contracting COVID-19 following vaccination against the virus varies considerably based on which disease-modifying therapy (DMT) people with multiple sclerosis are taking.8

People receiving Ocrevus® (ocrelizumab) faced a 2.18 greater risk of developing COVID-19 post-vaccination relative to the general population, while those taking beta-interferon DMTs and glatiramer acetate (marketed as Copaxone® and by other names) had a lower risk than the general population. The post-vaccination risk of infection compared to that of the general population for people on other DMTs was:

  • Aubagio® (teriflunomide): 1.04
  • Mavenclad® (cladribine): 1.21
  • Tysabri (natalizumab): 1.22
  • Tecfidera® (dimethyl fumarate): 1.34
  • Gilenya® (fingolimod): 1.63

The investigators arrived at their findings by examining data on all 42,402 people in England who are receiving DMTs for treatment of MS. They found that more than 28,000 of those people had been tested for COVID-19, with 4,104 testing positive for coronavirus.

Clinicians and patients must weigh many factors when selecting a DMT. COVID-related considerations clearly are important, but need to be assessed in the larger context of different medications’ efficacy, overall safety profile, dosing regimen, and other characteristics in order to identify the disease-modifying therapy best suited to an individual.

People with MS at double the baseline risk of acquiring infection during hospital stay

People with multiple sclerosis face almost twice the risk of other people for acquiring an infection while hospitalized, according to a recent analysis involving more than 115,000 people with MS.9

Researchers examined data on adults admitted to hospitals within the United States in 2018 for non-infection-related causes. They found that 0.93% of people with MS acquired an infection during their time in the hospital, as opposed to 0.50% of other people. Those statistics translate into an adjusted related risk of 1.91, or just under double the chances for becoming infected.

Noting that the use of disease-modifying therapies (DMTs) increases the risk of opportunistic infections, the study’s authors noted that their findings “underscore the importance of hospital infection control measures, ensuring individuals with MS do not exceed the maximum duration of certain medications, are appropriately immunized, and receive necessary viral testing before and during treatment.”

Exploring how neighborhood type affects outcomes in progressive MS

The “where” factor long has been recognized as important in MS, with the location of lesions in the brain and spinal cord helping to determine the type and severity of a person’s symptoms. Now, however, it seems that the “where” factor also encompasses the impact of neighborhood on the extent of disability experienced in progressive forms of MS.10

Researchers from the Cleveland Clinic used data collected from 2015 through 2020 to assess 1,000 people with progressive MS. These individuals had an average age of 51.5 years, and 83.4% of the study subjects were Caucasian.

The researchers measured attributes including manual dexterity and cognitive processing speed, as well as quality of life in the setting of a neurological condition. They then used a validated measure of neighborhood-level disadvantage known as the Area Deprivation Index (ADI) to divide the subjects into four groups based on the degree of deprivation in their neighborhoods. People in Quartile 1 lived in areas with the least deprivation, while those in Quartile 4 resided in areas with the highest degree of deprivation.

At baseline measurement, people living in areas of greatest deprivation had manual dexterity test scores that were 2.5 seconds longer than their counterparts living in areas with the least deprivation. The researchers identified a similar difference in baseline tests of processing speed. Using a quality-of-life survey designed specifically for people with neurological disorders, the investigators also found that people in Quartile 1 had better functioning and fewer symptoms than those in Quartile 4 at baseline and over time. Results of a walking speed test did not differ significantly across the quartiles.

The researchers concluded that their study “provides evidence for socioeconomic disadvantage as a risk factor for disability accrual in progressive MS and may be targeted to improve care while informing resource allocation.” As clinicians, policy-makers, and patient advocates work to eliminate disparities in healthcare, this study and similar research can help guide the development of corrective strategies.

When steroids don’t tame relapses: New support for therapeutic plasma exchange

Intravenous administration of the steroid methylprednisolone is a cornerstone of managing severe MS relapses, but not all individuals respond adequately to the treatment, and others cannot tolerate its side effects. In such cases, clinicians sometimes order therapeutic plasma exchange, or TPE.

In TPE, modest amounts of blood are removed from the body through an intravenous needle or central line catheter and circulated through a machine that separates the blood into red cells, white cells, platelets, and plasma, which is the liquid portion of blood. Following this separation, the plasma is discarded, and a plasma substitute is combined with the red cells, white cells, and platelets before the blood is returned to the body through the intravenous needle or central venous catheter. The procedure is used to reduce circulating levels of antibodies, proteins that help the body fight infection but that can mistakenly attack the body’s tissues in autoimmune diseases such as MS.

While TPE has been used for many years as a second-line treatment for relapses, some clinicians question its effectiveness. A team of Czech and Canadian researchers set out to answer that question in a retrospective study involving 155 people with relapsing-remitting multiple sclerosis (RRMS).11 Study participants had an average age of 40.3 years, and 74% were women. Twenty-four participants received TPE only, without a course of steroids, while 131 received methylprednisolone and TPE. Most of these individuals (77) had three TPE procedures, while 10 had more than five plasma exchanges.

The researchers assessed the impact of treatment by looking at change from baseline to eight-week follow-up in scores on the Expanded Disability Status Scale (EDSS). The scale runs from 0 to 10, with higher scores indicating worse disability. The mean baseline EDSS score was 4.4, which rose to 4.7 after methylprednisolone. The mean EDSS score before TPE was 4.8, which declined to 4.4 after TPE, indicating improvement. The difference between pre- and post-TPE scores was statistically significant. The researchers found no differences in EDSS improvement based on age or number of TPE procedures. They did, however, find greater improvement in women relative to men.

Relapses are difficult, discouraging events, and failure to respond to steroids – or an inability to tolerate them – can compound the difficulty and sense of discouragement. These findings offer cause for continued hope for people contending with severe relapses despite or in the absence of treatment with methylprednisolone.

Tolebrutinib well-tolerated, effective over 18 months in relapsing MS, researchers report

Tolebrutinib, an investigational medicine being assessed for the treatment of MS, was well tolerated and associated with a low relapse rate over 18 months of use, researchers reported.12

The researchers monitored 124 people with relapsing MS who initially had participated in a 12-week, Phase IIb trial of the oral medication. Following that trial, the participants continued into a long-term extension study. At first, they continued on the daily dose of tolebrutinib they took in the 12-week study – 5 mg, 15 mg, 30 mg, or 60 mg. All of the participants then took 60 mg/day – the dose being studied in Phase III trials of the medication.

The most common adverse events seen in the long-term study were:

  • headache, reported by 12.8% of study participants
  • COVID-19 (12.8%)
  • nasopharyngitis, the medical term for a cold or cold symptoms (10.4%)
  • upper respiratory tract infection (8.0%)
  • arthralgia, meaning joint pain or stiffness (5.6%)

Researchers noted that no new safety signals emerged during the 18-month study period.

Almost 85% of the individuals were relapse-free at the end of the 18-month study, and the group had a collective annualized relapse rate (ARR) of 0.17, which roughly translates into one study subject in six having one relapse over the course of a year. Further, average scores on the Expanded Disability Status Scale, or EDSS, were stable over the length of the study.

Tolebrutinib, which is being developed by Sanofi, belongs to a class of medications called Bruton’s tyrosine kinase inhibitors. Sanofi notes that the medication works by reaching concentrations in the cerebrospinal fluid needed to target B lymphocytes and microglial cells, and so modulate neuroinflammation. Phase III trials are evaluating tolebrutinib for treatment of relapsing forms of MS, non-relapsing secondary-progressive MS, and primary-progressive MS.

Reassuring findings on increasing Tysabri® treatment intervals

Enabling people with MS to benefit from an effective medication while limiting their risks of experiencing side effects from that therapy can be quite challenging for clinicians, as is illustrated by the case of Tysabri® (natalizumab).

The disease-modifying therapy (DMT), which is given by infusion every four weeks, is approved for use in relapsing forms of MS, active secondary-progressive disease, and clinically isolated syndrome. While it has been shown to be effective in reducing relapses and slowing disease progression, it also is associated with a risk of developing a viral disease called progressive multifocal leukoencephalopathy (PML), which usually leads to death or severe disability if not diagnosed early.13

Researchers have identified three risk factors for developing PML in people treated with Tysabri: having proteins in the blood known as anti-JCV antibodies; longer treatment duration with Tysabri, particularly treatment that lasts more than two years; and prior treatment with an immunosuppressant medication. In people without the anti-JCV antibody, the incidence of PML in the United States is about one in 10,000. By contrast, the risk of PML in people who have the anti-JCV antibody and receive Tysabri, ranges from less than one in 1,000 for those with no prior immunosuppressant use who take Tysabri for 24 months or less, to six in 1,000 for those with a history of immunosuppressant use who take Tysabri for 73-96 months (about six to eight years).13

In an effort to enable more people with MS to get the benefits of Tysabri while limiting their risk for PML, researchers have explored extending the dose interval for the medication beyond four weeks. Retrospective analyses have shown that giving the medication roughly every six weeks lowers the risk of PML seen with four-week dosing. Following up on those findings, a team of researchers conducted a randomized trial to examine what impact the longer period between doses might have on the efficacy of Tysabri.14

The study involved 400 people with MS. All of those individuals had been receiving Tysabri every four weeks, had not experienced a relapse for at least 12 months before starting the trial, and had no enhancing lesions on magnetic resonance imaging (MRI) at the outset of the study.

Study subjects were assigned at random to continue four-week dosing (Q4W) of Tysabri or to move to treatment roughly every six weeks (Q6W). They then were followed for 72 weeks (approximately 17 months). The study’s primary endpoint was new or enlarging lesions measured by a particular type of MRI scan. Secondary endpoints included relapses and 24-week confirmed disability worsening (CDW).

One hundred and ninety five people in the four-week treatment arm and 207 people in the six-week arm completed the trial. In the four-week treatment group, 4.1% of people had new or newly enlarging lesions on MRI, as compared to 4.3% of people in the six-week group. Similarly, relapses occurred in 2.1% of those in the four-week group and 2.8% of those in the six-week group, and the rates of confirmed disability worsening were 8% and 10%, respectively. Meanwhile, safety data for the two groups were similar.

The study’s authors concluded that, “Despite a small difference in efficacy between arms, [the] data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinically meaningful loss of efficacy.”

Data support patients’ persistence with Vumerity®

Individuals with MS only benefit from medications they are willing to take, and how a medication makes them feel can have a huge impact on their willingness to take it on a regular basis.

With this reality in mind, Biogen, Inc. developed a disease-modifying therapy (DMT) called Vumerity® (diroximel fumarate) to address gastrointestinal (GI) issues that had prompted some people with relapsing forms of MS to stop taking an earlier-generation fumarate medicine. While Vumerity has the same active metabolite as the earlier medicine, it has been shown in studies to have better GI tolerability, which ideally would prompt people to continue taking it over the long term.

To assess the impact of this strategy, Biogen researchers recently examined rates of indipersistence (ongoing use) of Vumerity relative to that of other DMTs.15

Drawing on an insurance claims database to extract information on 1,985 people with MS, the researchers used a measure called proportion of days covered, or PDC, to track persistence with Vumerity and other DMTs including Aubagio® (teriflunomide), Gilenya® (fingolimod), and Mayzent® (siponimod), and the earlier-generation fumarate medicine, dimethyl fumarate, marketed as Tecfidera® and in generic forms.

Ninety-day persistence rates for the various DMTs were:

  • Vumerity: 85%
  • Tecfidera/other dimethyl fumarate medications: 83%
  • Aubagio: 90%
  • Gilenya: 89%
  • Mayzent: 92%

Those findings prompted the researchers to conclude that, “Real-world claims data demonstrated high persistence on DRF [Vumerity] after 90 days, supporting DRF as a well-tolerated treatment option. Adherence rates were high throughout time on treatment for patients on DRF.”


1 Katz Sand I, Fitzgerald K, Sorets T, Levy S, Sumowski J. Mediterranean Diet score is associated with disability and brain atrophy in multiple sclerosis. Neurology. 2022; 98 (18 Supplement): 1456.

2 Brenton JN, Lehner-Gulotta D, Woolbright E, et al. Ketogenic diet as a strategy for improved wellness and reduced disability in relapsing multiple sclerosis. Neurology. 2022; 98 (18 Supplement): 622.

3Magyari M, Koch-Henriksen N. Significant gender differences in clinical disease activity and severity of multiple sclerosis: a Danish nationwide cohort study. Neurology. 2022; 98 (18 Supplement): 1939.

4 Avila M, Hernandez Quintana R, Pan J, et al. Impact of vaginal estriol on urogenital symptoms in relapsing remitting multiple sclerosis. Neurology. 2022, 98 (18 Supplement): 1472.

5 Penner IK, De Las Heras V, Jones E, et al. Discordance between neurologists and people with multiple sclerosis on the perception of the presence and burden of cognitive impairment. Neurology. 2022; 98 (18 Supplement): 3398.

6 Benedict R, Sormani MP, McGinley M, et al. A multicenter, open label, single-arm, phase 3b study (CONSONANCE) to assess efficacy of ocrelizumab in patients with primary and secondary progressive multiple sclerosis: year 1 interim analysis of cognition outcomes. Neurology. 2022;98 (18 Supplement): 647.

7ClinicalTrials.gov, Identifier: NCT05210621

8 Garjani A, Patel S, Law GR, et al. Impact of multiple sclerosis disease-modifying therapies on effectiveness of SARS-Cov-2 vaccines: a longitudinal total population study of National Health Service (NHS) England. Neurology. 2022; 98 (18 Supplement): 3321.

9 Petrenchik L, Briggs F. The burden of opportunistic infections in hospitalized multiple sclerosis patients: a United States population-based study of 25.8 million patients. Neurology. 2022; 98 (18 Supplement): 1780.

10 Abbatemarco J, Carlson A, Ontaneda D, et al. Association of socioeconomic disadvantage and neighborhood disparities with clinical outcomes in progressive multiple sclerosis. Neurology. 2022; 98 (18 Supplement): 1334.

11 Bunganic R, Blahutova S, Revendova K, et al. Effect of therapeutic plasma exchange in treatment of severe multiple sclerosis relapse – a retrospective analysis. Neurology. 2022; 98 (18 Supplement): 2791.

12Oh J, Syed S, Orogun L, et al. Safety and clinical efficacy outcomes from the long-term extension study of tolebrutinib in patients with relapsing multiple sclerosis: 18-month results. Neurology. 2022; 98 (18 Supplement): 1648.

13 Tysabri Prescribing Information

14 Foley J, Defer G, Zhovtis Ryerson L. Primary results of NOVA: a randomized controlled study of the efficacy of 6-week dosing of natalizumab versus continued 4-week treatment for multiple sclerosis. Neurology. 2022; 98 (18 Supplement): 2056.

15 Belviso N, De Moor C, Shankar SL, Shen C, Miller C. Diroximel fumarate (DRF) has high rates of real-world adherence and persistence in patients with multiple sclerosis (MS): retrospective claims analysis. Neurology. 2022, 98 (18 Supplement): 2929.

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