What’s New in MS Research – March 2022

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

Hundreds of the world’s leading multiple sclerosis researchers gathered in February to share their study findings and chart a course for future investigations into all aspects of MS.

The Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022 was an occasion for renewed hope. This was not just because of the important research presented there, but also because the in-person gathering marked one more step on the slow path to resuming some semblance of normalcy two years into the COVID-19 pandemic.

This issue of “What’s New in MS Research” showcases the myriad of topics addressed at the meeting. That includes reports on everything from dietary strategies to reducing MS-related fatigue to the potential neuroprotective effects of stem cell transplantation. Findings on the efficacy and safety of both investigational and FDA-approved medications are included, as well as results from studies examining real-world issues with shared decision-making in MS, along with factors driving use or non-use of disease-modifying therapies. Please see below for these important updates and study results.

Cut dietary fat to cut daily fatigue, according to a new study

Researchers from Oregon Health Science University report that people with MS who reduced the proportion of calories they obtained from fat by a little more than 10% had significant reductions in fatigue after 12 weeks.1

That finding emerged from a study involving 39 people with MS. Twenty of the study participants were randomly assigned to receive one-to-two weeks of dietary counseling followed by 12 weeks on a low-fat diet. The other 19 participants, who were on a waiting list for dietary counseling, served as a control group. The mean body mass index for both groups was 31 kg/m2, which indicates obesity. All participants completed the Modified Fatigue Impact Scale and the Fatigue Severity Scale, two instruments used to measure fatigue, at the start of the study and again at the end of the trial.

People in the low-fat diet group saw their fatigue scores decrease significantly compared to people in the control group, researchers said.

While the investigators added that studies with more participants and a longer follow-up period are needed, reducing the proportion of calories obtained from fat by just 10% or so may be a goal that entails modest effort in return for notable reductions in fatigue.

Assessing the impact of obesity and depression on people with MS

The importance of people with MS attending to all aspects of their wellbeing – physical and mental – was reinforced in a recent study involving more than 4,500 adults treated at Cleveland Clinic’s Mellon Center for Multiple Sclerosis.2

Of these 4,500 adults:

  • 26% had obesity
  • 14% had depression
  • 11% had both obesity and depression
  • 49% had neither obesity nor depression

A total of 91% of individuals with both obesity and depression had some degree of MS-related disability, compared to only 65% of those who were not obese or depressed. People with both obesity and depression also had worse upper extremity fine-motor coordination and slower walking times, compared to those who were obese but not depressed, as well as those who had neither obesity nor depression. Interestingly, such differences were not seen between the group with both obesity and depression, when compared to the depression-only group.

The finding that people dealing with obesity and depression as well as MS would have worse health performance than those facing fewer burdens is not surprising, which the researchers acknowledged in outlining the rationale for their study. Further, there may be something akin to the chicken-and-the egg dynamic involved, with the challenges posed by depression, obesity, and MS reinforcing one another in ways that contribute to a less-active lifestyle, unhealthy eating habits, and discouragement or poor self-esteem. However, the finding that one in nine people with MS have both obesity and depression, and are likely to have worse health trajectories as a result, helps to identify a patient population in need of targeted, coordinated intervention.

Evidence of neuroprotective effects from stem cell transplant in progressive MS

Findings from a small study conducted by Israeli investigators suggest that stem cell transplantation may provide a degree of neuroprotection in people with progressive forms of multiple sclerosis.3

The Phase II, randomized, double-blind clinical trial involved 48 people with primary- or secondary-progressive MS. Sixteen of the study participants received stem cells administered intrathecally, meaning that the cells were delivered directly into the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Another 16 people received stem cells intravenously, while 16 people in a control group were given a sham (placebo) treatment.

Before administering the treatments, investigators measured the levels of two biomarkers in the patients’ cerebrospinal fluid (CSF). The first biomarker, neurofilament light chain (NF-L), is a protein that increases when there is damage to axons – the nerve fibers that extend from neurons – in MS and certain other neurological diseases. The second biomarker, CXCL 13, is a signaling protein that plays a role in immune response. It has been shown to correlate with inflammatory activity in the central nervous system and to predict future MS progression.

Six months after the stem cell transplants, investigators again measured the patients’ CSF levels of the two biomarkers.

Nine of the 16 patients receiving stem cells intrathecally had more than a 50% decline in their NF-L levels, as did five of the 16 subjects in the group receiving stem cells intravenously. By comparison, only one person in the sham treatment group had a decline of >50% in baseline level of NF-L. CXCL 13 levels also were reduced at six months in the intrathecal stem cell group, but not to a statistically significant extent.

Change in brain volume on MRI predicts disease progression in MS

“What does the future hold for me?” It’s a question that virtually every person newly diagnosed with MS asks his or her clinician. Unfortunately, it’s also a question that clinicians are unable to answer specifically for each individual patient.

Now, however, a study that examined long-term data on more than 150 people with various types of MS has identified change in brain volume on magnetic resonance imaging (MRI) as a predictor of clinical disease progression.4 To explain “change in brain volume,” radiologists or neurologists reading MRIs frequently comment on brain-volume loss or atrophy. Our brains change as we get older; just as our muscles decrease in size as we age, the brain also loses tissue over time. Unfortunately, MS can accelerate this tissue loss.

Researchers at the University of Massachusetts Medical School analyzed data obtained from 2007 to 2021. Their study looked at 122 people with relapsing-remitting MS, 37 with progressive forms of MS, and two with clinically isolated syndrome. The average patient was followed for 6.5 years.

As would be expected, people with progressive forms of MS were at significantly greater risk for worsening disability – defined as reaching an Expanded Disability Status Scale (EDSS) score of 4.5 or more – than people with relapsing MS. For anyone not familiar, the EDSS measures function largely in terms of ambulatory ability. Levels from zero to 4.5 refer to individuals who are fully ambulatory, but at 4.5, may have some mobility limitations or require minimal assistance. Levels of 5.0 or higher refer to a loss in ambulatory ability, with higher numbers referring to greater limitations.

However, the researchers also found that the 37 study participants who eventually had an EDSS of ≥4.5 had a greater change in brain volume, calculated on an annualized basis from MRI measurements, than those with a lower EDSS score.

The study’s findings give clinicians and people with MS one more piece of data to draw upon as they make and periodically revisit treatment decisions and long-term plans.

Reduction in lesion volume and number seen on MRI with ublituximab

T1-hypointense lesions seen on magnetic resonance imaging (MRI) of the brain and spinal cord are indicative of white matter destruction and axonal loss in people with MS. Recently presented data from two Phase III studies of ublituximab found that the investigational agent reduced those lesions to a greater extent than did the FDA-approved disease-modifying therapy Aubagio® (teriflunomide).5

The data are from the ULTIMATE I and ULTIMATE II studies, which involved almost 1,100 people with relapsing MS. Those studies evaluated outcomes with intravenous infusions of ublituximab, a monoclonal antibody, relative to daily use of Aubagio, an oral medication, over the course of 96 weeks.

The mean measured volume of T1-hypointense lesions in people receiving ublituximab decreased from 3.280 mL at baseline to 3.132 mL at week 96. By contrast, the mean measured volume for people receiving Aubagio increased from 3.343 mL to 3.475 mL during that period. Similarly, the mean number of new T1-hypointense lesions at 96 weeks was 1.5 for ublituximab and 5.4 for Aubagio, with the difference being statistically significant.

In December 2021, the FDA accepted an application to consider approving ublituximab for treatment of relapsing MS. The medication’s manufacturer, TG Therapeutics, filed that application after the ULTIMATE I and ULTIMATE II studies met their primary endpoint by demonstrating a statistically significant reduction in annualized relapse rate (ARR) compared to Aubagio over 96 weeks.6 Change in T1-hypointense lesion volume and number were other endpoints in those studies.

Study shows early treatment with Mavenclad® lessened MS burden in later years

People treated with the disease-modifying therapy Mavenclad® (cladribine) following an initial clinical demyelinating event took longer to convert to clinically definite multiple sclerosis and had less long-term disability than people who did not receive the oral medication.7

That finding emerged from an analysis that followed more than 200 people over the course of eight-to-11 years. Those people first participated in the ORACLE MS trial, which evaluated the impact of giving Mavenclad to people who had experienced a demyelinating event – such as optic neuritis or numbness in a leg – and so would be diagnosed with MS if they had another demyelinating event involving another region of the central nervous system.

While 78% of people who did not receive Mavenclad converted to clinically definite MS (CDMS), only 50% of those treated with Mavenclad after their first demyelinating event went on to CDMS.

Among people who ultimately were diagnosed with MS, the median time to conversion was 3.36 years for those treated with the DMT and 1.21 years for those who did not receive Mavenclad. Fifty-three percent of patients receiving Mavenclad remained relapse-free since receiving their last dose in the ORACLE MS study, compared to 28% of those who did not receive the medication. Similarly, during the multi-year follow-up period, higher proportions of people receiving Mavenclad were actively employed and able to move without an assistive device, compared to their counterparts who were not treated with the medication.

Sustained relapse control over four years with Zeposia®, while the benefit-to-risk profile remains unchanged

People with relapsing MS who took Zeposia® (ozanimod) for an average of 46.8 months had an adjusted annualized relapse rate of 0.103, which translates into slightly more than one person per 1,000 people having one relapse over the course of a year.8

That finding emerged from DAYBREAK, an open-label extension study that enrolled 2,494 people with MS who had participated in earlier trials that led to the FDA’s March 2020 approval of Zeposia for treatment of relapsing forms of MS. The disease-modifying therapy (DMT) is a sphingosine 1-phosphate receptor 1 and 5 modulator, which works to keep lymphocytes, a type of white blood cell with immune functions, away from sites of chronic inflammation.

Because medications that affect the immune system may have an impact on people’s susceptibility to infection, researchers also looked at outcomes in people taking Zeposia who contracted COVID-19. One hundred and ninety people in the study group reported having COVID. Of those, 93% had non-serious cases, while one person died from COVID-19 infection/pulmonary embolism and two died from complications following COVID. Sixty-three percent of study subjects continued taking Zeposia without interruption while they had COVID-19, and – even among those who temporarily discontinued the medication – no patients with COVID permanently discontinued Zeposia.

The study’s authors concluded, “The benefit:risk profile of ozanimod remains unchanged with most COVID-19 infections being non-serious, and the majority resolving without treatment interruption.”

Sketching a picture of those who do not receive disease-modifying therapy for their MS

Many people diagnosed with multiple sclerosis go for years before initiating treatment with a disease-modifying therapy (DMT), or do not receive such treatment at all. A recent study, drawing on healthcare claims’ information from two large databases, identified the extent of this trend and the patient characteristics associated with non-treatment.

The databases included information on thousands of patients. One database covered the period from 2010 to 2019, while the other had information on health claims from 2014 to 2019. All information was “de-identified,” meaning there were no details that would enable reviewers to identify a particular person.9

Forty-eight percent of people with MS included in the first database were untreated during the study period, as were 43% of people in the second database.

Compared to people who were being treated, those not receiving a DMT tended to be older (57.2 years vs. 42.7 years in one database), to have had fewer visits to a neurologist and more visits to primary care clinicians, and to be in a low-income group (15.6% vs. 4.1% in one database). Further, people not receiving a DMT were less likely to be commercially insured. All of those differences were statistically significant.

While the fact that, for instance, a person in a lower income group is less likely to be treated with a DMT than someone in a higher-income group, measuring the extent of these differences can help bring the disparity into sharper focus, provide greater impetus to correct it, and help inform strategies to expand access. Similarly, exploring the reasons for age-related differences in DMT use may help guide patient outreach and counseling strategies.

New ACTH gel available for acute exacerbations

People with MS have a new option for treating acute exacerbations with an adrenocorticotropic hormone (ACTH) preparation. ANI Pharmaceuticals, Inc. announced in late January 2022 that its Purified Cortrophin™ Gel (Repository Corticotropin Injection USP) 80 U/mL is commercially available in the United States.

ACTH is a hormone that stimulates the adrenal gland to secrete cortisol, corticosterone, and aldosterone, which can help ease exacerbations. Cortrophin Gel also is approved by the FDA for several other autoimmune conditions, including exacerbations of rheumatoid arthritis and psoriatic arthritis.

“Patients with certain chronic autoimmune conditions often need additional treatment options,” said Dr. Mary Pao Seideman, chief medical officer of ANI. “ACTH therapy can be effective across a number of inflammatory diseases. The reintroduction of Cortrophin Gel gives prescribers another ACTH option, which can mean a greater chance for an effective treatment for some patients.”10

Searching for the Causes of Ethnic Variations in MS

Studies show that African Americans with MS experience a faster disease progression and worse outcome in terms of disability, compared to Caucasian Americans with MS. However, the reasons for these differences are not completely understood. While these differences are generally thought to be related to biological factors, studies suggest that non-biological factors may play a role as well.

In an effort to learn more about these differences and why they occur, researchers from the Medical College of Wisconsin conducted a systemized review of 963 articles published between 1985 and 2021.11 According to the authors, these articles addressed race and treatment adherence, barriers to care, health disparity, disease severity or progression, clinical features, and biomarkers.

At the start of their care, African Americans were more likely to present with symptoms such as tremor and reduced coordination, while Caucasian Americans often present with sensory symptoms, such as numbness, tingling, or a burning sensation. African Americans also tend to present with a greater lesion burden, areas of more rapid brain atrophy, and other findings as shown on MRI, as well as higher oligoclonal bands, which are proteins in the spinal fluid that indicate inflammation in the central nervous system (CNS).

African Americans see a neurologist significantly less often than Caucasian Americans and are also less likely to adhere to a high-efficacy disease-modifying therapy (DMT) – although therapeutic satisfaction improved when switching to an oral medication from an injected medication. Low-income and seeing a health provider who was not a neurologist significantly reduced the chances of using a DMT.

The study’s authors concluded that the differences in outcomes between these two ethnic groups are not fully explained by biological factors. They suggest that future studies are needed to determine non-biological factors that contribute to these differences in outcomes.

Shared decision-making in MS: Study finds room for improvement

Seventeen percent of people with MS participating in a recent survey reported that their clinician prescribed their first disease-modifying therapy (DMT) for them without discussing their treatment options. Another 35% said that while their clinician did discuss treatment choices, only one or two options were presented.12

Those findings suggest a need for more shared decision-making (SDM), the process by which a patient and clinician consider treatment options or other important aspects of care together and agree on a plan of action. SDM has been shown to yield benefits including increased patient adherence to treatment regimens and patient satisfaction.

The survey involved 356 patients, 87% of whom are female. Sixty-three percent of the respondents have relapsing-remitting MS. While its results indicate that more communication between patients and clinicians is in order, those findings also need to be considered in context. First, survey respondents were diagnosed with MS between 1973 and 2021. While more than 20 disease-modifying therapies are available today, the first DMT wasn’t approved by the FDA until 1993, with two more approved in 1996. So people whose diagnosis dates back many years would have had far more-limited options – or no options at all – available to them. Second, the findings are based on how participants recall discussions that in some cases took place many years or even a few decades ago, and those memories may not always be accurate.

Even with those caveats, however, several aspects of the research point to opportunities to improve communication and collaboration. For example, 42% of female respondents who said that childbearing was an important consideration for them reported that pregnancy plans were not discussed prior to selection of a DMT. Further, 48% of respondents reported having switched clinicians for a reason other than relocation, and most of those who found a new clinician said they did so because they felt the original clinician was not listening to their concerns.

Shared decision-making and cognitive impairment: a dilemma in MS care

A recent study found that the greater the degree of cognitive impairment (CI) experienced by people with MS, the less likely they were to be interested in shared decision-making about their care.13

While many of the study subjects experiencing CI preferred to have their clinician make treatment decisions on their behalf, those with the highest accumulative cognitive impairment tended to prefer to make their own decisions without clinician input. And that, as the study’s authors noted, “…is a reason for concern, as CI can impact health literacy, decision making and might result in an inappropriate cognitive bias for treatment selection and adversely impact satisfaction and outcomes.”

The researchers based their findings on a retrospective chart review of 735 people with MS. Seventy-five percent of the study subjects were female, and the average age of the study group was 51.3 years. The investigators used a research instrument called the Control Preferences Scale to assess each patient’s preference for involvement in treatment decisions. People were categorized as “Active,” meaning that they wanted more say in treatment decisions; “Passive,” signifying that they preferred their healthcare provider to make the decisions; or “Collaborative,” which is between “Active” and “Passive.” Researchers also analyzed the study participants’ performance on various measures of cognitive function, and looked for correlations between cognitive status and decision-making preferences.

In terms of the overall group, 49% preferred a collaborative approach to treatment decisions, while 31% favored an active stance and 15% took a passive approach. However, as the degree of cognitive impairment increased, interest in collaborative decision-making gave way to greater support for a completely passive or completely active approach.

The findings underscore the dilemma faced by clinicians trying to navigate between respecting patients’ autonomy and making the treatment decisions they believe to be best for those patients. Those findings also point to the advantages of open communication and treatment initiation as early in the course of MS as possible to avoid or minimize the challenges that cognitive impairment can pose later on.

One more indicator of MS clinicians’ dedication to their patients

Being able to communicate with their clinician through secure patient portals has been a tremendous benefit to many people with MS, particularly during the COVID-19 pandemic, but that quick and easy access for patients increasingly is becoming time-consuming and challenging for their physicians, nurse practitioners, and therapists.

A recent survey of 106 MS clinicians found that 58% devote two hours or more each working day to indirect patient care tasks such as answering messages sent to them through patient portals and similar platforms. What’s more, 75% of those clinicians aren’t compensated for responding to patient messages. Just 5% reported being paid for handling this important task, although 31% said they could turn to other staffers to respond to many messages for them.14

The answer, of course, is not to stop asking questions or sharing information via the portal (although making thoughtful use of the platform would be appreciated). Rather, as the authors of a study reporting the survey results note, “Indirect patient care through portal messages is expected to grow. Future work should focus on strategies to decrease the burden on neurology and MS practices and to improve compensation for this type on MS indirect patient care.”


1 Chase E, Lane M, Wooliscroft L, et al. A randomized controlled trial of low-fat diet for fatigue in multiple sclerosis. ACTRIMS 2022. P264.

2 Galioto R, Pfoh E, McGinley M. Impact of comorbid obesity and depression on health trajectories in MS. ACTRIMS 2022. P116.

3 Petrou P, Kassis I, Ginzberg A, et al. Effects of mesenchymal stem cell transplantation on CSF biomarkers in progressive multiple sclerosis patients. ACTRIMS 2022. P028.

4 Garcia-Dominguez MA, Hemond C. Factors associated with clinical disease progression in MS: a retrospective longitudinal cohort analysis. ACTRIMS 2022. P078.

5 Cree BA, Selmaj KW, Steinman L, et al. Long-term efficacy and safety, including COVID-19 infections, among ozanimod-treated patients with relapsing multiple sclerosis in the DAYBREAK open-label extension trial. ACTRIMS 2022. P142.

6 TG Therapeutics, Inc. TG Therapeutics Announces FDA Acceptance of Biologics License Application for Ublituximab as a Treatment for Patients with Relapsing Forms of Multiple Sclerosis. December 14, 2021. Available at https://www.globenewswire.com/news-release/2021/12/14/2351552/8790/en/TG-Therapeutics-Announces-FDA-Acceptance-of-Biologics-License-Application-for-Ublituximab-as-a-Treatment-for-Patients-with-Relapsing-Forms-of-Multiple-Sclerosis.html. Accessed March 13, 2022.

7 Leist T, Giovannoni G, Aydemir A, et al. Primary results from 8-11 years of follow-up in the CLASSIC-MS study show long-term efficacy for patients who received cladribine tablets in ORACLE MS. ACTRIMS 2022. P107.

8 Cree BA, Fox E, Hartung H, et al. Reduction in T1 hypointense lesions with ublituximab vs. teriflunomide in the Phase III ULTIMATE I and ULTIMATE II studies in relapsing multiple sclerosis. ACTRIMS 2022. P108.

9 Mehta I, Krzywy H, Everage N, Eaton S, White K. Patient characteristics of treated and treatment-naïve patients with MS: a retrospective claims analysis. ACTRIMS 2022. P185.

10 ANI Pharmaceuticals announces commercial availability of Purified Cortrophin™ Gel (Repository Corticotropin Injection USP) for multiple chronic autoimmune disorders. January 24, 2021. Available at https://investor.anipharmaceuticals.com/news/news-details/2022/ANI-Pharmaceuticals-Announces-Commercial-Availability-of-Purified-Cortrophin-Gel-Repository-Corticotropin-Injection-USP-for-Multiple-Chronic-Autoimmune-Disorders/default.aspx. Accessed March 13, 2022.

11 Cairns D, Zeidler A, Obeidat AZ. Ethnic Variations in Multiple Sclerosis in the USA: Biology or Disparity? ACTRIMS 2022. P407.

12 Greenberg BM, Graves JS, Subel A, et al. The patient experience with shared decision-making in multiple sclerosis. ACTRIMS 2022. P396.

13 Kaczmarek O, Sethi A, Teng E, et al. Multiple sclerosis, cognitive function, and shared decision making preference. A process with a problem. ACTRIMS 2022. P393.

14 Mahmoud R, Callahan K, Schell D, et al. Time spent by multiple sclerosis providers in direct and indirect patient care and the burden of portal messages. ACTRIMS 2022. P191.

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