What’s New in MS Research – July 2021

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

The globe-spanning nature of the fight against multiple sclerosis is showcased in this edition of “What’s New in MS Research.” The items to follow summarize research conducted in countries as distant and diverse as Norway and Iran, Canada and Spain, along with several studies led by scientists and clinicians here in the United States.

The geographic range of the investigators is matched by the wide variety of topics they explore. From Phase III data on the investigational disease-modifying therapy (DMT) ublituximab to evaluation of dry needling for spasticity and cannabis for bladder symptoms, the studies highlighted here collectively illustrate how much work is being done on numerous fronts to improve the lives of people with MS.

Another recurrent theme in this edition of “What’s New in MS Research” is how much power people with multiple sclerosis have to optimize their own health. Whether by recognizing and seeking treatment for issues commonly seen in the first year after diagnosis, or by working to enhance their cardiovascular health – which a study below suggests has an impact on brain volume in MS – there are numerous ways to take a proactive approach. One easy way to do so is to check out the many resources available on the Multiple Sclerosis Association of America’s website at mymsaa.org.

Good cause to watch for anxiety and depression in the first year after MS diagnosis

Coming to terms with the reality of having a serious, life-long condition can be overwhelming, and new data underscore the importance of monitoring and addressing emotional well-being in the first year after a diagnosis of MS.

Researchers asked 230 adults who were either newly diagnosed with MS or who had clinically isolated syndrome to complete questionnaires that looked for the presence of depression, anxiety, fatigue, and pain. The study subjects completed those forms at six points over the course of the first 12 months following their diagnoses.1

Forty-seven percent of survey participants were identified as having depression during that first year, while 39% had anxiety. In findings that perhaps help explain why those people had depression and anxiety, even higher proportions of study subjects had fatigue (63%) and pain (51%). Additionally, 21% of participants had two of the four conditions studied… 19% had three of the four conditions… and 17% were contending with all four conditions.

While pain and fatigue are well-known symptoms of MS, conditions such as depression and anxiety may not necessarily be recognized as commonly accompanying MS, particularly in newly diagnosed people. Being on the lookout for these very treatable and – based on the survey results – very common aspects of living with MS, may help people avoid unnecessary suffering. As the study’s authors concluded, “Prompt screening and evidence-based interventions are necessary if quality of life is to be optimized.”

The case for “starting strong” with an initial disease-modifying therapy

MS clinicians and patients face an important decision when selecting an initial disease-modifying therapy (DMT). Should they begin with a more-powerful treatment whose benefits may be accompanied by more side effects, and often, greater cost… or should they start with a less-powerful and often less-expensive therapy, with the option of escalating to a more-powerful medication if the first therapy doesn’t provide enough benefit?

Many treatment guidelines call for limiting first-line use of more-powerful medications to people with highly active MS, such as those who have frequent relapses.

However, two recent studies suggest that “starting strong” may be the way to go for many people with MS, not just those whose condition is highly active.

The first study analyzed data on more than 700 people participating in the Italian MS Registry.2 Researchers identified 363 people with relapsing-remitting MS who had started with a less-powerful medication and then went on to receive a more-powerful therapy after one year or more on the first medication. These people were known as the “escalation treatment” or ESC group. The investigators then identified 363 other people with MS who had begun treatment with a more-powerful medication (the “early intensive treatment” or EIT group), and paired each of those study subjects with people in the first group who had similar characteristics. Next, the researchers looked at changes in Expanded Disability Status Scale (EDSS) scores for the people in each pair.

At one year, the people in the escalation treatment group had a modestly greater increase in their EDSS score – indicating worsening disability – than the people with whom they were matched. By five years, that initial difference had tripled, and by 10 years, it was significantly greater.

“Our results indicate that the EIT strategy is more effective than the ESC strategy in controlling disability progression over time,” the researchers wrote.

The second study examined data on 694 Norwegian people with MS for whom information was recorded in a national database.3 The researchers looked at what percentages of people who started therapy with a high-efficacy DMT had no evidence of disease activity (NEDA) one year and two years after starting treatment. They compared those percentages with the proportion of people who began treatment with a moderate-efficacy therapy who had achieved NEDA. NEDA was defined as no clinical relapse, no new activity on magnetic resonance imaging (MRI), and no sign of clinical disease progression as measured by the EDSS.

At one year, 68% of patients in the high-efficacy therapy group met the criteria for NEDA, as compared to 36% in the moderate-efficacy DMT group. At the end of the second year, 52% of people in the high-efficacy treatment group had no evidence of disease activity, as opposed to 19% of those on a moderate-efficacy medication.

Based on those results, the study’s authors called for updating treatment guidelines “to ensure early, high-efficacy therapy for the majority of patients diagnosed with MS.”

Positive results for the investigational disease-modifying therapy ublituximab

People with MS who took the investigational medication ublituximab in two studies had annualized relapse rates (ARRs) that were 50% to 60% lower than those of study subjects taking the disease-modifying therapy Aubagio® (teriflunomide), according to the company developing ublituximab.4

The two Phase III trials, ULTIMATE I and ULTIMATE II, involved 1,000 people with relapsing forms of MS. Participants were randomized to receive either infusions of ublituximab, which is given every six months after an initial regimen of two infusions given 14 days apart, or 14-mg tablets of Aubagio taken by mouth once a day.

TG Therapeutics, the company developing ublituximab, reported that in ULTIMATE I, 44.6% of people receiving the investigational therapy had no evidence of disease activity (NEDA), as measured by no clinical relapses, no new activity on magnetic resonance imaging (MRI), and no signs of clinical disease progression. This represented a 198% improvement over teriflunomide, the company said, adding that 43% of the ublituximab-treated patients in ULTIMATE II achieved NEDA, representing a 277% improvement over teriflunomide.

Summarizing study results reported by researchers at the American Academy of Neurology and European Academy of Neurology annual meetings earlier this year, TG Therapeutics also reported that ublituximab outperformed Aubagio in terms of MRI results and disability progression. The company added that ublituximab was generally well tolerated by study subjects, with no unexpected safety signals.

Ublituximab is a monoclonal antibody targeting B cells that express the protein CD20. These immune cells have been implicated in the development of multiple sclerosis, and are the target of other, recently approved disease-modifying therapies.

TG Therapeutics said that it will cite the data from the ULTIMATE I and ULTIMATE II studies in a Biologics License Application seeking FDA approval for use of ublituximab in relapsing forms of RMS. The company added that it hopes to file the application in the third quarter of 2021.

Measuring the long-term effects of relapses in MS

Relapses have a continuing impact on people with MS long after their symptoms have resolved, according to a team of Danish researchers.5

The investigators drew on data from the Danish Multiple Sclerosis Registry to identify 1,428 people with MS who experienced breakthrough relapses after starting a disease-modifying therapy (DMT). They then matched those study subjects with another 1,428 people with MS who had not had a relapse after starting treatment. Study participants were matched by sex, age, and Expanded Disability Status Scale (EDSS) score.

Overall, the adjusted annualized increase in EDSS score in the people with relapses was twice that of those who did not have a relapse. However, looking only at people with an EDSS score of 4.0 or more when they entered the registry, there was no difference between the two groups in annualized EDSS score increase.

People who had breakthrough relapses were 1.8 times more likely than those in the non-relapse group to have irreversible worsening of their EDSS score, and 1.62 times more likely to have an irreversible increase in the EDSS score to 6.0 or more.

“Our results indicate that breakthrough relapses [while taking a] DMT are associated with increasing permanent disability in patients with EDSS <4.0 at treatment start,” the investigators write, adding that this finding, “calls for effective prevention of relapses.”

Exploring the links between age, disease severity, and regular use of MS medications

Older apparently really is wiser when it comes to taking MS medications as prescribed, while greater disease severity often means greater deviation from scheduled use of those disease-modifying therapies (DMTs).

Those were two of the main findings to emerge from a review of data on more than 3,300 people in the United States.6 Analyzing information from the Humana Medicare Advantage claims database from 2013 through 2015, researchers found that people with MS who were aged 65 years and older were 1.55 times more likely than people aged 18 to 45 years to be adherent to their treatment schedule. People aged 46 to 64 years were 1.33 times more likely than the younger adults to be adherent.

Interestingly, people whose medical records indicated that they had a high level of MS severity were 53% less likely to be adherent to their medication schedule than people with a low level of disease severity. The researchers found no gender-related differences in adherence.

It may seem paradoxical that people with more-severe MS are less likely than those with a milder disease course to take their medications as scheduled. However, the finding underscores the importance of identifying and addressing the many factors – potentially including mental attitudes and physical challenges – that affect how closely a person follows a treatment plan.

“MS disease severity should be considered when assessing risk for low DMT adherence,” the researchers noted.

In MS, what’s good for your heart may also be good for your brain

Higher scores on an algorithm developed to assess a person’s 10-year risk for cardiovascular disease were associated with increased loss of brain volume in people with MS, according to a team of Canadian and American researchers.7

The investigators, who are part of the Comorbidity and Cognition in Multiple Sclerosis Study Group, studied 98 people with MS.

They recorded each person’s medical history and medications taken. They then used the study subjects’ blood pressure, height, weight, and other characteristics to calculate those people’s Framingham Risk Score (FRS), which estimates a person’s chances of having a heart attack, stroke, heart failure, or other cardiovascular or cerebrovascular events and conditions over 10 years. Study subjects then had two brain MRIs, two years apart.

Looking at the study group as a whole, researchers found that as the Framingham Risk Score went up – indicating greater cardiovascular risk – brain volume went down. This association was seen at the start of the study, when people with a higher baseline FRS had lower brain volumes than people with a lower FRS. It also was seen over time, as a higher FRS was associated with greater brain volume loss during the two years between MRIs.

The investigators noted, “This effect was most pronounced for persons with higher brain volumes at baseline, which suggests that prevention, detection, and effective management of comorbidities associated with vascular risk in people with MS is particularly important early in the disease course.”

A very specific reason why people with relapsing-remitting MS shouldn’t smoke

All people have ample motive to avoid or stop smoking in terms of reduced risk for heart disease, lung disease, and several types of cancer. Now, however, researchers in Iran have identified another reason people with relapsing-remitting multiple sclerosis (RRMS) should not light up: the increased risk of transitioning to secondary-progressive multiple sclerosis (SPMS) associated with smoking.8

The researchers examined data on 1,903 people with RRMS. Fifteen percent of those people transitioned to SPMS during the period the investigators studied. Using sophisticated statistical analyses, the researchers found that smoking more than doubled the risk of going from RRMS to SPMS.

Other factors, such as older age and higher Expanded Disability Status Scale (EDSS) score at onset of RRMS, motor dysfunction, and the presence of spinal cord lesions, also were associated with an increased risk for moving from RRMS to SPMS. Unlike smoking, of course, those are not modifiable risk factors – characteristics or behaviors that a person can change.

While eventual transition to SPMS is common in RRMS, this study identified one step people can take to potentially reduce the risk for – or perhaps at least delay – that development.

A pinpoint approach to reducing spasticity in MS

A small study suggests that dry needling may help reduce the spasticity often experienced by people with MS.

Like acupuncture, dry needling is an intervention in which thin, stainless steel needles are placed in the skin. Beyond that similarity, however, the two practices differ in several ways. Acupuncture is based on ancient Chinese medicine approaches and philosophies, while dry needling is a more-recent treatment strategy informed by Western medicine’s focus on anatomical pain points.

Spanish researchers recently used dry needling to treat lower-limb spasticity in nine women and three men with MS.9 After 12 consecutive sessions, all 12 patients showed improvement from their pre-treatment status on several measures of spasticity and on an instrument used to assess quality of life. Ninety percent of the study subjects also reported experiencing fewer muscle spasms.

While the study involved only 12 people, its findings may encourage clinicians to further investigate the potential benefits of dry needling.

Cannabis and bladder symptoms in MS: A small, but intriguing, signal

Add bladder issues to the list of MS symptoms some people are trying to manage with cannabis.

A recent Canadian survey examined reasons for cannabis use among 734 people with MS. Seventy-eight percent reported taking cannabis primarily for medical or therapeutic – as opposed to recreational – purposes.10

The most common reasons for cannabis use were to help with sleep (cited by 58% of respondents), pain (52%), relaxation (44%), muscle spasms (40%), anxiety (34%), and depression (23%).

However, 19 participants – just over 2% of the total – said bladder symptoms were a main reason for their cannabis use. What’s more, 90% of the people in that small group said their bladder symptoms were better when they took cannabis. Researchers said that cannabis use in the past three months doubled the chance of a person reporting improvements in urinary frequency, urgency to urinate, bladder leakage, and other measures of bladder function.

The researchers added that the survey results provide “some initial glimpses” into the use of cannabis to address bladder issues. While the numbers involved are small, and the results focus on people’s impressions rather than on objectively measured criteria, the findings suggest that further investigating this approach may be worthwhile.

Which assistive devices for walking help people with MS make the greatest strides?

While most people with MS have some degree of walking impairment, many don’t use assistive devices such as canes, according to researchers who assessed the psychosocial impact and mobility effects of different types of assistive devices.11

Those researchers recruited 25 people with MS who reported walking difficulty. They trained the study subjects in the use of three different types of assistive devices: a single point cane (SPC); a four-point cane (FPC); and a trekking pole (a device favored by mountain climbers and hikers).

Participants used each device in turn for a fixed period of time while performing their usual activities. The researchers evaluated the impact of each device using measures such as the 6-Minute Walk Distance test, walking speed, cadence, stride length, and the 5-item Modified Fatigue Impact Scale. They also employed the Psychosocial Impact of Assistive Devices Scale (PIADS) to gauge how people felt about using each type of device.

The results suggest that when it comes to cane points, less may be more. The single point cane and trekking pole had more favorable ratings than the four-point cane in the adaptability, competence, and self-esteem sections of the PIADS. Use of the SPC and TP also resulted in greater 6-minute walk distances, walking speed, and stride length than the FPC. No differences between devices were found with a scale used to assess balance.

The researchers concluded, “Clinicians should consider suggesting an SPC or TP to patients who may benefit from assistive device use and for whom psychosocial impact is an important consideration.”

Another factor to weigh when considering pregnancy: Time since last relapse

Becoming pregnant within one year of a relapse increases the chances that a woman with MS will experience worsening disability over the long term, Italian investigators recently reported.12

The researchers examined data on 332 women with MS. Of these women, 230 had pregnancies, while 102 similarly aged women did not. After an average follow-up of 6.5 years, the researchers found that women who experienced a relapse in the year prior to conceiving had a risk of worsening disability that was 1.75 times greater than that of the women who did not have a pregnancy. Other factors associated with increased risk for disability worsening included a higher Expanded Disability Status Scale (EDSS) score initially, younger age, and shorter exposure to disease-modifying therapy (DMT) over the follow-up period. However, those factors did not confer as great an increased risk as a relapse in the 12 months before becoming pregnant.

Identifying the optimal time to pursue pregnancy can be challenging for any woman, but women with MS face an additional set of considerations regarding their treatment regimens and other issues specific to multiple sclerosis. While this study is not the definitive word on the subject, it provides important information for each woman to take into account while arriving at the decision that is best for her.


1 Valentine TR, Altschuler KN, Ehde DM, Kratz AL. Prevalence, co-occurrence, and trajectories of pain, fatigue, depression, and anxiety in the year following multiple sclerosis diagnosis. Mult Scler. 2021 June 16; 13524585211023352. doi:10.1177/13524585211023352.

2 Iaffaldano P, Lucisano G, Caputo F, et al. Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies. Ther Adv Neurol Disord. 2021 May 31;14:17562864211019574. doi: 10.1177/17562864211019574.

3 Simonsen CS, Flemmen HO, Broch L, et al. Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in Norwegian population-based registry. Front Neurol. 2021. 12:693017. doi: 10.3389/fneur.2021.693017

4 TG Therapeutics, Inc. TG Therapeutics announces presentation of data from the ULTIMATE I & II Phase 3 trials of ublituximab in multiple sclerosis at the 7th Congress of the European Academy of Neurology. June 18, 2021. Available at https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-presentation-data-ultimate-i-ii-phase. Accessed July 1, 2021.

5 Koch-Henriksen N, Sorensen PS, Magyari M. Relapses add to permanent disability in relapsing multiple sclerosis patients. Mult Scler Relat Disord. 2021. May 17;53:103029. doi: 10.1016/j.msard.2021.103029.

6 Burkhardt A, Toliver J, Rascati K. Association between multiple sclerosis disease severity and adherence to disease-modifying therapies. J Manag Care Spec Pharm. 2021 Jul;27(7):915-923. doi: 10.18553/jmcp.2021.27.7.915.

7 Marrie RA, Patel R, Figley CR, et al. Higher Framingham Risk Scores are associated with greater loss of brain volume over time in multiple sclerosis. Mult Scler Relat Disord. 2021 Jun 17;54:103088. doi: 10.1016/j.msard.2021.103088.

8 Barzegar M, Najdaghi S, Afshari-Safavi A, et al. Early predictors of conversion to secondary progressive multiple sclerosis. Mult Scler Relat Disord. 2021 Jun 26;54:103115. doi: 10.1016/j.msard.2021.103115.

9 Perez-Trujillo MDP, Gonzalez-Platas M, Perez-Martin MY, Revert-Girobes M, Gonzalez-Platas J. Dry needling for treating spasticity in multiple
Sclerosis. J Phys Ther Sci. 2021;33(7):505-510.

10 Kim-Fine S, Greenfield J, Chaput KH, Robert M, Metz LM. Cannabinoids and bladder symptoms in multiple sclerosis. Mult Scler Relat Disord. 2021. Jun 23;54:103105. doi: 10.1016/j.msard.2021.103105.

11 Cohen ET, Huser S, Barone K, Barone DA. Trekking poles to aid multiple sclerosis walking impairment: an exploratory comparison of the effects of assistive devices on psychosocial impact and walking. Int J MS Care. 2021;23(3):135-141.

12 Portaccio E, Tudisco L, Pasto L, et al. Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening. Mult Scler. 2021 June 16;13524585

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

Webinar: MS research

MS Research Webinar

For additional information on the latest advancements in MS research, please access MSAA’s educational webinar What’s New In MS Research: A Look Into The Future of Multiple Sclerosis Treatment – July 2021 featuring Dr. Barry Singer.