What’s New in MS Research – January 2023

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

The studies featured in this edition of “What’s New in MS Research” speak to progress made and progress awaited. We start out by announcing two new disease-modifying therapies that are or soon will be available through one’s healthcare provider. This is followed by the news that the last four decades have seen a significant shortening of the interval from first symptoms of multiple sclerosis (MS) to diagnosis of the disease. There are also heartening findings about the role the Mediterranean diet can play in reducing MS disability, signifying progress in identifying lifestyle changes that people with MS can make to enhance their health.

Conversely, other studies highlighted this month examine the significant toll that spasticity takes on people with MS and the impact that a negative experience when receiving a diagnosis of MS can have on people’s perceptions and approach to dealing with the disease. Clearly, further progress is needed on those fronts.

A related theme emerging from the research summaries that follow is the steady progress being made in understanding risk – whether for developing MS, for disease progression, or for cognitive impairment. Knowledge of risk factors and risk drivers is a prerequisite for developing better strategies, and the insights generated today provide the foundation for future advances.

Recently approved Briumvi^™ now available for relapsing forms of MS

In late December, TG Therapeutics announced that the United States Food and Drug Administration (FDA) approved Briumvi^™ (ublituximab-xiiy) for the treatment of relapsing forms of multiple sclerosis (MS) in adults – including clinically isolated syndrome, relapsing-remitting MS, and active secondary-progressive MS. This medication is a monoclonal antibody that targets CD20, a protein found on the surface of B cells, and induces B-cell depletion within 24 hours. B cells are white blood cells shown to play a role in MS.

Briumvi is given by infusion, with two initial doses administered 14 days apart, followed by a one-hour infusion every 24 weeks. In studies, Briumvi met its primary end point of reducing annualized relapse rates when compared to individuals taking the oral medication, Aubagio^® (teriflunomide). It also met certain secondary endpoints, including the reduction of gadolinium-enhancing lesions as seen on magnetic resonance imaging (MRI), compared to individuals taking Aubagio.

The most common side effect was infusion-related reactions. This new therapy is now available to individuals with MS through their healthcare providers. For more information, please refer to MSAA’s online news item, “FDA approves Briumvi^™ for the treatment of relapsing forms of MS”; readers may also visit TG Therapeutics’ dedicated patient support website at www.briumvipatientsupport.com or call 1-833-BRIUMVI (1-833-274-8684).

First Orally Disintegrating Version of Fingolimod Available Soon

[INFORMATION REVISED OCTOBER 2023]

A new formulation of fingolimod has been approved by the United States Food and Drug Administration (FDA) for relapsing forms of MS and will soon be available. Marketed under the brand name, Tascenso ODT^® (fingolimod), this medication is the same as that found in Gilenya®, but rather than a solid pill that needs to be swallowed, Tascenso ODT is given by a pill that immediately dissolves on the tongue and does not require water. Clinical data shows that it has the same efficacy (effectiveness), safety, and purity as the original medication.

Tascenso ODT will be available in two strengths: 0.25mg and 0.5mg. This formulation dissolves on the tongue within seconds, providing an easy and convenient administration of a DMT. Parent company Cycle Pharmaceuticals Ltd (Cycle) will be offering an in-house patient-support program called Cycle Vita^™. This program will include services such as appropriate insurance navigation and financial assistance, as well as first-dose observation and baseline assessments. For those who want to initiate or continue treatment with fingolimod, the Cycle Vita program will help to take the place of Gilenya’s patient-support Go Program, which will no longer be available to individuals with MS after March 31st.

Tascenso ODT is specifically indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary-progressive disease, in adults as well as pediatric patients 10 years of age and older. The dose for adults and children weighing more than 88 pounds is 0.5mg daily; children weighing 88 pounds or less receive 0.25mg daily.

As a bioequivalent to Gilenya, which was originally FDA-approved in 2010, Tascenso ODT has the same benefits and risks as Gilenya. In studies over the course of two years, individuals taking Gilenya compared to both placebo as well as other approved DMTs, experienced significant reductions in: relapses; new or enlarging/enhancing lesions; three-month confirmed disability progression; and [reductions in] brain volume loss.

Common side effects with Gilenya include headache, flu, diarrhea, back pain, respiratory infections, abnormal liver tests, and cough. Possible adverse events include a reduction in heart rate (dose-related and transient); infrequent transient atrioventricular (AV) conduction block of the heart; increase in blood pressure; macular edema (swelling behind the eye); elevation of liver enzymes; and a slight increase in respiratory infections (including bronchitis).

For more information, the Cycle Vita patient-support team may be contacted by calling (888) 360-8482 or visiting www.cyclevita.life.

A welcome reduction in time from symptom onset to MS diagnosis

The time between a person’s first symptoms of demyelination and diagnosis of multiple sclerosis has been cut by more than two-thirds over the past 40 years, according to researchers with the New York State MS Consortium (NYSMC).¹

Drawing on data for 9,378 people with MS, the researchers reported that the average interval from symptom onset to official diagnosis declined from 4.15 years in the period from 1982 to 2001, to 1.15 years in the period from 2017 onward. Further, the percentage of people who went undiagnosed for one year or more after their first symptoms decreased from 59.1% in the 1982-2001 period, to 20.4% from 2017 to present.

That reduction in time to diagnosis is critical because numerous studies have shown that early initiation of disease-modifying therapy (DMT) improves long-term disability outcomes.

The investigators said that improved diagnostic criteria have played a major role in the prompt identification of MS. They noted, “Additional improvements and better implementation of the MS diagnostic criteria can further decrease the diagnosis lag.”

Diagnosis concealment: Common in MS, and tied to diagnosis experience

Just under half of people with MS participating in a recent study reported concealing their diagnosis at least some of the time.²

The research involved 428 adults from 18 countries, with 88% from the United States. Eighty percent of participants were female and 94% identified as white. Their average age was 56.2 years. Study participants completed a survey on their disclosure or concealment of their diagnosis, the consequences they anticipated from sharing their diagnosis, their experience with being diagnosed, and related topics.

Forty-nine percent of the respondents said they sometimes, often, or always conceal their diagnosis. Diagnosis concealment was associated with younger age, lower disability status, and shorter disease duration. College-educated participants were more likely than other people to report concealment behavior. Researchers did not find an association between sex or age at diagnosis and concealment behavior.

People who perceived that they had adequate time to express their feelings when they were diagnosed reported engaging in less concealment behavior than those who felt they weren’t accorded sufficient time to discuss their emotions at diagnosis. In a similar vein, people who felt they were given adequate information about MS when they were diagnosed anticipated less overall, personal, and professional negative consequences from disclosure than did people who reported not having received enough information at diagnosis. Participants who reported that their overall diagnosis experience was very positive engaged in much less concealment behavior than the 32% of people who reported a negative or very negative diagnosis experience.

Thirty-nine percent of survey respondents said they anticipated negative consequences from disclosing their diagnosis. Younger current age, younger age at diagnosis, and a relatively greater degree of disability were associated with expecting negative fall-out from disclosing an MS diagnosis.

Interestingly, only 23% of respondents said “Yes” when asked, “Have any of your MS providers ever asked you whether you share your MS diagnosis with others?” Those people reported less anticipation of negative consequences of disclosure and more expectation of positive consequences than participants who reported never having had a clinician ask them about disclosure.

Receiving a diagnosis of MS can be extremely difficult, but delivering the diagnosis isn’t easy, either. Clinicians have to determine how much information to provide and how best to provide it to a person who may understandably be overwhelmed by this life-changing news. While acknowledging those challenges and the many demands on clinicians, this study’s findings suggest that efforts to improve the diagnosis experience – particularly in terms of allowing people time to express their emotions and addressing the topic of disclosure – may play a major role in people’s subsequent outlook and behavior.

Meanwhile, the question of whether to disclose an MS diagnosis to relatives, friends, and professional associates remains a highly personal matter influenced not only by the diagnosis experience and an individual’s outlook, but also by family dynamics, the workplace environment, and other complex considerations. Seeking guidance from an MS clinician, a counselor, or others may be a worthwhile step when weighing what, if anything, to share with various people.

Going “Mediterranean” to reduce MS disability

A wealth of evidence shows that the Mediterranean diet cuts risk for heart disease. For people with MS, however, closely following this eating approach – which emphasizes plant-based foods and healthy fats – appears to confer the added benefit of reducing disability.

Researchers from the Icahn School of Medicine at Mount Sinai and Johns Hopkins University recently analyzed data on dietary practices, functional capacity, and degree and nature of disability in 563 adults with MS.³

Study participants completed the Mediterranean Diet Adherence Screener (MEDAS), a survey used to determine how closely a person follows the diet, which is centered on vegetables, fruits, whole grains, and olive oil, with little or no meat (particularly red meat), sweets and other sugary food, or alcohol. The people in the study also filled out the MS Functional Composite (MSFC), an instrument used to gauge degree of disability, as well as patient-reported outcome (PRO) measures of gait disturbance, fatigue, anxiety, depression, and other conditions often seen in MS.

The researchers used study participants’ MEDAS scores to divide the people into four groups based on how much or how little they followed the Mediterranean diet. The investigators then looked at the MSFC and PRO results for each group, making adjustments for demographic factors, such as age and sex, and for health-related factors, such as body mass index (BMI), exercise habits, and the presence of conditions such as diabetes and hypertension.

A clear pattern emerged from the analysis: Higher adherence to the Mediterranean diet translated into a lower degree of disability, as measured both by the MSFC and people’s own assessments. In fact, researchers said, each point a person had on the 14-point MEDAS was associated with a 15% lower risk for impairment as measured by the MSFC.

Quantifying the many ways spasticity affects people with MS

When it comes to identifying and addressing the challenges that MS poses, spasticity might be said to be “hiding in plain sight.” It is so common in its occurrence and so wide-ranging in its impact that people with MS and their clinicians can take the condition as a given and focus their attention on other aspects of multiple sclerosis.

The SEEN-MSS (Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity) online survey initiative is working to counter that tendency, and to bring spasticity to the forefront of patients’ and providers’ attention. Developed as a collaborative effort involving three US-based MS organizations, including the Multiple Sclerosis Association of America, the survey inquires about several aspects of spasticity and its impact on the daily lives of people with MS. More than 1,100 people completed the online survey between February and April 2021. The respondents had a mean age of 56.8 years. They had been diagnosed with MS for an average 16.8 years and had been living with spasticity for 11.5 years. More than three-quarters of survey participants were women.⁴

Most respondents said spasticity provided a constant reminder that they had MS. Additionally, the following percentages of people reported these impacts of spasticity:

• Pain – 92%
• Limitation of daily activities – 92%
• Impaired sleep – 89%
• Negative effect on emotional well-being – 87%
• Reduced self-confidence – 75%
• Negative effect on self-image – 70%
• Fostering a sense of dependence on others – 61%
• Negative effect on social connections – 62%
• Heightened sense of isolation – 40%

These findings, researchers note, “emphasize the need to fully understand the burden of spasticity” and to address the individual needs of people with MS. The findings also underscore the importance of talking with clinicians about the everyday impact of spasticity and working together to develop strategies to help counter the effects of spasticity.

Receiving the benefits while avoiding the pitfalls of taking multiple medications

A study involving 14,227 people with MS found that 28% regularly took five or more medications for various conditions, potentially placing them at increased risk from adverse reactions caused by drug-to-drug interactions.⁵

Researchers from the University of British Columbia in Canada drew on healthcare administrative data and pharmacy records to conduct the analysis, which focused on medications taken for 30 days or longer. They found that women were more likely than men to be taking multiple medications, as were people age 50 years and older compared to younger people. As would be expected, people with more health conditions beyond MS were more likely to be on multiple medications than those with no other health conditions. Additionally, people with lower socioeconomic status were more likely to take more medications than people with a greater degree of affluence.

Antidepressants were the most frequently prescribed medications and were taken by 67.9% of study participants. Other commonly prescribed medications included anti-epileptic drugs (51.6% of people), drugs for peptic ulcer disease or gastroesophageal reflux (45.4%), opioids (43.3%), and muscle relaxants (33.9%).

The study’s authors noted that earlier research has shown use of five or more medications by people with MS to be associated with increased fatigue and patient reports of cognitive impairment. At the same time, of course, regular medication use is critical for controlling conditions such as high blood pressure, depression, or diabetes, as well as for addressing MS symptoms such as muscle spasms or urinary incontinence.

So how can a person with MS manage various other conditions or MS manifestations with medication while safeguarding his or her overall health? An important first step is to ensure that each clinician providing care is aware of all the medications you are taking. A second step, the study’s authors said, is to consult with your healthcare providers to confirm that each medication is still necessary. They wrote: “Patients and prescribers may benefit from treatment recommendations that not only address when to start a drug, but [that] also provide guidance on a shared decision-making approach to stopping medication, as appropriate.”

Assessing pregnancy’s impact on the long-term course of MS

Pregnancy appears to have neither a positive or negative effect on long-term disability and relapse activity in MS.

That’s the conclusion of French researchers who analyzed data on 9,100 women with MS, including 2,125 who had experienced at least one pregnancy. The researchers said that while previous studies suggested that pregnancy provides a long-term beneficial effect on MS course, those findings may have been skewed because women with higher degrees of disability are less likely to have been or to become pregnant. To offset this issue that could potentially impact the findings, the investigators used an approach called causal inference to examine data on women who were 18 to 45 years of age when their MS symptoms began, had at least two years of data available, and had an Expanded Disability Status Scale (EDSS) of 3 or more, indicating a mild or greater degree of disability. The study participants were followed for an average 7.8 years.⁶

The investigators determined that pregnancy had no significant causal effect on the average EDSS score nine years after a study subject’s first pregnancy, nor on the probability of relapse over the longer term. However, among those women who experienced a relapse within three years of pregnancy, the researchers identified a pattern in which women had a reduced probability of relapse in the year in which they delivered but a greater chance of relapse in the first year after delivery.

Beyond the question of how pregnancy may affect the course of MS, there also have been concerns about how medical reproductive procedures may contribute to risk for developing the disease.

Thankfully, Danish investigators recently provided some reassuring news on that score. The researchers examined data on 587,716 women who had delivered at least one child. The study subjects included 63,791 women – or 11% of the total – who had undergone at least one in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle between 1996 and 2018. The women were followed for a median 12.8 years.⁷

The researchers reported that, overall, women who became pregnant through use of IVF or ICSI were not at greater risk for developing MS than women who conceived without employing an assisted reproductive technology (ART). Further, in an analysis focused solely on the women who had IVF or ICSI, the success or failure of that treatment – meaning conceiving or not conceiving – had no impact on risk for MS in the two years following fertility treatment. The investigators did report a non-significant trend toward increase in MS risk in conjunction with an increase in the number of ART cycles, but they emphasized that this signal was based on small numbers and was not statistically significant.

Researchers identify MRI finding associated with greater MS progression

People with MS who have both slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs) on magnetic resonance imaging (MRI) appear to be at greater risk for disease progression than people whose MRI studies show only one or the other type of lesion, according to a team of British and Spanish researchers.⁸

The researchers followed 61 people with MS over a median 3.2 years. At baseline, the study participants had a total of 1,492 lesions. Of that total, 616 lesions were classified as slowly expanding. Eighty lesions were categorized as paramagnetic rim lesions, meaning they had iron-enriched cellular components at their edges, indicating persistent active demyelination. (A lesion can be, but does not have to be, both slowly expanding and marked by a paramagnetic rim.)

Thirty-one study participants had both SELs and PRLs. From baseline to final follow-up, those people’s Expanded Disability Status Scale (EDSS) scores increased by a median 0.27 points. By contrast, the 25 study subjects who had one or more SELs but no paramagnetic rim lesions had a median 0.06 increase in EDSS score, while the five people with neither type of lesion had no median change in their EDSS score. The difference in EDSS changes between people with both types of lesions and those with only SELs was statistically significant.

“What does the future hold for me?” is one of the most common and pressing questions asked by people with MS. No one study finding holds all of the answers, of course, and two people who have the same test result can have markedly different courses based on a variety of factors. That said, researchers’ understanding of the significance of various MRI findings has increased in step with advances in imaging technology and techniques, providing people with MS and their clinicians with valuable insights as they make treatment decisions and long-term plans.

Blood levels of a protein predict cognitive decline in active, progressive MS

Neurofilament light chain (NfL) is a protein released from neurons following damage to their axons, the cable-like projections that help the nerve cells transmit signals. In recent years, researchers have found that the level of NfL in the blood and cerebrospinal fluid can serve as a marker of disease activity in MS and a measure of the neuroaxonal damage that marks the disease.

A recent study indicates that blood levels of the protein also may predict cognitive decline in people with active, progressive MS.⁹ Researchers from Boston’s Brigham and Women’s Hospital and Harvard Medical School assessed levels of serum NfL over time in 94 people with MS. All of the study participants had an Expanded Disability Status Scale (EDSS) score of 3 or more at baseline and throughout the follow-up period. The EDSS scale runs from 0 to 10, with 0 signifying no disability and 10 representing death due to complications of MS. A score of 3 reflects mild to moderate disability. Investigators noted that a sustained EDSS score of 3 or greater is a reliable means of identifying people with MS who are at high risk for an underlying progressive pathology.

Study participants had a mean age of 47.2 years at baseline and, on average, had experienced MS for 14 years. Their median EDSS score at the start of the study was 3.5, and their average score on the Symbol Digit Modalities Test (SDMT) – a measure of cognitive function – was 49.7. After a median follow-up of 3.1 years, the overall group’s median EDSS score had increased by one-half point, indicating increasing disability, and the median SDMT score had declined by 0.4 points, representing cognitive decline.

Researchers found that higher serum NfL levels at baseline were associated with a greater degree of cognitive decline over time than that seen in people with lower NfL levels at the start of the study. The researchers noted, however, that the value of NfL in predicting future declines in cognition was shown only in people with acute inflammatory disease activity, not in those with nonactive MS. They added that their findings may help clinicians target serum NfL levels in an attempt to prevent cognitive decline.

Evaluating the real-world impact of oral disease-modifying therapies

With more than 20 disease-modifying therapies (DMTs) now approved for the treatment of relapsing forms of MS, selecting a DMT can be a challenge – albeit a welcome one – for people with MS and their clinicians. A recent analysis of data from the international MSBase registry provided findings that may help patients and providers as they navigate that challenge.¹⁰

The study explored the experiences of more than 2,500 adults with MS who began treatment with one of four oral DMTs from 2018 to mid-2021. The four medications were Aubagio^® (teriflunomide), Gilenya^® (fingolimod), Mavenclad^® (cladribine), and Tecfidera^® (dimethyl fumarate). Researchers looked at endpoints including time to annualized relapse rate (ARR), time to first relapse, and time to a switch in treatment.

People starting Mavenclad had a lower ARR than study subjects on other medications, with matched-cohort annual relapse rates of 0.09 for Mavenclad vs. 0.15 for Gilenya, 0.10 for Mavenclad vs. 0.15 for Tecfidera, and 0.09 for Mavenclad vs. 0.17 for Aubagio. All of those differences were statistically significant. People with MS taking Mavenclad also had statistically significant longer times to first relapse and to treatment switch, when applicable, than their counterparts in matched cohorts for the other DMTs.

Those endpoints are three of many factors that people with MS and their clinicians should consider when determining which DMT is likely to be the best choice for a person given his or her specific situation.

Less sleep in adolescence may increase MS risk in adulthood

A Swedish study found that people who typically slept less than seven hours per night during adolescence were 1.4 times more likely to develop MS later in life than people who averaged seven to nine hours of sleep during their teenage years. Similarly, people who reported low sleep quality as teens were 1.5 times more likely to develop MS in adulthood than people who reported better sleep as adolescents.¹¹

The researchers who conducted the study noted that shift work is associated with an increased risk of MS, presumably because of its impact on sleep deprivation and the body’s circadian rhythms. Based on that finding, they decided to investigate how sleep patterns in adolescence might affect subsequent development of MS. The investigators analyzed information on 2,075 people with MS and 3,164 controls who were matched to the people with MS in terms of factors including age and sex.

While the typical number of hours slept and the quality of sleep in adolescence both were associated with risk for MS, the investigators did not find a link between risk for the disease and changes in sleep timing between school days and weekends.

The researchers concluded, “Sufficient restorative sleep at young age, needed for adequate immune functioning, may be a preventive factor against MS.”

References

¹ Jakimovski D, Kavak KS, Zakalik K, et al. Improvement in time to multiple sclerosis diagnosis: 25-year retrospective analysis for New York State MS Consortium (NYSMC). Mult Scler. 2022; DOI: 10.1177/13524585221140271.

² Leavitt VM, Kever AM, Weinstein SM, et al. Diagnosis concealment is prevalent in MS, and associated with diagnosis experience. Mult Scler Relat Disord. 2022 Dec;68:104373.doi: 10.1016/j.msard.2022.104373.

³ Katz Sand I, Levy S, Fitzgerald K, Sorets T, Sumowski JF. Mediterranean diet is linked to less objective disability in multiple sclerosis. Mult Scler. 2022. 1–13 DOI: 10.1177/13524585221127414.

⁴ Newsome SD, Thrower B, Hendin B, et al. Symptom burden, management and treatment goals of people with MS spasticity: results from SEEN-MSS, a large-scale, self-reported survey. Mult Scler Relat Disord. 2022 Dec; 68:104376. doi: 10.1016/j.msard.2022.104376. 

⁵ Chertcoff A, Ng HS, Zhi F, Zhao Y, Tremlett H. Polypharmacy and multiple sclerosis: a population-based study. Mult Scler. 2022. 1–12. DOI: 10.1177/13524585221122207.

⁶ Gavoille A, Rollot F, Casey R, et al. Investigating the long-term effect of pregnancy on the course of multiple sclerosis using causal inference. Neurology. 2022. Dec. 23;10.1212/WNL.0000000000206774.doi: 10.1212/WNL.0000000000206774. 

⁷ Kopp TI, Oinborg A, Glazer CH, Magyari M. Assisted reproductive technology treatment and risk of multiple sclerosis – a Danish cohort study. Fertil Steril. 2022 Dec. 24;S0015-0282(22)01977-X. doi: 10.1016/j.fertnstert.2022.10.027. 

⁸ Calvi A, Clarke MA, Prados F, et al. Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis. Mult Scler. 2022. 1–11 DOI: 10.1177/
13524585221141964.

⁹ Barro C, Healy BC, Saxena S, et al. Serum NfL but not GFAP predicts cognitive decline in active progressive multiple sclerosis. Mult Scler. 2022.1–6 DOI: 10.1177/13524585221137697.

¹⁰ Spelman T, Ozakbas S, Alroughani R, et al. Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry. Mult Scler. 2022. 1–15 DOI: 10.1177/13524585221137502.

¹¹ Akerstedt T, Olsson T, Alfredsson L, Hedstrom AK. Insufficient sleep during adolescence and risk of multiple sclerosis: results from a Swedish case-control Study. J Neurol Neurosurg Psychiatry. 2023;0:1–6. doi:10.1136/jnnp-2022-330123.

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