What’s New in MS Research – March 2024

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

From February 29th through March 2nd of this year, MS researchers and clinicians gathered in West Palm Beach for the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024. These healthcare professionals came not only to ask questions but also to provide answers obtained from recent studies addressing varied facets of multiple sclerosis.

This month’s edition of “What’s New in MS Research” provides a sampling of the findings from those studies, which looked at everything from the safety and efficacy of repeated stem cell transplants to the link between sleep and memory in people with MS. Information is also included on: the impact of spasticity and opportunities to improve the management of this common, challenging condition; predictors of disease progression; the effectiveness of disease-modifying therapies; and more.

We hope that you find this edition of “What’s New in MS Research” to be both informative and inspiring – not only in terms of the wide variety of research being conducted in the field of MS, but also the positive results coming from so many of these studies.

Reassuring news on safety and efficacy of repeated stem cell transplantation

As stem cell transplantation plays a growing role in the management of many diseases, including MS, researchers are delving into questions about the optimal use of the procedure – including how often it can be used to treat a condition, and whether safety concerns increase or effectiveness decreases with repeated use. A team of investigators from Israel recently reported favorable interim findings from an ongoing study examining these issues in people with MS.¹

The researchers provided data on 23 people who had at least two transplants of their own, bone marrow-derived stem cells. In these autologous (meaning from a person’s own body tissues) transplants, a physician removes stem cells from a patient’s blood, bone marrow, or other tissues. The cells are sent to a laboratory where they are treated and their numbers are increased. While this is happening, the patient receives powerful drugs to essentially “wipe out” their immune system. The treated cells are then reintroduced to the patient’s body, typically by intravenous infusion, in order to “reset” the immune system.

In the Israeli study, each patient’s treatments were separated by an interval of three to six months. No serious adverse events were reported. In the 16 patients who had multiple measurements of the time it took them to walk 25 feet, there was a median improvement of 17% after the initial injection and just a 1-second decline in 25-foot walk time at one year after the first treatment. Study participants’ average scores on the Symbol Digit Modalities Test, which assesses cognitive function, improved. Meanwhile, there was an average reduction of about 20% in blood levels of neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), which are biomarkers of disease progression and severity. Several patient-reported outcomes also showed improvement.

Stem cell transplantation is emerging as an important option for people who do not obtain sufficient benefit from high-efficacy disease-modifying therapies (DMTs). Studies such as this provide people with MS and their clinicians with key insights into approaches for integrating stem cell therapy into the management of aggressive, difficult-to-treat multiple sclerosis.

Exploring the “wearing-off” effect toward the end of treatment cycles

More than half of people with MS who take monoclonal antibody disease-modifying therapies (DMTs) experience a “wearing-off” effect shortly before they are due for the next dose of their medication, according to researchers from the Mellen Center for Multiple Sclerosis at the Cleveland Clinic.²

Those researchers surveyed 258 people, including 154 who were receiving Ocrevus^® (ocrelizumab), 39 receiving Kesimpta^® (ofatumumab), 37 receiving Tysabri^® (natalizumab), and 28 receiving Rituxan^® (rituximab). (Rituxan is not approved for the treatment of MS in the United States, although it is approved to treat several other conditions. Some clinicians use it “off-label” for multiple sclerosis.)

Fifty-five percent of patients reported that as they neared the end of a treatment period – which ranges from 28 days for Tysabri to six months for Ocrevus – they had indications that the medication’s effectiveness was diminished. Fatigue was the most commonly reported “wearing off” symptom, and was cited by 53.6% of people receiving Rituxan and 45.9% of patients taking Kesimpta. Other reported symptoms included increased tingling or prickling sensations (29.9% of respondents), worsened mobility (28.6%), and changes in cognitive functioning (26.0%).

The researchers also found an association between this “wearing-off phenomenon” and an elevated risk for depression. They identified the link by having study participants complete the Patient Health Questionnaire 9 (PHQ9), a self-administered diagnostic instrument for common emotional health disorders. Higher scores on the test are indicative of depression. The investigators found that each additional point on a person’s PHQ9 score added 2% to the odds that he or she experienced a wearing-off of treatment effects, with that association being statistically significant. Not surprisingly, the wearing-off phenomenon was also associated with diminished treatment satisfaction.

This study validates what many people with MS report to their clinicians. It also highlights an important counseling point to share with people taking monoclonal antibody DMTs. While the study wasn’t designed to answer the question of whether the “wearing-off phenomenon” contributes to depression or whether pre-existing depression heightens awareness of a medication’s diminishing effectiveness, it does provide further reason to screen for and treat depression in people with MS. Finally, while this wearing-off effect is obviously unwelcome, it serves to demonstrate that DMTs are having enough of an impact that people notice when they are near the end of their treatment cycle and ready for their next dose.

Examining risk factors for MS progression despite early, high-efficacy therapy

Recent years have seen many MS clinicians embrace a treatment strategy known as high-efficacy early treatment, or HEET. This approach involves treating recently diagnosed patients with high-efficacy disease-modifying therapies (DMTs) rather than “starting low and going slow” by initiating treatment with a DMT that has moderate efficacy but is less likely than a high-efficacy treatment to cause side effects. The rationale for HEET is that the disease-control benefits to be gained from “starting strong” may outweigh the potential downside of relatively more frequent or pronounced side effects.

As HEET has come into wider use, however, clinicians have seen some patients treated with this approach experience disease progression. A recent study sought to identify the demographic and clinical factors associated with progression among people receiving high-efficacy therapies from the early stages of their MS.³

Researchers from the University of California, San Francisco, analyzed data on 315 adults with an initial diagnosis of a relapsing form of MS who were started on a high-efficacy DMT within five years of diagnosis and who were followed at the researchers’ center for at least five years.

For purposes of the study, high-efficacy DMTs were defined as anti-CD20 medications (for example, Ocrevus^® [ocrelizumab]), Tysabri^® (natalizumab), Gilenya^® (fingolimod), Mavenclad^® (cladribine), and stem cell transplantation.

Progression at five years was judged by three criteria: clinician documentation of progressive MS, worsening as measured by change in Expanded Disability Status Scale (EDSS) score, and an increase of at least 20% in the time required to complete the Timed 25-Foot Walk test (T25FW).

Thirty-six percent of the people studied had progression at five years as judged by the T25FW, while 20.5% had progression based on change in their EDSS score, and 3.7% were deemed as having progression based solely on clinician assessment.

Analysis showed that increased time required to complete the T25FW was the most sensitive measure of disease progression. Initial findings indicated that male sex, Hispanic ethnicity, higher baseline EDSS score, and the presence of other health conditions all were associated with progression on HEET. However, on further analysis, only ethnicity was found to be a statistically significant risk factor for progression, with Hispanic people 2.6 times more likely than people of other racial/ethnic backgrounds to experience MS progression when high-efficacy therapies were initiated early.

The study’s authors concluded, “Disease progression represents the target for future interventions in MS, and establishment of more sensitive outcomes remains a key priority. Results also suggest [the] Hispanic population [is] at higher risk of disease progression. Further studies are needed to determine if progression is secondary to health disparities, or a biological component makes this population more susceptible.”

Encouraging one-year data on Zeposia^® and cognitive function

People with early relapsing MS who took the disease-modifying therapy Zeposia^® (ozanimod) saw improvement in measures of cognitive function after one year on the medication, researchers reported.⁴

The finding emerged from an interim analysis from the ENLIGHTEN Study, a prospective, multicenter, open-label, three-year trial examining the impact of Zeposia in adults with relapsing forms of MS (RMS) who have been diagnosed with multiple sclerosis for five years or less. Participation in the study is limited to those who either had not taken another DMT before starting Zeposia or who had taken only one DMT previously.

The FDA approved Zeposia for treatment of relapsing forms of MS in March 2020. The therapy belongs to a class of medications known as sphingosine-1-phosphate receptor agonists. These medications act by keeping lymphocytes contained within the peripheral lymphoid organs and away from areas of the body where they can cause chronic inflammation. Lymphocytes are white bloods cells, such as B cells and T cells, which play a role in immune function.

The study examined data on 116 people who completed one-year of follow-up on Zeposia. The people had an average age of 40.3 years. Eighty-eight percent were white and 79% were female. Sixty-five percent had not been treated with another DMT before Zeposia. At the start of the trial and after one year of treatment, study participants completed three tests assessing cognitive function: the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test Second Edition (CVLT-II), and the Brief Visuospatial Memory Test – Revised (BVMT-R). At the one-year mark, study participants had an average 10.1% increase in their SDMT score, as well as average increases of 6.6% for the CVLT-II, and 7.6% for the BVMT-R. Forty-seven percent of people had a clinically meaningful improvement in their SDMT results, which was defined before the start of the study as an increase in their SDMT score of either ≥4 points or an increase of ≥10% from baseline.

The researchers noted that “Impaired cognitive functioning can occur early in the disease course of relapsing multiple sclerosis.” They concluded, “Among patients with early RMS, of whom 64.7% were DMT-naive, ozanimod treatment appeared to prevent cognitive decline.”

Spasticity in MS: Study documents unmet needs and areas for improvement

Approximately 80% of people with MS experience spasticity. A recent online survey of 239 of those people identified numerous opportunities to improve their care.⁵ For example:

• Most said that their spasticity was not diagnosed until it was moderate (44%) or severe (14%).
• Half of respondents reported that they, rather than their clinicians, initiated the discussion about spasticity.
• Only 49% said they were asked about spasticity at every visit with their MS clinician; 21% said they were not asked about the condition at any clinic visits.
• Just 30% said their clinicians use formal assessments, such as instruments validated to measure a person’s degree of spasticity, to characterize their spasticity.

On the positive side, 68% reported that they were receiving pharmacologic treatment for their spasticity, with baclofen, gabapentin (Neurontin^®), and tizanidine (Zanaflex^®) being the medications most often prescribed. Thirty-two percent said that medication improved their pain, while 27% said treatment helped with walking, and 24% reported that medication eased spasticity-related insomnia. However, 29% said medication did not improve their ability to engage in daily activities. Further, 58% reported never being offered Botox^® injections. Among the 15% who had tried Botox injections, 73% received this treatment after having tried two or more other medications.

Thirty-nine percent of survey respondents reported having tried cannabis products, with two-thirds of the people in that group saying they did so without the guidance of a healthcare professional (HCP). More than half of people (58%) who had used cannabis products said they found cannabis as helpful or more helpful than other spasticity treatments.

The study was conducted in March 2023, with participants recruited through the MS Foundation network, and the results were reported at the ACTRIMS meeting.

After presenting their findings, the study’s authors concluded that spasticity may be under-assessed by many clinicians. They added, “Despite available spasticity treatments, patients still report an unmet need for proper management, and many may pursue non-traditional therapies like cannabis, often without the guidance of an HCP. Further exploration of optimal therapeutic strategies for MS spasticity is warranted.”

Might staying mum about an MS diagnosis cause changes to a person’s health?

An international team of researchers found that a higher degree of concealing an MS diagnosis is associated with a higher degree of anxiety and depression.⁶

The researchers had 263 people with MS complete the DISCO-MS measurement tool, which quantifies concealment behaviors and beliefs about the impact of disclosing a diagnosis, and the PROMIS-MS instrument, which has scales that assess several aspects of physical and mental health, social interaction, and quality of life.

After examining each study participant’s answers on the two instruments, the researchers found that people who concealed their diagnosis to a high degree also tended to have anxiety, depression, and a low degree of self-reported well-being. Similarly, people who had a higher anticipation of experiencing consequences from disclosing their MS tended to have poorer self-reported levels of physical and mental health, more sleep disturbances, and a higher perceived sense of stigma associated with MS.

The investigators concluded, “The issue of concealment and disclosure constitutes a major concern for [people with MS], the impact of which is only now becoming clear. Results of this study reveal potential consequences for multiple domains of function, overall physical and mental health, and quality of life. While raising awareness is important, implementing interventions that address this aspect of MS may be a key next step toward mitigating negative repercussions of the burden of disclosure.”

One such intervention might be for clinicians to routinely ask their patients about the extent to which they have shared their MS diagnosis with others and – while always respecting a patient’s autonomy and wishes in this regard – recognize a high degree of non-disclosure as a potential sign of depression and anxiety, following up accordingly.

Better sleep tied to better memory in people with MS

The old advice, “Remember to get enough sleep” might be recast for people with MS as “Get enough sleep to remember,” based on the results of a recent study.⁷

The study of 160 people with early-stage relapsing-remitting MS assessed sleep disturbances and memory dysfunction at baseline and then again three years later. Researchers wanted to see whether any link could be seen between changes in sleep and changes in memory.

To explore that connection, the investigators looked at the participants’ initial and Year 3 scores on the Insomnia Severity Index and divided the people into three groups: Improved (in terms of sleep), Stable, or Worsened over time. The researchers then examined the participants’ initial and Year 3 scores on two measures of verbal memory and two measures of non-verbal memory.

The 22 study participants whose sleep improved saw their verbal memory – but not their non-verbal memory – also improve relative to that of the 123 study subjects with no change in their sleep quality and the 15 people whose sleep worsened over time. The difference between groups was statistically significant. Researchers noted that changes in mood and fatigue were unrelated to changes in sleep.

The study’s authors, who are from the Icahn School of Medicine at Mount Sinai in New York City, noted, “Given the lack of validated treatments for memory deficits in MS, our findings highlight sleep disturbance as a potential [area for] intervention for some patients.”

Weight loss drugs and MS activity: Favorable findings from small study

The use of a newer class of drugs shown to reduce weight appears to be safe for people with MS, according to a small study conducted by researchers at Massachusetts General Hospital.⁸

The researchers evaluated the records of 33 people with MS who were taking glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic^® (semaglutide), Wegovy^® (semaglutide), and Mounjaro^® (tirzepatide). The patients had an average age of 53 years and 79% were female. They had an average duration of MS of 13 years, with 70% having relapsing-remitting MS. The participants’ average body mass index was 40 kg/m2, indicating severe obesity. Three-quarters of the people studied were taking a disease-modifying therapy during the period examined, with the largest single group receiving Ocrevus^® (ocrelizumab).

The study participants lost an average of 12 pounds, with individuals’ weight loss ranging from 10 pounds to 44 pounds. They took a GLP-1 receptor agonist for an average of 15 months, with a range of two to 58 months. None of the people had a clinical relapse while taking the weight-loss drugs, although two had new lesions on magnetic resonance imaging (MRI).

Twenty-four percent of the patients had gastrointestinal side effects while on the medications, including stomach pain, constipation, nausea, and vomiting, but none stopped their weight-loss medicine due to side effects.

The researchers concluded, “The GLP-1 class of drugs appears safe in the MS patient population in our experience. Future studies should query the effects of weight loss medications on mitigating MS risk and disease evolution.”

Study: Impact of MS on work seen even with mild impairment

MS exacts a considerable toll on work ability and productivity even in people in early stages of the disease, due in large measure to fatigue.⁹ That’s one of the main findings to emerge from an analysis of data provided by more than 1,000 people with MS enrolled in the North American Registry for Care and Research in MS (NARCRMS).

The 1,004 people had an average Expanded Disability Status Scale (EDSS) score of 1.5 – indicating a mild degree of MS-related impairment – when they enrolled in the registry. Sixty-nine percent reported that they worked full or part time. In answering questions about how MS had affected their work and other activities in the prior week:

• 31% said MS had impacted their work in some fashion
• 27% said MS had kept them from completing household chores
• 11% said it had kept them from work

Fatigue was the main MS symptom reported to affect work and household chores. Cognitive complaints and bladder disturbances were also reported, but neither complaint was statistically significant.

The researchers noted, “MS seems to impact patients from reaching their full potential at work/home from the earliest stages of this disease. Overwhelmingly, fatigue was identified as the cause. The impact of identifying an effective treatment for this symptom of MS cannot be overstated.”

Predictors of earlier onset of limiting pain in MS

Pain is, unfortunately, an extremely common consequence of multiple sclerosis, with the authors of a recent study noting that 70-80% of people with MS experience pain at some point in the course of their disease.¹⁰

But can certain factors predict which people with MS are most likely to experience limiting pain relatively soon after being diagnosed with MS? (“Limiting pain” may be described as pain that limits one’s mobility and/or other activities.) The study’s authors set out to answer that question by analyzing data on 241 people with MS who received care at the Cleveland Clinic between 2008 and 2015. The median age of the study participants was 36.7 years. Sixty-three percent of the people were female. Eighty-seven percent were white, while 11% were Black. All study participants were age 18 years of age of older, had no pain at baseline, and were diagnosed with MS within one year of experiencing symptoms.

Over an assessment period that lasted a median of 14 months, 118 (49%) of the participants developed pain. Ninety-six people reported minimal pain, while just two reported severe pain. The remainder of the 118 people affected had mild or moderate pain.

The researchers found that women were 1.5 times more likely than men to report earlier development of limiting pain. This difference between sexes was statistically significant. Black people were almost three times more likely than white people to have early, limiting pain, with the difference again being statistically significant. Being a current smoker also was associated with a higher likelihood of earlier development of limiting pain relative to never having smoked.

Another important finding was that people who were single and those who had private insurance coverage or self-pay coverage were more likely than married people and Medicare/Medicaid plan participants, respectively, to experience later development of limiting pain. Those differences also were statistically significant.

Of course, pain can affect anyone with MS at any time and ultimately will affect most people with this neurological condition. Regardless of whether you are or are not in one of the groups shown in this study to be at increased risk for earlier development of limiting pain, it is important to talk with your clinician about any pain you are experiencing. While no “magic cure-alls” exist, several practical strategies and medication regimens are available for managing pain in a safe, effective way.

Analyzing stool samples for predictors of clinical worsening in MS

Stool samples long have provided physicians with clues to the presence of diseases ranging from colorectal cancer to parasitic infection. Now, a team of researchers from Harvard Medical School suggests that analyzing stool may also help clinicians predict which people with MS are likely to experience clinical worsening.¹¹

The researchers measured levels of serum glial fibrillary acidic protein (GFAP) – a substance that has been shown to predict disease worsening in MS – in 26 healthy controls, 61 people with relapsing-remitting MS, and 28 people with progressive forms of MS.

Two years after the study participants provided stool samples, researchers determined the people’s Expanded Disability Status Scale (EDSS) scores. They also had the study subjects complete the Symbol Digit Modality Test (SDMT), which assesses cognitive function, and the NeuroQoL, which measures quality of life in people with neurological conditions.

The investigators found that stool levels of GFAP in people with progressive MS were 87% higher than in those with relapsing forms of the disease and 103% higher than in healthy volunteers. Those differences were statistically significant. Stool GFAP levels also correlated with baseline EDSS scores, an increase in EDSS score (indicating worsening) over two years, and worsening over two years for several components of the NeuroQoL instrument, including lower-extremity function, cognitive function, and anxiety, with those changes also being statistically significant.

The findings suggest that clinicians and patients one day may have another reliable means of predicting the course of an individual’s MS, which can be valuable in selecting disease-modifying therapies and in making plans for everything from financial arrangements to home modifications.

Additionally, the study offers indirect insights into the MS disease process, particularly in terms of the role played by the gut. The researchers note, “These data open the door for further investigation into enteric glial signaling throughout the MS disease course.”

References

1. Petrou P, Kassis I, Yaghmour N, et al. Effects of repeated autologous mesenchymal stem cell transplantation on cognition and serum biomarkers in progressive MS: interim analysis of an open label extension trial. ACTRIMS 2024. Session LB1.

2. Marian LM, Harris KA, Conway DS. Wearing-off effects with monoclonal antibodies for multiple sclerosis. ACTRIMS 2024. Abstract P515.

3. Paredes D, Sisodia N, Henderson K, et al. Disease progression despite early high efficacy therapy in multiple sclerosis patients: demographics and clinical predictors. ACTRIMS 2024. Abstract P464.

4. DeLuca J, Naismith RT, Morrow SA, et al. Changes in cognitive functioning over 1 year in ozanimod-treated patients with early relapsing multiple sclerosis: an interim analysis of the ENLIGHTEN Study. ACTRIMS 2024. Abstract P354

5. Newsome S, Bandari DS, Fox L, et al. Shifting the perspective in spasticity in multiple sclerosis – taking the patient viewpoint on diagnosis and treatment. ACTRIMS. P518.

6. Leavitt VM, Bae C, Shinohara R, et al. Diagnosis concealment behavior and disclosure beliefs are associated with health and quality of life in people with multiple sclerosis. ACTRIMS 2024. Abstract V457.

7. Levy S, Graney R, Sumowski JF. Longitudinal evidence linking improved sleep with better memory in multiple sclerosis. ACTRIMS 2024. Abstract P358.

8. Udawataa M, Fidalgo NM, Patel A, Mateen FJ. Multiple sclerosis patients on glucagon-like peptide-1 (GLP-1) receptor agonists for obesity: cohort study. ACTRIMS 2024. P118.

9. Rammohan K, Mao-Draayer Y, Li D, et al. The economic impact of MS: a preliminary look at NARCRMS. ACTRIMS 2024. Abstract P383.

10. Amin M, Toljan K, Ontaneda D, et al. Predictors of pain in multiple sclerosis. ACTRIMS 2024. Abstract P434.

11. Schwerdtfeger LA, Monitni F, Ekwudo MN, et al. Stool protein biomarkers of MS with predictive value for clinical worsening. ACTRIMS 2024. Abstract P052.

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