What’s New in MS Research – January 2022
Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD
Progress on many fronts – from early imaging assessment of MS-related brain changes to early-stage trials of intriguing investigational therapies – is highlighted in this edition of “What’s New in MS Research.”
With January 2022 marking the two-year anniversary of the first COVID-19 case diagnosed in the United States, it is perhaps fitting that the initial item in this month’s edition focuses on the impact of disease-modifying therapies (DMTs) on response to vaccination against COVID. Beyond examining the many nuances of that issue, the other study synopses that follow examine topics including light therapy for treating fatigue in MS, how pregnancy affects a woman’s chances of developing multiple sclerosis, new research into blood levels of an emerging MS biomarker called neurofilament light chain (NfL), and more.
As the breadth of research summarized below illustrates, there are many facets to multiple sclerosis. We hope this information provides new insights into this intriguing research.
Since the outbreak of the COVID-19 pandemic, people with MS have had to contend with concerns about how their neurologic condition and its treatment(s) might affect their susceptibility to COVID-19, as well as the course of their MS, treatments, and COVID severity, should they become infected. Additionally, many questions also arose regarding COVID-19 vaccines and their effectiveness while taking a DMT.
Studies examining those questions have emerged steadily over the last two years, and have offered mostly encouraging, if often nuanced, findings. One of the latest studies on the topic continues that tradition of providing largely reassuring but somewhat involved results.
Researchers in the United Kingdom examined dried blood spot samples from 473 people with MS, testing those samples for antibodies to SARS-CoV-2, the scientific name for the virus that causes COVID-19.1 [Tallantyre] They also collected data on the study subjects’ vaccine history, medical history, and MS-treatment history, as well as other information. They then employed sophisticated statistical analyses to explore the impact of type of MS treatment, vaccine timing, and other factors on response to vaccination against COVID-19.
Using study subjects who had not received any disease-modifying therapy (DMT) as a reference point, the investigators looked at rates of post-vaccination seroconversion – meaning development of antibodies to SARS-CoV-2 – in people taking various DMTs for their MS. They found that the rates of seroconversion in people taking most DMTs were not significantly different from the rate for people who had not received a DMT.
They did, however, identify lower rates of seroconversion in patients taking Gilenya® (fingolimod) or an anti-CD20 monoclonal antibody, such as Ocrevus® (ocrelizumab). Among people taking anti-CD20 monoclonal antibody therapies – which work by depleting B cells, a component of the immune system – seroconversion rates were lower among people who had received treatment within five months of their initial COVID-19 vaccination compared to those who received their first vaccination seven months or more after their last DMT treatment.
In considering these findings, it is important to remember that the immune system has many “lines of defense” against infection. The investigators highlighted this point by examining T-cell response – another important component of immunity – in 16 study subjects who did not have a serological response, i.e., developing antibodies, following a full course of vaccination against SARS-CoV-2. Of the six people in that group receiving Ocrevus, four had a positive T-cell response, which the researchers said “provides some potential reassurance.”
Based on their findings, the study’s authors called for consideration of delaying initial treatment with anti-CD20 monoclonal antibodies and Gilenya until people can be vaccinated against COVID-19. They added that their study raised questions about the optimal timing of follow-on treatment with already initiated anti-CD20 monoclonal antibodies relative to COVID-19 vaccination.
The study’s findings are reason for people taking an anti-CD20 monoclonal antibody or Gilenya to talk with their clinician about treatment timing in terms of any needed COVID-19 vaccinations, including booster shots. However, they are not a reason to unilaterally change an appointment for treatment or otherwise alter the approach to MS care without close consultation with a clinician.
Turning up the lights each morning may be a way to turn up energy levels in people with MS who are experiencing fatigue, according to a recent study by Austrian researchers.2
The investigators conducted a six-week study involving 21 people with MS who had high scores on the Fatigue Severity Scale (FSS). For the first two weeks, all study subjects recorded their baseline level of fatigue through use of a visual analog scale (VAS) questionnaire completed four times each day. This type of scale provides a visual line with each question, extending between two extremes, such as “none of the time” to “all of the time,” for participants to mark their degree of difficulty with a certain fatigue-related issue. It is thought to be less restrictive than filling in a blank or choosing from multiple-choice options. Study participants also completed the FSS at the start and end of this two-week period and at other key points in the study.
During the next two weeks, 11 of the study participants had daily morning exposure to a bright white light, while the other 10 study subjects were exposed to a dim red light each morning. All study subjects again recorded their fatigue levels during this time, as they did during the last two weeks of the study, which served as a “washout” period in which neither group had light therapy.
People in the bright light therapy group reported less fatigue during the two weeks they were exposed to white light each morning, while the people in the dim red light group did not report reduced fatigue during this period. Notably, however, two weeks after the treatment period ended, the bright light group had no lasting reduction in fatigue, suggesting that the benefits of this approach may require “keeping the lights on.”
A new magnetic resonance imaging (MRI) technique developed by Austrian researchers may allow early identification of changes in the brain metabolism of people with MS, enabling clinicians to tailor treatment accordingly.3
MRI scans already play a critical role in diagnosing MS and monitoring its course, with the imaging currently used to identify focal white matter lesions that indicate demyelination, a hallmark of MS. However, the Austrian investigators explain that these images “represent only macroscopic [large-scale] tissue damage and are therefore unable to fully explain the topographic origin and severity of many clinical symptoms of MS, particularly in the progressive phase of the disease.”
To explore metabolic factors potentially linked to MS symptoms, those investigators employed a technique called proton MR spectroscopy to measure levels of several metabolites in the brain. Metabolites are substances created when the body carries out biochemical processes, such as breaking down nutrients to use for energy or creating molecules needed for growth.
Earlier research has shown that people with MS often have levels of various metabolites that differ significantly from the levels found in other people. For example, levels of the metabolite N-acetylaspartate (NAA) often are lower in people with MS than in the general population, while levels of myo-inositol (mI) are elevated. Because NAA is present mostly in neurons, lower levels of the metabolite in people with MS may reflect loss or impairment of those nerve cells.
The researchers recruited 65 people with MS and 20 people without MS for their study. They then matched the people with MS and healthy controls by age and sex, and used magnetic resonance with a very powerful magnet to assess the presence of NAA, mI, and other metabolites in their brains.
The investigators identified several differences between the two groups. People with MS had higher signal intensity for mI in normal-appearing white matter than the control group, regardless of NAA signal intensity. They also had a higher ratio of mI to total levels of the metabolite creatinine in white matter found in a part of the brain called the centrum semiovale. Further, compared to healthy controls and people with MS who did not have disabilities, study participants with MS who had disabilities had a lower ratio of NAA to total creatinine in both normal appearing white matter and cortical grey matter. Finally, in people with MS, there was a correlation between the ratio of mI to NAA and Expanded Disability Status Scale (EDSS) scores.
Summarizing their findings, the researchers wrote that the MR spectroscopic imaging technique they used “can help to depict and visualize pathologic manifestations of multiple sclerosis beyond focal demyelinating lesions that are associated with clinically measured disability. Taking these previously invisible changes into account could enhance measures for ongoing disease activity, thus improving the monitoring of disease progression and efficacy of current treatment and supporting decision-making for treatment switching.”
While the prospect of having an earlier measure of disease activity to guide treatment decisions is exciting, it should be noted that much more work needs to be done to map out how a particular finding on MR spectroscopy might translate into a specific treatment strategy. Further, the magnet the researchers used in their study is far more powerful than those available at most MS centers today.
On the Tesla scale used to denote a magnet’s power, the device the researchers used is a 7.0 Tesla, while most magnets used for imaging in clinical care today are 2.0 or 3.0 Tesla. As a result, for the foreseeable future, access to such assessments is likely to be limited to people participating in research at major academic medical centers. Nonetheless, the study raises the prospect of eventually offering people far more individualized care delivered at an early stage in their MS.
While emerging techniques such as MR spectroscopy promise to enhance the diagnostic value of magnetic resonance imaging (MRI) in the years ahead, a study suggests that there are benefits to be realized right now simply by increasing adherence to guidelines for use of currently available MRI modalities.
Researchers from Belgium and Canada reviewed 140 imaging sessions involving 58 different scanners and 83 people with MS to see how often the imaging was performed in accordance with 2018 guidelines issued by the Consortium of Multiple Sclerosis Centers (CMSC).4 Those guidelines, developed by a panel of experts, outlined the preferred approaches to obtaining various types of 3D – or, if 3D imaging was not available – 2D views of the brain.
The researchers found that just over one-half of the imaging studies they reviewed conformed to the recommended approaches. They concluded, “A higher compliance with the guidelines would provide more confidence in the use of brain MRI for diagnosis and follow-up of patients with MS.”
Neurofilament light chain (NfL) is a protein released into the blood and cerebrospinal fluid following damage to neurons and axons in multiple sclerosis and other neurologic diseases. In recent years, researchers have assessed the role of blood levels of this protein – or serum NfL – in diagnosing MS and predicting disease course.
One of the latest studies involving the biomarker examined whether it might be able to predict cognitive status in people with multiple sclerosis.5
Eighty-six people participated in the study. Fifty-one were females. The average age of study participants was 47 years, and the average duration of MS was 13 years. Based on neuropsychological examinations, 49 of the people were considered cognitively impaired, while 37 were deemed cognitively preserved.
The researchers found higher levels of serum NfL in the people who were cognitively impaired compared to those who were not. The difference between the groups in serum NfL levels was statistically significant. People in the cognitively impaired group also had higher blood levels of glial fibrillary acidic protein (GFAP), another biomarker of neurodegeneration.
The findings address an important topic, as 40% or more of people with MS eventually experience some degree of cognitive issues. However, while the study represents a valuable addition to the growing body of scientific knowledge in this area, far more research is needed to help clinicians understand how best to incorporate serum NfL values into their decision-making.
The optimal diet for people with MS is an evergreen and ever-evolving topic of debate, with the discussion reinvigorated with each new study on the subject.
One of the latest such studies examined how caloric restriction and an adapted ketogenic diet affect serum levels of neurofilament light chain (NfL). As noted in the immediately preceding item, NfL is a protein that enters the blood and cerebrospinal fluid in the aftermath of damage to neurons and axons. Caloric restriction entails consuming a fixed amount of calories each day, with the limit set well below typical American norms. A ketogenic diet is a high-fat, adequate protein, low-carbohydrate eating plan. Advocates of the ketogenic diet support its use in helping to control seizures in children with epilepsy who have not responded well to antiepileptic drugs.
A team of German researchers tracked serum NfL levels over six months in 17 people with MS who were on an adapted form of the ketogenic diet, 14 people with MS on a caloric restriction eating plan, and a control group of nine people with MS not following any particular diet.6
At the end of the six months, the people on a ketogenic diet had significantly lower serum NfL levels than they did at the start of the study (7.1 pg/mL, compared to 8.5 pg/mL at baseline). The change was statistically significant. Meanwhile, sNfL levels in the caloric restriction and control groups did not change significantly over the six-month study period.
While the results are intriguing, three caveats need to be kept in mind. First, this was a small study. Second, while serum NfL is emerging as a biomarker for assessing multiple sclerosis, its exact role in MS management has yet to be established. Third, the ability to change levels of a biomarker does not necessarily equate to an ability to change disease course. Nonetheless, this study reinforces the importance of being thoughtful about eating choices.
Much of the research into pregnancy and multiple sclerosis has focused on how conceiving and bearing a child may affect disease course in women already diagnosed with MS.
Recently, however, a team of German researchers examined whether a history of pregnancy may reduce a woman’s chances of subsequently being diagnosed with MS. Their answer: Apparently so.7
The investigators conducted a retrospective, case-control study in which they reviewed data on 5,720 women with MS and 26,729 women without MS. They reviewed those women’s health records to identify which contained one or more of 18 medical codes related to pregnancy. They found that pregnancy-related codes – indicating that the individual had been pregnant at some point – appeared less frequently in the records of women with MS than they did in the records for women in the control group.
“Our findings provide evidence for a protective effect of pregnancies on MS risk,” the researchers noted.
On a related note, a separate team of investigators found that changes in magnetic resonance imaging (MRI) of the brain in the year before pregnancy are predictive of early post-partum relapses in women with MS. Their findings were derived from a retrospective study of 172 pregnancies in 118 women with MS.8
“An active MRI pre-pregnancy is a strong and sensitive predictor of early post-partum relapse, regardless of whether the woman had clinical evidence of disease activity prior to conception and delivery,” the researchers said, adding, “this finding could provide clinicians with a strategy to minimize post-partum relapse risk in women with MS planning pregnancy.”
Two companies developing novel therapies to treat multiple sclerosis (MS) recently took key steps forward in conducting Phase I studies of their investigational medications. Phase I trials generally are the first studies conducted in humans following encouraging results in laboratory research or animal studies. The early-stage trials typically focus on assessing safety and identifying the optimal dose range for treatment.
Anokion SA, a Swiss biotechnology company with US offices in Cambridge, Massachusetts, announced this month that it has initiated patient enrollment in the multiple ascending dose portion of its MoveS-it trial. (In multiple ascending dose trials, separate groups of study subjects begin by taking different initial doses of a medication, with those starting doses then increased to assess whether and when people experience side effects or have difficulty tolerating the therapy.)
The MoveS-it trial is a randomized, double-blind, placebo-controlled Phase I trial of ANK-700 for the treatment of relapsing-remitting MS. In a press release, the company explained that ANK-700 is designed to “re-educate the immune system by introducing antigen-specific tolerance to myelin-based autoantigens in order to reduce neuroinflammation in the brain and spinal cord.” The company added that preclinical data in mouse models of MS supported the potential for ANK-700 to slow disease progression in MS.9
Anokion said that it expects to report initial results from the trial in the second half of 2022.
Meanwhile, NervGen Pharma announced in late December that it had received ethics board approval to proceed with the multiple ascending dose portion of the Phase I trial of its investigational therapy NVG-291.10 The company, which is based in Vancouver, British Columbia, said, “In preclinical studies, NVG-291 has been demonstrated to promote repair mechanisms in the nervous system, including axonal regeneration, remyelination, and enhanced plasticity.” NervGen added that it is screening healthy volunteers for the study, and expects to begin administering doses to them early this year.
In the multiple ascending dose portion of the trial, study subjects will receive NVG-291 or placebo in a blinded fashion once daily for 14 days. The company said it expects to complete the three planned dose cohorts in the first half of this year.
NervGen describes NVG-291 as a therapeutic peptide that mimics the activity of a cell surface receptor involved in regulating central nervous system repair. The company has plans to evaluate NVG-291 for a potential role in treating spinal cord injury and Alzheimer’s disease, as well as multiple sclerosis.
“What are the chances that I’m going to go on to have MS?”
It’s one of the first questions people ask after being told that they have radiologically isolated syndrome (RIS) – imaging identification of lesions characteristic of multiple sclerosis in the absence of MS symptoms. RIS often is diagnosed when magnetic resonance imaging (MRI) is ordered for an unrelated reason – such as to evaluate a person who has been in a car accident – and incidentally shows spinal or brain lesions indicative of the demyelinating process that marks MS.
A 2020 study found that roughly half of people with RIS will have a clinical event indicative of MS within 10 years of the MRI that first showed MS-like lesions.11 That finding prompted a focus on identifying which people with RIS are most likely to convert to MS, particularly in the first few years after an MRI yielded telltale signs of the disease.
Now, researchers have identified three characteristics associated with conversion to MS within two years of an RIS diagnosis:
- Being younger than 37 years
- Having spinal cord lesions
- Having gadolinium-enhancing lesions on the MRI that prompted the diagnosis of RIS12
Those findings were based on an analysis of 372 people with RIS. Forty-nine of the people studied – or 19% — had a clinical event suggestive of MS within two years of their RIS diagnosis. Among study subjects who had two of the three characteristics identified, the two-year risk of conversion was 27.9%, while that risk rose to 90% for those who had all three risk factors.
With several DMTs approved for use in MS now being studied in RIS, these findings may add to the case for initiating therapy in selected patients who, while asymptomatic, have concerning MRI findings.
The “hall walk” is a time-honored, time-focused approach to evaluating how MS is affecting a person’s mobility. Recording how long it takes a person to walk 25 feet down a corridor in a medical office provides clinicians with a simple, easily repeated way to track a patient’s status over months and years.
To answer that question, researchers from the University of South Florida recently conducted a retrospective analysis of data from 772 clinic visits involving more than 250 people with MS. In 78 of those visits, the time it took people to walk 25 feet was 20% or more longer than their previous visits. The researchers found that 60% of the people who had a significant increase in their walking time had an unstable neurological examination in roughly the same time period. By contrast, only 44.5% of people without a significant change in their walk time had an unstable neurological examination.13
Based on this difference, the researchers concluded, “The T25FW has long been considered one of the best clinical measures to quantify MS disability over time. Our research adds to this body of evidence by showing that a clinically meaningful change in the T25FW correlated with worsening of the neurologic examination. Given its ease of use and relationship to MS-related disability, we strongly encourage the use of the T25FW in routine clinical practice.”
1 Tallantyre EC, Vickaryous N, Anderson V, et al. COVID-19 vaccine response in people with multiple sclerosis. Ann Neurol. 2022;91:89-100.
2 Voggenberger L, Boeck M, Leutmezer F, Moser D, Seidel S. Bright light therapy as a non-pharmacological treatment option for fatigue in multiple sclerosis. Poster P201. ECTRIMS 2021.
3 Heckova E, Dal-Bianco A, Strasser B, et al. Extensive brain pathologic alterations detected with 7.0 MR spectroscopic imaging associated with disability in multiple sclerosis. Radiology. 2022. https://doi.org/10.1148/radiol.210614.
4 Vercruyssen S, Kolind S, Au S, et al. Compliance of real-world dataset with the Consortium of Multiple Sclerosis Centers 2018 guidelines. Poster IMG12. CMSC 2021.
5 van Dam M, Willemse EA, Nauta IM, et al. The role of serum biomarkers in predicting cognitive status in people with multiple sclerosis. Poster P070. ECTRIMS 2021.
6 Bock M, Steffen F, Zipp F, Bittner S. Impact of dietary intervention on serum neurofilament light chain in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022;9:e1102. doi:10.1212/NXI.0000000000001102.
7 C. Gasperi, A. Hapfelmeier, A. Schneider, E. Donnachie, B. Hemmer. Pregnancies are associated with lower risk of multiple sclerosis. Poster P162. ECTRIMS 2021.
8 Lehman H, Zveik O, Levin N, et al. Brain MRI activity during the year before pregnancy can predict post-partum clinical relapses. Poster P186. ECTRIMS 2021.
9 Anokion SA. Anokion announces progress across pipeline of novel autoimmune programs. January 6, 2022. Available at https://www.businesswire.com/news/home/20220106005288/en/Anokion-Announces-Progress-Across-Pipeline-of-Novel-Autoimmune-Programs. Accessed January 9, 2022.
10 NervGen Pharma Corp. NervGen Pharma receives ethics board approval for multiple ascending dose portion of NVG-291 Phase 1 trial. https://www.nervgen.com/2021/12/nervgen-pharma-receives-ethics-board-approval-for-multiple-ascending-dose-portion-of-nvg-291-phase-1-trial/. December 22, 2021. Accessed January 10, 2022.
11 Lebrun-Frenay C, Kantarci O, Siva A, et al. Radiologically isolated syndrome: 10-year risk estimate of a clinical event. Ann Neurol. 2020;88:407-417.
12 Lebrun-Frenay C, Rollot F, Mondot L, et al. Risk factors for early clinical conversion in radiologically isolated syndrome. Poster P125. European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Annual Meeting, 2021.
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