What’s New in MS Research – September 2022

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

If there’s one theme that emerges from the study findings that follow, it’s how much people with multiple sclerosis (MS) can do to enhance their health and wellbeing. We know that can be a challenging task, as many aspects of the disease and its course remain beyond a person’s control. Nonetheless, the research summarized here provides abundant reason for encouragement.

Key findings include:

• A major survival benefit from adhering to disease-modifying therapy (DMT)
• An association between receiving regular preventive care and staying out of the hospital
• The ability to reduce fatigue through exercise
• The impact of a high efficacy DMT on cognitive processing speed
• A potential new way to improve balance

Other studies included in this article look at a change in the average age of MS symptom onset, the potential protective effects of having been breastfed as an infant, factors contributing to COVID-19 severity in people with MS, and what the timing of epileptic seizures may signal about MS disease course.

Study: DMT adherence associated with significantly increased odds of survival

Veterans with MS who adhered to their disease-modifying therapies (DMTs) were 7.5 times more likely than their counterparts who did not follow their treatment regimens to reach the end of a long study period, researchers report.¹

The investigators analyzed 279 people with MS who were treated at the Oklahoma City Veterans Affairs Medical Center between January 1, 2000 and December 31, 2019. Forty-two percent of the veterans, or 118 patients, had good adherence to their treatment regimen, while 4.7% (13 people) had poor adherence, and 53% (148 people) were not adherent to any DMTs they were prescribed.

At the time of data analysis, the researchers found that 94.9% of the people who faithfully took their DMTs were alive, as opposed to 66.9% of those who were not adherent. After adjusting for factors that affect MS-related survival, such as age at study entry, type and duration of MS, body mass index and the presence of diabetes, the risk of death was 7.5 times greater in the non-adherent group than in the adherent group. Without adjusting for those factors, the odds of being alive were 12 times higher for the adherent patients.

The study was marked by certain limitations. Eighty percent of the people assessed in this Veterans Affairs Medical Center study were men, while the majority of people with MS are women. Additionally, with 279 subjects, the study was relatively small. At the same time, the study had the advantage of being able to draw on medical information over a long period of time – the average person who was alive at the time of data analysis had been followed for more than eight years and those who had passed away had been followed for an average 12.2 years.

A large and steadily growing body of evidence confirms the benefits that DMTs provide in terms of MS, such as reducing relapses and slowing disability progression. This study – which looked at death from all causes, not just those directly or indirectly related to MS – establishes an association between regular DMT use and an increased likelihood of survival. While the study did not address factors that might explain this association, it adds to the case for staying on your DMT regimen “for the long haul.”

Examining what lands people with MS in (and back in) the hospital

Avoiding preventable hospitalizations and hospital re-admissions soon after discharge is a major public health goal and is obviously important to patients, healthcare providers, and insurers.

Two recent studies looked at the rate of potentially preventable hospitalizations in people with MS and the reasons those people were re-admitted within 30 days of discharge.^2,3

The first study analyzed information on 6,198 people with MS who were matched to those with similar characteristics (age, sex, etc.) but who did not have MS.²

The researchers found that people with MS had a rate of potentially preventable hospitalization (PPH) twice that of their counterparts (131.6 per 10,000 people vs 62.5 per 10,000). People with MS were almost five times more likely than the matched group to be hospitalized for urinary tract infections and 1.65 more likely to be hospitalized for pneumonia. Those findings underscore the need for efforts to avoid infection and to seek medical attention promptly when symptoms of infection arise, so that early treatment can hopefully prevent more severe illness and the need for a hospital stay.

The importance of proactivity was reinforced by the study’s finding that receiving various types of preventive care reduced the likelihood of hospitalization. For example, people with MS who had annual wellness visits were about 40% less likely to be hospitalized than those who did not get a yearly check-up.

The second study drew on the federal government’s Nationwide Readmissions Database to examine rehospitalization trends among people with MS in 2017.³

Researchers found that 10.6% of people with MS who had a hospital stay that year were re-admitted within 30 days of discharge. Men were more likely to be re-admitted than women. Not surprisingly, people with MS who also had one or more other serious conditions – including heart failure, substance abuse, diabetes, cancer, and depression – were at an elevated risk for re-admission.

Infectious diseases and neurologic conditions were the most common reasons for readmission, representing 24.8% and 14.5% of all cases, respectively. Septicemia, or a bacterial infection in the bloodstream, was the most common specific reason for re-admission, representing 15.4% of all return hospital stays.

Fatigue in MS: New findings on IgG levels, exercise regimens, and stem cell transplants

Hypogammaglobulinemia, a word whose very pronunciation is enough to tire one out, may be a culprit in the fatigue that affects so many people with MS, according to a recent study by Swiss and Greek researchers.⁴

The multi-syllabic term describes low levels of immunoglobulin G, or IgG, an antibody in the body’s immune system that protects a person from bacterial or viral infections. Past research has shown that between 8% and 25% of people with multiple sclerosis are affected by the condition; these rates are higher than those seen in the general population.

In evaluating 134 people with MS who were receiving care in Bern, Switzerland or in Athens, Greece, the researchers found that 72% reported fatigue. Using sophisticated statistical analytical methods, the investigators found associations between low IgG levels and fatigue, daytime sleepiness, and depressive symptoms. When they explored further, they found that the impact of hypogammaglobulinemia remained significant in those people who reported fatigue but who did not experience daytime sleepiness or a depressive mood.

While the researchers note that they have identified an association between low IgG levels and fatigue, this is not a direct cause-and-effect relationship. However, if further studies show that hypogammaglobulinemia does contribute to fatigue in MS, it could open the door to treating people with MS with IgG replacement delivered intravenously or by subcutaneous injection.

While the feasibility of treating MS-related fatigue with immunoglobulin G replacement will need to be determined in the years ahead, another study suggests an immediately available remedy: high-intensity resistance training.⁵

Of course, the idea of treating fatigue with any exercise regimen, much less a high-intensity one, seems paradoxical, but a trio of Swedish investigators are just the latest in a long line of researchers to show that being active is an effective antidote to being tired.

The Swedish team recruited 71 people with MS whose scores on the Fatigue Scale for Motor and Cognitive Functions (FSMC) indicated a high degree of fatigue. They assigned half of the study participants to twice-weekly supervised high-intensity resistance training (HIRT) and the other half to once-weekly HIRT sessions. After 12 weeks, the people in the twice-weekly group had a greater average reduction in their FMSC scores than people in the weekly group, although the difference was not statistically significant. The twice-a-week group also had greater improvement in measures of anxiety and overall psychological status, and the difference between groups on these measures was statistically significant.

Moving east across the Baltic Sea from Sweden to Lithuania, and from high-intensity resistance training to high-tech medical interventions, researchers at the Vilnius Medical Center found that autologous hematopoietic stem cell transplantation (AHSCT) improved fatigue in 18 people with MS.⁶

The patients all had highly active relapsing MS. Their mean age was 36.3 years and 83% were female. They underwent procedures in which their own (autologous) stem cells – those with the potential for developing into various types of blood cells (hematopoietic) – were removed from their bodies and treated. The patients then underwent high-dose immunosuppression to allow a “resetting” of their immune system once the stem cells were infused back into their bodies.

The researchers found a statistically significant improvement in physical functioning and vitality, as well as a reduction in pain at three months post-transplant, with the improvement in fatigue scores maintained at one year and two years after the procedure. Measures of health-related quality of life also showed improvement.

While fatigue is widespread in multiple sclerosis, this research highlights the fact that a wide range of potential responses – from exercise to stem cell transplantation, with many lifestyle approaches and treatments in between – may help ease this very common and very significant aspect of MS.

Tysabri^® shows cognitive benefits in early relapsing MS in long-term study

The disease-modifying therapy Tysabri^® (natalizumab) improved cognitive processing speed in a four-year study involving 222 people with relapsing-remitting MS.⁷

The prospective, open-label study was conducted at several centers and had a single-arm design, meaning that all participants received Tysabri, rather than some being assigned to take Tysabri while others took another disease-modifying therapy (DMT) or placebo. All patients had early MS and were negative for the anti-JC virus antibody. (Tysabri has been shown to increase the risk of progressive multifocal leukoencephalopathy [PML], an opportunistic viral infection of the brain that usually leads to death or severe disability if not found early, when the DMT is taken by people who have the anti-JC virus antibody.)⁸

Study participants completed the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed, at four annual visits. At each of the annual visits, a large proportion of study subjects – ranging from 41.9% to 54% – showed a clinically meaningful improvement of at least four points on the test.

Other tests showed that there was an improvement in quality of life over all four years as well as a reduction in the impact MS had on participants’ regular activities.

The study adds to the evidence showing that high-efficacy DMTs such as Tysabri offer benefit when prescribed early in MS, rather than being reserved for use later in the course of disease, and can have a positive impact on cognition.

Textured insoles shown to aid balance in people with MS

Wearing shoes with a ground-gripping pattern on their soles is a long-established strategy for anyone who faces balance and walking challenges, but new research suggests there is further benefit to be gained from having the feet be in contact with a textured surface inside the shoe.⁹

Researchers assessed balance and walking in 41 people with MS as those people used different insole options (a) a novel textured insole, (b) a smooth insole, (c) shoes only, or (d) went barefoot. They had the study participants balance themselves on a firm surface and on foam, both with their eyes open and closed. The researchers also had the participants walk on even and uneven surfaces.

They found that wearing textured insoles led to reductions in center of pressure (CoP) velocity measures – essentially meaning an improvement in balance – when people had their eyes open and also when their eyes were closed. However, with regard to improving gait patterns, the use of textured insoles was not shown to be consistently superior to using smooth insoles or shoes without insoles.

The researchers concluded that “textured insoles offer a potential new treatment technique for balance rehabilitation in [people with MS] who show early signs of diminished foot sensation.”

Identifying factors that contribute to COVID-19 severity in people with MS

Being older, being a male, having a progressive form of MS, having a greater degree of disability, and being treated with a disease modifying therapy (DMT) that targets the CD20 protein on the surface of B cells, are all associated with more severe COVID-19 infections, according to the latest results from an international study.¹⁰

Those findings emerged from an analysis of data on 5,648 people with MS living in 27 different countries. Eighty-three percent of those patients had confirmed cases of COVID-19, while the remaining 17% had suspected cases.

Most of those risk factors for severe COVID-19, such as sex and age, are beyond a person’s control, but they serve to identify people who should be particularly careful about trying to avoid infection and who should seek prompt medical attention if they develop COVID symptoms.

Meanwhile, although anti-CD20 medications are associated with a greater risk for severe COVID-19 than other DMTs, they also are generally considered to have higher efficacy against MS than many DMTs with other mechanisms of action. As a result, this research reinforces the importance of people with MS talking with their clinician to examine the risk-benefit considerations that apply specifically to them and to agree on an informed, individualized treatment plan.

A reported change in the average age of onset for relapsing-remitting MS

The average age at which symptoms of relapsing-remitting MS appear has risen more than 10 years over the past five decades, according to a team of Spanish researchers.¹¹

Examining data on 1,622 people who experienced their first symptoms of MS between January 1970 and December 2019, the investigators found that the average age of onset increased from 23.8 years in the 1970s to 34.3 years in the 2010s.

The average ages by decade were:

• 1970 to 1979: 23.79 ±10.19 years
• 1980 to 1989: 27.86 ±9.22 years
• 1990 to 1999: 30.07 ±9.32 years
• 2000 to 2009: 32.12±9.47 years
• 2010 to 2019: 34.28±9.83 years

The researchers reported that this trend was seen in both men and women, and that their findings held up in analyses conducted once patients with early-onset and late-onset disease had been excluded.

It is important to note that the study focused on age at symptom onset rather than age at diagnosis. Diagnosis may follow an initial symptom by months or years, although that gap hopefully is closing given greater awareness of MS and improved diagnostic approaches.

Although the study did not investigate the reasons for this trend, the researchers cited several possible explanations, including:

• changes in diagnostic criteria that may have enhanced the ability to identify MS in relatively older people
• a reduction in smoking, which has been identified as a risk factor for MS
• increased sun exposure may also be a significant influence because it enhances the body’s production of the active form of Vitamin D. Low levels of Vitamin D have been implicated in increased risk for MS

Epileptic seizures and the course of MS: A question of timing

Editor’s note: readers should keep in mind that the percentage of individuals with MS who experience a seizure is extremely low and is not typically associated with MS.

Researchers long have known that people with multiple sclerosis are at elevated risk for epileptic seizures, but they haven’t fully understood how seizures affect the outlook for a person’s MS.

A recent study from France provides new information on that score and suggests that when people with MS begin experiencing seizures can help predict what awaits them.

Investigators analyzed data on 6,238 people with MS who live in Lorraine, a region in northeastern France. Just 2% of those people, or 134 patients, had experienced one or more epileptic seizures. Of those people, 82 had seizures that were deemed secondary to MS, while the remainder had seizures unrelated to their MS.

Focusing on the first group, those with seizures related to MS, the investigators found that people whose seizure was an initial symptom of their MS went on to experience the same disease progression as other people with relapsing-remitting MS. By contrast, those who began having seizures later in the course of their MS were more likely to go on to higher levels of disability than others with MS who had not experienced a seizure.
Meanwhile, patients with a history of seizures not related to their MS had worse outcomes than other people with MS but no seizures.

Based on their findings, the researchers concluded that the development of seizures after the early stages of multiple sclerosis is indicative of MS severity.

Scratching the surface of chronic itch in people with MS

More than one-third of people with MS participating in a small study reported experiencing chronic itch, or pruritis.¹²

The authors of the study, which was conducted at the University of Miami, explained that they undertook the research because “little is known about the prevalence of itch in multiple sclerosis.” To remedy that information gap, the investigators interviewed 77 people with MS, asking about their symptoms. Twenty-seven of the study participants (35% of the total) reported ongoing itch.

Among those with chronic pruritis, the average itch severity was 5.42 on a scale of 0 to 10. The extremities, face or scalp, and trunk were the areas of the body most affected by itch. Fifty-two percent of people said that heat aggravated their itch, while cold temperatures did not appear to be a factor.

Compared with people with MS who did not experience itch, those reporting pruritis were more likely to also have:

• fatigue (77% of those with itch vs. 44% without)
• cognitive impairment (62% vs. 26%)
• heat sensitivity (48% vs. 20%)
• depression or anxiety (48% vs. 16%)

Further, study subjects reporting pruritis were more likely than their counterparts to have T2 hyperintensities on magnetic resonance imaging (MRI) in the posterior cervical spinal cord and the anterior pons/ventromedial medulla region of the brain (74.1% vs 46.0%).

In a related finding that points to the connection between MS and pruritis, the researchers found a strong association between T2 hyperintensities in the anterior pons/ventromedial medulla and itch in the face or scalp.

This study provides further evidence of the far-reaching impact of multiple sclerosis and underscores the importance of people mentioning all symptoms they may be experiencing – no matter how seemingly unrelated to MS – to their clinician. There are a number of treatments available for itching of neurologic origin, so there is no reason to suffer – and scratch – in silence.

Having been breastfed appears to reduce MS risk

An analysis of 15 observational studies indicates that having been breastfed as an infant provides a modest protective effect against MS later in life.¹³

German researchers reviewed 13 case-control studies and 2 cohort studies on the subject, and deemed 12 of those studies to have been designed and conducted in a high-quality manner. After applying statistical adjustments to account for the heterogeneity – or differences in structure – of the various studies, analysis of all 15 studies showed that people who had been breastfed were about 14% less likely than their non-breastfed counterparts to develop MS. When the same adjustments were made and analysis performed on the 12 high-quality studies, there was a 17% reduction in risk with breastfeeding.

The study’s authors said that their research is part of a larger focus on how early-life risk factors may contribute to the chances that a person will develop MS. They noted, “Breast milk provides the new-born not only with essential nutrients and vitamins but also with numerous immune-active molecules, metabolites, oligosaccharides and microbial components that are important for the development of the immune system.”

They added that further research into the topic is needed, including an examination of whether this degree of protective effect differs between men and women.

References

1. Rabadi MH, Just K, Xu C, Impact of adherence with disease-modifying therapies on all-cause mortality rates among veterans with multiple sclerosis. Med Sci Monit. 2022;28:e938116.
2. Khan A, Lin P, Kamdar L, Peterson M, Mahmoudi E. Potentially preventable hospitalizations and use of preventive services among people with multiple sclerosis: Large cohort study, USA. Mult Scler Relat Disord. 2022 Aug 11;68:104105. doi: 10.1016/j.msard.2022.104105.
3. Padart A, Amritphale A, Kilgo W. Readmission rates in patients with multiple sclerosis: a nationwide cohort study. Int J MS Care. 2022;24(4):218-223.
4. Diem L, Evangelopoulos ME, Karathanassis D, et al. Hypogammaglobulinemia: a contributing factor to multiple sclerosis fatigue? Mult Scler Relat Disord. 2022 Aug 30;68:104148. doi: 10.1016/j.msard.2022.104148.
5. Englund S, Piehl F, Kierkegaard M. High-intensity resistance training in people with multiple sclerosis experiencing fatigue: a randomised controlled trial. Mult Scler Relat Disord. 2022 Aug 13;68:104106.doi: 10.1016/j.msard.2022.104106.ighH
6. Giedraitiene N, Gasciauskaite G, Kaubrys G. Impact of autologous HSCT on the quality of life and fatigue in patients with relapsing multiple sclerosis. Sci Rep. 2022 Sep 13;12(1):15404. doi: 10.1038/s41598-022-19748-7.
7. Perumal J, Balabanov R, Su R, et al. Improvements in cognitive processing speed, disability, and patient-reported outcomes in patients with early relapsing-remitting multiple sclerosis treated with natalizumab: results of a 4-year, real-world, open-label study. CNS Drugs. 2022 Sep;36(9):977-993. doi: 10.1007/s40263-022-00950-0.
8. Tysabri (natalizumab) injection, for intravenous use [prescribing information]. December 2021. Biogen Inc.: Cambridge, Massachusetts.
9. Hatton AL, Williams K, Chatfield MD, et al. Immediate effects of wearing textured versus smooth insoles on standing balance and spatiotemporal gait patterns when walking over even and uneven surfaces in people with multiple sclerosis. Disabil Rehabil. 2022 Sep 15;1-9. doi: 10.1080/09638288.2022.2122600.
10. Simpson-Yap S, Pirmani A, Kalinicik T, et al. Updated results of the COVID-19 in MS Global Data Sharing Initiative: anti-CD20 and other risk factors associated with COVID-19 severity. Neurol Neuroimmunol Neuroinflamm. 2022 Aug 29;9(6):e200021.
    doi: 10.1212/NXI.0000000000200021.
11. Romero-Pinel L, Bau L. Matas E, et al. The age at onset of relapsing-remitting multiple sclerosis has increased over the last five decades. Mult Scler Relat Disord. 2022 Aug 9;68:104103.doi: 10.1016/j.msard.2022.104103.
12. Ingrasci G, Tornes L, Brown A, et al. Chronic pruritis in multiple sclerosis and clinical correlates. J Eur Acad Dermatol Venereol. 2022 Aug 26. doi: 10.1111/jdv.18561.
13. Holz A, Riefflin M, Heesen C, et al. Breastfeeding and risk of multiple sclerosis: a systematic review and meta-analysis of observational studies. Neuroepidemiology. 2022 Sep 12.doi: 10.1159/000526895.

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