Cover Story – Aging Well with MS: Emerging Science & Enlightening Studies

Part Two in a Two-Part Series

By Tom Garry
Edited by Susan Wells Courtney
Reviewed by Barry A. Hendin, MD

Aging presents challenges – and opportunities – for all people, but the challenges can be tougher to navigate and the opportunities more difficult to seize when the passage of years is accompanied by progression of multiple sclerosis (MS).

In Part One of this article, which appeared in the Summer/Fall 2022 issue of The Motivator, several people with MS shared their encouraging stories about meeting the challenges of multiple sclerosis through the years. They also outlined effective strategies for making the most of opportunities to enhance health and to draw on one’s experience and hard-won wisdom for the benefit of others. Part One of the article also addressed key medical issues and research studies related to aging and MS.

This second part of the article takes a deeper look at those clinical and scientific topics, including: changes in the focus of MS care over a person’s lifespan, how age factors into decision-making with regard to disease-modifying therapies (DMTs), important unanswered questions on aging and MS, how cognition is affected by the interplay between growing older and having MS, the study of immunosenescence (age-related decline in immune system function), and the implications of older people historically having been under-represented in MS clinical trials.

As with Part One of this article, the pages that follow include several practical steps for readers to consider in consultation with their clinicians.

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Clinicians’ Evolving Approach to Managing MS as People Age

Does MS “settle down” or even become dormant as people age? It’s a controversial question with significant implications for what people with MS can expect and how the disease is treated.

MSAA Chief Medical Officer Barry Hendin, MD, says that the question is difficult to answer because so many of the manifestations of clinical worsening or disease progression that mark MS are also components of the aging process.

“Many, many people who do not have MS experience hearing loss, vision problems, slower cognitive processing, memory issues, difficulties with balance, bladder and bowel problems, and a decrease in brain and muscle mass as they get older,” Dr. Hendin notes. He adds that this makes it challenging to sort out which problems are attributable to MS, which reflect “normal aging,” and which may arise from interplay between the two.

“Secondary progression in MS and aging run parallel to each other and seem to interact, although exactly how is unclear,” Dr. Hendin explains.

In addition, he points out that the changes typically seen in MS as people age, such as fewer relapses but increased disability, don’t represent multiple sclerosis becoming dormant so much as they signal a shift in the prominence of the two processes that drive the disease.

He continues, “MS has both an inflammatory component and a degenerative component. Both are underway from the beginning of the disease process, but the trajectory of the two appears to differ. The inflammatory process predominates when you are younger, but diminishes decade by decade. This is why relapses usually occur less frequently as people age. The degenerative process becomes more of an issue later in life.

“In managing people across the lifespan, clinicians’ focus needs to move in step with that transition,” adds Dr. Hendin, a neurologist who has treated people with MS for more than 50 years, caring for many of his patients from their young adulthood to older age.

“In the past, we were so focused on relapses, and not focused enough on the degenerative process. The thrust in the last decade has been to pay more attention to aspects of MS that don’t manifest themselves as dramatically as a relapse, but that still have a significant impact on health and quality of life, such as walking speed, bladder control, cognition, and balance.”

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The Age-Old Dilemma: If and When to Modify Treatment

The question of how MS changes as people age, inevitably gives rise to the question of whether and how MS treatment approaches should change as people with MS grow older.

The answer is easy: “Yes” – in terms of increased use of medications, physical therapy, and other approaches to treat specific symptoms and aspects of the degenerative process, according to Dr. Hendin. But the answer is not clear-cut when it comes to whether to continue or discontinue disease-modifying therapies as people grow older, he says.

Dr. Hendin explains, “We know when to start DMTs in a person with MS, which is as soon as possible, but whether and when to stop a DMT in a specific individual remains a matter of debate. That’s because the agents mostly provide benefit through their anti-inflammatory activity, and – as noted – the inflammatory component of MS tends to decrease with age. As this happens, the risk-benefit calculus changes, with the benefits diminishing relative to the risk for infections or side effects. Because of this, some clinicians favor discontinuing DMTs altogether in a person’s latter years, while others recommend a de-escalation strategy, such as shifting an older person from a high-efficacy DMT to a medication that is less ­potent but also has a lower risk for side effects.”

The available evidence doesn’t provide clinicians and their patients with clear guidance on the issue. A 2017 analysis examined outcomes in more than 28,000 people with MS participating in clinical trials of immunomodulatory drugs. It found that the effect of DMTs on MS disability fell significantly with advancing age and calculated that the medications provide no efficacy beyond approximately 53 years of age. In another finding that lends support to de-escalation strategies, the analysis determined that high-efficacy DMTs outperform lower-potency medications in inhibiting MS disability only in people with MS younger than 40.5 years.¹

Conversely, a 2022 study conducted by physician researchers who belong to the New York State Multiple Sclerosis Consortium found that stopping a DMT in patients with stable MS led to disease worsening or progression regardless of patient age. The study looked at 161 people with MS who were classified as stable before stopping their DMTs. Fifty-three of those previously stable patients – or 32.9% of the total – subsequently saw their disability get worse or progress. Turning from the overall group to those with different types of MS, 29.2% of those with relapsing-remitting MS had worsening or progression, as did 40% of previously stable patients with secondary-progressive MS, which tends to be more common in older age.²

With such contradictory findings, many clinicians hoped that a study called DISCOMS would serve as a tiebreaker. It didn’t.

The DISCOMS (Discontinuation of Disease Modifying Therapies in Multiple Sclerosis) study was the first randomized trial of discontinuing MS drugs. The study was conducted at 20 MS centers across the United States, and enrolled more than 250 people with MS who were aged 55 years or older, and had not experienced a change in imaging results in three years or a relapse in the past five years. Study investigators randomly assigned 128 of those people to continue treatment with DMTs and 131 to discontinue therapy. The study subjects had an average age of 63 years at randomization, and the two groups were similar in terms of other demographic characteristics. More than 80% of the participants were women.

The primary endpoint of the study was a relapse or new brain lesion over the course of two years. Importantly, the trial was structured as a non-inferiority study, meaning that it was designed to show that stopping DMTs was not worse – or inferior – to continuing them.

In reporting the trial’s much-anticipated results at the Annual Meeting of the Consortium of Multiple Sclerosis Centers in June 2022, researchers explained that 4.69% of the participants continuing treatment and 12.21% of those discontinuing treatment had new disease activity. However, going into the trial, the investigators had specified an 8% margin for non-inferiority, so that stopping DMTs was not shown to be either statistically inferior or not inferior to continuing on therapy. Investigators did find, however, that stopping DMTs was not associated with worsening symptoms or quality of life.³

While an extension of the DISCOMS study and other discontinuation trials involving people with relapsing and secondary-progressive forms of MS may offer additional information, Dr. Hendin stresses that clinicians and patients need to work together to consider each person’s specific circumstances and come to an individualized decision.

“There’s an argument for considering de-escalation as people get older and the inflammatory aspect of MS is less prominent. At the same time, however, while relapses are less common in older people, they also are much harder to accommodate at 60 than at 30,” he says.

Dr. Hendin believes that identifying and understanding how to interpret biomarkers of disease activity, such as blood levels of the protein neurofilament light chain – which provide information on neuronal damage and increasingly are used to monitor response to DMT treatment – along with enhanced utilization of magnetic resonance imaging (MRI), will aid individualized decision-making.

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Still Far More Questions than Answers on Aging with MS

As noted in Part One of this article, which appeared in the Summer/Fall 2022 issue of The Motivator, a study on the impact of MS on health and functioning in aging women was conducted by Marianna Cortese, MD, PhD, a research scientist at the Harvard T.H. Chan School of Public Health.

Working with colleagues from other Harvard institutions and affiliated hospitals, Dr. Cortese drew on 25 years’ worth of data from more than 200,000 participants in the Nurses’ Health Study and Nurses’ Health Study II to examine how 733 women with MS compared with their unaffected peers in terms of several indicators of physical and mental health as well as memory, to assess the burden of aging with MS. The study was noteworthy not only for its findings, but also for its scope and even for the fact that such a study was conducted.⁴

As Dr. Cortese explains, until the study was published in the journal Multiple Sclerosis in January 2022, “There was overall little research on the topic of aging with MS, although there is a growing population aging with MS thanks to potent disease-modifying treatments. Previous studies were small, cross-sectional, and compared older and younger MS patients or MS patients to normative data unrelated to the study population. Our study is the first prospective study on this topic.”

The neuroepidemiologist adds, “Although we know that individuals with MS can accumulate substantial disability during life, the disease burden has to date not been systematically quantified. This is the first study which compared the aging and disability accumulation in individuals with MS to peers without MS drawn from the same study population, which makes them more comparable. By using health measures that are not disease-specific, such as the Physical Functioning-10 for assessing physical function, health surveys, and other health questions, we could conduct such a study and compare both groups.”

Having quantified the impact of MS on physical function and other aspects of health as women age, Dr. Cortese and her colleagues are now interested in assessing underlying factors and the role of various interventions. She explains, “Among women aging with MS, there is variability in the functional decline, even among women with the same initial disease course, with some women declining faster than others. It will be very important to investigate in future studies potential risk and protective factors that affect the speed of aging and disability accumulation.

“Modifiable factors are of special interest, as they would allow intervention. In our study, we adjusted for smoking, as smoking could both affect the risk of acquiring MS and lead to a faster functional decline directly or through smoking-related comorbidities, but smoking did not seem to explain the large difference in aging among women with MS and women without. The Harvard cohorts with their long follow-up of a large number of women throughout their life course and the collection of information on many exposures, including diet and other lifestyle factors, will be an ideal resource for future studies on potential modifiable factors of aging and disability accumulation in MS.”

Dr. Cortese adds, “We only had limited data on treatment in this study. It was limited to the first-approved, lower-potency treatments. It would be interesting to compare how women with MS treated with potent disease-modifying treatments age compared to peers over the years.”

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A Population Missing from Phase III Clinical Trials

The issue of how high-efficacy disease-modifying therapies affect aging in people with MS is just one of many unanswered questions concerning older people and DMTs. Many of those questions remain unanswered because people in their 60’s and older routinely are excluded from the Phase III clinical trials that pharmaceutical companies conduct when seeking Food and Drug Administration (FDA) approval of their investigational medications.

A review found that 16 recently conducted Phase III studies of DMTs set upper age limits for participation that ranged from 45 years to 55 years, with the latter being the most frequently selected cut-off.5 Only one trial included in the review, the open-label CONSONANCE study evaluating Ocrevus® (ocrelizumab) in patients with progressive MS, enabled people up to 65 years of age to enroll. (As of February 2023, the trial was still active but no longer recruiting. It has an estimated primary completion date of January 2026.)

Researchers note that the practice of excluding people age 65 and older from Phase III studies reflects safety concerns rather than a lack of interest in the older population. The historical rationale, they explain, is that older people tend to have more comorbid conditions and be on more medications than younger people, thus increasing their risk for adverse events and interactions between medications. Similarly, people who have age-related declines in kidney function or other processes that are essential for metabolizing drugs can face an elevated likelihood of problems. Further, they note that post-approval studies of DMTs often include people age 65 years and older or even focus specifically on that population.

Advocates for including older people in Phase III trials counter that the typical 65-year-old person today is in better overall health than their counterpart from earlier years, when the age limits often were established. They add that safety concerns can be addressed by establishing exclusion criteria that address specific risks – such as other diagnoses, medicines the person may be taking, or impaired renal function – rather than using an arbitrary age cut-off as a generalized substitute for those factors.

While the debate about age limits for Phase III trials continues, what seems beyond debate is that further research of all kinds is needed to better understand the nature, impact, and treatment of MS in the growing population of older individuals living with the disease.

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If You Are an Older Person with MS and Want to Participate in Research

Although Phase III trials of new therapies typically will not enroll people in their 60s, there are still many opportunities for older people to be part of the research that is driving advances in MS care.

The government’s clinicaltrials.gov website also has extensive information on clinical trials that are recruiting participants. If you’re using the site, however, just be sure to look at the Eligibility Criteria box on the left and check the appropriate “Age Group” box so that you’ll generate results applicable for you.

Finally, remember that not all research involves a trial evaluating a new therapy or other intervention. Some of the findings that have had the greatest impact on shaping MS care have emerged from patient registries and other observational studies that collect data on the lives and experiences of thousands and thousands of patients and then allow researchers to draw on that information (without patients’ identities being revealed) to answer all sorts of questions.

The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry collects information on roughly 42,000 people with MS, providing investigators with a treasure trove of insights into all aspects of living with MS. It is easy to enroll in NARCOMS, which is a project of the Consortium of Multiple Sclerosis Centers (CMSC), online at narcoms.org or via a paper form available at the same website address.

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The Science of Aging with MS: A Focus on Immunosenescence

A long word for a process that is a long time in the making, “immunosenescence” refers to an age-related decline in immune system function. This reduced immune capacity makes older people more susceptible to infection, autoimmune disease, cancer, and the effects of inflammatory processes.^5,6
While immunosenescence is a hallmark of aging in all people, it can take a particularly heavy toll on those with MS by:^5,6,7,8

• affecting production of the T cells and B cells that help regulate the immune system and fight off disease
• diminishing the brain’s capacity to repair tissue damaged by inflammation
• reducing response to disease-modifying therapies (DMTs)

The negative effects of aging on T cells begin not at age 65, or even at age 40, but at puberty, when the thymus – a small gland in the upper chest – stops growing and begins a process of involution, meaning a reduction in its size and function.⁶ This is significant because the thymus is where T cells, a type of white blood cell, mature before circulating throughout the body to find and attack specific harmful foreign substances, known as antigens.

Meanwhile, B cells, which also are white blood cells, fight antigens by creating antibodies, proteins that neutralize foreign substances by binding to their surface to prevent them from entering a normal cell. B cells and T cells cooperate with one another in the fight against antigens through molecular processes that help identify and target those foreign substances.

One result of thymic involution is that the thymus produces a smaller proportion of naïve T cells that can be “programmed” to respond to newly recognized antigens. In addition, the number of regulatory T cells is increased, and these inhibit the action of their antigen-hunting counterparts. At the same time, there is reduced production of other specialized T cells – such as those known as CD4+ T cells – that interact with B cells to generate an immune response. Meanwhile, the bone marrow produces fewer immature B cells as people age. While the processes are complex, and not yet fully elucidated, the net effect is that older people have a reduced ability to make antibodies and respond to newly introduced antigens.⁶

Ongoing, low-grade inflammation is another frequent aspect of the aging process, and immune cells affected by immunosenesence may facilitate this process by secreting cytokines and other substances that further fuel inflammation. Rather than playing a role in repairing tissue damage, as immune cells do in younger people, the senescent cells “switch sides” and instead facilitate tissue damage, including neurodegeneration in the brain. MS can compound the problem because the disease damages oligodendrocytes, the central nervous system (CNS) cells that produce myelin. When these cells are damaged, they release iron, which can accumulate in the CNS, contributing to oxidative stress that causes even more neurodegeneration.^6,9,10

Researchers’ understanding of how immunosenescence and aging overall affect the efficacy and safety of DMTs in older individuals remains unclear, in part because people over the age of 55 are routinely excluded from Phase III clinical trials of those therapies (see “Still Far More Questions than Answers on Aging with MS” on pages 12-13). What scientists have documented, however, is that many DMTs that are effective in treating relapsing-remitting MS, have less efficacy, or no demonstrated efficacy, when people move to non-active secondary- progressive multiple sclerosis (SPMS).

As one team of researchers noted, “Whether it is aging and age-related factors or the underlying immune senescence that qualitatively alter immune response as the disease transitions to SPMS that diminish DMT effectiveness, or both, is currently not known.” However, the researchers noted that immunosenescence has numerous effects on the immune system that could detract from the efficacy of DMTs.⁸

As scientists seek to better understand and then address the factors that affect the health of the growing population of older people with MS, unraveling the dynamics of immunosenescence promises to be a major focus of their investigations.

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Aging, MS, and Cognitive Changes: Thinking Through the Complexities

Sorting out the degree to which declining function is attributable to aging, multiple sclerosis, or a combination of the two, is not easy for any aspect of health, but it is particularly challenging when it comes to cognition.

Several factors contribute to the challenge. First, of course, MS is a condition of the central nervous system, one marked by the presence of lesions in the brain and changes in brain volume, so the organ directly responsible for cognition is directly affected. Second, there are many components of cognition, from short-term and long-term memory to processing speed, verbal fluency, and more. Emerging evidence indicates that MS affects these different domains in different ways. And third, people’s perception of their cognitive function is subjective and may itself be impaired by cognitive problems, so that a rigorous neuropsychological examination is often needed to obtain a reliable picture of a person’s cognitive status.

Despite those challenges, researchers are making steady progress in better characterizing the nature of cognitive decline in older people with MS. Here are some key findings thus far:

• Aging and MS appear to have independent effects on memory, but there are indications that MS accentuates age-related declines in higher executive functions, such as planning and problem solving, as well as processing speed.¹¹
• Older people with MS tend to have lower scores than people of the same age without MS on tests of processing speed and verbal fluency.¹²
• The main cause of cognitive decline appears to be from atrophy of the cerebral cortex. This outermost layer of the brain is composed mostly of grey matter and contains 14 billion to 16 billion nerve cells. A high number of MS lesions in this area of the brain is associated with a high degree of cognitive disability.^5,13

While those results are discouraging, research has also yielded a number of encouraging results, particularly regarding the role of disease-modifying therapies (DMTs) in slowing or reducing cognitive decline in people with MS:

• A review of several relatively large (more than 100 patients) studies of DMTs showed those medications to have positive effects on various aspects of cognition.¹⁴
• An ongoing, long-term study involving almost 695 people with MS indicates that early initiation of high-efficacy DMTs significantly lowers risk for cognitive worsening.¹⁵
• A study involving 279 military veterans with MS receiving care at the Oklahoma City Veterans Affairs Medical Center showed that study participants who adhered to their DMT regimens had significantly less cognitive decline than those who did not adhere or who poorly adhered to treatment.¹⁶

Studies of investigational MS treatments and recently approved medications are examining how those therapies affect various aspects of cognition. However, even more research is needed, and some investigators argue that obtaining definitive information on how DMTs affect cognition will require conducting randomized controlled trials that specify cognitive measures as their primary endpoints, not as secondary measures.¹⁷

While researchers gather more evidence, people with MS can help protect their cognitive health by adopting the brain-friendly practices that the National Institute on Aging recommends for all people, including keeping blood pressure at a healthy level, being physically active, not smoking, eating a healthy diet, and staying engaged with other people.¹⁷

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References

¹ Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.

² Jakimovski D, Kavk KS, Vaughn CB, et al. Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age. Mult Scler Relat Disord. 2022; 57:103406.

³ Rocky Mountain MS Center. Results of the DISCO-MS Trial with Dr. John Corboy. June 13, 2022. (Webinar). Available at https://mscenter.org/education/webinars/ webinar-results-of-the-disco-ms-trial-with-dr-john-corboy/. Accessed February 27, 2023.

⁴ Cortese M, Bjornevik K, Chitnis T, et al. Aging with multiple sclerosis – a longitudinal study of physical function, mental health, and memory in two cohorts of US women. Mult Scler. 2022;28(1):121-131.

⁵ Vaughn CB, Jakimovski D, Kavak KS, et al. Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. 2019;15(6):329-342.

⁶ Ostolaza Ibanez A, Lavineta JC, Ayuso Blano T. Immunosenescence: the role of age in multiple sclerosis. Neurologia (Engl Ed.). 2020;S0213-4853(20)30226-7. doi: 10.1016/j.nrl.2020.05.016.

⁷ Peterson JW, Trapp BD. Neuropathobiology of multiple sclerosis. Neurol Clin. 2005;23:107-129.
⁸ Manouchehri N, Salinas VH, Yeganeh NR, et al. Efficacy of disease modifying therapies in progressive MS and how immunosenescence may explain their failure. Front Neurol. 2022;12.854390.

⁹ Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci. 2013;333:1-4.­­

¹⁰ Grebenciucova E, Berger JR. Immunosenescence: the role of aging in the predisposition to neuroinfectious complications arising from the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. 2017;17:61.

¹¹ Tremblay A, Charest K, Brano E, et al. The effects of aging and disease duration on cognition in multiple sclerosis. Brain Cogn. 2020;146:105650.

¹² Jakimovski D, Weinstock-Guttman B, Roy S, et al. Cognitive profiles of aging in multiple sclerosis. Front Aging Neurosci. 2019;11(05):doi.10.3389/fnagi.2019.00105.

¹³ Calabrese M, Poretto V, Favaretto A, et al. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain. 2012;135: 2952-2961.

¹⁴ Niccolai C, Goretti B, Amato MP. Disease modifying treatments and symptomatic drugs for cognitive impairment in multiple sclerosis: where do we stand? Mult Scler Demyelin Disord. 2017;2:8. Doi: 10.1186/s40893-017-0025-3.

¹⁵ Labiano-Fontcuberta A, Costa-Frossard L, Sainz de la Maza S, et al. The effect of timing of high-efficacy therapy on processing speed performance in multiple scleross. Mult Scler Relat Disord. 2022;64:103959.

¹⁶ Rabadi MH, Just K, Xu C. The impact of adherence to disease-modifying therapies on functional outcomes in veterans with multiple sclerosis. J Cent Nerv Sys Dis. 2021;13:1-10.

¹⁷ Chen H, Goverover Y, Genova HM, DeLuca J. Cognitive efficacy of pharmacologic treatment in multiple sclerosis: a systematic review. CNS Drugs. 2020;34:599-628.

¹⁸ National Institute on Aging. Cognitive health and older adults. Available at https://www.nia.nih.gov/health/cognitive-health-and-older-adults. Accessed September 18, 2022.

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