The impact of multiple sclerosis on ageing patients

Ageing is associated with significant immunological changes that can influence both the progression of the disease and the response to treatment

By Nektaria Alexandri

As the population of individuals living with multiple sclerosis (MS) around the world continues to age, clinicians are faced with evolving and often complex challenges in managing these patients. While significant advances have been made in the treatment of relapsing MS (RMS), the needs of older patients require special attention. What considerations should physicians keep in mind when treating this patient population?

In many countries, older adults represent the largest age cohort among individuals with MS. This trend may be linked to improved life expectancy for MS patients, driven by advances such as improved healthcare approaches, including early therapy initiation, the use of high-efficacy disease-modifying treatments, advancements in symptomatic treatments and holistic treatment approaches. Additionally, the age of onset for MS has shifted forward, with cases diagnosed at age 50 or older categorised as late-onset MS (LOMS). There has been a notable rise in LOMS diagnoses, particularly among women. This increase may be attributed to greater awareness and improved diagnostic tools.

This shift in the age prevalence of the disease brings a host of considerations, as both MS itself and the immune system undergo significant changes with age. Understanding these shifts is essential to optimising care for this growing patient population.

Research has shown that as patients with MS get older, several key changes occur:

• A decline in magnetic resonance imaging (MRI) activity and relapse frequency, suggesting a reduced inflammatory disease burden
• An increased risk of progression, due to increased neurodegenerative processes or to less complete recovery from relapses
• A reduced efficacy of certain disease-modifying therapies (DMTs) beyond approximately 53 years of age, as predicted by regression models.

• A disproportionate increase in memory T cells that express more pro-inflammatory cytokines, which contributes to a shift in immune function, presenting with a non-specific inflammation
• A loss of ability to respond to new antigens, impacting overall immune resilience, including coping with infections and responding to vaccinations
• Persistent low-grade inflammation, under the term ‘inflamm-ageing’, which may exacerbate neurodegeneration and MS progression.

Beyond the direct effects of ageing on MS, older patients often face additional complications that can impact disease management:

• Comorbid conditions such as cardiovascular disease, diabetes and osteoporosis may influence treatment choices and overall health outcomes
• Polypharmacy and adherence challenges become more pronounced, increasing the risk of drug-to-drug interactions and adverse events
• Heightened susceptibility to infections, especially opportunistic, and particularly with chronic immunosuppressive therapies, as well as higher risk of infection-related mortality, requiring vigilant monitoring and preventive care.

So, what is the best course of action for physicians managing MS in older patients? Clearly, there is no one-size-fits-all solution. Staying current with the latest MS therapy developments and engaging in peer-to-peer knowledge sharing, along with building clinical experience, are essential foundations for effective clinical practice. Several key principles should guide clinical decision-making:

1. Reassessing treatment: regularly evaluate the risk-benefit of using a DMT.
2. Personalised risk-benefit analysis: weigh the potential benefits of treatment against the risks of continuous immunosuppression, considering comorbidities and the patient’s overall lifestyle and health status.
3. Monitoring for adverse effects: given the increased susceptibility to infections and other adverse events, regular screening and preventive healthcare measures should be emphasised.
4. Engaging in shared decision-making: patients should be actively involved in discussions about their treatment options, ensuring that decisions align with their individual goals and quality of life considerations.
5. Exploring therapies with favourable safety profiles: some advanced therapies may offer a more balanced approach by maintaining efficacy while minimising long-term immunosuppressive risks. Treatments that selectively modulate immune activity, rather than broadly suppressing it, could be particularly beneficial in this population.
6. Considering alternative strategies: symptomatic management, rehabilitation and lifestyle interventions should play an increasing role in care plans.

‘Engaging in peer-to-peer knowledge sharing and building clinical experience are essential foundations for effective clinical practice’

When treating older adults with RMS on a high-efficacy therapy, healthcare professionals (HCPs) generally face three options:

1. Staying on a continuous immunosuppressant DMT: many traditional MS therapies require continuous administration to maintain their effects. While this approach may keep disease activity at bay, it also prolongs immunosuppression, impacting comorbidities and potentially increasing infection risk over time.
2. Discontinuing therapy entirely: in some cases, HCPs may consider stopping treatment, especially if there has been no recent disease activity. However, this carries the potential risk of disease reactivation and even disease rebound, particularly in patients who have been on lymphocyte-trafficking inhibitors.
3. Switching to an immune reconstitution therapy (IRT): IRTs provide an alternative approach by targeting and resetting the immune system in a way that does not require continuous treatment.

IRTs work differently from traditional DMTs. Rather than continuously suppressing
the immune system, IRTs can induce short-term depletion of targeted immune cells (such as reactive B and T lymphocytes), allowing for controlled immune reconstitution over time, which likely induces an anti-inflammatory profile. This approach could align well with the needs of older adults for several reasons:

• Effects on dosing: IRTs typically require only relatively short treatment courses over a defined period, rather than ongoing daily, weekly or monthly administration. This can reduce treatment burden and improve adherence
• Impact on immune function: since IRTs are relatively quickly eliminated and do not require frequent administration, they may lower the cumulative risk of infections compared to therapies that require long-term cumulative drug intake. Additionally, unlike continuous immunosuppressants, IRTs can temporarily reduce auto-reactive immune cells, allowing them to gradually repopulate to a less pro-inflammatory state, helping to ‘reset’ the immune system. Some high-efficacy DMTs, particularly B-cell depleting therapies, have been associated with hypogammaglobulinaemia, which can lead to an increased risk of serious infections. IRTs can allow for a more balanced immune recovery, potentially mitigating this concern

‘As our understanding of age-related disease progression evolves, so too must our approach to treatment’

For older adults with MS, IRTs offer a treatment strategy by providing disease control without the drawbacks of continuous immune suppression. Their short, defined dosing schedules, long-lasting effects and lower long-term infection risks can make them particularly suitable for patients who face challenges with adherence, polypharmacy and age-related immune changes.

By leveraging the principles of immune reconstitution, IRTs help strike a balance between maintaining disease control and minimising safety concerns, making them a better choice for the ageing MS population.

In summary, the growing population of older adults with MS presents both challenges and opportunities for the medical community. As our understanding of age-related disease progression evolves, so too must our approach to treatment. By prioritising personalised care, reassessing therapeutic goals and integrating a holistic perspective on ageing, clinicians can better support their patients in navigating MS later in life.

Ultimately, effective management requires a careful balance between disease control and minimising treatment burden. Advanced therapies can or may provide durable efficacy, while reducing unnecessary immune suppression could play a vital role in the evolving treatment paradigm. With a patient-centred approach and including patients in the treatment decision-making process, we can ensure that older individuals with MS receive the highest standard of care tailored to their unique needs.

Nektaria Alexandri is Senior Medical Director, Global Medical Unit Neurology and Immunology, Global R&D at Merck KGaA, Darmstadt, Germany