“This morning we diagnosed a patient of 89-year-old with a first attack of multiple sclerosis (MS). We have no doubt about the diagnosis; it is a clear case of MS. She is a lovely, independent lady and we will treat her with high efficacy medications, but only for a while. We will follow her, take care of possible complications, but probably after 1 or 2 years, or even less, without focal inflammatory activity, we will de-escalate or, perhaps, stop the treatment. This is, I think, the main difference between this case and the case of a 28-year-old person who would probably be treated for many years”. This case is described by Professor Xavier Montalban, Chair of the Department of Neurology at the University Hospital in Vall d’Hebron (Barcelona), the Director of the MS center of Catalonia (Cemcat) and the Chair of the International Advisory Committee of Clinical Trials in MS, during our recent webinar. The webinar provides updates concerning the recent workshop on ageing and MS that took place in Philadelphia in April, organised by the International Advisory Committee of Clinical Trials in MS. The Committee is a global body jointly sponsored by ECTRIMS and the National MS Society.
During our webinar, top experts discuss how ageing may affect multiple sclerosis (MS) and highlight the main challenges in clinically managing older patients with MS. Dr. Tim Coetzee, Chief Advocacy, Service & Science Officer at the National MS Society in the United States, facilitates the discussion.
Among the esteemed panelists, there are Professor Jennifer Graves, Vice-Chair of Human Clinical Research at the University of California, in San Diego, and the Director of the Neuro-immunology Research Program for Adults and Children living with MS, and Dr. Eva Strijbis, an MS neurologist at the Amsterdam University Medical Center (UMC).
Chronological and biological age
Professor Graves gave the keynote presentation at the workshop in Philadelphia. During the webinar, she highlights that biological age may not perfectly correlate with chronological age – the number of birthdays celebrated. Chronological age is the strongest factor related with disease expression in MS, both in terms of relapse rate and disability progression. Not only are progressive forms of MS associated with ageing, but people living with MS may also experience accelerated ageing driven by the inflammatory process in MS. Biological age is a helpful construct to better understand the link between ageing and disability accumulation or loss of brain volume in people living with MS.
Each person with MS is unique
Dr Strijbis emphasises the clinical observation that each person with MS is unique. She says, “Some patients progress very early and aggressively, while some people do quite well even after living with the disease for 30 or 40 years”. This depends on multiple factors, including different subsets of immune phenotypes. We can see different subsets of immune phenotypes in peripheral blood but also different subsets of activated microglia in the central nervous system (CNS). They can differ not only between separate individuals, but also within different tissues of the same person. For example, there may be differences between the frontal lobes and the spinal cord. Dr. Strijbis continues, “If we want to group, to phenotype these patients, we will need to have repeated sampling of liquid biopsy: blood banking or cerebrospinal fluid (CSF) banking”. Two main challenges constrain the repeated CSF sampling. One is that the procedure of withdrawing cerebrospinal fluid is invasive. The other issue is that with the increased number of successful treatments, most of the natural history of the disease disappears. Therefore, there is a need to internationalise the research and combine datasets and databanks.
Sometimes biological ageing markers can be masked in the process of using DMTs. Professor Graves highlights the need to identify the most relevant underlying substrate for progressive MS and disability accumulation and to develop realistic treatment approaches. Many candidates are available, in terms of targets that may be related to CNS based inflammation, areas of inflammation that may not be very well addressed by the current disease modifying therapies (DMTs). We need to understand whether we should target resident cells in the CNS or there is an opportunity to target these processes in the periphery. This represents one of the most significant gaps to fill.
Treating MS in older people
Professor Montalban underscores that the same immune cells can work very differently in different patients and that some of the approved treatments do not have the same effect on all patients. Older patients do not show too much focal inflammatory activity measured by relapses. Furthermore, distinguishing neurodegeneration produced by MS from that generated by ageing is not so easy. This is complicated by the fact that clinical trials have so far only enrolled people with MS up to 55-60 years. Therefore, there is not much information coming from clinical trials. This represents a key point. It is essential to include older patients in clinical trials. Professor Montalban gives some recommendations, discussed during the workshop, on how to circumvent some of the challenges associated with enrolling older people. For example, one option, although expensive, would be to increase the total number of participants in the clinical trials. Another option is to keep the primary endpoint among patients under 55 and to enroll 20% of older patients for the main secondary endpoint. People older than 65 with or without comorbidities, who are typically excluded from clinical trials, should be involved.
Professor Graves agrees that the safest possible environment to understand how a treatment works is the setting of a clinical trial. She observes that over 50% of people currently living with MS are over the age of 50. Therefore, drugs developed for the progressive form of MS should be tested in the most affected ages. The immune system changes for all of us as we age. The approved drugs have largely been designed to target inflammation, lesion formation, and, to some degree, the accumulation of disability, but they have not been designed to target the ageing immune system — whether it is the peripheral or the central component. Given these issues, when deciding how to treat older people, the ratio of efficacy to safety should be considered. Professor Graves continues, “If the chance to get benefits is decreasing while the chance of infection is increasing, that is a substantial consideration. In my evaluation of patients, as well as in research, I try to consider more than just the birth date in my assessment. Do individuals have substantial comorbidities? Do they show evidence of a more advanced biological age? I use the tools at my disposal to look beyond the birthday, including examining their recent history and whether they have evidence of inflammatory activity in the last few years, or whether they have been experiencing a secondary progressive course. We can use chronological age as a general rule, but decisions must be tailored to each individual, considering each individual disease trajectory and, to the best of our ability, biological age”.
Measuring progression and disability accumulation
Another important challenge relates to the available measures. Professor Graves remarks that it is critical to develop tools, also digital, that help measure progression. She says, “When a patient cannot any longer play the piano with her right hand, we should be able to capture that in a clinical trial. When people are dragging the foot a little more regularly to the point where they can still walk but they cannot attend their son or grandson’s soccer game, we should be able to capture that with tools”. The problem is not only evaluating what a patient can or cannot do. It is important to capture the variability of performance and how many modifications it takes to complete a certain task.
Dr Coetzee underlines the importance of listening to patients’ voice in a meaningful manner and considering each person within an integrated approach that acknowledges their complexity. Dr. Strijbis adds that all caregivers should collaborate more closely to ensure awareness of the specific challenges associated with MS. An integrated approach facilitates the evaluation of the entire individual, who may also have comorbidities unrelated to MS. Dr Strijbis points out instances where individuals may think they have optic neuritis when, in fact, they need reading glasses, or they might mistake osteoarthritis for slowly progressive walking disturbances. These comorbidities must be detected and addressed, as they have a negative impact on the prognosis of MS. The prognosis of progressive MS may be better if, for example, cardiovascular comorbidities are treated.
We start ageing when we are born
“A fountain of youth is physical exercise”, says Professor Graves, “Physical activity is the best way to preserve our telomeres, reverse signs of ageing in multiple organ systems throughout the body. It is essential that people living with MS continue to engage in physical activity, even if they start to develop lower extremities disability. This can be challenging, but it is possible with the right rehabilitation partner. It is possible if the person has a recumbent bike or an arm bike. We need to keep our patients active”. It is also important to eat well, to prevent accelerated immunological ageing. There are attempts to reverse these processes pharmacologically, with stem-cells, for examples. However, while we are waiting for proven therapies that target these processes in an effective way, we do have these tools to consider.
In conclusion, Professor Montalban reminds us that we start ageing when we are born. These topics do not concern only older people. Everybody should do physical exercise, a good diet, quit smoking. We do not have to wait until we become old.