There are currently several ongoing clinical trials that examine whether disease-modifying treatments (DMTs) can be stopped in pwMS with stable disease or above 50 years old. They will evaluate whether clinical relapses and new MRI lesions are more frequent upon discontinuation vs. continuing therapy. Ironically, they coincide with the registration of siponimod as a DMT in secondary progressive pwMS. In the siponimod trial, the median age of pwMS was 49 years old with an upper age limit of 60. Admittedly, there were rather limited disability gains in the siponimod trials as confirmed disability progression was seen in on average 26% versus 32% of treated versus untreated individuals, respectively. Of note, the numbers are in sheer contrast with the MRI outcomes: 18% between-group differences in brain volume loss and 86% reduction in enhancing lesions. Although different study populations, siponimod’s efficacy in progressive MS is not that different from fingolimod in relapsing MS: 25.3% confirmed disability progression vs. 29% in treated vs. untreated individuals, respectively.
However, when moving from the trial bubble to the real MS world many clinicians are not convinced by the siponimod data, and are hesitating to initiate siponimod in secondary progressive MS. This attitude is driven by the fact that MS becomes progressively more invisible at older age:
- Older pwMS are less likely to have MS relapses. The relapse rate decreases by 17% every 5 years between years 5 to 30 after onset.
- PwMS over 50 years old are half as likely to have enhancing actively inflamed lesions compared to their peers of less than 30 years old. If new MRI lesions on interval scans do not enhance at older age, there is always this looming thought: Could this new lesion be of vascular origin? This means the lesions are not caused by demyelination but the consequence of clogged blood vessels.
- The rating scale for MS-related disability, EDSS, becomes less sensitive with time/advanced disability. The scale rates disability from 0 – no disability to 10 – death. In a large study of 2054 individuals with MS, it took 11.7 year to move between EDSS step 6 and 6.5. In clinics, this corresponds to the difference of being able to walk more or less than 50 m with a walking stick. Illustratively, the difference between a score of 2.5 and 2 is ‘only’ 4.9 year.
- The consequences of reduced cognition are less likely to be attributed to MS at older age, and their impact on professional performance and potentially accelerating retirement age are unknown.
- Although there is no direct evidence that immunosuppressive drugs at older age are more likely to be associated with malignancies than when initiated at younger age, the association of certain DMTs with malignancies subjectively becomes more of an issue when growing older.
Overall, the impact of MS on the ageing brain and on performance around retirement age is difficult to quantify, and this is irrespective of disease duration. On the contrary, inflammatory activity is still present in a significant proportion of pwMS at older age, and it’s undeniably damaging precious brain tissue. Hence, clinicians have doubts about the risks versus benefits of treating and suppressing MS lesions with DMTs in older pwMS. Part of the solution is gathering large ‘natural history’ datasets on the evolution of the disease in older pwMS. This will allow us to understand better how MS impacts on life after 50 and whether we are targeting this with a DMT. Moreover, I wonder whether it would be advantageous to group older pwMS in separate clinics dedicated to give them a more personalised advice on risks versus benefits of starting or stopping treatment.
To all pwMS (over 50 years old): Any ideas on how we could measure the impact of the disease on your life?
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Hans-Peter Hartung 1 2 3, Sven G Meuth 1, Deborah M Miller 4, Giancarlo Comi 5Affiliations expand
- PMID: 33990101
- DOI: 10.1097/WCO.0000000000000960
Purpose of review: To assess the reasons for considering discontinuation of disease-modifying therapies (DMTs)in patients with multiple sclerosis (MS). Relevant aspects of the natural history, pathology, and immunology are analyzed.
Recent findings: A number of retrospective observational studies in aggregate indicate that stopping DMTs may be attempted in older individuals with stable disease. Prognostic factors have been identified informing about the risk of recurrence of disease activity after DMT discontinuation.
Summary: Several clinical scenarios provide a rationale to stop DMTs in people with MS. Cumulative evidence has been gathered recently allowing us to more precisely weigh the risks against the benefits. This information aids in the decision process.