Starting certain MS drugs may get you stuck in a loop that you never bargained for when you started them in your early thirties or forties. The ability to stop taking drugs at an older age is something we more or less take for granted, especially if we have been disease free for ‘X’ many years.
However, in the MS world things are never that simple or straightforward; there is ‘recurrence of disease activity (RDA) or worse ‘rebound’ to consider before stopping treatment.
Rebound is when there is resurgence of disease activity to levels greater than pre-treatment activity.
It is unclear how much of this effect is drug specific (i.e. those drugs that block lymphocyte trafficking into the CNS are more likely to cause this phenomenon, for e.g. natalizumab/fingolimod) or simply person/disease specific. Moreover, much of the evidence comes from case reports and real world post marketing studies, which may over or under-estimate the true occurrence of this phenomenon.
In this recent study from Switzerland focused on fingolimod users (128 in total), they noted that discontinuation lead to recurrence of disease in about a third of individuals and of was severe in 1 in 8. Those with greater disease activity at the start of the disease and younger age at MS diagnosis were more likely to experience it. The former has also been demonstrated before in a meta-analysis of the two pivotal clinical trials for fingolimod in RRMS (FREEDOMS I and II).
But, what is of interest to me personally is the resurgence of disease activity in the older age group upon discontinuation despite being previously stable in their MS on treatment. In this study, the cut-off was 50 and being >50 years of age did not take away the risk of resurgence of disease activity; although it was half as likely to occur as those <50 years old (see Figure below). When they moved the cut-off to 60 years old (this included only 11 patients from the whole group), they noted no evidence of disease resurgence upon discontinuation.
Of course, we need to look at this type of data carefully to fully understand the mechanisms at play, and the factors that have positive and negative impact on it. What you want to avoid is starting treatments and then not have an exit plan should the need arise. With regard to fingolimod, its sister drug siponimod, which has recently been licensed in SPMS is expected to be used in a significantly greater number of individuals, and a significant number will be in the older age group with greater co-morbidities. These individuals may not fair as well with resurgence of disease activity at this point in life, especially if it is anything like what it was at the start of their disease or even worse rebound activity.
Mult Scler Relat Disord. 2021 Mar 21;51:102918. doi: 10.1016/j.msard.2021.102918. Online ahead of print.
Recurrence of disease activity after fingolimod discontinuation in older patients previously stable on treatment
Background: Discontinuing fingolimod (FTY) in older patients is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.
Objective: To estimate the incidence of recurrence of disease activity (RDA) and rebound after FTY withdrawal in patients older than 50 years.
Methods: Retrospective analysis of all MS patients in our clinic who discontinued FTY after at least 6 months of treatment, according to disease activity on FTY and age at discontinuation. RDA was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal and rebound when the levels of disease activity surpassed pretreatment activity.
Results: From the 128 patients who discontinued FTY since 2011, up to 35.2% of patients experienced evidence of disease activity and 12.5% had a rebound. The incidence of both RDA and rebound was not different among individuals who had persistent disease activity on FTY to those who stopped FTY for other reasons than inefficacy (RDA: 25.5% vs 20.5%, p = 0.353 rebound: 14.5% vs 11%, p = 0.596). Negative predictive factors for RDA were younger age at disease onset (p = 0.036), highly active disease at baseline (p = 0.003) and previous treatment with NTZ (p = 0.013). Older age at FTY discontinuation did not reduce the risk of RDA in patients previously stable on treatment (OR 0.972, 95% CI 0.871-1.085, p = 0.613), although the incidence of RDA/rebound was half less in the older patients (36.5% in the <50 vs 19% in the ≥50 year-old, p = 0.174) and none of the patients over 60 experienced RDA.
Conclusion: Although there is a tendency for a lower risk of disease reactivation in the older patients, the incidence of RDA, and even rebound, is not negligible between the age of 50 and 60 years, even in patients with previously stable MS on FTY.
Disclaimer – Please note that the opinions expressed here are those of Neuro Doc Gnanapavan and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.