Severe disease exacerbations in patients with multiple sclerosis after discontinuing fingolimod

Abstract

Discontinuation of fingolimod in patients with multiple sclerosis (MS) can lead to disease reactivation. In this review, we describe cases of severe exacerbations in patients with MS following discontinuation of fingolimod, including three cases from our center. We consider potential mechanisms of disease reactivation after cessation of fingolimod, and the evidence supporting this rebound effect. We conclude that discontinuation of fingolimod results in the return of disease activity, which then leads to severe exacerbations (i.e., rebounds) in a clinically significant proportion of patients. Lastly, we consider disease-modifying treatment options for patients who discontinue fingolimod.

Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations

“…Reported cases of unexpected increases in clinical and MRI activity after discontinuation of fingolimod began accumulating in 2012 [10,[25][26][27][28][29][30][31][32][33][34][35], with some including reports of tumefactive lesions on MRI [36][37][38][39][40]. While these cases exhibit a significant amount of clinical heterogeneity, a recently published case series has demonstrated three different MRI patterns of post-fingolimod rebound: tumefactive lesions, a punctated pattern with innumerable small T2 and gadolinium (Gd)enhancing lesions, and a pattern more typical of classical MS [40].…”

“…A rapid reentry of lymphocytes into the CNS upon drug discontinuation has been hypothesized to explain fingolimod rebound [41], but the phenomenon does not appear solely due to a repopulation of peripheral lymphocytes, as rebound has been noted even when lymphocyte counts have remained depressed [33,41,42]. Animal data has suggested a possible mechanism, as experimental withdrawal of fingolimod resulted in overexpression of lymphocytic S1P1 receptors leading to lymphocyte egress from lymph nodes and an increase in severity of relapse symptoms [43].…”

“…Several strategies have been proposed to mitigate risk when discontinuing fingolimod. Tapered withdrawal of fingolimod has been suggested [33,35], although this approach is untested. Monthly pulses of intravenous steroids have been offered as an option to bridge to the next therapy [41].…”

Clinical activity after Fingolimod cessation: disease reactivation or rebound?

“…Since 2012, several reports have described a "rebound syndrome" after fingolimod discontinuation [3,14]. There is not a shared definition of "clinical rebound syndrome"; the most widely used definition is "a disease reactivation which surpasses the pretreatment activity level," especially with regard to ARR [15,16]. The concept of "rebound" after discontinuation of treatment was first proposed for natalizumab, a monoclonal antibody approved in 2006 to…”

Multiple sclerosis: severe exacerbation after stopping disease‐modifying drugs

“…This may be due to the recovery of lymphocytes count or specific repopulation. Reports of young women who experienced severe rebound effects after fingolimod discontinuation are striking [4,5,7]. It is of great interest that Frau et al noted that females and younger patients had more severe reactivation [1].…”