Risk of T2 lesions when discontinuing fingolimod: a nationwide predictive and comparative study

Abstract

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T₂ lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T₂ lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T₂ lesions, and 124 (17%) had ≥3 new T₂ lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T₂ lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T₂ lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.

Keywords: cohort study; disease-modifying therapy; multiple sclerosis; safety; treatment discontinuation.

Graphical Abstract

Figure 1

Flow diagram—fingolimod. RRMS, relapsing–remitting multiple sclerosis.

Figure 2

Predicted risk of one or more new T₂ lesions on post-MRI. The plots are divided by the number of new T₂ lesions on pre-MRI and display the absolute predicted risk of having one or more new T₂ lesions on the post-MRI according to sex and age. Transparent areas represent 95% confidence intervals. The graphs shown are for an EDSS score of 2–3.5 (48.8% of the population). Hollow circles represent individuals. The statistical analysis performed to produce the plots was a logistic regression with a spline effect on age and an interaction term between the age spline and sex. The experimental unit was participants in the study. Pre-MRI: the last MRI prior to fingolimod discontinuation. Post-MRI: the first MRI post fingolimod discontinuation. EDSS, Expanded Disability Status Scale. Wald Chi-square (degrees of freedom, P-value): sex, 3.28 (1, 0.07); age spline, 6.55 (2, 0.04); ages spline * sex interaction, 7.08 (2, 0.03); Expanded Disability Status Scale, 3.71 (2, 0.16); new T₂ lesions on pre-MRI, 23.3 (2, <0.01); area under the curve (AUC), 0.73.