Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis

Abstract

Background and objectives: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.

Methods: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.

Results: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).

Discussion: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod).

Classification of evidence: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.

Figure 1. Consort Diagram of Patient Disposition

Patients excluded due to insufficient visit data did not have a baseline visit (with the EDSS score recorded) within an interval of 180 days before or 30 days after cessation of therapy or had fewer than 2 postbaseline visits >6 months apart. Insufficiently represented therapies are those with fewer than 200 recorded treatment discontinuation events (alemtuzumab: 101; cladribine: 36; daclizumab: 13; ocrelizumab: 3; and rituximab: 26). EDSS = Expanded Disability Status Scale; RRMS = relapsing-remitting multiple sclerosis.

Figure 2. Annualized Relapse Rate in the 12 Months Before Baseline (During Index Treatment) and After Treatment Cessation

Baseline (treatment cessation) is indicated by time point 0 and represents the last recorded date of medication administration. The period after treatment cessation is stratified by patients who remained untreated or have started a new treatment (for each 1- or 2-month period). The on-treatment period is indicated by the gray shaded area. Point and whiskers show the relapse rates in each epoch. Number of patients: patients who contribute some time to each period. Annualized relapse rates were calculated as the total number of relapses divided by the number of patient-years in each time period. The pretreatment relapse rate and 95% CI is indicated by the open circle and line. The relapse rate was calculated using up to 1 year of untreated time immediately before treatment start (number of patients with data available as indicated). The dashed black line is a visual reference of the mean relapse rate during the second year before treatment cessation, with the shaded area indicating 95% CIs. Only treated time was included. Number of contributing patients: mitoxantrone 211, natalizumab 2,558, fingolimod 1,229, dimethyl fumarate 552, teriflunomide 388, interferon 9,931, and glatiramer acetate 2,999.

Figure 3. Annualized Relapse Rate in the 12 Months Before Baseline (During Index Treatment) and After Treatment Cessation in Patients Without Relapses in the Year Before Baseline

Baseline (treatment cessation) is indicated by time point 0 and represents the last recorded date of medication administration. The period after treatment cessation is stratified by patients who remained untreated or have started a new treatment (for each 1- or 2-month period). The on-treatment period is indicated by the gray shaded area. Point and whiskers show the relapse rates in each epoch. Number of patients: patients who contribute some time to each period. The pretreatment relapse rate and 95% CI is indicated by the open circle and line. The relapse rate was calculated using up to 1 year of untreated time immediately before treatment start. The dashed black line is a visual reference of the mean relapse rate during the second year before treatment cessation, with the shaded area indicating 95% CIs. Only treated time was included.