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

Izanne Roos, Charles Malpas, Emmanuelle Leray, Romain Casey, Dana Horakova, Eva Kubala Havrdova, Marc Debouverie, Francesco Patti, Jerome De Seze, Guillermo Izquierdo, Sara Eichau, Gilles Edan, Alexandre Prat, Marc Girard, Serkan Ozakbas, Pierre Grammond, Helene Zephir, Jonathan Ciron, Elisabeth Maillart, Thibault MoreauMaria Pia Amato, Pierre Labauge, Raed Alroughani, Katherine Buzzard, Olga Skibina, Murat Terzi, David Axel Laplaud, Eric Berger, Francois Grand'maison, Christine Lebrun-Frenay, Elisabetta Cartechini, Cavit Boz, Jeannette Lechner-Scott, Pierre Clavelou, Bruno Stankoff, Julie Prevost, Ludwig Kappos, Jean Pelletier, Vahid Shaygannejad, Bassem I. Yamout, Samia J. Khoury, Oliver Gerlach, Daniele L.A. Spitaleri, Vincent Van Pesch, Olivier Gout, Recai Turkoglu, Olivier Heinzlef, Eric Thouvenot, Pamela Ann McCombe, Aysun Soysal, Bertrand Bourre, Mark Slee, Tamara Castillo-Trivino, Serge Bakchine, Radek Ampapa, Ernest Gerard Butler, Abir Wahab, Richard A. MacDonell, Eduardo Aguera-Morales, Philippe Cabre, Nasr Haifa Ben, Anneke Van der Walt, Guy Laureys, Liesbeth Van Hijfte, Cristina M. Ramo-Tello, Nicolas Maubeuge, Suzanne Hodgkinson, José Luis Sánchez-Menoyo, Michael H. Barnett, Celine Labeyrie, Steve Vucic, Youssef Sidhom, Riadh Gouider, Tunde Csepany, Javier Sotoca, Koen De Gans, Abdullah Al-Asmi, Yara Dadalti Fragoso, Sandra Vukusic, Helmut Butzkueven, Tomas Kalincik, on behalf of MSBase and OFSEP

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E1926-E1944
Number of pages19
JournalNeurology
Volume99
Issue number17
DOIs
Publication statusPublished - 25 Oct 2022

Keywords

  • multiple sclerosis (MS)
  • disease reactivation
  • recurrence risk
  • disease modifying therapy

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