Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
Izanne Roos, Charles B. Malpas, Emmanuelle Leray, Romain Casey, Dana Horáková, Eva Havrdová, Marc Debouverie, Francesco Patti, de Sèze, Guillermo Izquierdo, Sara Eichau, Gilles Edan, Alexandre Prat, Marc Girard, Serkan Özakbaş, Pierre Grammond, Hélène Zéphir, Jonathan Ciron, Élisabeth Maillart, Thibault Moreau, Maria Pia Amato, Pierre Labauge, Raed Alroughani, Katherine Buzzard, Olga Skibina, Murat Terzi, David Laplaud, Éric Berger, François Grand’Maison, Christine Lebrun‐Frénay, Elisabetta Cartechini, Cavit Boz, Jeannette Lechner‐Scott, Pierre Clavelou, Bruno Stankoff, Julie Prévost, Ludwig Kappos, Jean Pelletier, Vahid Shaygannejad, Bassem Yamout, Samia J. Khoury, Oliver Gerlach, Daniele Spitaleri, Vincent van Pesch, Olivier Gout, Recai Türkoğlu, Olivier Heinzlef, Éric Thouvenot, Pamela McCombe, Aysun Soysal, Bertrand Bourre, Mark Slee, Tamara Castillo‐Triviño, Serge Bakchine, Radek Ampapa, Ernest Butler, Abir Wahab, Richard Macdonell, Eduardo Agüera, Philippe Cabre, Nasr Haifa Ben, Anneke van der Walt, Guy Laureys, Liesbeth Van Hijfte, Cristina Ramo‐Tello, Nicolas Maubeuge, Suzanne Hodgkinson, José Luis Sánchez-Menoyo, Michael Barnett, Céline Labeyrie, Steve Vucic, Youssef Sidhom, Riadh Gouider, Tünde Csépány, Javier Sotoca, Koen de Gans, Abdullah Al‐Asmi, Yára Dadalti Fragoso, Sandra Vukusic, Helmut Butzkueven, Tomáš Kalinčík, on behalf of MSBase and OFSEP
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.