Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
Izanne Roos
(1)
,
Charles Malpas
,
Emmanuelle Leray
(2, 3, 4, 5, 6)
,
Romain Casey
(7, 8)
,
Dana Horakova
,
Eva Kubala Havrdova
,
Marc Debouverie
(9)
,
Francesco Patti
,
Jerome de Seze
(10)
,
Guillermo Izquierdo
,
Sara Eichau
,
Gilles Edan
(11, 5)
,
Alexandre Prat
,
Marc Girard
,
Serkan Ozakbas
,
Pierre Grammond
,
Helene Zephir
,
Jonathan Ciron
,
Elisabeth Maillart
,
Pamela Ann Mccombe
,
Thibault Moreau
(12)
,
Maria Pia Amato
,
Pierre Labauge
,
Bertrand Bourre
,
Raed Alroughani
,
Katherine Buzzard
,
Olga Skibina
,
Murat Terzi
,
David Axel Laplaud
(13, 14)
,
Eric Berger
,
Mark Slee
,
Francois Grand'Maison
,
Christine Lebrun-Frenay
(15)
,
Elisabetta Cartechini
,
Aysun Soysal
,
Cavit Boz
,
Jeannette Lechner-Scott
,
Pierre Clavelou
(16)
,
Bruno Stankoff
(17)
,
Julie Prevost
,
Ludwig Kappos
,
Jean Pelletier
(18)
,
Vahid Shaygannejad
,
Bassem Yamout
,
Samia Khoury
,
Oliver Gerlach
,
Daniele Spitaleri
,
Vincent van Pesch
,
Olivier Gout
,
Recai Turkoglu
,
Olivier Heinzlef
,
Eric Thouvenot
(19)
,
Tamara Castillo-Trivino
,
Serge Bakchine
,
Radek Ampapa
,
Ernest Gerard Butler
,
Abir Wahab
,
Richard Macdonell
,
Eduardo Aguera-Morales
,
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
,
Celine Labeyrie
,
Steve Vucic
,
Youssef Sidhom
,
Riadh Gouider
,
Tunde Csepany
,
Javier Sotoca
,
Koen de Gans
,
Abdullah Al-Asmi
,
Yara Dadalti Fragoso
,
Sandra Vukusic
(7, 8)
,
Helmut Butzkueven
,
Tomas Kalincik
(1)
1
University of Melbourne
2 ARENES - Arènes: politique, santé publique, environnement, médias
3 RSMS - Recherche sur les services et le management en santé
4 EHESP - École des Hautes Études en Santé Publique [EHESP]
5 CIC - Centre d'Investigation Clinique [Rennes]
6 REPERES - Recherche en Pharmaco-épidémiologie et Recours aux Soins
7 HCL - Hospices Civils de Lyon
8 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
9 APEMAC - Adaptation, mesure et évaluation en santé. Approches interdisciplinaires
10 Centre d’Investigation Clinique Plurithématique (CIC - P) - CIC Strasbourg
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital
12 CEP - Centre d'épidémiologie des populations
13 CIC Plurithématique de Nantes
14 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
15 URRIS UR2CA - Unité de Recherche Clinique de la Côte d’Azur
16 Neuro-Dol - Neuro-Dol
17 ICM - Institut du Cerveau = Paris Brain Institute
18 TIMONE - Hôpital de la Timone [CHU - APHM]
19 IGF - Institut de Génomique Fonctionnelle
2 ARENES - Arènes: politique, santé publique, environnement, médias
3 RSMS - Recherche sur les services et le management en santé
4 EHESP - École des Hautes Études en Santé Publique [EHESP]
5 CIC - Centre d'Investigation Clinique [Rennes]
6 REPERES - Recherche en Pharmaco-épidémiologie et Recours aux Soins
7 HCL - Hospices Civils de Lyon
8 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
9 APEMAC - Adaptation, mesure et évaluation en santé. Approches interdisciplinaires
10 Centre d’Investigation Clinique Plurithématique (CIC - P) - CIC Strasbourg
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital
12 CEP - Centre d'épidémiologie des populations
13 CIC Plurithématique de Nantes
14 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
15 URRIS UR2CA - Unité de Recherche Clinique de la Côte d’Azur
16 Neuro-Dol - Neuro-Dol
17 ICM - Institut du Cerveau = Paris Brain Institute
18 TIMONE - Hôpital de la Timone [CHU - APHM]
19 IGF - Institut de Génomique Fonctionnelle
Izanne Roos
- Function : Author
- PersonId : 1164212
- ORCID : 0000-0003-0371-3666
Charles Malpas
- Function : Author
Emmanuelle Leray
- Function : Author
- PersonId : 18386
- IdHAL : emmanuelle-leray
- ORCID : 0000-0001-8424-4499
- IdRef : 099858185
Romain Casey
- Function : Author
- PersonId : 1164213
- ORCID : 0000-0002-5918-9261
Dana Horakova
- Function : Author
Eva Kubala Havrdova
- Function : Author
Francesco Patti
- Function : Author
Guillermo Izquierdo
- Function : Author
Sara Eichau
- Function : Author
Alexandre Prat
- Function : Author
Marc Girard
- Function : Author
Serkan Ozakbas
- Function : Author
Pierre Grammond
- Function : Author
Helene Zephir
- Function : Author
Jonathan Ciron
- Function : Author
- PersonId : 795646
- ORCID : 0000-0002-3386-6308
- IdRef : 137599021
Elisabeth Maillart
- Function : Author
- PersonId : 1164214
- ORCID : 0000-0001-7699-0328
Pamela Ann Mccombe
- Function : Author
Maria Pia Amato
- Function : Author
Pierre Labauge
- Function : Author
Bertrand Bourre
- Function : Author
- PersonId : 1164218
- ORCID : 0000-0002-2459-2480
Raed Alroughani
- Function : Author
Katherine Buzzard
- Function : Author
Olga Skibina
- Function : Author
Murat Terzi
- Function : Author
Eric Berger
- Function : Author
Mark Slee
- Function : Author
Francois Grand'Maison
- Function : Author
- PersonId : 1164215
- ORCID : 0000-0003-0091-0074
Christine Lebrun-Frenay
- Function : Author
- PersonId : 770285
- ORCID : 0000-0002-3713-2416
- IdRef : 074517929
Elisabetta Cartechini
- Function : Author
Aysun Soysal
- Function : Author
Cavit Boz
- Function : Author
Jeannette Lechner-Scott
- Function : Author
Bruno Stankoff
- Function : Author
- PersonId : 1146488
- ORCID : 0000-0002-9631-4674
- IdRef : 070067988
Julie Prevost
- Function : Author
Ludwig Kappos
- Function : Author
Vahid Shaygannejad
- Function : Author
Bassem Yamout
- Function : Author
Samia Khoury
- Function : Author
Oliver Gerlach
- Function : Author
Daniele Spitaleri
- Function : Author
Vincent van Pesch
- Function : Author
- PersonId : 1164216
- ORCID : 0000-0003-2885-9004
Olivier Gout
- Function : Author
Recai Turkoglu
- Function : Author
- PersonId : 1164217
- ORCID : 0000-0001-9724-851X
Olivier Heinzlef
- Function : Author
Eric Thouvenot
- Function : Author
- PersonId : 758070
- ORCID : 0000-0001-8671-7747
- IdRef : 094970920
Tamara Castillo-Trivino
- Function : Author
- PersonId : 1164219
- ORCID : 0000-0002-9249-3185
Serge Bakchine
- Function : Author
Radek Ampapa
- Function : Author
Ernest Gerard Butler
- Function : Author
Abir Wahab
- Function : Author
Richard Macdonell
- Function : Author
Eduardo Aguera-Morales
- Function : Author
- PersonId : 1164220
- ORCID : 0000-0002-8604-2054
Philippe Cabre
- Function : Author
Nasr Haifa Ben
- Function : Author
Anneke van der Walt
- Function : Author
- PersonId : 1164221
- ORCID : 0000-0002-4278-7003
Guy Laureys
- Function : Author
- PersonId : 1164222
- ORCID : 0000-0002-1708-4373
Liesbeth van Hijfte
- Function : Author
Cristina Ramo-Tello
- Function : Author
Nicolas Maubeuge
- Function : Author
Suzanne Hodgkinson
- Function : Author
José Luis Sánchez-Menoyo
- Function : Author
- PersonId : 1164223
- ORCID : 0000-0003-2634-8294
Michael Barnett
- Function : Author
- PersonId : 1164224
- ORCID : 0000-0002-2156-8864
Celine Labeyrie
- Function : Author
Steve Vucic
- Function : Author
Youssef Sidhom
- Function : Author
Riadh Gouider
- Function : Author
Tunde Csepany
- Function : Author
- PersonId : 1164225
- ORCID : 0000-0002-8305-3209
Javier Sotoca
- Function : Author
Koen de Gans
- Function : Author
Abdullah Al-Asmi
- Function : Author
- PersonId : 1164226
- ORCID : 0000-0002-2851-8157
Yara Dadalti Fragoso
- Function : Author
- PersonId : 1164227
- ORCID : 0000-0001-8726-089X
Helmut Butzkueven
- Function : Author
Tomas Kalincik
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 1098429
Connectez-vous pour contacter l'auteur
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.