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Published on: December 9, 2015
Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple
Izanne Roos1, Charles Malpas1, Emmanuelle Leray1
1From the CORe (I.R., C.M., T.K.), Department of Medicine, University of Melbourne, Australia; Melbourne MS Centre (I.R., C.M., T.K.), Department of Neurology, Royal Melbourne Hospital, Australia; Rennes, University (E.L.), EHESP, REPERES EA 7449, France; Univ Rennes (E.L.), CHU Rennes, Inserm, CIC 1414 ([Centre d'Investigation Clinique de Rennes]), France; Université de Lyon (R.C.), Université Claude Bernard Lyon 1, France; Hospices Civils de Lyon (R.C.), Service de Neurologie, Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation, Bron, France; Observatoire Français de La Sclérose en Plaques (R.C.), Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, France; Eugène Devic EDMUS Foundation Against Multiple Sclerosis (R.C.), State-approved Foundation, Bron, France; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), First Faculty of Medicine, Charles University in Prague and General University Hospital, Czech Republic; Nancy University Hospital (M.D.), Department of Neurology, Nancy, France; Université de Lorraine (M.D.), APEMAC, Nancy, France; Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Catania, Italy; Multiple Sclerosis Center (F.P.), University of Catania, Italy; CHU de Strasbourg (J.D.S.), Department of Neurology and Clinical Investigation Center, CIC 1434, INSERM 1434, Strasbourg, France; Hospital Universitario Virgen Macarena (G.I., S.E.), Sevilla, Spain; CHU Pontchaillou (G.E.), CIC1414 INSERM, Rennes, France; CHUM MS Center and Universite de Montreal (A.P., M.G.), Canada; Dokuz Eylul University (S.O.), Konak/Izmir, Turkey; CISSS Chaudière-Appalache (P.G.), Levis, Canada; CHU Lille (H.Z.), CRCSEP Lille, Univ Lille, U1172, France; CHU de Toulouse (J.C.), Hôpital Pierre-Paul Riquet, Department of Neurology, CRC-SEP, France; Département de Neurologie (E.M.), Hôpital Pitié-Salpêtrière, APHP, Paris; CHU de Dijon (T.M.), Department of Neurology, EA4184, France; Department NEUROFARBA (M.P.A.), University of Florence, Italy; CHU de Montpellier (P.L.), MS Unit, France; University of Montpellier (MUSE) (P.L.), France; Division of Neurology (Raed Alroughani), Department of Medicine, Amiri Hospital, Sharq, Kuwait; Department of Neurology (K.B., O.S.), Box Hill Hospital, Melbourne, Australia; Monash University (K.B., O.S.), Melbourne, Australia; Melbourne MS Centre (K.B.), Royal Melbourne Hospital, Australia; The Alfred Hospital (O.S.), Melbourne, Australia; Medical Faculty (M.T.), 19 Mayis University, Samsun, Turkey; CHU de Nantes (D.A.L.), Service de Neurologie & CIC015 INSERM, France; CRTI-Inserm U1064 (D.A.L.), Nantes, France; CHU de Besançon (E.B.), Service de Neurologie 25 030 Besançon, France; Neuro Rive-Sud (F.G.M.), Quebec, Canada; Neurology (C.L.-F.), UR2CA, Centre Hospitalier Universitaire Pasteur2, Université Nice Côte d'Azur, Nice, France; UOC Neurologia (E.C.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; KTU Medical Faculty Farabi Hospital (C.B.), Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle, Australia; Department of Neurology (J.L.-S.), John Hunter Hospital, Hunter New England Health, Newcastle, Australia; CHU Clermont-Ferrand (Pierre Clavelou), Department of Neurology; Université Clermont Auvergne, Inserm, Neuro-Dol, Clermont-Ferrand, France; Sorbonne Universités (B.S.), UPMC Paris 06, Brain and Spine Institute, ICM, Hôpital de La Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, and Department of Neurology, AP-HP, Saint-Antoine Hospital, Paris, France; CSSS Saint-Jérôme (Julie Prevost), Saint-Jerome, Canada; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine and Clinical Research, University Hospital and University of Basel, Switzerland; Aix Marseille Univ (Jean Pelletier), APHM, Hôpital de La Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, France; Isfahan University of Medical Sciences (V.S.), Iran; Nehme and Therese Tohme Multiple Sclerosis Center (B.I.Y., S.J.K.), American University of Beirut Medical Center, Beirut, Lebanon; Department of Neurology (Oliver Gerlach), Zuyderland Medical Center, Sittard-Geleen, Netherlands; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.L.A.S.), Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Université Catholique de Louvain, Brussels, Belgium; Fondation Rotschild (Olivier Gout), Department of Neurology, Paris, France; Haydarpasa Numune Training and Research Hospital (R.T.), Istanbul, Turkey; Hôpital de Poissy (O.H.), Department of Neurology, France; Department of Neurology (E.T.), Nimes University Hospital, France; Institut de Génomique Fonctionnelle (E.T.), UMR5203, INSERM 1191, Univ. Montpellier, France; University of Queensland (P.A.M.), Brisbane, Australia; Royal Brisbane and Women's Hospital (P.A.M.), Australia; Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases (A.S.), Istanbul, Turkey; CHU de Rouen (B.B.), Department of Neurology, France; Flinders University (M.S.), Adelaide, Australia; Instituto de Investigación Sanitaria Biodonostia (T.C.-T.), Hospital Universitario Donostia, San Sebastián, Spain; CHU de Reims (S.B.), Department of Neurology, France; Nemocnice Jihlava (Radek Ampapa), Czech Republic; Monash Medical Centre (E.G.B.), Melbourne, Australia; APHP (A.W.), Hôpital Henri Mondor, Department of Neurology, Créteil, France; Austin Health (R.A.M.), Melbourne, Australia; University Hospital Reina Sofia (E.A.-M.), Cordoba, Spain; CHU de La Martinique (Philippe Cabre), Department of Neurology, Fort-de-France, France; Hôpital Sud Francilien (N.H.B.), Department of Neurology, Corbeil Essonnes, France; Department of Neurology (A.V.W., H.B.), The Alfred Hospital, Melbourne, Australia; Central Clinical School (A.V.W., H.B.), Monash University, Melbourne, Australia; Department of Neurology (G.L., L.V.H.), University Hospital Ghent, Belgium; Hospital Germans Trias I Pujol (C.M.R.-T.), Badalona, Spain; CHU La Milétrie (N.M.), Hôpital Jean Bernard, Department of Neurology, Poitiers, France; Liverpool Hospital (S.H.), Sydney, Australia; Hospital de Galdakao-Usansolo (J.L.S.-M.), Spain; Brain and Mind Centre (M.H.B.), Sydney, Australia; CHU Bicêtre (C.L.), Department of Neurology, F-94275 Le Kremlin Bicêtre, France; Westmead Hospital (Steve Vucic), Sydney, Australia; Department of Neurology (Y.S., R.G.), Razi Hospital, Manouba, Tunisia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Hospital Universitari MútuaTerrassa (J.S.), Barcelona, Spain; Groene Hart Ziekenhuis (K.G.), Gouda, Netherlands; Sultan Qaboos University Hospital (A.A.-A.), Al-Khodh, Oman; Universidade Metropolitana de Santos (Y.D.F.), Santos, Brazil; Service de Neurologie (Sandra Vukusic), Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France; Centre des Neurosciences de Lyon (Sandra Vukusic), Observatoire Français de La Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, France; and Université Claude Bernard Lyon 1 (Sandra Vukusic), Faculté de Médecine Lyon Est, France.
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.
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