From 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.
Neurology. 2022 Oct 25;99(17):e1926-e1944. doi: 10.1212/WNL.0000000000201029. Epub 2022 Aug 17.
To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.
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.
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).
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).
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.
评估多发性硬化症（MS）疾病修正治疗停药后疾病活动的复发率。
这是一项来自 2 个大型 MS 观察性登记处（MSBase 和 OFSEP）的回顾性队列研究。纳入了接受缓解-复发型 MS 治疗并随后随访 12 个月的已停止疾病修正治疗的患者。主要研究结局是根据是否开始后续治疗，将停药后 12 个月的年复发率分层。次要终点是停药后首次复发和残疾累积的预测因素。
共纳入了 14213 例患者，18029 个符合条件的治疗停药期，用于 7 种治疗。停药后 2 个月（2-4 月 ARR0.47，95%CI0.43-0.51）开始出现复发率（ARR）增加。在 2-4 个月内开始使用后续治疗可降低疾病再激活的幅度（ARR 差异的平均值：0.15，0.08-0.22）。停用芬戈莫德后，总体复发率增加（1-2 月 ARR：0.80，0.70-0.89），在 1-2 个月内开始新治疗的患者更快稳定（ARR 差异的平均值：0.14，-0.01 至 0.29）。其他治疗药物的疾病再激活幅度较低，但在停药后 1-10 个月开始使用另一种治疗药物时，进一步降低。复发的预测因素是停药前一年内的复发率较高、女性、年龄较小和 EDSS 评分较高。开始使用后续治疗可降低复发风险（HR0.76，95%CI0.72-0.81）和残疾累积（0.73，0.65-0.80）。
停药后疾病复发率因 MS 治疗药物而异，停止不同治疗药物后未经治疗的队列中，复发活动的高峰期为 1-10 个月。这些结果表明，停止抗贩运治疗（那他珠单抗和芬戈莫德）后，应尽量缩短无治疗间隔。
本研究提供了 III 级证据，表明在多发性硬化症疾病修正治疗停药后几个月内会发生疾病再激活。开始使用后续治疗可降低疾病活动的风险。
