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Brain. 2015 Nov;138(Pt 11):3275-86. doi: 10.1093/brain/awv260. Epub 2015 Sep 11.

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

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1 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.
1 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy 2 Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Foundation, Via Nazionale per Lanciano 8, 66030, Santa Maria Imbaro (CH), Italy.
3 Multiple Sclerosis Center, S.Andrea Hospital, Dept. of Neurology and Psychiatry, La Sapienza University, Via di Grottarossa, 1035, 00189, Rome, Italy.
4 Department of Neurosciences, Reproductive and Odontostomatological Sciences, University "Federico II", Via Pansini 5, 80131 Napoli, Italy.
5 Multiple Sclerosis Center, S.Antonio Abate Hospital, Via Pastori 4, 21013 Gallarate (VA), Italy.
6 Multiple Sclerosis Center, Policlinico Umberto I, La Sapienza University, Viale dell'Università 30, 00185, Rome, Italy.
7 Dipartimento di Scienze Mediche e Chirurgiche e Tecnologie Avanzate, GF Ingrassia, Sez. Neuroscienze, Centro Sclerosi Multipla, Università di Catania, Via Santa Sofia 78, 95123 Catania, Italy.
8 Department of Neuroscience, Imaging and Clinical Sciences, Multiple Sclerosis Center, "SS. Annunziata" Hospital, University "G. D'Annunzio", Via dei Vestini snc, 66100, Chieti, Italy.
9 Operative Unit of Neurology, "Dimiccoli" General Hospital, Viale Ippocrate 15, 76121, Barletta, Italy.
10 Multiple Sclerosis Center, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.
11 Department of NEUROFARBA, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
12 Neurologia 2, CRESM (Centro Riferimento Regionale Sclerosi Multipla), AOU S. Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
13 Inter-department Multiple Sclerosis Research Centre, C. Mondino National Institute of Neurology Foundation, Via Mondino 2, 27100, Pavia, Italy.
14 Department of Neurosciences, University of Parma, Via Volturno 39, 43125, Parma, Italy.
15 Neurology Unit, "Madonna delle Grazie" Hospital, Contrada Cattedra Ambulante snc, 75100, Matera, Italy.
16 Division of Neurology, Second University of Naples, Via Costantinopoli 104, 80138, Naples, Italy.
17 Department of Neurosciences, Neurology Unit, University of Modena and Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Via Giardini 1355, 41126, Modena, Italy.
18 Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Via Luciano Armanni 5, 80138, Napoli, Italy.
19 Neurological Department, "Maggiore" Hospital, Largo Dossena 2, 26013, Crema, Italy.
20 Department of Neurosciences, "S.Giovanni di Dio" Hospital, Largo Città di Ippocrate, 84131, Salerno, Italy.
21 Neurology Unit, "S.Giovanni Battista" Hospital, Via Arcamone, 06124, Foligno, Italy.
22 Multiple Sclerosis Center, Neurological Department, "Niguarda Ca' Granda" Hospital, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.
23 Multiple Sclerosis Center, Department of Neuroscience, University of Turin & City of Health and Science University Hospital of Turin, Via Verdi 8, 10124, Turin, Italy.
24 Multiple Sclerosis Center, Medicine Department, Fidenza Hospital, Via Don Enrico Tincati 5, 43125 Fidenza, Italy.
25 Department of Neurology, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Via Olgettina, 48 20132, Milan, Italy.
2 Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Foundation, Via Nazionale per Lanciano 8, 66030, Santa Maria Imbaro (CH), Italy.


The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.


fingolimod; glatiramer acetate; interferon beta; multiple sclerosis; natalizumab discontinuation

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