title: Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.
abstract: 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.
authors.affiliation: 1 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Iaffaldano
authors.affiliation: 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.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucisano
authors.affiliation: 3 Multiple Sclerosis Center, S.Andrea Hospital, Dept. of Neurology and Psychiatry, La Sapienza University, Via di Grottarossa, 1035, 00189, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pozzilli
authors.affiliation: 4 Department of Neurosciences, Reproductive and Odontostomatological Sciences, University "Federico II", Via Pansini 5, 80131 Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brescia Morra
authors.affiliation: 5 Multiple Sclerosis Center, S.Antonio Abate Hospital, Via Pastori 4, 21013 Gallarate (VA), Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ghezzi
authors.affiliation: 6 Multiple Sclerosis Center, Policlinico Umberto I, La Sapienza University, Viale dell'Università 30, 00185, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millefiorini
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Patti
authors.affiliation: 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.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lugaresi
authors.affiliation: 9 Operative Unit of Neurology, "Dimiccoli" General Hospital, Viale Ippocrate 15, 76121, Barletta, Italy.
authors.forename: Giovanni Bosco
authors.initials: GB
authors.lastname: Zimatore
authors.affiliation: 10 Multiple Sclerosis Center, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.affiliation: 11 Department of NEUROFARBA, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.affiliation: 12 Neurologia 2, CRESM (Centro Riferimento Regionale Sclerosi Multipla), AOU S. Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertolotto
authors.affiliation: 13 Inter-department Multiple Sclerosis Research Centre, C. Mondino National Institute of Neurology Foundation, Via Mondino 2, 27100, Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bergamaschi
authors.affiliation: 14 Department of Neurosciences, University of Parma, Via Volturno 39, 43125, Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Granella
authors.affiliation: 15 Neurology Unit, "Madonna delle Grazie" Hospital, Contrada Cattedra Ambulante snc, 75100, Matera, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coniglio
authors.affiliation: 16 Division of Neurology, Second University of Naples, Via Costantinopoli 104, 80138, Naples, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Tedeschi
authors.affiliation: 17 Department of Neurosciences, Neurology Unit, University of Modena and Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Via Giardini 1355, 41126, Modena, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sola
authors.affiliation: 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.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Lus
authors.affiliation: 19 Neurological Department, "Maggiore" Hospital, Largo Dossena 2, 26013, Crema, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ferrò
authors.affiliation: 20 Department of Neurosciences, "S.Giovanni di Dio" Hospital, Largo Città di Ippocrate, 84131, Salerno, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Iuliano
authors.affiliation: 21 Neurology Unit, "S.Giovanni Battista" Hospital, Via Arcamone, 06124, Foligno, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Corea
authors.affiliation: 22 Multiple Sclerosis Center, Neurological Department, "Niguarda Ca' Granda" Hospital, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Protti
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Cavalla
authors.affiliation: 24 Multiple Sclerosis Center, Medicine Department, Fidenza Hospital, Via Don Enrico Tincati 5, 43125 Fidenza, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Guareschi
authors.affiliation: 25 Department of Neurology, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Via Olgettina, 48 20132, Milan, Italy.
authors.forename: Mariaemma
authors.initials: M
authors.lastname: Rodegher
authors.affiliation: 1 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Paolicelli
authors.affiliation: 1 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Tortorella
authors.affiliation: 2 Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Foundation, Via Nazionale per Lanciano 8, 66030, Santa Maria Imbaro (CH), Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lepore
authors.affiliation: 3 Multiple Sclerosis Center, S.Andrea Hospital, Dept. of Neurology and Psychiatry, La Sapienza University, Via di Grottarossa, 1035, 00189, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Prosperini
authors.affiliation: 4 Department of Neurosciences, Reproductive and Odontostomatological Sciences, University "Federico II", Via Pansini 5, 80131 Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Saccà
authors.affiliation: 5 Multiple Sclerosis Center, S.Antonio Abate Hospital, Via Pastori 4, 21013 Gallarate (VA), Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baroncini
authors.affiliation: 25 Department of Neurology, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Via Olgettina, 48 20132, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
mesh_terms: D000328:Adult; D015331:Cohort Studies; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D000068717:Glatiramer Acetate / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D007558:Italy; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D000069442:Natalizumab / Q000627:therapeutic use*; D016012:Poisson Distribution; D011446:Prospective Studies; D012042:Registries; D012044:Regression Analysis; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D000068717:Glatiramer Acetate; D016899:Interferon-beta; D000068876:Fingolimod Hydrochloride
keywords: fingolimod; glatiramer acetate; interferon beta; multiple sclerosis; natalizumab discontinuation