Marinella Clerico1, Irene Schiavetti2, Stefania F De Mercanti1, Federico Piazza1, Dario Gned3, Vincenzo Brescia Morra4, Roberta Lanzillo4, Angelo Ghezzi5, Anna Bianchi5, Giuseppe Salemi6, Sabrina Realmuto6, Patrizia Sola7, Francesca Vitetta7, Paola Cavalla8, Damiano Paolicelli9, Maria Trojano9, Maria Pia Sormani2, Luca Durelli1. 1. Division of Neurology, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy. 2. Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy. 3. Department of Oncology, University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy. 4. Department of Neurosciences, Reproductive, and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy. 5. Department of Neurology II, Center of Multiple Sclerosis, Azienda Ospedaliera Sant'Antonio Abate Hospital, Gallarate, Italy. 6. Section of Neurology, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy. 7. Neurology Unit, Department of Neurosciences, University of Modena and Reggio Emilia, Modena, Italy. 8. Division of Neurology and Multiple Sclerosis Center, Department of Neurosciences, University of Turin, Città della Salute e della Scienza University Hospital, Turin, Italy. 9. Department of Neuroscience and Sense Organs, University of Bari, Bari, Italy.
Abstract
IMPORTANCE: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE: To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE: This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION: Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.
IMPORTANCE: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE: To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS:Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE: This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION: Osservatorio Nazionale SullaSperimentazione Clinica dei Medicinali No. 131/2010.
Authors: Maria Trojano; Mar Tintore; Xavier Montalban; Jan Hillert; Tomas Kalincik; Pietro Iaffaldano; Tim Spelman; Maria Pia Sormani; Helmut Butzkueven Journal: Nat Rev Neurol Date: 2017-01-13 Impact factor: 42.937
Authors: Roderick P P W M Maas; Annemarie H G Muller-Hansma; Rianne A J Esselink; Jean-Luc Murk; Clemens Warnke; Joep Killestein; Mike P Wattjes Journal: J Neurol Date: 2016-07-11 Impact factor: 4.849