Tomas Kalincik1, J William L Brown2, Neil Robertson3, Mark Willis3, Neil Scolding4, Claire M Rice4, Alastair Wilkins4, Owen Pearson5, Tjalf Ziemssen6, Michael Hutchinson7, Christopher McGuigan7, Vilija Jokubaitis8, Tim Spelman8, Dana Horakova9, Eva Havrdova9, Maria Trojano10, Guillermo Izquierdo11, Alessandra Lugaresi12, Alexandre Prat13, Marc Girard13, Pierre Duquette13, Pierre Grammond14, Raed Alroughani15, Eugenio Pucci16, Patrizia Sola17, Raymond Hupperts18, Jeannette Lechner-Scott19, Murat Terzi20, Vincent Van Pesch21, Csilla Rozsa22, François Grand'Maison23, Cavit Boz24, Franco Granella25, Mark Slee26, Daniele Spitaleri27, Javier Olascoaga28, Roberto Bergamaschi29, Freek Verheul30, Steve Vucic31, Pamela McCombe32, Suzanne Hodgkinson33, Jose Luis Sanchez-Menoyo34, Radek Ampapa35, Magdolna Simo36, Tunde Csepany37, Cristina Ramo38, Edgardo Cristiano39, Michael Barnett40, Helmut Butzkueven41, Alasdair Coles42. 1. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia. Electronic address: tomas.kalincik@unimelb.edu.au. 2. NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London Institute of Neurology, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 3. Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK. 4. Department of Neurology, Southmead Hospital, Westbury-on-Trym, Bristol, UK; School of Clinical Sciences, University of Bristol, Bristol, UK. 5. Abertawe Bro Morgannwg University Local Health Board, Swansea, UK. 6. Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, Dresden, Germany; Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. 7. School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland. 8. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia. 9. Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University, Prague, Czech Republic. 10. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. 11. Hospital Universitario Virgen Macarena, Sevilla, Spain. 12. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 13. Hopital Notre Dame, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada; Université de Montreal, Montreal, QC, Canada. 14. Centres intégrés de santé et de services sociaux de Chaudière-Appalache, Levis, QC, Canada. 15. Amiri Hospital, Qurtoba, Kuwait City, Kuwait. 16. Azienda Sanitaria Unica Regionale Marche AV3, Macerata, Italy. 17. Nuovo Ospedale Civile Sant'Agostino-Estense, Modena, Italy. 18. Zuyderland Ziekenhuis, Sittard, Netherlands. 19. University of Newcastle, Newcastle, NSW, Australia. 20. Medical Faculty, 19 Mayis University, Kurupelit, Samsun, Turkey. 21. Cliniques Universitaires Saint-Luc, Brussels, Belgium. 22. Jahn Ferenc Teaching Hospital, Budapest, Hungary. 23. Neuro Rive-Sud, Greenfield Park, QC, Canada. 24. KTÜ Medical Faculty Farabi Hospital, Karadeniz Technical University, Trabzon, Turkey. 25. University of Parma, Parma, Italy. 26. Flinders University, Adelaide, SA, Australia. 27. Azienda Ospedaliera San Giuseppe Moscati di Avellino, Avellino, Italy. 28. Hospital Universitario Donostia, San Sebastián, Spain. 29. C Mondino National Neurological Institute, Pavia, Italy. 30. Groene Hart Ziekenhuis, Gouda, Netherlands. 31. Westmead Hospital, Sydney, NSW, Australia. 32. Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. 33. Liverpool Hospital, Sydney, NSW, Australia. 34. Hospital de Galdakao-Usansolo, Galdakao, Spain. 35. Nemocnice Jihlava, Jihlava, Czech Republic. 36. Semmelweis University Budapest, Budapest, Hungary. 37. University of Debrecen, Faculty of Medicine, Department of Neurology, Debrecen, Hungary. 38. Hospital Germans Trias i Pujol, Badalona, Spain. 39. Hospital Italiano, Buenos Aires, Argentina. 40. Brain and Mind Centre, Camperdown, NSW, Australia. 41. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia; Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia. 42. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Abstract
BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006). INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. FUNDING: National Health and Medical Research Council, and the University of Melbourne.
BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006). INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. FUNDING: National Health and Medical Research Council, and the University of Melbourne.
Authors: Carmen Tur; Marcello Moccia; Frederik Barkhof; Jeremy Chataway; Jaume Sastre-Garriga; Alan J Thompson; Olga Ciccarelli Journal: Nat Rev Neurol Date: 2018-01-12 Impact factor: 42.937
Authors: J William L Brown; Alasdair Coles; Dana Horakova; Eva Havrdova; Guillermo Izquierdo; Alexandre Prat; Marc Girard; Pierre Duquette; Maria Trojano; Alessandra Lugaresi; Roberto Bergamaschi; Pierre Grammond; Raed Alroughani; Raymond Hupperts; Pamela McCombe; Vincent Van Pesch; Patrizia Sola; Diana Ferraro; Francois Grand'Maison; Murat Terzi; Jeannette Lechner-Scott; Schlomo Flechter; Mark Slee; Vahid Shaygannejad; Eugenio Pucci; Franco Granella; Vilija Jokubaitis; Mark Willis; Claire Rice; Neil Scolding; Alastair Wilkins; Owen R Pearson; Tjalf Ziemssen; Michael Hutchinson; Katharine Harding; Joanne Jones; Christopher McGuigan; Helmut Butzkueven; Tomas Kalincik; Neil Robertson Journal: JAMA Date: 2019-01-15 Impact factor: 56.272