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.

Abertawe Bro Morgannwg University Local Health Board Swansea UK

Amiri Hospital Qurtoba Kuwait City Kuwait

Azienda Ospedaliera San Giuseppe Moscati di Avellino Avellino Italy

Azienda Sanitaria Unica Regionale Marche AV3 Macerata Italy

Brain and Mind Centre Camperdown NSW Australia

C Mondino National Neurological Institute Pavia Italy

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

Centre hospitalier de l'Université de Montréal Montreal QC Canada

Centres intégrés de santé et de services sociaux de Chaudière Appalache Levis QC Canada

Cliniques Universitaires Saint Luc Brussels Belgium

Department of Basic Medical Sciences Neuroscience and Sense Organs University of Bari Bari Italy

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Medicine University of Melbourne Melbourne VIC Australia

Department of Neurology and Center of Clinical Neuroscience General University Hospital and Charles University Prague Czech Republic

Department of Neurology Box Hill Hospital Monash University Melbourne VIC Australia

Department of Neurology Institute of Psychological Medicine and Clinical Neuroscience Cardiff University University Hospital of Wales Cardiff UK

Department of Neurology Royal Melbourne Hospital 300 Grattan St Melbourne 3050 Australia

Department of Neurology Southmead Hospital Westbury on Trym Bristol UK

Flinders University Adelaide SA Australia

Groene Hart Ziekenhuis Gouda Netherlands

Hopital Notre Dame Montreal QC Canada

Hospital de Galdakao Usansolo Galdakao Spain

Hospital Germans Trias i Pujol Badalona Spain

Hospital Italiano Buenos Aires Argentina

Hospital Universitario Donostia San Sebastián Spain

Hospital Universitario Virgen Macarena Sevilla Spain

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

Jahn Ferenc Teaching Hospital Budapest Hungary

KTÜ Medical Faculty Farabi Hospital Karadeniz Technical University Trabzon Turkey

Liverpool Hospital Sydney NSW Australia

Medical Faculty 19 Mayis University Kurupelit Samsun Turkey

Nemocnice Jihlava Jihlava Czech Republic

Neuro Rive Sud Greenfield Park QC Canada

NMR Research Unit Queen Square Multiple Sclerosis Centre University College London Institute of Neurology London UK

Nuovo Ospedale Civile Sant'Agostino Estense Modena Italy

Royal Brisbane and Women's Hospital Brisbane QLD Australia

School of Clinical Sciences University of Bristol Bristol UK

School of Medicine and Medical Sciences University College Dublin St Vincent's University Hospital Dublin Ireland

Semmelweis University Budapest Budapest Hungary

Université de Montreal Montreal QC Canada

University of Debrecen Faculty of Medicine Department of Neurology Debrecen Hungary

University of Newcastle Newcastle NSW Australia

University of Parma Parma Italy

Westmead Hospital Sydney NSW Australia

Zuyderland Ziekenhuis Sittard Netherlands

000      

00000naa a2200000 a 4500

001      

bmc17023289

003      

CZ-PrNML

005      

20170831102437.0

007      

ta

008      

170720s2017 enk f 000 0|eng||

009      

AR

024    7_

$a 10.1016/S1474-4422(17)30007-8 $2 doi

035    __

$a (PubMed)28209331

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a enk

100    1_

$a Kalincik, Tomas $u 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.

245    10

$a Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study / $c T. Kalincik, JWL. Brown, N. Robertson, M. Willis, N. Scolding, CM. Rice, A. Wilkins, O. Pearson, T. Ziemssen, M. Hutchinson, C. McGuigan, V. Jokubaitis, T. Spelman, D. Horakova, E. Havrdova, M. Trojano, G. Izquierdo, A. Lugaresi, A. Prat, M. Girard, P. Duquette, P. Grammond, R. Alroughani, E. Pucci, P. Sola, R. Hupperts, J. Lechner-Scott, M. Terzi, V. Van Pesch, C. Rozsa, F. Grand'Maison, C. Boz, F. Granella, M. Slee, D. Spitaleri, J. Olascoaga, R. Bergamaschi, F. Verheul, S. Vucic, P. McCombe, S. Hodgkinson, JL. Sanchez-Menoyo, R. Ampapa, M. Simo, T. Csepany, C. Ramo, E. Cristiano, M. Barnett, H. Butzkueven, A. Coles, . ,

520    9_

$a 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.

650    _2

$a dospělí $7 D000328

650    _2

$a humanizované monoklonální protilátky $x terapeutické užití $7 D061067

650    _2

$a kohortové studie $7 D015331

650    _2

$a databáze bibliografické $x statistika a číselné údaje $7 D016206

650    _2

$a posuzování pracovní neschopnosti $7 D004185

650    _2

$a ženské pohlaví $7 D005260

650    _2

$a fingolimod hydrochlorid $x terapeutické užití $7 D000068876

650    _2

$a lidé $7 D006801

650    _2

$a imunologické faktory $x terapeutické užití $7 D007155

650    _2

$a interferon beta $x terapeutické užití $7 D016899

650    _2

$a mužské pohlaví $7 D008297

650    _2

$a relabující-remitující roztroušená skleróza $x farmakoterapie $7 D020529

650    _2

$a natalizumab $x terapeutické užití $7 D000069442

650    _2

$a výsledek terapie $7 D016896

650    _2

$a mladý dospělý $7 D055815

655    _2

$a časopisecké články $7 D016428

700    1_

$a Brown, J William L $u 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.

700    1_

$a Robertson, Neil $u Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK.

700    1_

$a Willis, Mark $u Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK.

700    1_

$a Scolding, Neil $u Department of Neurology, Southmead Hospital, Westbury-on-Trym, Bristol, UK; School of Clinical Sciences, University of Bristol, Bristol, UK.

700    1_

$a Rice, Claire M $u Department of Neurology, Southmead Hospital, Westbury-on-Trym, Bristol, UK; School of Clinical Sciences, University of Bristol, Bristol, UK.

700    1_

$a Wilkins, Alastair $u Department of Neurology, Southmead Hospital, Westbury-on-Trym, Bristol, UK; School of Clinical Sciences, University of Bristol, Bristol, UK.

700    1_

$a Pearson, Owen $u Abertawe Bro Morgannwg University Local Health Board, Swansea, UK.

700    1_

$a Ziemssen, Tjalf $u 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.

700    1_

$a Hutchinson, Michael $u School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland.

700    1_

$a McGuigan, Christopher $u School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland.

700    1_

$a Jokubaitis, Vilija $u Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

700    1_

$a Spelman, Tim $u Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

700    1_

$a Horakova, Dana $u Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University, Prague, Czech Republic.

700    1_

$a Havrdova, Eva $u Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University, Prague, Czech Republic.

700    1_

$a Trojano, Maria $u Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.

700    1_

$a Izquierdo, Guillermo $u Hospital Universitario Virgen Macarena, Sevilla, Spain.

700    1_

$a Lugaresi, Alessandra $u Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

700    1_

$a Prat, Alexandre $u Hopital Notre Dame, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada; Université de Montreal, Montreal, QC, Canada.

700    1_

$a Girard, Marc $u Hopital Notre Dame, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada; Université de Montreal, Montreal, QC, Canada.

700    1_

$a Duquette, Pierre $u Hopital Notre Dame, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada; Université de Montreal, Montreal, QC, Canada.

700    1_

$a Grammond, Pierre $u Centres intégrés de santé et de services sociaux de Chaudière-Appalache, Levis, QC, Canada.

700    1_

$a Alroughani, Raed $u Amiri Hospital, Qurtoba, Kuwait City, Kuwait. $7 gn_A_00004804

700    1_

$a Pucci, Eugenio $u Azienda Sanitaria Unica Regionale Marche AV3, Macerata, Italy.

700    1_

$a Sola, Patrizia $u Nuovo Ospedale Civile Sant'Agostino-Estense, Modena, Italy.

700    1_

$a Hupperts, Raymond $u Zuyderland Ziekenhuis, Sittard, Netherlands.

700    1_

$a Lechner-Scott, Jeannette $u University of Newcastle, Newcastle, NSW, Australia.

700    1_

$a Terzi, Murat $u Medical Faculty, 19 Mayis University, Kurupelit, Samsun, Turkey.

700    1_

$a Van Pesch, Vincent $u Cliniques Universitaires Saint-Luc, Brussels, Belgium.

700    1_

$a Rozsa, Csilla $u Jahn Ferenc Teaching Hospital, Budapest, Hungary.

700    1_

$a Grand'Maison, François $u Neuro Rive-Sud, Greenfield Park, QC, Canada.

700    1_

$a Boz, Cavit $u KTÜ Medical Faculty Farabi Hospital, Karadeniz Technical University, Trabzon, Turkey.

700    1_

$a Granella, Franco $u University of Parma, Parma, Italy.

700    1_

$a Slee, Mark $u Flinders University, Adelaide, SA, Australia.

700    1_

$a Spitaleri, Daniele $u Azienda Ospedaliera San Giuseppe Moscati di Avellino, Avellino, Italy.

700    1_

$a Olascoaga, Javier $u Hospital Universitario Donostia, San Sebastián, Spain.

700    1_

$a Bergamaschi, Roberto $u C Mondino National Neurological Institute, Pavia, Italy.

700    1_

$a Verheul, Freek $u Groene Hart Ziekenhuis, Gouda, Netherlands.

700    1_

$a Vucic, Steve $u Westmead Hospital, Sydney, NSW, Australia.

700    1_

$a McCombe, Pamela $u Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

700    1_

$a Hodgkinson, Suzanne $u Liverpool Hospital, Sydney, NSW, Australia.

700    1_

$a Sanchez-Menoyo, Jose Luis $u Hospital de Galdakao-Usansolo, Galdakao, Spain.

700    1_

$a Ampapa, Radek $u Nemocnice Jihlava, Jihlava, Czech Republic. $7 gn_A_00005737

700    1_

$a Simo, Magdolna $u Semmelweis University Budapest, Budapest, Hungary.

700    1_

$a Csepany, Tunde $u University of Debrecen, Faculty of Medicine, Department of Neurology, Debrecen, Hungary.

700    1_

$a Ramo, Cristina $u Hospital Germans Trias i Pujol, Badalona, Spain.

700    1_

$a Cristiano, Edgardo $u Hospital Italiano, Buenos Aires, Argentina.

700    1_

$a Barnett, Michael $u Brain and Mind Centre, Camperdown, NSW, Australia.

700    1_

$a Butzkueven, Helmut $u 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.

700    1_

$a Coles, Alasdair $u Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

700    1_

$a ,

773    0_

$w MED00006921 $t The Lancet. Neurology $x 1474-4465 $g Roč. 16, č. 4 (2017), s. 271-281

856    41

$u https://pubmed.ncbi.nlm.nih.gov/28209331 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20170720 $b ABA008

991    __

$a 20170831103027 $b ABA008

999    __

$a ok $b bmc $g 1238970 $s 984202

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2017 $b 16 $c 4 $d 271-281 $e 20170211 $i 1474-4465 $m Lancet neurology $n Lancet Neurol $x MED00006921

LZP    __

$a Pubmed-20170720