Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

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; Marco Onofrj; Giovanna De Luca; Valeria Di Tommaso; Daniela Travaglini; Erika Pietrolongo; Maria di Ioia; Deborah Farina; Luca Mancinelli; Suzanne Hodgkinson; Celia Oreja-Guevara; MSBase Study Grp

doi:10.1001/jama.2018.20588

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

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 TerziJeannette 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, Marco Onofrj, Giovanna De Luca, Valeria Di Tommaso, Daniela Travaglini, Erika Pietrolongo, Maria di Ioia, Deborah Farina, Luca Mancinelli, Suzanne Hodgkinson, Celia Oreja-Guevara, MSBase Study Grp

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressiveMS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remittingMS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.

EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressiveMS.

RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressiveMS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P

CONCLUSIONS AND RELEVANCE Among patients with relapsing-remittingMS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressiveMS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Original language	English
Pages (from-to)	175-187
Number of pages	13
Journal	JAMA-Journal of the American Medical Association
Volume	321
Issue number	2
DOIs	https://doi.org/10.1001/jama.2018.20588
Publication status	Published - 15 Jan 2019

Keywords

ALEMTUZUMAB
DISABILITY
FINGOLIMOD
GLATIRAMER ACETATE
INTERFERON-BETA
MULTICENTER
NATALIZUMAB
OUTCOMES
TIME

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Brown, J. W. L., Coles, A., Horakova, D., Havrdova, E., Izquierdo, G., Prat, A., Girard, M., Duquette, P., Trojano, M., Lugaresi, A., Bergamaschi, R., Grammond, P., Alroughani, R., Hupperts, R., McCombe, P., Van Pesch, V., Sola, P., Ferraro, D., Grand'Maison, F., ... MSBase Study Grp (2019). Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA-Journal of the American Medical Association, 321(2), 175-187. https://doi.org/10.1001/jama.2018.20588

@article{65579db2fc99460aae4c810f420e76f7,

title = "Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis",

abstract = "IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressiveMS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remittingMS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressiveMS.RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressiveMS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; PCONCLUSIONS AND RELEVANCE Among patients with relapsing-remittingMS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressiveMS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.",

keywords = "ALEMTUZUMAB, DISABILITY, FINGOLIMOD, GLATIRAMER ACETATE, INTERFERON-BETA, MULTICENTER, NATALIZUMAB, OUTCOMES, TIME",

author = "Brown, {J. William L.} and Alasdair Coles and Dana Horakova and Eva Havrdova and Guillermo Izquierdo and Alexandre Prat and Marc Girard and Pierre Duquette and Maria Trojano and Alessandra Lugaresi and Roberto Bergamaschi and Pierre Grammond and Raed Alroughani and Raymond Hupperts and Pamela McCombe and {Van Pesch}, Vincent and Patrizia Sola and Diana Ferraro and Francois Grand'Maison and Murat Terzi and Jeannette Lechner-Scott and Schlomo Flechter and Mark Slee and Vahid Shaygannejad and Eugenio Pucci and Franco Granella and Vilija Jokubaitis and Mark Willis and Claire Rice and Neil Scolding and Alastair Wilkins and Pearson, {Owen R.} and Tjalf Ziemssen and Michael Hutchinson and Katharine Harding and Joanne Jones and Christopher McGuigan and Helmut Butzkueven and Tomas Kalincik and Neil Robertson and Marco Onofrj and {De Luca}, Giovanna and {Di Tommaso}, Valeria and Daniela Travaglini and Erika Pietrolongo and {di Ioia}, Maria and Deborah Farina and Luca Mancinelli and Suzanne Hodgkinson and Celia Oreja-Guevara and {MSBase Study Grp}",

note = "Funding Information: supported by National Health and Medical Research Council of Australia (fellowships 1140766 and 1080518, project grants 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), a Next Generation Fellowship funded by the Grand Charity of the Freemason{\textquoteright}s (recipient JWLB), and the MSBase 2017 Fellowship (recipient JWLB). Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Publisher Copyright: {\textcopyright} 2019 American Medical Association. All rights reserved.",

year = "2019",

month = jan,

day = "15",

doi = "10.1001/jama.2018.20588",

language = "English",

volume = "321",

pages = "175--187",

journal = "JAMA-Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "2",

}

Brown, JWL, Coles, A, Horakova, D, Havrdova, E, Izquierdo, G, Prat, A, Girard, M, Duquette, P, Trojano, M, Lugaresi, A, Bergamaschi, R, Grammond, P, Alroughani, R, Hupperts, R, McCombe, P, Van Pesch, V, Sola, P, Ferraro, D, Grand'Maison, F, Terzi, M, Lechner-Scott, J, Flechter, S, Slee, M, Shaygannejad, V, Pucci, E, Granella, F, Jokubaitis, V, Willis, M, Rice, C, Scolding, N, Wilkins, A, Pearson, OR, Ziemssen, T, Hutchinson, M, Harding, K, Jones, J, McGuigan, C, Butzkueven, H, Kalincik, T, Robertson, N, Onofrj, M, De Luca, G, Di Tommaso, V, Travaglini, D, Pietrolongo, E, di Ioia, M, Farina, D, Mancinelli, L, Hodgkinson, S, Oreja-Guevara, C & MSBase Study Grp 2019, 'Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis', JAMA-Journal of the American Medical Association, vol. 321, no. 2, pp. 175-187. https://doi.org/10.1001/jama.2018.20588

TY - JOUR

T1 - Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

AU - Brown, J. William L.

AU - Coles, Alasdair

AU - Horakova, Dana

AU - Havrdova, Eva

AU - Izquierdo, Guillermo

AU - Prat, Alexandre

AU - Girard, Marc

AU - Duquette, Pierre

AU - Trojano, Maria

AU - Lugaresi, Alessandra

AU - Bergamaschi, Roberto

AU - Grammond, Pierre

AU - Alroughani, Raed

AU - Hupperts, Raymond

AU - McCombe, Pamela

AU - Van Pesch, Vincent

AU - Sola, Patrizia

AU - Ferraro, Diana

AU - Grand'Maison, Francois

AU - Terzi, Murat

AU - Lechner-Scott, Jeannette

AU - Flechter, Schlomo

AU - Slee, Mark

AU - Shaygannejad, Vahid

AU - Pucci, Eugenio

AU - Granella, Franco

AU - Jokubaitis, Vilija

AU - Willis, Mark

AU - Rice, Claire

AU - Scolding, Neil

AU - Wilkins, Alastair

AU - Pearson, Owen R.

AU - Ziemssen, Tjalf

AU - Hutchinson, Michael

AU - Harding, Katharine

AU - Jones, Joanne

AU - McGuigan, Christopher

AU - Butzkueven, Helmut

AU - Kalincik, Tomas

AU - Robertson, Neil

AU - Onofrj, Marco

AU - De Luca, Giovanna

AU - Di Tommaso, Valeria

AU - Travaglini, Daniela

AU - Pietrolongo, Erika

AU - di Ioia, Maria

AU - Farina, Deborah

AU - Mancinelli, Luca

AU - Hodgkinson, Suzanne

AU - Oreja-Guevara, Celia

AU - MSBase Study Grp

N1 - Funding Information: supported by National Health and Medical Research Council of Australia (fellowships 1140766 and 1080518, project grants 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), a Next Generation Fellowship funded by the Grand Charity of the Freemason’s (recipient JWLB), and the MSBase 2017 Fellowship (recipient JWLB). Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Publisher Copyright: © 2019 American Medical Association. All rights reserved.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressiveMS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remittingMS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressiveMS.RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressiveMS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; PCONCLUSIONS AND RELEVANCE Among patients with relapsing-remittingMS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressiveMS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

AB - IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressiveMS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remittingMS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressiveMS.RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressiveMS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; PCONCLUSIONS AND RELEVANCE Among patients with relapsing-remittingMS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressiveMS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

KW - ALEMTUZUMAB

KW - DISABILITY

KW - FINGOLIMOD

KW - GLATIRAMER ACETATE

KW - INTERFERON-BETA

KW - MULTICENTER

KW - NATALIZUMAB

KW - OUTCOMES

KW - TIME

U2 - 10.1001/jama.2018.20588

DO - 10.1001/jama.2018.20588

M3 - Article

SN - 0098-7484

VL - 321

SP - 175

EP - 187

JO - JAMA-Journal of the American Medical Association

JF - JAMA-Journal of the American Medical Association

IS - 2

ER -

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

Abstract

Keywords

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