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 & 20 others 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

Research output: Contribution to journalArticleResearchpeer-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 progressive MS. 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-remitting MS 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 progressive MS. 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 progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P <.001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P <.001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P =.005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P =.009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P =.046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P =.03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P <.001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS 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 languageEnglish
Pages (from-to)175-187
Number of pages13
JournalJAMA
Volume321
Issue number2
DOIs
Publication statusPublished - 15 Jan 2019

Cite this

Brown, J. W. L., Coles, A., Horakova, D., Havrdova, E., Izquierdo, G., Prat, A., ... Robertson, N. (2019). Association of Initial Disease-Modifying Therapy with Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA, 321(2), 175-187. https://doi.org/10.1001/jama.2018.20588
Brown, J. William L. ; Coles, Alasdair ; Horakova, Dana ; Havrdova, Eva ; Izquierdo, Guillermo ; Prat, Alexandre ; Girard, Marc ; Duquette, Pierre ; Trojano, Maria ; Lugaresi, Alessandra ; Bergamaschi, Roberto ; Grammond, Pierre ; Alroughani, Raed ; Hupperts, Raymond ; McCombe, Pamela ; Van Pesch, Vincent ; Sola, Patrizia ; Ferraro, Diana ; Grand'Maison, Francois ; Terzi, Murat ; Lechner-Scott, Jeannette ; Flechter, Schlomo ; Slee, Mark ; Shaygannejad, Vahid ; Pucci, Eugenio ; Granella, Franco ; Jokubaitis, Vilija ; Willis, Mark ; Rice, Claire ; Scolding, Neil ; Wilkins, Alastair ; Pearson, Owen R. ; Ziemssen, Tjalf ; Hutchinson, Michael ; Harding, Katharine ; Jones, Joanne ; McGuigan, Christopher ; Butzkueven, Helmut ; Kalincik, Tomas ; Robertson, Neil. / Association of Initial Disease-Modifying Therapy with Later Conversion to Secondary Progressive Multiple Sclerosis. In: JAMA. 2019 ; Vol. 321, No. 2. pp. 175-187.
@article{b46142c4c08e4c098dbbdcab2e7b6ea7,
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 progressive MS. 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-remitting MS 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 progressive MS. 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 progressive MS than matched untreated patients (HR, 0.71; 95{\%} CI, 0.61-0.81; P <.001; 5-year absolute risk, 12{\%} [49 of 407] vs 27{\%} [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95{\%} CI, 0.22-0.62; P <.001; 5-year absolute risk, 7{\%} [6 of 85] vs 32{\%} [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95{\%} CI, 0.43-0.86; P =.005; 5-year absolute risk, 19{\%} [16 of 82] vs 38{\%} [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95{\%} CI, 0.32-0.85; P =.009; 5-year absolute risk, 10{\%} [4 of 44] vs 25{\%} [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95{\%} CI, 0.44-0.99; P =.046); 5-year absolute risk, 7{\%} [16 of 235] vs 12{\%} [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95{\%} CI, 0.61-0.98; P =.03; 5-year absolute risk, 3{\%} [4 of 120] vs 6{\%} [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95{\%} CI, 0.66-0.88; P <.001; 5-year absolute risk, 8{\%} [25 of 307] vs 14{\%} [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.",
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",
year = "2019",
month = "1",
day = "15",
doi = "10.1001/jama.2018.20588",
language = "English",
volume = "321",
pages = "175--187",
journal = "JAMA",
issn = "0098-7484",
publisher = "American Medical Association (AMA)",
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 2019, 'Association of Initial Disease-Modifying Therapy with Later Conversion to Secondary Progressive Multiple Sclerosis', JAMA, vol. 321, no. 2, pp. 175-187. https://doi.org/10.1001/jama.2018.20588

Association of Initial Disease-Modifying Therapy with Later Conversion to Secondary Progressive Multiple Sclerosis. / Brown, J. William L.; Coles, Alasdair; Horakova, Dana; Havrdova, Eva; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Trojano, Maria; Lugaresi, Alessandra; Bergamaschi, Roberto; Grammond, Pierre; Alroughani, Raed; Hupperts, Raymond; McCombe, Pamela; Van Pesch, Vincent; Sola, Patrizia; Ferraro, Diana; Grand'Maison, Francois; Terzi, Murat; Lechner-Scott, Jeannette; Flechter, Schlomo; Slee, Mark; Shaygannejad, Vahid; Pucci, Eugenio; Granella, Franco; Jokubaitis, Vilija; Willis, Mark; Rice, Claire; Scolding, Neil; Wilkins, Alastair; Pearson, Owen R.; Ziemssen, Tjalf; Hutchinson, Michael; Harding, Katharine; Jones, Joanne; McGuigan, Christopher; Butzkueven, Helmut; Kalincik, Tomas; Robertson, Neil.

In: JAMA, Vol. 321, No. 2, 15.01.2019, p. 175-187.

Research output: Contribution to journalArticleResearchpeer-review

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

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 progressive MS. 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-remitting MS 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 progressive MS. 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 progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P <.001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P <.001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P =.005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P =.009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P =.046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P =.03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P <.001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS 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 progressive MS. 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-remitting MS 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 progressive MS. 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 progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P <.001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P <.001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P =.005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P =.009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P =.046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P =.03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P <.001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

UR - http://www.scopus.com/inward/record.url?scp=85059962064&partnerID=8YFLogxK

U2 - 10.1001/jama.2018.20588

DO - 10.1001/jama.2018.20588

M3 - Article

VL - 321

SP - 175

EP - 187

JO - JAMA

JF - JAMA

SN - 0098-7484

IS - 2

ER -