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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

49 Citations (Scopus)
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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 - Journal of the American Medical Association
Volume321
Issue number2
Early online date15 Jan 2019
DOIs
Publication statusPublished - 15 Jan 2019

Keywords

  • Adult
  • Alemtuzumab/therapeutic use
  • Cohort Studies
  • Disease Progression
  • Female
  • Fingolimod Hydrochloride/therapeutic use
  • Glatiramer Acetate/therapeutic use
  • Humans
  • Immunologic Factors/therapeutic use
  • Immunosuppressive Agents/therapeutic use
  • Interferon-beta/therapeutic use
  • Male
  • Multiple Sclerosis, Relapsing-Remitting/drug therapy
  • Natalizumab/therapeutic use
  • Time-to-Treatment

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  • Cite this

    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., ... Robertson, N. (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