Medicine (RMH) - Research Publications

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Author: Diouf, Ibrahima × Author: Roos, Izanne × Start date: 2020 × Type: Journal Article ×

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    Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial
    Diouf, I ; Malpas, CB ; Sharmin, S ; Roos, I ; Horakova, D ; Kubala Havrdova, E ; Patti, F ; Shaygannejad, V ; Ozakbas, S ; Eichau, S ; Onofrj, M ; Lugaresi, A ; Alroughani, R ; Prat, A ; Duquette, P ; Terzi, M ; Boz, C ; Grand'Maison, F ; Sola, P ; Ferraro, D ; Grammond, P ; Yamout, B ; Altintas, A ; Gerlach, O ; Lechner-Scott, J ; Bergamaschi, R ; Karabudak, R ; Iuliano, G ; McGuigan, C ; Cartechini, E ; Hughes, S ; Sa, MJ ; Solaro, C ; Kappos, L ; Hodgkinson, S ; Slee, M ; Granella, F ; de Gans, K ; McCombe, PA ; Ampapa, R ; van der Walt, A ; Butzkueven, H ; Sanchez-Menoyo, JL ; Vucic, S ; Laureys, G ; Sidhom, Y ; Gouider, R ; Castillo-Trivino, T ; Gray, O ; Aguera-Morales, E ; Al-Asmi, A ; Shaw, C ; Al-Harbi, TM ; Csepany, T ; Sempere, AP ; Frenk, IT ; Stuart, EA ; Kalincik, T (BMJ PUBLISHING GROUP, 2023-12)
    BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
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    Disability accrual in primary and secondary progressive multiple sclerosis
    Harding-Forrester, S ; Roos, I ; Nguyen, A-L ; Malpas, CB ; Diouf, I ; Moradi, N ; Sharmin, S ; Izquierdo, G ; Eichau, S ; Patti, F ; Horakova, D ; Kubala Havrdova, E ; Prat, A ; Girard, M ; Duquette, P ; Maison, FG ; Onofrj, M ; Lugaresi, A ; Grammond, P ; Ozakbas, S ; Amato, MP ; Gerlach, O ; Sola, P ; Ferraro, D ; Buzzard, K ; Skibina, O ; Lechner-Scott, J ; Alroughani, R ; Boz, C ; Van Pesch, V ; Cartechini, E ; Terzi, M ; Maimone, D ; Ramo-Tello, C ; Yamout, B ; Khoury, SJ ; La Spitaleri, D ; Sa, MJ ; Blanco, Y ; Granella, F ; Slee, M ; Butler, E ; Sidhom, Y ; Gouider, R ; Bergamaschi, R ; Karabudak, R ; Ampapa, R ; Sanchez-Menoyo, JL ; Prevost, J ; Castillo-Trivino, T ; McCombe, PA ; Macdonell, R ; Laureys, G ; Van Hijfte, L ; Oh, J ; Altintas, A ; de Gans, K ; Turkoglu, R ; van der Walt, A ; Butzkueven, H ; Vucic, S ; Barnett, M ; Cristiano, E ; Hodgkinson, S ; Iuliano, G ; Kappos, L ; Kuhle, J ; Shaygannejad, V ; Soysal, A ; Weinstock-Guttman, B ; Van Wijmeersch, B ; Kalincik, T (BMJ Publishing Group, 2023-04-17)
    Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.