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2. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Author

Sharmin, S, Roos, I, Simpson-Yap, S, Malpes, C, Sanchez, MM, Ozakbas, S, Horakova, D, Havrdova, EK, Patti, F, Alroughani, R, Izquierdo, G, Eichau, S, Boz, C, Zakaria, M, Onofrj, M, Lugaresi, A, Weinstock-Guttman, B, Prat, A, Girard, M, Duquette, P, Terzi, M, Amato, MP, Karabudak, R, Grand'Maison, F, Khoury, SJ, Grammond, P, Lechner-Scott, J, Buzzard, K, Skibina, O, van der Walt, A, Butzkueven, H, Turkoglu, R, Altintas, A, Maimone, D, Kermode, A, Shalaby, N, Pesch, VV, Butler, E, Sidhom, Y, Gouider, R, Mrabet, S, Gerlach, O, Soysal, A, Barnett, M, Kuhle, J, Hughes, S, Sa, MJ, Hodgkinson, S, Oreja-Guevara, C, Ampapa, R, Petersen, T, Ramo-Tello, C, Spitaleri, D, McCombe, P, Taylor, B, Prevost, J, Foschi, M, Slee, M, McGuigan, C, Laureys, G, Hijfte, LV, de Gans, K, Solaro, C, Oh, J, Macdonell, R, Aguera-Morales, E, Singhal, B, Gray, O, Garber, J, Wijmeersch, BV, Simu, M, Castillo-Trivino, T, Sanchez-Menoyo, JL, Khurana, D, Al-Asmi, A, Al-Harbi, T, Deri, N, Fragoso, Y, Lalive, PH, Sinnige, LGF, Shaw, C, Shuey, N, Csepany, T, Sempere, AP, Moore, F, Decoo, D, Willekens, B, Gobbi, C, Massey, J, Hardy, T, Parratt, J, Kalincik, T, Sharmin, S, Roos, I, Simpson-Yap, S, Malpes, C, Sanchez, MM, Ozakbas, S, Horakova, D, Havrdova, EK, Patti, F, Alroughani, R, Izquierdo, G, Eichau, S, Boz, C, Zakaria, M, Onofrj, M, Lugaresi, A, Weinstock-Guttman, B, Prat, A, Girard, M, Duquette, P, Terzi, M, Amato, MP, Karabudak, R, Grand'Maison, F, Khoury, SJ, Grammond, P, Lechner-Scott, J, Buzzard, K, Skibina, O, van der Walt, A, Butzkueven, H, Turkoglu, R, Altintas, A, Maimone, D, Kermode, A, Shalaby, N, Pesch, VV, Butler, E, Sidhom, Y, Gouider, R, Mrabet, S, Gerlach, O, Soysal, A, Barnett, M, Kuhle, J, Hughes, S, Sa, MJ, Hodgkinson, S, Oreja-Guevara, C, Ampapa, R, Petersen, T, Ramo-Tello, C, Spitaleri, D, McCombe, P, Taylor, B, Prevost, J, Foschi, M, Slee, M, McGuigan, C, Laureys, G, Hijfte, LV, de Gans, K, Solaro, C, Oh, J, Macdonell, R, Aguera-Morales, E, Singhal, B, Gray, O, Garber, J, Wijmeersch, BV, Simu, M, Castillo-Trivino, T, Sanchez-Menoyo, JL, Khurana, D, Al-Asmi, A, Al-Harbi, T, Deri, N, Fragoso, Y, Lalive, PH, Sinnige, LGF, Shaw, C, Shuey, N, Csepany, T, Sempere, AP, Moore, F, Decoo, D, Willekens, B, Gobbi, C, Massey, J, Hardy, T, Parratt, J, and Kalincik, T

Abstract

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients wa

Published
2023

3. Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

Author

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, 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, and Kalincik, T

Abstract

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.

Published
2023

4. Disability accrual in primary and secondary progressive multiple sclerosis

Author

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, 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, and Kalincik, T

Abstract

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.

Published
2023

5. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Author

Butler, E., Van Pesch, V., Shalaby, N., Kermode, A., Maimone, D., Blanco, Y., Altintas, A., Turkoglu, R., Butzkueven, H., Van der Walt, A., Skibina, O., Buzzard, K., Lechner-Scott, J., Grammond, P., Khoury, S. J., Yamout, B., Grand'Maison, F., Karabudak, R., Amato, M. P., Terzi, M., Duquette, P., Girard, M., Prat, A., Weinstock-Guttman, B., Lugaresi, A., Onofrj, M., Zakaria, M., Boz, C., Eichau, S., Izquierdo, G., Shaygannejad, V., Alroughani, R., Patti, F., Havrdova, E. K., Horakova, D., Ozakbas, S., Sanchez, M. Martinez, Malpas, C., Simpson-Yap, S., Roos, I., Sharmin, S., Sidhom, Y., Gouider, R., Gerlach, O., Soysal, A., Barnett, M., Kuhle, J., Hughes, S., Sa, M. Jose, and Kalincik, T.

Published
2022

6. Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

Author

Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., and Kalincik T.

Abstract

Background and purpose: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Method(s): In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Result(s): The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusion(s): Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.Copyright © 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behal

Published
2022

7. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.

Author

Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., Kalincik T., Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., and Kalincik T.

Abstract

OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHOD(S): This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULT(S): 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). CONCLUSION(S): The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different t

Published
2022

8. Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Author

Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., Kalincik, T., Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., and Kalincik, T.

Abstract

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Published
2022

9. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis

Author

Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, Kalincik, T, Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, and Kalincik, T

Abstract

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued di

Published
2022

11. Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national cohort

Author

Sharmin, S., Malpas, C., Izanne Roos, Diouf, I., Alroughani, R., Ozakbas, S., Izquierdo, G., Eichau, S., Horakova, D., Havrdova, E. K., Patti, F., Terzi, M., Boz, C., Yamout, B., Khoury, S. J., Onofrj, M., Lugaresi, A., Altintas, A., Prat, A., Girard, M., Duquette, P., Sa, M. J., Spitaleri, D., Sidhom, Y., Gouider, R., Soysal, A., Turkoglu, R., Amato, M. P., Fragoso, Y., and Kalincik, T.

Published
2021

12. Comparison of the effectiveness of ocrelizumab vs interferons, fingolimod and natalizumab on relapses in relapsing-remitting multiple sclerosis.

Author

Roos I., Sharmin S., Ozakbas S., Horakova D., Havrdova E.K., Boz C., Alroughani R., Patti F., Terzi M., Lechner-Scott J., Izquierdo G., Eichau S., Grammond P., Buzzard K., Skibina O., Prat A., Girard M., Duquette P., Soysal A., Grand'Maison F., Kuhle J., Van Der Walt A., Butzkueven H., Turkoglu R., Butler E., Laureys G., Van Hijfte L., Shaygannejad V., Yamout B., Khoury S., Prevost J., Sidhom Y., Gouider R., Cartechini E., Sanchez-Menoyo J.L., Jose Sa M., Macdonell R., Van Pesch V., Ramo-Tello C., McCombe P., Willekens B., Spitaleri D., Ampapa R., Al-Asmi A., Slee M., Besora S., Malpas C., Kalincik T., Roos I., Sharmin S., Ozakbas S., Horakova D., Havrdova E.K., Boz C., Alroughani R., Patti F., Terzi M., Lechner-Scott J., Izquierdo G., Eichau S., Grammond P., Buzzard K., Skibina O., Prat A., Girard M., Duquette P., Soysal A., Grand'Maison F., Kuhle J., Van Der Walt A., Butzkueven H., Turkoglu R., Butler E., Laureys G., Van Hijfte L., Shaygannejad V., Yamout B., Khoury S., Prevost J., Sidhom Y., Gouider R., Cartechini E., Sanchez-Menoyo J.L., Jose Sa M., Macdonell R., Van Pesch V., Ramo-Tello C., McCombe P., Willekens B., Spitaleri D., Ampapa R., Al-Asmi A., Slee M., Besora S., Malpas C., and Kalincik T.

Abstract

Introduction: Ocrelizumab, a monoclonal antibody targeted against CD20+ B cells, has become a popular treatment for relapsing-remitting multiple sclerosis (MS). The effectiveness of ocrelizumab compared to other treatments is however unknown. Aim(s): To compare the effectiveness of ocrelizumab with interferon-beta, fingolimod and natalizumab in relapsing-remitting MS. Method(s): Using the MSBase registry, we identified patients with relapsing-remitting MS treated for >=6 months with ocrelizumab, interferon- beta (interferon beta-1a, interferon beta-1b subcutaneous or interferon beta-1b intramuscular), fingolimod or natalizumab. All patients required >12-month pre-treatment follow up and the minimum dataset. Patients with comparable baseline characteristics were matched with propensity score on age, sex, MS duration, EDSS, prior relapse rate, prior therapy, disease activity, MRI lesion burden (missing values imputed), reason for discontinuation of preceding therapy (imputed) and country. Annualised rate of relapses (ARR) and cumulative hazard of relapses were compared in pairwise-censored groups. Result(s): 106 patients treated with ocrelizumab were matched with 209 patients on interferon therapies with a mean age of 39 years, 0.8 relapses per year and mean EDSS of 2.4-2.5. Over a pairwise-censored mean follow up of 1.3 years, ocrelizumab was associated with lower relapse rates (ARR 0.08 vs 0.27, p<0.001) and lower risk of relapse (HR 0.30, 95%CI 0.15-0.57) than interferon-beta. 297 patients treated with ocrelizumab were matched with 811 fingolimod-treated patients with a mean age of 41 years, 0.6 relapses per year and mean EDSS of 2.7-2.8. Over a pairwisecensored mean follow up of 1.5 years, ocrelizumab was associated with lower relapse rates (ARR 0.03 vs 0.14, p<0.001) and lower risk of relapse than fingolimod (HR 0.21, 0.13-0.32). 262 ocrelizumab- treated patients were matched with 343 natalizumab treated patients with a mean age of 39 years, 0.8 relapses per year

Published
2021

13. Disability accrual in primary-progressive & secondaryprogressive multiple sclerosis.

Author

Boz C., Diouf I., Malpas C., Nguyen A.-L., Moradi N., Horakova D., Kubala Havrdova E., Patti F., Izquierdo G., Eichau S., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Weinstock-Guttman B., Amato M.P., Grammond P., Gerlach O., Ozakbas S., Sola P., Ferraro D., Butzkueven H., Lechner-Scott J., Alroughani R., Van Pesch V., Cartechini E., Terzi M., Maimone D., Ramo-Tello C., Spitaleri D., Kappos L., Yamout B., Sa M., Slee M., Blanco Y., Bergamaschi R., Butler E., Iuliano G., Granella F., Sidhom Y., Gouider R., Ampapa R., Van Wijmeersch B., Karabudak R., Prevost J., Sanchez-Menoyo J.L., Verheul F., Mccombe P., Castillo-Trivino T., Macdonell R., Altintas A., Laureys G., Van Hijfte L., Van Der Walt A., Vucic S., Turkoglu R., Barnett M., Cristiano E., Zakaria M., Shaygannejad V., Hodgkinson S., Soysal A., Kalincik T., Harding-Forrester S., Roos I., Sharmin S., Boz C., Diouf I., Malpas C., Nguyen A.-L., Moradi N., Horakova D., Kubala Havrdova E., Patti F., Izquierdo G., Eichau S., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Weinstock-Guttman B., Amato M.P., Grammond P., Gerlach O., Ozakbas S., Sola P., Ferraro D., Butzkueven H., Lechner-Scott J., Alroughani R., Van Pesch V., Cartechini E., Terzi M., Maimone D., Ramo-Tello C., Spitaleri D., Kappos L., Yamout B., Sa M., Slee M., Blanco Y., Bergamaschi R., Butler E., Iuliano G., Granella F., Sidhom Y., Gouider R., Ampapa R., Van Wijmeersch B., Karabudak R., Prevost J., Sanchez-Menoyo J.L., Verheul F., Mccombe P., Castillo-Trivino T., Macdonell R., Altintas A., Laureys G., Van Hijfte L., Van Der Walt A., Vucic S., Turkoglu R., Barnett M., Cristiano E., Zakaria M., Shaygannejad V., Hodgkinson S., Soysal A., Kalincik T., Harding-Forrester S., Roos I., and Sharmin S.

Abstract

Background: Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS. Objective(s): We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016). Method(s): Inclusion required adult-onset progressive MS; >= 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS <= 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if >= 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over >= 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS >= 7 (wheelchair required) was assessed (Kaplan-Meier). Result(s): 5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 +/- 10.2, vs. 41.5 +/- 10.7 [mean +/- SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78-0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98-0.99); and higher in males (1.18; 1.12-1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71

Published
2021

15. of Therapeutic Lag in Relapsing Multiple Sclerosis

Author

Izanne Roos, Frascoli, F., Horakova, D., Havrdova, E. Kubala, Trojano, M., Izquierdo, G., Eichau, S., Patti, F., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grammond, P., Ozakbas, S., Sola, P., Ferraro, D., Bergamaschi, R., Cartechini, E., Sa, M. Jose, Boz, C., Grand Maison, F., Lechner-Scott, J., Terzi, M., Granella, F., Alroughani, R., Iuliano, G., Hupperts, R., Spitaleri, D., Pesch, V., Soysal, A., Prevost, J., Olascoaga, J., Aguera-Morales, E., Turkoglu, R., Slee, M., Ramo-Tello, C., Sidhom, Y., Gouider, R., Mccombe, P., Butzkueven, H., Malpas, C., and Kalincik, T.

Published
2020

16. Predicting long-term sustained disability progression in multiple sclerosis.

Author

Van Wijmeersch B., Malpas C., Hupperts R.M.M., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Spitaleri D.L.A., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic O., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Urtaza F.J.O., Saladino M.L., Barnett M., Deri N., Moore F., Rozsa C., Yamout B., Skibina O., Gray O., Campbell J., Sempere A., Singhal B., Fragoso Y., Shaw C., Kermode A., Petkovska-Boskova T., Taylor B., Simo M., Vella N., Shuey N., Alkhaboori J., Al-Harbi T., Macdonell R., Dominguez J.A., Kister I., Csepany T., Vrech C., Kovacs K., Sirbu C.A., Hughes S., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Horakova D., Havrdova E., Ayuso G.I., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Van Wijmeersch B., Malpas C., Hupperts R.M.M., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Spitaleri D.L.A., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic O., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Urtaza F.J.O., Saladino M.L., Barnett M., Deri N., Moore F., Rozsa C., Yamout B., Skibina O., Gray O., Campbell J., Sempere A., Singhal B., Fragoso Y., Shaw C., Kermode A., Petkovska-Boskova T., Taylor B., Simo M., Vella N., Shuey N., Alkhaboori J., Al-Harbi T., Macdonell R., Dominguez J.A., Kister I., Csepany T., Vrech C., Kovacs K., Sirbu C.A., Hughes S., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Horakova D., Havrdova E., Ayuso G.I., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., and Terzi M.

Abstract

Objective: Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS). Background(s): Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3-6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown. Design/Methods: A Cox proportional hazards model identified associations between patients' demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort. Result(s): 902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39-4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data. Conclusion(s): Estimate of the probability of disability progress

Published
2020

17. Predicting long-term sustained disability progression in multiple sclerosis.

Author

Terzi M., Sharmin S., Malpas C., Horakova D., Havrdova E.K., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Hupperts R., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic S., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Butzkueven H., Kalincik T., Terzi M., Sharmin S., Malpas C., Horakova D., Havrdova E.K., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Hupperts R., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic S., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Butzkueven H., and Kalincik T.

Abstract

Introduction: Prevention of disability over the long-term is currently the main treatment goal in multiple sclerosis (MS). Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3-6-month confirmed disability progression. Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials. Method(s): A Cox proportional hazards model in the development cohort identified associations between demographic and clinical variables at the time of disability progression and the probability of an event not being sustained in the future. The coefficients from this model were used to calculate a sustained progression score. Its association with the risk that an event will be sustained over timewas evaluated with a Cox model in the validation cohort. Result(s): 11,435 confirmed progression events identified in 6,902 patients constituted the development cohort. Patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal(HR=0.79) functional system score (p< 0.05). The strength of the association with pyramidal score decreased with time(HR=1.01). Occurrence of a relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The associations were confirmed by two sensitivity analyses. The sustained progression score, ranged 0.39-4.79 in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement with each unit increase in the score (HR=0.47, 95% confidence interval

Published
2020

18. Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Author

Roos, I, Leray, E, Frascoli, F, Casey, R, Brown, WJL, Horakova, D, Havrdova, EK, Trojano, M, Patti, F, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Prat, A, Girard, M, Grammond, P, Sola, P, Ferraro, D, Ozakbas, S, Bergamaschi, R, Sá, MJ, Cartechini, E, Boz, C, Granella, F, Hupperts, R, Terzi, M, Lechner-Scott, J, Spitaleri, D, van Pesch, V, Soysal, A, Olascoaga, J, Prevost, J, Aguera-Morales, E, Slee, M, Csepany, T, Turkoglu, R, Sidhom, Y, Gouider, R, van Wijmeersch, B, McCombe, P, Macdonell, R, Coles, A, Malpas, CB, Butzkueven, H, Vukusic, S, Kalincik, T, Duquette, P, Grand'Maison, F, Iuliano, G, Ramo-Tello, C, Solaro, C, Cabrera-Gomez, JA, Rio, ME, Bolaños, RF, Shaygannejad, V, Oreja-Guevara, C, Sanchez-Menoyo, JL, Petersen, T, Altintas, A, Barnett, M, Flechter, S, Fragoso, Y, Amato, MP, Moore, F, Ampapa, R, Verheul, F, Hodgkinson, S, Cristiano, E, Yamout, B, Laureys, G, Dominguez, JA, Zwanikken, C, Deri, N, Dobos, E, Vrech, C, Butler, E, Rozsa, C, Petkovska-Boskova, T, Karabudak, R, Rajda, C, Alkhaboori, J, Saladino, ML, Shaw, Cameron, Shuey, N, Vucic, S, Sempere, AP, Campbell, J, Piroska, I, Taylor, B, van der Walt, A, Kappos, L, Roullet, E, Gray, O, Simo, M, Sirbu, CA, Brochet, B, Cotton, F, de Sèze, J, Dion, A, Douek, P, Roos, I, Leray, E, Frascoli, F, Casey, R, Brown, WJL, Horakova, D, Havrdova, EK, Trojano, M, Patti, F, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Prat, A, Girard, M, Grammond, P, Sola, P, Ferraro, D, Ozakbas, S, Bergamaschi, R, Sá, MJ, Cartechini, E, Boz, C, Granella, F, Hupperts, R, Terzi, M, Lechner-Scott, J, Spitaleri, D, van Pesch, V, Soysal, A, Olascoaga, J, Prevost, J, Aguera-Morales, E, Slee, M, Csepany, T, Turkoglu, R, Sidhom, Y, Gouider, R, van Wijmeersch, B, McCombe, P, Macdonell, R, Coles, A, Malpas, CB, Butzkueven, H, Vukusic, S, Kalincik, T, Duquette, P, Grand'Maison, F, Iuliano, G, Ramo-Tello, C, Solaro, C, Cabrera-Gomez, JA, Rio, ME, Bolaños, RF, Shaygannejad, V, Oreja-Guevara, C, Sanchez-Menoyo, JL, Petersen, T, Altintas, A, Barnett, M, Flechter, S, Fragoso, Y, Amato, MP, Moore, F, Ampapa, R, Verheul, F, Hodgkinson, S, Cristiano, E, Yamout, B, Laureys, G, Dominguez, JA, Zwanikken, C, Deri, N, Dobos, E, Vrech, C, Butler, E, Rozsa, C, Petkovska-Boskova, T, Karabudak, R, Rajda, C, Alkhaboori, J, Saladino, ML, Shaw, Cameron, Shuey, N, Vucic, S, Sempere, AP, Campbell, J, Piroska, I, Taylor, B, van der Walt, A, Kappos, L, Roullet, E, Gray, O, Simo, M, Sirbu, CA, Brochet, B, Cotton, F, de Sèze, J, Dion, A, and Douek, P

Published
2020

19. Therapeutic lag in relapsing multiple sclerosis

Author

Roos, I., Frascoli, F., Horakova, D., Havrdova, E. K., Trojano, M., Izquierdo, G., Eichau, S., Patti, F., Onofr, M., Lugaresi, A., Prat, A., Girard, M., Duquette, P., Ozakbas, S., Grammond, P., Sola, P., Ferraro, D., Bergamaschi, R., Boz, C., Cartechini, E., Sa, M. J., Terzi, M., Alroughani, R., Grand Maison, F., Granella, F., Iuliano, G., Hupperts, R., Lechner-Scott, J., Spitaleri, D., Pesch, V., Soysal, A., Prevost, J., Aguera-Morales, E., Olascoaga, J., Recai Turkoglu, Sidhom, Y., Gouider, R., Wijmeersch, B., Butzkueven, H., Malpas, C., and Kalincik, T.

Published
2019

20. Predicting long-term sustained disability progression in multiple sclerosis

Author

Sharmin, S., Malpas, C., Horakova, D., Havrdova, E. K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Hupperts, R., Alroughani, R., Boz, C., Shaygannejad, V., Pesch, V., Cartechini, E., Kappos, L., Lechner-Scott, J., Bergamaschi, R., Recai Turkoglu, Solaro, C., Ramo-Tello, C., Iuliano, G., Granella, F., Wijmeersch, B., Spitaleri, D., Bolanos, R. F., Slee, M., Mccombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez-Menoyo, J. L., Soysal, A., Vucic, S., Petersen, T., Verheul, F., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Butzkueven, H., and Kalincik, T.

Published
2019

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

Author

Brown J, 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 O, 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, Boz C, Prevost J, Olascoaga J, Van Wijmeersch B, Barnett M, Verheul F, Rojas J, Spitaleri D, Rio M, Taylor B, Sanchez-Menoyo J, Ramo-Tello C, Solaro C, Csepany T, Iuliano G, Skibina O, Petersen T, Bolanos R, Sidhom Y, Riadh, Vucic S, Macdonell R, Sempere A, Simo M, Kister I, Shuey N, Radek, Dominguez J, Amato M, Saladino M, Kermode A, Butler E, Moore F, Hughes S, McDonnell G, Piroska I, Yamout B, Soysal A, Ozakbas S, Zwanikken C, and MSBase Study Grp

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

Published
2019

40. Aggressive form of multiple sclerosis can be predicted early after disease onset

Author

Malpas, C. B., Manouchehrinia, A., Sharmin, S., Izanne Roos, Horakova, D., Havrdova, E. K., Trojano, M., Izquierdo, G., Eichau, S., Bergamaschi, R., Sola, P., Ferraro, D., Lugaresi, A., Prat, A., Girard, M., Duquette, P., Grammond, P., Grand Maison, F., Ozakbas, S., Pesch, V., Granella, F., Hupperts, R., Pucci, E., Boz, C., Iuliano, G., Sidhom, Y., Gouider, R., Spitaleri, D., Butzkueven, H., Soysal, A., Petersen, T., Verheul, F., Karabudak, R., Turkoglu, R., Ramo-Tello, C., Terzi, M., Cristiano, E., Slee, M., Mccombe, P., Macdonell, R., Fragoso, Y., Olascoaga, J., Altintas, A., Olsson, T., Hillert, J., and Kalincik, T.

41. Determinants of therapeutic lag in relapsing multiple sclerosis

Author

Izanne Roos, Frascoli, F., Horakova, D., Havrdova, E. K., Trojano, M., Izquierdo, G., Eichau, S., Patti, F., Prat, A., Girard, M., Duquette, P., Onofr, M., Lugaresi, A., Grammond, P., Ozakbas, S., Sola, P., Ferraro, D., Bergamaschi, R., Cartechini, E., Sa, M. J., Boz, C., Grand Maison, F., Lechner-Scott, J., Terzi, M., Granella, F., Alroughani, R., Iuliano, G., Hupperts, R., Spitaleri, D., Pesch, V., Soysal, A., Prevost, J., Olascoaga, J., Aguera-Morales, E., Turkoglu, R., Slee, M., Ramo-Tello, C., Sidhom, Y., Gouider, R., Mccombe, P., Butzkueven, H., Malpas, C., and Kalincik, T.

42. Risk of secondary progressive multiple sclerosis: a longitudinal study

Author

Fambiatos, A., Jokubaitis, V., Spelman, T., Horakova, D., Havrdova, E., Trojano, M., Prat, A., Girard, M., Duquette, P., Lugaresi, A., Izquierdo, G., Grand Maison, F., Grammond, P., Sola, P., Ferraro, D., Alroughani, R., Terzi, M., Hupperts, R., Boz, C., Lechner-Scott, J., Pucci, E., Bergamaschi, R., Pesch, V., Ozakbas, S., Granella, F., Ramo, C., Recai Turkoglu, Iuliano, G., Spitaleri, D., Mccombe, P., Solaro, C., Slee, M., Fernandez-Bolanos, R., Ampapa, R., Soysal, A., Petersen, T., Sanchez-Menoyo, J. L., Verheul, F., Prevost, J., Sidhom, Y., Gouider, R., Wijmeersch, B., Vucic, S., Cristiano, E., Saladino, M. L., Deri, N., Barnett, M., Walt, A., Butzkueven, H., and Kalincik, T.

43. Disability accrual in primary-progressive & secondary-progressive multiple sclerosis

Author

Harding-Forrester, S., Izanne Roos, Sharmin, S., Diouf, I., Malpas, C., Nguyen, A. -L, Moradi, N., Horakova, D., Havrdova, E. Kubala, Patti, F., Izquierdo, G., Eichau, S., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand Maison, F., Weinstock-Guttman, B., Amato, M. P., Grammond, P., Gerlach, O., Ozakbas, S., Sola, P., Ferraro, D., Butzkueven, H., Lechner-Scott, J., Boz, C., Alroughani, R., Pesch, V., Cartechini, E., Terzi, M., Maimone, D., Ramo-Tello, C., Spitaleri, D., Kappos, L., Yamout, B., Sa, M., Slee, M., Blanco, Y., Bergamaschi, R., Butler, E., Iuliano, G., Granella, F., Sidhom, Y., Gouider, R., Ampapa, R., Wijmeersch, B., Karabudak, R., Prevost, J., Sanchez-Menoyo, J. L., Verheul, F., Mccombe, P., Castillo-Trivino, T., Macdonell, R., Altintas, A., Laureys, G., Hijfte, L., Walt, A., Vucic, S., Turkoglu, R., Barnett, M., Cristiano, E., Zakaria, M., Shaygannejad, V., Hodgkinson, S., Soysal, A., and Kalincik, T.

44. Comparison of the effectiveness of ocrelizumab vs interferons, fingolimod and natalizumab on relapses in relapsing-remitting multiple sclerosis

Author

Izanne Roos, Sharmin, S., Ozakbas, S., Horakova, D., Havrdova, E. K., Boz, C., Alroughani, R., Patti, F., Terzi, M., Lechner-Scott, J., Izquierdo, G., Eichau, S., Grammond, P., Buzzard, K., Skibina, O., Prat, A., Girard, M., Duquette, P., Soysal, A., Grand Maison, F., Kuhle, J., Walt, A., Butzkueven, H., Turkoglu, R., Butler, E., Laureys, G., Hijfte, L., Shaygannejad, V., Yamout, B., Khoury, S., Prevost, J., Sidhom, Y., Gouider, R., Cartechini, E., Sanchez-Menoyo, J. L., Sa, M. Jose, Macdonell, R., Pesch, V., Ramo-Tello, C., Mccombe, P., Willekens, B., Spitaleri, D., Ampapa, R., Al-Asmi, A., Slee, M., Besora, S., Malpas, C., and Kalincik, T.

45. Early clinical predictors of severe MS

Author

Malpas, C., Sharmin, S., Horakova, D., Havrdova, E. K., Trojano, M., Izquierdo, G., Bergamaschi, R., Sola, P., Ferraro, D., Lugaresi, A., Prat, A., Girard, M., Duquette, P., Grammond, P., Grand Maison, F., Ozakbas, S., Pesch, V., Granella, F., Hupperts, R., Pucci, E., Boz, C., Iuliano, G., Sidhom, Y., Gouider, R., Spitaleri, D., Butzkueven, H., Soysal, A., Petersen, T., Verheul, F., Karabudak, R., Recai Turkoglu, Ramo-Tello, C., Terzi, M., Cristiano, E., Slee, M., Mccombe, P., Macdonell, R., Fragoso, Y., Olascoaga, J., Altintas, A., and Kalincik, T.

47. The risk of relapse following on-treatment clinically silent lesions in patients with relapsing-remitting multiple sclerosis

Author

Brown, J. W. L., Lugaresi, A., Horakova, D., Havrdova, E., Jokubaitis, V., Lechner-Scott, J., Trojano, M., Min, M., Shaw, C., Shuey, N., Slee, M., Mccombe, P., Pesch, V., Wijmeersch, B., Prevost, J., Moore, F., Prat, A., Girard, M., Duquette, P., Ayrignac, X., Sempere, A. Perez, Sanchez-Menoyo, J. L., Cristina Ramo-Tello, Csepany, T., Hutchinson, M., Luca, G., Bergamaschi, R., Granella, F., Curti, E., Tsantes, E., Sola, P., Ferraro, D., Alroughani, R., Hupperts, R., Al-Harbi, T., Sidhom, Y., Boz, C., Terzi, M., Ozakbas, S., Soysal, A., Pucci, E., Izquierdo, G., Iuliano, G., Rio, M. Edite, Spitaleri, D., Grammond, P., Grand Maison, F., Butzkueven, H., and Kalincik, T.

48. Determinants of therapeutic lag in multiple sclerosis

Author

Tomas Kalincik, Marc Girard, Corinne Pottier, Murat Terzi, Jean Pelletier, Oliver Gerlach, Julie Prevost, Dana Horakova, Francois Grand'Maison, Raed Alroughani, Guillermo Izquierdo, Francesco Patti, Federico Frascoli, Maria Trojano, Franco Granella, Pamela A. McCombe, Charles B Malpas, Recai Turkoglu, Aurélie Ruet, Jonathan Ciron, Tünde Csépány, Nicolas Maubeuge, Helmut Butzkueven, Pierre Clavelou, Tamara Castillo Trivino, Marco Onofrj, Jean Philippe Camdessanche, Pierre Labauge, Vincent Van Pesch, Pierre Grammond, Abir Wahab, Roberto Bergamaschi, Aysun Soysal, Diana Ferraro, Bertrand Bourre, Olivier Gout, Jeannette Lechner-Scott, Sara Eichau, Emmanuelle Leray, Alexis Montcuquet, Pierre Duquette, Olivier Casez, Youssef Sidhom, Patrizia Sola, Bart Van Wijmeersch, Izanne Roos, Gilles Edan, Serkan Ozakbas, David Laplaud, Sandra Vukusic, Abdullatif Al Khedr, Céline Labeyrie, Philippe Cabre, Eric Thouvenot, Céline Louapre, Romain Casey, Alessandra Lugaresi, Riadh Gouider, Alasdair Coles, Eric Berger, Ivania Patry, Gerardo Iuliano, Elisabetta Cartechini, Cavit Boz, Karolina Hankiewicz, Eva Havrdova, Eduardo Aguera-Morales, J William L Brown, Jérôme De Seze, Bruno Stankoff, Olivier Heinzlef, Gilles Defer, Alexandre Prat, Chantal Nifle, Maria José Sá, Marc Debouverie, Daniele Spitaleri, Aude Maurousset, Thibault Moreau, Christine Lebrun-Frenay, Hélène Zéphir, University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Méthodes quantitatives en santé publique (METIS), Collectif de recherche handicap, autonomie et société inclusive (CoRHASI), Swinburne University of Technology [Melbourne], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Charles University [Prague], Università degli studi di Catania [Catania], Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Università degli Studi di Modena e Reggio Emilia (UNIMORE), University of Queensland [Brisbane], Monash University [Clayton], UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Charles University [Prague] (CU), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Bari Aldo Moro (UNIBA), University of Catania [Italy], Hospital Virgen Macarena, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), CHU Toulouse [Toulouse], INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Fernando Pessoa University, Azienda Ospedaleria Universitaria di Modena, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Karadeniz Technical University (KTU), Università degli Studi di Macerata = University of Macerata (UNIMC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Newcastle [Australia] (UoN), Zuyderland Hospital [Heerlen, The Netherlands], Ondokuz Mayis University, University of Parma = Università degli studi di Parma [Parme, Italie], Amiri hospital, University of Salerno (UNISA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hasselt University (UHasselt), San Giuseppe Moscati Hospital [Avellino, Italie], Bakirkoy Matern & Childrens State Hosp, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Universidad de Córdoba [Cordoba], Hospital Donostia, CHU Clermont-Ferrand, Hôpital de la Timone [CHU - APHM] (TIMONE), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHI Poissy-Saint-Germain, Université de la Manouba [Tunisie] (UMA), University of Debrecen, Hôpital Charles Nicolle [Rouen], CHU Amiens-Picardie, CHU de la Martinique [Fort de France], CHU Limoges, CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], This study was supported by the EDMUS Foundation and NHMRC [1140766,1129189, 1157717]. IR is supported by a MSIF-ARSEP McDonald fellowship grantand a Melbourne Research Scholarship. The MSBase Foundation is a not-for-profitorganization that receives support from Biogen, Novartis, Merck, Roche, Teva andSanofi Genzyme. The study was conducted separately and apart from the guidanceof the sponsors. The Observatoire Français de la Sclérose en Plaques (OFSEP) issupported by a grant provided by the French State and handled by the 'AgenceNationale de la Recherche,' within the framework of the 'Investments for the Future'program, under the reference ANR-10-COHO-002, by the Eugène Devic EDMUSFoundation against multiple sclerosis and by the ARSEP Foundation., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Roos I., Leray E., Frascoli F., Casey R., Brown J.W.L., Horakova D., Havrdova E.K., Debouverie M., Trojano M., Patti F., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grammond P., Ciron J., Ruet A., Ozakbas S., De Seze J., Louapre C., Zephir H., Sa M.J., Sola P., Ferraro D., Labauge P., Defer G., Bergamaschi R., Lebrun-Frenay C., Boz C., Cartechini E., Moreau T., Laplaud D., Lechner-Scott J., Grand'Maison F., Gerlach O., Terzi M., Granella F., Alroughani R., Iuliano G., Van Pesch V., Van Wijmeersch B., Spitaleri D.L.A., Soysal A., Berger E., Prevost J., Aguera-Morales E., McCombe P., Castillo Trivino T., Clavelou P., Pelletier J., Turkoglu R., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Sidhom Y., Gouider R., Csepany T., Bourre B., Al Khedr A., Casez O., Cabre P., Montcuquet A., Wahab A., Camdessanche J.-P., Maurousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Coles A., Malpas C.B., Vukusic S., Butzkueven H., Kalincik T., Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli studi di Catania = University of Catania (Unict), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), University of Newcastle [Callaghan, Australia] (UoN), Ondokuz Mayis University (OMU), Università degli studi di Parma = University of Parma (UNIPR), Universidad de Córdoba = University of Córdoba [Córdoba], University of Debrecen Egyetem [Debrecen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Registrie, Male, medicine.medical_specialty, Treatment response, Pediatrics, Neurology, Lag, [SDV]Life Sciences [q-bio], Aucun, multiple sclerosis, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Recurrence, medicine, Humans, Treatment effect, Disabled Persons, Registries, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Delayed onset, medicine.disease, 3. Good health, Clinical neurology, therapeutic lag, multiple sclerosi, Disease Progression, Disabled Person, Observational study, Female, observational study, Neurology (clinical), business, 030217 neurology & neurosurgery, Human
Abstract

International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS

Published
2021

49. Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis

Author

Bassem Yamout, Alessandra Lugaresi, Pierre Duquette, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Alexandre Prat, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Jeannette Lechner-Scott, Francois Grand’ Maison, Guillermo Izquierdo, Steve Vucic, Roberto Bergamaschi, Cavit Boz, Ayse Altintas, Vahid Shaygannejad, Aysun Soysal, Youssef Sidhom, Tomas Kalincik, Charles B Malpas, Marc Girard, Serkan Ozakbas, Julie Prevost, Raed Alroughani, Catherine Larochelle, Michael Barnett, Daniele Spitaleri, Pamela A. McCombe, Thor Petersen, Mark Slee, Helmut Butzkueven, Maria Trojano, Franco Granella, Minh Le, Yara Dadalti Fragoso, Pierre Grammond, Radek Ampapa, Riadh Gouider, Gerardo Iuliano, Recai Turkoglu, Murat Terzi, Eugenio Pucci, Sifat Sharmin, Diana Ferraro, Sara Eichau, Patrizia Sola, Dana Horakova, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Le M., Malpas C., Sharmin S., Horakova D., Havrdova E., Trojano M., Izquierdo G., Eichau S., Ozakbas S., Lugaresi A., Prat A., Girard M., Duquette P., Larochelle C., Alroughani R., Bergamaschi R., Sola P., Ferraro D., Grammond P., Grand' Maison F., Terzi M., Boz C., Hupperts R., Butzkueven H., Pucci E., Granella F., Van Pesch V., Soysal A., Yamout B.I., Lechner-Scott J., Spitaleri D.L.A., Ampapa R., Turkoglu R., Iuliano G., Ramo-Tello C., Sanchez-Menoyo J.L., Sidhom Y., Gouider R., Shaygannejad V., Prevost J., Altintas A., Fragoso Y.D., McCombe P.A., Petersen T., Slee M., Barnett M.H., Vucic S., Van Der Walt A., and Kalincik T.

Subjects
Pediatrics, medicine.medical_specialty, Multivariate analysis, Multiple Sclerosis, brainstem, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, Therapeutic approach, Disability Evaluation, 0302 clinical medicine, disability outcome, medicine, Humans, Multiple sclerosi, Disabled Persons, 030304 developmental biology, 0303 health sciences, Expanded Disability Status Scale, cerebellar, early symptomatology, prognostic marker, business.industry, medicine.disease, Natural history, Neurology, Cohort, Disease Progression, Neurology (clinical), Brainstem, Presentation (obstetrics), business, 030217 neurology & neurosurgery, Brain Stem
Abstract

Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Published
2020

50. Early clinical markers of aggressive multiple sclerosis

Author

Tomas Kalincik, Marc Girard, Guillermo Izquierdo, Cristina Ramo-Tello, Francois Grand'Maison, Ali Manouchehrinia, Youssef Sidhom, Charles B Malpas, Alexandre Prat, Maria Trojano, Franco Granella, Pamela A. McCombe, Rana Karabudak, Murat Terzi, Eugenio Pucci, Raymond Hupperts, Vincent Van Pesch, Pierre Grammond, Sifat Sharmin, Richard A L Macdonell, Ayse Altintas, Riadh Gouider, Recai Turkoglu, Diana Ferraro, Alessandra Lugaresi, Pierre Duquette, Helmut Butzkueven, Serkan Ozakbas, Sara Eichau, Izanne Roos, Daniele Spitaleri, Yara Dadalti Fragoso, Mark Slee, Roberto Bergamaschi, Jan Hillert, Edgardo Cristiano, Thor Petersen, Eva Havrdova, Javier Olascoaga, Cavit Boz, Patrizia Sola, Freek Verheul, Aysun Soysal, Tomas Olsson, Dana Horakova, Ondokuz Mayıs Üniversitesi, Malpas C.B., Manouchehrinia A., Sharmin S., Roos I., Horakova D., Havrdova E.K., Trojano M., Izquierdo G., Eichau S., Bergamaschi R., Sola P., Ferraro D., Lugaresi A., Prat A., Girard M., Duquette P., Grammond P., Grand'Maison F., Ozakbas S., van Pesch V., Granella F., Hupperts R., Pucci E., Boz C., Sidhom Y., Gouider R., Spitaleri D., Soysal A., Petersen T., Verheul F., Karabudak R., Turkoglu R., Ramo-Tello C., Terzi M., Cristiano E., Slee M., McCombe P., Macdonell R., Fragoso Y., Olascoaga J., Altintas A., Olsson T., Butzkueven H., Hillert J., Kalincik T., Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), School of Medicine, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Male, PROGRESSION, Disease, multiple sclerosis, 01 natural sciences, THERAPY, Severity of Illness Index, Aggressive disease, 010104 statistics & probability, Disability Evaluation, 0302 clinical medicine, PROGNOSTIC-FACTORS, Multiple Sclerosi, Disability, Multiple sclerosis, Precision medicine, Prediction, R PACKAGE, Age of Onset, AcademicSubjects/SCI01870, Neurosciences and neurology, IMPAIRMENT, Cohort, Disease Progression, RELAPSE RATE, Female, Cohort study, Human, Adult, medicine.medical_specialty, Multiple Sclerosis, precision medicine, BRAIN MRI, Sensitivity and Specificity, 03 medical and health sciences, Internal medicine, Severity of illness, medicine, Humans, 0101 mathematics, Letters to the Editor, Expanded Disability Status Scale, business.industry, NATURAL-HISTORY, prediction, medicine.disease, PREDICTIVE-VALUE, Confidence interval, disability, AcademicSubjects/MED00310, Neurology (clinical), Age of onset, business, aggressive disease, 030217 neurology & neurosurgery, LONG-TERM DISABILITY
Abstract

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

Published
2020

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