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3. 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

4. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, MSBase, SG, Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, and MSBase, SG

Abstract

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Published
2023

5. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background: the prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: to determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: we redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: people who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: this study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (fellowship nos.1140766 and 1080518, project grant nos. 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), National Institute for Health and Care Research (UK) Advanced Fellowship (grant no. 301728; recipient JWLB) and Academic Clinical Fellowship (grant no. EAN/ACA-006/7488627/C; recipient CD). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Role of the Funder/Sponsor: The National Health and Medical Research Council of Australia, the University of Melbourne and the National Institute for Health and Care Research (UK) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Published
2023

42. Early non-disabling relapses are associated with a higher risk of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Coles, A., Daruwalla, C., Shaygannejad, V., Ozakbas, S., Havrdova, E. K., Alroughani, R., Patti, F., Onofrj, M., Eichau, S., Girard, M., Grand'Maison, F., Yamout, B., Sajedi, S. A., Amato, M. P., Altintas, A., Skibina, O., Grammond, P., Butzkueven, H., Maimone, D., Lechner-Scott, J., Soysal, A., John, N., Gerlach, O., Iuliano, G., Foschi, M., Van Pesch, V., Cartechini, E., Kuhle, J., Sa, M. J., Kermode, A., Gouider, R., Hodgkinson, S., McCombe, P., Sanchez-Menoyo, J. L., Singhal, B., Blanco, Y., Hughes, S., McGuigan, C., Taylor, B., Habek, M., Al-Asmi, A., Mihaela, S., Castillo Trivino, T., Al-Harbi, T., Rojas, J. I., Gray, O., Khurana, D., Van Wijmeersch, B., Kalincik, T., and Brown, J. W. L.

Published
2022

43. 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

44. 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

48. Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years

Author

Kalincik, T, Diouf, I, Sharmin, S, Malpas, C, Spelman, T, Horakova, D, Havrdova, EK, Trojano, M, Izquierdo, G, Lugaresi, A, Prat, A, Girard, M, Duquette, P, Grammond, P, Jokubaitis, V, Van der Walt, A, Grand'Maison, F, Sola, P, Ferraro, D, Shaygannejad, V, Alroughani, R, Hupperts, R, Terzi, M, Boz, C, Lechner-Scott, J, Pucci, E, Van Pesch, V, Granella, F, Bergamaschi, R, Spitaleri, D, Slee, M, Vucic, S, Ampapa, R, McCombe, P, Ramo-Tello, C, Prevost, J, Olascoaga, J, Cristiano, E, Barnett, M, Saladino, ML, Sanchez-Menoyo, JL, Hodgkinson, S, Rozsa, C, Hughes, S, Moore, F, Shaw, C, Butler, E, Skibina, O, Gray, O, Kermode, A, Csepany, T, Singhal, B, Shuey, N, Piroska, I, Taylor, B, Simo, M, Sirbu, C-A, Sas, A, Butzkueven, H, Kalincik, T, Diouf, I, Sharmin, S, Malpas, C, Spelman, T, Horakova, D, Havrdova, EK, Trojano, M, Izquierdo, G, Lugaresi, A, Prat, A, Girard, M, Duquette, P, Grammond, P, Jokubaitis, V, Van der Walt, A, Grand'Maison, F, Sola, P, Ferraro, D, Shaygannejad, V, Alroughani, R, Hupperts, R, Terzi, M, Boz, C, Lechner-Scott, J, Pucci, E, Van Pesch, V, Granella, F, Bergamaschi, R, Spitaleri, D, Slee, M, Vucic, S, Ampapa, R, McCombe, P, Ramo-Tello, C, Prevost, J, Olascoaga, J, Cristiano, E, Barnett, M, Saladino, ML, Sanchez-Menoyo, JL, Hodgkinson, S, Rozsa, C, Hughes, S, Moore, F, Shaw, C, Butler, E, Skibina, O, Gray, O, Kermode, A, Csepany, T, Singhal, B, Shuey, N, Piroska, I, Taylor, B, Simo, M, Sirbu, C-A, Sas, A, and Butzkueven, H

Abstract

OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.

Published
2021

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