84 results on '"Buzzard K"'
Search Results
2. Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom
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Spelman, T, primary, Herring, WL, additional, Acosta, C, additional, Hyde, R, additional, Jokubaitis, VG, additional, Pucci, E, additional, Lugaresi, A, additional, Laureys, G, additional, Havrdova, EK, additional, Horakova, D, additional, Izquierdo, G, additional, Eichau, S, additional, Ozakbas, S, additional, Alroughani, R, additional, Kalincik, T, additional, Duquette, P, additional, Girard, M, additional, Petersen, T, additional, Patti, F, additional, Csepany, T, additional, Granella, F, additional, Grand’Maison, F, additional, Ferraro, D, additional, Karabudak, R, additional, Jose Sa, M, additional, Trojano, M, additional, van Pesch, V, additional, Van Wijmeersch, B, additional, Cartechini, E, additional, McCombe, P, additional, Gerlach, O, additional, Spitaleri, D, additional, Rozsa, C, additional, Hodgkinson, S, additional, Bergamaschi, R, additional, Gouider, R, additional, Soysal, A, additional, Castillo-Triviño, T, additional, Prevost, J, additional, Garber, J, additional, de Gans, K, additional, Ampapa, R, additional, Simo, M, additional, Sanchez-Menoyo, JL, additional, Iuliano, G, additional, Sas, A, additional, van der Walt, A, additional, John, N, additional, Gray, O, additional, Hughes, S, additional, De Luca, G, additional, Onofrj, M, additional, Buzzard, K, additional, Skibina, O, additional, Terzi, M, additional, Slee, M, additional, Solaro, C, additional, Oreja-Guevara, C, additional, Ramo-Tello, C, additional, Fragoso, Y, additional, Shaygannejad, V, additional, Moore, F, additional, Rajda, C, additional, Aguera Morales, E, additional, and Butzkueven, H, additional
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- 2023
- Full Text
- View/download PDF
3. Real-world experience with ocrelizumab in primary Progressive multiple sclerosis: Insights from the MSOCR-P cohort, a MSBase Registry sub-study
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Terzi, M., Rojas, J. I., Barnett, M., Fragoso, Y., Cartechini, E., Pucci, E., Willekens, B., Butler, E., Blanco, Y., Grigoriadis, N., Van Hijfte, L., Dirks, P., Liu, C., Rouzic, E. Muros-Le, Butzkueven, H., Al-Harbi, T., Laureys, G., Ozakbas, S., Spelman, T., Alroughani, R., Menoyo, J. L. Sanchez, Van Pesch, V., Kalincik, T., Lechner-Scott, J., Van der Walt, A., Grand'Maison, F., Boz, C., Buzzard, K., and Skibina, O.
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- 2022
4. Comparative effectiveness of autologous haematopoietic stem cell transplantation vs. fingolimod, ocrelizumab and natalizumab in relapsing-remitting MS
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Atkins, H., Burman, J., Massey, J., Sutton, I., Withers, B., Macdonell, R., Grigg, A., Torkildsen, O., Bo, L., Lehmann, A., Horakova, D., Havrdova, E., Krasulova, E., Trneny, M., Kozak, T., van der Walt, A., Butzkueven, H., McCombe, P., Van Wijmeersch, B., Buzzard, K., Skibina, O., Lechner-Scott, J., Willekens, B., Barnett, M., Cartechini, E., Ozakbas, S., Alroughani, R., Izquierdo, G., Boz, C., Kalincik, T., Sharman, S., Roos, I., Freedman, M., Eichau, S., Snowden, J., Sharrack, B., Turkoglu, R., Prevost, J., Slee, M., Soysal, A., Khoury, S., Lugaresi, A., Onofrj, M., Grammond, P., Duquette, P., Girard, M., Prat, A., Terzi, M., Patti, F., and Kuhle, J.
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- 2022
5. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable
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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.
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- 2022
6. Efficacy and persistence between dimethyl fumarate, fingolimod, and ocrelizumab after natalizumab cessation
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Macdonell, R., Zhu, C., Kalincik, T., Horakova, D., Zhen, Z., Buzzard, K., Skibina, O., Alroughani, R., Izquierdo, G., Eichau, S., Kuhle, J., Patti, F., Grand'Maison, F., Hodgkinson, S., Grammond, P., Lechner-Scott, J., Butler, E., Prat, A., Girard, M., Butzkueven, H., Van der Walt, A., Merlo, D., Monif, M., Jokubaitis, V., Khoury, S. J., Yamout, B., Garber, J., Kermode, A., Van Hijfte, L., Laureys, G., Boz, C., Terzi, M., Prevost, J., Gerlach, O., Van Wijmeersch, B., Barnett, M., Van Pesch, V., Sa, M. Jose, Slee, M., Ozakbas, S., Weinstock-Guttman, B., and Duquette, P.
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- 2022
7. A non-inferiority study of rituximab versus ocrelizumab in relapsing-remitting multiple sclerosis
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Skibina, O., Msbase and Danish Sclerosis Registry Study Grp, Msbase and Danish Sclerosis Registry Study Grp, Kalincik, T., Magyari, M., Gray, O., Sellebjerg, F., Soysal, A., Grand'Maison, F., Grammond, P., John, N., Van Hijfte, L., Laureys, G., Terzi, M., Kuhle, J., Lechner-Scott, J., Butzkueven, H., Van der Walt, A., Buzzard, K., Ozakbas, S., Alroughani, R., Boz, C., MacDonnell, G., Hughes, S., and Roos, I.
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- 2022
8. Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression (vol 208, 106180, 2021)
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De Brouwer, E, Becker, T, Moreau, Y, Havrdova, EK, Trojano, M, Eichau, S, Ozakbas, S, Onofrj, M, Grammond, P, Kuhle, J, Kappos, L, Sola, P, Cartechini, E, Lechner-Scott, J, Alroughani, R, Gerlach, O, Kalincik, T, Granella, F, Grand'Maison, F, Bergamaschi, R, Sa, MJ, Van Wijmeersch, B, Soysal, A, Sanchez-Menoyo, JL, Solaro, C, Boz, C, Iuliano, G, Buzzard, K, Aguera-Morales, E, Terzi, M, Trivio, TC, Spitaleri, D, Van Pesch, V, Shaygannejad, V, Moore, F, Oreja-Guevara, C, Maimone, D, Gouider, R, Csepany, T, Ramo-Tello, C, and Peeters, L
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- 2022
9. High and low efficacy therapy in secondary progressive multiple sclerosis
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Roos, I., Leray, E., Buzzard, K., Skibina, O., Lechner-Scott, J., Malpas, C. B., Butzkueven, H., Vukusic, S, Kalincik, T., University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Monash university, The Royal Melbourne Hospital, University of Newcastle [Callaghan, Australia] (UoN), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), 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), and Hospices Civils de Lyon (HCL)
- Subjects
[SDV]Life Sciences [q-bio] - Abstract
International audience; Meeting Abstract
- Published
- 2022
10. Real-world experience with ocrelizumab in relapsing multiple sclerosis: insights from the MSOCR-R cohort, an MSBase registry sub-study
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Sotoca, J., Rojas, J. I., Sanchez Menoyo, J. L., Kermode, A., Barnett, M., Grand'Maison, F., Van Pesch, V., Terzi, M., Van Hijfte, L., Laureys, G., Alroughani, R., van der Walt, A., Kalincik, T., Skibina, O., Buzzard, K., Boz, C., Spelman, T., Butzkueven, H., Ozakbas, SERKAN, Lechner-Scott, J., Muros-Le Rouzic, E., Liu, C., Dirks, P., and Skromne, E.
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- 2021
11. Relapse during the washout period predicts time to relapse after switching to cladribine
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Van Pesch, V., Ozakbas, SERKAN, Lechner-Scott, J., Jokubaitis, V., Butzkueven, H., Oh, J., Duquette, P., Girard, M., Prat, A., Prevost, J., Butler, E., McCombe, P., Grand'Maison, F., Skibina, O., Buzzard, K., Kalincik, T., Eichau, S., Izquierdo, G., Hodgkinson, S., van der Walt, A., and Zhong, M.
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- 2021
12. Real-world experience with cladribine in the MSBase Registry
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Prevost, J., Van der Walt, A., Kalincik, T., Grand-Maison, F., McCombe, P., Butler, E., Lechner-Scott, J., di Cantogno, E. Verdun, Van Hijfte, L., Laureys, G., Ozakbas, SERKAN, Girard, M., Prat, A., Hodgkinson, S., Spelman, T., Butzkueven, H., Van Pesch, V., Macdonell, R., Oh, J., Alroughani, R., Grammond, P., Sanchez-Menoyo, J. -L., Terzi, M., Duquette, P., Madueno, S. Eichau, Izquierdo, G., Buzzard, K., and Skabina, O.
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- 2021
13. Real-world experience with ocrelizumab in the msbase registry
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Butzkueven, H., Spelman, T., Ozakbas, S., Kalincik, T., Boz, C., Buzzard, K., Skibina, O., Alroughani, R., Karabudak, R., Walt, A., Lechner-Scott, J., Hodgkinson, S., Laureys, G., Hijfte, L., Terzi, M., Butler, E., Macdonell, R., Patti, F., Pesch, V., Slee, M., Barnett, M., Grammond, P., Prevost, J., Grand-Maison, F., Taylor, B., Allan Kermode, Mccombe, P., Duquette, P., Prat, A., Girard, M., Eichau Madueno, S., Izquierdo, G., Soysal, A., Sanchez-Menoyo, J. L., Sotoca, J., Muros-Le Rouzic, E., and Dirks, P.
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- 2020
14. Defining secondary progressive multiple sclerosis
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Lorscheider, J., Buzzard, K., Jokubaitis, V., Spelman, T., Havrdova, E., Horakova, D., Van Pesch, V., and Ondokuz Mayıs Üniversitesi
- Abstract
31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) -- OCT 07-10, 2015 -- Barcelona, SPAIN McCombe, Pamela/0000-0003-2704-8517; Slee, Mark/0000-0003-4323-2453; Kubala Havrdova, Eva/0000-0002-9543-4359; Horakova, Dana/0000-0003-1915-0036 WOS: 000365729402388 … European Comm Treatment & Res Multiple Sclerosis
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- 2015
15. The occurrence of dystonia in upper-limb multiple sclerosis tremor
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Van der Walt, A, primary, Buzzard, K, additional, Sung, S, additional, Spelman, T, additional, Kolbe, SC, additional, Marriott, M, additional, Butzkueven, H, additional, and Evans, A, additional
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- 2015
- Full Text
- View/download PDF
16. Explicit Reduction Modulo p of Certain Two-Dimensional Crystalline Representations
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Buzzard, K., primary and Gee, T., additional
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- 2009
- Full Text
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17. Heat shock protein 72 modulates pathways of stress-induced apoptosis.
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Buzzard, K A, Giaccia, A J, Killender, M, and Anderson, R L
- Abstract
The resistance to stress-induced apoptosis conferred by the thermotolerant state or by exogenous expression of HSP72 was measured in mouse embryo fibroblasts. The induction of thermotolerance protects cells from heat, tumor necrosis factor alpha (TNFalpha), and ceramide-induced apoptosis but not from ionizing radiation. Because the development of thermotolerance is associated with increased levels of heat shock proteins, we determined whether constitutive expression of one of the major inducible heat shock proteins, HSP72, could also protect cells from stress-induced apoptosis. Cells expressing constitutive HSP72 were shown to have significantly reduced levels of apoptosis after heat, TNFalpha, and ceramide but not after ionizing radiation. Activation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) was found to be strongly inhibited in thermotolerant cells after heat shock but not after other stresses. Cells that constitutively express HSP72 did not demonstrate decreased SAPK/JNK activation after any of these stresses. Thus, factors other than HSP72 that are induced in the thermotolerant state are able to reduce activation of SAPK/JNK after heat stress. Notably, the level of activation of SAPK/JNK did not correlate with the amount of apoptosis detected after different stresses. Constitutive HSP72 expression inhibited poly(ADP-ribose) polymerase cleavage in cells after heat shock and TNFalpha but not after ceramide or ionizing radiation. The results suggest either that SAPK/JNK activation is not required for apoptosis in mouse embryo fibroblasts or that HSP72 acts downstream of SAPK/JNK. Furthermore, the data support the concept that caspase activity, which can be down-regulated by HSP72, is a crucial step in stress-induced apoptosis. Based on data presented here and elsewhere, we propose that the heat shock protein family can be classified as a class of anti-apoptotic genes, in addition to the Bcl-2 and inhibitor of apoptosis protein families of genes.
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- 1998
18. Comparison of multiple disease modifying therapies in multiple sclerosis with marginal structural models
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Diouf, I., Malpas, C., Sharmin, S., Izanne Roos, Horakova, D., Havrdova, E. K., Patti, F., Shaygannejad, V., Ozakbas, S., Izquierdo, G., Eichau, S., Onofrj, M., Lugaresi, A., Alroughani, R., Duquette, P., Terzi, M., Boz, C., Grand Maison, F., Hamdy, S., Sola, P., Grammond, P., Turkoglu, R., Skibina, O., Buzzard, K., Yamout, B., Altintas, A., Gerlach, O., Pesch, V., Blanco, Y., Maimone, D., Lechner-Scott, J., Bergamaschi, R., Karabudak, R., Barnet, M., Hughes, S., Sa, M. J., Kappos, L., Hodgkinson, S., Butzkueven, H., Prevost, J., Laureys, G., Moore, F., and Kalincik, T.
19. Disease reactivation after cessation of disease-modifying therapy in relapsing-remitting multiple sclerosis
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Izanne Roos, Malpas, C., Leray, E., Casey, R., Horakova, D., Havrdova, E. Kubala, Debouverie, M., Patti, F., 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., 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., Gerlach, O., Spitaleri, D., Pesch, V., Gout, O., Turkoglu, R., Heinzlef, O., Thouvenot, E., Vukusic, S., Butzkueven, H., and Kalincik, T.
20. Comparison of the effectiveness of ocrelizumab vs interferons, fingolimod and natalizumab on relapses in relapsing-remitting multiple sclerosis
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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.
21. Defining secondary progressive multiple sclerosis
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Lorscheider, J., Buzzard, K., Jokubaitis, V., Spelman, T., Havrdova, E., Horakova, D., Trojano, M., Izquierdo, G., Girard, M., Duquette, P., Prat, A., Lugaresi, A., Grand Maison, F., Grammond, P., Hupperts, R., Alroughani, R., Sola, P., Boz, C., Terzi, M., Pucci, E., Lechner-Scott, J., Bergamaschi, R., Eva Kubala Havrdova, Iuliano, G., Pesch, V., Bolanos, R. F., Granella, F., Rio, M. E., Ramo, C., Spitaleri, D. L., Petersen, T., Slee, M., Verheul, F., Ampapa, R., Amato, M. P., Mccombe, P., Vucic, S., Menoyo, J. L. S., Cristiano, E., Barnett, M., Hodgkinson, S., Cabrera-Gomez, J. A., Olascoaga, J., Saladino, M. L., Flechter, S., Gray, O., Deri, N., Butzkueven, H., Kalincik, T., and Sbase Study Grp, M.
22. Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts
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Mark Slee, Guillermo Izquierdo, Per Soelberg Soerensen, Karen Schreiber, Alexandre Prat, Francois Grand'Maison, Maria Trojano, Franco Granella, Pierre Duquette, David Laplaud, Elisabeth Maillart, Henrik Kahr Mathiesen, Bassem Yamout, Cavit Boz, Jean Pelletier, Corinne Pottier, Jette L. Frederiksen, Claudia Christina Pfleger, Tomas Kalincik, Olivier Gout, Daniele Spitaleri, Marc Girard, Marco Onofrj, Jérôme De Seze, Helmut Butzkueven, Emmanuelle Leray, Philippe Cabre, Julie Prevost, Abullatif Al-Khedr, Aude Maurousset, Eric Berger, Sifat Sharmin, Ivania Patry, Pamela A. McCombe, Patrizia Sola, Olga Skibina, Diana Ferraro, Pierre Clavelou, Francesco Patti, Finn Sellebjerg, Niels Koch-Henriksen, Alexis Montcuquet, Recai Turkoglu, Romain Casey, Bart Van Wijmeersch, Hélène Zéphir, Pierre Grammond, Dana Horakova, Davide Maimone, Serkan Ozakbas, Céline Labeyrie, Murat Terzi, Aurélie Ruet, Steve Vucic, Jonathan Ciron, Tünde Csépány, Nicolas Maubeuge, Bruno Stankoff, Mathilde Lefort, Katherine Buzzard, Karolina Hankiewicz, Jean-Philippe Camdessanché, Raed Alroughani, Michael Broksgaard Jensen, Pierre Labauge, Olivier Casez, Peter Vestergaard Rasmussen, Bertrand Bourre, Olivier Heinzlef, Gilles Defer, Gilles Edan, Alessandra Lugaresi, Abir Wahab, Melinda Magyari, Anneke van der Walt, Eva Havrdova, Johanna Balslev Andersen, Chantal Nifle, Stephan Bramow, Marc Debouverie, Thibault Moreau, Sandra Vukusic, Christine Lebrun-Frenay, Jeannette Lechner-Scott, Eric Thouvenot, Sharmin S., Lefort M., Andersen J.B., Leray E., Horakova D., Havrdova E.K., Alroughani R., Izquierdo G., Ozakbas S., Patti F., Onofrj M., Lugaresi A., Terzi M., Grammond P., Grand'Maison F., Yamout B., Prat A., Girard M., Duquette P., Boz C., Trojano M., McCombe P., Slee M., Lechner-Scott J., Turkoglu R., Sola P., Ferraro D., Granella F., Prevost J., Maimone D., Skibina O., Buzzard K., Van der Walt A., Van Wijmeersch B., Csepany T., Spitaleri D., Vucic S., Casey R., Debouverie M., Edan G., Ciron J., Ruet A., De Seze J., Maillart E., Zephir H., Labauge P., Defer G., Lebrun-Frenay C., Moreau T., Berger E., Clavelou P., Pelletier J., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Al-Khedr A., Bourre B., 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., Laplaud D., Koch-Henriksen N., Sellebjerg F.T., Soerensen P.S., Pfleger C.C., Rasmussen P.V., Jensen M.B., Frederiksen J.L., Bramow S., Mathiesen H.K., Schreiber K.I., Magyari M., Vukusic S., Butzkueven H., Kalincik T., University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH), École des Hautes Études en Santé Publique [EHESP] (EHESP), Charles University [Prague] (CU), Amiri hospital, Hospital Virgen Macarena, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), University of Catania [Italy], G.F. Ingrassia Hospital, Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Neurological Science of Bologna (IRCCS), Ondokuz Mayis University (OMU), American University of Beirut Faculty of Medicine and Medical Center (AUB), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Karadeniz Technical University (KTU), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of Queensland [Brisbane], Royal Brisbane & Women's Hospital [Brisbane, Australia] (RBWH), Flinders University [Adelaide, Australia], University of Newcastle [Callaghan, Australia] (UoN), Azienda Ospedaleria Universitaria di Modena, Università degli studi di Parma = University of Parma (UNIPR), University Hospital Parma, Monash University [Melbourne], The Alfred Hospital, Hasselt University (UHasselt), University of Debrecen Egyetem [Debrecen], San Giuseppe Moscati Hospital [Avellino, Italie], Westmead Hospital [Sydney], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), Fondation Eugène Devic EDMUS, 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), 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), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Pasteur [Nice] (CHU), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Service de neurologie [Amiens], CHU Amiens-Picardie, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU de la Martinique [Fort de France], Service de Neurologie [CHU Limoges], CHU Limoges, CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de Neurologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Hôpital Sud Francilien Corbeil Essonne, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier de Versailles André Mignot (CHV), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Aarhus University Hospital, Aalborg University [Denmark] (AAU), University Hospital of Northern Sealand, Rigshospitalet [Copenhagen], Copenhagen University Hospital, The Royal Melbourne Hospital, 1140766, National Health and Medical Research Council, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (KU), Università degli Studi di Bologna, University of Bari Aldo Moro (UNIBA), University of Newcastle [Australia] (UoN), University of Parma = Università degli studi di Parma [Parme, Italie], University of Debrecen, 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), CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Ondokuz Mayis University, Centre de recherche en neurosciences de Lyon (CRNL), Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, 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), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Internationality ,Subgroup analysis ,Rate ratio ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Natalizumab ,Multiple Sclerosis, Relapsing-Remitting ,030225 pediatrics ,Internal medicine ,Secondary Prevention ,Medicine ,Humans ,Immunologic Factors ,Pharmacology (medical) ,Longitudinal Studies ,Registries ,10. No inequality ,Expanded Disability Status Scale ,business.industry ,Proportional hazards model ,Fingolimod Hydrochloride ,Multiple sclerosis ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Middle Aged ,medicine.disease ,Fingolimod ,3. Good health ,multiple sclerosis, sex, age, natalizumab, fingolimod, big data ,Psychiatry and Mental health ,Cohort ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Immunosuppressive Agents ,medicine.drug ,Follow-Up Studies - Abstract
Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients’ sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed withweighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15–41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65–0.88); in those aged ≤38 years (0.64; 0.54–0.76); in those withdisease duration ≤7 years (0.63; 0.53–0.76); in those with EDSS score 38 years (1.34; 1.04–1.73); those with disease duration >7 years (1.33; 1.01–1.74); those with EDSS score
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- 2021
23. Risk of relapse phenotype recurrence in multiple sclerosis
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Daniele Spitaleri, Joseph Herbert, Jeannette Lechner-Scott, Bhim Singhal, Tomas Kalincik, Carmen Adella Sirbu, Maria Edite Rio, Marc Girard, Celia Oreja-Guevara, Norbert Vella, Pierre Duquette, Raymond Hupperts, Francois Grand'Maison, Vincent Van Pesch, Alessandra Lugaresi, Maria Pia Amato, Raed Alroughani, Thor Petersen, Marcela Fiol, Gerardo Iuliano, Steve Vucic, Giorgio Giuliani, Ricardo Fernandez-Bolanos, Guillermo Izquierdo, Tatjana Petkovska-Boskova, Freek Verheul, Michael Barnett, Helmut Butzkueven, Mark Paine, Maria Laura Saladino, Jose Antonio Cabrera-Gomez, Erik van Munster, Maria Trojano, Roberto Bergamaschi, S. Flechter, Danny Liew, Orla Gray, Katherine Buzzard, Edgardo Cristiano, Cavit Boz, Mark Slee, Cameron Shaw, Aldo Savino, Vilija Jokubaitis, Csilla Rozsa, Fraser Moore, Pierre Grammond, John Parratt, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Kalincik T, Buzzard K, Jokubaitis V, Trojano M, Duquette P, Guillermo I, Girard M, Lugaresi A, Grammond P, Grand'maison F, Oreja-Guevara C, Boz C, Hupperts R, Petersen T, Giuliani G, Iuliano G, Lechner-Scott J, Barnett M, Bergamaschi R, Van Pesch V, Amato MP, van Munster E, Fernandez-Bolanos R, Verheul F, Fiol M, Cristiano E, Slee M, Rio ME, Spitaleri D, Alroughani R, Gray O, Saladino ML, Flechter S, Herbert J, Cabrera-Gomez JA, Vella N, Paine M, Shaw C, Moore F, Vucic S, Savino A, Singhal B, Petkovska-Boskova T, Parratt J, Sirbu CA, Rozsa C, Liew D, Butzkueven H, and on behalf of the MSBase Study Group
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Adult ,Male ,Risk ,medicine.medical_specialty ,phenotype ,Disease ,Logistic regression ,MSBase ,Multiple sclerosis ,Disability Evaluation ,Multiple Sclerosis, Relapsing-Remitting ,Recurrence ,Internal medicine ,medicine ,Humans ,multiple sclerosis, relapse, symptom, prognosis ,Aged ,business.industry ,Age Factors ,presentation of neurological diseases ,Middle Aged ,medicine.disease ,Phenotype ,Natural history ,Institutional repository ,Neurology ,Immunology ,Disease Progression ,Female ,Observational study ,prognosis ,Neurology (clinical) ,business ,Progressive disease - Abstract
Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
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- 2014
24. A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.
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Lal AP, Foong YC, Sanfilippo PG, Spelman T, Rath L, Levitz D, Fabis-Pedrini M, Foschi M, Habek M, Kalincik T, Roos I, Lechner-Scott J, John N, Soysal A, D'Amico E, Gouider R, Mrabet S, Gross-Paju K, Cárdenas-Robledo S, Moghadasi AN, Sa MJ, Gray O, Oh J, Reddel S, Ramanathan S, Al-Harbi T, Altintas A, Hardy TA, Ozakbas S, Alroughani R, Kermode AG, Surcinelli A, Laureys G, Eichau S, Prat A, Girard M, Duquette P, Hodgkinson S, Ramo-Tello C, Maimone D, McCombe P, Spitaleri D, Sanchez-Menoyo JL, Yetkin MF, Baghbanian SM, Karabudak R, Al-Asmi A, Jakob GB, Khoury SJ, Etemadifar M, van Pesch V, Buzzard K, Taylor B, Butzkueven H, and Van der Walt A
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- Humans, Longitudinal Studies, Male, Female, Adult, Middle Aged, Practice Patterns, Physicians' statistics & numerical data, Immunologic Factors therapeutic use, Cladribine therapeutic use, Alemtuzumab therapeutic use, Multiple Sclerosis drug therapy, Multiple Sclerosis epidemiology, COVID-19 epidemiology, Natalizumab therapeutic use, Fingolimod Hydrochloride therapeutic use, Immunosuppressive Agents therapeutic use
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Background: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset., Methods: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use., Results: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]., Conclusions: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges., (© 2024. The Author(s).)
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- 2024
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25. Memory function in autoimmune encephalitis: a cross-sectional prospective study utilising multiple memory paradigms.
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Griffith SP, Wesselingh R, Seery N, Rushen T, Kyndt C, Long B, Seneviratne U, Kalincik T, Buzzard K, Butzkueven H, O'Brien TJ, Alpitsis R, Malpas CB, and Monif M
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- Humans, Cross-Sectional Studies, Female, Male, Middle Aged, Adult, Prospective Studies, Aged, Neuropsychological Tests, Hashimoto Disease physiopathology, Hashimoto Disease complications, Memory physiology, Young Adult, Encephalitis physiopathology, Encephalitis immunology, Encephalitis complications, Memory Disorders etiology, Memory Disorders physiopathology
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Background and Objective: Autoimmune encephalitis (AE) is often associated with clinically significant memory impairment. This study aimed to evaluate memory in a cross-sectional prospective AE cohort using multiple memory paradigms., Methods: 52 patients (50% seropositive) meeting Graus criteria for possible AE were prospectively recruited between October 2019 and August 202. A comprehensive examination of memory was performed, including tests of supraspan verbal memory (list learning), logicosemantic memory (story learning), figural memory (learning of geometric designs), and verbal associative learning (verbal paired associates). Memory scores were compared to demographically adjusted normative data. Pattern analysis was conducted to assist in the identification of patterns in memory performances., Results: Mean memory scores were not significantly below the normative mean. At an individual patient level, over 20% of the cohort exhibited impaired delayed figural memory, supraspan verbal memory learning and recall. Observed performances were significantly below expected performance for story learning (p = 0.017) and recall (p = 0.003), figural recall (p < 0.0001), initial acquisition (p < 0.001) and final acquisition of a list (p < 0.001) and all delayed recall measures of the list (p < 0.00001). 54.76% of patients exhibited intact psychometrics, and 16 distinct patterns of impairment emerged, indicating variability in memory outcomes., Discussion: While statistical evidence for memory impairment did not emerge at an aggregate level, a proportion of patients present with evidence of abnormal memory performance on psychometrics. Variability in impaired memory measures argues for an individualised patient-focused approach to clinical assessment in AE. Future research should validate these findings with a larger sample size and explore the relationships between memory profiles and other cognitive functions., (© 2024. The Author(s).)
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- 2024
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26. The clinical relevance of MOG antibody testing in cerebrospinal fluid.
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Reynolds M, Tan I, Nguyen K, Merheb V, Lee FXZ, Trewin BP, Lerch M, Shah S, Wolfe N, Buzzard K, Lechner-Scott J, Fabis-Pedrini M, Fok A, John N, Kneebone C, Yiannikas C, Brown DA, Kermode AG, Reddel S, Dale RC, Brilot F, and Ramanathan S
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Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is diagnosed by serum MOG-immunoglobulin G (MOG-IgG) in association with typical demyelination. 111/1127 patients with paired CSF/serum samples were seropositive for MOG-IgG. Only 7/1016 (0.7%) seronegative patients had CSF-restricted MOG-IgG. While 3/7 patients had longitudinally extensive transverse myelitis, four had a confirmed alternate diagnosis (three multiple sclerosis, one CNS vasculitis). In a national referral setting, CSF-restricted MOG-IgG had a low sensitivity (2.63%, 95%CI 0.55-7.50%) and low positive predictive value (1.97%, 95%CI 0.45-8.13%). We strongly recommend serum as the preferred diagnostic biospecimen, and urge caution in the interpretation of CSF-restricted MOG-IgG in patients without clinico-radiological features consistent with MOGAD., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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27. Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60.
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Foong YC, Merlo D, Gresle M, Buzzard K, Zhong M, Yeh WZ, Jokubaitis V, Monif M, Skibina O, Ozakbas S, Patti F, Grammond P, Amato MP, Kalincik T, Horakova D, Kubala Havrdova E, Weinstock-Guttman B, Lechner Scott J, Boz C, Sa MJ, Butzkueven H, van der Walt A, and Zhu C
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- Humans, Male, Female, Middle Aged, Aged, Immunologic Factors therapeutic use, Immunologic Factors adverse effects, Multiple Sclerosis drug therapy, Treatment Outcome, Cohort Studies, Interferons therapeutic use, Interferons adverse effects, Recurrence, Registries, Glatiramer Acetate therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects
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Background: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60., Methods: Using data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI)., Results: A total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years., Conclusion: In older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group., Competing Interests: Competing interests: YCF received travel compensation from Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia and Australian and New Zealand Association of Neurologists. MG is currently working on observational studies funded by Biogen and Roche. DM has received honoraria from Novartis. CZ has nothing to disclose. KB has received honoraria for presentations and/or educational support from Biogen, Sanofi Genzyme, Merck, Roche, Alexion and Teva and serves on medical advisory boards for Merck and Biogen. MZ has received conference travel support from Novartis and Roche, and research support from the Australian Government Research Training Program and MS Research Australia. WZY: received honoraria from Merck and Novartis. VJ receives research grant support form F.Hoffmann La-Roche, MS Research Australia and the National Health and Medical Research Council of Australia (NHMRC 1156519). MM has received research support from National Health and Medical Research Council, Medical Research Future Fund, Brain Foundation, Charles and Sylvia Viertel Foundation, MS Research Australia, Merck and Ku Leuven University, served on advisory board for Merck, has received speaker honoraria from Merck and Biogen. OS received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme. SO has nothing to disclose. FP received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Merck, Novartis and Roche and received research grant by Biogen, Merck and Roche and by FISM, Reload Association (Onlus), Italian Health Minister, University of Catania. PG has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. MPA received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. DH supported by the Charles University: Cooperatio Programme in Neuroscience, by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107)—funded by the European Union – Next Generation EU, General University Hospital in Prague project MH CZ-DRO-VFN64165 and received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Inc. EKH received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars and Sanofi Genzyme; and has been supported by the Czech Ministry of Education—project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107)—funded by the European Union-Next Generation EU. BW-G participated in speaker’s bureaus and/or served as a consultant and received grants from Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon; she also serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. JLS received travel compensation from Novartis, Biogen, Roche and Merck and her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. MJS: Received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. AvdW served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen, received research grants from National Health and Medical Research Council of Australia, MS Research Australia, Novartis, Biogen, Merck and Roche, received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck and is currently a coprincipal investigator on a cosponsored observational study with Roche. HB’s Institution has received compensation for advisory boards or lecture fees from Novartis, Biogen, Merck, UCB Pharma and Roche and receives research funding from Novartis, Biogen, Merck, Roche, The National Health and Medical Research Council of Australia, The Medical Research Future Fund (Australia), Monash Partners, the Trish MS Foundation, The Pennycook Foundation, and MS Australia; he also receives personal compensation as the Managing Director of the MSBase Foundation and from the Oxford Health Policy Forum Brain Health Initiative., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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28. Language impairments in seropositive and seronegative autoimmune encephalitis.
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Griffith SP, Wesselingh R, D'Aprano F, Seery N, Rushen T, Kyndt C, Long B, Seneviratne U, Kalincik T, Buzzard K, Butzkueven H, O'Brien TJ, Alpitsis R, Malpas CB, and Monif M
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- Humans, Female, Male, Middle Aged, Adult, Aged, Language Tests, Hashimoto Disease diagnosis, Hashimoto Disease complications, Hashimoto Disease blood, Cohort Studies, Encephalitis diagnosis, Encephalitis complications, Encephalitis blood, Encephalitis immunology, Language Disorders etiology, Language Disorders diagnosis
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Background and Objective: Autoimmune encephalitis (AE) is a rare neuroinflammatory disease affecting the central nervous system. To examine language functions in patients with different subsets of AE consisting of seropositive and seronegative groups., Methods: Fifty-two patients were recruited from neurology departments in Melbourne, Australia, who met clinical criteria for possible AE. Language tests include the Naming Test from the Sydney Language Battery (SydBat), the semantic fluency trial from the Controlled Oral Word Association Test (COWAT), and the Vocabulary and Similarities subtests of the Weschler Abbreviated Scale of Intelligence-Second Edition. The results were standardised with normative data., Results: The mean age of our cohort was 52.5 years old, with the average time from hospital admission to recruitment being 38.41 months. At an aggregate level, none of the mean language test z-scores were below normative data. At the patient level, impairment rates were 18.37% for COWAT (animals), 28.57% for SydBat (naming), 4.65% for Similarities, and 4.55% for Vocabulary. Chi-squared goodness of fit tests indicated that observed performances were significantly below expected performances for the SydBat (naming) test (p < 0.0001) and COWAT (animals) (p = 0.004)., Discussion: While, on average, language functions were within normal limits in patients with AE, but a subgroup exhibited lower performance in semantic fluency and visual confrontation naming, with impairment rates below expected norms. To advance understanding of language in chronic AE patients, exploring the impact of seizure burden, antiseizure medication use, and the relationship of language functions with other cognitive functions is crucial., (© 2024. The Author(s).)
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- 2024
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29. Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies.
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Butzkueven H, Kalincik T, Patti F, Slee M, Weinstock-Guttman B, Buzzard K, Skibina O, Alroughani R, Prat A, Girard M, Horakova D, Havrdova EK, Van der Walt A, Eichau S, Hyde R, Campbell N, Bodhinathan K, and Spelman T
- Abstract
Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance., Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate)., Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD., Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW)., Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients ( p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42-0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients., Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy., (© The Author(s), 2024.)
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- 2024
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30. Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies.
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Bridge F, Brotherton J, Stankovich J, Sanfilippo PG, Skibina OG, Buzzard K, Kalincik T, Nguyen AL, Guo K, Monif M, Wrede CD, Rath L, Taylor L, Butzkueven H, Jokubaitis VG, and Van Der Walt A
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- Female, Humans, Child, Preschool, Cohort Studies, Early Detection of Cancer methods, Victoria epidemiology, Uterine Cervical Neoplasms epidemiology, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms pathology, Uterine Cervical Dysplasia diagnosis, Uterine Cervical Dysplasia pathology, Papillomavirus Infections complications, Papillomavirus Infections epidemiology, Papillomavirus Infections prevention & control, Multiple Sclerosis drug therapy, Multiple Sclerosis epidemiology, Multiple Sclerosis complications
- Abstract
Background and Objectives: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs)., Methods: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects., Results: We included 248 wwMS. The incidence of abnormal CSTs was lower ( p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age., Discussion: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs., Classification of Evidence: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.
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- 2024
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31. Characterizing cognitive function in patients with autoimmune encephalitis: an Australian prospective study.
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Griffith SP, Wesselingh R, Seery N, Rushen T, Kyndt C, Long B, Seneviratne U, Buzzard K, Butzkueven H, O'Brien TJ, Alpitsis R, Malpas CB, and Monif M
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- Adult, Humans, Prospective Studies, Neuropsychological Tests, Australia, Memory, Short-Term, Cognition, Autoimmune Diseases of the Nervous System
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Objective: This study uses the Wechsler intelligence and memory scales to characterize the cognitive function of patients with autoimmune encephalitis (AE) in the chronic stage of the disease. AE is a group of neuroinflammatory disorders, and cognitive impairment is a significant source of chronic morbidity in these patients., Methods: Fifty patients with an average disease duration of 3.2 years after diagnosis were prospectively recruited from four hospitals. They underwent a comprehensive cognitive examination using the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Adult Intelligence Scale (WAIS-IV) and Wechsler Memory Scale (WMS-IV). Summary statistics were computed, and single-sample and independent-samples t tests were used to compare the cohort to normative data., Results: The results revealed significantly reduced performances in perceptual reasoning, processing speed, and working memory among AE patients. Seropositive AE patients exhibited below-norm processing speed, while the seronegative group showed reduced working memory and processing speed. Delayed memory performance was significantly below expectations only in seronegative patients. Pattern analysis indicated that intact cognition was the most observed outcome after AE, but significant heterogeneity was observed among the impaired patients., Conclusions: The study identified deficits in perceptual reasoning, processing speed, and working memory among chronic AE patients. Pattern analysis highlighted positive long-term cognitive outcomes for many but varied outcomes for those with ongoing difficulties. Although severely cognitively impaired patients were not included, the findings apply to AE cohorts who attend outpatient clinical neuropsychology consultations emphasizing the need for thorough cognitive assessment. The results suggest a need for further research targeting other cognitive domains, including executive functions., (© 2023. The Author(s).)
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- 2024
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32. The Patient-Determined Disease Steps scale is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis.
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Foong YC, Merlo D, Gresle M, Zhu C, Buzzard K, Lechner-Scott J, Barnett M, Taylor B, Kalincik T, Kilpatrick T, Darby D, Dobay P, van Beek J, Hyde R, Butzkueven H, and van der Walt A
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- Humans, Reproducibility of Results, Disability Evaluation, Outcome Assessment, Health Care, Multiple Sclerosis diagnosis, Multiple Sclerosis, Relapsing-Remitting diagnosis
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Background and Purpose: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS., Methods: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP)., Results: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS., Conclusion: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2024
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33. Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.
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Spelman T, Herring WL, Acosta C, Hyde R, Jokubaitis VG, Pucci E, Lugaresi A, Laureys G, Havrdova EK, Horakova D, Izquierdo G, Eichau S, Ozakbas S, Alroughani R, Kalincik T, Duquette P, Girard M, Petersen T, Patti F, Csepany T, Granella F, Grand'Maison F, Ferraro D, Karabudak R, Jose Sa M, Trojano M, van Pesch V, Van Wijmeersch B, Cartechini E, McCombe P, Gerlach O, Spitaleri D, Rozsa C, Hodgkinson S, Bergamaschi R, Gouider R, Soysal A, Castillo-Triviño, Prevost J, Garber J, de Gans K, Ampapa R, Simo M, Sanchez-Menoyo JL, Iuliano G, Sas A, van der Walt A, John N, Gray O, Hughes S, De Luca G, Onofrj M, Buzzard K, Skibina O, Terzi M, Slee M, Solaro C, Oreja-Guevara, Ramo-Tello C, Fragoso Y, Shaygannejad V, Moore F, Rajda C, Aguera Morales E, and Butzkueven H
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- Humans, Natalizumab therapeutic use, Fingolimod Hydrochloride therapeutic use, Immunosuppressive Agents therapeutic use, Cost-Effectiveness Analysis, Cost-Benefit Analysis, State Medicine, United Kingdom, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis drug therapy
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Aim: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS)., Methods: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources., Results: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses., Conclusions: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.
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- 2024
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34. Risk of secondary progressive multiple sclerosis after early worsening of disability.
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Dzau W, Sharmin S, Patti F, Izquierdo G, Eichau S, Prat A, Girard M, Duquette P, Onofrj M, Lugaresi A, Ozakbas S, Gerlach O, Boz C, Grammond P, Terzi M, Amato MP, La Spitaleri D, Ramo-Tello C, Maimone D, Cartechini E, Buzzard K, Skibina O, van der Walt A, Butzkueven H, Iuliano G, Soysal A, and Kalincik T
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- Male, Humans, Adult, Female, Disease Progression, Australia epidemiology, Recurrence, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis, Chronic Progressive drug therapy, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting epidemiology, Multiple Sclerosis, Relapsing-Remitting drug therapy
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Background: Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy., Methods: This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression., Results: 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found., Conclusions: Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12605000455662)., Competing Interests: Competing interests: WD has nothing to declare. SS has nothing to declare. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. AP has nothing to declare. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. MO has nothing to declare. AL has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva. Her institutions have receved research grants from Novartis [last 4 yrs]. SO has nothing to declare. OG has nothing to declare. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. PG has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. MPA received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. DS received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. CR-T received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. DM received speaker honoraria for Advisory Board and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. EC has nothing to declare. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck, CSL and Grifols. OS has nothing to declare. AvdW has nothing to declare. HB Institution (Monash university) has received compensation for consulting, talks, advisory/steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA. HB has received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis. GI had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. AS has nothing to declare., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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35. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.
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Sharmin S, Roos I, Simpson-Yap S, Malpas C, Sánchez 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-Triviño 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
- Subjects
- Humans, Ultraviolet Rays, Disease Progression, Neoplasm Recurrence, Local, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis epidemiology, Multiple Sclerosis diagnosis, Multiple Sclerosis, Relapsing-Remitting epidemiology
- 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 was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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36. Disability accrual in primary and secondary progressive multiple sclerosis.
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Harding-Forrester S, Roos I, Nguyen AL, 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, Grand'Maison F, 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, Sánchez-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
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- Humans, Disease Progression, Proportional Hazards Models, Multiple Sclerosis, Chronic Progressive drug therapy, Multiple Sclerosis, Disabled Persons
- 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., Competing Interests: Competing interests: IR served on scientific advisory boards for Novartis and Merck, and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi Genzyme, and Merck. A-LN received grants from MS Research Australia; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Sanofi Genzyme. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall, and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and the University of Catania. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, and support for research activities from Biogen and the Czech Ministry of Education (project PROGRES Q27/LF1). EVH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and received research support from the Czech Ministry of Education (project PROGRES Q27/LF1). MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Canada Innovation, Novartis, and EMD; and research support from the Canadian Institutes of Health Research. PD served on editorial boards for, and has been supported to attend meetings by, EMD, Biogen, Novartis, Genzyme, and Teva Neuroscience; he holds grants from the Canadian Institutes of Health Research and the MS Society of Canada, and received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. FG’M received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. AL received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva; her institutions have received research grants from Novartis (in the past 4 years). PG served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, and Pendopharm; received grant support from Genzyme and Roche; and received research grants for his institution from Biogen Idec, Sanofi Genzyme, and EMD Serono. MPA received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Teva, and Sanofi-Aventis, and received research grants by Biogen, Bayer Schering, Merck, Teva, and Novartis. PS served on scientific advisory boards for Biogen Idec and Teva; received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; and received research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. DF received travel grants and/or speaker honoraria from Merck, Teva, Novartis, Biogen, and Sanofi Genzyme. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Sanofi Genzyme, Roche, Merck, CSL, and Grifols. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck; her institution received honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, Teva, and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. VVP received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche; his institution received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. MT received travel grants from Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. DM received speaker honoraria for advisory board service and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. CR-T received research funding, compensation for travel, or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. DLS received honoraria as a consultant on scientific advisory boards from Bayer Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva, and Merck. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme, and Roche; and received funding for travel and speaker honoraria from Biogen, Merck, and Sanofi-Aventis. MS participated in, but did not receive honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis, and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; and congress, travel, and accommodation expense compensations from Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. RA received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck, and participated in clinical trials by Biogen, Novartis, Teva, and Actelion. JLS-M received travel compensation from Novartis and Biogen; received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in a clinical trial by Biogen. JP received travel compensation from Novartis, Biogen, Genzyme, and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. TC-T received speaking or consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. GL received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, and Biogen. JO received research funding from the MS Society of Canada, the National MS Society, Brain Canada, Biogen Idec, Roche, and EMD Serono, and personal compensation for consulting or speaking from EMD Serono, Sanofi Genzyme, Biogen Idec, Roche, Celgene, and Novartis. AA received personal fees and speaker honoraria from Teva, Merck, Biogen Gen Pharma, Roche, Novartis, Bayer, and Sanofi Genzyme, and received travel and registration grants from Merck, Biogen Gen Pharma, Roche, Sanofi Genzyme, and Bayer. HB received compensation for consulting, talks, and advisory or steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health, and Oxford Health Policy Forum, and research support from Novartis, Biogen, Roche, Merck, the National Health and Medical Research Council of Australia, Pennycook Foundation, and MS Research Australia MB served on scientific advisory boards for Biogen, Novartis, and Genzyme, received conference travel support from Biogen and Novartis, and serves on steering committees for trials conducted by Novartis; his institution received research support from Biogen, Merck, and Novartis. EC Cristiano received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Genzyme, and Novartis, and participated in clinical trials or other research projects by Merck, Roche, and Novartis. SH received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. GI received compensation for travel, accommodations, and meeting expenses from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, the Swiss MS Society, the Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. BW-G participated in speakers' bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon; received grant/research support from these same agencies; and serves on editorial boards for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. BVW received research and travel grants and honoraria for advisory and speaking fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for the Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi Genzyme, Teva, BioCSL, and Merck; and received support for research or educational events from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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37. Acute intermittent porphyria presenting with first episode seizure and rhabdomyolysis.
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Redmond J, Fazio T, and Buzzard K
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- Humans, Seizures etiology, Porphyria, Acute Intermittent complications, Porphyria, Acute Intermittent diagnosis, Rhabdomyolysis complications
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- 2023
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38. Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis.
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Roos I, Hughes S, McDonnell G, Malpas CB, Sharmin S, Boz C, Alroughani R, Ozakbas S, Buzzard K, Skibina O, van der Walt A, Butzkueven H, Lechner-Scott J, Kuhle J, Terzi M, Laureys G, Van Hijfte L, John N, Grammond P, Grand'Maison F, Soysal A, Jensen AV, Rasmussen PV, Svendsen KB, Barzinji I, Nielsen HH, Sejbæk T, Prakash S, Stilund MLM, Weglewski A, Issa NM, Kant M, Sellebjerg F, Gray O, Magyari M, and Kalincik T
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- Humans, Female, Rituximab therapeutic use, Cohort Studies, Neoplasm Recurrence, Local, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting diagnostic imaging, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Importance: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab., Objective: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS., Design, Setting, and Participants: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country., Exposure: Treatment with ocrelizumab or rituximab after 2015., Main Outcomes and Measures: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups., Results: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses., Conclusion: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.
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- 2023
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39. Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.
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Zhu C, Kalincik T, Horakova D, Zhou Z, Buzzard K, Skibina O, Alroughani R, Izquierdo G, Eichau S, Kuhle J, Patti F, Grand'Maison F, Hodgkinson S, Grammond P, Lechner-Scott J, Butler E, Prat A, Girard M, Duquette P, Macdonell RAL, Weinstock-Guttman B, Ozakbas S, Slee M, Sa MJ, Van Pesch V, Barnett M, Van Wijmeersch B, Gerlach O, Prevost J, Terzi M, Boz C, Laureys G, Van Hijfte L, Kermode AG, Garber J, Yamout B, Khoury SJ, Merlo D, Monif M, Jokubaitis V, van der Walt A, and Butzkueven H
- Subjects
- Humans, Female, Adult, Natalizumab adverse effects, Dimethyl Fumarate adverse effects, Neoplasm Recurrence, Local drug therapy, Immunosuppressive Agents adverse effects, Immunologic Factors adverse effects, Recurrence, Fingolimod Hydrochloride therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses., Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab., Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023., Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab., Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method., Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab., Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
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- 2023
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40. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.
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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 Triviño 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, and Brown JWL
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- Humans, Prognosis, Recurrence, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis
- 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.
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- 2023
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41. Smartphone monitoring of cognition in people with multiple sclerosis: A systematic review.
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Foong YC, Bridge F, Merlo D, Gresle M, Zhu C, Buzzard K, Butzkueven H, and van der Walt A
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- Humans, Reproducibility of Results, Cross-Sectional Studies, Cognition, Smartphone, Multiple Sclerosis complications, Multiple Sclerosis diagnosis
- Abstract
Background: Current cognitive monitoring of people with multiple sclerosis (pwMS) is sporadic, resource intensive and insensitive for detection of real-world cognitive performance and decline. Smartphone applications may provide us with a more sensitive biomarker for cognitive decline that reflects real-world performance. The goal of this study was to perform a systematic review and qualitative synthesis of all current smartphone apps monitoring cognition in pwMS., Methods: A systematic search of five major online databases (PubMed/Medline, Scopus, Web of Science, Cumulative Index of Nursing and Allied Health Literature and IEEE Xplore) was performed in accordance with the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We included all studies with at least one measure of phone-based digital biomarkers for monitoring cognition in pwMS above the age of 18. Two authors independently screened the articles retrieved. Data on test-retest reliability, validity coefficients, feasibility and practice effects were extracted from the studies identified. Critical appraisal of the studies was performed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies., Results: 12 articles covering six smartphone apps were included in this review. All articles had a low risk of bias, though sample size calculation was rarely performed. Of the six apps, five used smartphone versions of the symbol digit modalities test. The final app examined keystroke features passively. Test-retest reliability ranged from good to excellent. Concurrent validity was demonstrated through moderate to strong correlation with neuropsychological tests and weak to moderate correlations with EDSS, radiological biomarkers and patient-reported outcomes. Mobile apps performed comparably, and in some cases outperformed established cognitive tests. Whilst reported acceptability was high, significant attrition rates were present in longitudinal cohorts. There were significant short and long-term practice effects. Overall, smartphone versions of the SDMT showed strong psychometric properties across multiple apps., Conclusion: Smartphone applications are reliable and valid biomarkers of real-world cognition in pwMS. Further longitudinal data would allow for a better understanding of their predictive and ecological validity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yi Chao Foong reports a relationship with Biogen that includes: travel reimbursement. Francesca Bridge reports a relationship with Biogen that includes: travel reimbursement. Anneke van der Walt reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Anneke van der Walt reports a relationship with Biogen that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Anneke van der Walt reports a relationship with Merck & Co Inc that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Anneke van der Walt reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Anneke van der Walt reports a relationship with National Health and Medical Research Council that includes: funding grants. Anneke van der Walt reports a relationship with Multiple Sclerosis Research Australia that includes: funding grants. Melissa Gresle reports a relationship with Biogen that includes: funding grants. Melissa Gresle reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. Daniel Merlo reports a relationship with Novartis that includes: speaking and lecture fees. Helmut Butzkueven reports a relationship with Novartis that includes: consulting or advisory, funding grants, and speaking and lecture fees. Helmut Butzkueven reports a relationship with Biogen Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Helmut Butzkueven reports a relationship with Merck & Co Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Helmut Butzkueven reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory, funding grants, and speaking and lecture fees. Helmut Butzkueven reports a relationship with UCB Pharma SA that includes: consulting or advisory and speaking and lecture fees. Helmut Butzkueven reports a relationship with National Health and Medical Research Council that includes: funding grants. Helmut Butzkueven reports a relationship with Medical Research Future Fund that includes: funding grants. Helmut Butzkueven reports a relationship with Monash partners that includes: funding grants. Helmut Butzkueven reports a relationship with Trish MS research foundation that includes: funding grants. Helmut Butzkueven reports a relationship with Pennycook Foundation that includes: funding grants. Helmut Butzkueven reports a relationship with Multiple Sclerosis Research Australia that includes: funding grants. Helmut Butzkueven reports a relationship with MSBase Foundation that includes: consulting or advisory. Helmut Butzkueven reports a relationship with Oxford Health Policy Forum Brain Health Initiative that includes: consulting or advisory. Yi Chao Foong reports a relationship with National Health and Medical Research Council that includes: funding grants. Yi Chao Foong reports a relationship with Avant Foundation that includes: funding grants. Yi Chao Foong reports a relationship with Multiple Sclerosis Research Australia that includes: funding grants. Yi Chao Foong reports a relationship with Australian and New Zealand Association of Neurologists that includes: funding grants., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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42. Neuroimaging characteristics may aid in diagnosis, subtyping, and prognosis in autoimmune encephalitis.
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Broadley J, Wesselingh R, Beech P, Seneviratne U, Kyndt C, Buzzard K, Nesbitt C, D'Souza W, Brodtmann A, Macdonell R, Kalincik T, O'Brien TJ, Butzkueven H, and Monif M
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- Humans, Retrospective Studies, Magnetic Resonance Imaging methods, Prognosis, Atrophy, Neuroimaging, Autoimmune Diseases of the Nervous System
- Abstract
Objective: To examine the utility of neuroimaging characteristics as biomarkers of prognosis in seropositive autoimmune encephalitis (AE)., Methods: In this multi-center study, we retrospectively analyzed 66 cases of seropositive AE. The MRI and PET imaging was assessed by independent visual inspection. Whole brain and regional volumes were imputed by IcoMetrix, an automated volumetric assessment package. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability. Other outcomes were mortality, first line treatment failure, medial temporal lobe (MTL) atrophy, and clinical relapse. Univariate and multivariable regression analysis was performed., Results: Abnormalities on MRI were detected in 35.1% of patients, while PET was abnormal in 46.4%. Initial median whole brain and hippocampal volumes were below the 5th and 20th percentile respectively compared to an age-matched healthy database. After a median follow-up of 715 days, 85.2% had good functional outcome (mRS ≤ 2). Nine patients developed MTL atrophy during follow-up. On multivariable analysis, inflammatory MTL changes were associated with development of MTL atrophy (HR 19.6, p = 0.007) and initial hippocampal volume had an inverse relationship with mortality (HR 0.04, p = 0.011). Patients who developed MTL atrophy had a reduced chance of good final mRS (HR 0.16, p = 0.015)., Conclusions: Neuroimaging on initial hospital admission may be provide important diagnostic and prognostic information. This study demonstrates that structural and inflammatory changes of the MTL may have importance in clinical and radiological prognosis in seropositive AE., (© 2022. Fondazione Società Italiana di Neurologia.)
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- 2023
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43. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.
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Diouf I, Malpas CB, Sharmin S, Roos I, Horakova D, Havrdova EK, Patti F, Shaygannejad V, Ozakbas S, Izquierdo G, Eichau S, Onofrj M, Lugaresi A, Alroughani R, Prat A, Girard M, Duquette P, Terzi M, Boz C, Grand'Maison F, Hamdy S, Sola P, Ferraro D, Grammond P, Turkoglu R, Buzzard K, Skibina O, Yamout B, Altintas A, Gerlach O, van Pesch V, Blanco Y, Maimone D, Lechner-Scott J, Bergamaschi R, Karabudak R, Iuliano G, McGuigan C, Cartechini E, Barnett M, Hughes S, Sa MJ, Solaro C, Kappos L, Ramo-Tello C, Cristiano E, Hodgkinson S, Spitaleri D, Soysal A, Petersen T, Slee M, Butler E, Granella F, de Gans K, McCombe P, Ampapa R, Van Wijmeersch B, van der Walt A, Butzkueven H, Prevost J, Sinnige LGF, Sanchez-Menoyo JL, Vucic S, Laureys G, Van Hijfte L, Khurana D, Macdonell R, Gouider R, Castillo-Triviño T, Gray O, Aguera-Morales E, Al-Asmi A, Shaw C, Deri N, Al-Harbi T, Fragoso Y, Csepany T, Perez Sempere A, Trevino-Frenk I, Schepel J, Moore F, and Kalincik T
- Subjects
- Humans, Immunotherapy, Proportional Hazards Models, Recurrence, Multiple Sclerosis therapy, Multiple Sclerosis, Chronic Progressive, Multiple Sclerosis, Relapsing-Remitting
- Abstract
Background and Purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS)., Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics., Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity., Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2023
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44. Comparative effectiveness in multiple sclerosis: A methodological comparison.
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Roos I, Diouf I, Sharmin S, Horakova D, Havrdova EK, Patti F, Shaygannejad V, Ozakbas S, Izquierdo G, Eichau S, Onofrj M, Lugaresi A, Alroughani R, Prat A, Girard M, Duquette P, Terzi M, Boz C, Grand'Maison F, Sola P, Ferraro D, Grammond P, Turkoglu R, Buzzard K, Skibina O, Yamou B, Altintas A, Gerlach O, van Pesch V, Blanco Y, Maimone D, Lechner-Scott J, Bergamaschi R, Karabudak R, McGuigan C, Cartechini E, Barnett M, Hughes S, Sa MJ, Solaro C, Ramo-Tello C, Hodgkinson S, Spitaleri D, Soysal A, Petersen T, Granella F, de Gans K, McCombe P, Ampapa R, Van Wijmeersch B, van der Walt A, Butzkueven H, Prevost J, Sanchez-Menoyo JL, Laureys G, Gouider R, Castillo-Triviño T, Gray O, Aguera-Morales E, Al-Asmi A, Shaw C, Deri N, Al-Harbi T, Fragoso Y, Csepany T, Sempere AP, Trevino-Frenk I, Schepel J, Moore F, Malpas C, and Kalincik T
- Subjects
- Humans, Fingolimod Hydrochloride therapeutic use, Natalizumab therapeutic use, Immunosuppressive Agents therapeutic use, Immunologic Factors therapeutic use, Treatment Outcome, Propensity Score, Recurrence, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models., Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models., Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement., Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods., Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.
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- 2023
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45. Peripheral monocytes and soluble biomarkers in autoimmune encephalitis.
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Wesselingh R, Griffith S, Broadley J, Tarlinton D, Buzzard K, Seneviratne U, Butzkueven H, O'Brien TJ, and Monif M
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- Humans, Interleukin-6, Cross-Sectional Studies, Cytokines, Biomarkers, Receptors, IgG, Monocytes, Autoimmune Diseases of the Nervous System
- Abstract
Background and Objectives: Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system which can result in long-term seizures and cognitive dysfunction despite treatment with immunotherapy. The role of the innate immune system in AE is not well established. To investigate the contribution of innate immunity to AE and its long-term outcomes we evaluated peripheral monocytes and serum cytokines in the periphery of patients with AE., Methods and Results: We recruited 40 patients with previously diagnosed AE and 28 healthy volunteers to our cross-sectional observation study and evaluated their peripheral blood monocytes via flow cytometry and serum cytokines (CCL-2, CCL-17, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, TNFα) via ELISA.Compared with controls the AE cohort had expansion of the 'pro-inflammatory' CD14
+ CD16+ monocyte sub-population (7.13% vs 5.46%, p < 0.01) with higher levels of serum IL-6 (2.34 pg/mL vs 0.54 pg/mL, p < 0.001). These changes were most significant in anti-LGI-1 antibody mediated AE, an AE subtype with poor long-term cognitive outcomes., Conclusion: Expansion of the peripheral CD14+ CD16+ monocyte population and increased serum IL-6 in AE is reflective of changes seen in other systemic inflammatory and neurodegenerative conditions. These changes may indicate a persistent pro-inflammatory state in AE and may contribute to poor long-term outcomes., Competing Interests: Declaration of competing interest Prof Helmut Butzkueven's institution receives funding from Biogen, Roche, Merck and Novartis for speaker engagements, study steering and advisory committee service. He is on the editorial board of Multiple Sclerosis and Related Disorders and the Steering committee of the Brain Health Initiative (Oxford Health Policy Forum). Prof Terence J. O'Brien receives research funding from Biogen, UCB Pharma, Eisai Pharma, Anavex Pharmaceuticals, Zynerba Pharmaceuticals, and serves on the scientific advisory boards for UCB Pharma, Eisai Pharmaceuticals, Zynerba Pharmaceuticals, ESTherapeutics, Seqirus Pharmaceuticals. Dr Mastura Monif's has served on advisory board for Merck and has received speaker honoraria from Merck and Biogen. Her institution receives funding from Merck, Australian.National Health Medical Research Council, Brain Foundation, Charles and Sylvia.Viertel Foundation, and MS Research Australia. The remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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46. Acute haemorrhagic necrotizing encephalopathy in the setting of SARS-CoV-2 vaccination: a case report and literature review.
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Siriratnam P, Buzzard K, and Yip G
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- Humans, SARS-CoV-2, Vaccination, COVID-19 Vaccines, COVID-19
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- 2023
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47. Sixteen syndrome: a rare presentation of central demyelination.
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Bridge F, Bennett T, and Buzzard K
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- Humans, Eye Movements, Pontine Tegmentum, Demyelinating Diseases diagnosis
- Abstract
This case illustrates two diagnostic challenges for clinicians: the rarely described sixteen syndrome and the relationship between tumour necrosis factor (TNF)-alpha inhibitors and central demyelination. Sixteen syndrome affects horizontal eye movements and the facial nerve bilaterally reflecting a lesion in the posterior pontine tegmentum, adjacent to the fourth ventricle. Given its rarity and complexity of clinical signs, this syndrome risks misdiagnosis and mismanagement. The relationship between TNF-alpha inhibitors and demyelination is a complex issue in which causality is yet to be established. This diagnostic challenge poses a management dilemma for clinicians., Competing Interests: Competing interests: FB has received travel funding from Biogen., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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48. Prediction of relapse activity when switching to cladribine for multiple sclerosis.
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Zhong M, van der Walt A, Monif M, Hodgkinson S, Eichau S, Kalincik T, Lechner-Scott J, Buzzard K, Skibina O, Van Pesch V, Butler E, Prevost J, Girard M, Oh J, Butzkueven H, and Jokubaitis V
- Subjects
- Humans, Cladribine therapeutic use, Immunosuppressive Agents therapeutic use, Immunologic Factors, Fingolimod Hydrochloride, Natalizumab, Chronic Disease, Recurrence, Multiple Sclerosis chemically induced, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Background: Patients with relapsing-remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes., Objective: To determine predictors of relapse hazard when switching to cladribine., Methods: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined., Results: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03-5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01-4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65-14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35-12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91-0.99)., Conclusion: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.
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- 2023
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49. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.
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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 BI, 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, Sánchez-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
- Subjects
- Humans, Female, Natalizumab therapeutic use, Fingolimod Hydrochloride therapeutic use, Retrospective Studies, Recurrence, Immunosuppressive Agents adverse effects, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis, Relapsing-Remitting epidemiology, Multiple Sclerosis chemically induced
- 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 different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod)., Classification of Evidence: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy., (© 2022 American Academy of Neurology.)
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- 2022
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50. Confirmed disability progression as a marker of permanent disability in multiple sclerosis.
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Sharmin S, Bovis F, Malpas C, Horakova D, Havrdova EK, 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 JL, Soysal A, Vucic S, Petersen T, de Gans K, Butler E, Hodgkinson S, Sidhom Y, Gouider R, Cristiano E, Castillo-Triviño T, Saladino ML, Barnett M, Moore F, Rozsa C, Yamout B, Skibina O, van der Walt A, Buzzard K, Gray O, Hughes S, Sempere AP, Singhal B, Fragoso Y, Shaw C, Kermode A, Taylor B, Simo M, Shuey N, Al-Harbi T, Macdonell R, Dominguez JA, Csepany T, Sirbu CA, Sormani MP, Butzkueven H, and Kalincik T
- Subjects
- Cladribine therapeutic use, Cohort Studies, Disease Progression, Female, Humans, Male, Multiple Sclerosis, Relapsing-Remitting, Randomized Controlled Trials as Topic, Disability Evaluation, Multiple Sclerosis drug therapy, Multiple Sclerosis pathology
- 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., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
- Published
- 2022
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