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1. A real-world clinical validation for AI-based MRI monitoring in multiple sclerosis

Author

Barnett, Michael, Wang, Dongang, Beadnall, Heidi, Bischof, Antje, Brunacci, David, Butzkueven, Helmut, Brown, J. William L., Cabezas, Mariano, Das, Tilak, Dugal, Tej, Guilfoyle, Daniel, Klistorner, Alexander, Krieger, Stephen, Kyle, Kain, Ly, Linda, Masters, Lynette, Shieh, Andy, Tang, Zihao, van der Walt, Anneke, Ward, Kayla, Wiendl, Heinz, Zhan, Geng, Zivadinov, Robert, Barnett, Yael, and Wang, Chenyu

Published
2023
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5. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Author

Brown, J William L, Cunniffe, Nick G, Prados, Ferran, Kanber, Baris, Jones, Joanne L, Needham, Edward, Georgieva, Zoya, Rog, David, Pearson, Owen R, Overell, James, MacManus, David, Samson, Rebecca S, Stutters, Jonathan, ffrench-Constant, Charles, Gandini Wheeler-Kingshott, Claudia A M, Moran, Carla, Flynn, Paul D, Michell, Andrew W, Franklin, Robin J M, Chandran, Siddharthan, Altmann, Daniel R, Chard, Declan T, Connick, Peter, and Coles, Alasdair J

Published
2021
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6. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Daruwalla, Cyrus, primary, Shaygannejad, Vahid, additional, Ozakbas, Serkan, additional, Havrdova, Eva Kubala, additional, Horakova, Dana, additional, Alroughani, Raed, additional, Boz, Cavit, additional, Patti, Francesco, additional, Onofrj, Marco, additional, Lugaresi, Alessandra, additional, Eichau, Sara, additional, Girard, Marc, additional, Prat, Alexandre, additional, Duquette, Pierre, additional, Yamout, Bassem, additional, Khoury, Samia J, additional, Sajedi, Seyed Aidin, additional, Turkoglu, Recai, additional, Altintas, Ayse, additional, Skibina, Olga, additional, Buzzard, Katherine, additional, Grammond, Pierre, additional, Karabudak, Rana, additional, van der Walt, Anneke, additional, Butzkueven, Helmut, additional, Maimone, Davide, additional, Lechner-Scott, Jeannette, additional, Soysal, Aysun, additional, John, Nevin, additional, Prevost, Julie, additional, Spitaleri, Daniele, additional, Ramo-Tello, Cristina, additional, Gerlach, Oliver, additional, Iuliano, Gerardo, additional, Foschi, Matteo, additional, Ampapa, Radek, additional, van Pesch, Vincent, additional, Barnett, Michael, additional, Shalaby, Nevin, additional, D’hooghe, Marie, additional, Kuhle, Jens, additional, Sa, Maria Jose, additional, Fabis-Pedrini, Marzena, additional, Kermode, Allan, additional, Mrabet, Saloua, additional, Gouider, Riadh, additional, Hodgkinson, Suzanne, additional, Laureys, Guy, additional, Van Hijfte, Liesbeth, additional, Macdonell, Richard, additional, Oreja-Guevara, Celia, additional, Cristiano, Edgardo, additional, McCombe, Pamela, additional, Sanchez-Menoyo, Jose Luis, additional, Singhal, Bhim, additional, Blanco, Yolanda, additional, Hughes, Stella, additional, Garber, Justin, additional, Solaro, Claudio, additional, McGuigan, Chris, additional, Taylor, Bruce, additional, de Gans, Koen, additional, Habek, Mario, additional, Al-Asmi, Abdullah, additional, Mihaela, Simu, additional, Castillo Triviño, Tamara, additional, Al-Harbi, Talal, additional, Rojas, Juan Ignacio, additional, Gray, Orla, additional, Khurana, Dheeraj, additional, Van Wijmeersch, Bart, additional, Grigoriadis, Nikolaos, additional, Inshasi, Jihad, additional, Oh, Jiwon, additional, Aguera-Morales, Eduardo, additional, Fragoso, Yara, additional, Moore, Fraser, additional, Shaw, Cameron, additional, Baghbanian, Seyed Mohammad, additional, Shuey, Neil, additional, Willekens, Barbara, additional, Hardy, Todd A, additional, Decoo, Danny, additional, sempere, Angel Perez, additional, Field, Deborah, additional, Wynford-Thomas, Ray, additional, Cunniffe, Nick G, additional, Roos, Izanne, additional, Malpas, Charles B, additional, Coles, Alasdair J, additional, Kalincik, Tomas, additional, and Brown, J William L, additional

Published
2023
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7. sj-docx-1-msj-10.1177_13524585231151951 – Supplemental material for Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Daruwalla, Cyrus, Shaygannejad, Vahid, Ozakbas, Serkan, Havrdova, Eva Kubala, Horakova, Dana, Alroughani, Raed, Boz, Cavit, Patti, Francesco, Onofrj, Marco, Lugaresi, Alessandra, Eichau, Sara, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Yamout, Bassem, Khoury, Samia J, Sajedi, Seyed Aidin, Turkoglu, Recai, Altintas, Ayse, Skibina, Olga, Buzzard, Katherine, Grammond, Pierre, Karabudak, Rana, van der Walt, Anneke, Butzkueven, Helmut, Maimone, Davide, Lechner-Scott, Jeannette, Soysal, Aysun, John, Nevin, Prevost, Julie, Spitaleri, Daniele, Ramo-Tello, Cristina, Gerlach, Oliver, Iuliano, Gerardo, Foschi, Matteo, Ampapa, Radek, van Pesch, Vincent, Barnett, Michael, Shalaby, Nevin, D’hooghe, Marie, Kuhle, Jens, Sa, Maria Jose, Fabis-Pedrini, Marzena, Kermode, Allan, Mrabet, Saloua, Gouider, Riadh, Hodgkinson, Suzanne, Laureys, Guy, Van Hijfte, Liesbeth, Macdonell, Richard, Oreja-Guevara, Celia, Cristiano, Edgardo, McCombe, Pamela, Sanchez-Menoyo, Jose Luis, Singhal, Bhim, Blanco, Yolanda, Hughes, Stella, Garber, Justin, Solaro, Claudio, McGuigan, Chris, Taylor, Bruce, de Gans, Koen, Habek, Mario, Al-Asmi, Abdullah, Mihaela, Simu, Castillo Triviño, Tamara, Al-Harbi, Talal, Rojas, Juan Ignacio, Gray, Orla, Khurana, Dheeraj, Van Wijmeersch, Bart, Grigoriadis, Nikolaos, Inshasi, Jihad, Oh, Jiwon, Aguera-Morales, Eduardo, Fragoso, Yara, Moore, Fraser, Shaw, Cameron, Baghbanian, Seyed Mohammad, Shuey, Neil, Willekens, Barbara, Hardy, Todd A, Decoo, Danny, sempere, Angel Perez, Field, Deborah, Wynford-Thomas, Ray, Cunniffe, Nick G, Roos, Izanne, Malpas, Charles B, Coles, Alasdair J, Kalincik, Tomas, and Brown, J William L

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110904 Neurology and Neuromuscular Diseases
Abstract

Supplemental material, sj-docx-1-msj-10.1177_13524585231151951 for Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis by Cyrus Daruwalla, Vahid Shaygannejad, Serkan Ozakbas, Eva Kubala Havrdova, Dana Horakova, Raed Alroughani, Cavit Boz, Francesco Patti, Marco Onofrj, Alessandra Lugaresi, Sara Eichau, Marc Girard, Alexandre Prat, Pierre Duquette, Bassem Yamout, Samia J Khoury, Seyed Aidin Sajedi, Recai Turkoglu, Ayse Altintas, Olga Skibina, Katherine Buzzard, Pierre Grammond, Rana Karabudak, Anneke van der Walt, Helmut Butzkueven, Davide Maimone, Jeannette Lechner-Scott, Aysun Soysal, Nevin John, Julie Prevost, Daniele Spitaleri, Cristina Ramo-Tello, Oliver Gerlach, Gerardo Iuliano, Matteo Foschi, Radek Ampapa, Vincent van Pesch, Michael Barnett, Nevin Shalaby, Marie D’hooghe, Jens Kuhle, Maria Jose Sa, Marzena Fabis-Pedrini, Allan Kermode, Saloua Mrabet, Riadh Gouider, Suzanne Hodgkinson, Guy Laureys, Liesbeth Van Hijfte, Richard Macdonell, Celia Oreja-Guevara, Edgardo Cristiano, Pamela McCombe, Jose Luis Sanchez-Menoyo, Bhim Singhal, Yolanda Blanco, Stella Hughes, Justin Garber, Claudio Solaro, Chris McGuigan, Bruce Taylor, Koen de Gans, Mario Habek, Abdullah Al-Asmi, Simu Mihaela, Tamara Castillo Triviño, Talal Al-Harbi, Juan Ignacio Rojas, Orla Gray, Dheeraj Khurana, Bart Van Wijmeersch, Nikolaos Grigoriadis, Jihad Inshasi, Jiwon Oh, Eduardo Aguera-Morales, Yara Fragoso, Fraser Moore, Cameron Shaw, Seyed Mohammad Baghbanian, Neil Shuey, Barbara Willekens, Todd A Hardy, Danny Decoo, Angel Perez sempere, Deborah Field, Ray Wynford-Thomas, Nick G Cunniffe, Izanne Roos, Charles B Malpas, Alasdair J Coles, Tomas Kalincik and J William L Brown in Multiple Sclerosis Journal

Published
2023
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8. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Rojas, Juan Ignacio, Gray, Orla, Khurana, Dheeraj, Van Wijmeersch, Bart, Grigoriadis, Nikolaos, Inshasi, Jihad, Oh, Jiwon, Aguera-Morales, Eduardo, Fragoso, Yara, Moore, Fraser, Shaw, Cameron, Baghbanian, Seyed Mohammad, Shuey, Neil, Willekens, Barbara, Hardy, Todd A., Decoo, Danny, Sempere, Angel Perez, Field, Deborah, Wynford-Thomas, Ray, Cunniffe, Nick G., Roos, Izanne, Malpas, Charles B., Coles, Alasdair J., Kalincik, Tomas, Brown, J. William L., MSBase Study Grp, MSBase Study Grp, Shaygannejad, Vahid, Daruwalla, Cyrus, ÖZAKBAŞ, SERKAN, Havrdova, Eva Kubala, Horakova, Dana, Alroughani, Raed, BOZ, CAVİT, Patti, Francesco, Onofrj, Marco, Lugaresi, Alessandra, Eichau, Sara, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Yamout, Bassem, Khoury, Samia J., Sajedi, Seyed Aidin, Turkoglu, Recai, Altintas, Ayse, Skibina, Olga, Buzzard, Katherine, Grammond, Pierre, Karabudak, Rana, van der Walt, Anneke, Butzkueven, Helmut, Maimone, Davide, Lechner-Scott, Jeannette, Soysal, Aysun, John, Nevin, Prevost, Julie, Spitaleri, Daniele, Ramo-Tello, Cristina, Gerlach, Oliver, Iuliano, Gerardo, Foschi, Matteo, Ampapa, Radek, van Pesch, Vincent, Barnett, Michael, Shalaby, Nevin, D'hooghe, Marie, Kuhle, Jens, Sa, Maria Jose, Fabis-Pedrini, Marzena, Kermode, Allan, Mrabet, Saloua, Gouider, Riadh, Hodgkinson, Suzanne, Laureys, Guy, Van Hijfte, Liesbeth, Macdonell, Richard, Oreja-Guevara, Celia, Cristiano, Edgardo, McCombe, Pamela, Sanchez-Menoyo, Jose Luis, Singhal, Bhim, Blanco, Yolanda, Hughes, Stella, Garber, Justin, Solaro, Claudio, McGuigan, Chris, Taylor, Bruce, de Gans, Koen, Habek, Mario, Al-Asmi, Abdullah, Mihaela, Simu, Castillo Trivino, Tamara, Al-Harbi, Talal, MSBase Study Group, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Faculty of Medicine and Pharmacy, Daruwalla, Cyrus [0000-0002-2329-5329], Shaygannejad, Vahid [0000-0001-5511-509X], Horakova, Dana [0000-0003-1915-0036], Alroughani, Raed [0000-0001-5436-5804], Patti, Francesco [0000-0002-6923-0846], Lugaresi, Alessandra [0000-0003-2902-5589], Eichau, Sara [0000-0001-9159-3128], Duquette, Pierre [0000-0001-7231-1754], Sajedi, Seyed Aidin [0000-0002-6704-9787], van der Walt, Anneke [0000-0002-4278-7003], Lechner-Scott, Jeannette [0000-0002-3850-447X], Barnett, Michael [0000-0002-2156-8864], Oreja-Guevara, Celia [0000-0002-9221-5716], Habek, Mario [0000-0002-3360-1748], Castillo Triviño, Tamara [0000-0002-9249-3185], Inshasi, Jihad [0000-0001-5892-751X], Oh, Jiwon [0000-0001-5519-6088], Fragoso, Yara [0000-0001-8726-089X], Baghbanian, Seyed Mohammad [0000-0002-8138-7504], Hardy, Todd A [0000-0003-4145-3172], Decoo, Danny [0000-0001-7689-3114], Roos, Izanne [0000-0003-0371-3666], Kalincik, Tomas [0000-0003-3778-1376], Brown, J William L [0000-0002-7737-5834], Apollo - University of Cambridge Repository, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Neuroscience(all), Multiple sclerosis, prognosis, multiple sclerosis, Prognosis, Multiple Sclerosis, Relapsing-Remitting, Neurology, Recurrence, Medicine and Health Sciences, Humans, Human medicine, Neurology (clinical)
Abstract

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

Published
2023

9. Remyelination varies between and within lesions in multiple sclerosis following bexarotene

Author

Brown, J. William L., primary, Prados, Ferran, additional, Altmann, Daniel R., additional, Kanber, Baris, additional, Stutters, Jonathan, additional, Cunniffe, Nick G., additional, Jones, Joanne L., additional, Georgieva, Zoya G., additional, Needham, Edward J., additional, Daruwalla, Cyrus, additional, Wheeler‐Kingshott, Claudia Gandini, additional, Connick, Peter, additional, Chandran, Siddharthan, additional, Franklin, Robin, additional, MacManus, David, additional, Samson, Rebecca, additional, Coles, Alasdair, additional, and Chard, Declan, additional

Published
2022
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13. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

Author

Wilkins, Alastair, Slee, Mark, TERZİ, MURAT, Grand'Maison, Francois, Ferraro, Diana, Sola, Patrizia, Van Pesch, Vincent, McCombe, Pamela, Hupperts, Raymond, Alroughani, Raed, Grammond, Pierre, Bergamaschi, Roberto, Lugaresi, Alessandra, Shaygannejad, Vahid, Pucci, Eugenio, Granella, Franco, Jokubaitis, Vilija, Pearson, Owen R., Ziemssen, Tjalf, Hutchinson, Michael, McGuigan, Christopher, Butzkueven, Helmut, Kalincik, Tomas, Onofrj, Marco, Trojano, Maria, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Izquierdo, Guillermo, Havrdova, Eva, Horakova, Dana, Zwanikken, Cees, Soysal, Aysun, Yamout, Bassem, Piroska, Imre, McDonnell, Gavin, Moore, Fraser, Butler, Ernest, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Hodgkinson, Suzanne, Oreja-Guevara, Celia, BOZ, CAVİT, Prevost, Julie, Olascoaga, Javier, Van Wijmeersch, Bart, Barnett, Michael, Verheul, Freek, Rojas, Juan Ingacio, Spitaleri, Daniele, Rio, Maria Edite, Taylor, Bruce, Luis Sanchez-Menoyo, Jose, Ramo-Tello, Cristina, Solaro, Claudio, Csepany, Tunde, Iuliano, Gerardo, Skibina, Olga, Petersen, Thor, Bolanos, Ricardo Fernandez, Sidhom, Youssef, Riadh, Riadh, Vucic, Steve, Macdonell, Richard, Sempere, Angel Perez, Simo, Magdolna, Kister, Ilya, Shuey, Neil, Radek, Radek, Dominguez, Jose Andres, Pia Amato, Maria, Saladino, Maria Laura, Kermode, Allan, Brown, J. William L., Coles, Alasdair, Lechner-Scott, Jeannette, Willis, Mark, Rice, Claire, Scolding, Neil, Flechter, Schlomo, Harding, Katharine, Jones, Joanne, Robertson, Neil, Hughes, Stella, ÖZAKBAŞ, SERKAN, Brown, J William L, Coles, Alasdair, Horakova, Dana, Havrdova, Eva, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Trojano, Maria, Lugaresi, Alessandra, Bergamaschi, Roberto, Grammond, Pierre, Alroughani, Raed, Hupperts, Raymond, McCombe, Pamela, Van Pesch, Vincent, Sola, Patrizia, Ferraro, Diana, Grand'Maison, Francoi, Terzi, Murat, Lechner-Scott, Jeannette, Flechter, Schlomo, Slee, Mark, Shaygannejad, Vahid, Pucci, Eugenio, Granella, Franco, Jokubaitis, Vilija, Willis, Mark, Rice, Claire, Scolding, Neil, Wilkins, Alastair, Pearson, Owen R, Ziemssen, Tjalf, Hutchinson, Michael, Harding, Katharine, Jones, Joanne, McGuigan, Christopher, Butzkueven, Helmut, Kalincik, Toma, Robertson, Neil, Brown, Will [0000-0002-7737-5834], Coles, Alasdair [0000-0003-4738-0760], Jones, Joanna [0000-0003-4974-1371], Apollo - University of Cambridge Repository, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and OMÜ

Subjects
Male, INTERFERON-BETA, MULTICENTER, Interferon-beta/therapeutic use, multiple sclerosis, 01 natural sciences, Cohort Studies, 0302 clinical medicine, Natalizumab, 030212 general & internal medicine, Alemtuzumab, Original Investigation, GLATIRAMER ACETATE, NATALIZUMAB, Natalizumab/therapeutic use, OUTCOMES, treatment, ALEMTUZUMAB, Absolute risk reduction, General Medicine, Immunologic Factors/therapeutic use, Fingolimod, TIME, Disease Progression, Female, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, medicine.medical_specialty, Alemtuzumab/therapeutic use, Lower risk, Time-to-Treatment, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, medicine, Humans, Immunologic Factors, 0101 mathematics, Glatiramer acetate, Fingolimod Hydrochloride/therapeutic use, business.industry, Fingolimod Hydrochloride, Multiple sclerosis, DISABILITY, 010102 general mathematics, Glatiramer Acetate, Interferon-beta, Multiple Sclerosis, Relapsing-Remitting/drug therapy, medicine.disease, FINGOLIMOD, Immunosuppressive Agents/therapeutic use, multiple sclerosis, progression, treatment, progression, business, Glatiramer Acetate/therapeutic use
Abstract

none 40 si his study was financially supported by National Health and Medical Research Council of Australia (fellowships 1140766 and 1080518, project grants 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), a Next Generation Fellowship funded by the Grand Charity of the Freemason’s (recipient JWLB), and the MSBase 2017 Fellowship (recipient JWLB). Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS. RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P

Published
2019

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

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Roos, Izanne, Leray, Emmanuelle, Frascoli, Federico, Casey, Romain, Brown, J William L, Horakova, Dana, Havrdova, Eva K, Trojano, Maria, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ozakbas, Serkan, Bergamaschi, Roberto, Sá, Maria José, Cartechini, Elisabetta, Boz, Cavit, Granella, Franco, Hupperts, Raymond, Terzi, Murat, Lechner-Scott, Jeannette, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Olascoaga, Javier, Prevost, Julie, Aguera-Morales, Eduardo, Slee, Mark, Csepany, Tunde, Turkoglu, Recai, Sidhom, Youssef, Gouider, Riadh, Van Wijmeersch, Bart, McCombe, Pamela, Macdonell, Richard, Coles, Alasdair, Malpas, Charles B, Butzkueven, Helmut, Vukusic, Sandra, Kalincik, Tomas, MSBase, OFSEP investigators, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Roos, Izanne, Leray, Emmanuelle, Frascoli, Federico, Casey, Romain, Brown, J William L, Horakova, Dana, Havrdova, Eva K, Trojano, Maria, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ozakbas, Serkan, Bergamaschi, Roberto, Sá, Maria José, Cartechini, Elisabetta, Boz, Cavit, Granella, Franco, Hupperts, Raymond, Terzi, Murat, Lechner-Scott, Jeannette, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Olascoaga, Javier, Prevost, Julie, Aguera-Morales, Eduardo, Slee, Mark, Csepany, Tunde, Turkoglu, Recai, Sidhom, Youssef, Gouider, Riadh, Van Wijmeersch, Bart, McCombe, Pamela, Macdonell, Richard, Coles, Alasdair, Malpas, Charles B, Butzkueven, Helmut, Vukusic, Sandra, Kalincik, Tomas, MSBase, and OFSEP investigators

Abstract

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 1

Published
2020

17. Determinants of therapeutic lag in multiple sclerosis

Author

Roos, Izanne, primary, Leray, Emmanuelle, additional, Frascoli, Federico, additional, Casey, Romain, additional, Brown, J William L, additional, Horakova, Dana, additional, Havrdova, Eva Kubala, additional, Debouverie, Marc, additional, Trojano, Maria, additional, Patti, Francesco, additional, Izquierdo, Guillermo, additional, Eichau, Sara, additional, Edan, Gilles, additional, Prat, Alexandre, additional, Girard, Marc, additional, Duquette, Pierre, additional, Onofrj, Marco, additional, Lugaresi, Alessandra, additional, Grammond, Pierre, additional, Ciron, Jonathan, additional, Ruet, Aurélie, additional, Ozakbas, Serkan, additional, De Seze, Jérôme, additional, Louapre, Céline, additional, Zephir, Hélène, additional, Sá, Maria José, additional, Sola, Patrizia, additional, Ferraro, Diana, additional, Labauge, Pierre, additional, Defer, Gilles, additional, Bergamaschi, Roberto, additional, Lebrun-Frenay, Christine, additional, Boz, Cavit, additional, Cartechini, Elisabetta, additional, Moreau, Thibault, additional, Laplaud, David, additional, Lechner-Scott, Jeannette, additional, Grand’Maison, Francois, additional, Gerlach, Oliver, additional, Terzi, Murat, additional, Granella, Franco, additional, Alroughani, Raed, additional, Iuliano, Gerardo, additional, Van Pesch, Vincent, additional, Van Wijmeersch, Bart, additional, Spitaleri, Daniele LA, additional, Soysal, Aysun, additional, Berger, Eric, additional, Prevost, Julie, additional, Aguera-Morales, Eduardo, additional, McCombe, Pamela, additional, Castillo Triviño, Tamara, additional, Clavelou, Pierre, additional, Pelletier, Jean, additional, Turkoglu, Recai, additional, Stankoff, Bruno, additional, Gout, Olivier, additional, Thouvenot, Eric, additional, Heinzlef, Olivier, additional, Sidhom, Youssef, additional, Gouider, Riadh, additional, Csepany, Tunde, additional, Bourre, Bertrand, additional, Al Khedr, Abdullatif, additional, Casez, Olivier, additional, Cabre, Philippe, additional, Montcuquet, Alexis, additional, Wahab, Abir, additional, Camdessanche, Jean-Philippe, additional, Maurousset, Aude, additional, Patry, Ivania, additional, Hankiewicz, Karolina, additional, Pottier, Corinne, additional, Maubeuge, Nicolas, additional, Labeyrie, Céline, additional, Nifle, Chantal, additional, Coles, Alasdair, additional, Malpas, Charles B, additional, Vukusic, Sandra, additional, Butzkueven, Helmut, additional, and Kalincik, Tomas, additional

Published
2021
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19. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

Author

UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Brown, J William L, Coles, Alasdair, Horakova, Dana, Havrdova, Eva, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Trojano, Maria, Lugaresi, Alessandra, Bergamaschi, Roberto, Grammond, Pierre, Alroughani, Raed, Hupperts, Raymond, McCombe, Pamela, Van Pesch, Vincent, Sola, Patrizia, Ferraro, Diana, Grand'Maison, Francois, Terzi, Murat, Lechner-Scott, Jeannette, Flechter, Schlomo, Slee, Mark, Shaygannejad, Vahid, Pucci, Eugenio, Granella, Franco, Jokubaitis, Vilija, Willis, Mark, Rice, Claire, Scolding, Neil, Wilkins, Alastair, Pearson, Owen R, Ziemssen, Tjalf, Hutchinson, Michael, Harding, Katharine, Jones, Joanne, McGuigan, Christopher, Butzkueven, Helmut, Kalincik, Tomas, Robertson, Neil, MSBase Study Group, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Brown, J William L, Coles, Alasdair, Horakova, Dana, Havrdova, Eva, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Trojano, Maria, Lugaresi, Alessandra, Bergamaschi, Roberto, Grammond, Pierre, Alroughani, Raed, Hupperts, Raymond, McCombe, Pamela, Van Pesch, Vincent, Sola, Patrizia, Ferraro, Diana, Grand'Maison, Francois, Terzi, Murat, Lechner-Scott, Jeannette, Flechter, Schlomo, Slee, Mark, Shaygannejad, Vahid, Pucci, Eugenio, Granella, Franco, Jokubaitis, Vilija, Willis, Mark, Rice, Claire, Scolding, Neil, Wilkins, Alastair, Pearson, Owen R, Ziemssen, Tjalf, Hutchinson, Michael, Harding, Katharine, Jones, Joanne, McGuigan, Christopher, Butzkueven, Helmut, Kalincik, Tomas, Robertson, Neil, and MSBase Study Group

Abstract

IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS. RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolim

Published
2019

20. Keratinocyte growth factor impairs human thymic recovery from lymphopenia

Author

Coles, Alasdair J., primary, Azzopardi, Laura, additional, Kousin-Ezewu, Onajite, additional, Mullay, Harpreet Kaur, additional, Thompson, Sara A.J., additional, Jarvis, Lorna, additional, Davies, Jessica, additional, Howlett, Sarah, additional, Rainbow, Daniel, additional, Babar, Judith, additional, Sadler, Timothy J., additional, Brown, J. William L., additional, Needham, Edward, additional, May, Karen, additional, Georgieva, Zoya G., additional, Handel, Adam E., additional, Maio, Stefano, additional, Deadman, Mary, additional, Rota, Ioanna, additional, Holländer, Georg, additional, Dawson, Sarah, additional, Jayne, David, additional, Seggewiss-Bernhardt, Ruth, additional, Douek, Daniel C., additional, Isaacs, John D., additional, and Jones, Joanne L., additional

Published
2019
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21. Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab

Author

Brown, J William L, primary, Prados Carrasco, Ferran, additional, Eshaghi, Arman, additional, Sudre, Carole H, additional, Button, Tom, additional, Pardini, Matteo, additional, Samson, Rebecca S, additional, Ourselin, Sebastien, additional, Wheeler-Kingshott, Claudia AM Gandini, additional, Jones, Joanne L, additional, Coles, Alasdair J, additional, and Chard, Declan T, additional

Published
2019
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22. Association of inflammation and disability accrual in patients with progressive-onset multiple sclerosis

Author

Hughes, Jordana, Jokubaitis, Vilija, Lugaresi, Alessandra, Hupperts, Raymond, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grand'maison, Francois, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ramo-Tello, Cristina, Trojano, Maria, Slee, Mark, Shaygannejad, Vahid, Boz, Cavit, Lechner-Scott, Jeanette, Van Pesch, Vincent, Pucci, Eugenio, Solaro, Claudio, Verheul, Freek, Terzi, Murat, Granella, Franco, Spitaleri, Daniele, Alroughani, Raed, Jun, Jae-Kwan, Fambiatos, Adam, Van Der Walt, Anneke, Butzkueven, Helmut, Kalincik, Tomas, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, Di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Vitetta, Francesca, Simone, Anna Maria, Haartsen, Jodi, Spelman, Tim, Marriott, Mark, Kilpatrick, Trevor, King, John, Buzzard, Katherine, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Brown, J William L, Kunchok, Amy, Diamanti, Matteo, Cartechini, Elisabetta, Curti, Erica, Tsantes, Elena, Zwanikken, Cees, Rio, Maria Edite, Hughes, Stella, Amato, Maria Pita, Van Wijmeersch, Bart, Sanchez-Menoyo, Jose Luis, Bolaños, Ricardo Fernandez, Sajedi, Seyed Aidin, Iuliano, Gerardo, Den Braber-Moerland, Leontien, Prevost, Julie, Sempere, Angel Perez, Sidhom, Youssef, Butler, Ernest, Vucic, Steve, Taylor, Bruce, Cabrera-Gomez, Jose Antonio, Oreja-Guevara, Celia, Bergamaschi, Roberto, Turkoglu, Recai, Olascoaga, Javier, Cristiano, Edgardo, Rojas, Juan Ingacio, Hodgkinson, Suzanne, Skibina, Olga, Al-Harbi, Talal, Altintas, Ayse, McCombe, Pamela, Sinnige, LGF, Ozakbas, Serken, Saladino, Maria Laura, Bacile, Elizabeth Alejandra, Vrech, Carlos, Shaw, Cameron, Hughes, Jordana, Jokubaitis, Vilija, Lugaresi, Alessandra, Hupperts, Raymond, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grand'maison, Francois, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ramo-Tello, Cristina, Trojano, Maria, Slee, Mark, Shaygannejad, Vahid, Boz, Cavit, Lechner-Scott, Jeanette, Van Pesch, Vincent, Pucci, Eugenio, Solaro, Claudio, Verheul, Freek, Terzi, Murat, Granella, Franco, Spitaleri, Daniele, Alroughani, Raed, Jun, Jae-Kwan, Fambiatos, Adam, Van Der Walt, Anneke, Butzkueven, Helmut, Kalincik, Tomas, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, Di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Vitetta, Francesca, Simone, Anna Maria, Haartsen, Jodi, Spelman, Tim, Marriott, Mark, Kilpatrick, Trevor, King, John, Buzzard, Katherine, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Brown, J William L, Kunchok, Amy, Diamanti, Matteo, Cartechini, Elisabetta, Curti, Erica, Tsantes, Elena, Zwanikken, Cees, Rio, Maria Edite, Hughes, Stella, Amato, Maria Pita, Van Wijmeersch, Bart, Sanchez-Menoyo, Jose Luis, Bolaños, Ricardo Fernandez, Sajedi, Seyed Aidin, Iuliano, Gerardo, Den Braber-Moerland, Leontien, Prevost, Julie, Sempere, Angel Perez, Sidhom, Youssef, Butler, Ernest, Vucic, Steve, Taylor, Bruce, Cabrera-Gomez, Jose Antonio, Oreja-Guevara, Celia, Bergamaschi, Roberto, Turkoglu, Recai, Olascoaga, Javier, Cristiano, Edgardo, Rojas, Juan Ingacio, Hodgkinson, Suzanne, Skibina, Olga, Al-Harbi, Talal, Altintas, Ayse, McCombe, Pamela, Sinnige, LGF, Ozakbas, Serken, Saladino, Maria Laura, Bacile, Elizabeth Alejandra, Vrech, Carlos, and Shaw, Cameron

Published
2018

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

Author

Roos, Izanne, Leray, Emmanuelle, Frascoli, Federico, Casey, Romain, Brown, J William L, Horakova, Dana, Havrdova, Eva K, Trojano, Maria, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ozakbas, Serkan, and Bergamaschi, Roberto

Subjects
MONTE Carlo method, MULTIPLE sclerosis, TREATMENT effectiveness, CLINICAL trials, RANDOMIZED response, DISEASE progression, RESEARCH, TIME, RESEARCH methodology, ACQUISITION of data, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, IMMUNOLOGICAL adjuvants, IMMUNOSUPPRESSIVE agents, LONGITUDINAL method
Abstract

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag. [ABSTRACT FROM AUTHOR]

Published
2020
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24. Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab.

Author

Brown, J William L, Prados Carrasco, Ferran, Eshaghi, Arman, Sudre, Carole H, Button, Tom, Pardini, Matteo, Samson, Rebecca S, Ourselin, Sebastien, Wheeler-Kingshott, Claudia AM Gandini, Jones, Joanne L, Coles, Alasdair J, and Chard, Declan T

Subjects
*MULTIPLE sclerosis, *ALEMTUZUMAB, *MAGNETIC resonance imaging, *SYMPTOMS
Abstract

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions. Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient's evolution, and whether baseline gradients predict on-treatment relapses. Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups' baseline gradients and evolution. Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (−0.045 pu/band/year, p = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number (p = 0.568) nor brain parenchymal fraction (p = 0.187) between those who relapsed within 4 years (n = 4) and those who did not (n = 15). However, the baseline gradient was significantly different (p = 0.020). Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients – but not lesion loads or brain volumes – may predict on-treatment relapses. Larger confirmatory studies are required. [ABSTRACT FROM AUTHOR]

Published
2020
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25. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kalincik, Tomas, Brown, J William L, Robertson, Neil, Willis, Mark, Scolding, Neil, Rice, Claire M, Wilkins, Alastair, Pearson, Owen, Ziemssen, Tjalf, Hutchinson, Michael, McGuigan, Christopher, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Alroughani, Raed, Pucci, Eugenio, Sola, Patrizia, Hupperts, Raymond, Lechner-Scott, Jeannette, Terzi, Murat, Van Pesch, Vincent, Rozsa, Csilla, Grand'Maison, François, Boz, Cavit, Granella, Franco, Slee, Mark, Spitaleri, Daniele, Olascoaga, Javier, Bergamaschi, Roberto, Verheul, Freek, Vucic, Steve, McCombe, Pamela, Hodgkinson, Suzanne, Sanchez-Menoyo, Jose Luis, Ampapa, Radek, Simo, Magdolna, Csepany, Tunde, Ramo, Cristina, Cristiano, Edgardo, Barnett, Michael, Butzkueven, Helmut, Coles, Alasdair, MSBase Study Group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kalincik, Tomas, Brown, J William L, Robertson, Neil, Willis, Mark, Scolding, Neil, Rice, Claire M, Wilkins, Alastair, Pearson, Owen, Ziemssen, Tjalf, Hutchinson, Michael, McGuigan, Christopher, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Alroughani, Raed, Pucci, Eugenio, Sola, Patrizia, Hupperts, Raymond, Lechner-Scott, Jeannette, Terzi, Murat, Van Pesch, Vincent, Rozsa, Csilla, Grand'Maison, François, Boz, Cavit, Granella, Franco, Slee, Mark, Spitaleri, Daniele, Olascoaga, Javier, Bergamaschi, Roberto, Verheul, Freek, Vucic, Steve, McCombe, Pamela, Hodgkinson, Suzanne, Sanchez-Menoyo, Jose Luis, Ampapa, Radek, Simo, Magdolna, Csepany, Tunde, Ramo, Cristina, Cristiano, Edgardo, Barnett, Michael, Butzkueven, Helmut, Coles, Alasdair, and MSBase Study Group

Abstract

BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcome

Published
2017

26. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

Author

Kalincik, Tomas, primary, Brown, J William L, additional, Robertson, Neil, additional, Willis, Mark, additional, Scolding, Neil, additional, Rice, Claire M, additional, Wilkins, Alastair, additional, Pearson, Owen, additional, Ziemssen, Tjalf, additional, Hutchinson, Michael, additional, McGuigan, Christopher, additional, Jokubaitis, Vilija, additional, Spelman, Tim, additional, Horakova, Dana, additional, Havrdova, Eva, additional, Trojano, Maria, additional, Izquierdo, Guillermo, additional, Lugaresi, Alessandra, additional, Prat, Alexandre, additional, Girard, Marc, additional, Duquette, Pierre, additional, Grammond, Pierre, additional, Alroughani, Raed, additional, Pucci, Eugenio, additional, Sola, Patrizia, additional, Hupperts, Raymond, additional, Lechner-Scott, Jeannette, additional, Terzi, Murat, additional, Van Pesch, Vincent, additional, Rozsa, Csilla, additional, Grand'Maison, François, additional, Boz, Cavit, additional, Granella, Franco, additional, Slee, Mark, additional, Spitaleri, Daniele, additional, Olascoaga, Javier, additional, Bergamaschi, Roberto, additional, Verheul, Freek, additional, Vucic, Steve, additional, McCombe, Pamela, additional, Hodgkinson, Suzanne, additional, Sanchez-Menoyo, Jose Luis, additional, Ampapa, Radek, additional, Simo, Magdolna, additional, Csepany, Tunde, additional, Ramo, Cristina, additional, Cristiano, Edgardo, additional, Barnett, Michael, additional, Butzkueven, Helmut, additional, and Coles, Alasdair, additional

Published
2017
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27. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

Author

Brown, J. William L., Coles, Alasdair, Horakova, Dana, Havrdova, Eva, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Trojano, Maria, Lugaresi, Alessandra, Bergamaschi, Roberto, Grammond, Pierre, Alroughani, Raed, Hupperts, Raymond, McCombe, Pamela, Van Pesch, Vincent, Sola, Patrizia, Ferraro, Diana, Grand'Maison, Francois, and Terzi, Murat

Subjects
*MULTIPLE sclerosis treatment, *THERAPEUTICS research, *DISEASE progression, *DISEASE relapse, *FINGOLIMOD, *NATALIZUMAB, *ALEMTUZUMAB, *IMMUNOLOGICAL adjuvants, *THERAPEUTIC use of interferons, *IMMUNOSUPPRESSIVE agents, *COMPARATIVE studies, *LONGITUDINAL method, *RESEARCH methodology, *MEDICAL care, *MEDICAL cooperation, *MULTIPLE sclerosis, *PATIENTS, *RESEARCH, *RESEARCH funding, *EVALUATION research, *THERAPEUTICS
Abstract

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).Main Outcome and Measure: Conversion to objectively defined secondary progressive MS.Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection. [ABSTRACT FROM AUTHOR]

Published
2019
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29. Alemtuzumab: evidence for its potential in relapsing–remitting multiple sclerosis

Author

Brown,J William L, Coles,Alasdair J, Brown,J William L, and Coles,Alasdair J

Abstract

J William L Brown, Alasdair J ColesDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UKAbstract: Alemtuzumab (previously known as Campath®) is a humanized monoclonal antibody directed against the CD52 antigen on mature lymphocytes that results in lymphopenia and subsequent modification of the immune repertoire. Here we explore evidence for its efficacy and safety in relapsing–remitting multiple sclerosis. One Phase II and two Phase III trials of alemtuzumab versus active comparator (interferon beta-1a) have been reported. Two of these rater-blinded randomized studies assessed clinical and radiological outcomes in treatment-naïve patients; one explored patients who had relapsed despite first-line therapy. Compared to interferon beta-1a, alemtuzumab reduced the relapse rate by 49%–74% (P < 0.0001), and in two studies it reduced the risk of sustained disability accumulation by 42%–71% (P < 0.01). In one study (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; CARE-MS1), there was no significant difference compared to interferon, perhaps reflecting the surprisingly low frequency of disability events in the comparator group. After alemtuzumab, the Expanded Disability Status Scale score improved by 0.14–1.2 points, culminating in a net advantage with alemtuzumab of 0.41–0.77 points over interferon in the CAMMS223 and CARE-MS2 trials (both P < 0.001). Radiological markers of new lesion formation and brain atrophy following alemtuzumab were significantly improved when compared to interferon in all studies. Adverse events were more common following alemtuzumab than interferon beta-1a (7.2–8.66 versus 4.9–5.7 events per person-year). While infusion reactions are the most common, autoimmunity is the most concerning; within Phase III studies, thyroid disorders (17%–18% versus 5%–6%) and immune thrombocytopenic

Published
2013

30. The role of MRI in the evaluation of secondary progressive multiple sclerosis.

Author

Brown, J. William L. and Chard, Declan T.

Abstract

Magnetic resonance imaging already has an established role in the diagnosis of multiple sclerosis, but it also has the potential to provide prognostic information, and to monito disease progression in clinical trials and practice. Magnetic resonance imaging measures are increasingly being used as the primary outcome in early phase clinical trials of immunomodulatory therapies (for example brain white matter lesion counts or volumes, and gadolinium contrast enhancing lesions) and putatively neuroprotective agents (for example measures of whole brain atrophy), and trials of agents that promote remyelination are also likely to follow suit. In this review we consider the use of magnetic resonance imaging measures as predictors and markers of disease progression in multiple sclerosis, and explore possible future directions in this rapidly developing field. [ABSTRACT FROM PUBLISHER]

Published
2016
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32. Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Author

Roos, Izanne, Leray, Emmanuelle, Frascoli, Federico, Casey, Romain, Brown, J William L, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ozakbas, Serkan, Bergamaschi, Roberto, Sá, Maria José, Cartechini, Elisabetta, Boz, Cavit, Granella, Franco, Hupperts, Raymond, Terzi, Murat, Lechner-Scott, Jeannette, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Olascoaga, Javier, Prevost, Julie, Aguera-Morales, Eduardo, Slee, Mark, Csepany, Tunde, Turkoglu, Recai, Sidhom, Youssef, Gouider, Riadh, Van Wijmeersch, Bart, McCombe, Pamela, Macdonell, Richard, Coles, Alasdair, Malpas, Charles, Butzkueven, Helmut, Vukusic, Sandra, Kalincik, Tomas, Duquette, Pierre, Grand'Maison, Francois, Iuliano, Gerardo, Ramo-Tello, Cristina, Solaro, Claudio, Cabrera-Gomez, Jose Antonio, Rio, Maria Edite, Bolaños, Ricardo Fernandez, Shaygannejad, Vahid, Oreja-Guevara, Celia, Sanchez-Menoyo, Jose Luis, Petersen, Thor, Altintas, Ayse, Barnett, Michael, Flechter, Shlomo, Fragoso, Yara, Amato, Maria Pia, Moore, Fraser, Ampapa, Radek, Verheul, Freek, Hodgkinson, Suzanne, Cristiano, Edgardo, Yamout, Bassem, Laureys, Guy, Dominguez, Jose Andres, Zwanikken, Cees, Deri, Norma, Dobos, Eniko, Vrech, Carlos, Butler, Ernest, Rozsa, Csilla, Petkovska-Boskova, Tatjana, Karabudak, Rana, Rajda, Cecilia, Alkhaboori, Jabir, Saladino, Maria Laura, Shaw, Cameron, Shuey, Neil, Vucic, Steve, Sempere, Angel Perez, Campbell, Jamie, Piroska, Imre, Taylor, Bruce, van der Walt, Anneke, Kappos, Ludwig, Roullet, Etienne, Gray, Orla, Simo, Magdolna, Sirbu, Carmen-Adella, Brochet, Bruno, Cotton, François, De Sèze, Jérôme, Dion, Armelle, Douek, Pascal, Guillemin, Francis, Laplaud, David, Lebrun-Frenay, Christine, Moreau, Thibault, Olaiz, Javier, Pelletier, Jean, Rigaud-Bully, Claire, Stankoff, Bruno, Marignier, Romain, Debouverie, Marc, Edan, Gilles, Ciron, Jonathan, Ruet, Aurélie, Collongues, Nicolas, Lubetzki, Catherine, Vermersch, Patrick, Labauge, Pierre, Defer, Gilles, Cohen, Mikaël, Fromont, Agnès, Wiertlewsky, Sandrine, Berger, Eric, Clavelou, Pierre, Audoin, Bertrand, Giannesini, Claire, Gout, Olivier, Thouvenot, Eric, Heinzlef, Olivier, Al-Khedr, Abdullatif, Bourre, Bertrand, Casez, Olivier, Cabre, Philippe, Montcuquet, Alexis, Créange, Alain, Camdessanché, Jean-Philippe, Faure, Justine, Maurousset, Aude, Patry, Ivania, Hankiewicz, Karolina, Pottier, Corinne, Maubeuge, Nicolas, Labeyrie, Céline, Nifle, Chantal, University of Melbourne, The Royal Melbourne Hospital, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Méthodes quantitatives en santé publique (METIS), Swinburne University of Technology [Melbourne], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, University of Cambridge [UK] (CAM), Medicine Charles University and General Faculty Hospital in Prague, University of Bari Aldo Moro (UNIBA), University of Catania [Italy], Hospital Universitario Virgen Macarena [Seville, Spain], University 'G. d'Annunzio' of Chieti-Pescara [Chieti], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Université de Montréal (UdeM), University of Modena and Reggio Emilia, Partenaires INRAE, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), IRCCS Mondino Foundation, Universidade Fernando Pessoa, KTU Medical Faculty Farabi Hospital, University of Parma = Università degli studi di Parma [Parme, Italie], Zuyderland Ziekenhuis, Medical Faculty [Samsun, Turkey], University of Newcastle [Australia] (UoN), Université Catholique de Louvain = Catholic University of Louvain (UCL), Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Hospital Universitario Donostia, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Haydarpasa Numune Training and Research Hospital, Hasselt University (UHasselt), University of Queensland [Brisbane], Hitachi Cambridge Laboratory [University of Cambridge], Hitachi, Ltd-University of Cambridge [UK] (CAM), Monash University [Melbourne], Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Ospedali Riuniti di Salerno, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), 1157717, National Health and Medical Research Council, Biogen, MSIF-ARSEP McDonald, Melbourne Research Scholarship, French State, ‘Agence Nationale de la Recherche,’, ANR-10-COHO-002, ‘Investments for the Future’, Eugène Devic EDMUS Foundation, ARSEP Foundation, Novartis, Merck, Roche, Teva Pharmaceutical Industries, Sanofi Genzyme, EDMUS Foundation, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Roos I., Leray E., Frascoli F., Casey R., Brown W.J.L., Horakova D., Havrdova E.K., Trojano M., Patti F., Izquierdo G., Eichau S., Onofrj M., Lugaresi A., Prat A., Girard M., Grammond P., Sola P., Ferraro D., Ozakbas S., Bergamaschi R., Sa M.J., Cartechini E., Boz C., Granella F., Hupperts R., Terzi M., Lechner-Scott J., Spitaleri D., van Pesch V., Soysal A., Olascoaga J., Prevost J., Aguera-Morales E., Slee M., Csepany T., Turkoglu R., Sidhom Y., Gouider R., van Wijmeersch B., McCombe P., Macdonell R., Coles A., Malpas C.B., Butzkueven H., Vukusic S., Kalincik T., Duquette P., Grand'Maison F., Iuliano G., Ramo-Tello C., Solaro C., Cabrera-Gomez J.A., Rio M.E., Bolanos R.F., Shaygannejad V., Oreja-Guevara C., Sanchez-Menoyo J.L., Petersen T., Altintas A., Barnett M., Flechter S., Fragoso Y., Amato M.P., Moore F., Ampapa R., Verheul F., Hodgkinson S., Cristiano E., Yamout B., Laureys G., Dominguez J.A., Zwanikken C., Deri N., Dobos E., Vrech C., Butler E., Rozsa C., Petkovska-Boskova T., Karabudak R., Rajda C., Alkhaboori J., Saladino M.L., Shaw C., Shuey N., Vucic S., Sempere A.P., Campbell J., Piroska I., Taylor B., van der Walt A., Kappos L., Roullet E., Gray O., Simo M., Sirbu C.-A., Brochet B., Cotton F., de Seze J., Dion A., Douek P., Guillemin F., Laplaud D., Lebrun-Frenay C., Moreau T., Olaiz J., Pelletier J., Rigaud-Bully C., Stankoff B., Marignier R., Debouverie M., Edan G., Ciron J., Ruet A., Collongues N., Lubetzki C., Vermersch P., Labauge P., Defer G., Cohen M., Fromont A., Wiertlewsky S., Berger E., Clavelou P., Audoin B., Giannesini C., Gout O., Thouvenot E., Heinzlef O., Al-Khedr A., Bourre B., Casez O., Cabre P., Montcuquet A., Creange A., Camdessanche J.-P., Faure J., Maurousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Brown, Will [0000-0002-7737-5834], Coles, Alasdair [0000-0003-4738-0760], Apollo - University of Cambridge Repository, McCombe, Pamela/0000-0003-2704-8517, Slee, Mark/0000-0003-4323-2453, Brown, William/0000-0002-7737-5834, Laplaud, David/0000-0001-6113-6938, Ciron, Jonathan/0000-0002-3386-6308, Roos, Izanne/0000-0003-0371-3666, Lugaresi, Alessandra/0000-0003-2902-5589, Aguera-Morales, Eduardo/0000-0002-8604-2054, Kalincik, Tomas, Girard, Marc, Patti, Francesco, Horakova, Dana, Malpas, Charles B., Olascoaga, Javier, Prevost, Julie, Roos, Izanne, Hupperts, Raymond, Csepany, Tunde, VAN WIJMEERSCH, Bart, Ferraro, Diana, Aguera-Morales, Eduardo, Cartechini, Elisabetta, Vukusic, Sandra, Frascoli, Federico, Lugaresi, Alessandra, Sa, Maria Jose, Butzkueven, Helmut, Spitaleri, Daniele, Macdonell, Richard, Coles, Alasdair, Havrdova, Eva K., Granella, Franco, Turkoglu, Recai, Trojano, Maria, Sola, Patrizia, Van Pesch, Vincent, Onofrj, Marco, Grammond, Pierre, Bergamaschi, Roberto, Izquierdo, Guillermo, McCombe, Pamela, Slee, Mark, Eichau, Sara, Prat, Alexandre, Leray, Emmanuelle, Soysal, Aysun, Terzi, Murat, Brown, J. William L., Boz, Cavit, Sidhom, Youssef, Gouider, Riadh, Ozakbas, Serkan, Casey, Romain, Lechner-Scott, Jeannette, Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Hospital Universitario Virgen Macarena [Séville], Università degli studi di Parma = University of Parma (UNIPR), University of Newcastle [Callaghan, Australia] (UoN), University of Cambridge [UK] (CAM)-Hitachi, Ltd, and ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010)

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Time Factors, multiple sclerosis, law.invention, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Natalizumab, Randomized controlled trial, law, Internal medicine, medicine, Humans, Immunologic Factors, Multiple sclerosi, 030212 general & internal medicine, Prospective Studies, Registries, Prospective cohort study, therapeutic lag, business.industry, Multiple sclerosis, Interferon beta-1a, Middle Aged, medicine.disease, Fingolimod, 3. Good health, Treatment Outcome, Cohort, Disease Progression, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Neurology (clinical), business, Immunotherapies, 030217 neurology & neurosurgery, Immunosuppressive Agents, Therapeutic lag, prognosis, treatment, medicine.drug, Cohort study, Follow-Up Studies
Abstract

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag. This study was supported by the EDMUS Foundation, Biogen and NHMRC (1140766, 1129189, 1157717). I.R. is supported by a MSIF-ARSEP McDonald fellowship grant and a Melbourne Research Scholarship. The MSBase Foundation is a not-for-profit organization that receives support from Biogen, Novartis, Merck, Roche, Teva and Sanofi Genzyme. The Observatoire Francais de la Sclerose en Plaques (OFSEP) is supported by a grant provided by the French State and handled by the 'Agence Nationale de la Recherche,' within the framework of the 'Investments for the Future' program, under the reference ANR-10-COHO-002, by the Eugene Devic EDMUS Foundation against multiple sclerosis and by the ARSEP Foundation. The study was conducted separately and apart from the guidance of the sponsors. Kalincik, T (corresponding author), Univ Melbourne, Dept Med, CORe, 300 Grattan St, Melbourne, Vic 3050, Australia. tomas.kalincik@unimelb.edu.au

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

Author

Roos, Izanne, Leray, Emmanuelle, Frascoli, Federico, Casey, Romain, Brown, J William L, Horakova, Dana, Havrdova, Eva K, Trojano, Maria, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ozakbas, Serkan, Bergamaschi, Roberto, Sá, Maria José, Cartechini, Elisabetta, Boz, Cavit, Granella, Franco, Hupperts, Raymond, Terzi, Murat, Lechner-Scott, Jeannette, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Olascoaga, Javier, Prevost, Julie, Aguera-Morales, Eduardo, Slee, Mark, Csepany, Tunde, Turkoglu, Recai, Sidhom, Youssef, Gouider, Riadh, Van Wijmeersch, Bart, McCombe, Pamela, Macdonell, Richard, Coles, Alasdair, Malpas, Charles B, Butzkueven, Helmut, Vukusic, Sandra, Kalincik, Tomas, MSBase, and OFSEP Investigators

Subjects
Adult, Male, Multiple Sclerosis, Time Factors, Natalizumab, Middle Aged, 3. Good health, therapeutic lag, Cohort Studies, Treatment Outcome, Disease Progression, Humans, Immunologic Factors, Female, Prospective Studies, Registries, Immunosuppressive Agents, Follow-Up Studies
Abstract

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

34. Remyelination varies between and within lesions in multiple sclerosis following bexarotene

Author

J. William L. Brown, Ferran Prados, Daniel R. Altmann, Baris Kanber, Jonathan Stutters, Nick G. Cunniffe, Joanne L. Jones, Zoya G. Georgieva, Edward J. Needham, Cyrus Daruwalla, Claudia Gandini Wheeler‐Kingshott, Peter Connick, Siddharthan Chandran, Robin Franklin, David MacManus, Rebecca Samson, Alasdair Coles, Declan Chard, Brown, J William L [0000-0002-7737-5834], Prados, Ferran [0000-0002-7872-0142], Kanber, Baris [0000-0003-2443-8800], Stutters, Jonathan [0000-0002-9151-0844], Cunniffe, Nick G [0000-0002-7562-2838], Jones, Joanne L [0000-0003-4974-1371], Georgieva, Zoya G [0000-0002-9531-8884], Needham, Edward J [0000-0001-7042-7462], Daruwalla, Cyrus [0000-0002-2329-5329], Connick, Peter [0000-0002-3892-8037], Chandran, Siddharthan [0000-0001-6827-1593], MacManus, David [0000-0002-0902-977X], Coles, Alasdair [0000-0003-4738-0760], Chard, Declan [0000-0003-3076-2682], and Apollo - University of Cambridge Repository

Subjects
Multiple Sclerosis, Remyelination, Bexarotene, General Neuroscience, Brain, Humans, Neurology (clinical), Magnetic Resonance Imaging, Research Articles, Research Article
Abstract

Funder: MS Society of the United Kingdom, Funder: NIHR UCLH Biomedical Research Centre, Funder: UCL, Funder: University College London, Funder: NIHR, Funder: Thorne Family Foundation, Funder: Adeslon Medical Research Foundation, OBJECTIVE: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). METHODS: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. RESULTS: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. INTERPRETATION: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

Published
2022
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35. Clinician and patient experience of neurology telephone consultations during the COVID-19 pandemic

Author

Tagore Nakornchai, Elena Conci, Anke Hensiek, J William L Brown, Nakornchai, Tagore [0000-0003-1573-9812], Brown, J William L [0000-0002-7737-5834], and Apollo - University of Cambridge Repository

Subjects
Patient Outcome Assessment, Neurology, COVID-19, Humans, adult neurology, General Medicine, telemedicine, Pandemics, Referral and Consultation, Telephone, Original Research
Abstract

Background Telephone consultations are already employed in specific neurological settings. At Cambridge University Hospitals, the COVID-19 pandemic initially prompted almost all face-to-face appointments to be delivered by telephone, providing a uniquely unselected population to assess. Objectives We explored patient and clinician experience of telephone consultations; and whether telephone consultations might be preferable for preidentifiable subgroups of patients after the pandemic. Methods Clinicians delivering neurological consultations converted to telephone between April and July 2020 were invited to complete a questionnaire following each consult (430 respondents) and the corresponding patients were subsequently surveyed (290 respondents). The questionnaires assessed clinician and patient goal achievement (and the reasons for any dissatisfaction). Clinicians also described consultation duration (in comparison to face to face) while patients detailed comparative convenience and preference. Results The majority of clinicians (335/430, 78%) and patients (227/290, 78%) achieved their consultation goals by telephone, particularly during follow-up consultations (clinicians 272/329, 83%, patients 176/216, 81%) and in some disease subgroups (eg, seizures/epilepsy (clinicians 114/122 (93%), patients 71/81 (88%)). 95% of telephone consultations were estimated to take the same or less time than an equivalent face-to-face consultation. Most patients found telephone consultations convenient (69%) with 149/211 (71%) indicating they would like telephone or video consultations to play some role in their future follow-up. Conclusion Telephone consultations appear effective, convenient and popular in prespecified subgroups of neurological outpatients. Further work comparing telephone, video and face-to-face consultations across multiple centres is now needed.

Published
2021

36. Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab

Author

Joanne L. Jones, Declan T. Chard, Arman Eshaghi, Alasdair Coles, M Pardini, Claudia Am Gandini Wheeler-Kingshott, J William L Brown, Ferran Prados Carrasco, Rebecca S. Samson, Tom Button, Sebastien Ourselin, Carole H. Sudre, Brown, J William L [0000-0002-7737-5834], Samson, Rebecca S [0000-0002-0197-702X], Chard, Declan T [0000-0003-3076-2682], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, magnetisation transfer ratio, 030218 nuclear medicine & medical imaging, Multiple sclerosis, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Internal medicine, alemtuzumab, Humans, Medicine, Magnetisation transfer, business.industry, alemtuzumab, magnetisation transfer ratio, Multiple sclerosis, periventricular gradient, Brain, medicine.disease, Magnetic Resonance Imaging, White Matter, Neurology, periventricular gradient, Cardiology, Alemtuzumab, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions. Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient’s evolution, and whether baseline gradients predict on-treatment relapses. Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups’ baseline gradients and evolution. Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (−0.045 pu/band/year, p = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( p = 0.568) nor brain parenchymal fraction ( p = 0.187) between those who relapsed within 4 years ( n = 4) and those who did not ( n = 15). However, the baseline gradient was significantly different ( p = 0.020). Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients – but not lesion loads or brain volumes – may predict on-treatment relapses. Larger confirmatory studies are required.

Published
2019

37. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

Author

Murat Terzi, Eugenio Pucci, Pamela A. McCombe, Alasdair Coles, Dana Horakova, Csilla Rozsa, Cavit Boz, Alessandra Lugaresi, Pierre Duquette, Michael Hutchinson, Michael Barnett, Raed Alroughani, Neil Robertson, Javier Olascoaga, Jeannette Lechner-Scott, Steve Vucic, Alexandre Prat, Patrizia Sola, Pierre Grammond, Guillermo Izquierdo, Maria Trojano, Franco Granella, Neil J Scolding, Raymond Hupperts, Vincent Van Pesch, Vilija Jokubaitis, J William L Brown, Mark Slee, Tünde Csépány, Daniele Spitaleri, Tim Spelman, Jose Luis Sanchez-Menoyo, Tjalf Ziemssen, Owen R Pearson, Tomas Kalincik, Marc Girard, Claire M Rice, Eva Havrdova, Suzanne Hodgkinson, Cristina Ramo, Alastair Wilkins, Helmut Butzkueven, Francois Grand'Maison, Edgardo Cristiano, Magdolna Simó, Radek Ampapa, Mark Willis, Freek Verheul, Roberto Bergamaschi, Christopher McGuigan, OMÜ, Brown, Will [0000-0002-7737-5834], Coles, Alasdair [0000-0003-4738-0760], Apollo - University of Cambridge Repository, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, Kalincik, Toma, Brown, J William L, Robertson, Neil, Willis, Mark, Scolding, Neil, Rice, Claire M, Wilkins, Alastair, Pearson, Owen, Ziemssen, Tjalf, Hutchinson, Michael, Mcguigan, Christopher, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Alroughani, Raed, Pucci, Eugenio, Sola, Patrizia, Hupperts, Raymond, Lechner-Scott, Jeannette, Terzi, Murat, Van Pesch, Vincent, Rozsa, Csilla, Grand'Maison, Françoi, Boz, Cavit, Granella, Franco, Slee, Mark, Spitaleri, Daniele, Olascoaga, Javier, Bergamaschi, Roberto, Verheul, Freek, Vucic, Steve, Mccombe, Pamela, Hodgkinson, Suzanne, Sanchez-Menoyo, Jose Lui, Ampapa, Radek, Simo, Magdolna, Csepany, Tunde, Ramo, Cristina, Cristiano, Edgardo, Barnett, Michael, Butzkueven, Helmut, and Coles, Alasdair

Subjects
Oncology, Adult, Male, medicine.medical_specialty, PLACEBO-CONTROLLED TRIAL, ORAL FINGOLIMOD, Antibodies, Monoclonal, Humanized, Klinikai orvostudományok, Cohort Studies, REGRESSION-MODEL, 03 medical and health sciences, Disability Evaluation, Young Adult, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, Fingolimod Hydrochloride, medicine, Clinical endpoint, SWITCH, Humans, Immunologic Factors, 030212 general & internal medicine, Alemtuzumab, Expanded Disability Status Scale, business.industry, Neurology (clinical), multiple sclerosis, prognosis, Multiple sclerosis, Hazard ratio, MS, Interferon-beta, Orvostudományok, medicine.disease, R1, Fingolimod, Databases, Bibliographic, Treatment Outcome, Immunology, Female, Neurology (clinical), business, CONTROLLED PHASE-3 TRIAL, 030217 neurology & neurosurgery, medicine.drug
Abstract

Lugaresi, Alessandra/0000-0003-2902-5589; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Ziemssen, Tjalf/0000-0001-8799-8202; Slee, Mark/0000-0003-4323-2453; Havrdova, Eva Kubala/0000-0002-9543-4359; Horakova, Dana/0000-0003-1915-0036; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Trojano, Maria/0000-0002-6329-8946; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Brown, William/0000-0002-7737-5834; Rice, Claire/0000-0002-9851-4426; Scolding, Neil/0000-0001-9177-1043; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; Vucic, Steve/0000-0002-8323-873X WOS: 000396336600016 PubMed: 28209331 Background Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. Methods In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6.5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Findings Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0.19 [95% CI 0.14-0.23] vs 0.53 [0.46-0.61], p

Published
2017

38. Bexarotene leads to durable improvements in visual evoked potential latency: A follow-up study of the Cambridge Centre for Myelin Repair One trial.

Author

McMurran CE, Mukherjee T, Brown JWL, Coles AJ, and Cunniffe NG

Subjects
Humans, Male, Female, Adult, Follow-Up Studies, Middle Aged, Tetrahydronaphthalenes pharmacology, Tetrahydronaphthalenes administration & dosage, Treatment Outcome, Double-Blind Method, Evoked Potentials, Visual drug effects, Bexarotene pharmacology, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis, Relapsing-Remitting physiopathology
Abstract

The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis (MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was -7.79 (95% confidence interval (CI) = -14.76, -0.82) ms, p  = 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: C.E.M. and T.M. have nothing to disclose. J.W.L.B. reports consulting and lecture fees from The Corpus, Biogen Idec and Novartis. A.J.C. and N.G.C. report grants from MS Society of GB, during the conduct of the study. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Published
2024
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39. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

Author

Daruwalla C, Shaygannejad V, Ozakbas S, Havrdova EK, Horakova D, Alroughani R, Boz C, Patti F, Onofrj M, Lugaresi A, Eichau S, Girard M, Prat A, Duquette P, Yamout B, Khoury SJ, Sajedi SA, Turkoglu R, Altintas A, Skibina O, Buzzard K, Grammond P, Karabudak R, van der Walt A, Butzkueven H, Maimone D, Lechner-Scott J, Soysal A, John N, Prevost J, Spitaleri D, Ramo-Tello C, Gerlach O, Iuliano G, Foschi M, Ampapa R, van Pesch V, Barnett M, Shalaby N, D'hooghe M, Kuhle J, Sa MJ, Fabis-Pedrini M, Kermode A, Mrabet S, Gouider R, Hodgkinson S, Laureys G, Van Hijfte L, Macdonell R, Oreja-Guevara C, Cristiano E, McCombe P, Sanchez-Menoyo JL, Singhal B, Blanco Y, Hughes S, Garber J, Solaro C, McGuigan C, Taylor B, de Gans K, Habek M, Al-Asmi A, Mihaela S, Castillo 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

Subjects
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.

Published
2023
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40. Determinants of therapeutic lag in multiple sclerosis.

Author

Roos I, Leray E, Frascoli F, Casey R, Brown JWL, Horakova D, Havrdova EK, Debouverie M, Trojano M, Patti F, Izquierdo G, Eichau S, Edan G, Prat A, Girard M, Duquette P, Onofrj M, Lugaresi A, Grammond P, Ciron J, Ruet A, Ozakbas S, De Seze J, Louapre C, Zephir H, Sá MJ, Sola P, Ferraro D, Labauge P, Defer G, Bergamaschi R, Lebrun-Frenay C, Boz C, Cartechini E, Moreau T, Laplaud D, Lechner-Scott J, Grand'Maison F, Gerlach O, Terzi M, Granella F, Alroughani R, Iuliano G, Van Pesch V, Van Wijmeersch B, Spitaleri D, Soysal A, Berger E, Prevost J, Aguera-Morales E, McCombe P, Castillo Triviño T, Clavelou P, Pelletier J, Turkoglu R, Stankoff B, Gout O, Thouvenot E, Heinzlef O, Sidhom Y, Gouider R, Csepany T, Bourre B, Al Khedr A, Casez O, Cabre P, Montcuquet A, Wahab A, Camdessanche JP, Maurousset A, Patry I, Hankiewicz K, Pottier C, Maubeuge N, Labeyrie C, Nifle C, Coles A, Malpas CB, Vukusic S, Butzkueven H, and Kalincik T

Subjects
Disability Evaluation, Disease Progression, Female, Humans, Male, Recurrence, Registries, Disabled Persons, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting
Abstract

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups., Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation., Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants., Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5)., Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Published
2021
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41. Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

Author

Roos I, Leray E, Frascoli F, Casey R, Brown JWL, Horakova D, Havrdova EK, Trojano M, Patti F, Izquierdo G, Eichau S, Onofrj M, Lugaresi A, Prat A, Girard M, Grammond P, Sola P, Ferraro D, Ozakbas S, Bergamaschi R, Sá MJ, Cartechini E, Boz C, Granella F, Hupperts R, Terzi M, Lechner-Scott J, Spitaleri D, Van Pesch V, Soysal A, Olascoaga J, Prevost J, Aguera-Morales E, Slee M, Csepany T, Turkoglu R, Sidhom Y, Gouider R, Van Wijmeersch B, McCombe P, Macdonell R, Coles A, Malpas CB, Butzkueven H, Vukusic S, and Kalincik T

Subjects
Adult, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Sclerosis diagnostic imaging, Natalizumab administration & dosage, Prospective Studies, Registries, Time Factors, Treatment Outcome, Disease Progression, Immunologic Factors administration & dosage, Immunosuppressive Agents administration & dosage, Multiple Sclerosis drug therapy, Multiple Sclerosis physiopathology
Abstract

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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42. Alemtuzumab: evidence for its potential in relapsing-remitting multiple sclerosis.

Author

Brown JW and Coles AJ

Subjects
Adjuvants, Immunologic adverse effects, Alemtuzumab, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized immunology, Antigens, CD immunology, Antigens, Neoplasm immunology, CD52 Antigen, Glycoproteins immunology, Humans, Interferon beta-1a, Interferon-beta adverse effects, Interferon-beta pharmacology, Interferon-beta therapeutic use, Multiple Sclerosis, Relapsing-Remitting immunology, Multiple Sclerosis, Relapsing-Remitting physiopathology, Treatment Outcome, Adjuvants, Immunologic therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy
Abstract

Alemtuzumab (previously known as Campath(®)) is a humanized monoclonal antibody directed against the CD52 antigen on mature lymphocytes that results in lymphopenia and subsequent modification of the immune repertoire. Here we explore evidence for its efficacy and safety in relapsing-remitting multiple sclerosis. One Phase II and two Phase III trials of alemtuzumab versus active comparator (interferon beta-1a) have been reported. Two of these rater-blinded randomized studies assessed clinical and radiological outcomes in treatment-naïve patients; one explored patients who had relapsed despite first-line therapy. Compared to interferon beta-1a, alemtuzumab reduced the relapse rate by 49%-74% (P < 0.0001), and in two studies it reduced the risk of sustained disability accumulation by 42%-71% (P < 0.01). In one study (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; CARE-MS1), there was no significant difference compared to interferon, perhaps reflecting the surprisingly low frequency of disability events in the comparator group. After alemtuzumab, the Expanded Disability Status Scale score improved by 0.14-1.2 points, culminating in a net advantage with alemtuzumab of 0.41-0.77 points over interferon in the CAMMS223 and CARE-MS2 trials (both P < 0.001). Radiological markers of new lesion formation and brain atrophy following alemtuzumab were significantly improved when compared to interferon in all studies. Adverse events were more common following alemtuzumab than interferon beta-1a (7.2-8.66 versus 4.9-5.7 events per person-year). While infusion reactions are the most common, autoimmunity is the most concerning; within Phase III studies, thyroid disorders (17%-18% versus 5%-6%) and immune thrombocytopenic purpura (1% versus 0%) were reported in patients taking alemtuzumab and interferon beta-1a, respectively. All patients responded to conventional therapy. One patient taking alemtuzumab in the Phase II study suffered a fatal intracranial hemorrhage following immune thrombocytopenic purpura, heralding assiduous monitoring of all patients thereafter. Alemtuzumab has been submitted for licensing in relapsing-remitting multiple sclerosis in the United States and Europe.

Published
2013
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