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

Author: Roos, Izanne, Malpas, Charles, Leray, Emmanuelle, Casey, Romain, Horakova, Dana, Havrdova, Eva Kubala, Debouverie, Marc, Patti, Francesco, De Seze, Jerome, Izquierdo, Guillermo, Eichau, Sara, Edan, Gilles, Prat, Alexandre, Girard, Marc, Ozakbas, Serkan, Grammond, Pierre, Zephir, Helene, Ciron, Jonathan, Maillart, Elisabeth, Moreau, Thibault, Amato, Maria Pia, Labauge, Pierre, Alroughani, Raed, Buzzard, Katherine, Skibina, Olga, Terzi, Murat, Laplaud, David Axel, Berger, Eric, Grand'Maison, Francois, Lebrun-Frenay, Christine, Cartechini, Elisabetta, Boz, Cavit, Lechner-Scott, Jeannette, Clavelou, Pierre, Stankoff, Bruno, Prevost, Julie, Kappos, Ludwig, Pelletier, Jean, Shaygannejad, Vahid, Yamout, Bassem I, Khoury, Samia J, Gerlach, Oliver, Spitaleri, Daniele L A, Van Pesch, Vincent, Gout, Olivier, Turkoglu, Recai, Heinzlef, Olivier, Thouvenot, Eric, McCombe, Pamela Ann, Soysal, Aysun, Bourre, Bertrand, Slee, Mark, Castillo-Trivino, Tamara, Bakchine, Serge, Ampapa, Radek, Butler, Ernest Gerard, Wahab, Abir, Macdonell, Richard A, Aguera-Morales, Eduardo, Cabre, Philippe, Ben, Nasr Haifa, Van der Walt, Anneke, Laureys, Guy, Van Hijfte, Liesbeth, Ramo-Tello, Cristina M, Maubeuge, Nicolas, Hodgkinson, Suzanne, Sánchez-Menoyo, José Luis, Barnett, Michael H, Labeyrie, Celine, Vucic, Steve, Sidhom, Youssef, Gouider, Riadh, Csepany, Tunde, Sotoca, Javier, de Gans, Koen, Al-Asmi, Abdullah, Fragoso, Yara Dadalti, Vukusic, Sandra, Butzkueven, Helmut, Kalincik, Tomas, MSBase and OFSEP, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, University of Melbourne, Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), Recherche sur les services et le management en santé (RSMS), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Pontchaillou [Rennes], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Unité de Recherche Clinique de la Côte d’Azur (URRIS UR2CA), Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génomique Fonctionnelle (IGF), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Fingolimod Hydrochloride, Recurrence, [SDV]Life Sciences [q-bio], Natalizumab, Humans, Female, Neurology (clinical), Immunosuppressive Agents, Research Article, Retrospective Studies
Abstract: Objectives:To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.Methods:This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.Results:14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).Conclusion:The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimised after stopping anti-trafficking therapies (natalizumab and fingolimod).Classification of evidence:This study provides class III that disease reactivation occurs within months of discontinuation of multiple sclerosis disease-modifying therapies. Risk of disease activity is reduced by commencement of a subsequent therapy.
Published: 2022

2. Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS

Author: Kalincik, Tomas, Kister, Ilya, Bacon, Tamar E, Malpas, Charles B, Sharmin, Sifat, Horakova, Dana, Kubala-Havrdova, Eva, Patti, Francesco, Izquierdo, Guillermo, Eichau, Sara, Ozakbas, Serkan, Onofrj, Marco, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Alroughani, Raed, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Bergamaschi, Roberto, Gerlach, Oliver, Sa, Maria J, Kappos, Ludwig, Cartechini, Elisabetta, Lechner-Scott, Jeannette, Van Pesch, Vincent, Shaygannejad, Vahid, Granella, Franco, Spitaleri, Daniele, Iuliano, Gerardo, Maimone, Davide, Prevost, Julie, Soysal, Aysun, Turkoglu, Recai, Ampapa, Radek, Butzkueven, Helmut, Cutter, Gary, for MSBase Study Group, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Adult, Male, Multiple Sclerosis, Multiple Sclerosis Severity Score (MSSS), Middle Aged, Severity of Illness Index, Disability Evaluation, Neurology, prognostics, relapse prediction, Recurrence, Disease Progression, Humans, Female, Neurology (clinical), Prospective Studies
Abstract: Background: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. Objective: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. Methods: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients’ demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. Results: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. Conclusion: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.
Published: 2022

3. Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study

Author: Vitkova, Marianna, Diouf, Ibrahima, Malpas, Charles, Horakova, Dana, Kubala Havrdova, Eva, Patti, Francesco, Ozakbas, Serkan, Izquierdo, Guillermo, Eichau, Sara, Shaygannejad, Vahid, Onofrj, Marco, Lugaresi, Alessandra, Alroughani, Raed, Prat, Alexandre, Larochelle, Catherine, Girard, Marc, Duquette, Pierre, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Sola, Patrizia, Ferraro, Diana, Grammond, Pierre, Butzkueven, Helmut, Buzzard, Katherine, Skibina, Olga, Yamout, Bassem I, Karabudak, Rana, Gerlach, Oliver, Lechner-Scott, Jeannette, Maimone, Davide, Bergamaschi, Roberto, Van Pesch, Vincent, Iuliano, Gerardo, Cartechini, Elisabetta, José Sà, Maria, Ampapa, Radek, Barnett, Michael, Hughes, Stella E, Ramo-Tello, Cristina M, Hodgkinson, Suzanne, Spitaleri, Daniele L A, Petersen, Thor, Butler, Ernest Gerard, Slee, Mark, McGuigan, Chris, McCombe, Pamela Ann, Granella, Franco, Cristiano, Edgardo, Prevost, Julie, Taylor, Bruce V, Sãnchez-Menoyo, Josã Luis, Laureys, Guy, Van Hijfte, Liesbeth, Vucic, Steve, Macdonell, Richard A, Gray, Orla, Olascoaga, Javier, Deri, Norma, Fragoso, Yara Dadalti, Shaw, Cameron, Kalincik, Tomas, MSBase Study Group, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Male, Disability Evaluation, Multiple Sclerosis, Ultraviolet Rays, Sunlight, Humans, Female, Neurology (clinical), Registries, Severity of Illness Index, Research Article
Abstract: Background and ObjectivesThe severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS.MethodsThis observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration’s Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS.ResultsThe 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35′ and 56°16′) were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes DiscussionIn temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
Published: 2022

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

Author: Kalincik, Tomas, Diouf, Ibrahima, Sharmin, Sifat, Malpas, Charles, Spelman, Tim, Horakova, Dana, Havrdova, Eva Kubala, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Jokubaitis, Vilija, van der Walt, Anneke, Grand'Maison, Francois, Sola, Patrizia, Ferraro, Diana, Shaygannejad, Vahid, Alroughani, Raed, Hupperts, Raymond, Terzi, Murat, Boz, Cavit, Lechner-Scott, Jeannette, Pucci, Eugenio, Van Pesch, Vincent, Granella, Franco, Bergamaschi, Roberto, Spitaleri, Daniele, Slee, Mark, Vucic, Steve, Ampapa, Radek, McCombe, Pamela, Ramo-Tello, Cristina, Prevost, Julie, Olascoaga, Javier, Cristiano, Edgardo, Barnett, Michael, Saladino, Maria Laura, Sanchez-Menoyo, Jose Luis, Hodgkinson, Suzanne, Rozsa, Csilla, Hughes, Stella, Moore, Fraser, Shaw, Cameron, Butler, Ernest, Skibina, Olga, Gray, Orla, Kermode, Allan, Csepany, Tunde, Singhal, Bhim, Shuey, Neil, Piroska, Imre, Taylor, Bruce, Simo, Magdolna, Sirbu, Carmen-Adella, Sas, Attila, Butzkueven, Helmut, MSBase Study Group, UCL - (SLuc) Service de neurologie, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Kalincik, Toma, Diouf, Ibrahima, Sharmin, Sifat, Malpas, Charle, Spelman, Tim, Horakova, Dana, Havrdova, Eva Kubala, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Jokubaitis, Vilija, van der Walt, Anneke, Grand'Maison, Francoi, Sola, Patrizia, Ferraro, Diana, Shaygannejad, Vahid, Alroughani, Raed, Hupperts, Raymond, Terzi, Murat, Boz, Cavit, Lechner-Scott, Jeannette, Pucci, Eugenio, Van Pesch, Vincent, Granella, Franco, Bergamaschi, Roberto, Spitaleri, Daniele, Slee, Mark, Vucic, Steve, Ampapa, Radek, McCombe, Pamela, Ramo-Tello, Cristina, Prevost, Julie, Olascoaga, Javier, Cristiano, Edgardo, Barnett, Michael, Saladino, Maria Laura, Sanchez-Menoyo, Jose Lui, Hodgkinson, Suzanne, Rozsa, Csilla, Hughes, Stella, Moore, Fraser, Shaw, Cameron, Butler, Ernest, Skibina, Olga, Gray, Orla, Kermode, Allan, Csepany, Tunde, Singhal, Bhim, Shuey, Neil, Piroska, Imre, Taylor, Bruce, Simo, Magdolna, Sirbu, Carmen-Adella, Sas, Attila, and Butzkueven, Helmut
Subjects: Adult, Male, medicine.medical_specialty, Article, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, multiple sclerosis, treatment, prognosis, Internal medicine, medicine, Humans, Immunologic Factors, Disease Progression, Female, Fingolimod Hydrochloride, Glatiramer Acetate, Immunosuppressive Agents, Interferon-beta, Longitudinal Studies, Middle Aged, Proportional Hazards Models, 030212 general & internal medicine, Glatiramer acetate, Expanded Disability Status Scale, Proportional hazards model, business.industry, Multiple sclerosis, Hazard ratio, medicine.disease, Confidence interval, Cohort, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: ObjectiveTo test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.MethodsWe studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.ResultsA total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43–0.82, p = 0.0016), worsening of disability (0.56, 0.38–0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19–0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p = 10−9) and worsening of disability (0.81, 0.67–0.99, p = 0.043).ConclusionContinued treatment with MS immunotherapies reduces disability accrual by 19%–44% (95% CI 1%–62%), the risk of need of a walking aid by 67% (95% CI 41%–81%), and the frequency of relapses by 40–41% (95% CI 18%–57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.Classification of EvidenceThis study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
Published: 2021

5. 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

6. Long-term outcomes in patients presenting with optic neuritis: Analyses of the MSBase registry

Author: Kenney, Rachel, Liu, Mengling, Patil, Sachi, Alroughani, Raed, Ampapa, Radek, Bergamaschi, Roberto, Boz, Cavit, Butzkueven, Helmut, Gomez, Jose Cabrera, Cartechini, Elisabetta, Madueño, Sara Eichau, Ferraro, Diana, Grand-Maison, Francois, Granella, Franco, Horakova, Dana, Izquierdo Ayuso, Guillermo, Kalincik, Tomas, Lizrova Preiningerova, Jana, Lugaresi, Alessandra, Onofrj, Marco, Ozakbas, Serkan, Patti, Francesco, Sola, Patrizia, Soysal, Aysun, Spitaleri, Daniele Litterio A, Terzi, Murat, Turkoglu, Recai, Van Pesch, Vincent, Saidha, Shiv, Thorpe, Lorna E, Galetta, Steven L, Balcer, Laura J, Kister, Ilya, Spelman, Tim, MSBase Study Group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Kenney R., Liu M., Patil S., Alroughani R., Ampapa R., Bergamaschi R., Boz C., Butzkueven H., Gomez J.C., Cartechini E., Madueno S.E., Ferraro D., Grand-Maison F., Granella F., Horakova D., Izquierdo Ayuso G., Kalincik T., Lizrova Preiningerova J., Lugaresi A., Onofrj M., Ozakbas S., Patti F., Sola P., Soysal A., Spitaleri D.L.A., Terzi M., Turkoglu R., van Pesch V., Saidha S., Thorpe L.E., Galetta S.L., Balcer L.J., Kister I., and Spelman T.
Subjects: Registrie, Adult, Optic neuriti, medicine.medical_specialty, Multiple Sclerosis, Optic Neuritis, Adolescent, Expanded disability status scale (EDSS), Vision, Cohort Studies, Disability Evaluation, Young Adult, Internal medicine, Multiple Sclerosi, medicine, Humans, Optic neuritis, Registries, Young adult, Survival analysis, Clinically isolated syndrome, Expanded Disability Status Scale, business.industry, Demyelinating Disease, medicine.disease, Clinical research, MSBase registry, Neurology, Cohort, Disease Progression, Female, Neurology (clinical), Cohort Studie, business, Human, Demyelinating Diseases, Cohort study
Abstract: Background: Short-term outcomes of optic neuritis (ON) have been well characterized. Limited data exists on longer-term visual outcomes in patients who present with ON. The large MSBase registry allows for characterization of long-term visual outcomes after ON. Methods: Via the MSBase Registry, data on patients from 41 centers was collected during routine clinical and research visits. Physical and visual disability were measured using the expanded disability status scale (EDSS) and the visual function score (VFS). Inclusion criteria for this analysis included age ≥ 18 years, clinically isolated syndrome (CIS), ON-onset, baseline visit within 6 months of onset, and at least one follow-up visit. Survival analysis was used to evaluate the association of disease-modifying treatment with time to conversion to clinically definite MS or sustained EDSS/VFS progression. Results: Data from 60,933 patients were obtained from the MSBase registry in July 2019. Of these, 1317 patients met inclusion criteria; 935 were treated at some point in disease course, while 382 were never treated. At baseline, mean age was 32.3 ± 8.8 years, 74% were female, median EDSS was 2 (IQR 1–2), and median VFS was 1 (IQR 0–2). Median follow-up time was 5.2 years (IQR 2.4–9.3). Treatment was associated with reduced risk and delayed conversion to clinically definite MS (HR = 0.70, p < 0.001), sustained EDSS progression (HR = 0.46, p < 0.0001) and sustained VFS (HR = 0.41, p < 0.001) progression. Conclusions: In the MSBase cohort, treatment after ON was associated with better visual and neurological outcomes compared to no treatment. These results support early treatment for patients presenting with ON as the first manifestation of MS.
Published: 2021

7. Quantifying risk of early relapse in patients with first demyelinating events: Prediction in clinical practice

Author: Spelman, Tim, Meyniel, Claire, Rojas, Juan Ignacio, Lugaresi, Alessandra, Izquierdo, Guillermo, Grand'Maison, Francois, Boz, Cavit, Alroughani, Raed, Havrdova, Eva, Horakova, Dana, Iuliano, Gerardo, Duquette, Pierre, Terzi, Murat, Grammond, Pierre, Hupperts, Raymond, Lechner-Scott, Jeannette, Oreja-Guevara, Celia, Pucci, Eugenio, Verheul, Freek, Fiol, Marcela, Van Pesch, Vincent, Cristiano, Edgardo, Petersen, Thor, Moore, Fraser, Kalincik, Tomas, Jokubaitis, Vilija, Trojano, Maria, Butzkueven, Helmut, MSBasis (an MSBase Substudy) Investigators, Ondokuz Mayıs Üniversitesi, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Spelman, Tim, Meyniel, Claire, Rojas, Juan Ignacio, Lugaresi, Alessandra, Izquierdo, Guillermo, Grand'Maison, Francoi, Boz, Cavit, Alroughani, Raed, Havrdova, Eva, Horakova, Dana, Iuliano, Gerardo, Duquette, Pierre, Terzi, Murat, Grammond, Pierre, Hupperts, Raymond, Lechner-Scott, Jeannette, Oreja-Guevara, Celia, Pucci, Eugenio, Verheul, Freek, Fiol, Marcela, Van Pesch, Vincent, Cristiano, Edgardo, Petersen, Thor, Moore, Fraser, Kalincik, Toma, Jokubaitis, Vilija, Trojano, Maria, Butzkueven, Helmut, and MSBase (an MSBase Substudy) Investigators
Subjects: Adult, Male, medicine.medical_specialty, clinically definite multiple sclerosis, Multiple Sclerosis, Early Relapse, clinically definite multiple sclerosi, CSF, disease-modifying drugs, Nomogram, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Risk Factors, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, Age of Onset, Proportional Hazards Models, CIS, Clinically isolated syndrome, Proportional hazards model, business.industry, Multiple sclerosis, Interferon beta-1a, MS, disease-modifying drug, Middle Aged, medicine.disease, Prognosis, Surgery, Nomograms, Neurology, clinically isolated syndrome, second attack, Disease Progression, Female, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Immunosuppressive Agents, medicine.drug, Demyelinating Diseases, MRI
Abstract: Havrdova, Eva Kubala/0000-0002-9543-4359; Lugaresi, Alessandra/0000-0003-2902-5589; Horakova, Dana/0000-0003-1915-0036; Oreja-Guevara, Celia/0000-0002-9221-5716; Jokubaitis, Vilija G./0000-0002-3942-4340; van Pesch, Vincent/0000-0003-2885-9004; Kalincik, Tomas/0000-0003-3778-1376; Petersen, Thor/0000-0001-5633-2600; pucci, eugenio/0000-0001-7606-7330; Trojano, Maria/0000-0002-6329-8946; Butzkueven, Helmut/0000-0003-3940-8727 WOS: 000407918800009 PubMed: 27885062 Background: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs). Objective: To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion. Methods: Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices. Results: A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities. Conclusion: This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion. NHMRCNational Health and Medical Research Council of Australia [ID628856, 1032484]; NHMRC Centre of Research Excellence [1001216]; MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; Biogen IdecBiogen; Novartis Pharma; Bayer-ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL; Journees de Neurologie de Langue Francaise The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The work was supported by the NHMRC Career Development Award (Clinical) to HB (ID628856), NHMRC Project Grant (1032484), NHMRC Centre of Research Excellence (grant ID 1001216) and the MSBase Foundation. The MSBasis study was specifically supported by Merck Serono, between 2004 and 2009. The MSBase Foundation is a not-for-profit organisation that receives support from Merck Serono, Biogen Idec, Novartis Pharma, Bayer-Schering, Sanofi-Aventis and BioCSL. Claire Meyniel was supported by the Journees de Neurologie de Langue Francaise.
Published: 2017

8. Prognostic indicators in pediatric clinically isolated syndrome

Author: Iaffaldano, Pietro, Simone, Marta, Lucisano, Giuseppe, Ghezzi, Angelo, Coniglio, Gabriella, Brescia Morra, Vincenzo, Salemi, Giuseppe, Patti, Francesco, Lugaresi, Alessandra, Izquierdo, Guillermo, Bergamaschi, Roberto, Cabrera-Gomez, Jose Antonio, Pozzilli, Carlo, Millefiorini, Enrico, Alroughani, Raed, Boz, Cavit, Pucci, Eugenio, Zimatore, Giovanni Bosco, Sola, Patrizia, Lus, Giacomo, Maimone, Davide, Avolio, Carlo, Cocco, Eleonora, Sajedi, Seyed Aidin, Costantino, Gianfranco, Duquette, Pierre, Shaygannejad, Vahid, Petersen, Thor, Fernández Bolaños, Ricardo, Paolicelli, Damiano, Tortorella, Carla, Spelman, Tim, Margari, Lucia, Amato, Maria Pia, Comi, Giancarlo, Butzkueven, Helmut, Trojano, Maria, Spitaleri, Daniele, Rottoli, Maria Rosa, Ardito, Bonaventura, Iuliano, Gerardo, Montanari, Enrico, Granieri, Enrico, Tedeschi, Gioacchino, Bertolotto, Antonio, Granella, Franco, Di Battista, Giancarlo, Gallo, Paolo, Cavalla, Paola, Bellantonio, Paolo, De Robertis, Francesca, Durelli, Luca, Scarpini, Elio, Rezzonico, Monica, Protti, Alessandra, Solaro, Claudio, Corea, Francesco, Bosco, Antonio, Vianello, Marika, Ferrò, Maria Teresa, Balgera, Roberto, Grasso, Roberta, De Luca, Giovanna, Farina, Deboah, Travaglini, Daniela, di Ioia, Maria, Di Tommaso, Valeria, Mancinelli, Luca, Pietrolongo, Erika, Hupperts, Raymond, Rio, Maria Edite, Terzi, Murat, Barnett, Michael, Slee, Mark, Van Pesch, Vincent, Savino, Aldo, Lechner-Scott, Jeannette, Grammond, Pierre, Singhal, Bhim, Zwanikken, Cees, Fiol, Marcela, Patrucco, Liliana, Paine, Mark, Mccombefrom, Pamela, Grand'Maison, Francois, Iaffaldano, Pietro, Simone, Marta, Lucisano, Giuseppe, Ghezzi, Angelo, Coniglio, Gabriella, Brescia Morra, Vincenzo, Salemi, Giuseppe, Patti, Francesco, Lugaresi, Alessandra, Izquierdo, Guillermo, Bergamaschi, Roberto, Cabrera-Gomez, Jose Antonio, Pozzilli, Carlo, Millefiorini, Enrico, Alroughani, Raed, Boz, Cavit, Pucci, Eugenio, Zimatore, Giovanni Bosco, Sola, Patrizia, Lus, Giacomo, Maimone, Davide, Avolio, Carlo, Cocco, Eleonora, Sajedi, Seyed Aidin, Costantino, Gianfranco, Duquette, Pierre, Shaygannejad, Vahid, Petersen, Thor, Fernández Bolaños, Ricardo, Paolicelli, Damiano, Tortorella, Carla, Spelman, Tim, Margari, Lucia, Amato, Maria Pia, Comi, Giancarlo, Butzkueven, Helmut, Trojano, Maria, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, Morra, Vincenzo Brescia, Cabrera Gomez, Jose Antonio, and Bolaños, Ricardo Fernández
Subjects: Registrie, Male, Multiple Sclerosis, Adolescent, Age of Onset, Child, Demyelinating Diseases, Female, Follow-Up Studies, Humans, Prognosis, Retrospective Studies, Risk Factors, Disease Progression, Registries, Neurology, Neurology (clinical), Prognosi, ONSET MULTIPLE-SCLEROSIS, CHILDHOOD, CHILDREN, PARACLINICAL FEATURES, DISABILITY PROGRESSION, NO, Follow-Up Studie, Retrospective Studie, prognostic indicators, Multiple Sclerosi, pediatric, multiple sclerosis, prognosis, indicators, OPTIC NEURITIS, Risk Factor, Demyelinating Disease, NATURAL-HISTORY, multiple sclerosis, clinically isolated syndrome, prognostic indicators, TRANSVERSE MYELITIS, clinically isolated syndrome, INTERFERON BETA-1B, Settore MED/26 - Neurologia, FOLLOW-UP, Human
Abstract: To assess prognostic factors for a second clinical attack and a first disability worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of Multiple Sclerosis (MS) patients. Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06â1.55; 1.42, 1.10â1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60â0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42â0.83; 0.75, 0.71â0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46â7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729â739.
Published: 2017

9. Predictors of long-term disability accrual in relapse-onset multiple sclerosis

Author: Jokubaitis, Vilija G, Spelman, Tim, Kalincik, Tomas, Lorscheider, Johannes, Havrdova, Eva, Horakova, Dana, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Izquierdo, Guillermo, Grammond, Pierre, Van Pesch, Vincent, Pucci, Eugenio, Grand'Maison, François, Hupperts, Raymond, Granella, Franco, Sola, Patrizia, Bergamaschi, Roberto, Iuliano, Gerardo, Spitaleri, Daniele, Boz, Cavit, Hodgkinson, Suzanne, Olascoaga, Javier, Verheul, Freek, McCombe, Pamela, Petersen, Thor, Rozsa, Csilla, Lechner-Scott, Jeannette, Saladino, Maria Laura, Farina, Deborah, Iaffaldano, Pietro, Paolicelli, Damiano, Butzkueven, Helmut, Lugaresi, Alessandra, Trojano, Maria, and MSBase Study Group
Subjects: Adult, Male, Multiple Sclerosis, Glatiramer Acetate, Interferon-beta, Protective Factors, Prognosis, Disability Evaluation, Young Adult, Pregnancy, Recurrence, Risk Factors, Humans, Female, Registries, Follow-Up Studies
Abstract: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009). We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
Published: 2016

10. The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis

Author: Warrender-Sparkes, Matthew, Spelman, Tim, Izquierdo, Guillermo, Trojano, Maria, Lugaresi, Alessandra, Grand'Maison, François, Havrdova, Eva, Horakova, Dana, Boz, Cavit, Oreja-Guevara, Celia, Alroughani, Raed, Iuliano, Gerardo, Duquette, Pierre, Girard, Marc, Terzi, Murat, Hupperts, Raymond, Grammond, Pierre, Petersen, Thor, Fernandez-Bolanos, Ricardo, Fiol, Marcela, Pucci, Eugenio, Lechner-Scott, Jeannette, Verheul, Freek, Cristiano, Edgardo, Van Pesch, Vincent, Petkovska-Boskova, Tatjana, Moore, Fraser, Kister, Ilya, Bergamaschi, Roberto, Saladino, Maria Laura, Slee, Mark, Barnett, Michael, Amato, Maria Pia, Shaw, Cameron, Shuey, Neil, Young, Carolyn, Gray, Orla, Kappos, Ludwig, Butzkueven, Helmut, Kalincik, Tomas, Jokubaitis, Vilija, MSBase study group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Ondokuz Mayıs Üniversitesi, Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'Maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, Alroughani R, Iuliano G, Duquette P, Girard M, Terzi M, Hupperts R, Grammond P, Petersen T, Fernandez-Bolaños R, Fiol M, Pucci E, Lechner-Scott J, Verheul F, Cristiano E, Van Pesch V, Petkovska-Boskova T, Moore F, Kister I, Bergamaschi R, Saladino Ml, Slee M, Barnett M, Amato Mp, Shaw C, Shuey N, Young C, Gray O, Kappos L, Butzkueven H, Kalincik T, Jokubaitis V, and Msbase study group.
Subjects: Oncology, Male, Time Factors, Administration, Oral, Kaplan-Meier Estimate, Pharmacology, Persistence (computer science), 0302 clinical medicine, Natalizumab, Risk Factors, 030212 general & internal medicine, Prospective Studies, Registries, Prospective cohort study, Drug Substitution, Research Support, Non-U.S. Gov't, Middle Aged, Fingolimod, disease-modifying therapy, Treatment Outcome, Neurology, Cohort, Female, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, MSBase, Medication Adherence, Multiple sclerosis, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, Fingolimod Hydrochloride, medicine, Journal Article, Humans, Multiple sclerosi, fingolimod, Aged, Proportional Hazards Models, business.industry, medicine.disease, Medication Persistence, Multivariate Analysis, Neurology (clinical), business, 030217 neurology & neurosurgery, medication persistence, Demyelinating Diseases
Abstract: Lugaresi, Alessandra/0000-0003-2902-5589; Horakova, Dana/0000-0003-1915-0036; amato, Maria Pia/0000-0003-3325-3760; Havrdova, Eva Kubala/0000-0002-9543-4359; Slee, Mark/0000-0003-4323-2453; Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Petersen, Thor/0000-0001-5633-2600; pucci, eugenio/0000-0001-7606-7330; , Carolyn/0000-0001-6971-8203; van Pesch, Vincent/0000-0003-2885-9004; Butzkueven, Helmut/0000-0003-3940-8727; Trojano, Maria/0000-0002-6329-8946; Young, Carolyn/0000-0003-1745-7720; Kalincik, Tomas/0000-0003-3778-1376; Kister, Ilya/0000-0003-3549-949X WOS: 000372890900008 PubMed: 26199347 Objective: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). Methods: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. Results: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p
Published: 2016

11. Predictors of long-term disability accrual in relapse-onset multiple sclerosis

Author: Jokubaitis, Vilija G., Spelman, Tim, Kalincik, Tomas, Lorscheider, Johannes, Havrdova, Eva, Horakova, Dana, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Izquierdo, Guillermo, Grammond, Pierre, Van Pesch, Vincent, Pucci, Eugenio, Grand'Maison, Francois, Hupperts, Raymond, Granella, Franco, Sola, Patrizia, Bergamaschi, Roberto, Iuliano, Gerardo, Spitaleri, Daniele, Boz, Cavit, Hodgkinson, Suzanne, Olascoaga, Javier, Verheul, Freek, McCombe, Pamela, Petersen, Thor, Rozsa, Csilla, Lechner-Scott, Jeannette, Laura Saladino, Maria, Farina, Deborah, Iaffaldano, Pietro, Paolicelli, Damiano, Butzkueven, Helmut, Lugaresi, Alessandra, Trojano, Maria, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Neurologie (9), and Klinische Neurowetenschappen
Subjects: Adult, Male, Multiple Sclerosis, Glatiramer Acetate, Interferon-beta, Protective Factors, Prognosis, Disability Evaluation, Young Adult, Pregnancy, Recurrence, Risk Factors, Journal Article, Humans, Female, Registries, Follow-Up Studies
Abstract: OBJECTIVE: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.METHODS: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.RESULTS: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).INTERPRETATION: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
Published: 2015

12. Seasonal variation of relapse rate in multiple sclerosis is latitude dependent

Author: Spelman, Tim, Gray, Orla, Trojano, Maria, Petersen, Thor, Izquierdo, Guillermo, Lugaresi, Alessandra, Hupperts, Raymond, Bergamaschi, Roberto, Duquette, Pierre, Grammond, Pierre, Giuliani, Giorgio, Boz, Cavit, Verheul, Freek, Oreja-Guevara, Celia, Barnett, Michael, Grand'Maison, Francois, Edite Rio, Maria, Lechner-Scott, Jeannette, Van Pesch, Vincent, Fernandez Bolanos, Ricardo, Flechter, Shlomo, Den Braber-Moerland, Leontien, Iuliano, Gerardo, Amato, Maria Pia, Slee, Mark, Cristiano, Edgardo, Saladino, Maria Laura, Paine, Mark, Vella, Norbert, Kasa, Krisztian, Deri, Norma, Herbert, Joseph, Moore, Fraser, Petkovska-Boskova, Tatjana, Alroughani, Raed, Savino, Aldo, Shaw, Cameron, Vucic, Steve, Santiago, Vetere, Bacile, Elizabeth Alejandra, Skromne, Eli, Poehlau, Dieter, Cabrera-Gomez, Jose Antonio, Lucas, Robyn, Butzkueven, Helmut, Spelman T, Gray O, Trojano M, Petersen T, Izquierdo G, Lugaresi A, Hupperts R, Bergamaschi R, Duquette P, Grammond P, Giuliani G, Boz C, Verheul F, Oreja-Guevara C, Barnett M, Grand'Maison F, Edite Rio M, Lechner-Scott J, Van Pesch V, Fernandez Bolanos R, Flechter S, Den Braber-Moerland L, Iuliano G, Amato MP, Slee M, Cristiano E, Saladino ML, Paine M, Vella N, Kasa K, Deri N, Herbert J, Moore F, Petkovska-Boskova T, Alroughani R, Savino A, Shaw C, Vucic S, Santiago V, Bacile EA, Skromne E, Poehlau D, Cabrera-Gomez JA, Lucas R, Butzkueven H, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience
Subjects: Adult, Male, Internationality, Databases, Factual, Ultraviolet Rays, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Sunlight, Humans, Female, seasonal, variation, multiple sclerosis,relapse, Longitudinal Studies, Prospective Studies, Registries, Seasons
Abstract: OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude.METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak.RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028).INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere. Ann Neurol 2014;76:880-890.
Published: 2014

13. 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

14. Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis

Author: Maggi, Pietro, Kuhle, Jens, Schädelin, Sabine, van der Meer, Franziska, Weigel, Matthias, Galbusera, Riccardo, Mathias, Amandine, Lu, Po-Jui, Rahmanzadeh, Reza, Benkert, Pascal, La Rosa, Francesco, Bach Cuadra, Meritxell, Sati, Pascal, Théaudin, Marie, Pot, Caroline, Van Pesch, Vincent, Leppert, David, Stadelmann, Christine, Kappos, Ludwig, Du Pasquier, Renaud, Reich, Daniel S, Absinta, Martina, Granziera, Cristina, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie
Subjects: Adult, Inflammation, Male, axonal damage, Multiple Sclerosis, iron rim lesions, Middle Aged, Magnetic Resonance Imaging, Severity of Illness Index, White Matter, Axons, susceptibility, Axons/pathology, Female, Humans, Inflammation/blood, Inflammation/diagnostic imaging, Inflammation/pathology, Multiple Sclerosis/blood, Multiple Sclerosis/diagnostic imaging, Multiple Sclerosis/pathology, Multiple Sclerosis/physiopathology, Neurofilament Proteins/blood, White Matter/diagnostic imaging, White Matter/pathology, disability, Neurofilament Proteins, pathology, progression
Abstract: To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage. In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases. In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (β add , 16.3; 95% confidence interval [CI], 4.6-28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; β add , 30.4; 95% CI, 15.6-45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (β add , 1.1; 95% CI, 0.3-1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively). Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

15. 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.

16. Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

Author: Suzanne Hodgkinson, Patrizia Sola, Jose Luis Sanchez-Menoyo, Mark Slee, Vahid Shaygannejad, Alexandre Prat, Jeannette Lechner-Scott, Lukas Sobisek, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Csilla Rozsa, Guillermo Izquierdo, Helmut Butzkueven, Fraser Moore, Pamela A. McCombe, Maria Laura Saladino, Murat Terzi, Vilija Jokubaitis, Cavit Boz, Eugenio Pucci, Raed Alroughani, Shlomo Flechter, Pierre Grammond, Roberto Bergamaschi, G. Iuliano, Daniele Spitaleri, Francois Grand'Maison, Ali Manouchehrinia, Pierre Duquette, Tomas Kalincik, Marc Girard, Radek Ampapa, Michael Barnett, Jan Hillert, Freek Verheul, Maria Trojano, Franco Granella, Edgardo Cristiano, Maria Pia Amato, Dana Horakova, Alessandra Lugaresi, Celia Oreja-Guevara, Steve Vucic, Eva Havrdova, Tim Spelman, Javier Olascoaga, Kalincik, Toma, Manouchehrinia, Ali, Sobisek, Luka, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Grammond, Pierre, Sola, Patrizia, Hupperts, Raymond, Grand'Maison, Francoi, Pucci, Eugenio, Boz, Cavit, Alroughani, Raed, Van Pesch, Vincent, Lechner-scott, Jeannette, Terzi, Murat, Bergamaschi, Roberto, Iuliano, Gerardo, Granella, Franco, Spitaleri, Daniele, Shaygannejad, Vahid, Oreja-guevara, Celia, Slee, Mark, Ampapa, Radek, Verheul, Freek, Mccombe, Pamela, Olascoaga, Javier, Amato, Maria Pia, Vucic, Steve, Hodgkinson, Suzanne, Ramo-tello, Cristina, Flechter, Shlomo, Cristiano, Edgardo, Rozsa, Csilla, Moore, Fraser, Sanchez-menoyo, Jose Lui, Saladino, Maria Laura, Barnett, Michael, Hillert, Jan, Butzkueven, Helmut, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, OMÜ, [Kalincik, Tomas] Univ Melbourne, CORE, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Kalincik, Tomas] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Jokubaitis, Vilija] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Manouchehrinia, Ali] Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden, [Sobisek, Lukas] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Univ Econ Prague, Dept Stat & Probabil, Winston Churchill Sq 1938-4, Prague 13067, Czech Republic, [Jokubaitis, Vilija] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Trojano, Maria] Univ Bari, Via Calefati 53, I-70122 Bari, Italy, [Izquierdo, Guillermo] Hosp Univ Virgen Macarena, Amador De Los Rios 48-50 4a, Seville 41003, Spain, [Lugaresi, Alessandra] Univ G DAnnunzio, Dept Neurosci Imaging & Clin Sci, Via Vestini, I-66100 Chieti, Italy, [Lugaresi, Alessandra] Univ Bologna, Dept Biomed & Neuromotor Sci, Via Vestini, I-66100 Bologna, Italy, [Girard, Marc] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Prat, Alexandre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Duquette, Pierre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Girard, Marc] CHUM, Montreal, PQ, Canada, [Prat, Alexandre] CHUM, Montreal, PQ, Canada, [Duquette, Pierre] CHUM, Montreal, PQ, Canada, [Girard, Marc] Univ Montreal, Montreal, PQ, Canada, [Prat, Alexandre] Univ Montreal, Montreal, PQ, Canada, [Duquette, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Ctr Readaptat Deficience Phys Chaudiere Appalache, 9500 Blvd Ctr Hosp, Levis, AB G6X 0A1, Canada, [Sola, Patrizia] Nuovo Osped Civile St Agostino Estense, Via Giardini 1355, I-41100 Modena, Italy, [Hupperts, Raymond] Zuyderland Ziekenhuis, Walramstr 23, NL-6131 BK Sittard, Netherlands, [Grand'Maison, Francois] Neuro Rive Sud, 4896 Boul Taschereau,Suite 250, Greenfield Pk, PQ J4V 2J2, Canada, [Pucci, Eugenio] Azienda Sanitaria Unica Reg Marche AV3, Via Santa Lucia 2, I-62100 Macerata, Italy, [Boz, Cavit] Karadeniz Tech Univ, Farabi Hosp, Med Fac, TR-61080 Trabzon, Turkey, [Alroughani, Raed] Amiri Hosp, POB 1661, Kuwait 73767, Kuwait, [Van Pesch, Vincent] Clin Univ St Luc, Ave Hippocrate,10 UCL10-80, BXL-1200 Brussels, Belgium, [Lechner-Scott, Jeannette] Univ Newcastle, Lookout Rd, Newcastle, NSW 2305, Australia, [Terzi, Murat] Ondokuz Mayis Univ, Fac Med, TR-55160 Kurupelit, Turkey, [Bergamaschi, Roberto] C Mondino Natl Neurol Inst, Via Mondino 2, I-27100 Pavia, Italy, [Iuliano, Gerardo] Osped Riuniti Salerno, Via S Leonardo, I-84100 Salerno, Italy, [Granella, Franco] Univ Parma, Via Gramsci 14, I-43100 Parma, Italy, [Spitaleri, Daniele] Azienda Osped Rilievo Nazl San Giuseppe Moscati A, I-83100 Avellino, Italy, [Shaygannejad, Vahid] Isfahan Univ Med Sci, Soffeh St, Esfahan 81744, Iran, [Oreja-Guevara, Celia] Hosp Univ La Paz, Paseo Castellana 261, Madrid 28050, Spain, [Slee, Mark] Flinders Med Ctr, Flinders Dr, Adelaide, SA 5042, Australia, [Ampapa, Radek] Nemocnice Jihlava, Vrchlickeho 59, Jihlava 58633, Czech Republic, [Verheul, Freek] Groene Hart Ziekenhuis, Bleulandweg 10, NL-2800 BB Gouda, Netherlands, [McCombe, Pamela] Royal Brisbane & Womens Hosp, 33 North St, Spring Hill, Qld 4000, Australia, [Olascoaga, Javier] Hosp Donostia, Paseo Begiristain, San Sebastian 20014, Spain, [Amato, Maria Pia] Univ Florence, Viale Morgagni 85, I-50134 Florence, Italy, [Vucic, Steve] Westmead Hosp, Hawkesbury Rd, Sydney, NSW 2145, Australia, [Hodgkinson, Suzanne] Liverpool Hosp, Elizabeth St,21, Liverpool, SA, Australia, [Ramo-Tello, Cristina] Hosp Germans Trias i Pujol, Crtra Canyet S-N, Badalona 8916, Spain, [Flechter, Shlomo] Assaf Harofeh Med Ctr, IL-70100 Zerifin, Israel, [Cristiano, Edgardo] Hosp Italiano Buenos Aires, Guise 1870, RA-1425 Buenos Aires, DF, Argentina, [Rozsa, Csilla] Jahn Ferenc Teaching Hosp, Koves 1, H-1101 Budapest, Hungary, [Moore, Fraser] Jewish Gen Hosp, 3755 Cote St Catherine, Montreal, PQ J7A 4T8, Canada, [Luis Sanchez-Menoyo, Jose] Hosp Galdakao Usansolo, Barrio Labeaga S-N, Galdakao 48660, Spain, [Laura Saladino, Maria] INEBA Inst Neurosci Buenos Aires, Guardia Vieja 4435,C1192AAW, Buenos Aires, DF, Argentina, [Hillert, Jan] Univ Sydney, Brain & Mind Ctr, 100 Mallett, Camperdown, NSW 2050, Australia, [Butzkueven, Helmut] Monash Univ, Box Hill Hosp, Dept Neurol, Melbourne, Vic, Australia, National Health and Medical Research Council, National Health and Medical Research Council (centre for research excellence), University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), Biogen, Novartis, Merck, Roche, Teva, Sanofi Genzyme, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience
Subjects: Male, 0301 basic medicine, relapses, Databases, Factual, Failure, disability, multiple sclerosis, precision medicine, prediction, Disability Evaluation, Glatiramer acetate, 0302 clinical medicine, Natalizumab, Recurrence, Risk Factors, Medicine, Relapse, Progression, Precision medicine, Switch, Prognosis, Clinical Trial, Fingolimod, Multicenter Study, Treatment Outcome, Cohort, Disease Progression, Female, Algorithms, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, Registry, medicine.medical_specialty, Multiple Sclerosis, Interferon-beta therapy, External validity, Disability, Multiple sclerosis, Prediction, Relapses, Neurology (clinical), Databases, Young Adult, 03 medical and health sciences, Internal medicine, Journal Article, Humans, Multiple sclerosi, Internal validity, Factual, Disease burden, Demography, business.industry, Prognostic-factors, Reproducibility of Results, Discontinuation, 030104 developmental biology, Physical therapy, business, 030217 neurology & neurosurgery, Forecasting
Abstract: none 47 si Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. none Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut
Published: 2017

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

Author: Sifat Sharmin, Francesca Bovis, Charles Malpas, Dana Horakova, Eva Kubala Havrdova, Guillermo Izquierdo, Sara Eichau, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Murat Terzi, Oliver Gerlach, Raed Alroughani, Cavit Boz, Vahid Shaygannejad, Vincent van Pesch, Elisabetta Cartechini, Ludwig Kappos, Jeannette Lechner‐Scott, Roberto Bergamaschi, Recai Turkoglu, Claudio Solaro, Gerardo Iuliano, Franco Granella, Bart Van Wijmeersch, Daniele Spitaleri, Mark Slee, Pamela McCombe, Julie Prevost, Radek Ampapa, Serkan Ozakbas, Jose Luis Sanchez‐Menoyo, Aysun Soysal, Steve Vucic, Thor Petersen, Koen de Gans, Ernest Butler, Suzanne Hodgkinson, Youssef Sidhom, Riadh Gouider, Edgardo Cristiano, Tamara Castillo‐Triviño, Maria Laura Saladino, Michael Barnett, Fraser Moore, Csilla Rozsa, Bassem Yamout, Olga Skibina, Anneke van der Walt, Katherine Buzzard, Orla Gray, Stella Hughes, Angel Perez Sempere, Bhim Singhal, Yara Fragoso, Cameron Shaw, Allan Kermode, Bruce Taylor, Magdolna Simo, Neil Shuey, Talal Al‐Harbi, Richard Macdonell, Jose Andres Dominguez, Tunde Csepany, Carmen Adella Sirbu, Maria Pia Sormani, Helmut Butzkueven, Tomas Kalincik, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Sirbu, Carmen Adella/0000-0002-1982-1066, Malpas, Charles/0000-0003-0534-3718, Sharmin, Sifat, Bovis, Francesca, Malpas, Charle, Horakova, Dana, Havrdova, Eva Kubala, Izquierdo, Guillermo, Eichau, Sara, Trojano, Maria, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Onofrj, Marco, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Terzi, Murat, Gerlach, Oliver, Alroughani, Raed, Boz, Cavit, Shaygannejad, Vahid, van Pesch, Vincent, Cartechini, Elisabetta, Kappos, Ludwig, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Turkoglu, Recai, Solaro, Claudio, Iuliano, Gerardo, Granella, Franco, Van Wijmeersch, Bart, Spitaleri, Daniele, Slee, Mark, McCombe, Pamela, Prevost, Julie, Ampapa, Radek, Ozakbas, Serkan, Sanchez-Menoyo, Jose Lui, Soysal, Aysun, Vucic, Steve, Petersen, Thor, de Gans, Koen, Butler, Ernest, Hodgkinson, Suzanne, Sidhom, Youssef, Gouider, Riadh, Cristiano, Edgardo, Castillo-Triviño, Tamara, Saladino, Maria Laura, Barnett, Michael, Moore, Fraser, Rozsa, Csilla, Yamout, Bassem, Skibina, Olga, van der Walt, Anneke, Buzzard, Katherine, Gray, Orla, Hughes, Stella, Sempere, Angel Perez, Singhal, Bhim, Fragoso, Yara, Shaw, Cameron, Kermode, Allan, Taylor, Bruce, Simo, Magdolna, Shuey, Neil, Al-Harbi, Talal, Macdonell, Richard, Dominguez, Jose Andre, Csepany, Tunde, Sirbu, Carmen Adella, Sormani, Maria Pia, Butzkueven, Helmut, and Kalincik, Tomas
Subjects: Male, risk scoring, sustained disability progression, Multiple Sclerosis, CLARITY, clinical trial, functional system impairment, Cohort Studies, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Neurology, Disease Progression, Cladribine, Humans, Female, Neurology (clinical), Randomized Controlled Trials as Topic
Abstract: Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries
Published: 2022

18. Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study

Author: Steven Jacobson, Tianxia Wu, Avindra Nath, Pascal Sati, Vincent Van Pesch, Daniel S. Reich, Marie Théaudin, Irene Cortese, Caroline Pot, Massimo Filippi, Vittorio Martinelli, Peter A. Calabresi, Renaud Du Pasquier, M. Absinta, Pietro Maggi, Govind Nair, Roberta Scotti, Gaetano Perrotta, Bryan Smith, Joan Ohayon, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Maggi, Pietro, Sati, Pascal, Nair, Govind, Cortese, Irene C M, Jacobson, Steven, Smith, Bryan R, Nath, Avindra, Ohayon, Joan, van Pesch, Vincent, Perrotta, Gaetano, Pot, Caroline, Théaudin, Marie, Martinelli, Vittorio, Scotti, Roberta, Wu, Tianxia, Du Pasquier, Renaud, Calabresi, Peter A, Filippi, Massimo, Reich, Daniel S, and Absinta, Martina
Subjects: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Multiple Sclerosis, Neuroimaging, Sensitivity and Specificity, Article, Diagnosis, Differential, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Prevalence, medicine, Humans, Diagnostic biomarker, Aged, Retrospective Studies, medicine.diagnostic_test, Chronic Active, business.industry, Multiple sclerosis, Magnetic resonance imaging, Middle Aged, medicine.disease, Clinical disease, Magnetic Resonance Imaging, Hyperintensity, 030104 developmental biology, Neurology, Female, Neurology (clinical), Nervous System Diseases, Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract: In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.
Published: 2020

19. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author: Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P
Published: 2020

20. Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study

Author: Cristina Ramo-Tello, Vilija Jokubaitis, Raed Alroughani, Pamela A. McCombe, Pierre Duquette, Mark Slee, Steve Vucic, Jeannette Lechner-Scott, Olga Skibina, Klaus Gregaard Madsen, Anneke van der Walt, Pierre Grammond, Eva Havrdova, Radek Ampapa, Freek Verheul, José Luis Sánchez Menoyo, Guillermo Izquierdo, Francois Grand'Maison, Vincent Van Pesch, Murat Terzi, Alexandre Prat, Recai Turkoglu, Aysun Soysal, Eugenio Pucci, Cameron Shaw, Tomas Kalincik, Claudio Solaro, Marc Girard, Kerisha Naidoo, Patrizia Sola, Alessandra Lugaresi, Cavit Boz, Julie Prevost, Daniele Spitaleri, Ai Lan Nguyen, Dana Horakova, Javier Olascoaga, Celia Oreja-Guevara, Diana Ferraro, Michael Barnett, Helmut Butzkueven, Maria Trojano, Franco Granella, Robert Hyde, Suzanne Hodgkinson, OMÜ, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Nguyen, Ai-Lan, Havrdova, Eva Kubala, Horakova, Dana, Izquierdo, Guillermo, Kalincik, Toma, van der Walt, Anneke, Terzi, Murat, Alroughani, Raed, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Boz, Cavit, Sola, Patrizia, Ferraro, Diana, Lugaresi, Alessandra, Lechner-Scott, Jeannette, Barnett, Michael, Grand'Maison, Francoi, Grammond, Pierre, Ramo-Tello, Cristina, Turkoglu, Recai, McCombe, Pamela, Pucci, Eugenio, Trojano, Maria, Granella, Franco, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Oreja-Guevara, Celia, Verheul, Freek, Vucic, Steve, Hodgkinson, Suzanne, Slee, Mark, Ampapa, Radek, Prevost, Julie, Menoyo, Jose Luis Sanchez, Skibina, Olga, Solaro, Claudio, Olascoaga, Javier, Shaw, Cameron, Madsen, Klaus Gregaard, Naidoo, Kerisha, Hyde, Robert, Butzkueven, Helmut, and Jokubaitis, Vilija
Subjects: Adult, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Population, Exposure therapy, Clinical Neurology, Outcomes, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, symbols.namesake, Young Adult, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Pregnancy, medicine, Humans, Immunologic Factors, Multiple sclerosi, 030212 general & internal medicine, Poisson regression, Registries, Young adult, education, Outcome, Retrospective Studies, education.field_of_study, Obstetrics, business.industry, Incidence (epidemiology), Incidence, Pregnancy Outcome, Retrospective cohort study, General Medicine, medicine.disease, Pregnancy Complications, Neurology, symbols, Female, Neurology (clinical), Therapy, business, 030217 neurology & neurosurgery, Cohort study, Follow-Up Studies
Abstract: Turkoglu, Recai/0000-0001-9724-851X; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Ramo-Tello, Cristina/0000-0001-8643-5053; Vucic, Steve/0000-0002-8323-873X; Nguyen, Ai-Lan/0000-0003-0378-6005; Kalincik, Tomas/0000-0003-3778-1376; van Pesch, Vincent/0000-0003-2885-9004; Skibina, Olga/0000-0002-6275-8138; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453 WOS: 000459833100045 PubMed: 30623864 Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RAMS) may be increasing. Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RAMS. Methods: We identified all women with RAMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed. Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births. Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month. National Health and Medical Research Council of Australia centre for research excellence grant [1001216]; BiogenBiogen; MerckMerck & Company; NovartisNovartis; RocheRoche Holding; Sanofi-Genzyme This study was financially supported by a National Health and Medical Research Council of Australia centre for research excellence grant [1001216]. The MSBase Foundation is a not-for-profit organisation that receives support from Biogen, Merck, Novartis, Roche and Sanofi-Genzyme. The study was conducted separately and apart from the guidance of the sponsors.
Published: 2019

21. Contribution of different relapse phenotypes to disability in multiple sclerosis

Author: Tamasine Stewart, Erik van Munster, Mark Slee, Patrizia Sola, Eva Havrdova, Dana Horakova, Orla Gray, Helmut Butzkueven, Cameron Shaw, Eugenio Pucci, Michael Barnett, Csilla Rozsa, Pamelo McCombe, Vincent Van Pesch, Maria Trojano, Franco Granella, Bhim Singhal, Fraser Moore, Javier Olascoaga, Neil Shuey, Pierre Duquette, Christina Ramo, Tomas Kalincik, Marc Girard, Freek Verheul, José Luis Sánchez Menoyo, Edgardo Cristiano, Pierre Grammond, Julie Prevost, Guillermo Izquierdo, Tim Spelman, Tatjana Petkovska-Boskova, Francois Grand'Maison, Celia Oreja-Guevara, Vahid Shaygannejad, Maria Laura Saladino, Suzanne Hodgkinson, Allan G. Kermode, Norma Deri, Alexandre Prat, Raymond Hupperts, Bruce V. Taylor, Gerardo Iuliano, Daniele Spitaleri, Cavit Boz, Roberto Bergamaschi, Raed Alroughani, Radek Ampapa, Vilija Jokubaitis, Jeannette Lechner-Scott, Maria Pia Amato, Olga Skibina, Alessandra Lugaresi, Steve Vucic, Ilya Kister, Stewart, Tamasine, Spelman, Tim, Havrdova, Eva, Horakova, Dana, Trojano, Maria, Izquierdo, Guillermo, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Sola, Patrizia, Shaygannejad, Vahid, Hupperts, Raymond, Alroughani, Raed, Oreja-Guevara, Celia, Pucci, Eugenio, Boz, Cavit, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Van Pesch, Vincent, Iuliano, Gerardo, Ramo, Cristina, Taylor, Bruce, Slee, Mark, Spitaleri, Daniele, Granella, Franco, Verheul, Freek, Mccombe, Pamela, Hodgkinson, Suzanne, Amato, Maria Pia, Vucic, Steve, Gray, Orla, Cristiano, Edgardo, Barnett, Michael, Sanchez Menoyo, Jose Lui, van Munster, Erik, Saladino, Maria Laura, Olascoaga, Javier, Prevost, Julie, Deri, Norma, Shaw, Cameron, Singhal, Bhim, Moore, Fraser, Rozsa, Csilla, Shuey, Neil, Skibina, Olga, Kister, Ilya, Petkovska-Boskova, Tatjana, Ampapa, Radek, Kermode, Allan, Butzkueven, Helmut, Jokubaitis, Vilija, Kalincik, Toma, and MSBase Study Group
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Multiple Sclerosis, Prognosi, multiple sclerosis, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, cohort studies, Recurrence, Internal medicine, medicine, Humans, Disabled Persons, Prospective Studies, Prospective cohort study, Expanded Disability Status Scale, business.industry, Incidence (epidemiology), Multiple sclerosis, Interferon-beta, Middle Aged, Prognosis, medicine.disease, Functional system, Phenotype, Confidence interval, relapse phenotype, 030104 developmental biology, Neurology, multiple sclerosi, Chronic Disease, Disease Progression, Physical therapy, Female, observational study, outcome research, Neurology (clinical), business, 030217 neurology & neurosurgery, cohort studie, Cohort study
Abstract: Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.
Published: 2016

22. Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in multiple sclerosis

Author: Francois Grand'Maison, Raed Alroughani, Jeannette Lechner-Scott, Vincent Van Pesch, Michael Barnett, Maria Trojano, Franco Granella, Raymond Hupperts, Cavit Boz, Jose Luis Sanchez-Menoyo, Daniele Spitaleri, Eugenio Pucci, Patrizia Sola, Pierre Grammond, Pierre Duquette, Tomas Kalincik, Helmut Butzkueven, Marc Girard, Steve Vucic, Tim Spelman, Guillermo Izquierdo, Alessandra Lugaresi, Myintzu Min, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Min, Myintzu, Spelman, Tim, Lugaresi, Alessandra, Boz, Cavit, Spitaleri, Daniele LA, Pucci, Eugenio, Grand'Maison, Francoi, Granella, Franco, Izquierdo, Guillermo, Butzkueven, Helmut, Sanchez-Menoyo, Jose Lui, Barnett, Michael, Girard, Marc, Trojano, Maria, Grammond, Pierre, Duquette, Pierre, Sola, Patrizia, Alroughani, Raed, Hupperts, Raymond, Vucic, Steve, Kalincik, Toma, Van Pesch, Vincent, and Lechner-Scott, Jeannette
Subjects: Adult, Male, medicine.medical_specialty, Treatment response, Databases, Factual, Mri imaging, Clinical Decision-Making, Drug Substitution, subclinical lesions, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, medicine, Humans, Disease-modifying therapy, magnetic resonance imaging, 030212 general & internal medicine, medicine.diagnostic_test, business.industry, Multiple sclerosis, Brain, Magnetic resonance imaging, Middle Aged, medicine.disease, Clinical neurology, Neurology, Current practice, Female, Neurology (clinical), Treatment decision making, Radiology, business, 030217 neurology & neurosurgery
Abstract: Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.
Published: 2018

23. Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis

Author: Raed Alroughani, Maria Pia Amato, Patrizia Sola, Francois Grand'Maison, Eva Havrdova, Pierre Grammond, Ricardo Fernandez Bolanos, Murat Terzi, Bhim Singhal, Tomas Kalincik, Alessandra Lugaresi, Marc Girard, Jeannette Lechner-Scott, Dana Horakova, Freek Verheul, Alexandre Prat, Thor Petersen, Vahid Shaygannejad, Raymond Hupperts, Vilija Jokubaitis, Guillermo Izquierdo, Daniele Spitaleri, Jose Luis Sanchez-Menoyo, Maria Trojano, Franco Granella, Helmut Butzkueven, Mark Slee, Seyed Aidin Sajedi, Cavit Boz, Maria Pia Sormani, Pierre Duquette, Cristina Ramo, Eugenio Pucci, Alessio Signori, Celia Oreja-Guevara, Roberto Bergamaschi, Nastaran Majdinasab, Vincent Van Pesch, Bruce V. Taylor, Stella Hughes, Gerardo Iuliano, Maria Edite Rio, Ondokuz Mayıs Üniversitesi, Signori, Alessio, Izquierdo, Guillermo, Lugaresi, Alessandra, Hupperts, Raymond, Grand'Maison, Francoi, Sola, Patrizia, Horakova, Dana, Havrdova, Eva, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Boz, Cavit, Grammond, Pierre, Terzi, Murat, Singhal, Bhim, Alroughani, Raed, Petersen, Thor, Ramo, Cristina, Oreja-Guevara, Celia, Spitaleri, Daniele, Shaygannejad, Vahid, Butzkueven, Helmut, Kalincik, Toma, Jokubaitis, Vilija, Slee, Mark, Fernandez Bolaños, Ricardo, Sanchez-Menoyo, Jose Lui, Pucci, Eugenio, Granella, Franco, Lechner-Scott, Jeannette, Iuliano, Gerardo, Hughes, Stella, Bergamaschi, Roberto, Taylor, Bruce, Verheul, Freek, Edite Rio, Maria, Amato, Maria Pia, Sajedi, Seyed Aidin, Majdinasab, Nastaran, Van Pesch, Vincent, Sormani, Maria Pia, and Trojano, Maria
Subjects: 0301 basic medicine, Male, Pediatrics, Delayed Diagnosis, Placebo-controlled study, Disease, Disability Evaluation, Primary progressive multiple sclerosis, 0302 clinical medicine, Longitudinal Studies, Prospective Studies, Registries, Prospective cohort study, Age Factors, clinical trial, Middle Aged, Multiple Sclerosis, Chronic Progressive, Prognosis, Latent class model, Natural history, Neurology, Latent Class Analysis, Disease Progression, Female, Adult, medicine.medical_specialty, Primary Progressive Multiple Sclerosis, 03 medical and health sciences, Primary progressive multiple sclerosis, clinical trials, disability, heterogeneity, long-term, trajectories, Sex Factors, medicine, Humans, Disabled Persons, long-term, clinical trials, business.industry, Multiple sclerosis, Bayes Theorem, Long term disability, medicine.disease, Primary progressive multiple sclerosi, 030104 developmental biology, disability, Physical therapy, Neurology (clinical), heterogeneity, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Signori, Alessio/0000-0001-6289-9144; Sajedi, Seyed Aidin/0000-0002-6704-9787; Jokubaitis, Vilija G./0000-0002-3942-4340; Shaygannejad, Vahid/0000-0002-6226-0161; Oreja-Guevara, Celia/0000-0002-9221-5716; amato, Maria Pia/0000-0003-3325-3760; Lugaresi, Alessandra/0000-0003-2902-5589; Majdinasab, Nastaran/0000-0001-5163-7210; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Petersen, Thor/0000-0001-5633-2600; Prat, Alexandre/0000-0001-6188-0580; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Slee, Mark/0000-0003-4323-2453; SORMANI, MARIA PIA/0000-0001-6892-104X; Trojano, Maria/0000-0002-6329-8946 WOS: 000432098100013 PubMed: 28382837 Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild (n = 143; 16.8%), moderate (n = 378; 44.3%), or severe (n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis. MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.
Published: 2017

24. 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

25. Defining reliable disability outcomes in multiple sclerosis

Author: Jose Luis Sanchez-Menoyo, Cristina Ramo, Ricardo Fernandez-Bolanos, Tim Spelman, Jeannette Lechner-Scott, Alexandre Prat, Dana Horakova, Mark Slee, Gerardo Iuliano, Raymond Hupperts, Alessandra Lugaresi, Eugenio Pucci, Daniele Spitaleri, Vincent Van Pesch, Celia Oreja-Guevara, Raed Alroughani, Pierre Grammond, Pierre Duquette, Eva Havrdova, Vilija Jokubaitis, Marcela Fiol, Francois Grand'Maison, Gary Cutter, Roberto Bergamaschi, Cavit Boz, Murat Terzi, Freek Verheul, Orla Gray, Tomas Kalincik, Marc Girard, Edgardo Cristiano, Michael Barnett, Maria Trojano, Guillermo Izquierdo, Helmut Butzkueven, Jose Antonio Cabrera-Gomez, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, OMÜ, Kalincik, Toma, Cutter, Gary, Spelman, Tim, Jokubaitis, Vilija, Havrdova, Eva, Horakova, Dana, Trojano, Maria, Izquierdo, Guillermo, Girard, Marc, Duquette, Pierre, Prat, Alexandre, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Hupperts, Raymond, Oreja-Guevara, Celia, Boz, Cavit, Pucci, Eugenio, Bergamaschi, Roberto, Lechner-Scott, Jeannette, Alroughani, Raed, Van Pesch, Vincent, Iuliano, Gerardo, Fernandez-Bolaños, Ricardo, Ramo, Cristina, Terzi, Murat, Slee, Mark, Spitaleri, Daniele, Verheul, Freek, Cristiano, Edgardo, Sánchez-Menoyo, José Lui, Fiol, Marcela, Gray, Orla, Cabrera-Gomez, Jose Antonio, Barnett, Michael, and Butzkueven, Helmut
Subjects: Adult, Male, Registrie, medicine.medical_specialty, Concordance, Longitudinal Studie, Disease, Cohort Studies, Outcome Assessment (Health Care), Disability Evaluation, outcome measures, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, Age Factor, Longitudinal Studies, Registries, relapse, Expanded Disability Status Scale, outcome measure, business.industry, Medicine (all), Multiple sclerosis, Age Factors, clinical trial, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Clinical trial, Clinical research, disability, Disease Progression, Physical therapy, Population study, Female, prognosis, Neurology (clinical), Cohort Studie, business, prognosi, Human, Cohort study
Abstract: Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453; Horakova, Dana/0000-0003-1915-0036; Havrdova, Eva Kubala/0000-0002-9543-4359; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Prat, Alexandre/0000-0001-6188-0580; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; pucci, eugenio/0000-0001-7606-7330; van Pesch, Vincent/0000-0003-2885-9004; Trojano, Maria/0000-0002-6329-8946 WOS: 000365135700024 PubMed: 26359291 Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events. NHMRC Early Career FellowshipNational Health and Medical Research Council of Australia [1071124]; NHMRC Practitioner FellowshipNational Health and Medical Research Council of Australia [1080518]; NHMRCNational Health and Medical Research Council of Australia [1083539, 1032484]; NHMRC Centre for Research ExcellenceNational Health and Medical Research Council of Australia [1001216]; MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer-ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The work was supported by the NHMRC Early Career Fellowship (1071124), NHMRC Practitioner Fellowship (1080518), NHMRC Project Grants (1083539 and 1032484), NHMRC Centre for Research Excellence (Grant ID 1001216) and the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer-Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.

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25 results on '"van Pesch, Vincent"'

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

2. Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS

3. Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study

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

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

6. Long-term outcomes in patients presenting with optic neuritis: Analyses of the MSBase registry

7. Quantifying risk of early relapse in patients with first demyelinating events: Prediction in clinical practice

8. Prognostic indicators in pediatric clinically isolated syndrome

9. Predictors of long-term disability accrual in relapse-onset multiple sclerosis

10. The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis

11. Predictors of long-term disability accrual in relapse-onset multiple sclerosis

12. Seasonal variation of relapse rate in multiple sclerosis is latitude dependent

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

14. Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis

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

16. Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

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

18. Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study

19. Ofatumumab versus Teriflunomide in Multiple Sclerosis

20. Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study

21. Contribution of different relapse phenotypes to disability in multiple sclerosis

22. Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in multiple sclerosis

23. Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis

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

25. Defining reliable disability outcomes in multiple sclerosis

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