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1. Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Author

Restuadi, Restuadi, Steyn, Frederik J, Kabashi, Edor, Ngo, Shyuan T, Cheng, Fei-Fei, Nabais, Marta F, Thompson, Mike J, Qi, Ting, Wu, Yang, Henders, Anjali K, Wallace, Leanne, Bye, Chris R, Turner, Bradley J, Ziser, Laura, Mathers, Susan, McCombe, Pamela A, Needham, Merrilee, Schultz, David, Kiernan, Matthew C, van Rheenen, Wouter, van den Berg, Leonard H, Veldink, Jan H, Ophoff, Roel, Gusev, Alexander, Zaitlen, Noah, McRae, Allan F, Henderson, Robert D, Wray, Naomi R, Giacomotto, Jean, and Garton, Fleur C

Subjects
Biological Sciences, Genetics, Rare Diseases, Neurosciences, Neurodegenerative, Biotechnology, Human Genome, Brain Disorders, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Animals, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neurodegenerative Diseases, Polymorphism, Single Nucleotide, Zebrafish, Motor neurone disease, MND, Genome-wide association study, Computational biology, Neurodegenerative diseases, Quantitative trait loci, Genes, Regulator, Disease progression, Clinical Sciences
Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.MethodsThe Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).ResultsSMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

Published
2022

2. 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

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

Author

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

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

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

Published
2023

4. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS

Author

Hop, Paul J., Zwamborn, Ramona A. J., Hannon, Eilis, Shireby, Gemma L., Nabais, Marta F., Walker, Emma M., van Rheenen, Wouter, van Vugt, Joke J. F. A., Dekker, Annelot M., Westeneng, Henk-Jan, Tazelaar, Gijs H. P., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, Andre G., van Eijk, Kristel R., van Meurs, Joyce, Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, Moisse, Matthieu, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., Jansen, Rick, van ‘t Hof, Peter, Deelen, Patrick, Nooren, Irene, t Hoen, Peter A. C., Heijmans, Bastiaan T., Moed, Matthijs, Baird, Denis, Franke, Lude, Vermaat, Martijn, Luijk, Rene, Jan Bonder, Marc, van Dijk, Freerk, Arindrarto, Wibowo, Al Khleifat, Ahmad, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik W., Al-Chalabi, Ammar, Wray, Naomi R., Bensimon, Gilbert, Hardiman, Orla, Iacoangeli, Alfredo, Chio, Adriano, Smith, George Davey, Mill, Jonathan, Ticozzi, Nicola, Ratti, Antonia, Cooper-Knock, Jonathan, Morrison, Karen E., Shaw, Pamela J., Basak, A. Nazli, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Canosa, Antonio, Brunetti, Maura, Grassano, Maurizio, Gotkine, Marc, Lerner, Yossef, Zabari, Michal, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Mora Pardina, Jesus S., Salas, Teresa, Dion, Patrick, Ross, Jay P., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Nicholson, Garth, Rowe, Dominic B., Pamphlett, Roger, Mather, Karen A., Sachdev, Perminder S., Furlong, Sarah, Garton, Fleur C., Henders, Anjali K., Lin, Tian, Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Williams, Kelly L., Neto, Miguel Mitne, Cauchi, Ruben J., Blair, Ian P., Kiernan, Matthew C., Drory, Vivian, Povedano, Monica, Carvalho, Mamede, Pinto, Susana, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Landers, John E., Shaw, Christopher E., Andersen, Peter M., McRae, Allan F., van Es, Michael A., Pasterkamp, R. Jeroen, McLaughlin, Russell L., Kenna, Kevin P., Tsai, Ellen, Runz, Heiko, Van Damme, Philip, Boomsma, Dorret I., Pool, Rene, van Dongen, Jenny, Hottenga, Joukje J., van Greevenbroek, Marleen M. J., Stehouwer, Coen D.A., van der Kallen, Carla J.H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Sasha, Tigchelaar, Ettje F., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Laboratory Medicine, APH - Mental Health, Internal Medicine, Epidemiology, and Repositório da Universidade de Lisboa

Subjects
Cholesterol, Amyotrophic Lateral Sclerosis, Humans, Neurodegenerative Diseases, General Medicine, DNA Methylation, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Article, Epigenesis, Genetic, Genome-Wide Association Study
Abstract

Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works., Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions., The research reported in this publication was supported by grants from The Dutch Research Council (NWO) (VENI scheme grant 09150161810018 to W.v.R.) and Prinses Beatrix Spierfond (neuromuscular fellowship grant W.F19-03 to W.v.R.), The Prinses Beatrix Spierfonds (W.OR20-08 to J.J.F.A.v.V. and J.H.V.), The Canadian Institutes of Health Research (FRN 159279 to J.P.R.), The Dutch Research Council (NWO) (VIDI grant 91719350 to K.P.K.), The European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL to J.H.V.), the Swedish Brain Foundation (grant nos. 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2018-0310, and 2020-0353 to P.M.A.), the Swedish Research Council (grant nos. 2012-3167 and 2017-03100 to P.M.A.), the Knut and Alice Wallenberg Foundation (grant nos. 2012.0091, 2014.0305, and 2020.0232 to P.M.A.), the Ulla-Carin Lindquist Foundation and the Västerbotten County Council (grant no. 56103-7002829 to P.M.A.), and King Gustaf V’s and Queen Victoria’s Freemason’s Foundation. This is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND (www.jpnd.eu) [United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)] and through the Motor Neurone Disease Association (MNDA). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. A.A.-C. is supported by an NIHR Senior Investigator Award. Samples used in this research were entirely/in part obtained from the U.K. National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. R.J.P. is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (BRAINSCAPES). G.L.S. was supported by a PhD studentship from the Alzheimer’s Society. S.T.N. acknowledges support through a FightMND Mid-Career Fellowship. V.S. is supported by the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. A.A.K. is funded by the MNDA and NIHR Maudsley Biomedical Research Centre. D.B., E.T., and H.R. are employees of Biogen. L.H.v.d.B. reports grants from the Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community’s Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR) to L.H.v.d.B.], and grants from The Netherlands Organization for Health Research and Development (the STRENGTH project, funded through the EU Joint Programme–Neurodegenerative Disease Research, JPND), during the conduct of the study. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium, and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België, and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek”, and the “Valéry Perrier Race against ALS Fund”. This work was supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405 to A. Chiò), the Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research (grant 2017SNW5MB to A. Chiò); the European Commission’s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867 to A. Chiò), and the Joint Programme–Neurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects), granted by Italian Ministry of Education, University, and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the “Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy. We acknowledge funding from the Australian National Health and Medical Research (NHMRC) Council: 1151854, 1083187, 1173790, 1078901, 1113400, 1095215, and 1176913 Enabling Grant #402703 to N.R.W. Additional funding was provided by the Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant for the SALSA-SGC consortium. The OATS (used for controls) was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the Australian NHMRC Council (NHMRC 1079102 to N.R.W.). Funding for this study was awarded by the (NHMRC)/Australian Research Council Strategic Award (grant 401162 to N.R.W.) and NHMRC grants (1405325, 1024224, 1025243, 1045325, 1085606, 568969, and 1093083 to N.R.W.). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was supported by the ALS Foundation Netherlands. This work was sponsored by NWO Domain Science for the use of the national computer facilities. A.N.B. is grateful to the Suna and Inan Kirac Foundation and Koc University for the excellent research environment created and for financial support. G.A.R. is supported by the Canadian Institutes of Health. Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases EURO-NMD. French ALS patients of the Pitié-Salpêtrière hospital (Paris) have been collected with ARSla funding support.

Published
2022

5. 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

6. 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

7. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

Rheenen, Wouter van, Spek, Rick A. A. van der, Bakker, Mark K., Vugt, Joke J. F. A. van, Hop, Paul J., Zwamborn, Ramona A. J., Klein, Niek de, Westra, Harm Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Needham, Merrilee, Ceroni, Mauro, Simoncini, Costanza, Gagliardi, Stella, Corrado, Lucia, Garton, Fleur C., Mazzini, Letizia, Westeneng, Henk Jan, Ross, Jay P., Valluzzi, Francesco, Aguggia, Marco, Raggi, Flavia, Rini, Augusto, Traynor, Bryan J., Singleton, Andrew B., Ngo, Shyuan T., Corcia, Philippe, Olsen, Catherine M., Hofman, Albert, Van Eijk, Kristel R., Pasterkamp, R. Jeroen, Tittmann, Lukas, Iacoangeli, Alfredo, Mitne Neto, Miguel, Sproviero, Daisy, Cauchi, Ruben J., Ophoff, Roel A., Wiedau Pazos, Martina, Lomen-Hoerth, Catherine, Deerlin, Vivianna M. van, Nicholson, Garth A., Brylev, Lev, Whiteman, David C., Grosskreutz, Julian, Fan, Dongsheng, Couratier, Philippe, Roediger, Annekathrin, Gaur, Nayana, D’alfonso, Sandra, Uitterlinden, André G., Pamphlett, Roger, Fominykh, Vera, Byrne, Ross P., Lieb, Wolfgang, Iazzolino, Barbara, Dekker, Annelot M., Slap Consortium, Demeshonok, Vera, Millecamps, Stéphanie, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Franke, Andre, Mcrae, Allan F., Rowe, Dominic B., Peotta, Laura, Cooper-Knock, Johnathan, Glavač, Damjan, Doherty, Mark, Rietschel, Marcella, Stević, Zorica, Drory, Vivian, Meininger, Vincent, Zarrelli, Michele, Povedano, Monica, Gaunt, Tom R., Steyn, Frederik J., Williams, Kelly L., Smith, Bradley N., Cugnasco, Paolo, Papurello, Diego Maria, Nozzoli, Cecilia, Sorarù, Gianni, Mather, Karen A., Ripke, Stephan, Nöthen, Markus M., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, Carvalho, Mamede de, Gromicho, Marta, Pinto, Susana, Marco, Giovanni de, Al Khleifat, Ahmad, Eberle, Michael A., Braun, Alice, Gusmaroli, Graziano, Siciliano, Gabriele, Petri, Susanne, Breen, Gerome, Weber, Markus, Rouleau, Guy A., Rojas García, Ricardo, Silani, Vincenzo, Amouyel, Philippe, Ghiglione, Paolo, Davey Smith, George, Curtis, Charles J., Shatunov, Aleksey, Mill, Jonathan, Mclaughlin, Russell L., Filosto, Massimiliano, Comi, Cristoforo, Gerfo, Annalisa lo, Ferlini, Alessandra, Riva, Nilo, Mora Pardina, Jesus S., Chiveri, Luca, Hardiman, Orla, Torrieri, Maria Claudia, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Padovani, Alessandro, Chandran, Siddharthan, Al Chalabi, Ammar, Assialioui, Abdelilah, Labate, Carmelo, Damme, Philip van, Ticozzi, Nicola, Palumbo, Francesca, Inghilleri, Maurizio, Chiò, Adriano, Pal, Suvankar, Lunetta, Christian, Jörk, Alexander, Cichon, Sven, Kraft, Julia, Morrison, Karen E., Ruiz, Luigi, Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Dion, Patrick A., Calvo, Andrea, Kooyman, Maarten, Başak, Nazli, Gerardi, Francesca, Simone, Isabella L., Kooi, Anneke J. van der, Ratti, Antonia, Ferrandi, Delfina, Fogh, Isabella, Ludolph, Albert C., Moglia, Cristina, Brunetti, Maura, Diamanti, Luca, Barthel, Tabea, Blair, Ian P., Es, Michael A. van, Gallone, Salvatore, Canosa, Antonio, Guerra, Vito, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Ferrarese, Carlo, Nefussy, Beatrice, Theele, Erik, Rinaldi, Fabrizio, Weishaupt, Jochen H., Kiernan, Matthew C., Barberis, Marco, Osmanovic, Alma, Baloh, Robert H., Nordin, Angelica, Lerner, Yossef, Vito, Nicoletta di, Zabari, Michal, Zoccolella, Stefano, Heverin, Mark, Gotkine, Marc, Guaita, Maria Cristina, Brenner, David, Freischmidt, Axel, Sbaiz, Luca, Benyamin, Beben, Glass, Jonathan D., Landers, John E., Tazelaar, Gijs H. P., Rota, Eugenia, Bensimon, Gilbert, Ilse, Benjamin, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Gentile, Salvatore, Moisse, Matthieu, Topp, Simon, Henderson, Robert D., Rademakers, Rosa, Perrone, Patrizia, Stubendorff, Beatrice, Brown, Robert H., Restuadi, Restuadi, Tremolizzo, Lucio, Mundi, Ciro, Berg, Leonard H. van den, Passarella, Bruno, Delodovici, Maria Luisa, Furlong, Sarah, Bono, Giorgio, Manera, Umberto, Vasta, Rosario, Bombaci, Alessandro, Meineri, Piero, Mauro, Alessandro, Hannon, Eilis, Casale, Federico, Leone, Maurizio, Shaw, Christopher E., Fuda, Giuseppe, Salamone, Paolina, Mathers, Susan, Baird, Denis, Launaro, Nicola, Marchi, Fabiola de, Veldink, Jan H., Gellera, Cinzia, Salachas, François, Witte, Otto W., Andersen, Peter M., Bertolotto, Antonio, Gionco, Maurizio, Leotta, Daniela, Odddenino, Enrico, Slalom Consortium, Tamma, Filippo, Dotta, Michele, Lauria, Giuseppe, Steinbach, Robert, Imperiale, Daniele, Geda, Claudio, Dolzhenko, Egor, Cavallo, Roberto, Pignatta, Pietro, Groen, Ewout J. N., Cotelli, Maria Sofia, Mattei, Marco de, Calabrese, Gianluigi, Sapio, Alessia di, Giardini, Guido, Hübner, Christian A., Corti, Stefania, Bell, Shaughn, Comi, Giancarlo, Mccombe, Pamela A., Tiloca, Cinzia, Parals Consortium, Gawor, Klara, Peverelli, Silvia, Taroni, Franco, Pensato, Viviana, Castellotti, Barbara, Graff, Caroline, Comi, Giacomo P., Cereda, Cristina, Bo, Roberto del, Boero, Giovanni, Slagen Consortium, Vourc’h, Patrick, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), van Rheenen, Wouter, van der Spek, Rick AA, Bakker, Mark K, van Vugt, Joke JFA, Benyamin, Beben, Veldink, Jan H, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, van Rheenen, W, van der Spek, R, Bakker, M, van Vugt, J, Hop, P, Zwamborn, R, de Klein, N, Westra, H, Bakker, O, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, A, Gawor, K, Westeneng, H, Tazelaar, G, van Eijk, K, Kooyman, M, Byrne, R, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, B, Gromicho, M, Chandran, S, Pal, S, Morrison, K, Shaw, P, Hardy, J, Orrell, R, Sendtner, M, Meyer, T, Basak, N, van der Kooi, A, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, D'Alfonso, S, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, A, Calvo, A, Moglia, C, Brunetti, M, Canosa, A, Grassano, M, Beghi, E, Pupillo, E, Logroscino, G, Nefussy, B, Osmanovic, A, Nordin, A, Lerner, Y, Zabari, M, Gotkine, M, Baloh, R, Bell, S, Vourc'H, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Mora Pardina, J, Assialioui, A, Rojas-Garcia, R, Dion, P, Ross, J, Ludolph, A, Weishaupt, J, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, C, Saker-Delye, S, Wood, N, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, D, Olsen, C, Uitterlinden, A, Hofman, A, Rietschel, M, Cichon, S, Nothen, M, Amouyel, P, Traynor, B, Singleton, A, Mitne Neto, M, Cauchi, R, Ophoff, R, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, V, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, O, Steinbach, R, Hubner, C, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, I, Kiernan, M, Benyamin, B, Henderson, R, Furlong, S, Mathers, S, Mccombe, P, Needham, M, Ngo, S, Nicholson, G, Pamphlett, R, Rowe, D, Steyn, F, Williams, K, Mather, K, Sachdev, P, Henders, A, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, G, Silani, V, Curtis, C, Breen, G, Glass, J, Brown, R, Landers, J, Shaw, C, Andersen, P, Groen, E, van Es, M, Pasterkamp, R, Fan, D, Garton, F, Mcrae, A, Davey Smith, G, Gaunt, T, Eberle, M, Mill, J, Mclaughlin, R, Hardiman, O, Kenna, K, Wray, N, Tsai, E, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, L, Veldink, J, Ferrarese, C, Neurology, ANS - Neuroinfection & -inflammation, APH - Methodology, APH - Quality of Care, EURO-NMD, Internal Medicine, Epidemiology, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), van Rheenen, W., Van der Spek, R.A.A., Bakker, M.K., van Vugt, J.J.F.A., Hop, P.J., Zwamborn, R.A.J., de Klein, N., Westra, H.J., Bakker, O.B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A.M., Gawor, K., Westeneng, H.J., Tazelaar, G.H.P., van Eijk, K.R., Kooyman, M., Byrne, R.P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B.N., Gromicho, M., Chandran, S., Pal, S., Morrison, K.E., Shaw, P.J., Hardy, J., Orrell, R.W., Sendtner, M., Meyer, T., van der Kooi, A.J., Ratti, A., Fogh, I., Gellera, C., Lauria, G., Corti, S., Cereda, C., Sproviero, D., D'Alfonso, S., Sorarù, G., Siciliano, G., Filosto, M., Padovani, A., Chiò, A., Calvo, A., Moglia, C., Brunetti, M., Canosa, A., Grassano, M., Beghi, E., Pupillo, E., Logroscino, G., Nefussy, B., Osmanovic, A., Nordin, A., Lerner, Y., Zabari, M., Gotkine, M., Baloh, R.H., Bell, S., Vourc'h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J.S., Assialioui, A., Rojas-García, R., Dion, P.A., Ross, J.P., Ludolph, A.C., Weishaupt, J.H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C.A.M., Saker-Delye, S., Wood, N.W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Kraft, J.,Whiteman, David C., Olsen, Catherine M., Uitterlinden, A.G., Hofman, A., Rietschel, M., Cichon, S., Nothen, M.M., Amouyel, P., Comi, G., Riva, N., Lunetta, C., Gerardi, F., Cotelli, M.S., Rinaldi, F., Chiveri, L., Guaita, M.C., Perrone, P., Ceroni, M., Diamanti, L., Ferrarese, C., Tremolizzo, L., Delodovici, M.L., Bono, G., Manera, U., Vasta, R., Bombaci, A., Casale, F., Fuda, G., Salamone, P., Iazzolino, B., Peotta, L., Cugnasco, P., De Marco, G., Torrieri, M.C., Palumbo, F., Gallone, S., Barberis, M., Sbaiz, L., Gentile, S., Mauro, A., Mazzini, L., De Marchi, F., Corrado, L., Bertolotto, A., Gionco, M., Leotta, D., Odddenino, E., Imperiale, D., Cavallo, R., Pignatta, P., De Mattei, M., Geda, C., Papurello, D.M., Gusmaroli, G., Comi, C., Labate, C., Ruiz, L., Ferrandi, D., Rota, E., Aguggia, M., Di Vito, N., Meineri, P., Ghiglione, P., Launaro, N., Dotta, M., Di Sapio, A., Giardini, G., Tiloca, C., Peverelli, S., Taroni, F., Pensato, V., Castellotti, B., Comi, G.P., Del Bo, R., Gagliardi, S., Raggi, F., Simoncini, C., Lo Gerfo, A., Inghilleri, M., Ferlini, A., Simone, I.L., Passarella, B., Guerra, V., Zoccolella, S., Nozzoli, C., Mundi, C., Leone, M., Zarrelli, M., Tamma, F., Valluzzi, F., Calabrese, G., Boero, G., Rini, A., Traynor, B.J., Singleton, A.B., Neto, M.M., Cauchi, R.J., Ophoff, R.A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V.M., Grosskreutz, J., Roediger, A., Gaur, N., Jork, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O.W., Steinbach, R., Hubner, C.A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavac, M., Glavac, D., Stevic, Z., Drory, V., Povedano, M., Blair, I.P., Kiernan, M.C., Benyamin, B., Henderson, R.D., Furlong, S., Mathers, S., McCombe, P.A, Needham, M., Ngo, S.T., Nicholson, G.A., Pamphlett, R., Rowe, D.B., Steyn, F.J., Williams, K.L., Mather, K.A., Sachdev, P.S., Henders, A.K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G.A., Silani, V., Curtis, C.J., Breen, G., Glass, J.D., Brown, R.H., Landers, J.E., Shaw, C.E., Andersen, P.M., Groen, E.J.N, van Es, M.A., Pasterkamp, R.J., Fan, D.S., Garton, F.C., McRae, A.F., Smith, G.D., Gaunt, T.R., Eberle, M.A., Mill, J., McLaughlin, R.L., Hardiman, O., Kenna, K.P., Wray, N.R., Tsai, E.L., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L.H., Veldink, J.H., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Subjects
Male, Genetics and heredity, amyotrophic lateral sclerosis, Neurologi, Glutamine, Medizin, Genome-wide association study, Disease, SUSCEPTIBILITY, Genome-wide association studies, DISEASE, Genètica mèdica, 0302 clinical medicine, neurodegenerative disease, genome-wide association study, ALS, gene, autophagy, Risk Factors, amyotrophic lateral sclerosi, RNA-Seq, Amyotrophic lateral sclerosis, disease-modifying therapies, blood [Cholesterol], Genetics, Genetics & Heredity, Neurons, 0303 health sciences, Medical genetics, Neurodegenerative diseases, Genome-wide association, Mendelian randomization, Frontotemporal dementia, Hexanucleotide repeat, Mutant SOD1, Metaanalysis, ALS, Susceptibility, Identification, Brain, Amyotrophic Lateral Sclerosis, Cholesterol, Disease Progression, Female, Humans, Mendelian Randomization Analysis, Microsatellite Repeats, Neurodegenerative Diseases, Quantitative Trait Loci, Genome-Wide Association Study, Mutation, MUTANT SOD1, genetics [Amyotrophic Lateral Sclerosis], medicine.anatomical_structure, Neurology, risk factor, metabolism [Neurons], MENDELIAN RANDOMIZATION, nerve cell, Life Sciences & Biomedicine, quantitative trait locu, Biology, 03 medical and health sciences, Amyotrophic lateral sclerosis -- Diagnosis, blood, ddc:570, medicine, degenerative disease, Motor neuron disease, human, Genomes, GENOME-WIDE ASSOCIATION, gene, Gene, metabolism [Glutamine], METAANALYSIS, 030304 developmental biology, Mendelian randomization analysi, Science & Technology, HEXANUCLEOTIDE REPEAT, meta analysi, IDENTIFICATION, metabolism [Amyotrophic Lateral Sclerosis], FRONTOTEMPORAL DEMENTIA, medicine.disease, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, disease exacerbation, Neuron, gemone, genetic, Vesicle-mediated transport, metabolism, Nervous system -- Degeneration, Esclerosi lateral amiotròfica, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., Dutch Research Council (NWO); VENI Scheme Grant; VIDI Grant; Prinses Beatrix Spierfonds; Neuromuscular Fellowship Grant; Medical Research Council (MRC); Clinical Infrastructure Award; Epidemiology Unit; Integrative Epidemiology Unit; Canadian Institutes of Health Research; IWT; National Institute on Aging; National Health and Medical Research Council (NHMRC); Enabling Grant; NHMRC/Australian Research Council Strategic Award; NHMRC; NHMRC Centre of Research Excellence Grant; National Health and Medical Research Council of Australia (NHMRC) Research Fellowship; United Kingdom, Medical Research Council; Economic and Social Research Council; European Union (EU); Horizon 2020; European Community's Health Seventh Framework Programme; EuroMOTOR; European Research Council (ERC); Research and Innovation Programme; EScORIAL; ALS Foundation Netherlands; Alzheimer’s Society PhD Studentship; ARSla Funding; Biogen; University of Bristol; Motor Neurone Disease Association (MNDA); NIHR Maudsley Biomedical Research Centre; Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO; BRAINSCAPES); Gravitation Program; ALS Liga België; National Lottery of Belgium; KU Leuven Opening the Future Fund; KU Leuven Funds, “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Liga België; “Live now” Charity Foundation; Moscow ALS palliative Care Service; Canadian Institutes of Health; Research Australia; Ice Bucket Challenge Grant; NIH Intramural Research Programs; FightMND Mid-Career Fellowship; NIHR Senior Investigator; Sheffield NIHR Biomedical Research Centre; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre; Maudsley NHS Foundation Trust; King’s College London; NIHR Senior Investigator Award; Netherlands Organization for Health Research and Development; Vici Scheme; Netherlands Organization for Health Research and Development STRENGTH Project; PPP Allowance

Published
2021

8. 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

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. 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

11. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis

Author

Kalincik, Tomas, Horakova, Dana, Spelman, Tim, Jokubaitis, Vilija, Trojano, Maria, Lugaresi, Alessandra, Izquierdo, Guillermo, Rozsa, Csilla, Grammond, Pierre, Alroughani, Raed, Duquette, Pierre, Girard, Marc, Pucci, Eugenio, Lechner-Scott, Jeannette, Slee, Mark, Fernandez-Bolanos, Ricardo, Grand'Maison, Francois, Hupperts, Raymond, Verheul, Freek, Hodgkinson, Suzanne, Oreja-Guevara, Celia, Spitaleri, Daniele, Barnett, Michael, Terzi, Murat, Bergamaschi, Roberto, McCombe, Pamela, Sanchez-Menoyo, Jose, Simo, Magdolna, Csepany, Tunde, Rum, Gabor, Boz, Cavit, Havrdova, Eva, Butzkueven, Helmut, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Adult, Male, Fingolimod Hydrochloride, Natalizumab, Orvostudományok, Middle Aged, Klinikai orvostudományok, Antibodies, Monoclonal, Humanized, Severity of Illness Index, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Propylene Glycols, Recurrence, Sphingosine, Disease Progression, Humans, Female, Registries, Immunosuppressive Agents
Abstract

In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents.Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses.Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p 0.001).This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.

Published
2014

12. 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

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 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.

14. 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

15. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Author

Ibrahima Diouf, Charles B. Malpas, Sifat Sharmin, Izanne Roos, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Guillermo Izquierdo, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Marc Girard, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand'Maison, Sherif Hamdy, Patrizia Sola, Diana Ferraro, Pierre Grammond, Recai Turkoglu, Katherine Buzzard, Olga Skibina, Bassem Yamout, Ayse Altintas, Oliver Gerlach, Vincent van Pesch, Yolanda Blanco, Davide Maimone, Jeannette Lechner‐Scott, Roberto Bergamaschi, Rana Karabudak, Gerardo Iuliano, Chris McGuigan, Elisabetta Cartechini, Michael Barnett, Stella Hughes, Maria José Sa, Claudio Solaro, Ludwig Kappos, Cristina Ramo‐Tello, Edgardo Cristiano, Suzanne Hodgkinson, Daniele Spitaleri, Aysun Soysal, Thor Petersen, Mark Slee, Ernest Butler, Franco Granella, Koen de Gans, Pamela McCombe, Radek Ampapa, Bart Van Wijmeersch, Anneke van der Walt, Helmut Butzkueven, Julie Prevost, L. G. F. Sinnige, Jose Luis Sanchez‐Menoyo, Steve Vucic, Guy Laureys, Liesbeth Van Hijfte, Dheeraj Khurana, Richard Macdonell, Riadh Gouider, Tamara Castillo‐Triviño, Orla Gray, Eduardo Aguera‐Morales, Abdullah Al‐Asmi, Cameron Shaw, Norma Deri, Talal Al‐Harbi, Yara Fragoso, Tunde Csepany, Angel Perez Sempere, Irene Trevino‐Frenk, Jan Schepel, Fraser Moore, Tomas Kalincik, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Laureys, Guy/0000-0002-1708-4373, Lugaresi, Alessandra/0000-0003-2902-5589, Aguera-Morales, Eduardo/0000-0002-8604-2054, Petersen, Thor/0000-0001-5633-2600, Roos, Izanne/0000-0003-0371-3666, Slee, Mark/0000-0003-4323-2453, patti, francesco/0000-0002-6923-0846, Diouf, Ibrahima, Malpas, Charles B., Sharmin , Sifat, Roos, Izanne, Horakova, Dana, Havrdova, Eva Kubala, Patti, Francesco, Shaygannejad, Vahid, Ozakbas, Serkan, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Alroughani, Raed, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Hamdy, Sherif, Sola, Patrizia, Ferraro, Diana, Grammond, Pierre, Turkoglu, Recai, Buzzard, Katherine, Skibina, Olga, Yamout, Bassem, Altintas, Ayse, Gerlach, Oliver, van Pesch, Vincent, Blanco, Yolanda, Maimone, Davide, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Karabudak, Rana, Iuliano, Gerardo, McGuigan, Chris, Cartechini, Elisabetta, Barnett, Michael, Hughes, Stella, Sa, Maria Jose, Solaro, Claudio, Kappos, Ludwig, Ramo-Tello, Cristina, Cristiano, Edgardo, Hodgkinson, Suzanne, Spitaleri, Daniele, Soysal, Aysun, Petersen, Thor, Slee, Mark, Butler, Ernest, Granella, Franco, de Gans, Koen, McCombe, Pamela, Ampapa, Radek, VAN WIJMEERSCH, Bart, van der Walt, Anneke, Butzkueven, Helmut, Prevost, Julie, Sinnige, L. G. F., Sanchez-Menoyo, Jose Luis, Vucic, Steve, Laureys, Guy, Van Hijfte, Liesbeth, Khurana, Dheeraj, Macdonell, Richard, Gouider, Riadh, Castillo-Trivino, Tamara, Gray, Orla, Aguera-Morales, Eduardo, Al-Asmi, Abdullah, Shaw, Cameron, Deri, Norma, Al-Harbi, Talal, Fragoso, Yara, Csepany, Tunde, Sempere, Angel Perez, Trevino-Frenk, Irene, Schepel, Jan, Moore, Fraser, and Kalincik, Tomas

Subjects
marginal structural model, relapse, Multiple Sclerosis, Multiple Sclerosis, Chronic Progressive, multiple sclerosis, Multiple Sclerosis, Relapsing-Remitting, Neurology, Recurrence, Medicine and Health Sciences, Humans, Neurology (clinical), EDSS, immunotherapy, Proportional Hazards Models
Abstract

Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow -up >= 1 year, and Expanded Disability Status Scale (EDSS) score >= 3, with >= 1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12 -month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45- 0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41- 0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09- 1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Published
2023

16. 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

17. 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

18. 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

19. 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

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