43 - Late Breaking Abstracts
P361/3186
The Central Vein Sign in Multiple Sclerosis (CAVS-MS): A North American Imaging in MS Cooperative Prospective Diagnostic Biomarker Study
Daniel Ontaneda1, Meghan Kilbane1, elaina gombos2, Meredith Dever1, Karlo Toljan1, Enrique Alvarez3, Christina Azevedo4, Peter Calabresi5, Jeffrey Cohen1, Salim Chahin6, Leorah Freeman7, Erin Longbrake8, Ruth Ann Marrie9, Aaron Miller10, Nandita Mitra11, Ellen Mowry5, Jiwon Oh12, Elias Sotirchos5, Emmanuelle Waubant13, Gary Cutter14, Russell Shinohara11, Daniel Reich15, Andrew Solomon16, Nancy Sicotte2, Pascal Sati2
1Cleveland Clinic, Mellen Center, Cleveland, United States, 2Cedars Sinai, Los Angeles, United States, 3University of Colorado, Aurora, United States, 4University of Southern California, Los Angeles, United States, 5Johns Hopkins University, Baltimore, United States, 6Washington University, St. Louis, United States, 7University of Texas Austin, Austin, United States, 8Yale University, New Haven, United States, 9University of Manitoba, Winnipeg, Canada, 10Mount Sinai School of Medicine, New York, United States, 11University of Pennsylvania, Philadelphia, United States, 12University of Toronto, Toronto, Canada, 13University of California San Francisco, San Francisco, United States, 14University of Alabama, Birmingham, United States, 15NIH, NINDS, Bethesda, United States, 16University of Vermont, Burlington, United States
Introduction: Specificity and proper implementation of current MRI-based diagnostic criteria are imperfect. Up to 20% of individuals diagnosed with multiple sclerosis (MS) are later determined not to have the disease. The central vein sign (CVS) is a proposed diagnostic imaging biomarker for MS. Prospective multicenter studies of the CVS including patients presenting for clinical evaluation for MS could provide support for incorporating simplified CVS methods into MS diagnostic criteria and clinical practice implementation.
Objectives/Aims: To examine the baseline diagnostic performance of CVS in a prospective, multicenter, diagnostic biomarker study of the CVS in MS (CAVS-MS).
Methods: CAVS-MS is a 2-year, prospective, international multicenter study to evaluate the CVS as a diagnostic biomarker for translation into clinical care. Patients presenting for evaluation of MS across 11 North American Imaging in MS Cooperative (NAIMS) sites were recruited. T2*-weighted, high-isotropic-resolution, segmented echo-planar imaging was acquired at baseline and 24 months on 3-tesla scanners encompassing different manufactures and models. FLAIR* images were generated from FLAIR and T2* sequences. Site PIs assessed the presence of CVS in up to 3 or 6 lesions on post-contrast FLAIR* (“Select3” and “Select6”) following NAIMS criteria. Clinical onset (typical attacks, progressive disability, radiologically isolated syndrome [RIS], atypical presentations) and fulfillment of 2017 McDonald criteria were adjudicated by neurologists who served on the 2017 International Panel on Diagnosis of MS. The diagnostic accuracy of Select3 and Select6 was evaluated from baseline data.
Results: 420 patients were enrolled across 11 study sites: 329 women (79%) with a mean age of 39 years (SD: 11). Onset was adjudicated as a typical clinical attack in 200 (48%), progressive in 16 (3.8%), RIS in 7 (1.7%), and atypical in 197 (47%). 148 patients fulfilled McDonald criteria at baseline: 137 with relapsing-remitting MS and 11 with primary progressive MS. The sensitivity/specificity for MS was 77%/63% for Select3 and 57%/78% for Select 6. In patients with typical clinical attacks, sensitivity/specificity for MS was 78%/63% for Select3 and 59%/75% for Select6.
Conclusion: Multicenter application of the CVS using abbreviated methods shows good diagnostic performance in patients with typical and atypical clinical syndromes presenting for evaluation of MS. Longitudinal follow-up over 2 years will assess CVS performance for prediction of a future diagnosis of MS.
Disclosure of interest: DO: Received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Novartis, and Merck.
KM: Nothing to disclose
EG: Nothing to disclose
MD: Nothing to disclose
KT: Research support from National Multiple Sclerosis Society.
EA: Compensation for activities (advisory boards, lectures and consultancy) with the following companies and organizations: Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, Sanofi, and TG Therapeutics and research support from: Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center.
CA: Grant support from the National Multiple Sclerosis Society and the NIH; consulting fees from Horizon Therapeutics, Genentech, Sanofi Genzyme, TG Therapeutics, and EMD Serono; honoraria for serving on grant review committees for the Department of Defense and the NIH and for participation in unbranded CME activities from the American Academy of Neurology, Efficient LLC, Spire Learning, and Catamount Medical Education.
PC: PI on a grant to JHU from Genentech and the Myelin Repair Foundation. Consulting fees from Biogen, Lilly, Idorsia, and Novartis.
JC: Compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI; and serving as an Editor of Multiple Sclerosis Journal.
SC: Research support from Bristol Meyer Squibb and BMS Foundation. Consulting fees from Novartis, Biogen, Sanofi Genzyme, Jansen, Horizon, EMD Serono and BMS.
LF: LF has received consultancy fees from Genentech, Novartis, Celgene/Bristol Myers Squibb, EMD Serono, Horizon Therapeutics and TG Therapeutics; has received program sponsorship from EMD Serono; and has grant support from NIH/NINDS, PCORI, Genentech, and EMD Serono.
EL: : Research support from Genentech, Biogen, NIH. Consulting for Genentech, Genzyme, Alexion, EMD Serono, Biogen, TG Therapeutics, NGM Bio, Janssen, Bristol Myers Squibb.
RAM: Receives research funding from: Canadian Institutes of Health Research, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, Consortium of MS Centers, the Arthritis Society, US Department of Defense. She is a co-investigator on a study funded in part by Biogen Idec and Roche (no funds to her or her institution).
AM: Research support from Novartis, Roche /Genentech, MedDay. Consulting from Accordant Health Services, (Caremark), Corevitas, Janssen, Mapi-Pharma, Sangamo, Verana Health, Veritas (Mylan). Speakers bureau from Biogen Idec (unbranded disease awareness programs only); Alexion (unbranded disease awareness programs only); Horizon Therapeutics (unbranded disease awareness programs only)
NM: Nothing to disclose
EM: PI of grants to JHU as well as site PI of studies from Genentech, Biogen; free medication for a clinical trial of which I am PI from Teva; royalties for editorial duties for UpToDate. Research support from PCORI, National MS Society, Department of Defense, National Institutes of Health. Consulting from for BeCareLink LLC.
JO: Grants from MS Society of Canada, National MS Society, Brain Canada, Biogen-Idec, Roche, EMD-Serono, and consulting fees from Biogen-Idec, BMS, EMD-Serono, Eli-Lilly, Novartis, RocheSanofi-Genzyme.
ES: Reports scientific advisory boards and/or consulting for Alexion, Horizon Therapeutics, Genentech, Ad Scientiam, and speaking honoraria from Alexion.
EW: Grants from the National MS Society, Race to Erase MS, PCORI, NIH, CMSC, DoD. Site PI for ongoing trials with Roche, Alexion and Biogen, Advisory board of a Novartis trial (volunteer), Honoraria for pharma consulting: none, Honoraria for talks (NeurologyLive, Yoga moves MS, Advanced Curriculum), Chair (volunteer), international Women in MS, ACTRIMS president-elect.
GC: Data and Safety Monitoring Boards: Applied Therapeutics, AI therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb/Celgene, CSL Behring, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Kezar Life Sciences, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc. Consulting or Advisory Boards: Alexion, Antisense Therapeutics, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Hoya Corporation, Immunic, Immunosis Pty Ltd, Klein-Buendel Incorporated, Linical, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, SAB Biotherapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL.
AJS: Consulting: EMD Serono, Biogen, Alexion, Celgene, Greenwich Biosciences, Octave Bioscience,
TG Therapeutics, Sanofi; Non-promotional speaking: EMD Serono; Research Funding: Biogen, Bristol
Myers Squibb; Contracted Research: Biogen, Novartis, Actelion, Genentech/Roche
TS: Supported NIH R01NS112274, R01MH112847, R01MH123550. Consulting income from Octave
Bioscience.
DSR: Supported by the Intramural Research Program of NINDS; additional research support from
Abata Therapeutics and Sanofi.
RTS: Supported NIH R01NS112274, R01MH112847, R01MH123550. Consulting income from Octave
Bioscience.
NLS: Research support from the National Institutes of Health, National Multiple Sclerosis Society,
Patient Centered Outcomes Research Institute, Race to Erase MS Foundation and Biogen-Idec
PS: Research support from the National Institutes of Health and the National Multiple Sclerosis
Society.
P362/3105
Long-term efficacy of satralizumab in patients with AQP4-IgG+ NMOSD: Updated analysis from the open-label SAkuraMoon study
Jacqueline Palace1, Anthony Traboulsee2, Albert Saiz3, Jérôme De Seze4, Ingo Kleiter5, Jeffrey L. Bennett6, Daniela Stokmaier7, Gaelle Klingelschmitt7, Audrey Yeo Te-Ying7, Ivana Vodopivec7, Takashi Yamamura8
1John Radcliffe Hospital, Oxford, United Kingdom, 2University of British Columbia, Vancouver, Canada, 3Service of Neurology, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain, 4Hautepierre Hospital, Strasbourg, France, 5Ruhr University Bochum, Bochum, Germany, 6University of Colorado School of Medicine, Aurora, United States, 7F. Hoffmann-La Roche Ltd, Basel, Switzerland, 8National Center of Neurology and Psychiatry, Tokyo, Japan
Introduction: Satralizumab (SAT) significantly reduced the risk of protocol-defined relapse (PDR) in 2 pivotal phase 3 trials in patients with neuromyelitis optica spectrum disorder (NMOSD): SAkuraSky (NCT02028884; SAT + baseline immunosuppressants [IST]) and SAkuraStar (NCT02073279; SAT monotherapy).
Objectives/Aims: To assess the long-term efficacy of SAT in patients with aquaporin-4-IgG-seropositive (AQP4 IgG+) NMOSD.
Methods: Patients who completed the double-blind periods (DBPs) and open-label extensions (OLEs) of SAkuraSky and SAkuraStar were rolled-over into SAkuraMoon (NCT04660539), a single-arm, open-label study, and continued receiving SAT 120mg Q4W +/- IST. Efficacy analyses are based on the overall SAT treatment period, from patients’ first dose in the DBPs of SAkuraSky and SAkuraStar to the clinical cut-off date of 31 January 2023. PDRs were adjudicated by a Clinical Endpoint Committee in the DBPs and were determined by the investigator (iPDRs) in the OLEs and SAkuraMoon. Key analyses included annualised iPDR rate (ARR), time to first iPDR, severe iPDR (⩾2 point increase in the Expanded Disability Status Scale [EDSS] score), and sustained EDSS worsening (EDSS increase of ⩾2, ⩾1, or ⩾0.5 points for patients with baseline scores of 0, 1–5, or ⩾5.5, respectively, confirmed ⩾24 weeks post-initial-worsening).
Results: Overall, 111 AQP4+ patients were included. The median (range) duration of SAT exposure was 5.9 (0.1–8.9) years. The overall adjusted ARR (95% CI) was 0.08 (0.06–0.10), where the ARR did not increase with additional years of exposure (Y1: 0.17 [0.10–0.28]; Y2: 0.10 [0.05–0.19]; Y3: 0.04 [0.01–0.14]; Y4: 0.08 [0.02–0.25]; Y5: 0.05 [0.01–0.17]). At Week 288 (5.5 years), 72% (95% CI: 62–80%) of SAT-treated patients were free from iPDR, 91% (83–95%) were free from severe iPDR, and 83% (73–90%) had no sustained EDSS worsening. 3 patients dropped out from SAkuraMoon; 2 patients switched to commercial satralizumab and 1 patient discontinued treatment due to pregnancy.
Conclusion: These results demonstrate the effective long-term management of NMOSD with SAT over 5.5 years of treatment. The ARR remained consistently low in SAT-treated patients, with high proportions of patients remaining free from relapse, severe relapse, and worsening in disability.
Disclosure of interest: AT received consulting fees from Genzyme, Roche, and Novartis and is part of a speaker’s bureau for Genzyme and Roche.
AS received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck Serono, Sanofi, Biogen, Roche, Teva, Novartis, Alexion, and Janssen.
JDS received grants and personal fees from Roche and Chugai and has served on advisory boards in the expert committee for the clinical trial conducted by Chugai.
IK received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi.
JP received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, Sanofi and grants from Alexion, Roche, Medimmune, UCB, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZeneca. Acknowledges Partial funding by Highly specialised services NHS England.
JLB reports payment for consultation from MedImmune/Viela Bio; personal fees from AbbVie, Alexion, Antigenomycs, Beigene, Chugai, Clene Nanomedicine, EMD Serono, Genentech, Genzyme, Mitsubishi-Tanabe, Novartis, Reistone Bio, Roche, Imcyse, and TG Therapeutics; grants from the National Institutes of Health, Novartis, Alexion, and Mallinckrodt; speaker bureau for Alexion, and has a patent for Aquaporumab issued.
DS, GK, AYT and IV are all full-time employees of F. Hoffmann La-Roche Ltd.
TY served on scientific advisory boards for Chugai, Roche, Biogen Japan, Biogen MA, Novartis, and Mitsubishi Tanabe; received research grants from Chugai, Novartis, Biogen Japan, Chiome Bioscience, Sanofi, UCB Japan and Mebix; received speaker honoraria from Chugai, Biogen Japan, Novartis, Mitsubishi Tanabe, Takeda, Miyarisan, Alexion, Sumitomo and Teijin.
This study was funded by F. Hoffman-La Roche. ClinicalTrials.gov, NCT02028884/NCT02073279/ NCT04660539. Medical writing assistance was provided by Meta Leshabane (MSc) of ApotheCom, London, UK. Medical writing support was funded by F. Hoffman-La Roche.
P363/3205
Implications of late-onset disease: an in-depth look at prognosis
Alvaro Cobo Calvo1, Pere Carbonell1, Carmen Tur1, Susana Otero-Romero1,2, Georgina Arrambide1, Helena Ariño1, Cristina Auger3, Javier Villacieros-Alvarez1, Luca Bollo1, Joaquin Castillo-Justribo1, Manuel Comabella1, Carmen Espejo1, Victoria Fernández1, Claudia Guio-Sanchez1, Ingrid Galán1, Delon La Puma1, Luciana Midaglia1, Neus Mongay-Ochoa1, Andreu Vilaseca1, René Carvajal1, Maria Jesus Arevalo1, Carlos Nos1, Agustín Pappolla1, Jordi Rio1, Breogán Rodríguez1, Ana Zabalza1, Angela Vidal-Jordana1, Deborah Pareto3, Jaume Sastre-Garriga1, Alex Rovira Cañellas3, Xavier Montalban1, Mar Tintoré1
1Multiple Sclerosis Centre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain, 2Dept. of Preventive Medicine-Vall Hebron University Hospital, Barcelona, Spain, 3Dept. of Radiology, Neuroradiology-Vall Hebron University Hospital, Barcelona, Spain
Introduction: Older ages at first attack could be associated with a worse prognosis.
Objectives/Aims: To assess the prognostic implications of age at disease onset in a prospective cohort of patients with a first attack.
Methods: The study included patients from the deeply phenotyped Barcelona inception CIS cohort, since 1994. Patients were classified into age groups based on their age at first attack: 18-29, 30-39 and 40-50. CIS characteristics were compared across groups including sex, CIS topography, number of brain T2 lesions (0,1-3, 4-8, ⩾9), presence of infratentorial and spinal cord (SC) lesions (0, 1, 2-3, >3), contrast-enhancing lesions (CEL) in brain and SC (0, 1, 1-2, >2) and oligoclonal bands. Treatments regiments were classified into three arbitrary lines: Intermediate (injectables, teriflunomide, azathioprine), high (dimethyl fumarate, S1P, cladribine) and very high (monoclonal antibodies, mitoxantrone). The percentage of disease exposed to each treatment line was calculated, and linear models were utilized to explore the association between these percentages and age. Kaplan-Meier survival estimates according to the age group were built for the risk of McDonald 2017, second relapse, presence of >2 new T2 lesions/yr., relapse associated worsening (RAW) after the first attack or in subsequent relapses, first progression independent of relapse activity (PIRA), confirmed and sustained disability accumulation (CSDA) and confirmed EDSS 3.0. Splines mixed models were built to study the association between the EDSS trajectories and the age groups.
Results: We included 1149 patients (follow-up (IQR): 11 (5,18) yrs)). Patients with a first attack at 40-50 yrs showed fewer brain CEL than younger patients (p<0.001) and were less exposed to high (p=0.009) and very high efficacy (p<0.001) treatments. Patients in 40-50 yrs were at higher risk of RAW at first attack (p=0.030) and early PIRA (within 5 yrs since the first attack) (p<0.001). In addition, they were at lower risk of McDonald 2017 criteria (p=0.021), second relapse (p<0.001) or displaying new T2 (p<0.001). They also showed EDSS trajectories with a higher rate of disability accumulation than younger patients (p=0.039).
Conclusion: This study highlights that patients with a first attack at older ages exhibit a less inflammatory disease compared to younger patients. Despite the lower disease activity, these older patients might be at higher risk for significant prognostic milestones in a real-world setting.
Disclosure of interest: Mar Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.
Pere Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació privada Cemcat for statistical analysis.
Carmen Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.
Álvaro Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.
J Villacieros-Álvarez has received grant from Instituto de Salud Carlos III, Spain; FI21/00282
C. Guío-Sánchez is an ECTRIMS clinical fellowship awardee 2022-2023 and she has received
travel expenses and speaking honoraria for scientific meetings from Sanofi-Genzyme, Biogen-
Inc and Merck.
V. Fernández is an ECTRIMS clinical fellowship awardee 2022-2023.
A Pappolla has received funding travel from Roche and speaking honoraria from Novartis. He performed an ECTRIMS Clinical Training Fellowship program during 2021, and is currently performing an MSIF-ARSEP Fellowship program
Jordi Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck, Mylan, Novartis, Roche, Teva, and Sanofi-
Aventis.
Luca Bollo’s research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in
2022.
Neus Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018). She also has received speaking honoraria and travel expenses
from Merck and Roche.
Andreu Vilaseca has received a Rio Hortega grant (CM22/00247) by Institute of Health Carlos III (ISCIII).
Georgina Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. G. Arrambide is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.
R. Carvajal is currently being funded by the “Vall d’Hebron Institut de Recerca” grant, he also was awarded by ECTRIMS Clinical Training Fellowship program during 2022. He has also received speaking honoraria and personal compensation for participating on Advisory Boards and from Roche, Novartis, BIIB-Colombia, Merck and Sanofi.
B. Rodríguez-Acevedo has received honoraria for consulting services from Wellspect.
Ana Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III,
Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-
Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant
from Novartis.
Angela Vidal-Jordana has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.
Jaume Sastre-Garriga serves as co-Editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the last twelve months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck.
Manolo Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis.
D. Pareto has received a research contract with Biogen Idec, and a grant from Instituto Salud
Carlos III (PI18/00823).
Alex Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain.
X. Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.
P364/3168
HLA associations differ by race/ethnicity and aquaporin-4 antibody status in neuromyelitis optica spectrum disorders
Moritz Niederschweiberer1, Georgia Panagiotaropoulou2, Megan Behne3, Andre Franke4, Wolfgang Lieb5, Sven Jarius6, Friedemann Paul7,8, Lawrence Cook9, Jorge R Oksenberg10, Michael Yeaman11,12, Stephan Ripke2,13,14, Klemens Ruprecht1
Study Group: Guthy-Jackson Charitable Foundation CIRCLES Study Group
1Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, 2Broad Institute, Departmend of Medical and Population Genetics, Cambridge, United States, 3Guthy-Jackson Charitable Foundation, Beverly Hills, CA, United States, 4Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany, 5Institute of Epidemiology, Christian-Albrechts-University, Kiel, Germany, 6Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany, 1Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, 8Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universiätsmedizin Berlin, Berlin, Germany, 9Department of Pediatrics Division of Critical Care University of Utah, Salt Lake City, United States, 10Department of Neurology and UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States, 11Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States, 12Department of Medicine, Divisions of Molecular Medicine and Infectious Diseases Harbor-UCLA Medical Center; Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States, 13Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Boston, MA, United States, 14Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Introduction: Neuromyelitis optica spectrum disorders (NMOSD) comprise severe inflammatory central nervous system diseases. About 75% of patients with a clinical phenotype of NMOSD have serum immunoglobulin (Ig)G autoantibodies to the astrocytic water channel aquaporin-4 (AQP4-IgG). Autoantibody-mediated diseases are often associated with human leukocyte antigen (HLA) alleles. Limitations of previous HLA association studies in patients with NMOSD included low patient numbers, lack of racial/ethnic diversity, absent stratification for AQP4-IgG status, and low-resolution HLA genotyping.
Objectives/Aims: Using sequence-based HLA class I and II genotyping data, we conducted an HLA association study in a large cohort of patients with NMOSD stratified by race/ethnicity and AQP4-IgG status.
Methods: Sequence-based HLA class I and II genotyping data of a total of 317 patients with NMOSD participating in the North American Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) were compared to genotyping data from publicly available control cohorts (US National Marrow Donor Program). Patients with NMOSD were stratified by race/ethnicity and AQP4-IgG antibody status. Correction for multiple testing was performed by the Bonferroni method.
Results: Allele frequencies of HLA-DRB1*03 (29.8% vs. 12.3%, odds ratio (OR) 3.04, 95%-confidence interval (CI) 2.39-3.84, corrected p=5.58E-15) and HLA-B*08 (26.3% vs. 11.4%, OR 2.77, CI 2.15-3.54, corrected p=4.09E-11) were higher in White AQP4-IgG-positive patients with NMOSD (n=173 for HLA-DRB1*03, n=171 for HLA-B*08) than in White controls (n=1,249,890). In White AQP4-IgG-positive patients, the median age (years) at clinical disease onset increased with the number of HLA-DRB1*03 alleles (0 alleles: 40.1 (n=80); 1 allele: 46 (n=81); 2 alleles: 57.3 (n=11)) as well as with the number of HLA-B*08 alleles (0 alleles: 40 (n=87); 1 allele 46.9 (n=76), 2 alleles: 55.9 (n=7)). The frequency of HLA-DRB1*08 (22.7% vs. 6.5%, OR 4.22, CI 2.42-7.04, corrected p=8.55E-04) was higher in Black AQP4-IgG-positive patients with NMOSD (n=44) than in Black controls (n=16,178). No significant HLA associations were observed in White AQP4-IgG-negative patients (n=49).
Conclusion: This study identifies a differential association of HLA alleles with NMOSD according to race/ethnicity and aquaporin-4 antibody status, thereby contributing to the clarification of the immunogenetic background of NMOSD.
Disclosure of interest: M.N. has received support for attending meetings from Sanofi and his work was supported by a research grant from GJCF. G.P. has no disclosures to declare. M.B. has received personal compensation for serving as an independent contractor with The Guthy-Jackson Charitable Foundation. A.F. has no disclosures to declare. W.F. has no disclosures to declare. S.J. has no disclosures to declare. F.P. has received honoraria and research support from Alexion, AstraZeneca Rare Disease; has received research grant support from Biogen and F. Hoffmann-La Roche; has received honoraria for lectures, presentations, and speakers bureaus and support for attending meetings from Alexion, AstraZeneca Rare Disease, Biogen, and F. Hoffmann-La Roche; and has served as an advisory board member for F. Hoffmann-La Roche. L.C. received funding from Guthy-Jackson-Charitable Foundation. J.O. has no disclosures to declare. M.Y. has received honoraria as a consultant for Genentech-Roche, Horizon, and Alexion pertaining to NMOSD. He is an advisor to the Guthy-Jackson Charitable Foundation. He receives research support from the US NIH, National Institute of Allergy and Infectious Disease, and the US Department of Defense. He holds numerous patents and has received intellectual property interests from discoveries and technologies relating to health care. S.R. has no disclosures to declare. K.R. has received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité, Guthy-Jackson Charitable Foundation, and Arthur Arnstein Foundation; received travel grants from Guthy-Jackson Charitable Foundation; received speaker’s honoraria from Virion Serion and Novartis.
Appendix: Extramural Members of The Guthy-Jackson Charitable Foundation CIRCLES Study Group:
Lilyana Amezcua, MD, MS, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Jacinta M. Behne, The Guthy-Jackson Charitable Foundation, Beverly Hills, CA, USA; Megan K. Behne, The Guthy-Jackson Charitable Foundation, Beverly Hills, CA, USA; Jeffrey L. Bennett, MD, PhD, Departments of Neurology and Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA; Terrence F. Blaschke, MD, Stanford University, Stanford, CA, USA; Robert L. Carruthers, MD, Department of Medicine & Neurology, University of British Columbia, Vancouver BC, Canada; Tanuja Chitnis, MD, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Jeffrey A. Cohen, MD, Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Lawrence J. Cook, PhD, University of Utah, Salt Lake City, UT, USA; May H. Han, MD, Department of Neurology and Neurological Sciences, Division of Neuroimmunology and Multiple Sclerosis Center, Stanford University, Stanford, CA, USA; Ilana Katz Sand, MD, Mount Sinai Hospital, New York, NY; Ilya Kister, MD, NYU Langone Health, New York, NY, USA; Eric C. Klawiter, MD, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Michael Levy, MD, PhD, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Nancy M. Nealon, MD, Weill Cornell Medicine, New York, NY, USA; Sarah M. Planchon, PhD, Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Pavle Repovic, MD, Swedish Medical Center, Seattle, WA, USA; Claire S. Riley, MD, Department of Neurology, Columbia University Medical Center, New York, NY, USA; Nancy Sicotte, MD, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Terry J. Smith, MD, University of Michigan Medical School, Ann Arbor, MI, USA; Ben Thrower, MD, Shepherd Center, Atlanta, GA, USA; Leticia Tornes, MD, University of Miami, Miama, FL, USA; Anthony Traboulsee, MD, Department of Medicine & Neurology, University of British Columbia, Vancouver BC, Canada; Michael Yeaman, PhD, 1) Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, USA, 2) David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
P365/3185
Uncovering a systematic bias in the estimation of treatment effect on PIRA as a primary endpoint in MS clinical trials
Noemi Montobbio1,2, Alessio Signori1, Alessandro Cagol1,3, Cristina Granziera3, Carmen Tur4, Ludwig Kappos5, Maria Pia Sormani1
1University of Genoa, Department of Health Sciences (DISSAL), Genoa, Italy, 2Istituto Italiano di Tecnologia (IIT), Genoa, Italy, 3University Hospital and University of Basel, Translational Imaging in Neurology (ThINk) Basel - Department of Biomedical Engineering, Neurologic Clinic and Policlinic, MS Center, and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland, 4Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Multiple Sclerosis Centre of Catalonia (Cemcat), Barcelona, Spain, 5University Hospital and University of Basel, Neurologic Clinic and Policlinic, MS Center, and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland
Introduction: There has been growing interest in “disability progression independent of relapse activity (PIRA)” as a primary endpoint in multiple sclerosis (MS) clinical trials. However, the detection of PIRA events is inevitably influenced by the relative timing of visits and relapses.
Objectives/Aims: To uncover and correct a potential bias in estimating a treatment’s effect on PIRA, using synthetic data simulating a randomized controlled clinical trial.
Methods: We simulated 3-monthly spaced Extended Disability Status Scale (EDSS) values over a follow-up of two years resulting from a relapse-independent linear growth. Relapses were randomly generated over time sampling from a negative binomial distribution. Relapse-associated worsening (RAW) events were associated with a subset of relapses. We simulated a control and an experimental arm (n=800) with varying true treatment effects on relapses and on PIRA. We then computed the treatment effect on PIRA that would be estimated after the application of the PIRA definitions applied to date by using Cox models. We assessed the bias on the treatment effect on PIRA as the difference between the estimated HR on PIRA and the true HR on PIRA when changing different parameters (relapse rate in the control arm, treatment effect on relapses, and true treatment effect on PIRA). We tested the impact of different definitions of PIRA on the treatment effect detection bias.
Results: The true PIRA HR was systematically underestimated as the effect of treatment on relapses increased. For a scenario with a treatment-induced reduction of relapses by 60%, when the true HR on PIRA was 0.69, 95% confidence interval (CI) = (0.66,0.83), the estimated HR was 0.84, CI=(0.79, 1.02), bias=0.15, CI=(0.02, 0.31). Assuming no true effect on PIRA (true HR=1.02, CI=(0.96,1.19), the estimated HR was 1.20, CI=(1.14, 1.44), bias=0.18, CI=(0.02, 0.39). Defining PIRA as every non-RAW event (i.e. without applying the PIRA definitions that had been applied to date) provided a more accurate estimate of the true PIRA effect (maximum bias=0.07, CI=(-0.09, 0.25)), under the requirement of introducing a visit within the influence window of every relapse. Different scenarios will be presented.
Conclusion: A high treatment effect on relapses can mask a treatment’s effect on PIRA when applying standard PIRA definitions. For clinical trials aiming to analyse PIRA as a primary endpoint, we thus suggest the adoption of a “complementary” definition of PIRA, relying on accurate detection of all RAW events enforced by appropriate visit timing.
Disclosure of interest: Noemi Montobbio: nothing to disclose.
Alessio Signori: nothing to disclose.
Alessandro Cagol: nothing to disclose.
Cristina Granziera: nothing to disclose.
Carmen Tur: nothing to disclose.
Ludwig Kappos: nothing to disclose.
Maria Pia Sormani received consulting fees from Biogen, Merck, Novartis, Roche, Sanofi, Immunic, Alexion.
P366/3175
A new histopathological classification in tumefactive inflammatory demyelinating lesions
Yoshiki Takai1, Tatsuro Misu1, Kazuo Fujihara2
1Tohoku University Graduate School of Medicine, Neurology, Sendai, Japan, 2Fukushima Medical University, Multiple Sclerosis Therapeutics, Fukushima, Japan
Introduction: Tumefactive inflammatory demyelinating lesion (TDL) is defined as one with >2 cm in diameter and features of inflammatory demyelinating pathology. Its neuropathological findings are diverse and comprise a variety of pathologies, but there have been no attempts on its histopathological classification.
Objectives/Aims: To classify the histopathological features of TDLs and identify unique subgroups.
Methods: We used samples of brain biopsies from 42 cases of TDLs collected during the period between 1998 and 2022. Using immunohistochemistry, all demyelinating lesions were classified on the basis of established features of inflammatory demyelinating disease.
Results: The mean age at onset in the analyzed patients was 45.8 years (range: 14-85 years), with a sex ratio of 25(F):17(M). Confluent demyelinating lesions with well-defined borders and myelin-phagocytic macrophages localized throughout or at the margins of the lesion, typically seen in multiple sclerosis, accounted for 26% (11/42) of all cases. This was followed by perivenous demyelinating lesions, a feature of acute disseminated encephalomyelitis, in 17% (7/42) of them, and those with combinations of these pathologies were present in two cases. Balo’s disease-like concentric demyelinating lesions were also seen in three other cases. In addition, an unclassified demyelinating pattern characterized by widespread infiltration of myelin-phagocytosing macrophages in the tissue with nearly intact myelin sheath or myelin paler on KB staining was observed in five cases.
On the other hand, there were 14 other cases with necrotic tissue damage with loss of aquaporin 4 and astrocytes. Among them, seven had relatively minor perivascular tissue damage and necrotic demyelinating lesions around them, and four others showed inflammatory demyelinating lesions around extensive coagulation necrosis.
Conclusion: TDL are a group of diseases with a very diverse demyelinating pattern, but there are some cases with a common background pathology.
Disclosure of interest: Yoshiki Takai: nothing to disclose
Tatsuro Misu: nothing to disclose
Kazuo Fujihara: nothing to disclose
P367/3182
Radiological lag and brain MRI lesion dynamics within MOGAD attacks
Yael Hacohen1,2, Laura Cacciaguerra3, Dimitrios Champsas1,2, Omar Abdel Mannan1,2, John Chen3,4,5, Sean Pittock3,4, Eoin Flanagan3,4
1UCL Queen Square Institute of Neurology, Queen Square MS Centre, London, United Kingdom, 2University College London, Faculty of Brain Sciences, London, United Kingdom, 3Mayo Clinic, Neurology and Center for MS and Autoimmune Neurology, Rochester, United States, 4Mayo Clinic, Laboratory Medicine and Pathology, Rochester, United States, 5Mayo Clinic, Ophthalmology, Rochester, United States
Introduction: Long-term MRI follow-up after myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) attacks shows complete resolution of over 70% of brain T2-lesions. However, MRI studies focused on the dynamics of brain lesions within an acute attack are lacking.
Objectives/Aims: To analyze the dynamics of brain MRI in MOGAD patients during an acute attack including identifying those with an initial normal brain MRI.
Methods: This retrospective observational multicenter study included patients from two tertiary referral centers. Inclusion criteria were: (1) MOGAD diagnosis per 2023 consensus criteria; (2) presence of brain lesions during a clinical attack; and (3) availability of at least two brain MRIs acquired within one month from attack onset. First and follow-up brain MRIs were compared, and MRI dynamics evaluated.
Results: Our cohort included 51 patients (female sex, 28 [55%]; childhood onset, 32 [63%]) for a total of 54 attacks and 122 MRIs. Baseline MRI was acquired after a median of 5 days from symptom onset (interquartile range [IQR] 3-9). The initial brain MRI scan was normal whilst patients symptomatic (i.e., radiological latency) in 7/54 (13%) attacks. Of the patients given contrast, leptomeningeal enhancement was seen in 17/43 (40%) and parenchymal enhancement in 15/43 (35%). First follow-up MRI was performed after a median of 8 (4-12) days from baseline MRI and was due to worsening of patients’ clinical state (n=18) or transfer from other hospitals (n=7). Steroid treatment was initiated before the first follow-up MRI in 26/54 (48%). Compared to baseline, first follow-up brain MRI showed resolution of all lesions, 1 (2%); improvement, 7 (13%); no significant changes, 10 (19%); mixed changes (i.e., worsening of some lesions/new lesions and improvement/resolution of others), 11 (20%); and worsening or new lesions, 25 (46%). Leptomeningeal and parenchymal enhancement at first follow-up was seen in 12/49 (25%) and 22/49 (45%) respectively. Of these, 3/12 (25%) and 8/22 (36%) had no leptomeningeal or parenchymal enhancement at baseline.
Conclusion: Radiologic lag is common in MOGAD with normal MRI in 13% of patients in attack onset. MOGAD lesions are extremely dynamic with frequent appearance and disappearance within a single attack. This has both diagnostics and management implications.
Disclosure of interest: Y. Hacohen reports no disclosures.
L. Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, Sanofi and travel support for conferences by Merck Serono.
D. Champas reports no disclosures.
O. Abdel-Mannan reports no disclosures.
J.J. Chen reports payment for consultation from UCB, Horizon, and Roche.
S.J. Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants, personal fees, and non-financial support from MedImmune /Viela Bio; and personal fees for consulting from Genentech, Roche, UCB, and Astellas. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive). He also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B.
E.P. Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics, has received funding from the NIH (R01NS113828), and is a member of the medical advisory board of the MOG project. Dr. Flanagan is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports, and a patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity.
P368/3053
Relapse-Associated Worsening and Progression-Independent Relapse Activity in Ozanimod-Treated Participants With Relapsing Multiple Sclerosis From the RADIANCE and DAYBREAK Trials
Massimo Filippi1, Jon Riolo2, Jeffrey Cohen3, Hans-Peter Hartung4, Xavier Montalban5, Sven Meuth6, Leorah Freeman7, Tanjua Chitnis8, Cristina Granziera9,10,11, Diego Silva2, Erik DeBoer2, Chun-Yen Cheng2, Jennifer Reardon2, Chahin Pachai2, James Sheffield2, Bruce Cree12, Ludwig Kappos11
1Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy, 2Bristol Myers Squibb, Princeton, United States, 3Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, United States, 4Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf Germany; Brain and Mind Centre, University of Sydney, Australia; Department of Neurology, Medical University of Vienna, Austria; and Palacky University Olomouc, Olomouc, Czech Republic, 5Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain, 6Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany, 7Dell Medical School, The University of Texas at Austin, Austin, United States, 8Brigham and Women’s Hospital, and Massachusetts General Hospital, Harvard Medical School, Boston, United States, 9Translational Imaging in Neurology (ThINk) Basel, University Hospital Basel and University of Basel, Basel, Switzerland, Department of Biomedical Engineering, Faculty of Medicine, Basel, Switzerland, 10University Hospital Basel, Switzerland, Department of Neurology, Basel, Switzerland, 11Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital and University of Basel, Basel, Switzerland, Departments of Head, Spine and Neuromedicine, Clinical Research, Biomedicine, and Biomedical Engineering, Basel, Switzerland, 12Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, United States
Introduction: Ozanimod treatment was associated with significantly fewer relapses than interferon beta 1-a (IFN) in phase 3 relapsing multiple sclerosis (RMS) trials and provided sustained control of disability progression for up to 5 years in an open-label study.
Objectives/Aims: To determine the incidence and predictors of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in RADIANCE and DAYBREAK participants.
Methods: Participants were treated with ozanimod 0.46 mg/d or 0.92 mg/d or IFN 30 μg/wk for 24 months in phase 3 RADIANCE (NCT02047734), and completers were eligible to enrol in an ozanimod 0.92 mg open-label extension trial (DAYBREAK‒NCT02576717; data cutoff: 1Feb2022). We assessed 6-month confirmed disability progression (CDP, ⩾1-point increase in Expanded Disability Status Scale [EDSS] score from baseline), and participants were considered to have RAW if CDP onset occurred ⩽90 days of a relapse or PIRA if CDP onset occurred without relapse or >90 days after a relapse. For relapse with incomplete recovery, baseline EDSS was reset >90 days after relapse onset to identify the next PIRA event. Kaplan-Meier analysis and univariable Cox proportional hazards regression assessed incidence over time and predictors, respectively. P values were determined via Wald chi-square test.
Results: A total of 363 participants who received continuous ozanimod and 346 who switched from IFN were included. In up to 8 yrs of follow-up, 85.8% of participants were free of 6-month CDP. Among participants with CDP, 44.3% and 54.5% of those treated with continuous ozanimod had RAW or PIRA, 8% had both, and 57.8% and 43.4% of participants who switched from IFN to ozanimod had RAW or PIRA, respectively, 4.8% had both. RAW was observed in 10.7% of participants treated with continuous ozanimod and 13.9% of those who switched from IFN to ozanimod; PIRA was observed in 13.2% of participants treated with continuous ozanimod and 10.4% of those who switched from IFN to ozanimod. In both treatment groups, predictors of RAW with nominal P<0.05 included RADIANCE baseline EDSS score (positive association) and whole brain, cortical grey matter, and thalamic volumes (negative associations); these variables were not predictors of PIRA.
Conclusion: In ozanimod-treated participants with RMS, RAW and PIRA contributed similarly to disability progression over 8 yrs. Higher baseline EDSS scores and lower baseline whole brain, cortical grey matter, and thalamic volumes were predictive of RAW.
Disclosure of interest: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.
MF: Editor-in-Chief of the Journal of Neurology and associate editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen Pharmaceuticals, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva; participation in advisory boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Bristol Myers Squibb, Celgene, Lilly, Merck, Novartis, Roche, and Sanofi-Genzyme; and receives research support from Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck-Serono, Novartis, and Roche.
JVR, DS, ED, CYC JR, CP, and JKS: are employees and/or shareholders of Bristol Myers Squibb.
JAC: reports personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI, and serving as an editor of Multiple Sclerosis Journal
HPH: reports personal fees for consulting, serving on steering committees, and speaking from Bayer Healthcare, Biogen, Celgene, GeNeuro, Genzyme, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi, and Teva.
SGM: reports honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Bristol Myers Squibb/Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, Ono Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research, Bundesinstitut für Risikobewertung, Deutsche Forschungsgemeinschaft, Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Research Muenster, German Foundation Neurology, and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, Ono Pharma, Roche, and Teva.
XM: has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials, or participated in advisory boards of clinical trials in the past years with AbbVie, Actelion, Alexion, Biogen, Bristol Myers Squibb/Celgene, EMD Serono, Excemed, Genzyme, Immunic, Janssen Pharmaceuticals, MedDay, Merck, MSIF, Mylan, Nervgen, NMSS, Novartis, R. Hoffmann-La Roche, Sandoz, Sanofi-Genzyme, Teva, and TG Therapeutics
LF: has received consultancy fees from Genentech, Novartis, Celgene/Bristol Myers Squibb, EMD Serono, Horizon Therapeutics and TG Therapeutics; has received program sponsorship from EMD Serono; and has grant support from NIH/NINDS, PCORI, Genentech, and EMD Serono.
TC: reports having served on clinical trial advisory boards for Genzyme-Sanofi and Novartis Pharmaceutical; consulted for Biogen Idec, Genentech Roche, Genzyme-Sanofi, and Novartis; and received research support from Biogen, the Consortium for MS Centers, EMD Serono, Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Novartis, the Peabody Foundation, and Octave Biosciences.
CG: is an employee of The University Hospital Basel and has received the following fees, which were used exclusively for research support: advisory board and consultancy fees from Actelion, F. Hoffmann-La Roche, Janssen, Novartis, and Sanofi-Genzyme; speaker fees from Biogen, F. Hoffmann-La Roche, Genzyme-Sanofi, Janssen, and Novartis; and research support from F. Hoffmann-La Roche.
BACC: reports personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics and received research support from Genentech.
LK: receives no personal compensation. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from Actelion, Aurigia Vision AG, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera; license fees for Neurostatus-UHB products; and grants from Novartis, Innosuisse, and Roche.
P369/3110
Quantitative T1 identifies remyelinated cortical lesions in multiple sclerosis patients: a postmortem MRI study
Riccardo Galbusera1,2,3, Matthias Weigel1,2,3,4, Erik Bahn5, Sabine Schädelin1,2,3,6, Alessandro Cagol1,2,3,7, Po-Jui Lu1,2,3, Muhamed Barakovic1,2,3, Lester Melie-Garcia1,2,3, Jonas Franz5, Peter Dechent8, Govind Bhagavatheeshwaran9, Ludwig Kappos1,2,3, Wolfgang Brück5, Christine Stadelmann-Nessler5, Cristina Granziera1,2,3
1Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland, 2Department of Neurology, University Hospital Basel, Basel, Switzerland, 3Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland, 4Division of Radiological Physics, Department of Radiology, University Hospital Basel, Basel, Switzerland, 5Institute of Neuropathology, University Medical Center, Göttingen, Germany, 6Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland, 7Department of Health Sciences, University of Genova, Genova, Italy, 8Department of Cognitive Neurology, MR-Research in Neurosciences, University Medical Center Göttingen, Göttingen, Germany, 9National Institute of Neurological Disorders and Stroke, Bethesda, United States
Introduction: Recent studies have shown that remyelination in focal cortical lesions in multiple sclerosis (MS) is extensive, and even more pronounced than remyelination in white matter lesions (WML). While numerous MRI studies assessed remyelination in WML, none has been so far performed to investigate the role of MRI in the evaluation of cortical grey matter repair.
Objectives/Aims: To investigate whether postmortem quantitative MRI (qMRI) can detect areas of remyelination in the cerebral cortex of MS patients.
Methods: Five whole brains of deceased MS patients were imaged on a 3T whole-body MR-scanner using magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative T1 (qT1), and quantitative susceptibility mapping (QSM). Brain cutting was facilitated by using an individualized 3D-printed cutting box. We selected 41 excised blocks including the cerebral cortex, and we performed immunohistochemistry for Myelin Basic Protein (MBP). An experienced neuropathologist identified 16 areas of cortical demyelination (DM), 16 areas of remyelinated cortex (RM) and correspondent areas of normal-appearing cortex (NAC) close to the lesions on digitized MBP images. We then compared mean qMRI measures in DM and RM with NAC by means of Wilcoxon matched pairs tests and applied Bonferroni correction.
Results: In comparison to the adjacent NAC, qT1 and QSM were significantly different in DM areas (p value = 0.005 and 0.002 respectively), while only QSM differed significantly between RM and corresponding NAC areas (p value < 0.05). Specifically, mean qT1 was higher and mean susceptibility from QSM lower (hypointense) in DM areas (DM vs NAC: qT1 343.9±53.38 vs 293.1±67.21ms, QSM -6.271±14.46 vs 8.953±12.59 ppm), whereas mean susceptibility from QSM was lower in RM areas (RM vs NAC: -0.2151±9.831 vs 11.39±16.07 ppm). Both DM and RM regions did not show any significant alteration of MWF and MTR when compared to the corresponding NAC.
Conclusion: Among the qMRI parameters examined in this postmortem study, qT1 and QSM were the most sensitive measures of focal damage in the cerebral cortex of MS patients. While QSM remained hypointense in RM areas – as it was the case for DM areas -, in RM areas qT1 recovered to levels that were comparable to the surrounding NAC. Our data show that qT1 is sensitive to cortical remyelination and in combination with QSM – which permits to identify cortical lesions - can be used to identify focal areas of remyelination in the cortical ribbon of MS patients.
Disclosure of interest: Riccardo Galbusera: nothing to disclose.
Matthias Weigel: has received research funding by Biogen for developing spinal cord MRI.
Erik Bahn: nothing to disclose.
Sabine Schaedelin: nothing to disclose.
Alessandro Cagol: is supported by EUROSTAR E!113682 HORIZON2020, and received speaker honoraria from Novartis.
Lu Po-Jui: nothing to disclose.
Muhamed Barakovic: is an employee of Hays plc and a consultant for F. Hoffmann-La Roche Ltd.
Lester Melie-Garcia: nothing to disclose.
Jonas Franz: nothing to disclose.
Peter Dechent: nothing to disclose.
Govind Bhagavatheeshwaran: nothing to disclose.
Ludwig Kappos: has received no personal compensation. His institutions (University Hospital Basel/Foundation Clinical Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support: payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from: Actelion, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche.
Wolfgang Brück: nothing to disclose.
Christine Stadelmann: nothing to disclose.
Cristina Granziera: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (iii) research support from Siemens, GeNeuro, Roche. Cristina Granziera is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E!113682 HORIZON2020.
P370/3140
Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase III OCARINA II Study
Scott D. Newsome1, Ewa Krzystanek2, Krzysztof Selmaj3, Catarina Figueiredo4, Christian Wolf5, Hans-Martin Schneble4, Oscar Bortolami4, Heidemarie Kletzl4, Linda Bursic4, Dusanka Zecevic4, Diego Centonze6,7
1Johns Hopkins University, Baltimore, United States, 2Medical University of Silesia, Department of Neurology, School of Health Sciences in Katowice, Katowice, Poland, 3Centrum Neurologii, Lodz, Poland, 4F. Hoffman-La Roche Ltd, Basel, Switzerland, 5Lycalis sprl, Brussels, Belgium, 6Tor Vergata University, Department of Systems Medicine, Rome, Italy, 7IRCCS Neuromed, Unit of Neurology, Pozzilli, Italy
Introduction: Ocrelizumab (OCR) is an effective treatment for people with relapsing and primary progressive multiple sclerosis (RMS/PPMS). The currently available formulation is administered intravenously (IV) every 6 months. A novel OCR subcutaneous (SC) formulation in combination with recombinant human hyaluronidase is being developed.
Objectives/Aims: OCARINA II (NCT05232825) is a Phase III, randomised, open-label, controlled study designed to demonstrate non-inferiority in serum exposure of OCR when administered via SC versus IV route. This study assesses the pharmacokinetics, pharmacodynamics, safety, tolerability, immunogenicity, radiological and clinical effects of OCR SC versus OCR IV in patients with RMS or PPMS.
Methods: Patients with RMS or PPMS (18–65 years; Expanded Disability Status Scale [EDSS] score 0.0–6.5) were randomised 1:1 to receive OCR 920 mg SC or OCR 600 mg IV (administered as 300 mg x 2 IV infusions, 2 weeks apart) as first dose (Day 1; baseline [BL]). From Week 24, all patients were scheduled to receive OCR 920 mg SC every 24 weeks up to Week 96. The primary endpoint is the serum OCR area under the concentration-time curve from BL to Week 12 after SC administration compared with IV infusion. Brain MRI, changes in EDSS score, B-cell count, safety, tolerability, immunogenicity and patient satisfaction will also be assessed.
Results: Two-hundred-and-thirty-six patients across 41 sites were randomized to OCR SC (n=118) and IV (n=118). At BL, mean (standard deviation [SD]) age was 39.9 (11.4)/40.0 (11.9) years, median weight was 75 kg/72 kg and 65.3%/59.3% of patients were female in the SC and IV cohorts, respectively. The majority of participants have RMS (90.7%, 89.8%), the remainder have PPMS (9.3%, 10.2%). The mean (SD) duration since MS symptom onset was 7.7 (8.3) and 6.8 (7.1) years, and mean (SD) duration since MS diagnosis was 5.7 (6.8) and 4.8 (5.8) years in patients receiving OCR SC and IV, respectively. At BL, the mean (SD) number of gadolinium-enhancing T1 lesions was 0.5 (1.7) in OCR SC and 1.0 (2.5) in OCR IV-treated patients. Primary pharmacokinetic results and additional clinical and radiological outcomes from the first 12 weeks of OCARINA II will be presented.
Conclusion: The BL data of patients enrolled in OCARINA II reflect a typical MS population for which ocrelizumab IV is currently indicated. The new route of administration has the potential to deliver the clinical benefits of ocrelizumab while providing treatment flexibility along with an additional treatment choice.
Disclosure of interest: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
SD Newsome received consultancy fees for scientific advisory boards from Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, Novartis and TG Therapeutics; study lead PI for a Roche clinical trial programme; received research funding (paid directly to institution) from Biogen, Lundbeck, Roche, Genentech, National MS Society, The Stiff Person Syndrome Research Foundation, Department of Defense and Patient Centered Outcomes Research Institute.
E Krzystanek received consultancy fees for scientific advisory boards from Biogen, Merck-Serono, Bayer, Roche, Novartis and the Polish Multiple Sclerosis Society; study lead PI for Roche, TG Therapeutics, Merck, Biogen, Lundbeck and Janssen clinical trial programmes; received compensation for speaking services from Biogen, Bayer, Novartis, UCB, Roche, Merck-Serono, Teva, Lundbeck, Pfizer, Sandoz and Sanofi-Genzyme.
K Selmaj received honoraria for speaking, consulting and serving for advisory boards for Merck, Novartis, Roche, Biogen, Celgene, BMS and TG Therapeutics.
C Figueiredo is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
C Wolf is a partner at Lycalis sprl and reports compensation for his organisation for consulting from BMS, Celgene, Desitin, Immunic, Merck KGaA, Novartis, Roche, Synthon, Teva and Viatris; and for speaking from Synthon and Viatris.
H-M Schneble is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
O Bortolami is a contractor for F. Hoffmann-La Roche Ltd.
H Kletzl is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
L Bursic is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
D Zecevic is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
D Centonze acted as an advisory board member and received honoraria for speaking or consultancy fees from Alexion, Almirall, Amicus, Bayer, Biogen, BMS, Celgene, Chiesi, GW Pharmaceuticals, Horizon, Janssen, Lundbeck, Merck-Serono, Novartis, Roche, Sandoz, Sanofi-Genzyme, Viatris and Teva; he is also the Principal Investigator in clinical trials of Biogen, BMS, Merck-Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme and Actelion; preclinical and clinical research was supported by grants from Bayer Schering, BMS, Biogen, Celgene, Lundbeck, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva.
P371/3133
Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase Ib Dose-Finding OCARINA I Study
Scott D. Newsome1, Lawrence Goldstick2, Ben Townsend3, Catarina Figueiredo3, Christian Wolf4, Oscar Bortolami3, Heidemarie Kletzl3, Linda Bursic3, Johannes Schmidt3, Susanne Clinch3, Francesca Tessaro3, Dusanka Zecevic3, Robert Bermel5
1Johns Hopkins University, School of Medicine, Baltimore, MD, United States, 2University of Cincinnati, Waddell Centre for Multiple Sclerosis, Cincinnati, OH, United States, 3F. Hoffman-La Roche Ltd, Basel, Switzerland, 4Lycalis sprl, Brussels, Belgium, 5Mellen Centre for MS, Department of Neurology, Cleveland Clinic, Cleveland, OH, United States
Introduction: Ocrelizumab (OCR) is approved for the treatment of relapsing and primary progressive multiple sclerosis (RMS/PPMS) as an intravenous (IV) 600 mg formulation administered every 6 months. A novel OCR subcutaneous (SC) formulation utilising recombinant human hyaluronidase is being developed.
Objectives/Aims: OCARINA I (NCT03972306) is a Phase Ib, dose-escalation, open-label study designed to select the appropriate OCR SC dose for the subsequent Phase III trial. The dose selection was based on safety, tolerability and pharmacokinetic data in patients with RMS or PPMS.
Methods: Patients with RMS or PPMS (18–65 years; Expanded Disability Status Scale score 0.0–6.5) were enrolled into two groups: Previously treated with OCR IV (group A) or naive to OCR (group B). Patients received single ascending doses of OCR SC (40, 200, 600, 1,200 mg). Following dose escalation, new patients in group A were randomised (1:1) to receive either a single 600 mg OCR IV or the candidate SC dose, which was predicted to result in similar exposure as the 600 mg IV dose, while being safe and well tolerated. The area under the concentration-time curve for both formulations was used to select the OCR SC dose. Patients in all cohorts could enter a dose continuation phase receiving the candidate dose, then later the final selected dose, for up to 3 years.
Results: In cohort A (n=53 OCR SC; n=35 OCR IV) and cohort B OCR SC (n=46), the majority of patients were female (72.7%/63.0%); mean age (standard deviation) at baseline was 45.7 (10.2) and 39.7 (9.2) years, respectively. During the dose escalation phase, OCR SC was well tolerated across all doses tested. Initially 1,200 mg was selected as the candidate SC dose, but subsequently 920 mg was chosen as the final SC dose based on all data available. Median treatment duration with OCR SC 1,200 mg or 920 mg was 96 weeks, with 94.7% receiving ⩾3 doses. Injection site reactions were the most common adverse events, with erythema, pain and swelling being the most common symptoms, all of which were mild/moderate. Additional safety and tolerability data, results on immunogenicity and patient satisfaction will be reported.
Conclusion: The selected ocrelizumab SC 920 mg dose was well tolerated and is expected to provide a similar exposure to the approved 600 mg ocrelizumab IV dose in a larger cohort, which is being assessed in the Phase III OCARINA II (NCT05232825) study.
Disclosure of interest: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
SD Newsome received consultancy fees for scientific advisory boards from Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, Novartis and TG Therapeutics; study lead PI for a Roche clinical trial programme; received research funding (paid directly to institution) from Biogen, Lundbeck, Roche, Genentech, National MS Society, The Stiff Person Syndrome Research Foundation, Department of Defense and Patient Centered Outcomes Research Institute.
L Goldstick received consultancy fees from EMD Serono, Bristol Myers Squibb, Biogen, Sanofi-Genzyme, VieloBio/Horizon Therapeutics, Lilly, TG Therapeutics, and Roche/Genentech; he has also received research support from Biogen, Roche/Genentech and Sanofi-Genzyme.
B Townsend is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
C Figueiredo is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
C Wolf is a partner at Lycalis sprl and reports compensation for his organization for consulting from BMS, Celgene, Desitin, Immunic, Merck KGaA, Novartis, Roche, Synthon, Teva, and Viatris; and for speaking from Synthon and Viatris.
O Bortolami is a contractor for F. Hoffmann-La Roche Ltd.
H Kletzl is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
L Bursic is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
J Schmidt is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
S Clinch is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
F Tessaro is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
D Zecevic is an employee of and a shareholder in F. Hoffmann-La Roche Ltd.
R Bermel received consultancy fees from Astra Zeneca, Biogen, EMD Serono/Merck, Genzyme/Sanofi, Roche/Genentech, LabCorp, Lilly, Novartis, TG Therapeutics, and VielaBio/Horizon; and he receives research support from Biogen, Genentech, and Novartis.
P372/3212
The effect of ethnicity and other comorbidities in creating normative reference values for blood NfL levels
Carlos de Miguel Sánchez1,2, Francesca Ammoscato2, Afrah Shibu3, Bader Mohamed3, Jens Kuhle4, Pascal Benkert4, Sharmilee Gnanapavan2,3
1Hospital General Universitario Gregorio Marañón, Neurology, Madrid, Spain, 2Queen Mary University of London, Neuroscience, Surgery and Trauma, London, United Kingdom, 3Barts Health NHS, Royal London Hospital, Neurology, London, United Kingdom, 4MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience, Clinical Research, Basel, Switzerland
Introduction: Neurofilament light chain (NfL) levels have been demonstrated to be a good prognostic tool in MS. However, blood NfL test is more attractive due to its less invasiveness. For this to be possible a representative reference population is needed; cohorts vary between countries, and are influenced by age, BMI, diabetes and GFR. Moreover, their composition is mainly Caucasian in makeup and the influence of ethnicity has not been studied.
Objectives/Aims: To assess the normal control range of blood NfL levels in an ethnically diverse UK population and to study the influence of ethnicity and comorbidities on blood NfL levels.
Methods: 466 participants were recruited from the Royal London Hospital (staff and patients) in the UK. Each individual completed a questionnaire about their medical history. Subjects with neurological or severe comorbidities were excluded. NfL levels were measured using Simoa HD-X Analyzer by Quanterix®. Correlation between serum and plasma levels was assessed using Passing-Bablok regression and quantified using Spearman’s rho. The association between NfL and factors influencing the biomarker concentration were investigated in separate linear models with log(NfL) and NfL Z-score as dependent variables.
Results: 424 subjects were analyzed; 57.1% were male, mean age was 46 and mean BMI was 26.61, 48.1% of the subjects were White, followed by Asian, Black, Mixed, Arab and others, 22.2% had hypertension, 11.6% diabetes, and 17.1% dyslipidemia, 70.3% were non-smokers, 13.4% ex-smokers and 16.3% current smokers, 87.3% were abstinent or casual consumers, the rest moderate to heavy consumers. Between ethnicities variables were similar, except smoking and alcohol use which was more prevalent in Whites. Median for serum and plasma NfL (sNfL and pNfL) were 14.88pg/mL (13.52-16.24 95%CI) and 12.97pg/mL (11.82-14.12 95%CI). Both were correlated (Spearman’s rho=0.484), but sNfL levels were on average 19% higher compared to pNfL. When comparing sNfL levels with the published Swiss cohort (n=4532) and calculation NfL Z-scores, the shift in median Z-score was 0.32 (1/3 of a standard deviation). Modelling log(NfL) as dependent variable, and age, BMI, diabetes and ethnicity as predictors explained 30.7% of the variation in raw NfL. Conversely, modelling using NfL Z-scores (which are already adjusted for age and BMI), diabetes and ethnicity explained less than 1% of the variation in NfL Z-scores.
Conclusion: We saw some small differences in NfL Z-score by ethnicity, but largely the main factors that influenced NfL were age and BMI.
Disclosure of interest: Carlos: Nothing to disclose.
Franchesca: Nothing to disclose.
Bader: Nothing to disclose.
Afrah: Nothing to disclose.
Jens: J.K. received speaker fees, research support, travel support, and/or served on advisory boards by the Progressive MS Alliance, Swiss MS Society, Swiss National Research Foundation (320030_189140 /1), University of Basel, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi.
Pascal: Nothing to disclose.
Sharmilee: Consulting fees from Novartis, Merck, Roche, Biogen, Sanofi Genzyme, CMSC, medscape. Grants from Merck, Takeda, Sanofi Genzyme, Novartis, UK MS Society, NMSS.
P373/3217
Serum neurofilament light chain z-scores and glial fibrillary acidic protein levels decrease at 1 year of DMT initiation, mostly under monoclonal antibodies, and said decrease could predict NEDA at 2 years in subjects with RRMS
Victoria Fernández1, Agustín Pappolla1, Pere Carbonell1, Mar Tintoré1, Marta Rodríguez-Barranco1, Mireia Castillo1, Lucia Gutierrez1, Nicolas Fissolo1, Olmo Leon-Plaza2, Helena Ariño1, Cristina Auger3, Luca Bollo1, Joaquin Castillo-Justribo1, René Carvajal1, Alvaro Cobo Calvo1, Carmen Espejo1, Ingrid Galán1, Claudia Guio-Sanchez1, Delon La Puma1, Luciana Midaglia1, Neus Mongay-Ochoa1, Carlos Nos1, Breogán Rodríguez1, Jaume Sastre-Garriga1, Paula Tagliani1, Carmen Tur1, Angela Vidal-Jordana1, Andreu Vilaseca1, Javier Villacieros-Alvarez1, Ana Zabalza1, Alex Rovira Cañellas3, Manuel Comabella1, Xavier Montalban1, Jordi Rio1, Georgina Arrambide1
1Multiple Sclerosis Centre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain, 2Hospital Universitario Virgen de la Victoria, Servicio de Neurología, Malaga, Spain, 3Dept. of Radiology, Neuroradiology-Vall Hebron University Hospital, Barcelona, Spain
Introduction: Serum NfL (sNfL) decrease after DMT initiation but evidence using sNfL z-scores or serum GFAP (sGFAP) is limited.
Objectives/Aims: We aimed to assess sNfL z-scores and sGFAP levels with clinical and MRI data before and 1 year after DMT and their predictive value for NEDA in RRMS.
Methods: Real-life study of 352 DMT initiations. We measured sNfL and sGFAP at baseline and year 1 (Y1) of DMT. We studied sNfL and sGFAP correlations with relapses, EDSS and MRI activity before and at Y1 of DMT; their changes at Y1; and used uni and multivariate logistic regression to assess them at Y1 as predictors of NEDA at years 2 (Y2) and 3 (Y3) of DMT initiation. We did similar analyses in treatment naïves (n=198).
Results: Of 352 DMT, 153 (43.4%) were injectables, 89 (25.3%) orals and 110 (31.3%) monoclonal antibodies (Mabs). At baseline, sNfL z-scores correlated (rho) with relapses in the prior 2 years (0.268, p<0.001), new T2 lesions (0.514, p<0.001) and contrast-enhancing lesions (CEL) (0.506, p<0.001); sGFAP correlated with EDSS (0.244, p<0.001) and CEL (0.236, p<0.001). Results were similar at Y1 in 342 DMT (10 excluded due to discontinuation before Y1). Results in naïves were similar. sNfL z-scores decreased at Y1 [mean (SD) baseline-Y1 difference]: injectables -0.56 (1.27), orals -0.40 (1.18), Mabs -0.87 (1.13) in all; -0.65 (1.17), -84 (1.02) and -1.67 (1.16) in naïves. sGFAP [median (IQR)] remained stable with orals and Mabs but increased with injectables [8.8 (-18.7-32.4); naïves 7.9 (-18.4-32.4)]. It decreased in naïves treated with Mabs [-11.4 (-42.1-14.9)]. As for Y2 NEDA (n=192), univariate OR (95% CI) were: sNfL z-score at Y1 1.414 (1.077-1.856), p=0.013; sNfL z-score change 1.303 (1.029-1.650), p=0.028; sGFAP at Y1 1.004 (0.999-1.008), p=0.125; sGFAP change 1.004 (0.998-1.009), p=0.175. Naïves 1.754 (1.155-2.661), p=0.008; 1.544 (1.066-2.236), p=0.022; 1.009 (1.001-1.018), p=0.036; 1.009 (0.999-1.018), p=0.076. sNfL z-score change remained significant in multivariate models: all 1.477 (1.013-2.152), p=0.043; naïves 1.966 (1.050-3.680), p=0.035. sGFAP change results were: all 1.008 (0.999-1.017), p=0.073; naïves 1.011 (0.997-1.026), p=0.121. Neither biomarker at Y1 predicted Y3 NEDA.
Conclusion: sNfL correlate with inflammatory activity and decrease after DMT, especially with Mabs. sGFAP correlates with EDSS and CEL and decreases with Mabs in naïves. Whereas results are limited by sample size, they suggest sNfL and sGFAP changes at Y1 of DMT are predictors of NEDA at Y2, especially in treatment naïves.
Disclosure of interest: V. Fernández is an ECTRIMS clinical fellowship awardee 2022-2023.
A. Pappolla has received travel expenses from Roche and speaking honoraria from Novartis. He was an ECTRIMS Clinical Training Fellowship awardee during 2021, and is currently performing an MSIF-ARSEP Fellowship program.
P. Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació
privada Cemcat for statistical analysis.
M. Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.
M. Rodríguez-Barranco reports no disclosures.
M. Castillo reports no disclosures.
L. Gutiérrez reports no disclosures.
N. Fissolo reports no disclosures.
O. León Plaza reports no disclosures.
H. Ariño received a grant from Instituto de Salud Carlos III, Spain; JR22/00072.
C. Auger reports no disclosures.
L. Bollo's research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022.
J. Castilló reports no disclosures.
A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.
M. Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis.
C. Espejo reports no disclosures.
I. Galan reports no disclosures.
C. Guío-Sánchez is an ECTRIMS clinical fellowship awardee 2022-2023 and has received travel expenses from Sanofi-Genzyme, Biogen-Inc and Merck.
D. Lapuma reports no disclosures.
L. Midaglia reports no disclosures.
N. Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018). She has also received speaking honoraria and travel expenses from Merck and Roche.
C. Nos reports no disclosures related to this work.
S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed and MSD; as well as research support from Novartis.
B. Rodriguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis.
J. Sastre-Garriga serves as co-Editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the last twelve months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck.
P. Tagliani was an ECTRIMS clinical fellowship awardee 2019-2020.
C. Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.
A. Vidal-Jordana has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.
A. Vilaseca has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00247)
J. Villacieros-Álvarez has received a grant from Instituto de Salud Carlos III, Spain; FI21/00282
A. Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant from Novartis.
A. Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950) from Instituto de Salud Carlos III, Spain.
X. Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.
J. Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck- Serono, Novartis, Teva, Roche, and Sanofi-Aventis.
G. Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. GA is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.
P374/3235
Increased risk of cancer in multiple sclerosis: a birth cohort study in Wales using routinely collected data
Madeeha Khan1, James Witts2, Rod Middleton2, Tim Friede3, Richard Nicholas1
1Imperial College, Brain Sciences, London, United Kingdom, 2Swansea University, Swansea, United Kingdom, 3University Medical Centre Göttingen, Department of Medical Statistics, Göttingen, Germany
Introduction: Multiple sclerosis (MS) has been associated with a range of cancers. However, a more recent concern is the cancer risk associated with the use of increasingly effective disease modifying treatments (DMTs). A recent meta-analysis and meta-regression did not confirm an effect of DMTs within the timeframe of a trial but did show cancer was increasing in the MS population compared to controls (Papadopoulos et al., 2022). A major issue with any study on cancer risk, is differences between the collection of the target population and the comparator population together with the systematic identification of cancer making comparisons difficult due to differing environmental exposures.
Objectives/Aims: To determine if MS is associated with an increased risk of cancer in the population of Wales using routinely collected health data and compare this to the known risk of cancer from Epstein-Barr virus (EBV).
Methods: The Secure Anonymized Information Linkage (SAIL) databank, a database that collects data on 90% of the primary care population and 100% of the hospital population in Wales from 1970 onwards. We utilized an algorithm that identified subjects with MS within this population with 96% sensitivity (Witts et al., 2022). The SAIL databank collects all secondary care data and cancer cases were identified using ICD10 codes and their date of onset. EBV results were extracted from linked pathology data.
Results: In the population of 4.6 million people from 1st January 1970 to 31st December 2020 we identified 9586 people with MS. Cancer risk was higher in MS subjects (10.9%) compared to the unaffected population (8.1%, p<0.0001). Onset of the first cancer occurred earlier in MS than in the control population. Birth cohort analysis (1930-1960, 1960-1990, 1990-2020) found this effect was present in those born after 1960. In contrast, the risk of cancer with EBV infection was present in all birth cohorts. Cox analysis controlling for the effects of EBV and birth cohort found that cancer with still significantly elevated in pwMS compared to the control population.
Conclusion: MS is associated high rates of cancer and earlier onset compared to control population. The increased rate appears to be a more recent phenomenon associated with those born after 1960. In contrast in EBV the increased rate of cancer was present in all birth cohorts.
Disclosure of interest: Richard Nicholas: attended paid advisory boards with Roche, Novartis and Biogen
James Witts: nothing to disclose
Madeeha Khan: nothing to disclose
Rodden Middleton: nothing to disclose
Tim Friede: personal fees from Bayer, BiosenseWebster, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Fresenius Kabi, Galapagos, Immunic, Janssen, LivaNova, Novartis, Roche, Vifor; all outside the submitted work
P375/3125
Similarities in Brain Damage Across the Spectrum of Multiple Sclerosis
Robert Bermel1, Marius Thomas2, Laura Gaetano2, Michela Azzarito2, Piet Aarden2, Amy Racine2, Yang Sun3, Habib Ganjgahi4, Thomas Nichols3, Heinz Wiendl5,6, Bernd C. Kieseier2, Dieter Häring2, Douglas L. Arnold7
1Department of Neurology, Mellen MS Center, Cleveland Clinic, Cleveland, Ohio, United States, 2Novartis Pharma AG, Basel, Switzerland, 3Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom, 4Department of Statistics, University of Oxford, Oxford, United Kingdom, 5Department of Neurology, University Hospital Münster, Münster, Germany, 6Brain and Mind Institute, University of Sydney, Sydney, Australia, 7Brain Imaging Centre, Montréal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada
Introduction: Multiple Sclerosis (MS) clinical phenotype descriptors have been defined and revised based on consensus definition. However, relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive MS (PPMS) have no biologically distinct features.
Objectives/Aims: Our objective was to study disease related brain damage across the MS disease spectrum and to investigate whether PPMS could be integrated into the RRMS-SPMS continuum.
Methods: Using clinical and imaging data from ~8000 patients across the spectrum of MS (RRMS n=5986; SPMS n=1445, PPMS n=625) from the Novartis-Oxford MS database (9 clinical trials), we first selected key baseline variables (among demographics, clinical and MRI measures including the T2 lesion volume) in determining the baseline normalized brain volume (NBV) using random forest variable importance in the RRMS-SPMS continuum. Secondly, we used a linear regression with the selected covariates to model baseline NBV in RRMS/SPMS patients. To compare NBV prediction accuracy for RRMS/SPMS versus PPMS, 10-fold cross-validation was used and the prediction accuracy of the model on the corresponding RRMS/SPMS hold-out data was compared to the prediction accuracy of the same model on the PPMS dataset. Accuracy for NBV was measured with mean absolute percentage error (MAPE) with a scale-invariant approach. Jacobian maps derived from MRIs of placebo-treated relapsing-onset MS vs PPMS patients over two years were qualitatively compared.
Results: At baseline, the cumulative level of brain damage (reflected by higher T2 lesion volume and lower NBV) and disability levels were higher in SPMS patients compared to RRMS patients. Comparing PPMS patients to patients in the RRMS-SPMS continuum, PPMS patients had a notable T2 lesion volume and a NBV more comparable to SPMS rather than RRMS. From the tested variables, T2 lesion volume was the most relevant disease related predictor of the NBV (other relevant baseline predictors were age, duration of MS, EDSS and sex). Across the RRMS-SPMS continuum, NBV was predicted with a MAPE of 3.74%. Similar accuracy (MAPE=3.63%) was obtained when the RRMS-SPMS model was used to predict PPMS patients’ NBV. The averaged Jacobian maps showed that regional contraction and expansion in PPMS patients were similar to those in relapsing-onset MS.
Conclusion: Our analysis supports the view that, biologically, at the level of the brain, RRMS-SPMS can be regarded as a disease spectrum over time, and that PPMS is fundamentally part of that same spectrum.
Disclosure of interest: Funding statement: The study was supported by Novartis Pharma AG, Switzerland. Robert Bermel has served as a consultant for Astra Zeneca, Biogen, EMD Serono, Genzyme/Sanofi, Genentech/Roche, Novartis, TG Therapeutics, and VielaBio. He receives research support from Biogen, Genentech, and Novartis, and shares rights to intellectual property underlying the Multiple Sclerosis Performance Test, currently licensed to Qr8 Health and Biogen.
Marius Thomas, Laura Gaetano, Michela Azzarito, Piet Aarden, Amy Racine, Bernd Kieseier, Dieter Häring are employees of Novartis.
Yang Sun, Habib Ganjgahi, Thomas E. Nichols is an employee of University of Oxford
Heinz Wiendl received honoraria for acting as a member of Scientific Advisory Boards for Janssen, Merck and Novartis as well as speaker honoraria and travel support from Alexion, Amicus Therapeuticus, Biogen, Biologix, Bristol Myers Squibb, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Medison, Merck, Novartis, Roche Pharma AG, Genzyme, TEVA and WebMD Global. He is acting as a paid consultant for Biogen, Bristol Myers Squibb, EMD Serono, Idorsia, Immunic, Immunovant, Janssen, Johnson & Johnson, Novartis, Roche, Sanofi, the Swiss Multiple Sclerosis Society and UCB. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics Inc., Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma, UCB Biopharma.
Douglas Arnold has received consulting fees from Biogen, Celgene, Frequency Therapeutics, Genentech, Merck, Novartis, Race to Erase MS, Roche, and Sanofi-Aventis, Shionogi, Xfacto Communications; grants from Immunotec and Novartis, and an equity interest in NeuroRx.
P376/3029
real word efficacy of cladribine treatment in multiple sclerosis patients using objective biomarkers: quantitative MRI and serum neurofilament levels
Petrou Panayiota1, Ibrahim Kassis1, Nour Eddine Yaghmour1, Tehila Epstein1, Ariel Ginzberg1, Dimitrios Karussis1
1
Unit of Neuroimmunology and Multiple Sclerosis Center and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel., Jerusalem, Israel
Introduction: High efficacy therapies (HET) have become the mainstay therapy in the majority of active Multiple sclerosis (MS) patients. Still there are non-responders to HET and there are only limited data on the effect of such therapies on objective biomarkers of MS activity
Objectives/Aims: Quantitative automated MRI in conjunction with other biomarkers such as Neurofilament (NF-L), are useful tools for the detection of “silent” disease activity and objective response to treatments.
Methods: This study included 103 patients with active MS, who started treatment with Cladribine and followed up for at least 2 years. Inclusion criteria: ⩾1 relapse during the last 2 years, or EDSS worsening by ⩾1 in subjects with a baseline EDSS score of ⩽4.0, and of ⩾0.5 in patients with a baseline EDSS >4.5, ⩾3 new T2 lesions or ⩾2 Gd-enhancing T1 lesions during last one year. Three groups of patients were included: (A)34 patients with active disease under other treatment (B)23 Naïve patients (C)51 untreated patients, matched for age and EDSS,as control group. (A) mean EDSS: 3.4,mean age 38.6, (B) mean EDSS 2.5,mean age 38.6,(C) mean EDSS 2.82,mean age 41.7.All patients underwent MRI scan at two time points: at baseline and one year after treatment. Quantitative measurements of MRI included total FLAIR volume lesions measured by ICOMETRIX® and NEUROQUANT®. Serum NFL were collected in a subgroup of 7 patients. Levels of NF-L were be measured by SIMOA technique.
Results: Mean total lesion load in Group A reduced after treatment, from 9.4 ml to 8.79 (DELTA: -0.736 +/- 2.57). In Group B, the reduction was more prominent (DELTA: 1.334+/-1.53ml). In the control group C, there was an increase in total lesion load from 6.26 ml to 8.06 ml (DELTA + 1.620ml +/- 2.14). Difference in lesion load changes between group B and C was highly significant (P<0.0001, Wilcoxon sum-rank test). Mean serum NFL levels were 17.4pg/ml at baseline and reduced to 11.4pg/ml one year after treatment. (p=0.11).
Conclusion: In this study, we found significant indications of stabilization and even reduction in MRI T2 lesion load in patients with active MS treated with cladribine.Both previously-treated and naïve patients showed a similar trend, but the beneficial effect was more significant in the naïve-to-treatments patients. In the matched untreated group, we observed an increase of lesion load. A trend of reduction in serum NFL levels in a subgroup of cladribine-treated patients, was also noticeable. These data support the concept of early aggressive immunotherapy in active MS.
Disclosure of interest: Nothing to disclose
P377/3038
effects of repeated autologous mesenchymal stem cells transplantation on cognition and serum biomarkers in progressive multiple sclerosis: interim analysis of an open label extension trial
Petrou Panayiota1, Ibrahim Kassis1, Nour Eddine Yaghmour1, Tehila Epstein1, Ariel Ginzberg1, Dimitrios Karussis1
1
Unit of Neuroimmunology and Multiple Sclerosis Center and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel., Jerusalem, Israel
Introduction: Intrathecal injection (IT) of autologous, bone marrow-derived mesenchymal stem cells (MSC) was shown robust clinical and radiological effects in a previous double-blind randomized study from our center (NCT02166021).
Objectives/Aims: We evaluate here the effect of repeated MSC transplantations on cognition and objective serum biomarkers of neuroinflammation and neurodegeneration, namely, neurofilaments light chains (NFL) and glial fibrillary acidic protein (GFAP), in an open-label extension trial.
Methods: 48 patients with progressive MS (PPMS and SPMS) who participated in the previous double-blind trial with MSC injections, were included in the current extension study. Four cognitive tests (SDMT, CVLT, BVMT, COWAT) and testing for serum NFL and GFAP levels using Quanterix technology (SIMOA) were performed at baseline before treatment, and at 4-5 time points following the first MSC-injection.
Results: 17 patients were treated with at least 2 intrathecal injections of MSC, 3-6 months apart, and 12 received 3 MSC injections. Nine out of 15 tested patients, treated by at least two injections of MSC, improved in 25 feet walking, by 5-18 %. The average z-score of 4 cognitive tests (SDMT, CVLT, BVMT, COWAT) improved from 0.11 at baseline to 0.33 after three MSC injections, in a period of one year. Thirteen out of 22 patients who received at least one MSC treatment, showed improvement in the SDMT scores. Six out of 17 patients improved by more than 4 degrees in SDMT, in three consecutive tests over a year. The NFL levels were reduced from a mean of 15.7 pmol/ml at baseline to 12.8 pmol/ml during the whole post-treatment period. GFAP levels were reduced from 191.4 pmol/ml at baseline, to 155.4 pmol/ml during the whole post-treatment year.
Conclusion: The interim analysis of this extension trial reveal indications of significant beneficial effects on cognition, and on objective biomarkers of neuroinflammation and neurodegeneration, in patients treated with repeated IT injections of autologous MSC.
Disclosure of interest: Nothing to disclose
P378/3082
Safety Findings in Patients With AQP4+ NMOSD Who Received Eculizumab or Ravulizumab in the PREVENT and CHAMPION-NMOSD Studies and Had Received Rituximab Within 1 Year Prior to Enrolment
Michael Levy1, Becky Parks2, Kerstin Allen2, Arshad Mujeebuddin2, Melissa Taney2, Yasmin Mashhoon2, Jérôme de Seze3
1Massachusetts General Hospital, Department of Neurology, Boston, United States, 2Alexion, AstraZeneca Rare Disease, Boston, United States, 3Hopitaux Universitaires Strasbourg, Department of Neurology, Strasbourg, France
Introduction: Rituximab (RTX) is often prescribed off-label in early lines of therapy for patients with anti-aquaporin-4-positive neuromyelitis optical spectrum disorder (AQP4+ NMOSD); however, patients frequently need to be transitioned to more efficacious therapies such as C5 complement inhibitors (C5ITs) to prevent relapses. Safety outcomes in patients who transition from RTX to C5IT is an important consideration. PREVENT (NCT01892345) and CHAMPION-NMOSD (NCT04201262) were phase 3 C5IT studies evaluating safety and efficacy of eculizumab and ravulizumab, respectively, in adult patients with AQP4+ NMOSD.1,2
Objectives/Aims: To assess safety outcomes in patients who initiated C5IT treatment within 1 year of last RTX exposure in the PREVENT and CHAMPION-NMOSD studies.
Methods: A post hoc analysis was conducted in C5IT-treated patients from both PREVENT and CHAMPION-NMOSD comparing safety outcomes between those who had or had not received prior RTX treatment within >3 to ⩽12 months of first-dose eculizumab or ravulizumab. Patients who received RTX within ⩽3 months of screening were not permitted to enrol in either trial. Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and deaths or withdrawals due to TEAEs were analysed.
Results: Thirty-eight patients received RTX within >3 to ⩽12 months prior to first C5IT dose and 116 patients did not. In prior-RTX-treated patients, mean time from last RTX dose to first C5IT dose was 6.53 months (SD 1.96). The incidence of patients experiencing TEAEs (94.7% vs 90.5%) and TESAEs (21.2% vs 24.1%) was similar in both groups. Most events were mild or moderate in severity and were assessed by investigators as unrelated to C5IT. Infections and infestations were the most common type of TEAE in both groups (71.1% vs 71.6%, respectively). In the prior-RTX group, no deaths occurred, and no patients experienced a TEAE or TESAE leading to C5IT withdrawal. When analysed by time since last RTX use, no differences in TEAE/TESAE incidence rates were detected in patients who had RTX within 3–6 months of receiving C5IT versus those who received RTX within 6–9 or 9–12 months.
Conclusion: No differences in safety outcomes were observed among patients with RTX use within >3 to ⩽12 months prior to first C5IT dose in the PREVENT and CHAMPION-NMOSD studies. These findings provide important information to guide clinical decision-making when considering a switch from RTX to C5IT in patients with AQP4+ NMOSD who received RTX within the preceding 3–12 months.
Disclosure of interest: Dr Levy: receives fees from Alexion, Horizon Therapeutics, and Genentech.
Becky Parks, Kerstin Allen, Arshad Mujeebuddin, Melissa Taney, and Yasmin Mashhoon: are employed by Alexion, AstraZeneca Rare Disease, and hold stock in AstraZeneca.
Professor Jérôme de Sèze: has received consulting fees from Biogen, Teva, BMS/Celgene, Roche, Novartis, Janssen, Merck, Alexion, UCB, Sanofi Genzyme, Horizon Therapeutics; and honoraria from Biogen, Teva, BMS/Celgene, Roche, Novartis, Janssen, Merck, and Alexion.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
P379/3094
Validation of the 2023 diagnostic criteria for MOGAD at a tertiary care center
Linda Nguyen1, Sumit Singh2, Fabricio Feltrin2, Rebekah Clarke2, Cynthia Wang1, Lauren Tardo1, Benjamin M. Greenberg1
1UT Southwestern Medical Center, Neurology, Dallas, United States, 2UT Southwestern Medical Center, Radiology, Dallas, United States
Introduction: An international panel recently proposed a diagnostic criteria for myelin oligodendrocyte glycoprotein associated disease (MOGAD).
Objectives/Aims: To evaluate the application of the 2023 criteria to cases with MOG-IgG seropositivity and MRI at disease onset.
Methods: A retrospective study was conducted analyzing MOG-IgG positive pediatric and adult patients seen at a tertiary care center in Dallas, Texas from January 2014 to April 2023. Only patients with MRI and MOG-IgG titer available at onset were included. Cases were reviewed for fulfillment of MOGAD criteria, determined by the treating neurologists/neuroimmunologists and study authors. In conjunction, MRIs were reviewed for both typical features of MOGAD and atypical features more suggestive of multiple sclerosis or neuromyelitis optica spectrum disorder by neuroradiologists blinded to the patient’s disease course. MOG-IgG titer at onset was stratified into low (<1:100) vs high (⩾1:100). Patients with positive MOG-IgG and meeting MOGAD criteria were considered true positives.
Results: Of the 268 patients with positive serum MOG-IgG detection at least once, 101 (60 children, 41 adults) had positive MOG-IgG titer and MRI at onset available for review. Fourteen (13.9%) patients (3 children, 11 adults) had their results designated as false positive. The positive predictive value (PPV) was 86.1% (total), 49.3% (low titer; 1:20, 43.8%; 1:40, 81.8%), and 95.9% (high titer; 1:100, 91.9%; ⩾1:1000, 100.0%). In children only, the PPV was 95.0% (total), 75.0% (low titer; 1:20, 60.0%; 1:40, 85.7%), and 100.0% (high titer). In adults only, the PPV was 73.2% (total), 46.7% (low titer; 1:20, 36.4%; 1:40, 75.0%), and 88.5% (high titer; 1:100, 78.6%; ⩾1:1000, 100.0%).
Conclusion: In our cohort, the PPV was high at titer of ⩾1:40. Children had a higher PPV than adults at low and high titers.
Disclosure of interest: Nothing to disclose.
P380/3122
Healthier dietary intake is associated with less clinical severity in people with multiple sclerosis: a cross-sectional study within the UK MS Register
Steve Simpson-Yap1,2,3, Shelly Coe4, Sandra Neate1, Thanasis Tektonidis4, Lucinda Black5, Nupur Nag1, Yasmine Probst6,7, Rod Middleton8, Richard Nicholas9, Jeanette Reece1
1The University of Melbourne, Neuroepidemiology Unit, Melbourne School of Population & Global Health, Carlton, Australia, 2The University of Melbourne, CORe, School of Medicine, Parkville, Australia, 3University of Tasmania, Menzies Institute for Medical Research, Hobart, Australia, 4Oxford Brookes University, Department of Sport, Health Sciences and Social Work, Oxford, United Kingdom, 5Deakin University, Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Burnley, Australia, 6University of Wollongong, School of Medical, Indigenous and Health Sciences, Wollongong, Australia, 7Illawarra Health and Medical Research Institute, Wollongong, Australia, 8Swansea University, Population Data Science, FHMLS, Swansea, United Kingdom, 9Imperial College London, London, United Kingdom
Introduction: Multiple sclerosis (MS) is a progressive neurological disorder with diverse symptoms, commonly including fatigue, disability, and depression. Diet has been implicated in MS progression, but the relationship is not well-defined.
Objectives/Aims: To assess relationships between dietary intake and clinical severity of disease in a population of people with MS.
Methods: Data were extracted from the UK MS Register, a national register capturing clinical, lifestyle, and health outcomes, in 2016 and 2022. Dietary intake was assessed using EPIC-Norfolk Food Frequency Questionnaire (FFQ). Principal components analysis with orthogonal rotation was applied to the FFQ data at each timepoint, from which component scores were estimated for each participan t. Clinical severity measures included ambulatory disability (MS Walking Scale (MSWS) and MS Impact Scale-Physical (MSIS)), fatigue (Fatigue Severity Scale), and depression and anxiety (Hospital and Anxiety Depression Scale). Diet-outcome relationships assessed by quantile and log-binomial/multinomial regression, adjusted for total energy intake, age, sex, and MS phenotype.
Results: Of 2,278 and 2,887 participants from 2016 and 2022, most were female, Caucasian, and RRMS, with a mean age of ≈54 years, respectively. Two diet components were derived: 1. Prudent pattern: strongest loadings on vegetables, legumes, and fruits, 2. Western pattern: strongest loadings on biscuits, cakes/pies, chips, and takeaway. In both 2016 and 2022, Prudent score was associated with lower MSWS (aβ=-1.41 & aβ=-1.02), lower MSIS-Physical (aβ=-0.83 & aβ=-1.15), and lower frequencies of severe depression (PR=0.91 & aPR=0.86). Western score was associated with higher MSWS (aβ=+3.07 & aβ=+3.21), higher MSIS-Physical (aβ=+1.89 & +2.43), and higher frequencies of fatigue (aPR=1.09 & aPR=1.09), severe depression (aPR=1.20 & aPR=1.26), and severe anxiety (aPR=1.10 & aPR=1.15).
Conclusion: These findings suggest a role for diet in symptom management in pwMS; however, prospective studies are needed to confirm these relationships.
Disclosure of interest: SN receive royalties for her book, The Overcoming MS Handbook and previously received remuneration for conducting educational workshops for people with MS. No other authors have COIs to disclose.
P381/3189
retinal changes in patients with immunoglobulin a antibodies against myelin oligodendrocyte glycoprotein
Nuria Cerdá Fuertes1,2,3,4, Ayroza Galvao Ribeiro Gomes Ana Beatriz1,2,4,5, Laila Kulsvehagen1,2,4, Patrick Lipps1,2,4, Tradite Neziraj1,2,4, Julia Flammer1,2,4, Jasmine Lerner1,2,4, Anne-Catherine Lecourt1,2,4, Clarissa dos Reis Pereira6, Mario Luiz Monteiro6, Patrick Schindler7, Vinicius Andreoli Schoeps5, Aline Matos5,8, Natalia Mendes5, Carolin Schwake9, Thivya Pakeerathan9, Orhan Aktas10, Urs Fischer4, Tobias Derfuss1,2,4, Ludwig Kappos2,3, Ilya Ayzenberg9, Marius Ringelstein10,11, Friedemann Paul7,12,13, DAGOBERTO CALLEGARO5, Cristina Granziera2,3,4, Jens Kuhle1,2,4, Anne-Katrin Pröbstel1,2,4, Athina Papadopoulou1,2,3,4
1Departments of Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland, 2Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland, 3Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland, 4Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland, 5Departamento de Neurologia, Instituto Central, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil, 6Departamento de Oftalmologia e Laboratorio de Oftalmologia (LIM/33), Instituto Central, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil, 7Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neurocure Cluster of Excellence, Berlin, Germany, 8Instituto de Medicina Tropical de Sao Paulo, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil, 9Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Germany, Bochum, Germany, 10Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany, 11Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich Heine University Düsseldorf, Düsseldorf, Germany, 12Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center, Berlin, Germany, 13Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, Berlin, Germany
Introduction: Immunoglobulin A (IgA) antibodies against myelin oligodendrocyte glycoprotein (MOG) were recently described in a group of patients with central nervous system (CNS) demyelination, including optic neuritis (ON).
Objectives/Aims: To investigate if the retinal atrophy pattern in MOG-IgA-seropositive (+) patients with prior ON is similar to MOG-IgG. Moreover, to examine if there is subclinical retinal atrophy (without ON) in MOG-IgA+ patients vs healthy controls (HC).
Methods: This analysis was part of a multicenter study measuring MOG-IgA in serum of patients with suspected or confirmed CNS demyelination with a live cell-based assay. We included available optical coherence tomography images from 58 patients (n= 10 exclusively MOG-IgA+ and n= 48 MOG-IgG+ regardless of co-existing MOG-IgA/M) from tertiary centers (Basel n=23, Berlin=8, Bochum n=7, Düsseldorf n=4, São Paulo n=16) and 30 HC from Basel. We assessed the mean peripapillary retinal nerve fiber layer (pRNFL) thickness in the papillomacular bundle (PMB), the different quadrants (temporal, nasal, superior, inferior) and globally, as well as macular ganglion cell-inner plexiform- (GCIPL) and inner nuclear layers (INL) volume. The analysis was performed at eye-level using linear mixed models, including age, sex and ON number.
Results: We analyzed 17 eyes from MOG IgA+ patients (40% female(f), 42±19 years(y), 6/17 with prior ON), 92 eyes from MOG IgG+ patients (54%f, 43±14y, 52/92 prior ON) and 58 healthy eyes (50%f, 44±12y). 9 eyes were excluded (incidental finding or technical reason). Compared to HC, MOG IgA+ ON eyes showed lower pRNFL thickness globally (p<0.001), in the PMB (p=0.034), temporal (p=0.030), nasal (p=0.027), inferior (p=0.012) and superior quadrants (p=0.024) and lower GCIPL volume (p< 0.001). MOG IgA+ eyes without prior ON (non-ON) showed a trend towards lower pRNFL thickness globally (p= 0.081), in the PMB (p= 0.093) and the superior quadrant (p= 0.098) and lower GCIPL volume (p= 0.048) vs HC. We found no differences between MOG IgA+ and MOG IgG+ eyes regarding pRNFL thickness (globally or different segments), GCIPL or INL, neither in the ON- nor in non-ON-groups.
Conclusion: ON-eyes of MOG IgA+ patients show global retinal neuroaxonal thinning in a similar pattern to MOG IgG+. Our data suggest possible subclinical retinal atrophy in non-ON MOG-IgA eyes, although this should be interpreted with caution due to the low number of MOG-IgA+ patients. Larger prospective studies are needed to understand retinal affection in these patients
Disclosure of interest: Nuria Cerdá Fuertes: nothing to disclose
Ana Beatriz Ayroza Galvão Ribeiro Gomes has received an ECTRIMS Clinical Fellowship, a Swiss Government Excellence Scholarship, a research grant from Roche, travel grants from Roche and Biogen, and consultancy honoraria from Guidepoint.
Laila Kulsvehagen has received an individual travel grant from the Amsterdam University Fund, and a Trygve Tellefsens Legat Scholarship.
Patrick Lipps has received a a doctoral fellowship from the Goldschmidt Jacobson Foundation.
Tradite Neziraj: nothing to disclose.
Julia Flammer has received a Young Talents in Clinical Research Fellowship from the Swiss Academy of Medical Sciences, and a travel grant from Roche
Jasmine Lerner: nothing to disclose
Anne-Catherine Lecourt: nothing to disclose
Clarissa dos Reis Pereira has received a research grant from CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico during the conduct of the study.
Mario Luiz Ribeiro Monteiro has received a research grant from Dr Ribeiro Monteiro reports grants from CNPq-Conselho Nacional de Desenvolvimento Cientíico e Tecnológico during the conduct of the study.
Patrick Schindler P.S. has received travel support from UCB
Vinicius Andreoli Schoeps: nothing to disclose
Aline de Moura Brasil Matos received travel funds from Merck, Biogen and Roche, and received travel bursary and research seed funding from the Encephalitis Society, UK. She reports personal fees from Hoffmann LaRoche outside the submitted work
Natalia Trombini Mendes: nothing to disclose.
Carolin Schwake has received speaker honoraria from Alexion and travel support from Novartis and UCB outside the submitted work.
Thivya Pakeerathan nothing to disclose
Orhan Aktas O.A. reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics, and Zambon. He is a steering committee member and co-coordinator of the German Neuromyelitis Optica Study Group (NEMOS).
Urs Fischer’s institution has received grants and consultancy fees from Medtronic, Stryker, Rapid medical, Penumbra, Phenox Fees, and CSL Behring. He has participated in advisory boards for Alexion/Portola, Boehringer Ingelheim, Biogen and Acthera (fees paid to institution). Additionally, he is member of a clinical event committee (CEC) of the COATING study (Phenox) and member of the data and safety monitoring committee (DSMB) of the TITAN, LATE_MT and IN EXTREMIS trials; he is vice-president of the Swiss Neurological Society
Tobias Derfuss’s institution has received compensation for his activities in Advisory Boards, steering committees, or data safety monitoring boards of Actelion, Biogen, Celgene, Sanofi, GeNeuro, Merck, MedDay, Roche, Alexion, and Novartis. He has received grants from Novartis, Roche, and Alexion.
Ludwig Kappos has received no personal compensation for this work. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee, advisory board participation, consultancy services, and participation in educational activities from the following organizations: Actelion, Aurigia Vision AG, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche,
Ilya Ayzenberg has received personal fees from Roche, Alexion, Merck, Horizon and Sanofi; he has received grants from Diamed outside the submitted work.
Marius Ringelstein received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon and Merck
Friedemann Paul has received research support from NeuroCure Clinical Research Center . The center has received grants from the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almiral. He has received honoraria for honoraria for lectures, presentations, and speakers bureaus from the Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi, Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene. He has received travel grants from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono,
Sanofi, Genzyme, Novartis, Alexion, Viela Bio,
Roche, UCB, Mitsubishi Tanabe, and Celgene. He has participated on the Advisory Boards of Celgene, Roche, UCB and Merck. He is the Academic Editor of PLos One, and an Associate Editor of Neurology, Neuroimmunology & Neuroinflammation.
Dagoberto Callegaro has received a research grant from Roche for the conduction of this work, and a research grant from Biogen for activities outside of this work.
Cristina Granziera: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (iii) research support from Siemens, GeNeuro, Roche. Cristina Granziera is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E!113682 HORIZON2020.
Jens Kuhle J.K. has received speaker fees, research support, travel support, and/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Bayer, Biogen, Bristol Myers Squibb, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi.
Anne-Katrin Pröbstel received financial compensation for participation in advisory boards, and consultations from Biogen, Roche, and Novartis, all used for research support.
Athina Papadopoulou received financial compensation for participation in advisory boards and/or speaker-fees from Eli Lilly, Lundbeck, Sanofi-Genzyme, Abbvie and Teva, all used for research support; she also received travel support from Bayer AG, Elil Lilly, F. Hoffmann-La Roche and Teva.
P382/3020
The efficacity of a treadmill training program in Multiple Sclerosis patients on walking distance
Caroline Massot1, Cécile Donze1, Norberciak Laurene1, Guyot Marc-Alexandre1
1
GHICL, Lille, France
Introduction: People with Multiple sclerosis (MS) present commonly walking impairments which induce a decreased of endurance performance.
Objectives/Aims: To evaluate the efficacity of a treadmill training program for patients with MS (PwMS) to improve walking distance.
Methods: Multicentric prospective randomized controlled study included PwMS with an Expanded Disability Status Scale (EDSS) between 4 and 5.5. PwMS performed Cardiopulmonary exercise test (CPET) at T0 and after 7 weeks (T7) to evaluate the peak oxygen consumption (VO2peak), the ventilatory threshold (SV1), heart rate (HR) and the maximum walking speed (vmax). The 6 Minute Walk (6MW) test and the Timed 25 Foot Walk (T25FW) were done 48h after each CPET. The experimental group (EG) performed a treadmill training program (3 times/week, during 20 min, for 6 weeks) at SV1. The control group (CG) continued their usual physiotherapy.
Results: 46 PwMS were included, 23 patients in EG (52,2% women, 48.1+/- 9.5 years, EDSS 4 [4;5]) and 23 in CG (56,5% women, 51+/-10.4 years, EDSS 4 [4; 4.8] . At T7, the difference in walking distance in the 6MW test between groups was significant adjusted on baseline distance and balance (30.7 ; IC95% = [6.6; 54.6]; p = 0.02). the EG improved their performance at the T25FW compared to CG (difference = 0.93s; IC95% = [0.86; 1]; p = 0.063) without absolutely achieving significance and very largely influenced by balance disorders. At T7, the EG had a higher HR during the CPET (137.1+/-18.2) than CG (124.7+/-18.6) (p=0.036). No difference was found for vmax, SV1, VO2peak.
Conclusion: Exercise training in people with MS is commonly performed on a cyclo-ergometer which improved endurance but not the walking performance. This specific treadmill training increased walking distance, walking speed and could had a higher impact to improve quality of life and daily living.
Disclosure of interest: The french national health research program
P383/3025
Is Fatigue in MS the same one manifesting as Wearing-off Symptom in Natalizumab treated patients?
Giuseppe Magro1, Stefania Barone1, Angelo Pascarella1, Jolanda Buonocore1, Cataldo Mummolo1, Roberto Di Iorio1, Adriana Saraceno1, Giorgio Spano1, Antonio Gambardella1, Paola Valentino1
1
Magna Graecia University, Catanzaro, Italy
Introduction: Extended Interval Dosing (EID) up to 6 weeks in patients receiving NTZ is relatively safe. Patients receiving NTZ experience fatigue as the main Wearing-off Symptom (WoS), regardless of dosing interval. We previously found no significant increase of WoS in patients with an EID of 5-6 weeks.
Objectives/Aims: Primary objective of the study is investigate a possible correlation of fatigue with the symptom depression and with cognition, and its impact on patients quality of life.
Methods: 87 patients were asked on the day of infusion to specify whether fatigue is present and if so, whether it is habitual or occurs only as the next infusion approaches. Populations is divided in three main categories: chronic fatigue, end of does fatigue, no fatigue. All patients underwent a clinical evaluation, comprehensive of EDSS, FSMC, BDI-II, MSQoL-29, STAI-Y, and Symbol Digit.
Results: 73 (84%) patients complained of fatigue, 14 (16%) did not. Among the 73 patients, 30 (34.5%) complained of end of dose fatigue and 43 (49.4%) of chronic fatigue. FSMC scale is higher in those who suffer chronically of fatigue compared to those who exhibit end of dose fatigue only (74.7 vs 53, p<0.01) with a significantly lower quality of life measured by MSQoL-29 in these patients (82.4 vs 78.4, p<0.05). Symbol Digit is similar in all three populations. BDI-II was higher in those complaining of chronic fatigue compared to those complaining of end of dose fatigue only (16.6 vs 9.6 p<0.01), while we found no difference in BDI-II between the no fatigue and the end of dose fatigue population, with a normal mean value in both populations (7.2 vs 9.6). We obtained similar results for STAI-Y trait (49.5 vs 46.5, p<0.05).
Conclusion: These results show that fatigue as Wearing-off Symptom is different and probably strictly related to Natalizumab mechanism of action.
Disclosure of interest: Giuseppe Magro: nothing to disclose.
Stefania Barone: nothing to disclose.
Angelo Pascarella: nothing to disclose.
Jolanda Buonocore: nothing to disclose.
Cataldo Mummolo: nothing to disclose.
Roberto Di Iorio: nothing to disclose.
Adriana Saraceno: nothing to disclose.
Giorgio Spano: nothing to disclose.
Antonio Gambardella. nothing to disclose.
Paola Valentino: nothing to disclose.
P384/3045
Reduced Likelihood of High-efficacy Disease Modifying Therapy Prescription during the COVID-19 Pandemic
Anoushka Lal1, Yi Chao Foong1,2, Paul Sanfilippo1, Tim Spelman3,4, Louise Rath1, Angie Roldan1, David Levitz1, Mastura Monif1, Serkan Ozakbas5, Raed Alroughani6, Cavit Boz7, Murat Terzi8, Tomas Kalincik9,10, Yolanda Blanco11, Matteo Foschi12, Andrea Surcinelli12, Katherine Buzzard13, Olga Skibina13, Guy Laureys14, Liesbeth Van Hijfte14, cristina ramo tello15, Aysun Soysal16, Jose Luis Sanchez17, Mario Habek18,19, Elisabetta Cartechini20, Juan Ignacio Rojas21, Rana Karabudak10,22, Barbara Willekens23,24, Talal Muteb Al Harbi25, Tamara Castillo-Triviño26, Danny Decoo27,28, Maria Cecilia Aragon de Vecino29, Eli Skromne Eisenberg30, Carmen SIRBU31,32, Chao Zhu1, Daniel Merlo13, Melissa Gresle1, Helmut Butzkueven1,2, Anneke van der Walt1,2
1Monash University, Department of Neuroscience, Central Clinical School, Melbourne, Australia, 2Alfred Hospital, Department of Neurology, Melbourne, Australia, 3Karolinska Institute, Department of Clinical Neuroscience, Stockholm, Sweden, 4MSBase Foundation, Melbourne, Australia, 5Dokuz Eylul University Konak, Izmir, Turkey, 6Amiri Hospital, Division of Neurology, Department of Medicine Sharq, Kuwait, Sharq, Kuwait, 7KTU Medical Faculty Farabi Hospital, Trabzon, Turkey, 8Mayis University, Medical Faculty, Samsun, Turkey, 9Royal Melbourne Hospital, Neuroimmunology Centre, Department of Neurology, Melbourne, Australia, 10University of Melbourne, Department of Medicine, Melbourne, Australia, 11Hospital Clinic de Barcelona, Service of Neurology, Barcelona, Spain, 12Maria delle Croci Hospital of Ravenna, AUSL Romagna, Department of Neuroscience, Neurology Unit, Ravenna, Italy, 13Box Hill Hospital, Department of Neurology, Melbourne, Australia, 14University Hospital Ghent, Department of Neurology, Ghent, Belgium, 15- Hospital Germans Trias i Pujol, Badalona, Spain, 16Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istambul, Turkey, 17Hospital de Galdakao-Usansolo, Instituto de Investigacion sanitario Biocruces-Bizkaia, Galdako, Spain, 18Department of Neurology, University Hospital Center Zagreb, Zagreb, Croatia, 19University of Zagreb, School of Medicine, Zagreb, Croatia, 20Azienda Sanitaria Unica Regionale Marche, UOC Neurologia, Macerata, Italy, 21Hospital Universitario de CEMIC, Buenos Aires, Argentina, 22Kosuyolu Hospital, Neurological Sciences, Istanbul, Turkey, 23Antwerp University Hospital, Department of Neurology, Edegem, Belgium, 24University of L'Aquila, Department of Biotechnological and Applied Clinical Sciences (DISCAB), L'Aquila, Italy, 25King Fahad Specialist Hospital, Dammam, Saudi Arabia, 26Hospital Universitario Donostia and IIS Biodonostia, San Sebastián, Spain, 27AZ Alma Ziekenhuis, Sijsele, Damme, Belgium, 28University of Antwerp, Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, Wilrijk, Belgium, 29Hospital Moinhos de Vento, Porto Alegre, Brazil, 30Hospital Angeles de las Lomas., Instituto Mexicano de Neurociencias, Huixquilucan Estado de Mexico, Mexico, 31Central Military Emergency University Hospital, Bucharest, Romania, 32Titu Maiorescu University, Bucharest, Romania
Introduction: The COVID-19 pandemic had a significant impact on the care of people with multiple sclerosis (pwMS). Fear that exposure to immune-altering treatments could result in more severe COVID-19 infections, coupled with a lack of evidence, and change in access to resources, led clinicians to make empirical treatment choices. Subsequent studies demonstrated an association between certain high-efficacy disease modifying therapies (DMT) and greater COVID-19 severity.
Objectives/Aims: This study aimed to examine the impact of the COVID-19 pandemic on DMT prescribing patterns in pwMS.
Methods: A multi-centre longitudinal study was conducted using data from the MSBase COVID-19 sub-study. The overall trends in DMT prescribing rates between 2018-2022 were analysed using multivariable logistic regression. DMT initiation referred to the first prescription of any DMT in that timeframe. DMT switches denoted a change in DMT regimen within 6 months of last DMT use. Outcomes are reported in terms of model-derived marginal probability estimates averaged over individual covariate combinations. Primary outcomes were the probabilities of high-efficacy DMT use prior to and during the pandemic, and secondary outcomes the probabilities of oral/self-injectable/intravenous DMT use.
Results: A total of 1536 participants were included, with 2525 observations of treatment changes. There were 756 DMT initiations (29.94%), 940 switches (37.23%) and 829 records (32.83%) had no DMT change. There was a lower probability of high-efficacy DMTs being initiated during the pandemic (prior: 0.203 [95% CI; 0.172, 0.235], during: 0.108 [95% CI; 0.085, 0.130], during-prior difference: -0.096 [95% CI; -0.133, -0.058]). We observed increased initiations of oral DMTs, and decreased initiations of intravenous DMTs during 2020 and 2021. Over the entire time-period, patients were 85% less likely to be initiated on a high-efficacy DMT than on a moderate or low-efficacy DMT (OR = 0.15, p<0.01). There was no difference in the probability of high-efficacy DMT use or route of administration in treatment switching.
Conclusion: The COVID-19 pandemic resulted in a reduced likelihood of initiation of high-efficacy DMTs. Treatment choice when switching between DMTs were not affected. These findings may have long-term consequences for disease activity among pwMS and highlight the importance of developing rapid evidence-based guidance for clinicians and patients during global health events.
Disclosure of interest: Anoushka Lal: Nothing to disclose.
Yi Chao Foong: reports a relationship with Biogen that includes: travel reimbursement. Francesca Bridge reports a relationship with Biogen that includes: travel reimbursement
Paul Sanfilipino: Nothing to disclose.
Tim Spelman: received compensation for serving on scientific advisory board for Biogen and speaker honoraria from Novartis.
Louise Rath: Nothing to disclose.
Angie Roldan: Nothing to disclose
David Levitz: Nothing to disclose.
Mastura Monif: Nothing to disclose.
Serkan Ozakbas: Nothing to disclose.
Raed Alroughani: received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme.
Cavit Boz: received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis.
Murat Terzi: received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis.
Tomas Kalincik: Served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck.
Yolanda Blanco: received speaker honoraria/consulting fees from Merck, Biogen, Roche, Brystol, Novartis, Sanofi and Sandoz.
Matteo Foschi: received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck.
Andrea Surcinelli: Nothing to disclose.
Katherine Buzzard: received speaker honoraria and/or education support from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck and Alexion; has been a member of advisory boards for Merck and Biogen.
Olga Skibina: received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme.
Guy Laureys: received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen.
Liesbeth Van Hijfte: received travel compensation from Merck
Cristina Ramo-Tello: has received research funding, or compensation for consulting services and speaker honoraria, or meetings travels from Biogen, Novartis, Sanofi, Bristol, Roche, Almirall and Merck.
Aysun Soysal: Nothing to disclose.
Jose Luis Sanchez-Menoyo: accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche.
Mario Habek: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.
Elisabetta Cartechini: Nothing to disclose.
Juan Ignacio Rojas: Nothing to disclose.
Rana Karabudak: Nothing to disclose.
Barbara Willekens: received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme; research and/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme, Roche. Honoraria and grants were paid to UZA/UZA Foundation. Further, B.W. received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA.
Talal Al-Harbi: Nothing to disclose.
Yara Fragoso✝: received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck.
Tamara Castillo-Triviño: received speaking/consulting fees and/or travel funding from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.
Danny Decoo: received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck KGaA, Bayer, Sanofi/Genzyme, Roche and Teva, as well as support for research activities from Biogen, Novartis, Merck, Sanofi, Roche & Teva.
Maria Cecilia Aragon de Vecino: Nothing to disclose.
Eli Skromne: received speaking honoraria from Biogen, Novartis and Teva.
Carmen-Adella Sirbu: received speaking honoraria from Teva, and travel grants from Bayer-Schering and Teva.
Chao Zhu: Nothing to disclose
Daniel Merlo: reports a relationship with Novartis that includes: speaking and lecture fees.
Melissa Gresle: Reports a relationship with Biogen that includes: funding grants and a relationship with F Hoffmann-La Roche Ltd that includes: funding grants
Helmut Butzkueven: received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee.
Anneke van der Walt: served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.
P385/3050
The Economic Burden Of Multiple Sclerosis In An Italian Cohort Of Patients: Analysis Of Disease Cost And Quality Of Life
Michela Ponzio1, Laura Santoni2, ELEONORA TAVAZZI3, Roberto BERGAMASCHI3
1Italian Multiple Sclerosis Foundation (FISM), Scientific Research Area, Genoa, Italy, 2Biogen Italia, Milan, Italy, 3IRCCS Mondino Foundation, Multiple Sclerosis Research Center, Pavia, Italy
Introduction: The social costs associated with multiple sclerosis (MS) are high because of its chronicity, the early loss of productivity, and the need for long-term health care.
Objectives/Aims: This study aims to analyse the cost of MS in the societal perspective and the Quality of Life (QoL) in a cohort of Italian patients treated with disease modifying drugs (DMD).
Methods: In this cross-sectional cost-of-illness study, MS patients were recruited from a single Italian center. Cost data were collected through a questionnaire designed to capture MS costs with 3-months or 1-year recall periods. EQ-5D-3L questionnaire was also administered. Cost components included healthcare, non-healthcare resources and production losses. Cost of MS-relapses was also determined. Data are reported as number (percentage) or mean (standard deviation); costs are expressed per patient/year (2019). Incremental cost associated with relapse was reported using generalized linear model with log link and gamma distributions and adjusted for sex, age, and disability level.
Results: Of 393 MS patients, 65.9% were female, aged 45.0 (11.5) years; 373 (94.9%) had relapsing-remitting MS (RRMS) with Expanded Disability Status Scale (EDSS) of 1.9 (1.5); all patients received DMD. Overall, 290 (73.8%) patients were employed. The health profile resulted in some domains of Health-Related-QoL representing problems, some or extreme, for a relevant proportion of subjects: 50.9% pain/discomfort and 51.4% anxiety/depression; moderate in mobility (30.4%). The EQ-5D-3L utility index had a mean score of 0.87 (±0.11), with no difference between gender (male 0.88 vs. female 0.87, p=0.403). Total cost was estimated at euro 20,299 (13,954.4) and increased progressively with disease disability, from euro 16,812.4 (8,801.2) in patients with EDSS 0–1.5 to euro 44,042.5 (27,587.8) in patients with EDSS⩾6. Healthcare costs amounted to euro 14,587.5 (6,750.9), and non-healthcare costs totalled euro 1,176.6 (3,999.6). Productivity losses were generated by 124 (31.3%) patients and amounted to euro 4,535.3 (9,122.9). Relapses significantly increased MS cost by euro 1,499.5 (p=0.015) in 21 patients (5.3%).
Conclusion: This study provides a representation of MS cost and QoL in a cohort of Italian DMD-treated patients, mostly with RRMS, mean EDSS 1.9 and confirms that higher costs are associated with higher disability; relapses caused a significant cost increase.
Disclosure of interest: Ponzio M - no conflicts of interest to declare
Santoni L - is employee of and may hold stock/stock options in Biogen
Tavazzi E - received honoraria for speaking from Biogen Idec, Bristol-Meyers-Squibb
Bergamaschi R - received honoraria for speaking from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva; congress and travel/accommodation expenses funded by Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva
This study was sponsored by Biogen Italia (Milano, Italy).
Editorial assistance was provided by Alessandra Rossi (Polistudium SRL, Milan, Italy). This assistance was supported by Biogen Italia Srl, Italy.
P386/3056
Extended Serologic Responses to SARS-CoV-2 Vaccination in Healthy Volunteers and DAYBREAK Participants With Relapsing Multiple Sclerosis Receiving Ozanimod
Bruce Cree1, Rachel Maddux2, Amit Bar-Or3, Hans-Peter Hartung4, Amandeep Kaur2, Yicong Li2, Kai Fu2, Yanhua Hu2, James Sheffield2, Diego Silva2, Sarah Harris2
1Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, United States, 2Bristol Myers Squibb, Princeton, United States, 3Center for Neuroinflammation and Experimental Therapeutics, and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States, 4Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf Germany; Brain and Mind Centre, University of Sydney, Australia; Department of Neurology, Medical University of Vienna, Austria; and Palacky University Olomouc, Olomouc, Czech Republic
Introduction: Disease-modifying therapies may attenuate the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in participants (pts) with relapsing multiple sclerosis (RMS).
Objectives/Aims: Describe the extended serologic response to SARS-CoV-2 vaccination and/or infection during ozanimod (OZA) treatment in pts with RMS enroled in the open-label extension (OLE) trial DAYBREAK and compare serologic responses in healthy volunteers.
Methods: Pts with RMS who completed a phase 1‒3 OZA trial could enter the single-arm DAYBREAK OLE trial (NCT02576717) of OZA 0.92 mg/d. This analysis included DAYBREAK pts who received a full SARS-CoV-2 vaccination course and/or reported a COVID-19 adverse event between 13 Jan 2020 and 25 Aug 2022. Healthy controls were commercially sourced. SARS-CoV-2 spike receptor-binding domain (RBD) and nucleocapsid antibodies were measured with the Elecsys anti-SARS-CoV-2 assay and Cobas e analyser; seroconversion was defined as IgG levels ⩾0.8 U/mL for spike RBD, nucleocapsid antibody seroconversion was defined as IgG levels ⩾ 1 U/mL. Predictors of RBD antibody levels were assessed.
Results: Baseline characteristics of 369 pts in this analysis included median (range) age 39.1 (19‒56) y, 70% female, and OZA exposure 74.1 (48–110) m; 30 healthy controls were 43.4 (18‒66) y and 77% female. Postvaccination samples (n=253) in DAYBREAK pts without evidence of SARS-CoV-2 exposure (nucleocapsid antibody negative) showed 87% RBD antibody seroconversion; all postvaccination samples (n=112) with evidence of exposure (nucleocapsid antibody positive) showed seroconversion. All healthy control samples demonstrated seroconversion postvaccination with (n=6) or without (n=22) evidence of exposure. Samples from unvaccinated DAYBREAK pts with evidence of exposure (n=92) showed 95% seroconversion. In vaccinated pts, spike RBD antibody levels were maintained over 28 weeks with or without boosting. Spike RBD antibody levels were not associated with absolute lymphocyte count (ALC) in pts without (R=−0.11, P=0.07) or with SARS-CoV-2 exposure (R=−0.06, P=0.26). Time on OZA treatment was not associated with spike RBD antibody levels in pts without (R=0.02, P=0.84) or with exposure (R=0.02, P=0.77).
Conclusion: The majority of pts with RMS receiving OZA developed and maintained a serologic response to SARS-CoV-2 vaccination for at least 28 weeks, whereas healthy controls had 100% seroconversion. There was no significant association between spike RBD levels and ALC or OZA exposure.
Disclosure of interest: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.
BACC: reports personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics, and received research support from Genentech.
ABO: reports fees for advisory board participation and/or consulting from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer Bio, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme; and has received grant support to the University of Pennsylvania from Biogen Idec, Merck/EMD Serono, Novartis, and Roche/Genentech.
HPH: reports personal fees for consulting, serving on steering committees, and speaking from Bayer Healthcare, Biogen, Celgene, GeNeuro, Genzyme, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi, and Teva.
RM, AK, YL, KF, YH, JKS, DS, and SH: are employees and/or shareholders of Bristol Myers Squibb.
P387/3073
A Randomized, Double-Blind, Placebo Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Lucid-21-302 in Healthy Volunteers (NCT05821387): A potential candidate targeting demyelination
Andrzej Chruscinski1, Joanne Speed1, Justin Ryk1, Ashwini Joshi1, Lakshmi Kotra1,2,3
1Lucid Psycheceuticals (subsidiary of FSD Pharma), Toronto, Canada, 2University of Toronto, Pharmacy, Toronto, Canada, 3University Health Network, Toronto, Canada
Introduction: Current disease modifying therapies for multiple sclerosis (MS) target immune mechanisms, reducing activity, but they have only modest effects on delaying degeneration. Hypercitrullination and subsequent demyelination have been shown to contribute to MS pathology. The small molecule Lucid-21-302 inhibits hypercitrullination of myelin and prevents demyelination in several animal models of MS. Toxicology studies demonstrated that Lucid-21-302 was well tolerated in rats and dogs.
Objectives/Aims: To assess the safety, tolerability and pharmacokinetics (PK) of Lucid-21-302 in healthy volunteers.
Methods: This phase 1 clinical trial is a single center, randomized, double-blind, placebo-controlled, single ascending dose (SAD) study with Lucid-21-302 or placebo given orally. Lucid-21-302 was administered in the dose range of 50-300 mg p.o to healthy participants (18-60 years old). The SAD part consists of five cohorts including one cohort evaluating the effects of food (fed/fast cohort). Fed/fast cohort is a cross-over arm. Each SAD cohort includes eight participants (six participants receiving the study drug and two receiving placebo except for the food effect cohort where all participants receive study drug).
Results: Lucid-21-302 was well-tolerated with no serious adverse events observed during the current SAD cohorts in the dose range of 50 mg – 300 mg p.o. Following a 50 mg dose p.o., the Tmax was 1.3 ± 0.4 hrs, maximum concentration (Cmax) was 0.5 ± 0.2 µg/mL and area under the curve (AUC0-last) was 1.2 ± 0.4 hr·µg/mL. Following a 100 mg dose p.o., the Tmax was 0.9 ± 0.3 hrs, Cmax was 1.2 ± 0.6 µg/mL and AUC0-last was 2.6 ± 0.6 hr·µg/mL. Following a 150 mg dose p.o., the Tmax was 1.1 ± 0.6 hrs, Cmax was 2.4 ± 0.9 µg/mL and AUC0-last was 6.2 ± 1.1 hr·µg/mL. In the first three cohorts, AUC (hr·µg/mL) normalized to dose (mg/kg) ranged from 1.5 to 2.5. Bioavailability (F) for Lucid-21-302 was 79% based on the rodent data. This presentation will focus on the first-in-human trial for Lucid-21-302 in the dose range of 50-300 mg p.o.
Conclusion: Lucid-21-302, a first-in-class, non-immunomodulatory neuroprotective compound, is safe and well-tolerated at doses of 50-300 mg p.o. Lucid-21-302 has demonstrated good oral absorption with AUC normalized to dose consistent with nonclinical studies. This agent is ideally positioned to mitigate the late myelin degeneration characteristic of progressive MS by directly suppressing non-immune mechanisms of myelin loss and may represent an important therapeutic candidate for this stage of the disease.
Disclosure of interest: Andrzej Chruscinski: employee at Lucid Psycheceuticals. Joanne Speed: employee at Lucid Psycheceuticals. Justin Ryk: employee at Lucid Psycheceuticals. Ashwini Joshi: employee at Lucid Psycheceuticals. Lakshmi Kotra: CEO of Lucid Psycheceuticals, Director at FSD Pharma
P388/3102
Preventing oxidative stress-induced changes in mitochondrial dynamics - Investigation of neuroprotective effects of S1P receptor modulators ex vivo using a semi-automated live imaging set-up
Rebecca Ludwig1, Bimala Malla1, Maria Höhrhan2, Carmen Infante-Duarte1, Lina Anderhalten1
1Charité - Universitätsmedizin Berlin, Experimental and Clinical Research Center (ECRC), Experimental Neuroimmunology, Berlin, Germany, 2Medical University of Vienna, Wien, Austria
Introduction: In multiple sclerosis (MS), immune cells and activated microglia produce reactive oxygen species that may affect mitochondrial function in neurons and contribute to neuroaxonal damage and disease progression. Fingolimod and siponimod are sphingosine-1-phosphate (S1P) receptor modulators that regulate inflammatory responses and myelination. Fingolimod was reported to prevent oxidative stress-induced alterations in mitochondrial morphology. Siponimod is approved for the treatment of secondary progressive MS because of its anti-inflammatory and less understood neuroprotective effects.
Objectives/Aims: This study aimed to investigate the potential neuroprotective effects of siponimod, compared to fingolimod, on neuronal mitochondrial dynamics in oxidatively-stressed living brain tissue in an ex vivo model of chronic hippocampal slice cultures using a semi-automated in-house developed image analysis.
Methods: We have established a protocol for the use of chronic hippocampal slice cultures for live imaging, enabling semi-automated monitoring of neuroaxonal mitochondrial alterations. The assessment of mitochondria was conducted on brain slices from the B6.Cg-Tg(Thy1-CFP/COX8A)S2Lich/J mouse, which allows the specific detection of neuronal mitochondria using confocal fluorescence microscopy. Oxidative stress was induced with hydrogen peroxide for a period of 24h. Simultaneously, 1 nM fingolimod or siponimod was applied to the tissue culture to assess the effects of S1P-receptor modulators. After 24h of treatment, mitochondrial morphology and motility were assessed in 2 min. time lapses.
Results: Under oxidative stress, the fraction of motile mitochondria decreased, mitochondria were shorter and smaller, and covered slightly smaller distances compared to negative controls. Siponimod was able to prevent oxidatively-induced alterations in mitochondrial morphology, while for fingolimod a similar trend was observed. Siponimod partly prevented the decrease in mitochondrial displacement, while fingolimod did not. In addition, both compounds led to an increase in track speed. In slices treated with siponimod or fingolimod, the fractions of motile mitochondria approached that of control slices.
Conclusion: Thus, both siponimod and fingolimod at 1 nM partially prevented oxidative stress-induced mitochondrial alterations in living brain tissue ex vivo.
Disclosure of interest: This study has been supported by Novartis Pharma GmbH.
Rebecca Ludwig: supported by a scholarship from the Berlin Institute of Health.
Bimala Malla: supported by a research grant from Sanofi-Genzyme.
Maria Höhrhan: nothing to disclose.
Carmen Infante Duarte: received speaker honoraria from Sanofi-Genzyme and research support from Sanofi-Genzyme, Novartis, the Hertie Foundation, and the German Research Council.
Lina Anderhalten: supported by a scholarship from the Hertie-Foundation.
P389/3181
Progression independent of relapse activity (PIRA) is associated with accelerated retinal atrophy in patients with relapsing remitting multiple sclerosis
Eva-Maria Strauß1, Lilian Aly1, Achim Berthele1, Sebastian Lambrecht1, Bernhard Hemmer1,2, Benjamin Knier1
1Klinikum rechts der Isar, TUM school of medicine, Technical University of Munich, Department of Neurology, Munich, Germany, 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Introduction: Progression independent of relapse activity (PIRA) is the thought to be the major driver of irreversible disability accumulation in relapsing remitting multiple sclerosis (RRMS). Detection and prediction of PIRA during clinical practice, however, is challenging.
Objectives/Aims: To assess whether longitudinal retinal optical coherence tomography (OCT) allows for detection and prediction of PIRA in patients with RRMS.
Methods: Patients were retrospectively enrolled from an ongoing prospective cohort study on the disease course of patients with RRMS. Inclusion criteria consisted of a longitudinal OCT follow-up duration of at least 24 months and the absence of any relapse activity during this period. PIRA was defined as significant worsening of the expanded disability status scale (EDSS) confirmed at least 3 months later independent of relapses (EDSS increase of at least 1.5 points if baseline EDSS was 0, 1.0 or more points if baseline EDSS was 1.0 to 5.5 or at least 0.5 points if baseline EDSS was greater than 5.5). Patients underwent retinal OCT with segmentation of the peripapillary retinal nerve fiber layer (pRNFL) and the combined ganglion cell and inner plexiform layer (GCIPL). Eyes with a history of optic neuritis (ON) or assumed subclinical ON were excluded from the analysis. Cox multiple regression models were applied to assess the influence of longitudinal retinal alterations on PIRA.
Results: We enrolled 155 patients (93 females) aged 36 years (median, 25%-75% interquartile range [IQR] 31 to 45) and a median disease duration of 37 months (IQR 16 to 77) and a median EDSS of 1.5 (IQR 0 to 2.0) into the study. During a median follow-up of 72 months (IQR 51 to 84), 30 individuals developed PIRA, whereas the remaining 125 patients revealed stable EDSS value. There were no significant differences between patients with or without PIRA concerning age, sex, history of ON, EDSS at baseline and disease duration. Patients with PIRA revealed an increased loss of retinal ganglion cells before PIRA as compared to patients without PIRA (PIRA: change of GCIP -0.31 µm / year (IQR -0.21 to -0.74), no PRIA -0.19 µm / year (IQR -0.04 to 0.38), p=0.01). Here, an increase in GCIP atrophy by 1 µm per year was associated with a 6.7-fold (95% confidence interval 2.0 - 25.6, p=0.002) increased risk of PIRA in patients with RRMS.
Conclusion: Pronounced retinal ganglion cell loss independent of ON might be associated with an increased risk of developing PIRA. Retinal OCT might allow for early detection of PIRA in patients with early RRMS.
Disclosure of interest: Eva-Maria Strauß reports no conflict of interest.
Lilian Aly received travel and research support by Novartis.
Achim Berthele receives funding from the German Federal Ministry of Education and Research (BMBF; grant 01ZZ2102B). He has received consulting and/or speaker fees from Alexion, Biogen, Horizon, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; all outside the present work.
Bernhard Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. Bernhard Hemmer received funding for the study by the European Union’s Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198].
Sebastian Lambrecht reports no conflict of interest.
Benjamin Knier received travel support and speaking honoraria from Novartis, Teva and Heidelberg Engineering. He served on the advisory boards of Merck Deutschland GmbH. He was funded by the Else Kröner Fresenius-Stiftung (Else Kröner Fresenius Exzellenzstipendium 2019_EKES.09), the Gemeinnützige Hertie Foundation (medMS program) and received a research award from Novartis.
P390/3139
Reference change values of longitudinal sNfL to detect subclinical disease activity in individual patients with MS
Simon Thebault1,2, Gauruv Bose2, Giulia Fadda2, Mark S. Freedman2, Ronald Booth2
1University of Pennsylvania, Philadelphia, United States, 2University of Ottawa, Ottawa, Canada
Introduction: Serum levels of neurofilament light chain (sNfL) can detect subclinical disease activity in MS. A barrier to clinical interpretation is the confounding effects of physiological factors like age. Solutions such as Z-score adjustments based on normative datasets may be hard to implement in the clinical diagnostics settings. Reference Change Values (RCV) are a solution used elsewhere to assess the significance of the difference between two measurements by accounting for analytical variation (CVA) and biological variation (CVI).
Objectives/Aims: To calculate and then validate a cutoff for sNfL RCV associated with the emergence of new gadolinium-enhancing lesions in MRI scans.
Methods: At a single center, our discovery cohort included patients with MRI activity in the last 6 months who were monitored with 3-monthly MRI, clinical visits, and blood draws (total 5 visits). Our validation cohort consisted of patients on ocrelizumab with serial sNfL testing and interval MRI follow-up. sNfL was measured using SiMOA. Age-adjusted sNfL Z-scores (AAsNfL) were generated from normative Swiss data. RCV was calculated using the formula RCV=21/2 *Z*(CVA2 + CVI2)1/2
Results: In the discovery cohort, 58 patients were followed for 1 year with 3-monthly sNfL measurements (total 190), clinic visits, and MRI scans (total 252). 39/58 developed new gadolinium lesions. Patients who did versus did not develop new lesions over the follow-up had a median RCV of 92 (IQR 60-122) vs 57 (IQR 45-148, Mann-Whitney test p=0.008). An RCV of >76 had a 60% sensitivity and 75% specificity for detecting new lesions. In a multiple logistic regression that included baseline AAsNfL, both AAsNfL and sNfL RCV were independent predictors of new lesions; a 10 unit increase in RCV was associated with a 30% increase in odds of developing new MRI activity. Our validation cohort included 150 patients on ocrelizumab followed in our clinic with serial sNfL (total 481) in addition to >2 MRI scans per patient to assess for new MRI activity. 18/150 patients developed new MRI activity. 11/18 of these patients had an RCV>76. 98/132 patients who did not develop MRI activity had an RCV <76. This sNfL RCV cutoff had a positive likelihood ratio of 2.48 and a negative likelihood ratio of 0.53 for detecting new MRI activity.
Conclusion: RCV is an individualized statistic for assessing whether a longitudinal changes in sNfL are clinically significant or not. Here, we developed an RCV cut-off for detecting new MRI activity, which we validated it in a larger cohort.
Disclosure of interest: None
P391/3150
Clostridium perfringens epsilon toxin is associated with Multiple Sclerosis and epsilon toxin induces primary central nervous system demyelination
Yinghua Ma1, Hiroko Nobuta2, Jennifer Linden1, Baohua Zhao3, Richard Rudick4, Timothy Vartanian5
1Weill Medical College, Feil Family Brain and Mind Research Institute, New York, United States, 2Rutgers University, Department of Neuroscience and Cell Biology, Piscataway, United States, 3Weill Cornell Medicine, New York, United States, 4Optimal Brain Health Consultants, LLC, Stamford, United States, 5Weill Cornell Medical College, Cornell University, Feil Family Brain and Mind Research Institute, New York, United States
Introduction: In an analysis of human fecal samples by quantitative PCR, we previously demonstrated that epsilon toxin (ETX) producing strains of C. perfringens occur in greater frequency and at higher abundance in the MS gut microbiome compared with healthy individuals. We also showed that ETX overcomes CNS immune privilege in an active immunization model of EAE (Ma, Sannino, Linden, et al., J Clin Invest. 2023), suggesting a role for ETX in the initiation of inflammatory white matter lesions. The potential role of ETX in gray matter demyelination and in myelin disruption in non-lesion white matter remains less clear, although it is known that oligodendrocytes express the ETX receptor, the myelin and lymphocyte protein (MAL).
Objectives/Aims: To determine the effects of ETX on oligodendrocytes and myelin in rodent and human models.
Methods: We used: time-lapse microscopy to image myelin in cerebellar explants from PLP-EGFP mice; stereotactic administration of ETX into the CNS of rodents to assess its effects in vivo; and human embryonic CNS cultures to study sensitivity human oligodendrocytes.
Results: We find that ETX induces robust demyelination with preservation of other neural elements in organotypic and in vivo models. Inhibition of ETX pore formation either by using monoclonal antibodies that inhibit assembly of ETX oligomers, or using agents that disrupt MAL-rich lipid rafts, prevented demyelination. Using MS patient-derived C. perfringens type D strains, we show that bacterial supernatants induce demyelination in cerebellar explants and we identify ETX as the component driving demyelination by neutralization with ETX-specific antibodies.
We then studied long-term cultures generated from human fetal CNS tissue which contain all the major CNS cellular elements including oligodendrocyte progenitor cells, immature oligodendrocytes, and mature oligodendrocytes. We find that mature human oligodendrocytes are extraordinarily sensitive to ETX-mediated cell injury and death, while other CNS cell types are preserved. These findings indicate that oligodendrocytes from human CNS are specifically targeted by ETX.
Conclusion: These new data demonstrate that ETX induces CNS demyelination and injures human oligodendrocytes, potentially explaining primary demyelination within the CNS of MS patients. ETX may represent a unifying pathogenic factor, inducing both acute white matter inflammatory lesions as well as primary myelin injury in cerebral cortex and non-lesion white matter. Further studies of ETX in MS patients are warranted.
Disclosure of interest: Yinghua Ma: Inventor on a patent application (US Patent No: US 9,758,573 B2 ) for a method to diagnose and treat multiple sclerosis using anti-ETX monoclonal antibodies.
Hiroko Nobuta, no conflicts.
Jennifer Linden: Inventor on a patent application (US Patent No: US 9,758,573 B2 ) for a method to diagnose and treat multiple sclerosis using anti-ETX monoclonal antibodies.
Baohua Zhao: no conflicts.
Richard Rudick: no conflicts.
Timothy Vartanian: Inventor on a patent application (US Patent No: US 9,758,573 B2 ) for a method to diagnose and treat multiple sclerosis using anti-ETX monoclonal antibodies. Consulting for Sanofi, Genentech, TG Therapeutics, and Novartis. Non-promotional speaking for Biogen, Genentech, and TG Therapeutics.
This work was supported by National Multiple Sclerosis Society Research Grant RG4965A4 (TV), National Institutes of Health grant R21 RNS106581A (TV)
P392/3152
cholesterol esters in cerebrospinal fluid at the diagnostic stage: assessing the prognostic value of cholesteryl ester 18:2
CRISTINA González Mingot1, Pascual Torres Cabestany2, Gil Anna2, Eduardo San Pedro1, LAURA QUIBUS REQUENA1, Agustin Sancho Saldana1, emilio ruiz1, silvia peralta1, LUIS BRIEVA RUIZ1
1Hospital Arnau de Vilanova of Lleida, Neurology, Lleida, Spain, 2Institut de Recerca Biomèdica de LLeida, Lleida, Spain
Introduction: Cholesterol metabolism has been implicated in the pathogenesis and progression of multiple sclerosis (MS). Recent advances in lipidomics have provided insights into the complex lipid alterations occurring in MS, particularly in the cerebrospinal fluid (CSF).
Objectives/Aims: This study aimed to investigate the potential association between cholesterol esters in CSF at the diagnostic stage and disease progression, with a specific focus on the role of cholesteryl ester 18:2.
Methods: Using a targeted lipidomic approach, we analyzed CSF samples from a cohort of newly diagnosed MS patients (n = 114) at baseline and controls (n = 56) in a retrospective study with more than 10 years of follow-up.
Results: Quantitative analysis revealed a significant increase in cholesteryl ester 18:2 levels in patients exhibiting aggressive disease progression compared to those with milder forms of the disease (p < 0.05). Furthermore, significantly elevated levels were observed both in patients who reached an EDSS of 6 or higher at 10 years of follow-up and in cases that required high-efficacy treatment during the 10-year follow-up.
Conclusion: Our findings demonstrate the utility of targeted lipidomic analysis in identifying specific cholesterol esters, such as cholesteryl ester 18:2, as potential markers of disease progression in MS, probably linked to remyelination capacity. These results expand upon previous untargeted lipidomic studies and underscore the importance of cholesterol ester metabolism in MS pathogenesis. Further research is warranted to elucidate the underlying mechanisms and clinical implications of these findings, potentially paving the way for the development of personalized therapeutic strategies for MS patients.
Disclosure of interest: This project received funding from the grant of the Spanish Multiple Sclerosis Network (REEM) 2022.
cristina gonzalez: nothing to disclose
Pascual Torres: nothing to disclose
Anna Gil: nothing to disclose
Eduardo San Pedro:nothing to disclose
Laura Quibus: nothing to disclose
Agustin Sancho:nothing to disclose
Emilio Ruiz: nothing to disclose
Silvia Peralta: nothing to disclose
Luis Brieva: nothing to disclose
P393/3188
Identifying Informative Factors in Assessment of Disease Progression for Multiple Sclerosis Using Healthcare Records
Onur Dereli1, Anja Schramm2, Jochen Behringer2, Achim Berthele1, Alexander Hapfelmeier3,4, Bernhard Hemmer1,5, Christiane Gasperi1
1Department of Neurology, University Hospital rechts der Isar, Technical University Munich, Munich, Germany, 2AOK Bayern, Munich, Germany, 3Institute of AI and Informatics in Medicine, TUM School of Medicine, Technical University Munich, Munich, Germany, 4Institute of General Practice and Health Services Research, TUM School of Medicine, Technical University Munich, Munich, Germany, 5Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Introduction: Multiple Sclerosis (MS) has diverse clinical courses, from nearly asymptomatic to highly active forms having rapid disability progression. Early prediction of the disease course is vital, prompting the need for searching potential predictors in MS research.
Objectives/Aims: This study aims to identify informative parameters for the disability progression of MS patients using healthcare data without detailed clinical information by deploying a machine learning algorithm.
Methods: Data obtained from the Allgemeine Ortskrankenkasse (AOK Bayern) health insurance company includes prescription records for medical therapy, assistive devices, nursing care, inability to work, rehabilitation, and diagnosis of 18263 MS patients between the years 2010 and 2020. Using this dataset, we develop a gradient-boosting-based model that predicts the disability progression of MS patients that we define based on the care levels required by each patient.
Results: Experiments show that using three years of patients' records in the training model, including missing values up to 30% of the observation period, our model can successfully predict whether an MS patient will require a higher level of nursing care after two years from the last record used for training. Our model achieves an area under the receiver operating characteristic (AUC) value of 0.87 and an area under the precision-recall curve (AUPR) value of 0.22 (baseline AUC: 0.5, baseline AUPR: 0.036), while F1 and average balanced accuracy values are 0.21 and 0.81, respectively. Using mobility-related assistive devices is one of the most critical risk factors in requiring a higher level of nursing care. Using incontinence-related aid devices and disease-modifying therapies is also significantly associated with disability progression. Regarding comorbidities, urinary, nervous and musculoskeletal system-related symptoms or diseases arise as critical risk-increasing factors. Conversely, non-inflammatory diseases of the female genital tract show a decreasing effect on the risk of having a higher level of nursing care.
Conclusion: Our findings show that we can predict the disability progression of MS patients using health records better than baseline models, and records about assistive devices, nursing care, inability to work, rehabilitation, drug therapies, and diagnosis emerge as informative factors while predicting the disability progression. In future studies, we will use these data to identify possible risk factors for a more aggressive disease course.
Disclosure of interest: OD has nothing to report.
AS has nothing to report.
JB has nothing to report.
AB receives funding from the German Federal Ministry of Education and Research (BMBF; grant 01ZZ2102B). He has received consulting and/or speaker fees from Alexion, Biogen, Horizon, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; all outside the present work.
AH has nothing to report.
BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. Bernhard Hemmer received funding for the study by the European Union’s Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198].
CG received funding from the German Federal Ministry of Education and Research (BMBF), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), the Hertie Foundation and the Hans and Klementia Langmatz Stiftung.
P394/3197
Effects of Music Therapy with a "Monochord" on Anxiety, Pain and Body Perception in Patients with Multiple Sclerosis
Jenni Kuhlmann1, Katarina Ebner1, Nikki Rommers2, Nuria Cerdá Fuertes1,3, Bettina Fischer-Barnicol1, Lisa Dinsenbacher3, Andrea Zimmer4, Katrin Parmar1,5, Jens Kuhle1,2,4, Ludwig Kappos4, Athina Papadopoulou1,2
1University Hospital Basel and University of Basel, Multiple Sclerosis Centre, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, Basel, Switzerland, 2University of Basel, Department of Clinical Research, Basel, Switzerland, 3University Hospital Basel, Neurostatus AG, Basel, Switzerland, 4University Hospital and University of Basel, Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Basel, Switzerland, 5Rehabilitationsklinik Rheinfelden, Neurorehabilitation, Rheinfelden, Switzerland
Introduction: Prior studies with Music therapy (MT) in Multiple Sclerosis (MS) were typically performed at an in-patient setting and were uncontrolled or too small to detect a significant therapeutic effect.
Objectives/Aims: To investigate the effect of ambulatory MT on anxiety (primary end-point), as well as depression, fatigue, health-related quality of life, body perception and pain thresholds (secondary outcomes) in a randomized-controlled study design.
Methods: We included 57 patients from our MS center (age: 50.1 ± 12.4 years, sex: 47 women, disease course: 46 relapsing-remitting, median Expanded Disability Status Scale (EDSS) 3.0 (1.0 - 6.5), disease modifying treatment: 53). Patients were randomized 1:1 to two groups: 30 to the MT group (MTG) and 27 to the control group (CG). Patients in the MTG had six weekly sessions of MT, relaxing on top of the “monochord” instrument and perceiving its music played by the therapist, while patients in the CG had the same number of sessions (lying on the “monochord”), without music. A blinded rater assessed the endpoints with standardised questionnaires (Hospital Anxiety and Depression Scale, HADS; Modified Fatigue impact scale, MFIS; Short Form 36, SF36) and quantitative sensory testing (QST), examining pain thresholds (thermal-, mechanical- and pressure pain). Assessments took place at study baseline and after the last session. Additionally, effects on body perception were obtained by a non-validated questionnaire before and after each session (Questionnaires: Q A&B). Data was analysed using linear mixed models.
Results: The primary outcome, anxiety- (p= 0.109) and depressive symptoms (p= 0.667) did not differ between the two groups after six weeks. However in the MTG, the psychosocial aspect of fatigue (MFIS) was significantly reduced (p= 0.029). The threshold for heat pain was significantly higher in the MTG at the end of study visit (p= 0.024). Immediate effects of each session on body perception (Q A&B) were in favour of the MTG group (feeling relaxed: p< 0.001, balanced: p< 0.001, in touch with their body: p< 0.001 as well as less pain: p< 0.001).
Conclusion: In this controlled, rater-blinded trial we observed high adherence and positive effects on fatigue, pain and body perception, compared to relaxation alone. No significant group differences were shown in anxiety and depressive symptoms. Overall, MT with a “monochord” expands the non-pharmacological therapeutic options for people with MS in an outpatient setting.
Disclosure of interest: Jenni Kuhlmann has received a speaker fee from the MS-society of Switzerland.
Katarina Ebner: nothing to disclose
Nikki Rommers: nothing to disclose
Nuria Cerdá Fuertes: nothing to disclose
Bettina Fischer-Barnicol served on advisory boards from Biogen and Merck.
Lisa Dinsenbacher: nothing to disclose.
Andrea Zimmer: nothing to disclose.
Katrin Parmar holds a grant of the Baasch-Medicus foundation, her institution (University Hospital Basel) received speaker’s honoraria from Novartis and ExceMED and travel support by Novartis, Switzerland.
Jens Kuhle received speaker fees, research support, and travel support and/or served on advisory boards for ECTRIMS, Swiss MS Society, Swiss National Research Foundation (grant no. 320030_189140/1), University of Basel, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva.
Ludwig Kappos' institutions (University Hospital Basel and RC2NB) have received research support and payments that were used exclusively for research support for Dr Kappos' activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare, Celgene, CLC Behring, Genentech, GeNeuro, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono, Pfizer, Receptos, F. Hoffmann-La Roche, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and XenoPort; licence fees for Neurostatus products; research grants from the Swiss Multple Sclerosis Society, the Swiss National Research Foundation, the European Union, and the Roche Research Foundation.Stefano Magon has received research support from Swiss MS Society, Swiss National Science Foundation, University of Basel and Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung University Hospital Basel. He also received travel support from Biogen and Genzyme. Swiss Multiple Sclerosis Society and the Swiss National Science Foundation SPUM 33CM30_124115 and 33CM30_140338.s National Science Foundation (SPUM 33CM30_124115 and 33CM30_140338).
Athina Papadopoulou received speaker-fees/fees for advisory boards/for consulting from Sanofi-Genzyme, Eli Lilly, AbbVie, Lundbeck and TEVA (all used for her research in the University of Basel) and travel support from Bayer AG, Teva and Hoffmann-La Roche. Her research was supported by the University- and University Hospital of Basel, the Swiss Multiple Sclerosis Society, the “Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung”, the “Freie Akademische Gesellschaft Basel” and the Swiss National Science Foundation (Project number: P300PB_174480). The current research work was supported by the Swiss Multiple Sclerosis Society and the University of Basel.
P395/3219
Trait Conscientiousness and Multiple Sclerosis: Predicting Disease Progression and Assessing the Effects of an App-Supported Behavioral Intervention
Michael Jaworski1, Celeste Sanivasci1, Omid Mirmosayyeb1, Tom A Fuchs2, Hanneke Hulst3, Zachary Weinstock1, Michael Dwyer1, Dejan Jakimovski4, Niels Bergsland4, Svetlana Eckert4, David Hojnacki4, Robert Zivadinov4, Bianca Weinstock-Guttman4, Ralph Benedict4
1University at Buffalo (UB) Jacobs School of Medicine, Neurology, Buffalo, United States, 2VU, Amsterdam, Netherlands, 3Leiden University, Institute of Psychology, Health-, Medical-, and Neuropsychology, Leiden, Netherlands, 4University at Buffalo (UB) Jacobs School of Medicine, Buffalo, United States
Introduction: Like cognitive reserve, personality traits are associated with preserved functional status in people with multiple sclerosis (PwMS). The most robust evidence is found for the traits Neuroticism and Conscientiousness.
Objectives/Aims: [1] Do these traits predict MS disease progression as measured by transition from relapsing-remitting (RRMS) to secondary progressive (SPMS) course; and by EDSS worsening. [2] Can trait Conscientiousness be enhanced via a behavioral intervention.
Methods: For Aim 1, a retrospective chart review of 407 RRMS patients included measures of Neuroticism and Conscientiousness derived from the NEO Five-Factor Inventory (NEO-FFI). Using a logistic regression model, conversion vs non-conversion to SPMS was regressed on demographic variables, disease duration, time in study, and baseline personality traits. Next, using the same approach PwMS were categorized as EDSS stable vs worsening, by three-strata, Lorscheider (2016) criteria. For Aim 2, 26 participants were randomly assigned to an App-based, e-health, Conscientiousness intervention (n=12) vs waitlist control (n=14). Outcomes were Conscientiousness measured by the Big Five Inventory (BFI) and the NEO-FFI.
Results: For Aim 1, the demographics were as follows: age 45.5± 9.5 years; education = 14.4±2.2 years; 78.6% female. The median time of follow-up was 8.9 years. Of the 407 patients, 9.6% (n=39) transitioned to SPMS. Higher Conscientiousness was a significant buffer to progression (OR 0.95; p<0.01). There was no such effect for trait Neuroticism. 30.4% of PwMS showed EDSS worsening, and the regression model found Conscientiousness to be a significant predictor (OR 0.97; p<0.01). For Aim 2, the active and control arms were matched on demographic variables, cognitive performance, personality measures, and depression. Participants receiving Conscientiousness training evidenced greater change from baseline to follow-up in both BFI (d = 1.0, p = 0.018) NEO (d = 1.1, p = 0.009) Conscientiousness compared to controls.
Conclusion: These results add to the burgeoning literature showing reserve like buffering effects of Conscientiousness on MRI and clinical outcomes in MS. For the first time, these effects are demonstrated for disease progression and disability. We also find that this personality trait may be enhanced using an e-health, behavioral intervention.
Disclosure of interest: Michael Jaworski, Celeste Santivasci, Omid Mirmosayyeb, Zachary Weinstock and Niels Bergsland have nothing to disclose.
Tom Fuchs received consulting fees for Click Therapeutics.
Hanneke E. Hulst served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV.
Michael G. Dwyer received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd., and consulting fees from Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd.
Dejan Jakimovski received honoraria for serving on the advisory board of AstraZeneca. He also serves as an Associate Editor for Clinical Neurology and Neurosurgery and compensated by Elsevier B.V.
Dr. Svetlana Eckert has received compensation for speaking engagements from EMD Serono and has served on an advisory board for Genentech.
David Hojnacki served as speaker for Biogen, and as a consultant for Biogen and Genentech.
Robert Zivadinov received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Mapi Pharma, Filterlex, Sana Biotechnologies, 3D Communications, 415 Capital for speaking and consultant fees. He received financial support for research activities from Bristol Myers Squibb, Novartis, CorEvitas, Mapi Pharma and Protembis.
Bianca Weinstock-Guttman served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp and Horizon, served in speaker bureau for Biogen, and received grant/research support from the agencies listed in the previous sentence.
Ralph HB Benedict received research support from Biogen, Bristol Meyers Squibb, and Novartis, served as a consultant for Bristol Meyers Squibb, Novartis, Roche, and Sanofi, served as a speaker for Bristol Meyers Squibb, and EMD Serono, and has received royalties from Psychological Assessment Resources.
P396/3227
immune reconstitution following autologous haematopoietic stem cell therapy in patients with active relapsing-remitting multiple sclerosis
maria teresa cencioni1, Giacomo Boffa2, benedetta mazzanti3, Matilde Inglese4, Riccardo Saccardi5, Paolo Muraro1
1Imperial College London, Department of Brain Sciences, London, United Kingdom, 2IRCSS Ospedale Policlinico San Martino, Genova, Italy, 3Careggi University Hospital, Cell Therapy and Transfusion medicine Unit, Firenze, Italy, 4University of Genoa, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) and Center of Excellence for Biomedical Research (CEBR), Genova, Italy, 5Careggi University Hospital, Cell Therapy and Transfusion medicine Unit, Firenze, Italy
Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), where the immune system plays a crucial role. Autologous haematopoietic stem cell therapy (AHSCT) induces a long-lasting remission of disease activity in patients with relapsing-remitting (RR)-MS.
Objectives/Aims: Our study aims at identifying the mechanisms underlying the suppression of MS inflammation after AHSCT.
Methods: Ten patients with active RR-MS who had failed disease-modifying treatments received AHSCT with a BEAM (carmustine, etoposide, cytarabine and melphalan) and rabbit anti-thymocyte globulin (ATG) as conditioning. B and T lymphocyte reconstitution was studied in PBMCs by multiparametric flow cytometry before and at months 6 and 12 after AHSCT.
Results: In the CD4 subset, naïve CD4 T cells decreased at 6 months and returned to baseline at 12 months post-AHSCT, while IFNg-producing effector memory (EM) and terminally differentiated effector memory (TEMRA) increased at 6 months and reached the baseline at 12 months post-AHSCT. In the CD8 subset, naïve CD8 T cells and MAIT were lower than the baseline during follow-up while T memory stem cells (TSCM) decreased only at 12 months post-AHSCT. Granzyme b and interferon g-producing EM increased at 6 and 12 months, and granzyme b-producing EMRA and central memory (CM) increased at 12 months post-AHSCT. In the B cell compartment, transitional and naive B cells increased at 6 and 12 months while switched memory B cells decreased at 6 months post-HSCT
Conclusion: The T cell compartment after AHSCT shows the expansion of EM and CM and TEMRA supporting a potentially antigen-driven differentiation and maturation. The B cell compartment shows an expansion of regulatory and immature B cells. The observed changes suggest that T cell regeneration post-AHSCT occurs under increased regulatory B cell control promoting immune tolerance
Disclosure of interest: MTC Dr Maria Teresa Cencioni nothing to disclose.
GB: Dr Giacomo Boffa nothing to disclose.
BM: Dr Benedetta Mazzanti nothing to disclose.
MI: Prof Matilde Inglese nothing to disclose.
RS: Dr Riccardo Saccardi reports no conflict of interest related to this work. He discloses consulting to Therakos Therapeutics and Sanofi.
PM: Prof Paolo A. Muraro reports no conflict of interest related to this work. He discloses consulting to Magenta Therapeutics, Jasper Therapeutics and Rubius Therapeutics.
Funding: This study was supported by Ministero della Salute Italiana:PE-2013-02355346
