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1. Comparative study of clinical grade human tolerogenic dendritic cells

Author

Martínez-Cáceres E, Ramo-Tello C, Pujol-Borrell R, Grau-López L, Oñate C, Raïch-Regué D, Naranjo-Gómez M, and Borràs Francesc E

Subjects
Medicine
Abstract

Abstract Background The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy. Methods Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced. Results Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells. Conclusions Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.

Published
2011
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2. Recommendations for the Diagnosis and Treatment of Multiple Sclerosis Relapses

Author

Cristina Ramo-Tello, Yolanda Blanco, Luis Brieva, Bonaventura Casanova, Eva Martínez-Cáceres, Daniel Ontaneda, Lluís Ramió-Torrentá, Àlex Rovira, Institut Català de la Salut, [Ramo-Tello C] Multiple Sclerosis and Clinical Neuroimmunology Unit, Germans Trias University Hospital, 08916 Badalona, Spain. [Blanco Y] Multiple Sclerosis Unit, Clínic Hospital, 08036 Barcelona, Spain. [Brieva L] Multiple Sclerosis Unit, IRBLLEIDA. Arnau de Vilanova Hospital, 25198 Lleida, Spain. [Casanova B] Multiple Sclerosis and Clinical Neuroimmunology Unit, La Fe Hospital, 46026 Valencia, Spain. [Martínez-Cáceres E] Immunology Service, LCMN, Germans Trias University Hospital, 08916 Badalona, Spain. [Ontaneda D] Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH 44195, USA. [Rovira À] Unitat de Neuroradiologia, Servei de Radiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
relapse, pseudo-relapses, Medicine (miscellaneous), Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], treatment algorithm, Other subheadings::Other subheadings::/drug therapy [Other subheadings], calidad, acceso y evaluación de la atención sanitaria::calidad de la atención sanitaria [ATENCIÓN DE SALUD], multiple sclerosis, methylprednisolone, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple::esclerosis múltiple recurrente-remitente [ENFERMEDADES], Article, Health Care Quality, Access, and Evaluation::Quality of Health Care [HEALTH CARE], Esclerosi múltiple - Diagnòstic, Avaluació de resultats (Assistència sanitària), Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis::Multiple Sclerosis, Relapsing-Remitting [DISEASES], Medicine, Esclerosi múltiple - Tractament
Abstract

Metilprednisolona; Esclerosi múltiple; Recaiguda Metilprednisolona; Esclerosis múltiple; Recaída Methylprednisolone; Multiple sclerosis; Relapse Minimizing the risk of relapse is essential in multiple sclerosis (MS). As none of the treatments currently available are capable of completely preventing relapses, treatment of these episodes remains a cornerstone of MS care. The objective of this manuscript is to reduce uncertainty and improve quality of care of this neurological process. This article addresses definitions of key concepts, recommendations for clinical examination, classification criteria, magnetic resonance imaging, biomarkers, and specific therapeutic counsels including special populations such as pregnant and breastfeeding women, and children. An algorithm for treating MS relapses is also provided. This research was funded by NOVARTIS FARMACÉUTICA, SA, for the two expert panel meetings held and the recording and transcription of the content of the first meeting performed by the contract research organization, Dynamic.

Published
2021
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3. Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis

Author

Bassem Yamout, Alessandra Lugaresi, Pierre Duquette, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Alexandre Prat, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Jeannette Lechner-Scott, Francois Grand’ Maison, Guillermo Izquierdo, Steve Vucic, Roberto Bergamaschi, Cavit Boz, Ayse Altintas, Vahid Shaygannejad, Aysun Soysal, Youssef Sidhom, Tomas Kalincik, Charles B Malpas, Marc Girard, Serkan Ozakbas, Julie Prevost, Raed Alroughani, Catherine Larochelle, Michael Barnett, Daniele Spitaleri, Pamela A. McCombe, Thor Petersen, Mark Slee, Helmut Butzkueven, Maria Trojano, Franco Granella, Minh Le, Yara Dadalti Fragoso, Pierre Grammond, Radek Ampapa, Riadh Gouider, Gerardo Iuliano, Recai Turkoglu, Murat Terzi, Eugenio Pucci, Sifat Sharmin, Diana Ferraro, Sara Eichau, Patrizia Sola, Dana Horakova, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Le M., Malpas C., Sharmin S., Horakova D., Havrdova E., Trojano M., Izquierdo G., Eichau S., Ozakbas S., Lugaresi A., Prat A., Girard M., Duquette P., Larochelle C., Alroughani R., Bergamaschi R., Sola P., Ferraro D., Grammond P., Grand' Maison F., Terzi M., Boz C., Hupperts R., Butzkueven H., Pucci E., Granella F., Van Pesch V., Soysal A., Yamout B.I., Lechner-Scott J., Spitaleri D.L.A., Ampapa R., Turkoglu R., Iuliano G., Ramo-Tello C., Sanchez-Menoyo J.L., Sidhom Y., Gouider R., Shaygannejad V., Prevost J., Altintas A., Fragoso Y.D., McCombe P.A., Petersen T., Slee M., Barnett M.H., Vucic S., Van Der Walt A., and Kalincik T.

Subjects
Pediatrics, medicine.medical_specialty, Multivariate analysis, Multiple Sclerosis, brainstem, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, Therapeutic approach, Disability Evaluation, 0302 clinical medicine, disability outcome, medicine, Humans, Multiple sclerosi, Disabled Persons, 030304 developmental biology, 0303 health sciences, Expanded Disability Status Scale, cerebellar, early symptomatology, prognostic marker, business.industry, medicine.disease, Natural history, Neurology, Cohort, Disease Progression, Neurology (clinical), Brainstem, Presentation (obstetrics), business, 030217 neurology & neurosurgery, Brain Stem
Abstract

Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Published
2020

4. Early clinical markers of aggressive multiple sclerosis

Author

Tomas Kalincik, Marc Girard, Guillermo Izquierdo, Cristina Ramo-Tello, Francois Grand'Maison, Ali Manouchehrinia, Youssef Sidhom, Charles B Malpas, Alexandre Prat, Maria Trojano, Franco Granella, Pamela A. McCombe, Rana Karabudak, Murat Terzi, Eugenio Pucci, Raymond Hupperts, Vincent Van Pesch, Pierre Grammond, Sifat Sharmin, Richard A L Macdonell, Ayse Altintas, Riadh Gouider, Recai Turkoglu, Diana Ferraro, Alessandra Lugaresi, Pierre Duquette, Helmut Butzkueven, Serkan Ozakbas, Sara Eichau, Izanne Roos, Daniele Spitaleri, Yara Dadalti Fragoso, Mark Slee, Roberto Bergamaschi, Jan Hillert, Edgardo Cristiano, Thor Petersen, Eva Havrdova, Javier Olascoaga, Cavit Boz, Patrizia Sola, Freek Verheul, Aysun Soysal, Tomas Olsson, Dana Horakova, Ondokuz Mayıs Üniversitesi, Malpas C.B., Manouchehrinia A., Sharmin S., Roos I., Horakova D., Havrdova E.K., Trojano M., Izquierdo G., Eichau S., Bergamaschi R., Sola P., Ferraro D., Lugaresi A., Prat A., Girard M., Duquette P., Grammond P., Grand'Maison F., Ozakbas S., van Pesch V., Granella F., Hupperts R., Pucci E., Boz C., Sidhom Y., Gouider R., Spitaleri D., Soysal A., Petersen T., Verheul F., Karabudak R., Turkoglu R., Ramo-Tello C., Terzi M., Cristiano E., Slee M., McCombe P., Macdonell R., Fragoso Y., Olascoaga J., Altintas A., Olsson T., Butzkueven H., Hillert J., Kalincik T., Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), School of Medicine, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Male, PROGRESSION, Disease, multiple sclerosis, 01 natural sciences, THERAPY, Severity of Illness Index, Aggressive disease, 010104 statistics & probability, Disability Evaluation, 0302 clinical medicine, PROGNOSTIC-FACTORS, Multiple Sclerosi, Disability, Multiple sclerosis, Precision medicine, Prediction, R PACKAGE, Age of Onset, AcademicSubjects/SCI01870, Neurosciences and neurology, IMPAIRMENT, Cohort, Disease Progression, RELAPSE RATE, Female, Cohort study, Human, Adult, medicine.medical_specialty, Multiple Sclerosis, precision medicine, BRAIN MRI, Sensitivity and Specificity, 03 medical and health sciences, Internal medicine, Severity of illness, medicine, Humans, 0101 mathematics, Letters to the Editor, Expanded Disability Status Scale, business.industry, NATURAL-HISTORY, prediction, medicine.disease, PREDICTIVE-VALUE, Confidence interval, disability, AcademicSubjects/MED00310, Neurology (clinical), Age of onset, business, aggressive disease, 030217 neurology & neurosurgery, LONG-TERM DISABILITY
Abstract

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

Published
2020

5. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis

Author

Uccelli, Antonio, Laroni, Alice, Brundin, Lou, Clanet, Michel, Fernandez, Oscar, Nabavi, Seyed Massood, Muraro, Paolo A., Oliveri, Roberto S., Radue, Ernst W., Sellner, Johann, Soelberg Sorensen, Per, Sormani, Maria Pia, Wuerfel, Jens Thomas, Battaglia, Mario A., Freedman, Mark S., Bonetti, Bruno, Rush, Carolina, Herrera, Concepción, Ramo Tello, Cristina, Miller, David, Szwajcer, David, Strunk, Dirk, Wall, Donna, Aguera-Morales, Eduardo, Rohde, Eva, Dazzi, Francesco, Comi, Giancarlo, Martino, Gianvito, Izquierdo Ayuso, Guillermo, Rabinovitch, H., MacLean, Heather, Marriott, James, Racosta, Juan, Arab, Leila, Gimona, Mario, Introna, Martino, Blinkenberg, Morten, Aghdami, Naser, Ali, Rehiana, Vosoughi, Reza, Nicholas, Richard, Marrie, Ruth Ann, Karimi, Shahedeh, The UK Stem Cell Foundation, Multiple Sclerosis Society, MESEMS study group, [Uccelli,A, Laroni,A] Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy. [Uccelli,A, Laroni,A] IRCCS Ospedale Policlinico San Martino, Genoa, Italy. [Brundin,L] Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden [Clanet,M] CHU Toulouse, Université Paul Sabatier, Toulouse, France. [Fernandez,O] Instituto de Investigación Biomédica de Málaga (IBIMA), Regional University Hospital of Malaga, Malaga, Spain. [Nabavi,SM] Department of Brain and Cognitive Sciences, Royan Institute for Stem Cell Biology and Technology, Royan, Iran. [Nabavi,SM] ACCR, Iran and Regenerative Biomedicine Center, MS, Neurology Clinic and Research Unit, Tehran, Iran. [Muraro,PA] Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK. [Oliveri,RS] Cell Therapy Unit, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. [Radue,EW, Wuerfel,JT] Medical Image Analysis Centre Basel (MIAC AG), Basel, Switzerland. [Sellner,J] Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria. [Soelberg Sorensen,P] Danish MS Center Department of Neurology, University of Copenhagen and Rigshospitalet, Copenhagen, Denmark. [Sormani,MP] Department of Health Sciences, University of Genoa, Genoa, Italy. [Wuerfel,JT] Department of Biomedical Engineering, University Basel, Basel, Switzerland. [Battaglia,MA] Italian Multiple Sclerosis Foundation, Genoa, Italy. [Battaglia,MA] Department of Life Sciences, University of Siena, Siena, Italy. [Freedman,MS] Department of Medicine (Neurology), University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., The MESEMS network received a grant from Fondazione Italiana Sclerosi Multipla (FISM, sponsor of the Italian Clinical Trial, of the CRO activities and of part of centralized MRI activities), European Committee for Multiple Sclerosis (ECTRIMS), Multiple Sclerosis International Foundation (MSIF) for centralized activities. Individual trials participating in the MESEMS network are funded by: FISM (Italy), The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark), Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria (Austria), ARSEP Foundation, AFM (France). The UK trial (London) is supported by a Collaborative Grant from the UK MS Society [938/10], by the NIHR Biomedical Research Centre funding scheme to Imperial College and by the NIHR Imperial Clinical Research Facility., Uccelli, A., Laroni, A., Brundin, L., Clanet, M., Fernandez, O., Nabavi, S. M., Muraro, P. A., Oliveri, R. S., Radue, E. W., Sellner, J., Soelberg Sorensen, P., Sormani, M. P., Wuerfel, J. T., Battaglia, M. A., Freedman, M. S., Bonetti, B., Rush, C., Herrera, C., Ramo Tello, C., Miller, D., Szwajcer, D., Strunk, D., Wall, D., Aguera-Morales, E., Rohde, E., Dazzi, F., Comi, G., Martino, G., Izquierdo Ayuso, G., Rabinovitch, H., Maclean, H., Marriott, J., Racosta, J., Arab, L., Gimona, M., Introna, M., Blinkenberg, M., Aghdami, N., Ali, R., Vosoughi, R., Nicholas, R., Marrie, R. A., and Karimi, S.

Subjects
Male, Time Factors, Phenomena and Processes::Physical Phenomena::Time::Time Factors [Medical Subject Headings], Mesenchymal stromal cells, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Magnetic Resonance Imaging [Medical Subject Headings], Medicine (miscellaneous), Phases of clinical research, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Transplantation, Autologous [Medical Subject Headings], NEUROLOGICAL DISEASES, Research & Experimental Medicine, Geographical Locations::Geographic Locations::Europe::Europe, Eastern [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Clinical Trials, Phase I as Topic [Medical Subject Headings], Study Protocol, Disability Evaluation, Clinical trial, Mesenchymal stem cells, Mesenchymal stromal cells, Multiple sclerosis, 0302 clinical medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Multicenter Studies as Topic [Medical Subject Headings], Multicenter Studies as Topic, Pharmacology (medical), 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Controlled Clinical Trials as Topic::Randomized Controlled Trials as Topic [Medical Subject Headings], Cross over, lcsh:R5-920, Cross-Over Studies, Clinical Trials, Phase I as Topic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Clinical Trials, Phase II as Topic [Medical Subject Headings], Middle Aged, Magnetic Resonance Imaging, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Disability Evaluation [Medical Subject Headings], Clinical trial, Europe, Treatment Outcome, Medicine, Research & Experimental, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, Female, lcsh:Medicine (General), Autologous, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Células madre mesenquimatosas, Check Tags::Male [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Cell Transplantation::Stem Cell Transplantation::Mesenchymal Stem Cell Transplantation [Medical Subject Headings], Phase I as Topic, Diseases::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Mesenchymal Stem Cell Transplantation, Placebo, Transplantation, Autologous, Persons::Persons::Age Groups::Adolescent [Medical Subject Headings], Double blind, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Double-Blind Method, General & Internal Medicine, Internal medicine, Ensayo clínico, medicine, Humans, Clinical Trials, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], Science & Technology, TRANSPLANTATION, business.industry, Multiple sclerosis, Phase II as Topic, Mesenchymal stem cell, MESEMS study group, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], 1103 Clinical Sciences, Recovery of Function, medicine.disease, Phenomena and Processes::Biological Phenomena::Recovery of Function [Medical Subject Headings], Transplantation, Check Tags::Female [Medical Subject Headings], Cardiovascular System & Hematology, Esclerosis múltiple, Mesenchymal stem cells, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Cross-Over Studies [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Double-Blind Method [Medical Subject Headings], business, 030217 neurology & neurosurgery
Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS. This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses. Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials. Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010–024081–21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012–000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011–001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012–002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015–000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.

Published
2019

6. Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis

Author

Dana Horakova, Marco Onofrj, Jose Luis Sanchez-Menoyo, Roberto Bergamaschi, Patrizia Sola, Bassem Yamout, Jeannette Lechner-Scott, Vincent Van Pesch, Cavit Boz, Daniele Spitaleri, Tim Spelman, Ludwig Kappos, Claudio Solaro, Francois Grand'Maison, Alessandra Lugaresi, Radek Ampapa, Tomas Kalincik, Marc Girard, Vahid Shaygannejad, Jens Kuhle, Maria Trojano, Franco Granella, Steve Vucic, Julie Prevost, Rana Karabudak, Murat Terzi, Cristina Ramo-Tello, Eugenio Pucci, Alexandre Prat, Bart Van Wijmeersch, Recai Turkoglu, Pamela A. McCombe, Serkan Ozakbas, Raed Alroughani, Pierre Grammond, Vilija Jokubaitis, Diana Ferraro, Mark Slee, Eva Havrdova, Helmut Butzkueven, Ernest Butler, Suzanne Hodgkinson, Guillermo Izquierdo, Pierre Duquette, Ondokuz Mayıs Üniversitesi, Kalincik T., Kubala Havrdova E., Horakova D., Izquierdo G., Prat A., Girard M., Duquette P., Grammond P., Onofrj M., Lugaresi A., Ozakbas S., Kappos L., Kuhle J., Terzi M., Lechner-Scott J., Boz C., Grand'maison F., Prevost J., Sola P., Ferraro D., Granella F., Trojano M., Bergamaschi R., Pucci E., Turkoglu R., McCombe P.A., Pesch V.V., Van Wijmeersch B., Solaro C., Ramo-Tello C., Slee M., Alroughani R., Yamout B., Shaygannejad V., Spitaleri D., Sanchez-Menoyo J.L., Ampapa R., Hodgkinson S., Karabudak R., Butler E., Vucic S., Jokubaitis V., Spelman T., Butzkueven H., UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Toluidines, Dimethyl Fumarate, Hydroxybutyrates, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Natalizumab, Recurrence, multiple sclerosis, oral drugs, efficacy, persistence, safety, tolerability, Internal medicine, Fingolimod Hydrochloride, Nitriles, Teriflunomide, medicine, Humans, 030212 general & internal medicine, Propensity Score, Proportional Hazards Models, Dimethyl fumarate, business.industry, Multiple sclerosis, Standard treatment, Middle Aged, medicine.disease, Fingolimod, Discontinuation, Psychiatry and Mental health, chemistry, Crotonates, Female, Surgery, Neurology (clinical), business, Immunosuppressive Agents, 030217 neurology & neurosurgery, medicine.drug
Abstract

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; Jokubaitis, Vilija G./0000-0002-3942-4340; McCombe, Pamela/0000-0003-2704-8517; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453; Kalincik, Tomas/0000-0003-3778-1376; Vucic, Steve/0000-0002-8323-873X; Ramo-Tello, Cristina/0000-0001-8643-5053 WOS: 000471115600018 PubMed: 30636699 Objective Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. Methods We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring). Results The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p >= 0.59) or improvement (p >= 0.14) were found between the therapies. In patients with >= 3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p

Published
2019

7. Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study

Author

Ludwig Kappos, Tomas Kalincik, Marc Girard, Pierre Duquette, Francois Grand'Maison, Alexandre Prat, Jeannette Lechner-Scott, Pierre Grammond, Maria Trojano, Helmut Butzkueven, Eva Havrdova, Dana Horakova, J Lorscheider, Patrizia Sola, Guillermo Izquierdo, Vincent Van Pesch, C. Ramo-Tello, J. L. Sanchez Menoyo, Claudio Solaro, Jens Kuhle, R. Hupperts, Alessandra Lugaresi, A. Van der Walt, Mark Slee, Diana Ferraro, Eugenio Pucci, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Lorscheider, J, Kuhle, J, Izquierdo, G, Lugaresi, A, Havrdova, E, Horakova, D, Hupperts, R, Duquette, P, Girard, M, Prat, A, Grand'Maison, F, Grammond, P, Sola, P, Ferraro, D, Trojano, M, Ramo-Tello, C, Lechner-Scott, J, Pucci, E, Solaro, C, Slee, M, Van Pesch, V, Sanchez Menoyo, J L, van der Walt, A, Butzkueven, H, Kappos, L, and Kalincik, T

Subjects
Adult, Male, medicine.medical_specialty, Anti-Inflammatory Agents, clinical outcome, Disease, Antibodies, Monoclonal, Humanized, immunomodulation, multiple sclerosis, Cohort Studies, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, clinical outcomes, observational study, primary progressive, Neurology, Neurology (clinical), medicine, Humans, Disabled Persons, 030212 general & internal medicine, Expanded Disability Status Scale, business.industry, Hazard ratio, Middle Aged, Multiple Sclerosis, Chronic Progressive, Confidence interval, Quartile, multiple sclerosi, Propensity score matching, Disease Progression, Female, Ocrelizumab, business, 030217 neurology & neurosurgery, Follow-Up Studies, Cohort study, medicine.drug
Abstract

Background and purpose Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. Methods Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. Results Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). Conclusion Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Published
2018

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

Author

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

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

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

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