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1. Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

Author

Lefort, M, Sharmin, S, Andersen, J B, Vukusic, S, Casey, R, Debouverie, M, Edan, G, Ciron, J, Ruet, A, De Sèze, J, Maillart, E, Zephir, H, Labauge, P, Defer, G, Lebrun-Frenay, C, Moreau, T, Berger, E, Clavelou, P, Pelletier, J, Stankoff, B, Gout, O, Thouvenot, E, Heinzlef, O, Al-Khedr, A, Bourre, B, Casez, O, Cabre, P, Montcuquet, A, Wahab, A, Camdessanché, J P, Maurousset, A, Ben Nasr, H, Hankiewicz, K, Pottier, C, Maubeuge, N, Dimitri-Boulos, D, Nifle, C, Laplaud, D A, Horakova, D, Havrdova, E K, Alroughani, R, Izquierdo, G, Eichau, S, Ozakbas, S, Patti, F, Onofrj, M, Lugaresi, A, Terzi, M, Grammond, P, Grand'Maison, F, Yamout, B, Prat, A, Girard, M, Duquette, P, Boz, C, Trojano, M, McCombe, P, Slee, M, Lechner-Scott, J, Turkoglu, R, Sola, P, Ferraro, D, Granella, F, Shaygannejad, V, Prevost, J, Maimone, D, Skibina, O, Buzzard, K, Van der Walt, A, Karabudak, R, Van Wijmeersch, B, Csepany, T, Spitaleri, D, Vucic, S, Koch-Henriksen, N, Sellebjerg, F, Soerensen, P S, Hilt Christensen, C. C., Rasmussen, P V, Jensen, M B, Frederiksen, J L, Bramow, S, Mathiesen, H K, Schreiber, K I, Butzkueven, H, Magyari, M, Kalincik, T, Leray, E, Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), Recherche sur les services et le management en santé (RSMS), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], University of Melbourne, Copenhagen University Hospital, Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Eugène Devic EDMUS, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), i-SEP (i-SEP), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Saint-Antoine [AP-HP], Fondation Ophtalmologique Adolphe de Rothschild [Paris], Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHI Poissy-Saint-Germain, CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Monash University [Melbourne], The Royal Melbourne Hospital, École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR), Département Méthodes quantitatives en santé publique (METIS), Collectif de recherche handicap, autonomie et société inclusive (CoRHASI), OFSEP was 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 Eugène Devic EDMUS Foundation against multiple sclerosis and by the ARSEP Foundation. ML has recieved travel grant from ARSEP foundation for this project. The Clinical Outcomes Research unit at the University of Melbourne received funding from NHMRC (grant number 1140766, 1129789, and 1157717) to support this study. The MSBase Foundation is a not-for-profit organization that receives support from Biogen, Novartis, Merck, Roche, Teva Pharmaeutical Industries and Sanofi Genzyme. The Danish Multiple Sclerosis Registry did not receive any funding to collaborate in this study., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Rennes (UNIV-RENNES), Bramow, Stephan/0000-0001-9482-1771, Sellebjerg, Finn/0000-0002-1333-9623, Heinzlef, O., Camdessanche, J. P., Turkoglu, R., Boz, C., Shaygannejad, V, Moreau, T., Sellebjerg, F., Onofrj, M., De Seze, J., Wahab, A., VAN WIJMEERSCH, Bart, Mathiesen, H. K., Bramow, S., Andersen, J. B., Zephir, H., Ben Nasr, H., Ciron, J., Al-Khedr, A., Granella, F., Spitaleri, D., Lebrun-Frenay, C., Ferraro, D., Trojano, M., Labauge, P., Thouvenot, E., Skibina, O., Magyari, M., Patti, F., Maimone, D., Kalincik, T., Buzzard, K., Dimitri-Boulos, D., Alroughani, R., Maillart, E., Koch-Henriksen, N., Hankiewicz, K., Rasmussen, P., V, Jensen, M. B., Lechner-Scott, J., Csepany, T., Casez, O., Soerensen , P. S., Lugaresi, A., McCombe, P., Defer, G., Terzi, M., Christensen, C. C. Hilt, Girard, M., Ruet, A., Berger , E., Maurousset, A., Duquette, P., Horakova, D., Laplaud, D. A., Casey, R., Edan, G., Schreiber, K., I, Lefort, M., Cabre, P., Maubeuge, N., Grammond, P., Prevost, J., Havrdova, E. K., Gout, O., Prat, A., Sola, P., Slee, M., Sharmin , S., Leray, E., Ozakbas, S., Grand'Maison, F., Montcuquet, A., Nifle, C., Eichau, S., Butzkueven, H., Karabudak, R., Vukusic, S., Debouverie, M., Clavelou, P., Stankoff, B., Pottier, C., Yamout, B., Vucic, S., Van der Walt, A., Pelletier, J., Bourre, B., Izquierdo, G., Frederiksen, J. L., Lefort, M, Sharmin, S, Andersen, J B, Vukusic, S, Casey, R, Debouverie, M, Edan, G, Ciron, J, Ruet, A, De Sèze, J, Maillart, E, Zephir, H, Labauge, P, Defer, G, Lebrun-Frenay, C, Moreau, T, Berger, E, Clavelou, P, Pelletier, J, Stankoff, B, Gout, O, Thouvenot, E, Heinzlef, O, Al-Khedr, A, Bourre, B, Casez, O, Cabre, P, Montcuquet, A, Wahab, A, Camdessanché, J P, Maurousset, A, Ben Nasr, H, Hankiewicz, K, Pottier, C, Maubeuge, N, Dimitri-Boulos, D, Nifle, C, Laplaud, D A, Horakova, D, Havrdova, E K, Alroughani, R, Izquierdo, G, Eichau, S, Ozakbas, S, Patti, F, Onofrj, M, Lugaresi, A, Terzi, M, Grammond, P, Grand'Maison, F, Yamout, B, Prat, A, Girard, M, Duquette, P, Boz, C, Trojano, M, McCombe, P, Slee, M, Lechner-Scott, J, Turkoglu, R, Sola, P, Ferraro, D, Granella, F, Prevost, J, Maimone, D, Skibina, O, Buzzard, K, Van der Walt, A, Karabudak, R, Van Wijmeersch, B, Csepany, T, Spitaleri, D, Vucic, S, Koch-Henriksen, N, Sellebjerg, F, Soerensen, P S, Hilt Christensen, C C, Rasmussen, P V, Jensen, M B, Frederiksen, J L, Bramow, S, Mathiesen, H K, Schreiber, K I, Butzkueven, H, Magyari, M, Kalincik, T, and Leray, E

Subjects
MESH: Fingolimod Hydrochloride, Indication bias, Multiple Sclerosis, MESH: Multiple Sclerosis, Relapsing-Remitting, Propensity score, Epidemiology, Positivity assumption, [SDV]Life Sciences [q-bio], Health Informatics, Effectiveness, Multiple sclerosis, Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosi, Humans, Fingolimod Hydrochloride/therapeutic use, MESH: Treatment Outcome, Censoring, Natalizumab/therapeutic use, MESH: Humans, Fingolimod Hydrochloride, Natalizumab, Effectivene, Causal contrasts, MESH: Natalizumab, MESH: Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting/drug therapy, Causal contrast, Treatment Outcome, Multiple Sclerosis/drug therapy, Indication bia, Human
Abstract

Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled. OFSEP was 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 ANR10-COHO-002, by the Eugène Devic EDMUS Foundation against multiple sclerosis and by the ARSEP Foundation. ML has recieved travel grant from ARSEP foundation for this project. The Clinical Outcomes Research unit at the University of Melbourne received funding from NHMRC (grant number

Published
2022

2. Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients

Author

Stefan Diem, Oltin T Pop, Joachim Müller, Alexandre Moulin, Sandra S. Ring, Omar Ali, Stefanie Müller, Lukas Flatz, Christoph Jakob Ackermann, Thomas Hundsberger, Fiamma Berner, Eva Markert, University of Zurich, and Flatz, Lukas

Subjects
Research Report, Cancer Research, Lymphocyte, Immunology, 610 Medicine & health, chemical and pharmacologic phenomena, Pembrolizumab, Multiple sclerosis, Immune checkpoint inhibitors, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Female, Fingolimod Hydrochloride/pharmacology, Fingolimod Hydrochloride/therapeutic use, Humans, Immune Checkpoint Inhibitors/pharmacology, Immune Checkpoint Inhibitors/therapeutic use, Immunosuppressive Agents/pharmacology, Immunosuppressive Agents/therapeutic use, Lymphocytes/immunology, Lymphocytes, Tumor-Infiltrating/immunology, Middle Aged, Neoplasms/drug therapy, Neoplasms/immunology, Cancer, Fingolimod, Oncology, Tumor immunology, Neoplasms, medicine, Immunology and Allergy, 1306 Cancer Research, Lymphocytes, 2403 Immunology, Fingolimod Hydrochloride, Tumor-infiltrating lymphocytes, business.industry, Melanoma, 10177 Dermatology Clinic, medicine.disease, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, 2723 Immunology and Allergy, Cancer research, 2730 Oncology, business, Immunosuppressive Agents, 030217 neurology & neurosurgery, medicine.drug
Abstract

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing–remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

Published
2021

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

Author

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

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

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

Published
2019

4. The Swiss Multiple Sclerosis Cohort-Study (SMSC): A Prospective Swiss Wide Investigation of Key Phases in Disease Evolution and New Treatment Options

Author

Ludwig Kappos, Till Sprenger, Jens Kuhle, Johannes Lorscheider, Krassen Nedeltchev, Simon Ramseier, Oliver Findling, Ernst-Wilhelm Radue, Jean-François Louvion, Myriam Schluep, Giulio Disanto, Lutz Achtnichts, Renaud Du Pasquier, Claudio Gobbi, Christoph Stippich, Heinrich Mattle, Jochen Vehoff, Patrice H. Lalive, Pascal Benkert, Chiara Zecca, Christoph Lotter, Özgür Yaldizli, Smsc Scientific Board, Tobias Derfuss, Caroline Pot, Christian P. Kamm, Stefanie Karin Mueller, SMSC Scientific, Board, Ramseier, S., Achtnichts, L., Findling, O., Saxer, J., Nedeltchev, K., Remonda, L., Boxheimer, L., Kuhle, J., Kappos, L., Yaldizli£££Özguer£££ Ö., Derfuss, T., Sprenger, T., Limberg, M., Scheerer, I., Orleth, A., Treppke, F., Beregi, E., Stippich, C., Reinhardt, J., Fellner, I., Würfel, J., Radue, EW., Thoeni, A., Palatini, A., Pauli-Magnus, C., Fabbro, T., Benkert, P., Roesler, A., Mechati, S., Louvion, JF., Kamm, C., Chan, A., Mattle, H., Salmen, A., Kaeser, M., Wagner, F., Verma, R., Lalive, P., Di Marco, M., Haller, S., Lovblad, KO., Du Pasquier, R., Schluep, M., Pot, C., Granziera, C., Hagmann, P., Maeder, P., Gobbi, C., Zecca, C., Disanto, G., Tschuor, S., Cianfoni, A., Müller, S., Vehoff, J., Weber, J., and Lotter, C.

Subjects
Male, 0301 basic medicine, Physiology, Adult, Biomarkers/blood, Biomarkers/cerebrospinal fluid, Brain/radiography, Cohort Studies, Demography, Female, Fingolimod Hydrochloride/therapeutic use, Follow-Up Studies, Humans, Immunosuppressive Agents/therapeutic use, Magnetic Resonance Imaging, Middle Aged, Multiple Sclerosis/diagnosis, Multiple Sclerosis/drug therapy, Natalizumab/therapeutic use, Prognosis, Prospective Studies, Recurrence, Switzerland, lcsh:Medicine, ddc:616.07, Nervous System, Diagnostic Radiology, Geographical Locations, 0302 clinical medicine, Natalizumab, Medicine and Health Sciences, Medicine, 10. No inequality, Prospective cohort study, lcsh:Science, Cerebrospinal Fluid, Multidisciplinary, Clinically isolated syndrome, Radiology and Imaging, Brain, Neurodegenerative Diseases, Fingolimod, Body Fluids, 3. Good health, Europe, Neurology, Research Design, Cohort, Observational Studies, Anatomy, Immunosuppressive Agents, Research Article, medicine.drug, Cohort study, medicine.medical_specialty, Multiple Sclerosis, Imaging Techniques, Immunology, Research and Analysis Methods, Autoimmune Diseases, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, Expanded Disability Status Scale, Fingolimod Hydrochloride, business.industry, Multiple sclerosis, lcsh:R, Biology and Life Sciences, medicine.disease, Demyelinating Disorders, Long-Term Care, Surgery, Health Care, Radiography, 030104 developmental biology, People and Places, Clinical Immunology, lcsh:Q, Clinical Medicine, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.

Published
2016

5. Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia

Author

Ursula Felderhoff-Müser, Wiebke Hansen, Ivo Bendix, Josephine Herz, Marco Sifringer, Katharina Lumpe, Karina Kempe, Ralf Herrmann, Martin Hadamitzky, Xinlin Hou, Yohan van de Looij, Meray Serdar, Stéphane Sizonenko, Barbara S. Reinboth, and Rolf Heumann

Subjects
0301 basic medicine, Male, Medizin, Sphingosine/analogs & derivatives/metabolism, medicine.disease_cause, Nerve Fibers, Myelinated, Cognition Disorders/metabolism/pathology/prevention & control, Behavioral Neuroscience, Microglia/drug effects/metabolism/pathology, Random Allocation, 0302 clinical medicine, Sphingosine, Pregnancy, hemic and lymphatic diseases, CIBM-AIT, Hyperoxia, ddc:618, Nerve Fibers, Myelinated/drug effects, Microglia, Brain, White Matter, Fingolimod, Oligodendroglia, Receptors, Lysosphingolipid, medicine.anatomical_structure, Female, medicine.symptom, medicine.drug, Oligodendroglia/drug effects/metabolism/pathology, Immunology, Biology, Neuroprotection, White matter, 03 medical and health sciences, Oxygen/administration & dosage, medicine, Animals, Brain/metabolism, Rats, Wistar, Fingolimod Hydrochloride/therapeutic use, White Matter/drug effects/metabolism/pathology, Fingolimod Hydrochloride, Endocrine and Autonomic Systems, Multiple sclerosis, Lysophospholipids/metabolism, Neonatal brain injury, medicine.disease, Oligodendrocyte, Rats, Oxygen, 030104 developmental biology, Diffusion Magnetic Resonance Imaging, Receptors, Lysosphingolipid/antagonists & inhibitors/metabolism, Animals, Newborn, Lysophospholipids, White matter development, Cognition Disorders, Hyperoxia/drug therapy/pathology, 030217 neurology & neurosurgery, Oxidative stress
Abstract

Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal brain injury, therapeutic options are limited. In the adult demyelinating disease multiple sclerosis the sphingosine-1-phosphate (S1P) receptor modulating substance fingolimod (FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of FTY720 in a neonatal model of oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome.A single dose of FTY720 (1mg/kg) at the onset of neonatal hyperoxia (24h 80% oxygen on postnatal day 6) resulted in improvement of neuro-cognitive development persisting into adulthood. This was associated with reduced microstructural white matter abnormalities 4months after the insult. In search of the underlying mechanisms potential non-classical (i.e. lymphocyte-independent) pathways were analysed shortly after the insult, comprising modulation of oxidative stress and local inflammatory responses as well as myelination, oligodendrocyte degeneration and maturation. Treatment with FTY720 reduced hyperoxia-induced oxidative stress, microglia activation and associated pro-inflammatory cytokine expression. In vivo and in vitro analyses further revealed that oxygen-induced hypomyelination is restored to control levels, which was accompanied by reduced oligodendrocyte degeneration and enhanced maturation. Furthermore, hyperoxia-induced elevation of S1P receptor 1 (S1P1) protein expression on in vitro cultured oligodendrocyte precursor cells was reduced by activated FTY720 and protection from degeneration is abrogated after selective S1P1 blockade. Finally, FTY720s’ classical mode of action (i.e. retention of immune cells within peripheral lymphoid organs) was analysed demonstrating that FTY720 diminished circulating lymphocyte counts independent from hyperoxia. Cerebral immune cell counts remained unchanged by hyperoxia and by FTY720 treatment.Taken together, these results suggest that beneficial effects of FTY720 in neonatal oxygen-induced brain injury may be rather attributed to its anti-oxidative and anti-inflammatory capacity acting in concert with a direct protection of developing oligodendrocytes than to a modulation of peripheral lymphocyte trafficking. Thus, FTY720 might be a potential new therapeutic option for the treatment of neonatal brain injury through reduction of white matter damage.

Published
2016

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