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1. Epstein-Barr-negative MS: a true phenomenon?

Author

Dobson, Ruth, Kuhle, Jens, Middeldorp, Jaap, Giovannoni, Gavin, on behalf of the international CIS study investigators including Dalla Costa, G, Furlan, R, Martinelli, V, Comi, G, Runia, T, Hintzen, R, Evdoshenko, E, Lazareva, N, Lapin, S, Thouvenot, E, Lehmann, S, Castelnovo, G, Iaffaldano, P, Direnzo, V, Trojano, M, Khademi, . M, Piehl, F, Olsson, T, Comabella, M, Montalban, X, Tintoré, M, Sombekke, M, Killestein, J, Teunissen, C, Hegen, H, Deisenhammer, F, Rauch, S, D'Alfonso, S, Barizzone, N, Alvarez Cermeño, Jc, Villar, Lm, Kleinová, P, Horáková, D, Havrdová, E, Roesler, R, Lauda, F, Tumani, H, Llufriu, S, Villoslada, P, Saiz, A, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Siva, A, Menge, T, Kieseier, Bc, Hartung, Hp, Rajda, C, Vécsei, L, Bergamaschi, R, Colombo, E, Franciotta, D, Moll, N, Pelletier, J, Picard, C, Khalil, M, Enzinger, C, Fuchs, S, Marignier, R, Confavreux, C, Dujmovic, I, Drulovic, J, Larsson, H, Malmestrom, C, Lycke, J, Scarpini, E, C. Fenoglio, C, Galimberti, D, Wergeland, S, Torkildsen, Ø, Myhr, Km, Laroni, Alice, Uccelli, Antonio, Annibali, V, Romano, S, Salvetti, M, Martínez, Ad, Carra, A, Rejdak, K, Frederiksen, Jl, Brassat, D, Bosca, I, Casanova, B, Derfuss, T, Lindberg, R, Yaldizli, Ö, Kappos, L, Leone, M., and Pathology

Subjects
0301 basic medicine, business.industry, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Epstein barr, Phenomenon, Medicine, Neurology (clinical), business, Competence (human resources), Social psychology, Clinical/Scientific Notes, 030217 neurology & neurosurgery
Abstract

This work was supported by institutional funding and in part by the BMBF grant KKNMS (Competence Net Multiple Sclerosis) to H Tumani.

Published
2017
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2. Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome

Author

Disanto, G, Adiutori, R, Dobson, R, Martinelli, V, Costa, GD, Runia, T, Evdoshenko, E, Thouvenot, E, Trojano, M, Norgren, N, Teunissen, C, Kappos, L, Giovannoni, G, Kuhle, J, Bianchi, L, Topping, J, Bestwick, JP, Meier, UC, Lazareva, N, Iaffaldano, P, Direnzo, V, Khademi, M, Piehl, F, Comabella, M, Sombekke, M, Killestein, J, Hegen, H, Rauch, S, D'Alfonso, S, Alvarez-Cermeno, JC, Kleinova, P, Horakova, D, Roesler, R, Lauda, F, Llufriu, S, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Menge, T, Rajda, C, Bergamaschi, R, Moll, N, Khalil, M, Marignier, R, Dujmovic, I, Larsson, H, Malmestrom, C, Scarpini, E, Fenoglio, C, Wergeland, S, Laroni, A, Annibali, V, Romano, S, Martinez, AD, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, O, Myhr, K, Galimberti, D, Rejdak, K, Lycke, J, Frederiksen, JL, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, RL, Yaldizli, O, Vecsei, L, Kieseier, BC, Hartung, HP, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdova, E, Villar, LM, Leone, M, Barizzone, N, Deisenhammer, F, Montalban, X, Tintore, M, Olsson, T, Lehmann, S, Castelnovo, G, Lapin, S, Hintzen, R, Furlan, R, Comi, G, Ramagopalan, SV, and Int Clinically Isolated Syndrome S

Abstract

Background Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) and healthy controls. Methods We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79-139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3-7.9)); and 92 healthy controls. Results NfL levels were higher in FC (24.1 pg/mL (13.5-51.8)) and NC (19.3 pg/mL (13.6-35.2)) than in healthy controls (7.9 pg/mL (5.6-17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p=1.5x10(-5) and OR=7.03; 95% CI 2.85 to 17.34; p=2.3x10(-5), respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR=2.36; 95% CI 1.21 to 4.59; p=0.011), gadolinium-enhancing lesions (OR=2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR=2.54; 95% CI 1.21 to 5.31; p=0.013) at CIS diagnosis. Conclusions If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.

Published
2016

3. CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple Sclerosis Resistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study

Author

Belogurov A., Zakharov K., Lomakin Y., Surkov K., Avtushenko S., Kruglyakov P., Smirnov I., Makshakov G., Lockshin C., Gregoriadis G., Genkin D., Gabibov A., and Evdoshenko E.

Subjects
Clinical trial, Myelin basic protein, Xemys, Liposomes, Mannose, MRI
Abstract

© 2016, The Author(s).Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46–62, MBP124–139 and MBP147–170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.

Published
2016

4. Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis

Author

Villar LM, Casanova B, Ouamara N, Comabella M, Jalili F, Leppert D, de Andrés C, Izquierdo G, Arroyo R, Avsar T, Lapin SV, Johnson T, Montalbán X, Fernández O, Álvarez-Lafuente R, Masterman D, García-Sánchez MI, Coret F, Siva A, Evdoshenko E, Álvarez-Cermeño JC, and Bar-Or A

Subjects
Adult, Inflammation, Male, Cross-Sectional Studies, Phenotype, Immunoglobulin M, Oligoclonal Bands, Humans, Female, Longitudinal Studies, Middle Aged, Multiple Sclerosis, Chronic Progressive, Biomarkers
Abstract

Objective: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. Methods: The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. Results: Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. Interpretation: The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments.

Published
2013

5. Multivariate clinically isolated syndrome (CIS) risk factor study: towards individual prognosis and treatment indication in CIS

Author

Kuhle, J., Dobson, R., Bestwick, J. P., Topping, J., Dalla Costa, G., Khademi, M., Sombekke, M., Killestein, J., Evdoshenko, E., Lazareva, N., Runia, T., Zbornikova, P., Horakova, D., D Alfonso, S., Thouvenot, E., Moll, N., Hegen, H., Rauch, S., Khalil, M., Fuchs, S., Lindberg, R. L. P., Derfuss, T., Sara Llufriu, Franciotta, D., Roesler, R., Lauda, F., Rajda, C., Drulovic, J., Menge, T., Kieseier, B. C., Avsar, T., Marignier, R., Malmestrom, C., Myhr, K. M., Wergeland, S., Annibali, V., Romano, S., Carra, A., Laroni, A., Frederiksen, J. L., Larsson, H. B., Uccelli, A., Martinez, A. D., Salvetti, M., Torkildsen, O., Lycke, J., Confavreux, C., Rejdak, K., Bosca, I., Brassat, D., Scarpini, E., Fenoglio, C., Galimberti, D., Siva, A., Hartung, H. P., Dujmovic, I., Vecsei, L., Tumani, H., Bergamaschi, R., Colombo, E., Villoslada, P., Saiz, A., Enzinger, C., Kappos, L., Deisenhammer, F., Alvarez-Cermeno, J. C., Villar, L., Pelletier, J., Lehmann, S., Castelnovo, G., Barizzone, N., Leone, M., Havrdova, E., Trojano, M., Iaffaldano, P., Direnzo, V., Comabella, M., Tintore, M., Montalban, X., Hintzen, R., Lapin, S., Teunissen, C., Piehl, F., Olsson, T., Furlan, R., Martinelli, V., Comi, G., Ramagopalan, S., and Giovannoni, G.

6. Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome

Author

Disanto, G1, Adiutori, R2, Dobson, R2, Martinelli, V3, Dalla Costa G3, Runia, T4, Evdoshenko, E5, Thouvenot, E6, Trojano, M7, Norgren, N8, Teunissen, C9, Kappos, L10, Giovannoni, G2, Kuhle, J, Bianchi, L, Topping, J, Bestwick, Jp, Meier, Uc, Lazareva, N, Iaffaldano, P, Direnzo, V, Khademi, M, Piehl, F, Comabella, M, Sombekke, M, Killestein, J, Hegen, H, Rauch, S, D'Alfonso, S, Alvarez-Cermeño, Jc, Kleinová, P, Horáková, D, Roesler, R, Lauda, F, Llufriu, S, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Menge, T, Rajda, C, Bergamaschi, R, Moll, N, Khalil, M, Marignier, R, Dujmovic, I, Larsson, H, Malmestrom, C, Scarpini, E, Fenoglio, C, Wergeland, S, Laroni, A, Annibali, V, Romano, S, Martínez, Ad, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, Ø, Myhr, Km, Galimberti, D, Rejdak, K, Lycke, J, Frederiksen, Jl, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, Rl, Yaldizli, Ö, Vécsei, L, Kieseier, Bc, Hartung, Hp, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdová, E, Villar, Lm, Leone, M, Barizzone, N, Deisenhammer, F, Montalban, X, Tintoré, M, Olsson, T, Lehmann, S, Castelnovo, G, Lapin, S, Hintzen, R, Furlan, R, Comi, G, Ramagopalan, Sv., Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, Disanto, G., Adiutori, R., Dobson, R., Martinelli, V., Dalla Costa, G., Runia, T., Evdoshenko, E., Thouvenot, E., Trojano, M., Norgren, N., Teunissen, C., Kappos, L., Giovannoni, G., Kuhle, J., on behalf of the International ClinicallyIsolated Syndrome Study, Group, and Neurology

Subjects
Male, Pathology, Future studies, Gastroenterology, 0302 clinical medicine, Neurofilament Proteins, Multiple Sclerosi, 0303 health sciences, Clinically isolated syndrome, medicine.diagnostic_test, Medicine (all), Neurofilament Protein, Demyelinating Disease, Magnetic Resonance Imaging, Psychiatry and Mental Health, Predictive value of tests, Disease Progression, Biomarker (medicine), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Human, Adult, medicine.medical_specialty, Multiple Sclerosis, Neurofilament light, multiple sclerosis, adult, axons, biomarkers, demyelinating diseases, disease progression, female, follow-up studies, humans, magnetic resonance imaging, male, neurofilament proteins, predictive value of tests, neurology (clinical), psychiatry and mental health, surgery, arts and humanities (miscellaneous), medicine (all), [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Axon, Follow-Up Studie, 03 medical and health sciences, Arts and Humanities (miscellaneous), Predictive Value of Tests, Internal medicine, medicine, Humans, In patient, MULTIPLE SCLEROSIS, 030304 developmental biology, business.industry, Multiple sclerosis, Magnetic resonance imaging, Biomarker, medicine.disease, Axons, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers, Demyelinating Diseases, Follow-Up Studies
Abstract

International audience; BACKGROUND:Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) and healthy controls.METHODS:We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79-139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3-7.9)); and 92 healthy controls.RESULTS:NfL levels were higher in FC (24.1 pg/mL (13.5-51.8)) and NC (19.3 pg/mL (13.6-35.2)) than in healthy controls (7.9 pg/mL (5.6-17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p = 1.5 × 10(-5) and OR = 7.03; 95% CI 2.85 to 17.34; p = 2.3 × 10(-5), respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR = 2.36; 95% CI 1.21 to 4.59; p = 0.011), gadolinium-enhancing lesions (OR = 2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR = 2.54; 95% CI 1.21 to 5.31; p = 0.013) at CIS diagnosis.CONCLUSIONS:If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.

Published
2016
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7. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Author

Ruth Dobson, P. Kleinova, Tessel F. Runia, H.-P. Hartung, Maria Trojano, A.D. Martinez, Viviana Annibali, Sreeram V. Ramagopalan, Florian Deisenhammer, Mohsen Khademi, Jens Kuhle, Jan Lycke, Mar Tintoré, Ludwig Kappos, Pietro Iaffaldano, Antonio Uccelli, Dana Horakova, Kjell-Morten Myhr, Cecilia Rajda, Konrad Rejdak, Stig Wergeland, Monica Marta, Roberto Furlan, Florian Lauda, Jean Pelletier, Romain Marignier, G. Comi, Giulio Disanto, Romy Roesler, Vita Direnzo, Özgür Yaldizli, N. Moll, Silvia Romano, Sergey V. Lapin, Sylvain Lehmann, Irena Dujmovic, Elio Scarpini, Tomas Olsson, Rogier Q. Hintzen, Raija L.P. Lindberg, E. P. Evdoshenko, Siegrid Fuchs, B. C. Kieseier, Henrik Larsson, Eric Thouvenot, Jonathan P. Bestwick, Maurizio Leone, László Vécsei, S. Saip, Pablo Villoslada, Roberto Bergamaschi, Xavier Montalban, Øivind Torkildsen, José C. Álvarez-Cermeño, Joanne Topping, Albert Saiz, Isabel Bosca, Hayrettin Tumani, Adriana Carrá, Joep Killestein, Sara Llufriu, N. Barizzone, Ute-Christiane Meier, Diego Franciotta, David Brassat, Christian Enzinger, Michael Khalil, Gavin Giovannoni, Timucin Avsar, Scott L. Rauch, Aksel Siva, N. Lazareva, Clas Malmeström, Jette L. Frederiksen, Harald Hegen, Ugur Uygunoglu, Luisa M. Villar, Lucia Bianchi, Marco Salvetti, Tobias Derfuss, Giovanni Castelnovo, Ayse Altintas, Rocco Adiutori, E. Colombo, G. Dalla Costa, Daniela Galimberti, Madeleine H. Sombekke, Vittorio Martinelli, Sandra D'Alfonso, Manuel Comabella, Eva Havrdova, Fredrik Piehl, Charlotte E. Teunissen, Til Menge, Jelena Drulovic, C. Picard, Alice Laroni, Christian Confavreux, Chiara Fenoglio, Neurology, Laboratory Medicine, NCA - Neuroinflamation, Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), National Oceanography Centre (NOC), Department of Anatomy and Structural Biology Albert Einstein College of Medicine, Albert Einstein College of Medicine [New York], Department of public health, University of Turin, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Water Environment Technology, Chalmers University of Technology [Göteborg], Department of Neurology, A.O.U. Maggiore della Carità, and IRCAD, Novara, Leibniz-Institut für Gewässerökologie und Binnenfischerei (IGB), Leibniz Association, Department of Neurology, University of California [San Francisco] (UCSF), University of California-University of California, Center for Neuroimmunology, Service of Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Université européenne de Bretagne - European University of Brittany (UEB), Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Azm Center for Biotechnology Research, Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut] (LU), FOI, Linköping University (LIU), Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, IRMP-Louvain, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' (DIA), University of Pisa - Università di Pisa, International Centre for Hydrology 'Dino Tonini' and Dipartimento IMAGE, Universita degli Studi di Padova, Dept. of Neurology, University Hospital Rigshospitalet, University of California [Berkeley], University of California, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, The Weizmann Institute, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Laboratory of Neuroimmunology, IRCCS, Neurological Institute 'C. Mondino', University of Pavia, Pa, University of Pavia, Department of Neurology, Albert Szent-Gyorgyi Clinical Centre, University of Szeged [Szeged], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universitat de Barcelona (UB)-Hospital Clinic, University of Ulm, Department of Neurology, Service Anesthésie et Réanimation [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], University of Eastern Piedmont, Department of Medical Sciences, IRCAD, Novara, Vall d'Hebron University Hospital [Barcelona], Department of Public Health and Clinical Medicine, Umeå University, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Universitaire de Bâle, Laboratory of Molecular Virology, Université libre de Bruxelles (ULB), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] (AOPP), University of Oxford [Oxford], Blizard Institute of Cell and Molecular Science, Università degli studi di Torino = University of Turin (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), University of California [Berkeley] (UC Berkeley), University of California (UC), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Oxford, Direction des Applications Militaires ( DAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), National Oceanography Centre, University of Southampton [Southampton], Albert Einstein College of Medicine, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Neuropsychiatrie : recherche épidémiologique et clinique, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Leibniz-Institute, University of California [San Francisco] ( UCSF ), Université européenne de Bretagne ( UEB ), Laboratoire de l'intégration, du matériau au système ( IMS ), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique ( CNRS ), Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut], Linköping University ( LIU ), Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy, Università di Bologna [Bologna] ( UNIBO ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' ( DIA ), Università di Pisa, Universita degli Studi di Padova = University of Padua = Université de Padoue, Educational Testing Service, Graduate School of Education, University of California at Berkeley, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Universitat de Barcelona ( UB ) -Hospital Clinic, Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Department of Atmospheric, Oceanic and Planetary Physics [Oxford] ( AOPP ), Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, J. P., Meier, U. -C., Marta, M., Dalla Costa, G, Runia, T., Evdoshenko, E., Lazareva, N., Thouvenot, E., Iaffaldano, P., Direnzo, V., Khademi, M., Piehl, F., Comabella, M., Sombekke, M., Killestein, J., Hegen, H., Rauch, S., Dalfonso, S., Alvarez-Cermeno, J. C., Kleinova, P., Horakova, D., Roesler, R., Lauda, F., Llufriu, S., Avsar, T., Uygunoglu, U., Altintas, A., Saip, S., Menge, T., Rajda, C., Bergamaschi, R., Moll, N., Khalil, M., Marignier, R., Dujmovic, I., Larsson, H., Malmestrom, C., Scarpini, E., Fenoglio, C., Wergeland, S., Laroni, A., Annibali, V., Romano, S., Martinez, A. D., Carra, A., Salvetti, M., Uccelli, A., Torkildsen, O., Myhr, K. M., Galimberti, D., Rejdak, K., Lycke, J., Frederiksen, J. L., Drulovic, J., Confavreux, C., Brassat, D., Enzinger, C., Fuchs, S., Bosca, I., Pelletier, J., Picard, C., Colombo, E., Franciotta, D., Derfuss, T., Lindberg, R. L. P., Yaldizli, O., Vecsei, L., Kieseier, B. C., Hartung, H. P., Villoslada, P., Siva, A., Saiz, A., Tumani, H., Havrdova, E., Villar, L. M., Leone, M., Barizzone, N., Deisenhammer, F., Teunissen, C., Montalban, X., Tintore, M., Olsson, T., Trojano, M., Lehmann, S., Castelnovo, G., Lapin, S., Hintzen, R., Kappos, L., Furlan, R., Martinelli, V., Comi, G., Ramagopalan, S. V., and Giovannoni, G.

Subjects
Male, Pathology, serum 25-hydroxyvitamin D3 (25-OH-D), [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, sclerosis, clinically isolated syndrome (CIS), Vitamin D, 0303 health sciences, Clinically isolated syndrome, Nuclear Proteins, Prognosis, Magnetic Resonance Imaging, Neurology, Clinically definite multiple sclerosis (CDMS), Epstein-Barr nuclear antigen 1 (EBNA-1), oligoclonal bands (OCBs), Predictive value of tests, Cohort, Disease Progression, Female, Cohort study, Adult, medicine.medical_specialty, Multiple Sclerosis, clinic study, Risk Assessment, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Vitamin D and neurology, Humans, Survival analysis, 030304 developmental biology, business.industry, Multiple sclerosis, Oligoclonal Bands, Endonucleases, medicine.disease, Survival Analysis, chemistry, Immunoglobulin G, [ SHS.ANTHRO-BIO ] Humanities and Social Sciences/Biological anthropology, Neurology (clinical), business, Cotinine, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Published
2015
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