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20. Sodium intake and multiple sclerosis activity and progression in BENEFIT

Author

Fitzgerald, Kathryn C., Munger, Kassandra L., Hartung, Hans peter, Freedman, Mark S., Montalbã¡n, Xavier, Edan, Gilles, Wicklein, Eva maria, Radue, Ernst wilhelm, Kappos, Ludwig, Pohl, Christoph, Ascherio, Alberto, Strasser fuchs, S., Berger, T., Vass, K., Sindic, C., Dubois, B., Dive, D., Debruyne, J., Metz, L., Rice, G., Duquette, P., Lapierre, Y., Freedman, M., Traboulsee, A., O'Connor, P., Å touraä, P., Talab, R., Zapletalova, O., Kovaå™ova, I., Medova, E., Fiedler, J., Frederiksen, J., Brochet, B., Moreau, T., Vermersch, P., Pelletier, J., Edan, G., Clanet, M., Clavelou, P., Lebrun frenay, C., Gout, O., Kallela, M., Pirttila, T., Ruutiainen, J., Koivisto, K., Reunanen, M., Elovaara, I., Villringer, A., Altenkirch, H., Wessel, K., Hartung, H. . P., Steinke, W., Kã¶lmel, H., Oschmann, P., Diem, R., Dressel, A., Hoffmann, F., Baum, K., Jung, S., Petereit, H., Reske, D., Sailer, M., Kohler, J., Sommer, N., Hohlfeld, R., Henn, K. . H., Tumani, H., Gold, R., Rieckmann, P., Komoly, R., Gacs, G., Jakab, G., Csiba, L., Vecsei, L., Miller, A., Karussis, D., Chapman, J., Ghezzi, A., Gallo, P., Cosi, V., Durelli, L., Anten, B., Visser, L., Myhr, K. . M., Szczudlik, A., Selmaj, K., Stelmasiak, Z., Podemski, R., Maciejek, Z., Cunha, L., Sega jazbec, S., Montalban, X., Arbizu, T., Saiz, A., Barcena, J., Arroyo, R., Fernandez, O., Izquierdo, G., Casanova, B., Lycke, J., Kappos, L., Mattle, H., Beer, K., Coleman, R., Chataway, J., Riordan, J. O., Howell, S., COMI, GIANCARLO, Fitzgerald, Kathryn C., Munger, Kassandra L., Hartung, Hans peter, Freedman, Mark S., Montalbã¡n, Xavier, Edan, Gille, Wicklein, Eva maria, Radue, Ernst wilhelm, Kappos, Ludwig, Pohl, Christoph, Ascherio, Alberto, Strasser fuchs, S., Berger, T., Vass, K., Sindic, C., Dubois, B., Dive, D., Debruyne, J., Metz, L., Rice, G., Duquette, P., Lapierre, Y., Freedman, M., Traboulsee, A., O'Connor, P., Å touraä , P., Talab, R., Zapletalova, O., Kovaå ova, I., Medova, E., Fiedler, J., Frederiksen, J., Brochet, B., Moreau, T., Vermersch, P., Pelletier, J., Edan, G., Clanet, M., Clavelou, P., Lebrun frenay, C., Gout, O., Kallela, M., Pirttila, T., Ruutiainen, J., Koivisto, K., Reunanen, M., Elovaara, I., Villringer, A., Altenkirch, H., Wessel, K., Hartung, H. . P., Steinke, W., Kã¶lmel, H., Oschmann, P., Diem, R., Dressel, A., Hoffmann, F., Baum, K., Jung, S., Petereit, H., Reske, D., Sailer, M., Kohler, J., Sommer, N., Hohlfeld, R., Henn, K. . H., Tumani, H., Gold, R., Rieckmann, P., Komoly, R., Gacs, G., Jakab, G., Csiba, L., Vecsei, L., Miller, A., Karussis, D., Chapman, J., Ghezzi, A., Comi, Giancarlo, Gallo, P., Cosi, V., Durelli, L., Anten, B., Visser, L., Myhr, K. . M., Szczudlik, A., Selmaj, K., Stelmasiak, Z., Podemski, R., Maciejek, Z., Cunha, L., Sega jazbec, S., Montalban, X., Arbizu, T., Saiz, A., Barcena, J., Arroyo, R., Fernandez, O., Izquierdo, G., Casanova, B., Lycke, J., Kappos, L., Mattle, H., Beer, K., Coleman, R., Chataway, J., Riordan, J. O., and Howell, S.

Subjects
Adult, Male, Brain, Demyelinating Disease, Neuroimaging, Sodium, Dietary, Magnetic Resonance Imaging, Disability Evaluation, Young Adult, Neurology, Multiple Sclerosi, Disease Progression, Female, Neurology (clinical), Human, Interferon beta-1b
Abstract

Objective: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. Methods: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13–16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. Results: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67–1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97–1.13; relative change in T2 lesion volume: −0.11, 95% CI = −0.25 to 0.04; change in EDSS: −0.01, 95% CI = −0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56–1.07). Results were similar in categorical analyses using quintiles. Interpretation: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20–29.

Published
2017
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33. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome

Author

Hartung, Hp, Strasser Fuchs, S, Berger, T, Vass, K, Sindic, C, Dubois, B, Dive, D, Debruyne, J, Metz, L, Rice, G, Duquette, P, Lapierre, Y, Freedman, M, Traboulsee, A, O'Connor, P, Stourac, P, Taláb, R, Zapletalová, O, Kováøová, I, Medová, E, Fiedler, J, Frederiksen, J, Brochet, B, Moreau, T, Vermersch, P, Pelletier, J, Edan, G, Clanet, M, Clavelou, P, Lebrun Frenay, C, Gout, O, Kallela, M, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoffmann, F, Baum, K, Jung, S, Petereit, Hf, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalba, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, and Howell, S. .

Published
2012

34. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome

Author

Hartung, Hp, Strasser Fuchs, S, Berger, T, Vass, K, Sindic, C, Dubois, B, Dive, D, Debruyne, J, Metz, L, Rice, G, Duquette, P, Lapierre, Y, Freedman, M, Traboulsee, A, O'Connor, P, Stourac, P, Taláb, R, Zapletalová, O, Kováøová, I, Medová, E, Fiedler, J, Frederiksen, J, Brochet, B, Moreau, T, Vermersch, P, Pelletier, J, Edan, G, Clanet, M, Clavelou, P, Lebrun Frenay, C, Gout, O, Kallela, M, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoffmann, F, Baum, K, Jung, S, Petereit, Hf, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalba, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, Howell, S. ., Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Multiple Sclerosis, Injections, Subcutaneous, Relapse rate, Brain mri, Medicine, Humans, Longitudinal Studies, Prospective Studies, Clinically isolated syndrome, biology, business.industry, Immunogenicity, Interferon-beta, Antibodies, Neutralizing, Titer, Interferon β 1b, Cross-Sectional Studies, Immunology, biology.protein, Neurology (clinical), Antibody, business, Demyelinating Diseases, Follow-Up Studies, Interferon beta-1b
Abstract

To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years.NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers.Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.

Published
2011
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35. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study

Author

Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang auberson, L, Francis, G, Cohen, Ja, Cohen, J, Easton, Jd, Calandra, T, Dimarco, J, Hudson, L, Kesselring, J, Laupacis, A, Temkin, N, Weinshenker, B, Zarbin, M, Poppe, P, Luetic, G, Cristiano, E, Caceres, F, Garcea, O, Correale, J, Ballario, C, Piedrabuena, R, Pollard, J, Beran, R, Hodgkinson, S, Schwartz, R, Heard, R, King, J, Butzkueven, H, Maida, Em, Vass, K, Franta elmer, C, Berger, T, Aichner, F, Ladurner, G, Bissay, V, Sindic, C, D'Hooghe, M, Mulleners, E, Damasceno, B, Barreira, A, Naylor, R, Alvarenga, R, Bacellar, A, Haussen, S, Duquette, P, Antel, J, Lamontagne, A, Grand'Maison, F, Freedman, M, Christie, S, O'Connor, P, Vorobeychik, G, Devonshire, V, Ramadan, M, Hamdy, S, Reda, E, Hashem, S, Fouad, M, Lebrun frenay, C, Clanet, M, Brochet, B, Debouverie, M, Heinzlef, O, Ziemssen, T, Koehler, W, Tiel wilck, K, Bachus, R, Altmann, N, Faiss, J, Baum, K, Dressel, A, Luckner, K, Ebke, M, Stangel, M, Diener, Hc, Bethke, F, Limmroth, V, Maschke, M, Thoemke, F, Reifschneider, G, Diehm, R, Wildemann, B, Melms, A, Rauer, S, Karlbauer, G, Berthele, A, Lang, M, Tumani, H, Krauseneck, P, Klein, M, Papadimitriou, A, Karageorgiou, K, Liakopoulos, D, Tascos, N, Plaitakis, A, Papathanasopoulos, P, Panczel, G, Jakab, G, Csiba, L, Komoly, S, Csanyi, A, Bartos, L, Centonze, D, Pozzilli, C, Marrosu, Mg, Bertolotto, A, Mancardi, GIOVANNI LUIGI, Scarpini, E, Protti, A, Ghezzi, A, Capra, R, Bergamaschi, R, Gallo, P, Stecchi, S, Montanari, E, Tola, Mr, Amato, Mp, Silvestrini, M, Lugaresi, A, Trojano, M, Morra, Vb, Ruggieri, S, Patti, F, Kim, Sm, Lee, Kh, Kim, Hj, Park, Sp, Ginestal, R, Salgado, Av, Fontoura, P, Cunha, L, Sousa, L, Mj, Sá, Pedrosa, R, Arbizu, T, Arroyo, R, Merino, Ja, Fernandez, O, Izquierdo, G, Casanova, B, Antigüedad, A, Goebels, N, Young, C, Lee, M, Chaudhuri, A, Nicholas, R, Martinez, Ac, Preiningerova, J, Greco, D, Gross, J, Newman, S, Mitchell, G, Pawar, G, Freedman, Sm, Kaufman, M, Absher, J, Kantor, D, Ayala, R, Honeycutt, W, Shafer, S, Steingo, B, Delgado, S, Cascione, M, Brock, C, Keegan, A, Laganke, C, Hunter, S, Wilson, E, Mazhari, A, Bauer, W, Singer, B, Lynch, S, Rowe, V, Hutton, G, Gazda, S, Dihenia, B, Campagnolo, D, Chippendale, T, Ash, P, Jung, L, Olek, M., Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, Pelletier J, Stites T, Wu S, Holdbrook F, Zhang-Auberson L, Francis G, Cohen JA, TRANSFORMS Study Group, Lugaresi A, Diener, Hans Christoph (Beitragende*r), Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang Auberson, L, Francis, G, Cohen, Ja, BRESCIA MORRA, Vincenzo, Comi, Giancarlo, TRANSFORMS Study, Group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, medicine.medical_specialty, multiple sclerosis, interferon beta, fingolimod, treatment, Multiple Sclerosis, Adolescent, Medizin, Phases of clinical research, Relapsing-Remitting, Injections, Intramuscular, Young Adult, Humans, Adjuvants, Immunologic, Interferon-beta, Immunosuppressive Agents, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Middle Aged, Propylene Glycols, Sphingosine, Female, law.invention, Injections, Randomized controlled trial, law, Immunologic, analogs /&/ derivatives/therapeutic use, Internal medicine, Fingolimod Hydrochloride, Medicine, Adjuvants, Young adult, Intramuscular, business.industry, Multiple sclerosis, Interferon beta-1a, medicine.disease, Fingolimod, Surgery, drug therapy/pathology/physiopathology, Clinical research, therapeutic use, Adolescent, Adult, Female, Humans, Immunosuppressive Agents, therapeutic use, Injections, Intramuscular, Interferon-beta, therapeutic use, Male, Middle Aged, Multiple Sclerosis, drug therapy/pathology/physiopathology, Propylene Glycols, therapeutic use, Sphingosine, analogs /&/ derivatives/therapeutic use, Treatment Outcome, Young Adult, therapeutic use, Settore MED/26 - Neurologia, Neurology (clinical), business, medicine.drug
Abstract

In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p

Published
2011
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36. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Author

Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., Harbo, H.F., Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., and Harbo, H.F.

Abstract

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender

Published
2015

37. Neurofilament ELISA validation

Author

Petzold, A. Altintas, A. Andreoni, L. Bartos, A. Berthele, A. Blankenstein, M.A. Buee, L. Castellazzi, M. Cepok, S. Comabella, M. Constantinescu, C.S. Deisenhammer, F. Deniz, G. Erten, G. Espiño, M. Fainardi, E. Franciotta, D. Freedman, M.S. Giedraitis, V. Gilhus, N.E. Giovannoni, G. Glabinski, A. Grieb, P. Hartung, H.-P. Hemmer, B. Herukka, S.-K. Hintzen, R. Ingelsson, M. Jackson, S. Jacobsen, S. Jafari, N. Jalosinski, M. Jarius, S. Kapaki, E. Kieseier, B.C. Koel-Simmelink, M.J.A. Kornhuber, J. Kuhle, J. Kurzepa, J. Lalive, P.H. Lannfelt, L. Lehmensiek, V. Lewczuk, P. Livrea, P. Marnetto, F. Martino, D. Menge, T. Norgren, N. Papuć, E. Paraskevas, G.P. Pirttilä, T. Rajda, C. Rejdak, K. Ricny, J. Ripova, D. Rosengren, L. Ruggieri, M. Schraen, S. Shaw, G. Sindic, C. Siva, A. Stigbrand, T. Stonebridge, I. Topcular, B. Trojano, M. Tumani, H. Twaalfhoven, H.A.M. Vécsei, L. Van Pesch, V. Vanderstichele, H. Vedeler, C. Verbeek, M.M. Villar, L.M. Weissert, R. Wildemann, B. Yang, C. Yao, K. Teunissen, C.E.

Abstract

Background: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. Methods: The UmanDiagnostics NF-light ®enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68 kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories' accuracy and preparation of standards were documented and used for the statistical analyses. Results: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R = 0.60, p < 0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R = 0.98, p < 0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss' multi-rater kappa and Gwet's AC1 statistics. Conclusion: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online. © 2009 Elsevier B.V.

Published
2010

38. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Author

Strasser Fuchs, S, Berger, T, Vass, K, Sindic, C, Dubois, B, Dive, D, Debruyne, J, Metz, L, Rice, G, Duquette, P, Lapierre, Y, Freedman, M, Traboulsee, A, O'Connor, P, Stourac, P, Taláb, R, Zapletalová, O, Kovárová, I, Medová, E, Fiedler, J, Frederiksen, J, Brochet, B, Moreau, T, Vermersch, P, Pelletier, J, Edan, G, Clanet, M, Clavelou, P, Lebrun Frenay, C, Gout, O, Kallela, M, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Hartung, Hp, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoff, F, Baum, K, Jung, S, Felicitas Petereit, H, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalbán, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, Howell, S, Miller, Dh, Polman, Ch, Bauer, L, Ghazi, M, Pohl, C, Sandbrink, R, Barkhof, F, Uitdehaag, B, de Vera, A, Wu, S, Radü, Ew, Mcfarland, Hf, Kesselring, J, Petkau, Aj, Toyka, K. V., Dubois, Bénédicte, Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Adult, Male, Questionnaires, medicine.medical_specialty, Multiple Sclerosis, Kaplan-Meier Estimate, Placebo, Risk Assessment, Young Adult, Disability Evaluation, Double-Blind Method, Surveys and Questionnaires, Internal medicine, medicine, Humans, Proportional Hazards Models, Intention-to-treat analysis, Expanded Disability Status Scale, Clinically isolated syndrome, business.industry, Multiple sclerosis, Interferon beta-1b, Hazard ratio, Interferon-beta, medicine.disease, Magnetic Resonance Imaging, Surgery, Tolerability, Data Interpretation, Statistical, Disease Progression, Female, Neurology (clinical), business
Abstract

BACKGROUND: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. INTERPRETATION: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. FUNDING: Bayer Schering Pharma. ispartof: The Lancet Neurology vol:8 issue:11 pages:987-997 ispartof: location:England status: published

Published
2009
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39. Treatment of Guillain-Barre syndrome with mycophenolate mofetil: a pilot study (vol 78, pg 1012, 2007)

Author

Garssen, M. P. J., van Koningsveld, R., van Doorn, P. A., Merkies, I. S. J., Scheltens-de Boer, M., van Leusden, J. A., van Schaik, I. N., Linssen, W. H. J. P., Visscher, F., Boon, A. M., Faber, C. G., Meulstee, J., Prick, M. J. J., van den Berg, L. H., Franssen, H., Hiel, J. A. P., van den Bergh, P. Y. K., Sindic, C. J. M., AII - Amsterdam institute for Infection and Immunity, ANS - Amsterdam Neuroscience, and Neurology

Published
2007

43. Paucisymptomatic brainstem lesions revealing CNS schistosomiasis

Author

Rommel, D., Ragé, M., Thierry Duprez, Parent, M., Sindic, C. J. M., UCL - Cliniques universitaires Saint-Luc, UCL - MD/RAIM - Département de radiologie et d'imagerie médicale, UCL - (SLuc) Service de radiologie, UCL - MD/NOPS - Département de neurologie et de psychiatrie, and UCL - (SLuc) Service de neurologie

Subjects
parasitic cerebral disease, cerebral schistosomiasis, Schistosomia mansoni, human activities
Abstract

We describe clinical and magnetic resonance (MR) features in a 69-year-old, Caucasian woman presenting with an unusual meningeal onset of cerebral schistosomiasis. Magnetic resonance work-up demonstrated supra- and infratentorial lesions with prominent brain-stem involvement contrasting with the paucisymptomatic clinical presentation. Because of a recent stay in Uganda, including swimming in Lake Victoria, a diagnosis of neuroschistosomiasis was suggested. Serological tests and rectal biopsy confirmed the putative diagnosis. The patient was successfully treated with praziquantel at a dose of 50 mg/kg/day for 15 days. Brain MRI abnormalities improved dramatically within two months.

Published
2005

46. CSF-Phospho-tau (181P) as a Promising Marker for Discriminating Alzheimer's Disease from Dementia with Lewy Bodies

Author

Vanmechelen, E., primary, Van Kerschaver, E., additional, Blennow, K., additional, De Deyn, P. P., additional, Galasko, D., additional, Parnetti, L., additional, Sindic, C. J. M., additional, Arai, H., additional, Riemenschneider, M., additional, Hampel, H., additional, Pottel, H., additional, Valgaeren, A., additional, Hulstaert, F., additional, and Vanderstichele, H., additional

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48. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis

Author

Wyngaert, F. A., Beguin, C., Marie D'hooghe, Dooms, G., Lissoir, F., Carton, H., Sindic, C. J. M., Clinical sciences, Neuroprotection & Neuromodulation, and Neurology

Subjects
Adult, Male, Methylprednisolone/adverse effects, Patient Dropouts, Alopecia/chemically induced, Immunosuppressive Agents/adverse effects, Phlebitis/chemically induced, Vomiting/chemically induced, contrast media, Methylene Blue/therapeutic use, Severity of Illness Index, Nausea/chemically induced, Pyrrolidines/therapeutic use, Treatment Outcome, Double-Blind Method, Recurrence, Mitoxantrone/adverse effects, Humans, magnetic resonance imaging, Multiple Sclerosis/drug therapy, Female, Lymphocyte Count, Pulmonary Embolism/etiology, gadolinium, Follow-Up Studies
Abstract

A double-blind clinical trial of mitoxantrone versus methylprednisolone was performed in 49 patients with relapsing, secondary multiple sclerosis. Patients were randomized to receive 13 infusions of mitoxantrone 12 mg/m2 (n = 28), or 13 infusions of 1 g of methylprednisolone (n = 21), over 32 months. Twenty-four patients completed the trial. There were no statistical differences between the two groups of patients at study entry. A significant improvement in the Expanded Disability Scale Score (EDSS) was observed in the mitoxantrone group after one year of treatment (p < 0.0022). The total number of relapses, the mean number of relapses/patient/year, and the total number of gadolinium-enhanced lesions on bi-annual MRI scans were significantly decreased in the mitoxantrone group throughout the study period. Nausea, vomiting, and alopecia were more frequent in the mitoxantrone-treated patients. Mitoxantrone has a role in the treatment of MS patients with frequent exacerbations and rapid disease progression.

Published
2001

49. Novel cerebrospinal fluid and serum autoantibody targets for clinically isolated syndrome

Author

Rouwette, M., Somers, K., Govarts, C., Deyn, P.P. de, Hupperts, R., Van Wijmeersch, B., de Jong, B.A., Verbeek, M.M., Van Pesch, V., Sindic, C., Villar, L.M., Alvarez-Cermeno, J.C., Stinissen, P., Somers, V., Rouwette, M., Somers, K., Govarts, C., Deyn, P.P. de, Hupperts, R., Van Wijmeersch, B., de Jong, B.A., Verbeek, M.M., Van Pesch, V., Sindic, C., Villar, L.M., Alvarez-Cermeno, J.C., Stinissen, P., and Somers, V.

Abstract

Item does not contain fulltext, Limited information is available on the identity of antigens targeted by antibodies present in cerebrospinal fluid (CSF) of patients with clinically isolated syndrome (CIS). The aim of this study was to identify novel antigens for CIS and investigate their prognostic potential to predict conversion to multiple sclerosis (MS). We applied serological antigen selection (SAS) to identify antigens interacting with antibodies present in the pooled CSF from four CIS patients, who developed MS. Antibody reactivity towards CIS antigens identified by SAS was tested in CSF and serum from patients with CIS (n = 123/n = 108), MS (n = 65/n = 44), and other (inflammatory) neurological diseases (n = 75/n = 38) as well as in healthy control sera (n = 44). Using SAS, a panel of six novel CIS candidate antigens was identified. CSF antibody reactivity was detected in both CIS and relapsing-remitting (RR) MS. Serum reactivity was significantly increased in CIS and RR-MS as compared with controls (p = 0.03). For two antigens, the frequency of antibody-positive patients was higher in CIS patients who converted to MS as compared with CIS patients without conversion. We identified novel CIS antigens to which antibody reactivity was primarily detected in CIS and RR-MS as compared to controls. Possible prognostic potential could be demonstrated for two antigens.

Published
2012

50. Adverse events of interferon beta-1a: a prospective multi-centre international ICH-GCP-based CRO-supported external validation study in daily practice.

Author

Jongen, P.J.H., Sindic, C., Sanders, E., Hawkins, S., Linssen, W., Munster, E. van, Frequin, S.T.F.M., Borm, G.F., Jongen, P.J.H., Sindic, C., Sanders, E., Hawkins, S., Linssen, W., Munster, E. van, Frequin, S.T.F.M., and Borm, G.F.

Abstract

Contains fulltext : 95629.pdf (publisher's version ) (Open Access), BACKGROUND: Due to methodological shortcomings the available post-registration data on the adverse events (AEs) occurring in interferon beta-1a (INFb-1a)-treated patients fail to adequately validate phase III data and only partially inform on safety in daily practice. We assessed AEs in relapsing remitting multiple sclerosis (RRMS) patients treated with intramuscular (IM) INFb-1a in daily practice using data quality assurance measures similar to those in phase III trials. METHODS: A prospective, International Conference on Harmonization (ICH) - Good Clinical Practice (GCP)-based, clinical research organization (CRO)-supported study in 36 practices in the Netherlands, Belgium, the United Kingdom and Luxembourg. During 24 months after start of IM INFb-1a treatment 275 RRMS patients were assessed for AEs' severity (mild, moderate, severe) and relationship to treatment (not, unlikely, likely, definite). Data were compared with those reported in the pivotal phase III trial. FINDINGS: 75.3% of the patients experienced one or more AEs that were likely or definitely related to INFb-1a. Of all AEs 40.5% were likely or definitely treatment-related; 68.5% of these were mild, and 3% severe. 6.6% of the patients discontinued treatment because of an AE. Compared to the pivotal phase III trial, we found statistically significantly lower incidences for most of the common AEs: headache, muscle ache, fatigue, fever, chills, nausea. One patient died following two cerebral vascular events in study month 22, both AEs were assessed as not related to INFb-1a. CONCLUSION: Three out of four RRMS patients treated with IM INFb-1a in daily practice experience treatment-related AEs, most of these being mild. Our data externally validate the favorable phase III safety profile of IM INFb-1a and suggest that the real-life incidence of treatment-related AEs is less than reported in the pivotal phase III trial. Larger studies are needed to detect rare, potentially hazardous AEs of IM INFb-1a.

Published
2011

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