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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., and Leray, E.

Published
2022
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2. Artificial intelligence to predict clinical disability in patients with multiple sclerosis using FLAIR MRI

Author

Brochet, B., Casey, R., Cotton, F., De Sèze, J., Douek, P., Guillemin, F., Laplaud, D., Lebrun-Frenay, C., Mansuy, L., Moreau, T., Olaiz, J., Pelletier, J., Rigaud-Bully, C., Stankoff, B., Vukusic, S., Marignier, R., Debouverie, M., Edan, G., Ciron, J., Ruet, A., Collongues, N., Lubetzki, C., Vermersch, P., Labauge, P., Defer, G., Cohen, M., Fromont, A., Wiertlewsky, S., Berger, E., Clavelou, P., Audoin, B., Giannesini, C., Gout, O., Thouvenot, E., Heinzlef, O., Al-Khedr, A., Bourre, B., Casez, O., Cabre, P., Montcuquet, A., Créange, A., Camdessanché, J.-P., Faure, J., Maurousset, A., Patry, I., Hankiewicz, K., Pottier, C., Maubeuge, N., Labeyrie, C., Nifle, C., Ameli, R., Anxionnat, R., Attye, A., Bannier, E., Barillot, C., Ben Salem, D., Boncoeur-Martel, M.-P., Bonneville, F., Boutet, C., Brisset, J.-C., Cervenanski, F., Claise, B., Commowick, O., Constans, J.-M., Dardel, P., Desal, H., Dousset, Vincent, Durand-Dubief, F., Ferre, J.-C., Gerardin, E., Glattard, T., Grand, S., Grenier, T., Guillevin, R., Guttmann, C., Krainik, A., Kremer, S., Lion, S., Menjot de Champfleur, N., Mondot, L., Outteryck, O., Pyatigorskaya, N., Pruvo, J.-P., Rabaste, S., Ranjeva, J.-P., Roch, J.-A., Sadik, J.C., Sappey-Marinier, D., Savatovsky, J., Tanguy, J.-Y., Tourbah, A., Tourdias, T., Roca, P., Colas, L., Tucholka, A., Rubini, P., Cackowski, S., Ding, J., Budzik, J.-F., Renard, F., Doyle, S., Barbier, E.L., Bousaid, I., Lassau, N., and Verclytte, S.

Published
2020
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4. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.

Author

Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., Kalincik T., Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., and Kalincik T.

Abstract

OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHOD(S): This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULT(S): 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). CONCLUSION(S): The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different t

Published
2022

5. 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, JB, Vukusic, S, Casey, R, Debouverie, M, Edan, G, Ciron, J, Ruet, A, De Seze, 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, Camdessanche, JP, Maurousset, A, Ben Nasr, H, Hankiewicz, K, Pottier, C, Maubeuge, N, Nifle, C, Laplaud, DA, Horakova, D, Dimitri-Boulos, D, Havrdova, EK, 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, PS, Christensen, CCH, Rasmussen, P, Jensen, MB, Frederiksen, JL, Bramow, S, Mathiesen, HK, Schreiber, K, Butzkueven, H, Magyari, M, Kalincik, T, Leray, E, Lefort, M, Sharmin, S, Andersen, JB, Vukusic, S, Casey, R, Debouverie, M, Edan, G, Ciron, J, Ruet, A, De Seze, 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, Camdessanche, JP, Maurousset, A, Ben Nasr, H, Hankiewicz, K, Pottier, C, Maubeuge, N, Nifle, C, Laplaud, DA, Horakova, D, Dimitri-Boulos, D, Havrdova, EK, 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, PS, Christensen, CCH, Rasmussen, P, Jensen, MB, Frederiksen, JL, Bramow, S, Mathiesen, HK, Schreiber, K, Butzkueven, H, Magyari, M, Kalincik, T, and Leray, E

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 ful

Published
2022

6. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis

Author

Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, Kalincik, T, Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, and Kalincik, T

Abstract

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued di

Published
2022

7. 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., 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., and Leray, E.

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

Published
2022

9. Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event

Author

Lebrun-Frenay, C., Kantarci, O., Siva, A., Sormani, M. P., Pelletier, D., Okuda, D. T., Azevedo, C., Amato, M. P., Bensa, C., Berger, E., Brochet, B., Ciron, J., Cohen, M., Inglese, M., Keegan, B. M., Labauge, P., Laplaud, D. -A., Le Page, E., Louapre, C., Makhani, N., Mathey, G., Mondot, L., Montalban, X., Pelletier, J., de Seze, J., Destefano, N., Thouvenot, E., Tintore, M., Tutuncuoglu, M., Uygunoglu, U., Vermersch, P., Weinshenker, B., and Zeydan, B.

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Multiple Sclerosis, Time Factors, Adolescent, Journal Club, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, medicine, Humans, Young adult, Child, Event (probability theory), Aged, medicine.diagnostic_test, Clinical events, business.industry, Proportional hazards model, Multiple sclerosis, Magnetic resonance imaging, Middle Aged, medicine.disease, Demyelinating Diseases, Female, Magnetic Resonance Imaging, Disease Progression, 030104 developmental biology, Risk Estimate, Neurology, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract

Objective We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5-year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10-year, multinational, retrospectively identified RIS dataset. Methods RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models. Results Additional follow-up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11-74 years), with a median clinical follow-up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium-enhanced lesions during follow-up was also associated with the risk of a seminal event. The reason for MRI and gadolinium-enhancing lesions at baseline did not influence the risk of a subsequent clinical event. Interpretation Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407-417.

Published
2020

10. Artificial intelligence to predict clinical disability in patients with multiple sclerosis using FLAIR MRI

Author

Roca, P., primary, Attye, A., additional, Colas, L., additional, Tucholka, A., additional, Rubini, P., additional, Cackowski, S., additional, Ding, J., additional, Budzik, J.-F., additional, Renard, F., additional, Doyle, S., additional, Barbier, E.L., additional, Bousaid, I., additional, Casey, R., additional, Vukusic, S., additional, Lassau, N., additional, Verclytte, S., additional, Cotton, F., additional, Brochet, B., additional, De Sèze, J., additional, Douek, P., additional, Guillemin, F., additional, Laplaud, D., additional, Lebrun-Frenay, C., additional, Mansuy, L., additional, Moreau, T., additional, Olaiz, J., additional, Pelletier, J., additional, Rigaud-Bully, C., additional, Stankoff, B., additional, Marignier, R., additional, Debouverie, M., additional, Edan, G., additional, Ciron, J., additional, Ruet, A., additional, Collongues, N., additional, Lubetzki, C., additional, Vermersch, P., additional, Labauge, P., additional, Defer, G., additional, Cohen, M., additional, Fromont, A., additional, Wiertlewsky, S., additional, Berger, E., additional, Clavelou, P., additional, Audoin, B., additional, Giannesini, C., additional, Gout, O., additional, Thouvenot, E., additional, Heinzlef, O., additional, Al-Khedr, A., additional, Bourre, B., additional, Casez, O., additional, Cabre, P., additional, Montcuquet, A., additional, Créange, A., additional, Camdessanché, J.-P., additional, Faure, J., additional, Maurousset, A., additional, Patry, I., additional, Hankiewicz, K., additional, Pottier, C., additional, Maubeuge, N., additional, Labeyrie, C., additional, Nifle, C., additional, Ameli, R., additional, Anxionnat, R., additional, Bannier, E., additional, Barillot, C., additional, Ben Salem, D., additional, Boncoeur-Martel, M.-P., additional, Bonneville, F., additional, Boutet, C., additional, Brisset, J.-C., additional, Cervenanski, F., additional, Claise, B., additional, Commowick, O., additional, Constans, J.-M., additional, Dardel, P., additional, Desal, H., additional, Dousset, Vincent, additional, Durand-Dubief, F., additional, Ferre, J.-C., additional, Gerardin, E., additional, Glattard, T., additional, Grand, S., additional, Grenier, T., additional, Guillevin, R., additional, Guttmann, C., additional, Krainik, A., additional, Kremer, S., additional, Lion, S., additional, Menjot de Champfleur, N., additional, Mondot, L., additional, Outteryck, O., additional, Pyatigorskaya, N., additional, Pruvo, J.-P., additional, Rabaste, S., additional, Ranjeva, J.-P., additional, Roch, J.-A., additional, Sadik, J.C., additional, Sappey-Marinier, D., additional, Savatovsky, J., additional, Tanguy, J.-Y., additional, Tourbah, A., additional, and Tourdias, T., additional

Published
2020
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11. 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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13. Gender Inequities in the Multiple Sclerosis Community: A Call for Action

Author

Waubant, E, Amezcua, L, Sicotte, N, Hellwig, K, Krupp, L, Weinstock-Guttman, B, Yeh, A, Lucas, RM, Longbrake, EE, Yadav, V, Rensel, M, Mar, S, Hersh, C, Block, V, Zipp, F, Han, MH, Spain, R, Kelland, EE, Charvet, L, Dimitri, D, Papeix, C, Cross, AH, Inglese, M, Amato, MP, Airas, L, Leray, E, Sormani, MP, Van der Walt, A, Vukusic, S, Castillo-Trivino, T, Tenembaum, S, Ciccarelli, O, Bommarito, G, Petracca, M, Celius, EG, Carson, MJ, Hua, LH, Van der Mei, I, Lubetzki, C, Jokubaitis, V, Trojano, M, Voskuhl, R, Tintore, M, Harbo, H, Asgari, N, Piccio, L, Burton, JM, Tremlett, H, Goldman, MD, Michel, L, Zhang, Y, Bove, R, Quandt, JA, Costello, F, Ionete, C, Lebrun-Frenay, C, Pakpoor, J, Bevan, C, Morrow, SA, Waldman, AT, Oh, J, Jacobs, D, Palace, J, Marrie, RA, Tiwari-Woodruff, SK, Metz, LM, Cortese, R, Chitnis, T, Benson, L, Benveniste, ET, Conway, J, Sand, IK, Murphy, JO, Kita, M, Riley, C, Goverman, JM, Langer-Gould, AM, Azevedo, CJ, Morales, IB, Barcellos, LF, Crabtree, E, Plummer, P, Shirani, A, Whartenby, K, Brilot-Turville, F, Kingwell, E, Coyle, P, Mowry, E, Zabad, R, Bielekova, B, Monson, N, Laule, C, Burnett, M, Schreiner, T, Grinspan, J, Dobson, R, Akassoglou, K, Graves, J, Gray, O, Smyth, P, Havrdova, EK, Preiningerova, JL, Banwell, B, Makhani, N, Lucchinetti, C, Arrambide, G, Maillart, E, Macklin, W, Gilmore, W, Waubant, E, Amezcua, L, Sicotte, N, Hellwig, K, Krupp, L, Weinstock-Guttman, B, Yeh, A, Lucas, RM, Longbrake, EE, Yadav, V, Rensel, M, Mar, S, Hersh, C, Block, V, Zipp, F, Han, MH, Spain, R, Kelland, EE, Charvet, L, Dimitri, D, Papeix, C, Cross, AH, Inglese, M, Amato, MP, Airas, L, Leray, E, Sormani, MP, Van der Walt, A, Vukusic, S, Castillo-Trivino, T, Tenembaum, S, Ciccarelli, O, Bommarito, G, Petracca, M, Celius, EG, Carson, MJ, Hua, LH, Van der Mei, I, Lubetzki, C, Jokubaitis, V, Trojano, M, Voskuhl, R, Tintore, M, Harbo, H, Asgari, N, Piccio, L, Burton, JM, Tremlett, H, Goldman, MD, Michel, L, Zhang, Y, Bove, R, Quandt, JA, Costello, F, Ionete, C, Lebrun-Frenay, C, Pakpoor, J, Bevan, C, Morrow, SA, Waldman, AT, Oh, J, Jacobs, D, Palace, J, Marrie, RA, Tiwari-Woodruff, SK, Metz, LM, Cortese, R, Chitnis, T, Benson, L, Benveniste, ET, Conway, J, Sand, IK, Murphy, JO, Kita, M, Riley, C, Goverman, JM, Langer-Gould, AM, Azevedo, CJ, Morales, IB, Barcellos, LF, Crabtree, E, Plummer, P, Shirani, A, Whartenby, K, Brilot-Turville, F, Kingwell, E, Coyle, P, Mowry, E, Zabad, R, Bielekova, B, Monson, N, Laule, C, Burnett, M, Schreiner, T, Grinspan, J, Dobson, R, Akassoglou, K, Graves, J, Gray, O, Smyth, P, Havrdova, EK, Preiningerova, JL, Banwell, B, Makhani, N, Lucchinetti, C, Arrambide, G, Maillart, E, Macklin, W, and Gilmore, W

Published
2018

14. Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Author

Paul, O'Connor, Wolinsky, Jerry S., Christian, Confavreux, Giancarlo, Comi, Ludwig, Kappos, Olsson, Tomas P., Hadj, Benzerdjeb, Philippe, Truffinet, Lin, Wang, Aaron, Miller, Temso Trial Group Reingold, Freedman Ms S., Cutter, G., Antel, J., Barkhof, F., Maddrey, W., Ravnborg, M., Schenker, S., O'Connor, P., Wolinsky, J. S., Confavreux, C., Comi, G., Kappos, L., Olsson, T. P., Miller, A., Freedman, Mark S., Narayana, P. A., Nelson, F., Vainrub, I., Datta, S., He, R., Gates, B., Ton, K., Wamil, B., Truffinet, P., Igau, B., Nicolas, V., Notelet, L., Payrard, S., Wijnand, P., Devore, S., H. H., Li, Osho, T., Wang, L., Wei, L., Dukovic, D., Ling, Y., Benzerdjeb, H., Mednikova, Z., Trabelsi, N., Musset, M., Merrill, D., Turpault, S., Williams, B., Nortmeyer, H., Kirst, E., Witthaus, E., Chen, S., Maida, E., Auff, E., Fazekas, F., Berger, T., Bhan, V., Bouchard, J. P., Duquette, P., Freedman, M., Grand'Maison, F., Kremenchutzky, M., Bourque, C., Marrie, R. A., Melanson, M., Patry, D., Oger, J., Stefanelli, M., Jacques, F., Venegas, P., Miranda, M., Barrientos, N., Tenhamm, E., Gloger, S., Rohde, G., Mares, J., Frederiksen, J., Stenager, E., Haldre, S., Gross Paju, K., Elovaara, I., Sumelahti, M. L., Erälinna, J. P., Farkkila, M., Harno, H., Reunanen, M., Jolma, T., Camu, W., Clavelou, P., Magy, L., Debouverie, M., Edan, G., Lebrun Frenay, C., Moreau, T., Pelletier, J., Roullet, E., Alamowitch, S., Clanet, M., Hautecoeur, P., Damier, P., Rumbach, L., Chan, A., Schimrigk, S., Haas, J., Lensch, E., Diener, H., Limmroth, V., Anders, D., Berghoff, M., Oschmann, P., Stangel, M., Frese, A., Kiefer, R., Marziniak, M., Zettl, U., Stark, E., Jendroska, K., Reifschneider, G., Amato, M. P., Cosi, V., Gallo, P., Gasperini, Claudio, Ghezzi, A., Trojano, M., Pozzilli, Carlo, Montanari, E., Zwanikken, C. P., Jongen, P. J., Van Munster, E. T., Hupperts, R. M., Anten, B., Sanders, E. A., Celius, E., Hovdal, H., Krogseth, S. B., Kozubski, W., Kwiecinski, H., Czlonkowska, A., Stelmasiak, Z., Selmaj, K., Hasiec, T., Fryze, W., Drozdowski, W., Kochanowicz, J., Cunha, L., De Sa, J., Sena, A. H., Odinak, M., Skoromets, A., Gusev, E., Boiko, A., Lashch, N., Stolyarov, I., Belova, A., Malkova, N., Doronin, B., Yakupov, E., Brundin, L., Hillert, J., Karabudak, R., Irkec, C., Idiman, E., Turan, O., Efendi, H., Gedizlioglu, M., Buchakchyyska, N., Goloborodko, A., Ipatov, A., Kobets, S., Lebedynets, V., Moskovko, S., Sanotskyy, Y., Smolanka, V., Yavorskaya, V., Bates, D., Evangelou, N., Hawkins, C., Mclean, B., O'Riordan, J., Price, S., Turner, B., Barnes, D., Zajicek, J., Honeycutt, W., Khan, O., Spikol, L., Stevens, J., Klinische Neurowetenschappen, and RS: MHeNs School for Mental Health and Neuroscience

Subjects
medicine.medical_specialty, biology, Nausea, business.industry, Incidence (epidemiology), Placebo-controlled study, General Medicine, Placebo, Gastroenterology, Surgery, chemistry.chemical_compound, Alanine transaminase, chemistry, Internal medicine, Relative risk, Teriflunomide, medicine, biology.protein, medicine.symptom, business, Leflunomide, medicine.drug
Abstract

Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teri flunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P

Published
2011
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15. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study

Author

Barbin, L. (Laetitia), Rousseau, C. (Chloe), Jousset, N. (Natacha), Casey, R. (Romain), Debouverie, M. (Marc), Vukusic, S. (Sandra), De Seze, J. (Jerome), Brassat, D. (David), Wiertlewski, S. (Sandrine), Brochet, B. (Bruno), Pelletier, J. (Jean), Vermersch, P. (Patrick), Edan, G. (Gilles), Lebrun-Frenay, C. (Christine), Clavelou, P. (Pierre), Thouvenot, E. (Eric), Camdessanché, J. (Jean-Philippe), Tourbah, A. (Ayman), Stankoff, B. (Bruno), Al Khedr, A. (Abdullatif), Cabre, P. (Philippe), Papeix, C. (Caroline), Berger, E. (Eric), Heinzlef, O. (Olivier), Debroucker, T. (Thomas), Moreau, T. (Thibault), Gout, O. (Olivier), Bourre, B. (Bertrand), Créange, A. (Alain), Labauge, P. (Pierre), Magy, L. (Laurent), Defer, G. (Gilles), Foucher, Y. (Yohann), Laplaud, D. (David A), CFSEP and OFSEP groups, Jonchère, Laurent, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, PRES Université Nantes Angers Le Mans (UNAM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), ReLSEP, Lorraine Register of MS, EA 4360, Department of Neurology, CHU Nancy, Department of Neurology, CHU Lyon, Service de Neurologie [Lyon], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Pôle de Neurosciences Cliniques, Department of Neurology, Hôpital de la Timone [CHU - APHM] (TIMONE), Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service de neurologie D, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Clermont-Ferrand, CHU Saint-Etienne, Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU de la Martinique [Fort de France], CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Neurologie [CHRU Besançon], Service de Neurologie [CHU de Poissy], CHU De Poissy, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Fondation Ophtalmologique Rothschild, Excitabilité nerveuse et thérapeutique (ENT), Hôpital Henri Mondor-EA 4391, Service de Physiologie Explorations Fonctionnelles-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), CHU Limoges, 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), Biostatistique, Recherche Clinique et Mesures Subjectives en Santé, Université de Nantes (UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université de Rennes 1 (UR1), 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 Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-EA 4391, Service de Physiologie Explorations Fonctionnelles-Hôpital Henri Mondor, Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), and Service de Neurologie [CHU Besançon]

Subjects
Male, [SDV]Life Sciences [q-bio], Aucun, diagnosis, drug therapy, epidemiology, Cohort Studies, 0302 clinical medicine, Natalizumab, Medicine, 030212 general & internal medicine, 10. No inequality, Fingolimod, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Cohort, Female, France, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, medicine.medical_specialty, Multiple Sclerosis, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Article, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Fingolimod Hydrochloride, Internal medicine, Humans, Immunologic Factors, Expanded Disability Status Scale, business.industry, Multiple sclerosis, medicine.disease, Surgery, Propylene Glycols, therapeutic use, Propensity score matching, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

OBJECTIVE: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis. METHODS: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting). RESULTS: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation. CONCLUSION: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod. comparative study journal article multicenter study observational study research support, non-u.s. gov't 2016 Feb 23 2016 01 29 imported

Published
2016
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16. A decreasing CD4/CD8 ratio over time and lower CSF-penetrating antiretroviral regimens are associated with a higher risk of neurocognitive deterioration, independently of viral replication

Author

Vassallo, Matteo, primary, Fabre, R., additional, Durant, J., additional, Lebrun-Frenay, C., additional, Joly, H., additional, Ticchioni, M., additional, DeSalvador, F., additional, Harvey-Langton, A., additional, Dunais, B., additional, Laffon, M., additional, Cottalorda, J., additional, Dellamonica, P., additional, and Pradier, C., additional

Published
2016
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17. 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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18. 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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19. Prior suggestive symptoms in third of patients consulting for a 'first' demyelinating event

Author

Gout, O., Lebrun-Frenay, C., Labauge, P., Le Page, G. E., Clavelou, P., Allouche, S., Tourbah, Ayman, Department of Neurology, Fondation A de Rothschild, Hôpital Pasteur [Nice] (CHU), GHU Garemeau-Nîmes, Hôpital Pontchaillou, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Teva Pharma Paris La défense, 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), Service de neurologie [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Psychopathologie et Neuropsychologie (LPN), Université Paris 8 Vincennes-Saint-Denis (UP8), and Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Adolescent, Pilot Projects, Severity of Illness Index, Abnormal white blood cell count, Statistics, Nonparametric, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Initial visit, Surveys and Questionnaires, medicine, Humans, In patient, Prospective Studies, 030212 general & internal medicine, 10. No inequality, ComputingMilieux_MISCELLANEOUS, MULTIPLE SCLEROSIS, Chi-Square Distribution, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Brain, Mean age, McDonald criteria, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Surgery, Psychiatry and Mental health, Early Diagnosis, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cohort, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; Objective To evaluate the prevalence of prior inflammatory events in patients consulting for a first inflammatory neurological event and improve early diagnosis of multiple sclerosis.Methods During the initial visit, the neurologist gave patients a self-administered questionnaire containing 72 questions regarding previous symptoms lasting >24 h. During the follow-up visit, the neurologist validated the symptoms and collected information about the current attack.Results The cohort included 178 patients (74% women, mean age (SD) 33.7 (10.1) years). The main reason for the initial visit was visual disturbance and sensory troubles in limbs. Mean (SD) global Expanded Disability Status Scale score was 1.4 (1.1), 46% of brains MRIs were positive according to BarkhofeTintore ' criteria, 41% had abnormal white blood cell count in cerebrospinal fluid and 71% had immunoglobin G oligoclonal bands. Prior symptoms suggestive of demyelination were reported by 79 patients (44%), validated by the neurologist for 70% (55 patients) and identified only by the neurologist in four patients. Sequelae were observed in 14 patients with validated prior symptoms (26%). The self-administered questionnaire showed an overall sensitivity of 93% and specificity of 80% for identifying patients with prior symptoms suggestive of demyelination.Conclusion A patient-administered questionnaire subsequently validated by the neurologist demonstrated that 33% of patients consulting for a first demyelinating event had prior symptoms suggestive of central nervous system demyelination that had gone unnoticed, and almost 70% had either sequelae of prior demyelination or McDonald criteria for dissemination in space. Such a questionnaire could be a useful tool for earlier diagnosis of multiple sclerosis.

Published
2010
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21. 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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22. 250 mu g or 500 mu g interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study

Author

O'Connor, P., Filippi, M., Arnason, B., Comi, G., Cook, S., Goodin, D., Hartung, H., Jeffery, D., Kappos, L., Boateng, F., Filippov, V., Groth, M., Knappertz, V., Kraus, C., Sandbrink, R., Pohl, C., BogumilAbramsky O, T., Achiron, A, Agius, M, Aichner, F, Altenkirch, H, Amato, Mp, Anten, B, Arbizu, T, Ash, P, Ballario, C, Bashir, K, Baum, K, Baumhackl, U, Beaver, G, Belova, A, Berger, J, Berger, T, Berlit, P, Beuche, W, Bhan, V, Bigley, K, Bissay, V, Blake, C, Bö, L, Boyko, A, Brochet, B, Brown, M, Callegaro, D, Carra, A, Carroll, W, Cascione, M, Christie, S, Clanet, M, Clavelou, P, Clementino, Vi, Confavreux, C, Cooper, J, Cross, A, Csanyi, A, Czlonkowska, A, D'Hooghe, M, Damier, P, Debouverie, M, Defer, G, Demina, T, Deri, N, Diem, R, Dressel, A, Dubois, B, Dunne, P, Duquette, P, Durelli, L, Edan, G, Elias, S, Elovaara, I, Esfahani, F, Evtushenko, S, Fabijan, Th, Fernández, O, Ferreira, Ml, Fink, A, Flechter, S, Ford, C, Francesconi, C, Freedman, M, Fryze, W, Gabbai, A, Gács, G, Gallo, Paolo, Gazda, S, Gerloff, C, Glyman, S, Goodman, A, Gottesman, M, Grand'Maison, F, Guarnaccia, J, Gutierrez, A, Haas, J, Hansen, Hj, Hardiman, O, Heard, R, Heidenreich, F, Herbert, J, Herminia Scola, R, Hodgkinson, S, Hoffmann, F, Holub, R, Huddlestone, J, Hughes, B, Hughes, M, Hunter, S, Hurwitz, B, Izquierdo, G, Jacobasch, E, Jacques, F, Jakab, G, Jongen, P, Karageorgiou, C, Karni, A, Kasper, L, Kaufman, M, Keidel, M, Khatri, B, Kiefer, R, Kirzinger, S, Kita, M, Komoly, S, Kotov, S, Kozubski, W, Kumlien, E, Kwiecinski, H, Labouge, P, Laganke, C, Lapierre, Y, Lebrun Frenay, C, Leist, T, Leon, Sa, Luetic, G, Lynch, S, Lynch, T, Malkova, N, Maltezou, M, Markowitz, C, Martin, C, Mattle, H, Mattson, D, Metra, M, Meyding Lamadé, U, Milo, R, Milonas, I, Miller, A, Miller, T, Minagar, A, Mitchell, G, Moreau, T, Mosberg, R, Murphy, R, Nehrych, T, Nikl, J, Odinak, M, Oschmann, P, Owen King, J, Pagani, L, Pereira Damasceno, B, Podemski, R, Pöhlau, D, Pozzilli, C, Rammohan, K, Reunanen, M, Rice, G, Richardson, P, Rivera, V, Rizvi, S, Rogozhyn, V, Rolak, L, Rosenkranz, T, Rotta, R, Sanders, E, Sater, R, Satgur Gupta, A, Schwartz, R, Sedal, L, Sega Jazbec, S, Selchen, D, Selmaj, K, Sheremata, W, Shvets, T, Silver, D, Simsarian, J, Skoromets, A, Smiroldo, J, Sokolova, L, Solovyova, Y, Sommer, N, Spirin, N, Stangel, M, Stark, E, Steinbrecher, A, Stemper, B, Stolyarov, I, Strasser Fuchs, S, Sweeney, B, Tettenborn, B, Thrower, B, Tilbery, Cp, Traboulsee, A, Trojano, M, Tubridy, N, Tyor, W, Valikovics, A, Vermersch, P, Vollmer, T, Voloshyna, N, Vrech, C, Wajgt, A, Weller, B, Wendt, J, Yakhno, N, Yeung, M, Zavalishin, I., O'Connor, P, Filippi, Massimo, Arnason, B, Comi, G, Cook, S, Goodin, D, Hartung, Hp, Jeffery, D, Kappos, L, Boateng, F, Filippov, V, Groth, M, Knappertz, V, Kraus, C, Sandbrink, R, Pohl, C, Bogumil, T., and Dubois, Bénédicte

Subjects
Adult, Male, medicine.medical_specialty, interferon beta-1b, Adolescent, Pharmacology, relapsing-remitting multiple sclerosis, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Humans, Immunologic Factors, Glatiramer acetate, Adverse effect, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Interferon beta-1b, Brain, Glatiramer Acetate, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Tolerability, glatiramer acetate, Female, Neurology (clinical), business, Peptides, medicine.drug
Abstract

BACKGROUND: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. METHODS: Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. FINDINGS: We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p

Published
2009

23. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., McCauley, J.L., Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., and McCauley, J.L.

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

24. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, McCauley, JL, Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, and McCauley, JL

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

25. Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility

Author

Couturier, N., primary, Bucciarelli, F., additional, Nurtdinov, R. N., additional, Debouverie, M., additional, Lebrun-Frenay, C., additional, Defer, G., additional, Moreau, T., additional, Confavreux, C., additional, Vukusic, S., additional, Cournu-Rebeix, I., additional, Goertsches, R. H., additional, Zettl, U. K., additional, Comabella, M., additional, Montalban, X., additional, Rieckmann, P., additional, Weber, F., additional, Muller-Myhsok, B., additional, Edan, G., additional, Fontaine, B., additional, Mars, L. T., additional, Saoudi, A., additional, Oksenberg, J. R., additional, Clanet, M., additional, Liblau, R. S., additional, and Brassat, D., additional

Published
2011
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27. Determinants of therapeutic lag in multiple sclerosis

Author

Tomas Kalincik, Marc Girard, Corinne Pottier, Murat Terzi, Jean Pelletier, Oliver Gerlach, Julie Prevost, Dana Horakova, Francois Grand'Maison, Raed Alroughani, Guillermo Izquierdo, Francesco Patti, Federico Frascoli, Maria Trojano, Franco Granella, Pamela A. McCombe, Charles B Malpas, Recai Turkoglu, Aurélie Ruet, Jonathan Ciron, Tünde Csépány, Nicolas Maubeuge, Helmut Butzkueven, Pierre Clavelou, Tamara Castillo Trivino, Marco Onofrj, Jean Philippe Camdessanche, Pierre Labauge, Vincent Van Pesch, Pierre Grammond, Abir Wahab, Roberto Bergamaschi, Aysun Soysal, Diana Ferraro, Bertrand Bourre, Olivier Gout, Jeannette Lechner-Scott, Sara Eichau, Emmanuelle Leray, Alexis Montcuquet, Pierre Duquette, Olivier Casez, Youssef Sidhom, Patrizia Sola, Bart Van Wijmeersch, Izanne Roos, Gilles Edan, Serkan Ozakbas, David Laplaud, Sandra Vukusic, Abdullatif Al Khedr, Céline Labeyrie, Philippe Cabre, Eric Thouvenot, Céline Louapre, Romain Casey, Alessandra Lugaresi, Riadh Gouider, Alasdair Coles, Eric Berger, Ivania Patry, Gerardo Iuliano, Elisabetta Cartechini, Cavit Boz, Karolina Hankiewicz, Eva Havrdova, Eduardo Aguera-Morales, J William L Brown, Jérôme De Seze, Bruno Stankoff, Olivier Heinzlef, Gilles Defer, Alexandre Prat, Chantal Nifle, Maria José Sá, Marc Debouverie, Daniele Spitaleri, Aude Maurousset, Thibault Moreau, Christine Lebrun-Frenay, Hélène Zéphir, University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Méthodes quantitatives en santé publique (METIS), Collectif de recherche handicap, autonomie et société inclusive (CoRHASI), Swinburne University of Technology [Melbourne], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de recherche en neurosciences de Lyon (CRNL), 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), Hospices Civils de Lyon (HCL), Charles University [Prague], Università degli studi di Catania [Catania], Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Università degli Studi di Modena e Reggio Emilia (UNIMORE), University of Queensland [Brisbane], Monash University [Clayton], UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Charles University [Prague] (CU), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Bari Aldo Moro (UNIBA), University of Catania [Italy], Hospital Virgen Macarena, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), CHU Toulouse [Toulouse], INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Fernando Pessoa University, Azienda Ospedaleria Universitaria di Modena, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Karadeniz Technical University (KTU), Università degli Studi di Macerata = University of Macerata (UNIMC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Newcastle [Australia] (UoN), Zuyderland Hospital [Heerlen, The Netherlands], Ondokuz Mayis University, University of Parma = Università degli studi di Parma [Parme, Italie], Amiri hospital, University of Salerno (UNISA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hasselt University (UHasselt), San Giuseppe Moscati Hospital [Avellino, Italie], Bakirkoy Matern & Childrens State Hosp, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Universidad de Córdoba [Cordoba], Hospital Donostia, CHU Clermont-Ferrand, Hôpital de la Timone [CHU - APHM] (TIMONE), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHI Poissy-Saint-Germain, Université de la Manouba [Tunisie] (UMA), University of Debrecen, Hôpital Charles Nicolle [Rouen], CHU Amiens-Picardie, CHU de la Martinique [Fort de France], CHU Limoges, CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], This study was supported by the EDMUS Foundation and NHMRC [1140766,1129189, 1157717]. IR is supported by a MSIF-ARSEP McDonald fellowship grantand a Melbourne Research Scholarship. The MSBase Foundation is a not-for-profitorganization that receives support from Biogen, Novartis, Merck, Roche, Teva andSanofi Genzyme. The study was conducted separately and apart from the guidanceof the sponsors. The Observatoire Français de la Sclérose en Plaques (OFSEP) issupported by a grant provided by the French State and handled by the 'AgenceNationale de la Recherche,' within the framework of the 'Investments for the Future'program, under the reference ANR-10-COHO-002, by the Eugène Devic EDMUSFoundation against multiple sclerosis and by the ARSEP Foundation., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Roos I., Leray E., Frascoli F., Casey R., Brown J.W.L., Horakova D., Havrdova E.K., Debouverie M., Trojano M., Patti F., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grammond P., Ciron J., Ruet A., Ozakbas S., De Seze J., Louapre C., Zephir H., Sa M.J., Sola P., Ferraro D., Labauge P., Defer G., Bergamaschi R., Lebrun-Frenay C., Boz C., Cartechini E., Moreau T., Laplaud D., Lechner-Scott J., Grand'Maison F., Gerlach O., Terzi M., Granella F., Alroughani R., Iuliano G., Van Pesch V., Van Wijmeersch B., Spitaleri D.L.A., Soysal A., Berger E., Prevost J., Aguera-Morales E., McCombe P., Castillo Trivino T., Clavelou P., Pelletier J., Turkoglu R., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Sidhom Y., Gouider R., Csepany T., Bourre B., Al Khedr A., Casez O., Cabre P., Montcuquet A., Wahab A., Camdessanche J.-P., Maurousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Coles A., Malpas C.B., Vukusic S., Butzkueven H., Kalincik T., Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-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), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli studi di Catania = University of Catania (Unict), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), University of Newcastle [Callaghan, Australia] (UoN), Ondokuz Mayis University (OMU), Università degli studi di Parma = University of Parma (UNIPR), Universidad de Córdoba = University of Córdoba [Córdoba], University of Debrecen Egyetem [Debrecen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Registrie, Male, medicine.medical_specialty, Treatment response, Pediatrics, Neurology, Lag, [SDV]Life Sciences [q-bio], Aucun, multiple sclerosis, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Recurrence, medicine, Humans, Treatment effect, Disabled Persons, Registries, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Delayed onset, medicine.disease, 3. Good health, Clinical neurology, therapeutic lag, multiple sclerosi, Disease Progression, Disabled Person, Observational study, Female, observational study, Neurology (clinical), business, 030217 neurology & neurosurgery, Human
Abstract

International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS

Published
2021
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28. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.

Subjects
Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2016
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29. Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Author

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

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

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

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30. T2-fluid attenuated inversion recovery fat-suppressed mismatch in the identification and characterization of lesions related to radiologically isolated syndrome.

Author

Okuda DT and Lebrun-Frenay C

Abstract

The radiologically isolated syndrome is defined by the presence of incidentally identified T2-weighted hyperintense lesions, highly suggestive of central nervous system demyelination, following an MRI study that is performed for reasons other than for the investigation of symptoms related to multiple sclerosis (MS). These individuals also have no evidence of prior neurological symptoms associated with inflammatory demyelination and no alternative explanation for the observed MRI findings. Recently, the introduction of novel imaging techniques such as the "central vein sign" has improved lesion specificity for MS. In addition, the observation of T2-fluid attenuated inversion recovery (FLAIR) mismatch characteristics associated with gliomas and in those with MS with a higher disease burden appear to provide morphological data that relate to disease severity. The value of T2-FLAIR mismatch characteristics in discrete multi-focal lesions has not yet been well defined. Here, we present the value of a fat-suppressed T2-FLAIR sequence in the identification and characterization of T2-weighted hyperintensities resulting from inflammatory demyelination., Competing Interests: D.T.O. received personal compensation for consulting and advisory services from Biogen, Eisai, EMD Serono, Genentech, Genzyme/Sanofi, Moderna, RVL Pharmaceuticals, Inc., Zenas BioPharma, and research support from EMD Serono/Merck and Novartis. D.T.O. has issued national and international patents along with pending patents related to other developed technologies and has received royalties for intellectual property licensed by The Board of Regents of The University of Texas System. D.T.O. is the Founder of Revert Health Inc. C.L.-F. reports no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Published
2024
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31. Dental Adverse Effects of Anti-CD20 Therapies.

Author

Bartak H, Fareh T, Ben Othman N, Viard D, Cohen M, Rocher F, Ewig E, Drici MD, and Lebrun-Frenay C

Abstract

Introduction: Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or resistant forms of generalized myasthenia gravis (MG). They are generally well-tolerated, but recent reports have highlighted severe dental disorders in patients undergoing anti-CD20 therapies. The aim was to describe a series of cases and to compare with the available scientific literature., Methods: We reviewed 6 patient cases with dental disorders during anti-CD20 therapy that were reported to the pharmacovigilance center. A disproportionality analysis was also conducted on Vigibase® for each anti-CD20 and each adverse effect described in the cases., Results: Six cases of dental and gingival conditions in relatively young patients were reported (median age: 40.5 years old [min: 34; max: 79]). Oral conditions were developed in four patients with MS treated with ocrelizumab and in two patients receiving rituximab (one patient with MG and one with NMOSD). The onset of oral conditions ranged from 10 days to 2 years after treatment initiation. Notably, all patients treated with ocrelizumab experienced gingival recession. Various dental pathologies were observed, including tooth loss, dental pain, caries, brittle teeth, dental fractures, dental abscesses, and periodontitis. Analysis of Vigibase® revealed 284 worldwide cases of dental and gingival conditions under ocrelizumab, 386 cases under rituximab, and 80 under ofatumumab. Significant associations were found between these therapies and dental pathologies, particularly tooth abscesses and infections., Conclusion: To our knowledge, this is the first case series reporting dental conditions developed in patients long-term treated with anti-CD20 treatments. This issue, literature data, and Vigilyze® analysis might be considered a safety signal that necessitates being confirmed with more robust data, such as a retrospective study with a control group. Meanwhile, proactive measures are essential like frequent dental checkups and dental hygienic measures to prevent oral health problems associated with anti-CD20 therapies., (© 2024. The Author(s).)

Published
2024
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32. The diagnostic value of the central vein sign in radiologically isolated syndrome.

Author

Landes-Chateau C, Levraut M, Okuda DT, Themelin A, Cohen M, Kantarci OH, Siva A, Pelletier D, Mondot L, and Lebrun-Frenay C

Subjects
Humans, Magnetic Resonance Imaging methods, Sensitivity and Specificity, Biomarkers, Demyelinating Diseases diagnostic imaging, Demyelinating Diseases pathology, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology
Abstract

Objective: The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS., Methods: Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age-matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility-based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions., Results: 180 participants (45 RIS, 45 MS, 90 non-MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non-MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non-MS than MS from non-MS (p = 0.837). When a 6-lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis., Interpretation: This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non-MS, with similar performances to those in MS., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2024
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33. Impact of Immune Checkpoint Inhibitors on the Course of Multiple Sclerosis.

Author

Androdias G, Noroy L, Psimaras D, Birzu C, Pelletier J, Beigneux Y, Branger P, Ciron J, Dananchet Y, Depaz R, Froment Tilikete C, Gignoux L, Grosset-Janin C, Joubert B, Kerschen P, Kwiatkowski A, Lebrun-Frenay C, Maillart E, Maureille A, Nicolas P, Roux T, Marignier R, and Vukusic S

Subjects
Humans, Middle Aged, Immune Checkpoint Inhibitors adverse effects, Retrospective Studies, Prospective Studies, Recurrence, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis drug therapy
Abstract

Objectives: Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment. Their mechanism of action raises the question of possible exacerbation of preexisting multiple sclerosis (MS). The aim of our study was to assess the risk of increased MS activity, defined by the occurrence of a relapse and/or a new MRI lesion, after ICI initiation., Methods: This French multicentric study collected retrospective and prospective data on patients with MS treated with ICIs after a cancer diagnosis., Results: We identified 18 patients with a median age of 48 years. Three of them (17%), all aged 50 years or younger, with a relapsing-remitting course, showed clinical and/or radiologic signs of MS activity 3 to 6 months after ICI initiation. They had stopped disease-modifying treatment (DMT) several months earlier, at the time of cancer diagnosis. Only one had both clinical and MRI activity, with mild severity and complete recovery., Discussion: Our study suggests that the overall risk of MS activity under ICI is low and could be mainly driven by DMT discontinuation, as in MS in general. Although larger studies are needed for better risk assessment in younger patients with more active disease, ICI should be considered when needed in patients with MS.

Published
2024
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36. Kappa Free Light Chain Index Predicts Disease Course in Clinically and Radiologically Isolated Syndromes.

Author

Levraut M, Gavoille A, Landes-Chateau C, Cohen M, Bresch S, Seitz-Polski B, Mondot L, and Lebrun-Frenay C

Subjects
Female, Humans, Adult, Male, Syndrome, Immunoglobulin kappa-Chains, Disease Progression, Demyelinating Diseases diagnostic imaging, Autoimmune Diseases of the Nervous System, Multiple Sclerosis diagnostic imaging
Abstract

Background and Objectives: To evaluate whether the kappa free light chain index (K-index) can predict the occurrence of new T2-weighted MRI lesions (T2L) and clinical events in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS)., Methods: All consecutive patients presenting for the diagnostic workup, including CSF analysis, of clinical and/or MRI suspicion of multiple sclerosis (MS) since May 1, 2018, were evaluated. All patients diagnosed with CIS and RIS with at least 1-year follow-up were included. Clinical events and new T2L were collected during follow-up. The K-index performances in predicting new T2L and a clinical event were evaluated using time-dependent ROC analyses. The time to clinical event or new T2L was estimated using survival analysis according to the binarized K-index using an independent cutoff of 8.9, and the ability of each variable to predict outcomes was compared using the Harrell c-index., Results: One hundred and eighty two patients (146 CIS and 36 RIS, median age 39 [30; 48] y-o, 70% females) were included with a median follow-up of 21 [13, 33] months. One hundred five (58%) patients (85 CIS and 20 RIS) experienced new T2L, and 28 (15%; 21 CIS and 7 RIS) experienced a clinical event. The K-index could predict new T2L over time in CIS (area under the curve [AUC] ranging from 0.86 to 0.96) and in RIS (AUC ranging from 0.84 to 0.54) but also a clinical event in CIS (AUC ranging from 0.75 to 0.87). Compared with oligoclonal bands (OCBs), the K-index had a better sensitivity and a slight lower specificity in predicting new T2L and clinical events in both populations. In the predictive model, the K-index was the variable that best predict new T2L in both CIS and RIS but also clinical events in CIS (c-index ranging from 0.70 to 0.77), better than the other variables, including OCB., Discussion: This study provides evidence that the K-index predicts new T2L in CIS and RIS but also clinical attack in patients with CIS. We suggest adding the K-index in the further MS diagnosis criteria revisions as a dissemination-in-time biomarker., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2023
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37. Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

Author

Pelle J, Briant AR, Branger P, Derache N, Arnaud C, Lebrun-Frenay C, Cohen M, Mondot L, De Seze J, Bigaut K, Collongues N, Kremer L, Ricard D, Bompaire F, Ohlmann C, Sallansonnet-Froment M, Ciron J, Biotti D, Pignolet B, Parienti JJ, and Defer G

Abstract

Introduction: Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation., Methods: We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety., Results: Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12 months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent., Conclusion: These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab., Clinical Trials: gov identifier (NCT04580381)., (© 2023. The Author(s).)

Published
2023
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38. Immune Profiling Reveals the T-Cell Effect of Ocrelizumab in Early Relapsing-Remitting Multiple Sclerosis.

Author

Garcia A, Dugast E, Shah S, Morille J, Lebrun-Frenay C, Thouvenot E, De Sèze J, Le Page E, Vukusic S, Maurousset A, Berger E, Casez O, Labauge P, Ruet A, Raposo C, Bakdache F, Buffels R, Le Frère F, Nicot A, Wiertlewski S, Gourraud PA, Berthelot L, and Laplaud D

Subjects
Humans, Leukocytes, Mononuclear, Antibodies, Monoclonal, Humanized therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis drug therapy
Abstract

Background and Objectives: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology., Methods: A first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest., Results: Using an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4 + T cells: one corresponding to naive CD4 + T cells was increased, the other clusters corresponded to effector memory (EM) CD4 + CCR6 - T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8 + T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8 + CCR5 + T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells., Discussion: Our study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2023
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39. Sphingosine-1 Phosphate Receptor Modulators Increase In Vitro Melanoma Cell Line Proliferation at Therapeutic Doses Used in Patients with Multiple Sclerosis.

Author

Ruetsch-Chelli C, Okuda DT, Rocher F, Tartare-Deckert S, Deckert M, and Lebrun-Frenay C

Abstract

Introduction: S1P 1 receptor modulators (S1P 1 -RM) are oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). Several authorities have raised doubts that S1P 1 -RM are responsible for an increased risk of melanoma in patients with MS. We studied the in vitro effects of S1P 1 -RM on different melanoma cell lines to compare the effect of available S1P 1 -RM on the proliferation of human melanoma cells., Methods: Four S1P 1 -RM were studied which are currently approved for managing MS, namely fingolimod (Gilenya ® ), siponimod (Mayzent ® ), ozanimod (Zeposia ® ), and ponesimod (Ponvory ® ). We tested these four drugs at different concentrations, including therapeutic doses (0.5, 1.6, 5.5, 18, and 60 µM), on human melanoma cell lines (501Mel cells, 1205LU cells, and M249R cells) to analyze in vitro cell proliferation monitored with the IncuCyte ZOOM live cell microscope (Essen Bioscience)., Results: At therapeutic doses, median confluence increased overall for all lineages: + 122% for ozanimod (p < 0.001), + 71% for ponesimod (p < 0.001), + 67% for siponimod (NS), and + 41% for fingolimod (p = 0.094). Ozanimod- and ponesimod-treated cells increased confluency in 501Mel, 1205LU, and M249R cell lines (p < 0.001)., Conclusion: These data suggest an increased proliferation of various melanoma cell lines with S1P 1 -RM treatments used at therapeutic concentrations for patients with MS and should raise the question of increased dermatologic surveillance., (© 2022. The Author(s).)

Published
2023
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40. Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis: A Large Multicenter Cohort Study.

Author

Levraut M, Laurent-Chabalier S, Ayrignac X, Bigaut K, Rival M, Squalli S, Zéphir H, Alberto T, Pekar JD, Ciron J, Biotti D, Puissant-Lubrano B, Camdessanché JP, Tholance Y, Casez O, Toussaint B, Marion J, Moreau T, Lakomy D, Thomasset A, Maillart E, Sterlin D, Maurousset A, Rocher A, Laplaud DA, Bigot-Corbel E, Bertho PO, Pelletier J, Boucraut J, Labauge P, Vincent T, De Sèze J, Jahn I, Seitz-Polski B, Thouvenot E, and Lebrun-Frenay C

Subjects
Female, Humans, Immunoglobulin kappa-Chains, Oligoclonal Bands, Biomarkers, Cohort Studies, Multiple Sclerosis, Demyelinating Diseases diagnosis, Central Nervous System Diseases
Abstract

Background and Objectives: Kappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS., Methods: We conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC)., Results: One thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND ( p = 0.123 and p = 0.991 for area under the curve [AUC] comparisons) and performed better than CSF KFLC ( p < 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB ( p < 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB ( p = 0.065). In the multivariate analysis model, female gender ( p = 0.003), young age ( p = 0.013), and evidence of disease activity ( p < 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index., Discussion: KFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS., Classification of Evidence: This study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
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41. Neurofilament Light Chain Levels Are Predictive of Clinical Conversion in Radiologically Isolated Syndrome.

Author

Rival M, Thouvenot E, Du Trieu de Terdonck L, Laurent-Chabalier S, Demattei C, Uygunoglu U, Castelnovo G, Cohen M, Okuda DT, Kantarci OH, Pelletier D, Azevedo C, Marin P, Lehmann S, Siva A, Mura T, and Lebrun-Frenay C

Subjects
Humans, Biomarkers, Intermediate Filaments, Oligoclonal Bands, Autoimmune Diseases of the Nervous System, Demyelinating Diseases diagnostic imaging
Abstract

Background and Objectives: To evaluate the predictive value of serum neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with radiologically isolated syndrome (RIS) for evidence of disease activity (EDA) and clinical conversion (CC)., Methods: sNfL and cNfL were measured at RIS diagnosis by single-molecule array (Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using the Kaplan-Meier analysis and multivariate Cox regression models including age, spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase 3-like protein 1, and CSF white blood cells., Results: Sixty-one patients with RIS were included. At diagnosis, sNfL and cNfL were correlated (Spearman r = 0.78, p < 0.001). During follow-up, 47 patients with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1-86). When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0 pg/mL) levels were predictive of EDA (log rank, p < 0.01 and p = 0.02, respectively). Medium-high cNfL levels were predictive of CC (log rank, p < 0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA, while SC lesions, cNfL, and sNfL were independent factors of CC., Discussion: cNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity better, sNfL is more accessible than cNfL and can be considered when a lumbar puncture is not performed., Classification of Evidence: This study provides Class II evidence that in people with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are associated with subsequent evidence of disease activity or clinical conversion., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
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42. From the prodromal stage of multiple sclerosis to disease prevention.

Author

Marrie RA, Allegretta M, Barcellos LF, Bebo B, Calabresi PA, Correale J, Davis B, De Jager PL, Gasperi C, Greenbaum C, Helme A, Hemmer B, Kanellis P, Kostich W, Landsman D, Lebrun-Frenay C, Makhani N, Munger KL, Okuda DT, Ontaneda D, Postuma RB, Quandt JA, Roman S, Saidha S, Sormani MP, Strum J, Valentine P, Walton C, Zackowski KM, Zhao Y, and Tremlett H

Subjects
Humans, Prodromal Symptoms, Multiple Sclerosis diagnosis, Multiple Sclerosis prevention & control, Schizophrenia diagnosis, Schizophrenia prevention & control
Abstract

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome., (© 2022. Springer Nature Limited.)

Published
2022
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43. Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study.

Author

Papeix C, Castelnovo G, Leray E, Coustans M, Levy P, Visy JM, Kobelt G, Lamy F, Allaf B, Heintzmann F, Chouette I, Raponi E, Durand B, Grevat E, Kamar D, Debouverie M, and Lebrun-Frenay C

Abstract

Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS., Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion., Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9)., Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis., (© 2022. The Author(s).)

Published
2022
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44. Peripheral facial palsy following COVID-19 vaccination: a practical approach to use the clinical situation as a guide.

Author

Foirest C, Bihan K, Tankéré F, Junot H, Demeret S, Debs R, Maillart E, Lebrun-Frenay C, Vigouroux A, Caudron M, Canouï E, Lamas G, Weiss N, and Pourcher V

Subjects
Humans, Vaccination adverse effects, Bell Palsy chemically induced, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, Facial Paralysis chemically induced
Published
2022
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45. Kappa Free Light Chains, Soluble Interleukin-2 Receptor, and Interleukin-6 Help Explore Patients Presenting With Brain White Matter Hyperintensities.

Author

Levraut M, Landes C, Mondot L, Cohen M, Bresch S, Brglez V, Seitz-Polski B, and Lebrun-Frenay C

Subjects
Adult, Biomarkers cerebrospinal fluid, Brain diagnostic imaging, Female, Humans, Immunoglobulin kappa-Chains cerebrospinal fluid, Interleukin-10 cerebrospinal fluid, Interleukin-1beta cerebrospinal fluid, Interleukin-2 Receptor alpha Subunit analysis, Interleukin-6 cerebrospinal fluid, Male, Middle Aged, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis diagnosis, White Matter diagnostic imaging
Abstract

Introduction: Many patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases., Objective: This study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1β, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH., Methods: All patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups-MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups-according to clinical presentation, MRI characteristics, and biological workup., Results: A total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD ( n = 88), OIND ( n = 35), and NIND ( n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively)., Discussion: Our results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Levraut, Landes, Mondot, Cohen, Bresch, Brglez, Seitz-Polski and Lebrun-Frenay.)

Published
2022
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46. Treatment regimens for neuromyelitis optica spectrum disorder attacks: a retrospective cohort study.

Author

Demuth S, Guillaume M, Bourre B, Ciron J, Zephir H, Sirejacob Y, Kerbrat A, Lebrun-Frenay C, Papeix C, Michel L, Laplaud D, Vukusic S, Maillart E, Cohen M, Audoin B, Marignier R, and Collongues N

Subjects
Aquaporin 4, Autoantibodies, Cohort Studies, Humans, Retrospective Studies, Multiple Sclerosis, Neuromyelitis Optica drug therapy
Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy., Methods: We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome., Results: We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response., Conclusions: We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids., (© 2022. The Author(s).)

Published
2022
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47. Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal.

Author

Rollot F, Couturier J, Casey R, Wiertlewski S, Debouverie M, Pelletier J, De Sèze J, Labauge P, Ruet A, Thouvenot E, Ciron J, Berger E, Gout O, Clavelou P, Stankoff B, Casez O, Bourre B, Zephir H, Moreau T, Lebrun-Frenay C, Maillart E, Edan G, Neau JP, Montcuquet A, Cabre P, Camdessanché JP, Defer G, Nasr HB, Maurousset A, Hankiewicz K, Pottier C, Leray E, Vukusic S, and Laplaud DA

Subjects
Antigens, CD20, Fingolimod Hydrochloride therapeutic use, Humans, Immunologic Factors adverse effects, Immunosuppressive Agents therapeutic use, Natalizumab adverse effects, Recurrence, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting drug therapy
Abstract

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Published
2022
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48. Marburg Multiple Sclerosis Variant: Complete Remission with Very Early Administration of Mitoxantrone-A Case Report.

Author

Capet N, Levraut M, Delourme A, Thomel-Rocchi O, Bourg V, Cabre P, Vandenbos F, Mondot L, and Lebrun-Frenay C

Abstract

Marburg variant is a severe and fulminant pseudotumor form of multiple sclerosis (MS) with high morbidity and mortality rates. Because of its scarcity, it remains incompletely characterized and physicians' experiences will influence the treatment. We report the inflammatory explosive case of a 31-year-old woman presenting with rapid neurological degradation of histology proven Marburg's disease, successfully treated with early administration of Mitoxantrone (MITX). To our knowledge, it is the first case describing complete remission after MITX in a biopsy-proven condition., (© 2021. The Author(s).)

Published
2022
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49. Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy Presenting as Mild Encephalopathy with Reversible Splenium Lesion.

Author

Héraud C, Capet N, Levraut M, Hattenberger R, Bourg V, Thomas P, Mondot L, and Lebrun-Frenay C

Abstract

Introduction: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is scarce and usually presents as meningoencephalomyelitis. Here, we offer the case of an atypical presentation of GFAP-astrocytopathy., Case Presentation: We report the case of a 26-year-old woman admitted to our neurology department for a 3-week progressive and worsening neurologic picture, with secondary worsening. Initial imaging showed a Mild Encephalitis with Reversible Splenium of corpus callosum lesion (MERS). Full infectious and autoimmune workup then revealed positivity of GFAP antibodies, leading us to diagnose GFAP astrocytopathy., Discussion: Our case is the first reported association between MERS and GFAP astrocytopathy in an adult patient. Clinical presentation of GFAP astrocytopathy usually includes various neurologic symptoms and can lead to misdiagnosis., (© 2021. The Author(s).)

Published
2022
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50. CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments.

Author

Bernard-Valnet R, Moisset X, Maubeuge N, Lefebvre M, Ouallet JC, Roumier M, Lebrun-Frenay C, Ciron J, Biotti D, Clavelou P, Godeau B, Du Pasquier RA, and Martin-Blondel G

Subjects
Adult, CCR5 Receptor Antagonists administration & dosage, Female, Humans, Immune Reconstitution Inflammatory Syndrome chemically induced, Leukoencephalopathy, Progressive Multifocal chemically induced, Male, Maraviroc administration & dosage, Middle Aged, Outcome Assessment, Health Care, Retrospective Studies, Young Adult, CCR5 Receptor Antagonists pharmacology, Immune Reconstitution Inflammatory Syndrome drug therapy, Immune Reconstitution Inflammatory Syndrome prevention & control, Leukoencephalopathy, Progressive Multifocal drug therapy, Leukoencephalopathy, Progressive Multifocal prevention & control, Maraviroc pharmacology
Abstract

Background and Objectives: Progressive multifocal leukoencephalopathy (PML) is a disabling neurologic disorder resulting from the infection of the CNS by JC polyomavirus in immunocompromised individuals. For the last 2 decades, increasing use of immunotherapies leads to iatrogenic PML. Iatrogenic PML is often associated with signs of inflammation at onset (inflammatory PML) and/or after treatment withdrawal immune reconstitution inflammatory syndrome (PML-IRIS). Although immune reconstitution is a key element for viral clearance, it may also be harmful and induce clinical worsening. A C-C chemokine receptor type 5 (CCR5) antagonist (maraviroc) has been proposed to prevent and/or limit the deleterious immune responses underlying PML-IRIS. However, the data to support its use remain scarce and disputed., Methods: We conducted a multicenter retrospective cohort study at 8 university hospitals in France and Switzerland by collecting clinical, biological, and radiologic data of patients who developed inflammatory PML (iPML) or PML-IRIS related to immunosuppressive therapies used for chronic inflammatory diseases between 2010 and 2020. We added to this cohort, a meta-analysis of individual case reports of patients with iPML/PML-IRIS treated with maraviroc published up to 2021., Results: Overall, 27 cases were identified in the cohort and 9 from the literature. Among them, 27 met the inclusion criteria: 16 treated with maraviroc and 11 with standard of care (including corticosteroids use). Most cases were related to MS (92.6%) and natalizumab (88%). Inflammatory features (iPML) were present at onset in 12 patients (44.4%), and most patients (92.6%) received corticosteroids within the course of PML. Aggravation due to PML-IRIS was not prevented by maraviroc compared with patients who received only corticosteroids (adjusted odds ratio: 0.408, 95% CI: 0.06-2.63). Similarly, maraviroc did not influence time to clinical worsening due to PML-IRIS (adjusted hazard ratio = 0.529, 95% CI: 0.14-2.0) or disability at the last follow-up (adjusted odds ratio: 2, 95% CI: 0.23-17.3)., Discussion: The use of CCR5 blockade did not help to keep deleterious immune reconstitution in check even when associated with corticosteroids. Despite maraviroc's reassuring safety profile, this study does not support its use in iPML/PML-IRIS., Classification of Evidence: This study provides Class IV evidence showing that adding maraviroc to the management of iatrogenic iPML/PML-IRIS does not improve the outcome., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2021
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