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3. Introducing machine learning for full MS patient trajectories improves predictions for disability score progression.

Author

Bergamaschi R., Peeters L., Becker T., Altintas A., Soysal A., Van Wijmeersch B., Boz C., Gouider R., Fernandez Bolanos R., Kalincik T., Oreja-Guevara C., Gobbi C., Solaro C., Ramo C., Spitaleri D.L., Maimone D., De Brouwer E., Moreau Y., Aguera-Morales E., Cartechini E., Butler E., Havrdova E., Patti F., Granella F., Grand'Maison F., Moore F., Verheul F., Iuliano G., Butzkueven H., Lechner-Scott J., Kuhle J., Sanchez Menoyo J.L., Rojas J.I., Prevost J., Onofrj M., Rio M.E., Sa M.J., Saladino M.L., Slee M., Barnett M., Terzi M., Deri N., McCombe P., Sola P., Duquette P., Grammond P., Ampapa R., Alroughani R., Hupperts R., Turkoglu R., Bergamaschi R., Peeters L., Becker T., Altintas A., Soysal A., Van Wijmeersch B., Boz C., Gouider R., Fernandez Bolanos R., Kalincik T., Oreja-Guevara C., Gobbi C., Solaro C., Ramo C., Spitaleri D.L., Maimone D., De Brouwer E., Moreau Y., Aguera-Morales E., Cartechini E., Butler E., Havrdova E., Patti F., Granella F., Grand'Maison F., Moore F., Verheul F., Iuliano G., Butzkueven H., Lechner-Scott J., Kuhle J., Sanchez Menoyo J.L., Rojas J.I., Prevost J., Onofrj M., Rio M.E., Sa M.J., Saladino M.L., Slee M., Barnett M., Terzi M., Deri N., McCombe P., Sola P., Duquette P., Grammond P., Ampapa R., Alroughani R., Hupperts R., and Turkoglu R.

Abstract

A. Background and Goals: It is now well known that patient medical history (or trajectories) is of crucial importance for both prognosis and optimal treatment selection for Multiple Sclerosis (MS) patients. This longitudinal data is nowadays being collected more systematically and its availability in patient registries opens the way towards precision medicine in MS. However, this information is very challenging to process computationally. By their observational nature, longitudinal patient data are scarcely and irregularly observed (i.e. only few observations are scattered over the whole patient history). Several works have recently attempted to address this issue by substituting full patient history with summary statistics in the modelling (i.e. using metrics such as the maximum and minimum disability score over the patient history as a proxy for the full medical trajectory). This strategy potentially discards relevant prognostic information. In this work, we present a method capable of handling the full information about disease history and its value for individual prognostic modelling. B. Method(s): We propose a novel statistical method relying on state-of-the-art machine learning models (Bayesian Probabilistic Tensor Factorisation, BPTF). Due to its generative nature, this method is able to process the full MS patient trajectories as input to deliver predictions. We infer the tensor decomposition (rank 70) with Gibbs sampling. To illustrate the performances of our approach, we consider the challenging task of predicting patient worsening within 2 years from current visit using 3 years clinical history. Patient worsening was defined with the 2 strata definition of disability progression as in Kalincik et al. (Brain, 2015). Available longitudinal data include Expanded Disability Status Scale (EDSS), magnetic resonance imaging and relapses. Patient static covariates include, among others, age at onset, gender, disease course and first observed EDSS. C. Result(s): W

Published
2020

6. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Author

Lavie, Caroline, primary, Rollot, Fabien, additional, Durand-Dubief, Françoise, additional, Marignier, Romain, additional, Ionescu, Iuliana, additional, Casey, Romain, additional, Moreau, Thibault, additional, Tourniaire, Patricia, additional, Hutchinson, Michael, additional, D’Hooghe, Marie Béatrice, additional, Laplaud, David-Axel, additional, Clavelou, Pierre, additional, De Sèze, Jérôme, additional, Debouverie, Marc, additional, Brassat, David, additional, Pelletier, Jean, additional, Lebrun-Frenay, Christine, additional, Le Page, Emmanuelle, additional, Castelnovo, Giovanni, additional, Berger, Eric, additional, Hautecoeur, Patrick, additional, Heinzlef, Olivier, additional, Durelli, Luca, additional, Clerico, Marinella, additional, Trojano, Maria, additional, Patti, Francesco, additional, Vukusic, Sandra, additional, Alpérovitch, A., additional, Carton, H., additional, d’Hooghe, M.B., additional, Hommes, O., additional, Hutchinson, M., additional, Adeleine, P., additional, Biron, A., additional, Cortinovis-Tourniaire, P., additional, Grimaud, J., additional, Hours, M., additional, Moreau, T., additional, Vukusic, S., additional, Confavreux, C., additional, Chauplannaz, G., additional, Latombe, D., additional, Clanet, M., additional, Lau, G., additional, Rumbach, L., additional, Goas, J.Y., additional, Rouhart, F., additional, Mazingue, A., additional, Roullet, E., additional, Madigand, M., additional, Hautecoeur, P., additional, Brunet, P., additional, Edan, G., additional, Allaire, C., additional, Riffault, G., additional, Leche, J., additional, Benoit, T., additional, Simonin, C., additional, Ziegler, F., additional, Baron, J.C., additional, Rivrain, Y., additional, Dumas, R., additional, Loche, D., additional, Bourrin, J.C., additional, Huttin, B., additional, Delisse, B., additional, Gibert, I., additional, Boulay, C., additional, Verceletto, M., additional, Durand, G., additional, Bonneviot, G., additional, Gil, R., additional, Hedreville, M.A., additional, Belair, C., additional, Poitevin, R.J., additional, Devoize, J.L., additional, Wyremblewski, P., additional, Delestre, F., additional, Setiey, A., additional, Comi, G., additional, Filippi, M., additional, Ghezzi, A., additional, Martinelli, V., additional, Rossi, P., additional, Zaffaroni, M., additional, Tola, M.R., additional, Amato, M.P., additional, Fioretti, C., additional, Meucci, G., additional, Inglese, M., additional, Mancardi, G.L., additional, Gambi, D., additional, Thomas, A., additional, Cavazzuti, M., additional, Citterio, A., additional, Heltberg, A., additional, Hansen, H.J., additional, Fernandez, O., additional, Romero, F., additional, Arbizu, T., additional, Hernandez, J.J., additional, De Andres de Frutos, C., additional, Geffner Sclarky, D., additional, Aladro Benito, Y., additional, Reyes Yanes, P., additional, Aguilar, M, additional, Burguera, J.A., additional, Yaya, R., additional, Bonakim Dib, W., additional, Arzua-Mouronte, D., additional, Sindic, C.J.M., additional, Medaer, R., additional, Roose, H., additional, Geens, K.M.J., additional, Guillaume, D., additional, Van Zandycke, M., additional, Janssens, J., additional, Cornette, M., additional, Mol, L., additional, Weilbach, F., additional, Flachenecker, P., additional, Hartung, H.P., additional, Haas, J., additional, Tendolkar, I., additional, Sindrn, E., additional, Kölmel, H.W., additional, Reichel, D., additional, Rauch, M., additional, Preuss, S., additional, Poser, S., additional, Mauch, E., additional, Strausser-Fuchs, S., additional, Kolleger, H., additional, Hawkins, S., additional, Howell, S.J.L., additional, Rees, J.E., additional, Thompson, A., additional, Johnson, M., additional, Boggild, M., additional, Gregory, R.P., additional, Bates, D., additional, Bone, I., additional, Polman, C., additional, Frequin, S., additional, Jongen, P., additional, Correia de Sa, J., additional, Rio, M.E., additional, Huber, S., additional, Lechner-Scott, J., additional, Kappos, L., additional, Ionescu, I., additional, Cornu, C., additional, El-Etr, M., additional, Baulieu, E.E., additional, Schumacher, M, additional, Miller, D.H., additional, Pugeat, M., additional, d’Archangues, C., additional, Conard, J., additional, Ménard, J., additional, Sitruk-Ware, R., additional, Pelissier, C., additional, Dat, S., additional, Belaïsch-Allard, J., additional, Athéa, N., additional, Büschsenschutz, D., additional, Lyon-Caen, O., additional, Gonsette, R., additional, Boissel, J.P., additional, Ffrench, P., additional, Durand-Dubief, F., additional, Cotton, F., additional, Pachai, C., additional, Bracoud, L., additional, Androdias, G., additional, Marignier, R., additional, Laplaud, D.A., additional, Wiertlewski, S., additional, Lanctin-Garcia, C., additional, Couvreur, G., additional, Madinier, G., additional, Clavelou, P., additional, Taithe, F., additional, Aufauvre, D., additional, Guy, N., additional, Ferrier, A., additional, De Sèze, J., additional, Collongues, N., additional, Debouverie, M., additional, Viala, F., additional, Brassat, D., additional, Gerdelat-Mas, A., additional, Henry, P., additional, Pelletier, J., additional, Rico-Lamy, A., additional, Lebrun-Frenay, C., additional, Lepage, E., additional, Deburghraeve, V., additional, Castelnovo, G., additional, Berger, E., additional, Blondiau, M., additional, Heinzlef, O., additional, Coustans, M., additional, Clerc, C., additional, Rieu, L., additional, Lauxerois, M., additional, Hinzelin, G., additional, Ouallet, J.C., additional, Minier, D., additional, Vion, P., additional, Gromaire-Fayolle, N., additional, Derache, N., additional, Thouvenot, E., additional, Sallansonnet-Froment, M., additional, Tourniaire, P., additional, Toureille, L., additional, Borgel, F., additional, Stankoff, B., additional, Moroianu, C., additional, Guennoc, A.M., additional, Tournier-Gervason, C.L., additional, Peysson, S., additional, Trojano, M., additional, Patti, F., additional, D’Amico, E., additional, Motti, L., additional, Durelli, L., additional, and Tavella, A., additional

Published
2018
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7. Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

Author

Derfuss, T., Kalincik, T., Spelman, T., Trojano, M., Duquette, P., Izquierdo, G., Grammond, P., Lugaresi, A., Hupperts, R., Cristiano, E., van Pesch, V., Grand’Maison, F., La Spitaleri, D., Rio, M.E., Flechter, S., Oreja-Guevara, C., Giuliani, G., Savino, A., Amato, M.P., Petersen, T., Fernandez-Bolanos, R., Bergamaschi, R., Iuliano, G., Boz, C., Lechner-Scott, J., Deri, N., Gray, O., Verheul, F., Fiol, M., Barnett, M., van Munster, E., Santiago, V., Moore, F., Slee, M., Saladino, M.L., Alroughani, R., Shaw, C., Kasa, K., Petkovska-Boskova, T., den Braber-Moerland, L., Chapman, J., Skromne, E., Herbert, J., Poehlau, D., Needham, M., Bacile, E.A.B., Arruda, W.O., Paine, M., Singhal, B., Vucic, S., Cabrera-Gomez, J.A., Butzkueven, H., Derfuss, T., Kalincik, T., Spelman, T., Trojano, M., Duquette, P., Izquierdo, G., Grammond, P., Lugaresi, A., Hupperts, R., Cristiano, E., van Pesch, V., Grand’Maison, F., La Spitaleri, D., Rio, M.E., Flechter, S., Oreja-Guevara, C., Giuliani, G., Savino, A., Amato, M.P., Petersen, T., Fernandez-Bolanos, R., Bergamaschi, R., Iuliano, G., Boz, C., Lechner-Scott, J., Deri, N., Gray, O., Verheul, F., Fiol, M., Barnett, M., van Munster, E., Santiago, V., Moore, F., Slee, M., Saladino, M.L., Alroughani, R., Shaw, C., Kasa, K., Petkovska-Boskova, T., den Braber-Moerland, L., Chapman, J., Skromne, E., Herbert, J., Poehlau, D., Needham, M., Bacile, E.A.B., Arruda, W.O., Paine, M., Singhal, B., Vucic, S., Cabrera-Gomez, J.A., and Butzkueven, H.

Abstract

OBJECTIVES: To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. METHODS: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. RESULTS: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. CONCLUSIONS: Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of t

Published
2013

8. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis

Author

Kalincik, T., Vivek, V., Jokubaitis, V., Lechner-Scott, J., Trojano, M., Izquierdo, G., Lugaresi, A., Grand'Maison, F., Hupperts, R., Oreja-Guevara, C., Bergamaschi, R., Iuliano, G., Alroughani, R., van Pesch, V., Amato, M.P., Slee, M., Verheul, F., Fernandez-Bolanos, R., Fiol, M., Spitaleri, D.L., Cristiano, E., Gray, O., Cabrera-Gomez, J.A., Shaygannejad, V., Herbert, J., Vucic, S., Needham, M., Petkovska-Boskova, T., Sirbu, C-A, Duquette, P., Girard, M., Grammond, P., Boz, C., Giuliani, G., Rio, M.E., Barnett, M., Flechter, S., Moore, F., Singhal, B., Bacile, E.A., Saladino, M.L., Shaw, C., Skromne, E., Poehlau, D., Vella, N., Spelman, T., Liew, D., Kilpatrick, T.J., Butzkueven, H., Kalincik, T., Vivek, V., Jokubaitis, V., Lechner-Scott, J., Trojano, M., Izquierdo, G., Lugaresi, A., Grand'Maison, F., Hupperts, R., Oreja-Guevara, C., Bergamaschi, R., Iuliano, G., Alroughani, R., van Pesch, V., Amato, M.P., Slee, M., Verheul, F., Fernandez-Bolanos, R., Fiol, M., Spitaleri, D.L., Cristiano, E., Gray, O., Cabrera-Gomez, J.A., Shaygannejad, V., Herbert, J., Vucic, S., Needham, M., Petkovska-Boskova, T., Sirbu, C-A, Duquette, P., Girard, M., Grammond, P., Boz, C., Giuliani, G., Rio, M.E., Barnett, M., Flechter, S., Moore, F., Singhal, B., Bacile, E.A., Saladino, M.L., Shaw, C., Skromne, E., Poehlau, D., Vella, N., Spelman, T., Liew, D., Kilpatrick, T.J., and Butzkueven, H.

Abstract

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Published
2013

10. Changes in Muscle and Brain Electrolytes in Rats Fed Natural Imbalanced Diets1

Author

Closa, S., Portela, M.L., Rio, M.E., and Sanahuja, J.C.

Abstract

The influence of a natural dietary amino acid imbalance on composition and sodium and potassium content of muscle and brain of weanling rats was studied at 50 and 90 days of age. Muscle water, the distribution of potassium and sodium, and their ratios between the intra- and extracellular space were examined as indications of biochemical maturity. Rats fed an imbalanced diet up to 50 days of age showed changes in muscle, protein, and glycogen similar to those observed previously on the whole carcass, i.e., lower muscle protein and higher muscle glycogen, than in rats fed a balanced low protein diet. No significant differences in the muscle concentration of sodium or potassium were observed; however, there was a close correlation between the individual potassium and nitrogen/water ratio, indicating that muscle potassium content was dependent on the chemical maturity of tissue. Intracellular sodium concentration was higher, and the ratios intracellular potassium/extracellular potassium, extracellular sodium/extracellular potassium, and intracellular potassium/intracellular sodium were lower compared with the group fed the low protein balanced diet; all these differences are statistically significant. Brain potassium was also significantly lower than that in the group fed the balanced diet, especially when expressed as potassium to sodium ratio or potassium per gram of protein nitrogen. Animals fed an imbalanced diet up to 90 days of age showed no differences in composition in absolute values nor in relative proportions when compared with rats fed the balanced diet except for muscle glycogen, which was significantly higher in the rats fed the imbalanced diets. The distribution studies of sodium, potassium, and water showed no differences between the various body compartments of the two sets of animals.

Published
1974
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12. 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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