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1. Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Author

Sifat Sharmin, Francesca Bovis, Charles Malpas, Dana Horakova, Eva Kubala Havrdova, Guillermo Izquierdo, Sara Eichau, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Murat Terzi, Oliver Gerlach, Raed Alroughani, Cavit Boz, Vahid Shaygannejad, Vincent van Pesch, Elisabetta Cartechini, Ludwig Kappos, Jeannette Lechner‐Scott, Roberto Bergamaschi, Recai Turkoglu, Claudio Solaro, Gerardo Iuliano, Franco Granella, Bart Van Wijmeersch, Daniele Spitaleri, Mark Slee, Pamela McCombe, Julie Prevost, Radek Ampapa, Serkan Ozakbas, Jose Luis Sanchez‐Menoyo, Aysun Soysal, Steve Vucic, Thor Petersen, Koen de Gans, Ernest Butler, Suzanne Hodgkinson, Youssef Sidhom, Riadh Gouider, Edgardo Cristiano, Tamara Castillo‐Triviño, Maria Laura Saladino, Michael Barnett, Fraser Moore, Csilla Rozsa, Bassem Yamout, Olga Skibina, Anneke van der Walt, Katherine Buzzard, Orla Gray, Stella Hughes, Angel Perez Sempere, Bhim Singhal, Yara Fragoso, Cameron Shaw, Allan Kermode, Bruce Taylor, Magdolna Simo, Neil Shuey, Talal Al‐Harbi, Richard Macdonell, Jose Andres Dominguez, Tunde Csepany, Carmen Adella Sirbu, Maria Pia Sormani, Helmut Butzkueven, Tomas Kalincik, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Sirbu, Carmen Adella/0000-0002-1982-1066, Malpas, Charles/0000-0003-0534-3718, Sharmin, Sifat, Bovis, Francesca, Malpas, Charle, Horakova, Dana, Havrdova, Eva Kubala, Izquierdo, Guillermo, Eichau, Sara, Trojano, Maria, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Onofrj, Marco, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Terzi, Murat, Gerlach, Oliver, Alroughani, Raed, Boz, Cavit, Shaygannejad, Vahid, van Pesch, Vincent, Cartechini, Elisabetta, Kappos, Ludwig, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Turkoglu, Recai, Solaro, Claudio, Iuliano, Gerardo, Granella, Franco, Van Wijmeersch, Bart, Spitaleri, Daniele, Slee, Mark, McCombe, Pamela, Prevost, Julie, Ampapa, Radek, Ozakbas, Serkan, Sanchez-Menoyo, Jose Lui, Soysal, Aysun, Vucic, Steve, Petersen, Thor, de Gans, Koen, Butler, Ernest, Hodgkinson, Suzanne, Sidhom, Youssef, Gouider, Riadh, Cristiano, Edgardo, Castillo-Triviño, Tamara, Saladino, Maria Laura, Barnett, Michael, Moore, Fraser, Rozsa, Csilla, Yamout, Bassem, Skibina, Olga, van der Walt, Anneke, Buzzard, Katherine, Gray, Orla, Hughes, Stella, Sempere, Angel Perez, Singhal, Bhim, Fragoso, Yara, Shaw, Cameron, Kermode, Allan, Taylor, Bruce, Simo, Magdolna, Shuey, Neil, Al-Harbi, Talal, Macdonell, Richard, Dominguez, Jose Andre, Csepany, Tunde, Sirbu, Carmen Adella, Sormani, Maria Pia, Butzkueven, Helmut, and Kalincik, Tomas

Subjects
Male, risk scoring, sustained disability progression, Multiple Sclerosis, CLARITY, clinical trial, functional system impairment, Cohort Studies, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Neurology, Disease Progression, Cladribine, Humans, Female, Neurology (clinical), Randomized Controlled Trials as Topic
Abstract

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries

Published
2022

2. Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years

Author

Kalincik, Tomas, Diouf, Ibrahima, Sharmin, Sifat, Malpas, Charles, Spelman, Tim, Horakova, Dana, Havrdova, Eva Kubala, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Jokubaitis, Vilija, van der Walt, Anneke, Grand'Maison, Francois, Sola, Patrizia, Ferraro, Diana, Shaygannejad, Vahid, Alroughani, Raed, Hupperts, Raymond, Terzi, Murat, Boz, Cavit, Lechner-Scott, Jeannette, Pucci, Eugenio, Van Pesch, Vincent, Granella, Franco, Bergamaschi, Roberto, Spitaleri, Daniele, Slee, Mark, Vucic, Steve, Ampapa, Radek, McCombe, Pamela, Ramo-Tello, Cristina, Prevost, Julie, Olascoaga, Javier, Cristiano, Edgardo, Barnett, Michael, Saladino, Maria Laura, Sanchez-Menoyo, Jose Luis, Hodgkinson, Suzanne, Rozsa, Csilla, Hughes, Stella, Moore, Fraser, Shaw, Cameron, Butler, Ernest, Skibina, Olga, Gray, Orla, Kermode, Allan, Csepany, Tunde, Singhal, Bhim, Shuey, Neil, Piroska, Imre, Taylor, Bruce, Simo, Magdolna, Sirbu, Carmen-Adella, Sas, Attila, Butzkueven, Helmut, MSBase Study Group, UCL - (SLuc) Service de neurologie, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Kalincik, Toma, Diouf, Ibrahima, Sharmin, Sifat, Malpas, Charle, Spelman, Tim, Horakova, Dana, Havrdova, Eva Kubala, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Jokubaitis, Vilija, van der Walt, Anneke, Grand'Maison, Francoi, Sola, Patrizia, Ferraro, Diana, Shaygannejad, Vahid, Alroughani, Raed, Hupperts, Raymond, Terzi, Murat, Boz, Cavit, Lechner-Scott, Jeannette, Pucci, Eugenio, Van Pesch, Vincent, Granella, Franco, Bergamaschi, Roberto, Spitaleri, Daniele, Slee, Mark, Vucic, Steve, Ampapa, Radek, McCombe, Pamela, Ramo-Tello, Cristina, Prevost, Julie, Olascoaga, Javier, Cristiano, Edgardo, Barnett, Michael, Saladino, Maria Laura, Sanchez-Menoyo, Jose Lui, Hodgkinson, Suzanne, Rozsa, Csilla, Hughes, Stella, Moore, Fraser, Shaw, Cameron, Butler, Ernest, Skibina, Olga, Gray, Orla, Kermode, Allan, Csepany, Tunde, Singhal, Bhim, Shuey, Neil, Piroska, Imre, Taylor, Bruce, Simo, Magdolna, Sirbu, Carmen-Adella, Sas, Attila, and Butzkueven, Helmut

Subjects
Adult, Male, medicine.medical_specialty, Article, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, multiple sclerosis, treatment, prognosis, Internal medicine, medicine, Humans, Immunologic Factors, Disease Progression, Female, Fingolimod Hydrochloride, Glatiramer Acetate, Immunosuppressive Agents, Interferon-beta, Longitudinal Studies, Middle Aged, Proportional Hazards Models, 030212 general & internal medicine, Glatiramer acetate, Expanded Disability Status Scale, Proportional hazards model, business.industry, Multiple sclerosis, Hazard ratio, medicine.disease, Confidence interval, Cohort, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

ObjectiveTo test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.MethodsWe studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.ResultsA total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43–0.82, p = 0.0016), worsening of disability (0.56, 0.38–0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19–0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p = 10−9) and worsening of disability (0.81, 0.67–0.99, p = 0.043).ConclusionContinued treatment with MS immunotherapies reduces disability accrual by 19%–44% (95% CI 1%–62%), the risk of need of a walking aid by 67% (95% CI 41%–81%), and the frequency of relapses by 40–41% (95% CI 18%–57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.Classification of EvidenceThis study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.

Published
2021

3. Contribution of different relapse phenotypes to disability in multiple sclerosis

Author

Tamasine Stewart, Erik van Munster, Mark Slee, Patrizia Sola, Eva Havrdova, Dana Horakova, Orla Gray, Helmut Butzkueven, Cameron Shaw, Eugenio Pucci, Michael Barnett, Csilla Rozsa, Pamelo McCombe, Vincent Van Pesch, Maria Trojano, Franco Granella, Bhim Singhal, Fraser Moore, Javier Olascoaga, Neil Shuey, Pierre Duquette, Christina Ramo, Tomas Kalincik, Marc Girard, Freek Verheul, José Luis Sánchez Menoyo, Edgardo Cristiano, Pierre Grammond, Julie Prevost, Guillermo Izquierdo, Tim Spelman, Tatjana Petkovska-Boskova, Francois Grand'Maison, Celia Oreja-Guevara, Vahid Shaygannejad, Maria Laura Saladino, Suzanne Hodgkinson, Allan G. Kermode, Norma Deri, Alexandre Prat, Raymond Hupperts, Bruce V. Taylor, Gerardo Iuliano, Daniele Spitaleri, Cavit Boz, Roberto Bergamaschi, Raed Alroughani, Radek Ampapa, Vilija Jokubaitis, Jeannette Lechner-Scott, Maria Pia Amato, Olga Skibina, Alessandra Lugaresi, Steve Vucic, Ilya Kister, Stewart, Tamasine, Spelman, Tim, Havrdova, Eva, Horakova, Dana, Trojano, Maria, Izquierdo, Guillermo, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Sola, Patrizia, Shaygannejad, Vahid, Hupperts, Raymond, Alroughani, Raed, Oreja-Guevara, Celia, Pucci, Eugenio, Boz, Cavit, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Van Pesch, Vincent, Iuliano, Gerardo, Ramo, Cristina, Taylor, Bruce, Slee, Mark, Spitaleri, Daniele, Granella, Franco, Verheul, Freek, Mccombe, Pamela, Hodgkinson, Suzanne, Amato, Maria Pia, Vucic, Steve, Gray, Orla, Cristiano, Edgardo, Barnett, Michael, Sanchez Menoyo, Jose Lui, van Munster, Erik, Saladino, Maria Laura, Olascoaga, Javier, Prevost, Julie, Deri, Norma, Shaw, Cameron, Singhal, Bhim, Moore, Fraser, Rozsa, Csilla, Shuey, Neil, Skibina, Olga, Kister, Ilya, Petkovska-Boskova, Tatjana, Ampapa, Radek, Kermode, Allan, Butzkueven, Helmut, Jokubaitis, Vilija, Kalincik, Toma, and MSBase Study Group

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Multiple Sclerosis, Prognosi, multiple sclerosis, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, cohort studies, Recurrence, Internal medicine, medicine, Humans, Disabled Persons, Prospective Studies, Prospective cohort study, Expanded Disability Status Scale, business.industry, Incidence (epidemiology), Multiple sclerosis, Interferon-beta, Middle Aged, Prognosis, medicine.disease, Functional system, Phenotype, Confidence interval, relapse phenotype, 030104 developmental biology, Neurology, multiple sclerosi, Chronic Disease, Disease Progression, Physical therapy, Female, observational study, outcome research, Neurology (clinical), business, 030217 neurology & neurosurgery, cohort studie, Cohort study
Abstract

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Published
2016

4. Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in multiple sclerosis

Author

Francois Grand'Maison, Raed Alroughani, Jeannette Lechner-Scott, Vincent Van Pesch, Michael Barnett, Maria Trojano, Franco Granella, Raymond Hupperts, Cavit Boz, Jose Luis Sanchez-Menoyo, Daniele Spitaleri, Eugenio Pucci, Patrizia Sola, Pierre Grammond, Pierre Duquette, Tomas Kalincik, Helmut Butzkueven, Marc Girard, Steve Vucic, Tim Spelman, Guillermo Izquierdo, Alessandra Lugaresi, Myintzu Min, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Min, Myintzu, Spelman, Tim, Lugaresi, Alessandra, Boz, Cavit, Spitaleri, Daniele LA, Pucci, Eugenio, Grand'Maison, Francoi, Granella, Franco, Izquierdo, Guillermo, Butzkueven, Helmut, Sanchez-Menoyo, Jose Lui, Barnett, Michael, Girard, Marc, Trojano, Maria, Grammond, Pierre, Duquette, Pierre, Sola, Patrizia, Alroughani, Raed, Hupperts, Raymond, Vucic, Steve, Kalincik, Toma, Van Pesch, Vincent, and Lechner-Scott, Jeannette

Subjects
Adult, Male, medicine.medical_specialty, Treatment response, Databases, Factual, Mri imaging, Clinical Decision-Making, Drug Substitution, subclinical lesions, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, medicine, Humans, Disease-modifying therapy, magnetic resonance imaging, 030212 general & internal medicine, medicine.diagnostic_test, business.industry, Multiple sclerosis, Brain, Magnetic resonance imaging, Middle Aged, medicine.disease, Clinical neurology, Neurology, Current practice, Female, Neurology (clinical), Treatment decision making, Radiology, business, 030217 neurology & neurosurgery
Abstract

Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.

Published
2018

5. Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis

Author

Raed Alroughani, Maria Pia Amato, Patrizia Sola, Francois Grand'Maison, Eva Havrdova, Pierre Grammond, Ricardo Fernandez Bolanos, Murat Terzi, Bhim Singhal, Tomas Kalincik, Alessandra Lugaresi, Marc Girard, Jeannette Lechner-Scott, Dana Horakova, Freek Verheul, Alexandre Prat, Thor Petersen, Vahid Shaygannejad, Raymond Hupperts, Vilija Jokubaitis, Guillermo Izquierdo, Daniele Spitaleri, Jose Luis Sanchez-Menoyo, Maria Trojano, Franco Granella, Helmut Butzkueven, Mark Slee, Seyed Aidin Sajedi, Cavit Boz, Maria Pia Sormani, Pierre Duquette, Cristina Ramo, Eugenio Pucci, Alessio Signori, Celia Oreja-Guevara, Roberto Bergamaschi, Nastaran Majdinasab, Vincent Van Pesch, Bruce V. Taylor, Stella Hughes, Gerardo Iuliano, Maria Edite Rio, Ondokuz Mayıs Üniversitesi, Signori, Alessio, Izquierdo, Guillermo, Lugaresi, Alessandra, Hupperts, Raymond, Grand'Maison, Francoi, Sola, Patrizia, Horakova, Dana, Havrdova, Eva, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Boz, Cavit, Grammond, Pierre, Terzi, Murat, Singhal, Bhim, Alroughani, Raed, Petersen, Thor, Ramo, Cristina, Oreja-Guevara, Celia, Spitaleri, Daniele, Shaygannejad, Vahid, Butzkueven, Helmut, Kalincik, Toma, Jokubaitis, Vilija, Slee, Mark, Fernandez Bolaños, Ricardo, Sanchez-Menoyo, Jose Lui, Pucci, Eugenio, Granella, Franco, Lechner-Scott, Jeannette, Iuliano, Gerardo, Hughes, Stella, Bergamaschi, Roberto, Taylor, Bruce, Verheul, Freek, Edite Rio, Maria, Amato, Maria Pia, Sajedi, Seyed Aidin, Majdinasab, Nastaran, Van Pesch, Vincent, Sormani, Maria Pia, and Trojano, Maria

Subjects
0301 basic medicine, Male, Pediatrics, Delayed Diagnosis, Placebo-controlled study, Disease, Disability Evaluation, Primary progressive multiple sclerosis, 0302 clinical medicine, Longitudinal Studies, Prospective Studies, Registries, Prospective cohort study, Age Factors, clinical trial, Middle Aged, Multiple Sclerosis, Chronic Progressive, Prognosis, Latent class model, Natural history, Neurology, Latent Class Analysis, Disease Progression, Female, Adult, medicine.medical_specialty, Primary Progressive Multiple Sclerosis, 03 medical and health sciences, Primary progressive multiple sclerosis, clinical trials, disability, heterogeneity, long-term, trajectories, Sex Factors, medicine, Humans, Disabled Persons, long-term, clinical trials, business.industry, Multiple sclerosis, Bayes Theorem, Long term disability, medicine.disease, Primary progressive multiple sclerosi, 030104 developmental biology, disability, Physical therapy, Neurology (clinical), heterogeneity, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Signori, Alessio/0000-0001-6289-9144; Sajedi, Seyed Aidin/0000-0002-6704-9787; Jokubaitis, Vilija G./0000-0002-3942-4340; Shaygannejad, Vahid/0000-0002-6226-0161; Oreja-Guevara, Celia/0000-0002-9221-5716; amato, Maria Pia/0000-0003-3325-3760; Lugaresi, Alessandra/0000-0003-2902-5589; Majdinasab, Nastaran/0000-0001-5163-7210; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Petersen, Thor/0000-0001-5633-2600; Prat, Alexandre/0000-0001-6188-0580; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Slee, Mark/0000-0003-4323-2453; SORMANI, MARIA PIA/0000-0001-6892-104X; Trojano, Maria/0000-0002-6329-8946 WOS: 000432098100013 PubMed: 28382837 Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild (n = 143; 16.8%), moderate (n = 378; 44.3%), or severe (n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis. MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.

Published
2017

6. Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

Author

Suzanne Hodgkinson, Patrizia Sola, Jose Luis Sanchez-Menoyo, Mark Slee, Vahid Shaygannejad, Alexandre Prat, Jeannette Lechner-Scott, Lukas Sobisek, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Csilla Rozsa, Guillermo Izquierdo, Helmut Butzkueven, Fraser Moore, Pamela A. McCombe, Maria Laura Saladino, Murat Terzi, Vilija Jokubaitis, Cavit Boz, Eugenio Pucci, Raed Alroughani, Shlomo Flechter, Pierre Grammond, Roberto Bergamaschi, G. Iuliano, Daniele Spitaleri, Francois Grand'Maison, Ali Manouchehrinia, Pierre Duquette, Tomas Kalincik, Marc Girard, Radek Ampapa, Michael Barnett, Jan Hillert, Freek Verheul, Maria Trojano, Franco Granella, Edgardo Cristiano, Maria Pia Amato, Dana Horakova, Alessandra Lugaresi, Celia Oreja-Guevara, Steve Vucic, Eva Havrdova, Tim Spelman, Javier Olascoaga, Kalincik, Toma, Manouchehrinia, Ali, Sobisek, Luka, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Grammond, Pierre, Sola, Patrizia, Hupperts, Raymond, Grand'Maison, Francoi, Pucci, Eugenio, Boz, Cavit, Alroughani, Raed, Van Pesch, Vincent, Lechner-scott, Jeannette, Terzi, Murat, Bergamaschi, Roberto, Iuliano, Gerardo, Granella, Franco, Spitaleri, Daniele, Shaygannejad, Vahid, Oreja-guevara, Celia, Slee, Mark, Ampapa, Radek, Verheul, Freek, Mccombe, Pamela, Olascoaga, Javier, Amato, Maria Pia, Vucic, Steve, Hodgkinson, Suzanne, Ramo-tello, Cristina, Flechter, Shlomo, Cristiano, Edgardo, Rozsa, Csilla, Moore, Fraser, Sanchez-menoyo, Jose Lui, Saladino, Maria Laura, Barnett, Michael, Hillert, Jan, Butzkueven, Helmut, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, OMÜ, [Kalincik, Tomas] Univ Melbourne, CORE, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Kalincik, Tomas] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Jokubaitis, Vilija] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Manouchehrinia, Ali] Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden, [Sobisek, Lukas] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Univ Econ Prague, Dept Stat & Probabil, Winston Churchill Sq 1938-4, Prague 13067, Czech Republic, [Jokubaitis, Vilija] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Trojano, Maria] Univ Bari, Via Calefati 53, I-70122 Bari, Italy, [Izquierdo, Guillermo] Hosp Univ Virgen Macarena, Amador De Los Rios 48-50 4a, Seville 41003, Spain, [Lugaresi, Alessandra] Univ G DAnnunzio, Dept Neurosci Imaging & Clin Sci, Via Vestini, I-66100 Chieti, Italy, [Lugaresi, Alessandra] Univ Bologna, Dept Biomed & Neuromotor Sci, Via Vestini, I-66100 Bologna, Italy, [Girard, Marc] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Prat, Alexandre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Duquette, Pierre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Girard, Marc] CHUM, Montreal, PQ, Canada, [Prat, Alexandre] CHUM, Montreal, PQ, Canada, [Duquette, Pierre] CHUM, Montreal, PQ, Canada, [Girard, Marc] Univ Montreal, Montreal, PQ, Canada, [Prat, Alexandre] Univ Montreal, Montreal, PQ, Canada, [Duquette, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Ctr Readaptat Deficience Phys Chaudiere Appalache, 9500 Blvd Ctr Hosp, Levis, AB G6X 0A1, Canada, [Sola, Patrizia] Nuovo Osped Civile St Agostino Estense, Via Giardini 1355, I-41100 Modena, Italy, [Hupperts, Raymond] Zuyderland Ziekenhuis, Walramstr 23, NL-6131 BK Sittard, Netherlands, [Grand'Maison, Francois] Neuro Rive Sud, 4896 Boul Taschereau,Suite 250, Greenfield Pk, PQ J4V 2J2, Canada, [Pucci, Eugenio] Azienda Sanitaria Unica Reg Marche AV3, Via Santa Lucia 2, I-62100 Macerata, Italy, [Boz, Cavit] Karadeniz Tech Univ, Farabi Hosp, Med Fac, TR-61080 Trabzon, Turkey, [Alroughani, Raed] Amiri Hosp, POB 1661, Kuwait 73767, Kuwait, [Van Pesch, Vincent] Clin Univ St Luc, Ave Hippocrate,10 UCL10-80, BXL-1200 Brussels, Belgium, [Lechner-Scott, Jeannette] Univ Newcastle, Lookout Rd, Newcastle, NSW 2305, Australia, [Terzi, Murat] Ondokuz Mayis Univ, Fac Med, TR-55160 Kurupelit, Turkey, [Bergamaschi, Roberto] C Mondino Natl Neurol Inst, Via Mondino 2, I-27100 Pavia, Italy, [Iuliano, Gerardo] Osped Riuniti Salerno, Via S Leonardo, I-84100 Salerno, Italy, [Granella, Franco] Univ Parma, Via Gramsci 14, I-43100 Parma, Italy, [Spitaleri, Daniele] Azienda Osped Rilievo Nazl San Giuseppe Moscati A, I-83100 Avellino, Italy, [Shaygannejad, Vahid] Isfahan Univ Med Sci, Soffeh St, Esfahan 81744, Iran, [Oreja-Guevara, Celia] Hosp Univ La Paz, Paseo Castellana 261, Madrid 28050, Spain, [Slee, Mark] Flinders Med Ctr, Flinders Dr, Adelaide, SA 5042, Australia, [Ampapa, Radek] Nemocnice Jihlava, Vrchlickeho 59, Jihlava 58633, Czech Republic, [Verheul, Freek] Groene Hart Ziekenhuis, Bleulandweg 10, NL-2800 BB Gouda, Netherlands, [McCombe, Pamela] Royal Brisbane & Womens Hosp, 33 North St, Spring Hill, Qld 4000, Australia, [Olascoaga, Javier] Hosp Donostia, Paseo Begiristain, San Sebastian 20014, Spain, [Amato, Maria Pia] Univ Florence, Viale Morgagni 85, I-50134 Florence, Italy, [Vucic, Steve] Westmead Hosp, Hawkesbury Rd, Sydney, NSW 2145, Australia, [Hodgkinson, Suzanne] Liverpool Hosp, Elizabeth St,21, Liverpool, SA, Australia, [Ramo-Tello, Cristina] Hosp Germans Trias i Pujol, Crtra Canyet S-N, Badalona 8916, Spain, [Flechter, Shlomo] Assaf Harofeh Med Ctr, IL-70100 Zerifin, Israel, [Cristiano, Edgardo] Hosp Italiano Buenos Aires, Guise 1870, RA-1425 Buenos Aires, DF, Argentina, [Rozsa, Csilla] Jahn Ferenc Teaching Hosp, Koves 1, H-1101 Budapest, Hungary, [Moore, Fraser] Jewish Gen Hosp, 3755 Cote St Catherine, Montreal, PQ J7A 4T8, Canada, [Luis Sanchez-Menoyo, Jose] Hosp Galdakao Usansolo, Barrio Labeaga S-N, Galdakao 48660, Spain, [Laura Saladino, Maria] INEBA Inst Neurosci Buenos Aires, Guardia Vieja 4435,C1192AAW, Buenos Aires, DF, Argentina, [Hillert, Jan] Univ Sydney, Brain & Mind Ctr, 100 Mallett, Camperdown, NSW 2050, Australia, [Butzkueven, Helmut] Monash Univ, Box Hill Hosp, Dept Neurol, Melbourne, Vic, Australia, National Health and Medical Research Council, National Health and Medical Research Council (centre for research excellence), University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), Biogen, Novartis, Merck, Roche, Teva, Sanofi Genzyme, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Male, 0301 basic medicine, relapses, Databases, Factual, Failure, disability, multiple sclerosis, precision medicine, prediction, Disability Evaluation, Glatiramer acetate, 0302 clinical medicine, Natalizumab, Recurrence, Risk Factors, Medicine, Relapse, Progression, Precision medicine, Switch, Prognosis, Clinical Trial, Fingolimod, Multicenter Study, Treatment Outcome, Cohort, Disease Progression, Female, Algorithms, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, Registry, medicine.medical_specialty, Multiple Sclerosis, Interferon-beta therapy, External validity, Disability, Multiple sclerosis, Prediction, Relapses, Neurology (clinical), Databases, Young Adult, 03 medical and health sciences, Internal medicine, Journal Article, Humans, Multiple sclerosi, Internal validity, Factual, Disease burden, Demography, business.industry, Prognostic-factors, Reproducibility of Results, Discontinuation, 030104 developmental biology, Physical therapy, business, 030217 neurology & neurosurgery, Forecasting
Abstract

none 47 si Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. none Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

Published
2017

7. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

Author

Murat Terzi, Eugenio Pucci, Pamela A. McCombe, Alasdair Coles, Dana Horakova, Csilla Rozsa, Cavit Boz, Alessandra Lugaresi, Pierre Duquette, Michael Hutchinson, Michael Barnett, Raed Alroughani, Neil Robertson, Javier Olascoaga, Jeannette Lechner-Scott, Steve Vucic, Alexandre Prat, Patrizia Sola, Pierre Grammond, Guillermo Izquierdo, Maria Trojano, Franco Granella, Neil J Scolding, Raymond Hupperts, Vincent Van Pesch, Vilija Jokubaitis, J William L Brown, Mark Slee, Tünde Csépány, Daniele Spitaleri, Tim Spelman, Jose Luis Sanchez-Menoyo, Tjalf Ziemssen, Owen R Pearson, Tomas Kalincik, Marc Girard, Claire M Rice, Eva Havrdova, Suzanne Hodgkinson, Cristina Ramo, Alastair Wilkins, Helmut Butzkueven, Francois Grand'Maison, Edgardo Cristiano, Magdolna Simó, Radek Ampapa, Mark Willis, Freek Verheul, Roberto Bergamaschi, Christopher McGuigan, OMÜ, Brown, Will [0000-0002-7737-5834], Coles, Alasdair [0000-0003-4738-0760], Apollo - University of Cambridge Repository, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, Kalincik, Toma, Brown, J William L, Robertson, Neil, Willis, Mark, Scolding, Neil, Rice, Claire M, Wilkins, Alastair, Pearson, Owen, Ziemssen, Tjalf, Hutchinson, Michael, Mcguigan, Christopher, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Alroughani, Raed, Pucci, Eugenio, Sola, Patrizia, Hupperts, Raymond, Lechner-Scott, Jeannette, Terzi, Murat, Van Pesch, Vincent, Rozsa, Csilla, Grand'Maison, Françoi, Boz, Cavit, Granella, Franco, Slee, Mark, Spitaleri, Daniele, Olascoaga, Javier, Bergamaschi, Roberto, Verheul, Freek, Vucic, Steve, Mccombe, Pamela, Hodgkinson, Suzanne, Sanchez-Menoyo, Jose Lui, Ampapa, Radek, Simo, Magdolna, Csepany, Tunde, Ramo, Cristina, Cristiano, Edgardo, Barnett, Michael, Butzkueven, Helmut, and Coles, Alasdair

Subjects
Oncology, Adult, Male, medicine.medical_specialty, PLACEBO-CONTROLLED TRIAL, ORAL FINGOLIMOD, Antibodies, Monoclonal, Humanized, Klinikai orvostudományok, Cohort Studies, REGRESSION-MODEL, 03 medical and health sciences, Disability Evaluation, Young Adult, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, Fingolimod Hydrochloride, medicine, Clinical endpoint, SWITCH, Humans, Immunologic Factors, 030212 general & internal medicine, Alemtuzumab, Expanded Disability Status Scale, business.industry, Neurology (clinical), multiple sclerosis, prognosis, Multiple sclerosis, Hazard ratio, MS, Interferon-beta, Orvostudományok, medicine.disease, R1, Fingolimod, Databases, Bibliographic, Treatment Outcome, Immunology, Female, Neurology (clinical), business, CONTROLLED PHASE-3 TRIAL, 030217 neurology & neurosurgery, medicine.drug
Abstract

Lugaresi, Alessandra/0000-0003-2902-5589; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Ziemssen, Tjalf/0000-0001-8799-8202; Slee, Mark/0000-0003-4323-2453; Havrdova, Eva Kubala/0000-0002-9543-4359; Horakova, Dana/0000-0003-1915-0036; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Trojano, Maria/0000-0002-6329-8946; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Brown, William/0000-0002-7737-5834; Rice, Claire/0000-0002-9851-4426; Scolding, Neil/0000-0001-9177-1043; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; Vucic, Steve/0000-0002-8323-873X WOS: 000396336600016 PubMed: 28209331 Background Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. Methods In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6.5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Findings Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0.19 [95% CI 0.14-0.23] vs 0.53 [0.46-0.61], p

Published
2017

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