1. Predictors of disability accrual in multiple sclerosis patients
on first-line therapy
Multiple Sclerosis dataBase
Tim Spelman1, Vilija Jokubaitis1,2, Tomas Kalincik1,2, Daniela Travaglini3, Damiano Paolicelli4, Guillermo Izquierdo5, Pierre Duquette6, Marc Girard6, François Grand’Maison7, Pierre Grammond8, Raymond Hupperts9, Eva Havrdova10, Celia Oreja-Guevara11, Raed Alroughani 12, Thor Petersen13, Jeannette Lechner-Scott14, Cavit Boz15, Eugenio Pucci16, Vincent Van Pesch17, Roberto Bergamaschi18, Gerardo Iuliano19, Freek Verheul20, Michael Barnett21, Mark Slee22, Ricardo Fernandez-Bolaños23, Daniele LA Spitaleri24, Maria Pia Amato25, Edgardo Cristiano26, Eric Van Munster27, Marcela Fiol28, Suzanne Hodgkinson29, Orla Gray30, Maria Laura Saladino31, Danny Liew 32, Helmut Butzkueven1,2,33, Alessandra Lugaresi3# and Maria Trojano4# for the MSBase Study Group
1 Department of Medicine (RMH), The University of Melbourne, Parkville, Australia, 2 Department of Neurology, Royal Melbourne Hospital, Parkville, Australia, 3 MS Center, Department of Neuroscience and Imaging, University ‘G. d’Annunzio’, Chieti, Italy, 4 Department of Basic Medical sciences, Neuroscience and Sense Organs, University of Bari, Italy, 5 Hospital Universitario Virgen Macarena, Sevilla, Spain , 6 Hôpital Notre Dame, Montreal, Canada , 7 Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada, 8 Centre de réadaptation déficience physique Chaudière-Appalache, Levis, Canada, 9 Orbis Medical Centre, Sittard, The Netherlands, 10 Charles University, Prague, Czech Republic, 11 University Hospital La Paz, Madrid, Spain, 12 Amiri Hospital, Kuwait City, Kuwait, 13 Kommunehospitalet, Arhus C, Denmark, 14 John Hunter Hospital, Newcastle, Australia, 15 Karadeniz Technical University, Trabzon, Turkey, 16 Ospedale di Macerata, Macerata, Italy, 17 Cliniques Universitaires Saint-Luc, Brussels, Belgium, 18 Neurological Institute IRCCS Mondino, Pavia, Italy 19 Ospedali Riuniti di Salerno, Salerno, Italy , 20 Groene Hart ziekenhuis, Gouda, The Netherlands, 21 BMRI, Sydney, NSW, Australia, 22 Flinders University and Medical Centre, Adelaide, Australia, 23 Hospital Universitario Virgen de Valme, Seville, Spain, 24 AORN San Giuseppe Moscati, Avellino, Italy 25 Department of Neurology University of Florence, Florence, Italy, 26 Hospital Italiano, Buenos Aires, Argentina, 27 Jeroen Bosch Ziekenhuis, Den Bosch, The Netherlands, 28 FLENI, Buenos Aires, Argentina 29 Liverpool Hospital, NSW, Australia, 30 Craigavon Area Hospital, Portadown, UK 31 INEBA, Buenos Aires, Argentina, 32 Melbourne EpiCentre, University of Melbourne and Melbourne Health, Melbourne, Australia, 33 Department of Neurology, Box Hill Hospital, Monash University, Box Hill, Australia
Background
- Mean EDSS point increase at 5 and 8 years post-baseline was 0.47 (SD 1.49) and 0.68 (SD 1.63) respectively. Predictors of increasing median EDSS over the first 5 years from initiating first INFβ/GA on adjusted modelling included older age at baseline and larger Annualised Relapse Rate (ARR) across the 5-year period (Table 1).
- Increasing proportion of 5-year follow up on first IFNβ/GA initiation (coefficient -0.67; 95% CI -0.91, -0.42) or subsequent treatment initiation (coefficient -0.53; 95% CI -0.82, -0.24) were significantly associated with decreasing EDSS across the 5 year interval. Australian and Canadian sites predicted a median 5-year EDSS point change of (95% CI -0.74, -0.22; p<0.000) and (95% CI -0.41, -0.12; p<0.000) point respectively compared with Italian centres. Furthermore at least one pregnancy during the first 5 years post-baseline was predictive of a median 0.42-point decrease in EDSS (95% CI: -0.67, -0.17).
A principal objective when managing the clinical care of people with multiple sclerosis (MS) is to prevent the irreversible accumulation of neurological disability. Clinical trials provide evidence for clinical efficacy of disease modifying therapies (DMT) in reducing disease burden, however, the results of clinical trials are based on well-controlled environments, rigorous patient review, and do not necessarily reflect real-world patient characteristics or behaviours. Predictors of long-term EDSS score change in a cohort of patients treated with first-line disease modifying therapies in a real-world clinical setting is not known.
Objectives
5-year EDSS Outcome
EDSS unit change (95% CI) p-value
8-year EDSS Outcome
Predictor
Level
All DMT n = 3,367
Unadjusted model
All DMT, n = 3,367
#Adjusted model
All DMT, n = 1,870
Gender
Female
1.00
Male
0.00 (-0.14, 0.14) 1.00
0.10 (-0.23, 0.22) 0.112
0.00 (-0.16, 0.16) 1.000
-0.06 (-0.23, 0.11) 0.489
Age at baseline
– 10 year units
0.15 (0.08, 0.21) <0.000
0.20 (0.14, 0.26) <0.000
0.00 (-0.11, 0.11) 1.000
0.16 (0.07, 0.26) 0.001
Disease duration at baseline – 5 year units
0.10 (0.05, 0.15) 0.000
0.04 (-0.01, 0.09) 0.109
0.00 (-0.07, 0.07) 1.000
0.07 (0.01, 0.04) 0.035
Post-baseline relapses
ARR in first 5/8 years of follow-up
0.63 (0.56, 0.69) <0.000
0.63 (0.50, 0.75) <0.000
0.57 (0.37, 0.78) <0.001
0.47 (0.26, 0.68) <0.000
Proportion of 5/8 year follow-up on first-line DMT (continuous)
-0.55 (-0.73, -0.37) <0.000
-0.67 (-0.91, -0.42) <0.000
-0.80 (-1.01, -0.59) <0.000
-0.32 (-0.56, -0.07) 0.012
Proportion of 5/8 year follow-up on non-firstline DMT
0.51 (0.29, 0.74) <0.000
-0.53 (-0.82, -0.24) <0.000
-0.52 (-0.79, -0.25) <0.000
-0.17 (-0.38, 0.04) 0.104
Number of pregnancies in the first 5 years of follow-up ≥1
0.00 (-0.28, 0.28) 1.00
-0.42 (-0.67, -0.17) 0.001
-0.50 (-1.00, ) 0.049
-0.29 (-0.62, 0.04) 0.083
male
Co-linear
- To identify predictors of expanded disability status scale (EDSS) change in patients with relapsing-remitting multiple sclerosis (RRMS) treated with any interferon-beta (IFNβ) preparation or glatiramer acetate (GA) as a first therapy.
Methods
Data were derived from the MSBase Registry, an international online database accumulator that was established in 2004 and collects disease related information from consenting patients attending MS clinics in 28 countries.
Five and eight year proportions apply only to that subset of patients followed up for at least 5 and 8 years respectively. Only patients who were followed up for the entire year being analysed could contribute to the individual year ARRs. Annual percentages of pregnancies use women still in follow-up at a certain post-baseline year as denominator. Five and eight year EDSS is defined as median EDSS recorded within +/- 6 months of the 5 year and 8 year post-baseline marks respectively
Predictors of 5 and 8 year EDSS change were investigated using unadjusted and adjusted quantile median regression. As EDSS change demonstrated significant departures form normality using a Shapiro-Wilk normality test and was resistant to common transformations (log- or square-root transformation), quantile regression of the median was preferred over simple linear regression of the mean to model the influence of baseline demography and disease severity and within-interval treatment and relapse activity on both 5 and 8 year EDSS change. Collinearity and interactions between model covariates were examined using a likelihood ratio test. A He & Zhu Lack-Of-Fit test for Quantile Regression was used to assess goodness of fit for each model. Competing quantile median regression models were compared using an Akaike Information Criterion to assist in the identification of the most parsimonious model.
Table 1 – Predictors of 5 and 8-year EDSS change
Quantile median regression analysis.
#Adjusted modelling included adjustments for baseline EDSS score and clinic country.
EDSS Expanded disability status scale; CI Confidence Interval; DMT Disease Modifying Therapy
Conclusions
Results
- In a real-world setting, high ARR, particularly early on-treatment relapse activity, is a poor prognostic indicator. Pregnancy and the use of first-line disease modifying therapy, however, are associated with a suggested protective effect against future EDSS increase. These results provide a rationale for potentially switching therapy in patients with highly active disease whilst on therapy in early RRMS to avoid a poor future prognosis.
12,679 registry patients from 61 clinics across 26 countries recording IFNβ or GA as first DMT were followed up for a median 5.83 years (IQR: 2.82, 9.66). 3,367 (26.6%) were still being follow-up in the MSBase registry at 5 years post baseline and recorded a 5-year EDSS score, and similarly 1,871 (14.8%) were followed up for at least 8 years and recorded an 8-year EDSS score. 9,432 (74.4%) of patients were followed-up in clinics within Italy, Canada, Spain, the Netherlands, or Australia.
The mean annualised relapse rate (ARR), defined as the number of relapses per year of follow-up, was 0.22 (SD 0.63) across the entire follow-up period whilst 5 and 8-year ARR were 0.38 (SD 0.45) and 0.36 (SD 0.38) respectively. By comparison, mean ARRs for on-treatment relapses were 0.41 (SD 0.54) and 0.39 (SD 0.44) for the 5-year and 8-year post baseline intervals respectively.
Of the 12,679 patients for whom IFNβ/GA was their first DMT, 8,115 (64.0%) patients discontinued first IFNβ/GA during the observation period. Mean proportion of follow-up time on first IFNβ/GA was 0.66 (SD 0.36) and 0.45 (SD 0.41) for 5 and 8-year follow-up periods, respectively. Mean proportion of follow-up on a subsequent therapy (including an alternate IFNβ/GA, natalizumab or fingolimod) was 0.21 (SD 0.33) and 0.60 (SD 0.60) for the 5 and 8-year follow-up periods, respectively.
Acknowledgements and Disclosures
This study was supported by a project grant from the NHMRC ( ). In addition, this study was supported by the MSBase Foundation, a not-for-profit organisation that receives support from Merck Serono, Biogen Idec, Novartis, Bayer, Genzyme, Sanofi, and Bio-CSL. Vilija Jokubaitis’ salary is supported by NHMRC project grant # and has received conference travel support from Novartis. Timothy Spelman received compensation for travel from Biogen Idec. Tomas Kalincik received compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck Serono. Daniela Travaglini did not declare any competing interests. Damiano Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Bayer-Schering, Novartis and TEVA. Guillermo Izquierdo received speaking honoraria from Biogen-Idec, Novartis, Sanofi, Merck Serono and Teva. Pierre Duquette did not declare any competing interests. Marc Girard received consulting fees from Teva Canada Innovation, Biogen Idec, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD Serono. Dr Girard has also received a research grant from Canadian Institutes of Health Research. Francois Grand’Maison received honoraria from Biogen Idec, Genzyme, Novartis and Roche. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen Idec advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Raymond Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen-Idec, Genzyme-Sanofi and Teva, research funding from Merck-Serono and Biogen-Idec, and speaker honoraria from Sanofi-Genzyme. Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Celia Oreja-Guevara received honoraria as consultant on scientific advisory boards from Biogen-Idec, Bayer-Schering, Merck-Serono, Teva and Novartis; has participated in clinical trials/other research projects by Biogen-Idec, GSK, Teva and Novartis. Raed Alroughani received honororia from Biologix, Bayer, Merck Sorono, GSK and Novartis, and served on advisory board for Biologix, Novartis and Merck Sorono. Thor Petersen received funding or speaker honoraria from Biogen Idec, Merck Serono, Novartis, Bayer Schering, Sanofi-Aventis, Roche, and Genzyme. Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Cavit Boz has received travel grants from Merck Serono, Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Eugenio Pucci served on scientific advisory boards for Genzyme and Biogen-Idec; he has received honoraria and travel grants from Sanofi Aventis, UCB, Lundbeck, Novartis, Bayer Schering, Biogen Idec, Merck Serono, Genzyme and Teva; he has received travel grants from Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Vincent van Pesch has served on advisory boards for Biogen Idec and Genzyme; has received travel grants from Biogen Idec, Bayer Schering, Sanofi Aventis, Merck Serono and Novartis Pharma ; has received consultancy fees from Biogen Idec, Teva and Novartis Pharma; has received research grants from Bayer Schering. Roberto Bergamaschi received speaker honoraria from Bayer Schering, Biogen, Novartis, Sanofi-Aventis, Teva; research grants from Bayer Schering, Biogen, Novartis, Sanofi-Aventis, Teva; congress and travel expense compensations from Bayer Schering, Biogen, Novartis, Sanofi-Aventis, Teva. Gerardo Iuliano had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva. Freek Verheul is an advisory board member for Teva Biogen Merck Serono and Novartis. Michael Barnett has served on scientific advisory boards for Biogen-Idec, Novartis and Genzyme and has received conference travel support from Biogen-Idec and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen-Idec, Merck-Serono and Novartis. Mark Slee has participated in, but not received honoraria for, advisory board activity for Biogen Idec, MerckSerono, BayerSchering, Sanofi Aventis and Novartis. Ricardo Fernández-Bolaños did not declare any competing interests. Daniele La Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono. Maria Pia Amato received honoraria as consultant on scientific advisory boards by Biogen-Idec, Bayer-Schering, Merck-Serono, Teva and Sanofi-Aventis; has received research grants by Biogen-Idec, Bayer-Schering, Merck-Serono, Teva and Novartis. Edgardo Cristiano received honoraria as consultant on scientific advisory boards by Biogen-Idec, Bayer-Schering, Merck-Serono, Genzyme and Novartis; has participated in clinical trials/other research projects by Merck-Serono, Roche and Novartis. Erik van Munster did not declare any competing interests. Marcela Fiol received honoraria from Merck-Serono and Bayer. Suzanne Hodgkinson did not declare any competing interests. Orla Gray received honoraria as consultant on scientific advisory boards for Biogen Idec, Merck Serono and Novartis; has received travel grants from Biogen Idec, Merck Serono and Novartis; has participated in clinical trials by Biogen Idec and Merck Serono. Maria Laura Saladino did not declare any competing interests. Danny Liew did not declare any competing interests. Helmut Butzkueven has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen Idec and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen Idec and Novartis, and has received research support from Merck Serono, Novartis and Biogen Idec. Alessandra Lugaresi is a Bayer Schering, Biogen Idec, Genzyme, Merck Serono Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla and was a Consultant of “Fondazione Cesare Serono”. Maria Trojano has served on scientific advisory boards for Biogen Idec, Novartis and Merck Serono, received speaking honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva and Novartis; has received research grants from Biogen-Idec, Merck-Serono, and Novartis.
The MSBase Registry is operated by the independent MSBase Foundation, a non profit organisation based in Melbourne, Australia