Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis
© The Author(s). 2017
Received: 8 March 2017
Accepted: 28 April 2017
Published: 26 June 2017
Fingolimod is an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) and there is class I evidence that it is superior to standard care in reducing relapse rate. However, real-world data investigating its effectiveness and potential predictors of response are still scarce.
To estimate (i) the proportion of fingolimod-treated patients who achieved the no evidence of disease activity (NEDA-3) status; and (ii) to determine which baseline (i.e. at treatment start) clinical and magnetic resonance imaging (MRI) variables were associated with better outcomes.
We collected clinical and MRI data of RRMS patients treated with fingolimod and followed-up for 24 months. The proportion of patients who had NEDA-3 - i.e. absence of relapses, sustained Expanded Disability Status Scale (EDSS) worsening and radiological activity on MRI - was estimated. A Cox proportional hazard model was carried out to investigate which baseline characteristics were associated with the NEDA status at follow-up.
We collected data of 201 patients who started fingolimod. Of them, 24 (12%) were treatment-naïve, 115 (58%) were switched after failing a self-injectable drug, and 60 (30%) switching from natalizumab. Five patients who discontinued fingolimod early (within 3 months) (bradycardia, n = 2; leukopaenia, n = 2; macular oedema, n = 1) were removed from the analysis. At follow-up, 118 (60%) patients achieved the NEDA-3 status, while 78 experienced clinical and/or MRI activity. The risk of not achieving the NEDA-3 status was associated with higher baseline EDSS score (hazard ratio [HR] = 1.18, p = 0.024) and more relapses in the 12 months prior to fingolimod start (HR = 1.61, p = 0.014).
Our findings suggest that fingolimod may lead to a better control of the disease if started in patients with a less aggressive disease (i.e. fewer pre-treatment relapses and milder disability level), thus supporting its possible role as an early treatment for MS.
KeywordsMultiple sclerosis  Clinical outcome measures  Therapeutics  Fingolimod
Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating, immune mediate disease of the central nervous system (CNS) that affects almost 2.1 million people worldwide. At least 70–75% of these patients are suffering from the relapsing-remitting type of MS (RRMS) that is characterized by acute inflammatory episodes of CNS demyelination . Relapses may be also associated with disability worsening , therefore the main therapeutic aim in RRMS is to control disease activity by reducing the number of relapses and preventing disability progression . Relapses and disability worsening assessed by the Expanded Disability Status Scale (EDSS)  are indeed currently accepted as main endpoints in large, phase III, randomized clinical trials . More recently, the No Evidence of Disease Activity (NEDA-3) has been proposed as a new outcome measure for RRMS based on (i) absence of relapses; (ii) absence of sustained disability worsening, defined as ≥1-point increase in EDSS score confirmed 3-6 months apart; (iii) absence of radiological activity, seen on magnetic resonance imaging (MRI) as gadolinium-enhancing lesions or new/enlarged T2-hyperintense lesions .
Fingolimod 0.5 mg (Gilenya®, FTY720, Novartis Pharma AG, Basel Switzerland) is a sphingosine-1-phosphate receptor modulator which has been approved as once daily orally administered therapy for RRMS . As evidenced by the phase III trials FREEDOMS, FREEDOMS II and TRANSFORMS, fingolimod significantly reduces relapses rate compared with both placebo and intramuscular Interferon beta (IFNB)-1a [8–10]. Moreover, fingolimod is superior to both placebo and IFNB-1a with regard to MRI-related measures, namely the number of new or enlarged lesions on T2-weighted images, gadolinium-enhancing lesions, and brain-volume loss [7–9]. A post-hoc analysis of the FREEDOMS trial also demonstrated a higher proportion of patients treated with fingolimod achieving the NEDA-3 status than those treated with placebo (33 vs. 13%) .
However, real world data on the effectiveness of fingolimod are still scarce and post-marketing studies were mainly designed to either compare fingolimod with other DMTs (self-injectable drugs, natalizumab, dimethyl fumarate) [12–20] or investigate the role of fingolimod as an exit strategy after natalizumab discontinuation [21–27]. Therefore, here we aimed at estimating the proportion of patients achieving the NEDA-3 status in a real-world population. Baseline characteristics associated with a better chance to achieve the NEDA-3 status were also investigated.
Study design and participants
This was a 24-month, retrospective, independent, single-centre, post-marketing, study. Given its retrospective design, this study in no way interfered in the care received by patients. The present study was conducted in accordance with specific national laws, the International Conference on Harmonization Guidelines of Good Clinical Practice and the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
We collected clinical and MRI data of patients with RRMS according to revised McDonald criteria  and starting treatment with fingolimod at the MS Centre of S. Andrea Hospital in Rome according to the Italian regulatory criteria. Only patients having a regular follow-up for at least 24 months from fingolimod start were included in the present study.
Demographic and clinical information were collected at baseline visit (i.e. at fingolimod start) and included sex, time since first symptom, number of exacerbations in the previous year, EDSS score, treatment history, presence of contrast-enhancing lesions at MRI scan of brain and spinal cord.
This study was conducted in accordance with the International Conference on Harmonization Guidelines of Good Clinical Practice and the Declaration of Helsinki. In no way did this study interfere in the Care received by patients. The Ethical Committee of Sapienza University provided exemption of approval for post-authorisation observational studies. Each patient involved in this study signed an informed consent before collecting, storing and analysing individual data.
Clinical relapses and changes in EDSS score during treatment, as well as any other medical event occurred as a result of fingolimod treatment, were recorded.
We collected also MRI data after approximately 6, 12, and 24 months of fingolimod treatment, focusing on the presence of gadolinium-enhancing lesions on post-contrast T1-weighted scans and the appearance of new hyperintense lesions on T2-weighted sequences (when compared to the previous scan). Unscheduled MRI scans were also performed, if necessary, to confirm suspect relapses.
To ensure a more reliable comparison between each scan, images were acquired in the same outpatient centre using a superconducting 1.5 T magnet (GE Excite), according to published guidelines . Reproducible slice positioning was maintained throughout the follow-up using the same anatomical landmarks for each patient. All MRI scans were interpreted by experienced radiologists unaware of clinical data.
As primary outcome, we estimated the proportions of patients who achieved the NEDA-3 status at the end of the 24-month follow-up. As mentioned, NEDA-3 is a combined measure defined as absence of either a clinical relapse, or disability worsening, or radiological activity . The NEDA-3 has been recently proposed as a principal aim in management of relapsing MS because it leads to better long-term outcomes [6–30].
We also analyzed individually the subcomponents of disease activity as secondary outcomes (time to relapse, disability worsening, radiological activity).
A relapse was defined as the appearance or reappearance of one or more symptoms attributable to MS, accompanied by objective deterioration on neurological examination lasting at least 24 h, in the absence of fever and preceded by neurological stability for at least 30 days .
Disability worsening was defined as ≥1.5-point increase (if baseline EDSS score was 0), ≥1.0-point increase (if baseline EDSS score was <5.5), or ≥0.5-point increase (if baseline EDSS score was ≥5.5) confirmed 6 months apart .
Radiological activity was defined as the occurrence of ≥1 GD-enhancing lesion or ≥1 new T2-hyperintense lesion. We decided to not consider enlarged T2-hyperintense lesions since a previous study demonstrated a poor between-rater agreement for this metric under routine clinical setting .
All values are expressed as mean (standard deviation, SD), median (range), or proportion, as appropriate.
We considered the following baseline (i.e. at fingolimod start) characteristics: sex, age, time since first symptom, EDSS score, number of relapses in the previous 12 months, presence of gadolinium-enhancing lesions at brain MRI scan. The multiple sclerosis severity score (MSSS) was also estimated for each participant to obtain a variable accounting for the disease severity .
Patients were also divided according to their treatment history as ‘treatment-naïve’, ‘switchers for failure’, i.e. switching from self-injectable DMTs, ‘switchers for safety’, i.e. switching from natalizumab. Between-subgroup differences were tested using the Kruskall-Wallis test and the Chi-squared test for continuous and dichotomous variables, respectively.
A time-to-event multivariable model was performed to investigate which baseline characteristics were associated with NEDA-3 status and its subcomponents at the end of the 24-month follow-up. Specifically, we inserted the counterpart of NEDA-3 (i.e. the occurrence of any evidence of disease activity, such as relapses, disability worsening and/or radiological activity) as dependent variable in a Cox proportional hazards regressions. The aforementioned baseline patients’ characteristics and interaction terms were added in the model as independent variables in a stepwise fashion (for predictor inclusion: F ≥ 1 and p ≤ 0.05; for exclusion: F < 1 and p > 0.10). As main time variable we used the length of the observation (in months), between the baseline and the last visit over the 24-months period, or outcome reach, whichever came first.
Patients lost to follow-up and those who discontinued fingolimod within the first three months of treatment were excluded from the main analysis. A post-estimation sensitivity analysis was also done by applying the best-case scenario (i.e. the NEDA-3 status) and worst-case scenario (i.e. any evidence of disease activity due to relapses, and disability worsening and/or radiological activity) to patients who were excluded from the case-base analysis.
All p-values less than 0.05 in either directions were considered as significant. Analyses were carried out using a PC version of Statistical Package for Social Sciences 16.0 (IBM SPSS, Chicago, IL, USA).
Baseline characteristics of patients (n = 201)
Switchers for failure
Switchers for safety
Gender, n (%)
Time since first symptom, years
No. of relapses in previous year
Presence of gadolinium-enhancing lesions, n (%)
The disability level, assessed by EDSS score, was higher in switchers for safety than in both switchers for failure (p < 0.001) and treatment-naïve (p < 0.05). The number of relapses in previous year was lower in switchers for safety than in both switchers for failure (p < 0.05) and treatment-naïve (p < 0.05). Sex, age, presence of gadolinium-enhancement at baseline MRI scan did not differ between subgroups defined by treatment history.
Five (2.5%) patients who discontinued fingolimod within 3 months from treatment start were removed from subsequent analyses. They were discontinued early for the following reasons: bradycardia, n = 2; leukopaenia, n = 2; macular oedema, n = 1. There was no patient lost to follow-up.
Among the 78 patients who had any evidence of disease activity, 15 experienced relapses, disability worsening and radiological activity; 23 relapsed with concomitant radiological activity, but without disability worsening; three relapsed with subsequent disability worsening, but without evidence of radiological activity; 1 had MRI activity and subsequent disability worsening, but without any evident clinical exacerbation; the remaining 36 patients had only either relapses (n = 8), disability worsening (n = 8), or radiological activity (n = 20).
Baseline variables associated with NEDA-3 status
Stepwise Cox proportional hazard regression model showing baseline variables associated with evidence of disease activity (NEDA-3) at 24 months after fingolimod start (n = 196)
95% confidence intervals
Expanded Disability Status Scale (EDSS) score (each step)
Relapses (each unit)
Inserted variables that did not contribute to fit the model were as follows: sex, age, time since first symptom, multiple sclerosis severity score (MSSS), presence of gadolinium–enhancing lesions at brain MRI scan.
The post-estimation sensitivity analysis showed that all these estimates were not altered in the best-case and worst-case scenarios (data not shown).
The aim of the present study was two-fold: estimating the proportion of patients achieving the NEDA status in a real-world population taking fingolimod and identifying baseline characteristics associated with a better outcome after 24 months of follow-up.
We found 60% of patients achieving the NEDA-3 status, an almost double proportion with respect to post-hoc analysis (33%) from the FREEDOMS trial . This confirms data from other post-marketing studies showing that the effectiveness of DMTs for MS is often better than their efficacy . A very similar proportion (60%) of patients achieving NEDA-3 was instead reported in a 4.5-year extension phase of TRANSFORMS trial after switching from IFNB-1a to fingolimod .
The discrepancy in proportions with NEDA-3 between experimental and real world setting might be explained by the different way to assess relapses, change in disability and radiological activity . Most relapses were assessed retrospectively in our study, while new symptoms must have been coupled with an increase in EDSS score or functional systems to be defined as a qualified relapses in FREDOMS and TRANSFORMS trials [8, 9]. The time required to confirm disability worsening was 6 months in our study versus 3 months in RCTs. Another difference is that we did not consider enlarged T2 lesions in the assessment of MRI activity, since a previous study demonstrated a poor between-rater agreement for this metric under routine clinical setting .
As expected, patients switching from natalizumab (switchers for safety) were at higher risk of not achieving the NEDA-3 status . We also found a trend (p = 0.08) towards a worse outcome in patients who switched from self-injectable DMTs (switchers for failure) with respect to treatment-naïve patients, supporting previous suggestions about the role of fingolimod as first treatment option [11, 20].
However, there were relevant baseline differences across subgroups of patients defined by previous treatment history that are known to act as treatment effect modifiers . We found indeed that fingolimod may lead to a better control of the disease if started in patients with a less aggressive disease, i.e. fewer pre-treatment relapses and milder disability level, regardless of previous treatment history.
Our findings are partially in contrast with the subgroup analyses of the FREEDOMS and TRANSFORMS trials, where the pre-treatment number of relapses did not affect the on-treatment annualised relapse rate [37, 38] and patients with EDSS score ≤3.5 did not have a significant reduction in risk of disability progression compared to placebo . Moreover, subgroup analysis of pivotal trials did not reveal any clear advantage for treatment-naïves with respect to previously treated patients, except for a higher relative reduction in relapse rate for treatment-naive rapidly evolving severe RRMS patients (i.e. patients who had ≥2 relapses within the year before baseline and ≥1 gadolinium-enhancing lesion at baseline) .
However, these contradictions are attributable to the intrinsic differences between the NEDA-3 status, based on the absolute absence of clinical and radiological activity, and outcomes considered in RCTs, based on quantitative differences in outcomes with respect to placebo or an active comparator [5, 6, 34]. Lastly, we have also to bear in mind that the potential predictors of response to therapy are indeed strictly dependent on the outcome measure considered as criterion of response .
Our study suffers from some limitations, mainly due its retrospective design and lack of control group. Despite the adoption of a very stringent outcome such as NEDA-3, we were not able to estimate brain volume loss, thus missing the chance to obtain data on NEDA-4; therefore our data are mainly weighted towards focal inflammatory activity rather than neurodegeneration processes . Another drawback of our study is the short follow-up (24 months); in this regard, further effort is required to determine whether the NEDA-3 status achieved after 24 months of fingolimod may be sustained even in a longer-term follow-up. Long-term data suggest indeed that the NEDA-3 status is difficult to maintain after 7–10 years from starting self-injectable DMTs, while a longer-term disease remission has been described with natalizumab, but with a greater burden in terms of health cost, surveillance, and averse events [30, 41, 42].
Our study suggests that patients with fewer pre-therapy relapses and milder disability level are the best candidates for a more effective treatment with fingolimod. We hope that these findings might contribute to a more accurate identification of patients likely to have the maximum benefit from the fingolimod treatment in real world practice, despite several biases due to the retrospective study design.
This research was carried out using information collected during normal patient care, and extra time spent in data analysis and interpretation was part of educational programmes within the University; no external source of funding was required.
Availability of data and materials
The dataset supporting the conclusions of this article is available upon reasonable request from the corresponding author.
MG: acquisition of the data, analysis and interpretation of the clinical data; AL: acquisition of the data, analysis and interpretation of the clinical data; LP: conception and design of the study, analysis and interpretation of the data; drafting a significant portion of the manuscript/figures; MNH: analysis and interpretation of the MRI data; CP: conception and design of the study, drafting a significant portion of the manuscript/figures. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The Ethical Committee of Sapienza University provided exemption of approval for post-authorisation observational studies. Each patient involved in this study signed an informed consent before collecting, storing and analysing individual data.
LP has received consulting and/or lecture fees and travel grant from Biogen, Genzyme, Novartis and Teva. CP has received consulting and/or lecture fees and/or research funding and travel grant from Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva. The other Authors have nothing to disclose.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Pugliatti M. The epidemiology of multiple sclerosis in Europe. Eur J Neurol. 2006;13:700–22.View ArticlePubMedGoogle Scholar
- Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61:1528–32.View ArticlePubMedGoogle Scholar
- Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis-a quiet revolution. Nat Rev Neurol. 2015;11(3):134–42.View ArticlePubMedPubMed CentralGoogle Scholar
- Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.View ArticlePubMedGoogle Scholar
- Montalban X. Review of methodological issues of clinical trials in multiple sclerosis. J Neurol Sci. 2011;311 Suppl 1:S35–42.View ArticlePubMedGoogle Scholar
- Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4:329–33.View ArticlePubMedGoogle Scholar
- http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002202/WC500104530.pdf. Accessed 28 Feb 2017.
- Kappos L, Radue EW, O’Connor P, FREEDOMS Study Group, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.View ArticlePubMedGoogle Scholar
- Cohen JA, Barkhof F, Comi G, TRANSFORMS Study Group, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.View ArticlePubMedGoogle Scholar
- Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.View ArticlePubMedGoogle Scholar
- Nixon R, Bergvall N, Tomic D, et al. No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing– remitting multiple sclerosis. Adv Ther. 2014;31:1134–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Braune S, Lang M, Bergmann A, NTC Study Group. Second line use of fingolimod is as effective as natalizumab in a German out-patient RRMS-cohort. J Neurol. 2013;260:2981–5.View ArticlePubMedPubMed CentralGoogle Scholar
- He A, Spelman T, Jokubaitis V, et al. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis. JAMA Neurol. 2015;72:405–13.View ArticlePubMedGoogle Scholar
- Kalincik T, Horakova D, Spelman T, et al. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol. 2015;77:425–35.View ArticlePubMedGoogle Scholar
- Barbin L, Rousseau C, Jousset N, et al. Comparative efficacy of fingolimod vs natalizumab: a French multicenter observational study. Neurology. 2016;86:771–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Baroncini D, Ghezzi A, Annovazzi PO, et al. Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies. Mult Scler. 2016;22:1315–26.View ArticlePubMedGoogle Scholar
- Braune S, Lang M, Bergmann A, NTC Study Group. Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis. J Neurol. 2016;263:327–33.View ArticlePubMedGoogle Scholar
- Hersh CM, Love TE, Cohn S, Hara-Cleaver C, Bermel RA, Fox RJ, Cohen JA, Ontaneda D. Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up. Mult Scler Relat Disord. 2016;10:44–52.View ArticlePubMedGoogle Scholar
- Kalincik T, Brown JW, Robertson N, MSBase Study Group, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017;4422(17):30007–8.Google Scholar
- Prosperini L, Saccà F, Cordioli C, et al. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis. J Neurol. 2017;264(2):284–94.View ArticlePubMedGoogle Scholar
- Cohen M, Maillart E, Tourbah A, Club Francophone de la Sclérose en Plaques Investigators, et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436–41. doi:https://doi.org/10.1001/jamaneurol.2013.6240.View ArticlePubMedGoogle Scholar
- Jokubaitis VG, Li V, Kalincik T, MSBase Study Group, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014;82(14):1204–11.View ArticlePubMedPubMed CentralGoogle Scholar
- Comi G, Gold R, Dahlke F, et al. Relapses in patients treated with fingolimod after previous exposure to natalizumab. Mult Scler. 2015;21(6):786–90.View ArticlePubMedGoogle Scholar
- Iaffaldano P, Lucisano G, Pozzilli C, Italian iMed-Web database, et al. Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis. Brain. 2015;138(Pt11):3275–86.View ArticlePubMedGoogle Scholar
- Kappos L, Radue EW, Comi G, TOFINGO study group, et al. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29–39.View ArticlePubMedPubMed CentralGoogle Scholar
- Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, Svenningsson A, Piehl F. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016;79(6):950–8. doi:https://doi.org/10.1002/ana.24651.View ArticlePubMedGoogle Scholar
- Fragoso YD, Alves-Leon SV, Becker J, et al. Safety of switching from natalizumab straight into fingolimod in a group of JCV-positive patients with multiple sclerosis. Arq Neuropsiquiatr. 2016;74:650–52.Google Scholar
- Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.View ArticlePubMedPubMed CentralGoogle Scholar
- Filippi M, Rocca MA, Bastianello S, et al. Guidelines from the Italian neurological and Neuroradiological societies for the use of magnetic resonance imaging in daily life clinical practice of multiple sclerosis patients. Neurol Sci. 2013;34:2085–93.View ArticlePubMedGoogle Scholar
- Rotstein DL, Healy BC, Malik MT, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72:152–8.View ArticlePubMedGoogle Scholar
- Rio J, Nos C, Tintoré M, et al. Defining the response to interferon beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59:344–52.View ArticlePubMedGoogle Scholar
- Altay EE, Fisher E, Jones SE, et al. Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic. JAMA Neurol. 2013;70:338–44.View ArticlePubMed CentralGoogle Scholar
- Roxburgh RH, Seaman SR, Masterman T, et al. Multiple sclerosis severity score: using disability and disease duration to rate disease severity. Neurology. 2005;64:1144–51.View ArticlePubMedGoogle Scholar
- Trojano M, Tintore M, Montalban X, et al. Treatment decisions in multiple sclerosis - insights from real-world observational studies. Nat Rev Neurol. 2017;13(2):105–18.View ArticlePubMedGoogle Scholar
- Cohen JA, Khatri B, Barkhof F, TRANSFORMS Study Group. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87(5):468–75.View ArticlePubMedGoogle Scholar
- Signori A, Schiavetti I, Gallo F, Sormani MP. Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. 2015;22:960–6.View ArticlePubMedGoogle Scholar
- Devonshire V, Havrdova E, Radue EW, FREEDOMS study group, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012;11(5):420–8.View ArticlePubMedGoogle Scholar
- Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol. 2013;260(8):2023–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Portaccio E, Zipoli V, Siracusa G, Sorbi S, Amato MP. Response to interferon beta therapy in relapsing-remitting multiple sclerosis: a comparison of different clinical criteria. Mult Scler. 2006;12:281–6.View ArticlePubMedGoogle Scholar
- Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of’no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22:1297–05.Google Scholar
- De Stefano N, Stromillo ML, Giorgio A, et al. Long-term assessment of no evidence of disease activity in relapsing-remitting MS. Neurology. 2015;85:1722–3.View ArticlePubMedGoogle Scholar
- Prosperini L, Fanelli F, Pozzilli C. Long-term assessment of No evidence of disease activity with natalizumab in relapsing multiple sclerosis. J Neurol Sci. 2016;364:145–7.View ArticlePubMedGoogle Scholar