Article Text

Download PDFPDF

Systematic literature review and network meta-analysis in highly active relapsing–remitting multiple sclerosis and rapidly evolving severe multiple sclerosis
  1. Eline Huisman1,
  2. Katerina Papadimitropoulou1,
  3. James Jarrett2,
  4. Matthew Bending2,
  5. Zoe Firth2,
  6. Felicity Allen3,
  7. Nick Adlard3
  1. 1Mapi Group, Houten, The Netherlands
  2. 2Mapi Group, London, UK
  3. 3Novartis Pharmaceuticals, Frimley, UK
  1. Correspondence to Nick Adlard; nicholas.adlard{at}


Objective Multiple sclerosis (MS) is a chronic, neurodegenerative autoimmune disorder affecting the central nervous system. Relapsing–remitting MS (RRMS) is the most common clinical form of MS and affects ∼85% of cases at onset. Highly active (HA) and rapidly evolving severe (RES) RRMS are 2 forms of RRMS amenable to disease-modifying therapies (DMT). This study explored the efficacy of fingolimod relative to other DMTs for the treatment of HA and RES RRMS.

Methods A systematic literature review (SLR) was conducted to identify published randomised controlled trials in HA and RES RRMS. Identified evidence was vetted, and a Bayesian network meta-analysis (NMA) was performed to evaluate the relative efficacy of fingolimod versus dimethyl fumarate (DMF) in HA RRMS and versus natalizumab in RES RRMS.

Results For HA RRMS, the SLR identified 2 studies with relevant patient subgroup data: 1 comparing fingolimod with placebo and the other comparing DMF with placebo. 3 studies were found for RES RRMS: 1 comparing fingolimod with placebo and 2 studies comparing natalizumab with placebo. NMA results in the HA population showed a favourable numerical trend of fingolimod versus DMF assessed for annualised relapse rate (ARR) and 3-month confirmed disability progression. For the RES population, the results identified an increase of ARR and 3-month confirmed disability progression for fingolimod versus natalizumab (not statistically significant). Sparse study data and the consequently high uncertainty around the estimates restricted our ability to demonstrate statistical significance in the studied subgroups.

Conclusions Data limitations are apparent when conducting an informative indirect comparison for the HA and RES RRMS subgroups as the subgroups analyses were retrospective analyses of studies powered to indicate differences across entire study populations. Comparisons across treatments in HA or RES RRMS will be associated with high levels of uncertainty until new data are collected for these subgroups.

  • Fingolimod
  • Natalizumab
  • Dimethyl fumarate
  • Network meta-analysis
  • RRMS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

View Full Text

Statistics from


  • Contributors The study design and protocol were developed by ZF, JJ and MB in collaboration with FA and NA. ZF, JJ, MB, FA and NA collected the data and conducted the SLR. EH and KP performed the feasibility study and the network meta-analysis. The manuscript was written by EH, KP, JJ, MB and NA. All authors have been involved in reviewing the study outcomes and have approved the final version of the manuscript.

  • Funding The study and manuscript were funded by Novartis.

  • Competing interests FA and NA are employees of Novartis. EH, KP, ZF, JJ and MB are employees of Mapi, and served as paid consultants to Novartis to conduct the systematic literature review and preparation of this manuscript. All authors have been involved in the review of the systematic literature review, the model results and the manuscript.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.