title: Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis.
abstract: BACKGROUND
  Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis (RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies.
  
  
  OBJECTIVE
  To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS.
  
  
  METHODS
  A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted within a Bayesian framework to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome.
  
  
  RESULTS
  The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome. Interferon-beta-1b 250mcg ranked among the most efficacious treatments for disability progression confirmed after six months (92%) and among the least efficacious when the outcome was confirmed after three months (30%). No significant modification of relative treatment effects was identified from study-level covariates or baseline risk.
  
  
  CONCLUSIONS
  Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS.
authors.affiliation: National Centre for Pharmacoeconomics, Dublin, Ireland. Electronic address: efogarty@stjames.ie.
authors.forename: Emer
authors.initials: E
authors.lastname: Fogarty
authors.affiliation: Health Economics and Evidence Synthesis Research Unit, Department of Population Health, Luxembourg Institute of Health, Luxembourg.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmitz
authors.affiliation: Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Niall
authors.initials: N
authors.lastname: Tubridy
authors.affiliation: Department of Mathematics and Statistics, University of Limerick, Ireland.
authors.forename: Cathal
authors.initials: C
authors.lastname: Walsh
authors.affiliation: National Centre for Pharmacoeconomics, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Barry
mesh_terms: D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
keywords: Disability progression; Disease-modifying therapy; Multiple sclerosis; Network meta-analysis; Relapse; Systematic review