title: Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX).
  
  
  
  The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs.
  
  
  
  Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained.
  
  
  
  Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX.
  
  
  
  bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission).
  
  
  
  This study is registered as PROSPERO CRD42012003386.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Archer
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Tosh
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Simpson
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Everson-Hock
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: John
authors.initials: J
authors.lastname: Stevens
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Hernandez-Alava
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Suzy
authors.initials: S
authors.lastname: Paisley
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Kath
authors.initials: K
authors.lastname: Dickinson
authors.affiliation: Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Scott
authors.affiliation: Department of Rheumatology, West Hertfordshire Hospitals NHS Trust, Hertfordshire, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Young
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Wailoo
mesh_terms: D006801:Humans; D000069594:Abatacept / Q000627:therapeutic use; D000068879:Adalimumab / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D000068582:Certolizumab Pegol / Q000627:therapeutic use; D003362:Cost-Benefit Analysis; D000068800:Etanercept / Q000627:therapeutic use; D000069285:Infliximab / Q000627:therapeutic use; D008727:Methotrexate / Q000627:therapeutic use; D019057:Quality-Adjusted Life Years
chemical_list: D000069594:Abatacept; D000068879:Adalimumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000068582:Certolizumab Pegol; D000068800:Etanercept; C529000:golimumab; D000069285:Infliximab; D008727:Methotrexate; C502936:tocilizumab