title: Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation.
abstract: BACKGROUND
  Tumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE.
  
  
  OBJECTIVE
  To determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation).
  
  
  METHODS
  Systematic review and economic model.
  
  
  METHODS
  Fifteen databases were searched for relevant studies in July 2014.
  
  
  METHODS
  Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer's submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The model has a lifetime horizon (60 years) and considers costs from the perspective of the NHS and personal social services. Health effects were expressed in terms of quality-adjusted life-years.
  
  
  RESULTS
  In total, 28 eligible RCTs were identified and 26 were placebo controlled (mostly up to 12 weeks); 17 extended into open-label active treatment-only phases. Most RCTs were judged to have a low risk of bias overall. In both AS and nr-AxSpA populations, anti-TNFs produced clinically important benefits to patients in terms of improving function and reducing disease activity; for AS, the relative risks for ASAS 40 ranged from 2.53 to 3.42. The efficacy estimates were consistently slightly smaller for nr-AxSpA than for AS. Statistical (and clinical) heterogeneity was more apparent in the nr-AxSpA analyses than in the AS analyses; both the reliability of the nr-AxSpA meta-analysis results and their true relevance to patients seen in clinical practice are questionable. In AS, anti-TNFs are approximately equally effective. Effectiveness appears to be maintained over time, with around 50% of patients still responding at 2 years. Evidence for an effect of anti-TNFs delaying disease progression was limited; results from ongoing long-term studies should help to clarify this issue. Sequential treatment with anti-TNFs can be worthwhile but the drug survival response rates and benefits are reduced with second and third anti-TNFs. The de novo model, which addressed many of the issues of earlier evaluations, generated incremental cost-effectiveness ratios ranging from £19,240 to £66,529 depending on anti-TNF and modelling assumptions.
  
  
  CONCLUSIONS
  In both AS and nr-AxSpA populations anti-TNFs are clinically effective, although more so in AS than in nr-AxSpA. Anti-TNFs may be an effective use of NHS resources depending on which assumptions are considered appropriate.
  
  
  CONCLUSIONS
  Randomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs.
  
  
  BACKGROUND
  This study is registered as PROSPERO CRD42014010182.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors: Centre for Reviews and Dissemination, University of York, York, UK.
authors: Mark
authors: M
authors: Corbett
authors: Centre for Health Economics, University of York, York, UK.
authors: Marta
authors: M
authors: Soares
authors: Centre for Health Economics, University of York, York, UK.
authors: Gurleen
authors: G
authors: Jhuti
authors: Centre for Reviews and Dissemination, University of York, York, UK.
authors: Stephen
authors: S
authors: Rice
authors: Centre for Health Economics, University of York, York, UK.
authors: Eldon
authors: E
authors: Spackman
authors: Centre for Health Economics, University of York, York, UK.
authors: Eleftherios
authors: E
authors: Sideris
authors: Centre for Reviews and Dissemination, University of York, York, UK.
authors: Thirimon
authors: T
authors: Moe-Byrne
authors: Centre for Reviews and Dissemination, University of York, York, UK.
authors: Dave
authors: D
authors: Fox
authors: Division of Rheumatic and Musculoskeletal Disease, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK.
authors: Helena
authors: H
authors: Marzo-Ortega
authors: Division of Rheumatic and Musculoskeletal Disease, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK.
authors: Lesley
authors: L
authors: Kay
authors: Centre for Reviews and Dissemination, University of York, York, UK.
authors: Nerys
authors: N
authors: Woolacott
authors: Centre for Health Economics, University of York, York, UK.
authors: Stephen
authors: S
authors: Palmer
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000191:economics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000191:economics / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001499:Bayes Theorem; D003362:Cost-Benefit Analysis; D006801:Humans; D018803:Models, Economic; D016032:Randomized Controlled Trials as Topic; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000191:economics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha