title: Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor-methotrexate combination therapy versus triple therapy in rheumatoid arthritis.
abstract: OBJECTIVE
  Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi-methotrexate versus triple therapy in patients with RA.
  
  
  METHODS
  A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi-methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi-methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models.
  
  
  RESULTS
  We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi-methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi-methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate.
  
  
  CONCLUSIONS
  In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi-methotrexate, no clear differences were observed. The odds of infection were greater with TNFi-methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.
authors.affiliation: Department of Internal Medicine , University of Texas Southwestern Medical Center and Metroplex Clinical Research Center , Dallas, Texas , USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.affiliation: Oxford Outcomes, ICON plc , Morristown, New Jersey , USA.
authors.forename: Vanita
authors.initials: V
authors.lastname: Tongbram
authors.affiliation: Department of Medicine , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Vollenhoven
authors.affiliation: Amgen Inc., Thousand Oaks, California, USA; Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Derek H
authors.initials: DH
authors.lastname: Tang
authors.affiliation: Amgen Inc. , Thousand Oaks, California , USA.
authors.forename: James
authors.initials: J
authors.lastname: Chung
authors.affiliation: Amgen Inc. , Thousand Oaks, California , USA.
authors.forename: David
authors.initials: D
authors.lastname: Collier
authors.affiliation: Oxford Outcomes, ICON plc, Morristown, New Jersey, USA; Doctors' Hospital of Michigan, Pontiac, Michigan, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Urs
authors.affiliation: Oxford Outcomes, ICON plc , Morristown, New Jersey , USA.
authors.forename: Kerigo
authors.initials: K
authors.lastname: Ndirangu
authors.affiliation: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute , Ottawa, Ontario , Canada.
authors.forename: George
authors.initials: G
authors.lastname: Wells
authors.affiliation: Department of Rheumatology , St. Joseph's Health Care , London, Ontario , Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Pope
keywords: DMARDs (biologic); DMARDs (synthetic); Methotrexate; Rheumatoid Arthritis; TNF-alpha