title: Effect of combination therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).
  
  
  RESULTS
  The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989-2012 were as follows: Double DMARD: -0.32 SMD (CI: -0.42, -0.22); triple DMARD: -0.46 SMD (CI: -0.60, -0.31); 1 DMARD plus TNFi: -0.30 SMD (CI: -0.36, -0.25); 1 DMARD plus abatacept: -0.20 SMD (CI: -0.33, -0.07); 1 DMARD plus tocilizumab: -0.34 SMD (CI: -0.48, -0.20); 1 DMARD plus CD20i: -0.32 SMD (CI: -0.40, -0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (-0.26 SMD (CI: -0.45, -0.07)) and TNFi plus methotrexate (-0.16 SMD (CI: -0.31, -0.01)).
  
  
  CONCLUSIONS
  Combination treatment of a biologic agent with 1 DMARD is not superior to 2-3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.
authors.affiliation: Department of Rheumatology IR4242, Copenhagen University Hospital, Rigshospitalet, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Graudal
authors.affiliation: Department of Radiology, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Hubeck-Graudal
authors.affiliation: Musculoskeletal Statistics Unit, the Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Tarp
authors.affiliation: Musculoskeletal Statistics Unit, the Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Frederiksberg, Denmark; Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
authors.affiliation: Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg, Denmark.
authors.forename: Gesche
authors.initials: G
authors.lastname: Jürgens
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D006801:Humans; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic
chemical_list: D018501:Antirheumatic Agents; D001688:Biological Products