Effect of combination therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of randomized controlled trials

PLoS One. 2014 Sep 22;9(9):e106408. doi: 10.1371/journal.pone.0106408. eCollection 2014.


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).

Methods and findings: 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)).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antirheumatic Agents / pharmacology
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / pathology
  • Biological Products / pharmacology
  • Biological Products / therapeutic use*
  • Disease Progression
  • Drug Therapy, Combination
  • Humans
  • Joints / drug effects*
  • Joints / pathology
  • Randomized Controlled Trials as Topic


  • Antirheumatic Agents
  • Biological Products

Grant support

This study was supported by The A.P. Møller Foundation for the Advancement of Medical Science. The Musculoskeletal Statistics Unit, the Parker Institute are supported by grants from the The Oak Foundation, Frederiksberg Hospital, and The Danish Medicines Agency. The A.P.M. Foundation, The Oak Foundation, and The Danish Medicines Agency are non-profit funding sources and had no role in the design and conduct of the study or in the collection, analysis, and interpretation of the data or in the preparation, review, and approval of the manuscript.