Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials

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 alpha 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 (2 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.