Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70

Abstract

Background

Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate.

Methods

Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks’ follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data.

Results

The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-α inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results.

Conclusion

Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-α inhibitor combination therapies are not equally effective.

Keywords:

• bDMARD
• rheumatoid arthritis
• etanercept
• systematic review
• network metaanalysis
• comparative effectiveness

Supplementary materials

Table S1. Direct meta-analysis of American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 outcomes: combination therapy

Table S2. Bucher indirect meta-analysis of American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 outcomes: combination therapy

Table S3. Results from combination therapy NMA study arm level (patient characteristics) covariate analysis for American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 end point

Table S4. Combination therapy network meta-analysis sensitivity analysis results for American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 end point

Table S5. Direct meta-analysis of American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 outcomes: licensed DMARD monotherapy versus placebo in DMARD-experienced patients

Table S6. Bucher indirect meta-analysis of American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 outcomes: licensed DMARD monotherapy in DMARD-experienced patients

Table S7. Direct and indirect meta-analysis of ACR50 on Tocilizumab 4 mg/kg/4 weeks—Tocilizumab 8 mg/kg/4 weeks loop

Table S8. Direct and indirect meta-analysis of ACR20 on Tocilizumab 4 mg/kg/4 weeks—Tocilizumab 8 mg/kg/4 weeks loop

Table S9. Direct and indirect meta-analysis of ACR70 on Tocilizumab 4 mg/kg/4 weeks—Tocilizumab 8 mg/kg/4 weeks loop

Table S10. Monotherapy network meta-analysis sensitivity analysis results for American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 end point

Figure S1. Part of the monotherapy evidence network containing the tocilizumab 4 mg/kg/4 weeks–tocilizumab 8 mg/kg/4 weeks loop.

Notes: 6, Maini 2006 (CHARISMA); 10, Nishimoto 2004 (STREAM); 11, Nishimoto 2009 (SATORI).

Disclosure

This study was sponsored by Pfizer Ltd, UK. Michelle Orme, Katherine MacGilchrist, and Stephen Mitchell were paid consultants to Pfizer Ltd, UK in connection with this study. Dean Spurden and Alex Bird are paid employees of Pfizer Ltd, UK.