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; comparative effectiveness; etanercept; network metaanalysis; rheumatoid arthritis; systematic review.

Figure 1

Flow diagram of included/excluded studies. Abbreviations: ACR, American College of Rheumatology; bDMARD, biological disease-modifying anti-rheumatic drug; DMARD, disease-modifying anti-rheumatic drug; ETN, etanercept; HAQ, Health Assessment Questionnaire; MTX, Methotrexate; RCT, randomized controlled trial; TEMPO, Trial of Etanercept and Methotrexate with radiographic Patient Outcomes; TNF-α, tumour necrosis factor alpha.

Figure 2

Network diagram for ACR20/50/70 outcomes for bDMARD combination therapies. Notes: 1, Abe 2006; 2, Chen 2009; 3, Combe 2006; 4, Durez 2004; 5, Edwards 2004; 6, Emery 2010 (SERENE); 7, Genovese 2004; 8, Genovese 2008 (TOWARD); 9, Huang 2009; 10, Kameda 2010 (JESMR); 11, Kay 2008; 12, Keystone 2004 (DE019); 13, Keystone 2008 (RAPID 1); 14, Keystone 2009 (GO-FORWARD); 15, Kim 2007; 16, Kremer 2003; 17, Kremer 2006 (AIM); 18, Kremer 2010; 19, Lan 2004; 20, Maini 1999 (ATTRACT); 21, Maini 2006 (CHARISMA); 22, Schiff 2008 (ATTEST); 23, Smolen 2008 (OPTION); 24, Smolen 2009a (RAPID 2); 25, van Riel 2006 (ADORE); 26, Weinblatt 1999; 27, Weinblatt 2003 (ARMADA); 28, Westhovens 2006b (START); 29, Zhang 2006. DMARD 25 arms, 3039 patients; abatacept 10 mg/kg/4 weeks + DMARD 3 arms, 704 patients; adalimumab 40 mg/2 weeks + DMARD 5 arms, 495 patients; certolizumab pegol 200 mg/2 weeks + DMARD 2 arms, 639 patients; etanercept 2 × 25 mg/week + DMARD 6 arms, 500 patients; golimumab 50 mg/4 weeks + DMARD 2 arms, 124 patients; infliximab 3 mg/kg/8 weeks + DMARD 6 arms, 760 patients; rituximab 2 × 1000 mg + DMARD 2 arms, 212 patients; tocilizumab 8 mg/kg/4 weeks + DMARD 3 arms, 1058 patients.

Figure 3

Funnel plot comparing the log odds of response across combination study control arms: log odds of DMARD control achieving ACR20.

Figure 4

Funnel plot comparing the log odds of response across combination study control arms: log odds of DMARD control achieving ACR50.

Figure 5

Funnel plot comparing the log odds of response across combination study control arms: log odds of DMARD control achieving ACR70.

Figure 6

Network diagram for ACR20/50/70 outcomes for bDMARD monotherapy. Notes: 1, Combe 2006; 2, Edwards 2004; 3, Johnsen 2006; 4, Kameda 2010 (JESMR); 5, Keystone 2009 (GO-FORWARD); 6, Maini 2006 (CHARISMA); 7, Miyasaka 2008 (Change); 8, Moreland 1997; 9, Moreland 1999; 10, Nishimoto 2004 (STREAM); 11, Nishimoto 2009 (SATORI); 12, van de Putte 2003; 13, van de Putte 2004; 14, van Riel 2006 (ADORE). Placebo 6 arms, 444 patients; MTX 4 arms, 488 patients; etanercept 2 × 25 mg/week, 5 arms, 441 patients; tocilizumab 8 mg/kg/4 weeks, 3 arms, 168 patients; adalimumab 40 mg/2 weeks, 2 arms, 204 patients; sulfasalazine 1 arm, 50 patients.

Figure 7

Funnel plot comparing the log odds of response across monotherapy study control arms: log odds of placebo control achieving ACR20.

Figure 8

Funnel plot comparing the log odds of response across monotherapy study control arms: log odds of placebo control achieving ACR50.

Figure 9

Funnel plot comparing the log odds of response across monotherapy study control arms: log odds of placebo control achieving ACR70.