Comparison of the Efficacy and Safety of Disease-Modifying Antirheumatic Drugs Combination Therapies: A Systematic Review and Network Meta-Analysis

Abstract

There are several disease-modifying antirheumatic drugs currently available to treat rheumatoid arthritis (RA). However, the optimal combination therapy with methotrexate for treating RA remains unclear. We aimed to identify combination therapies with high-efficacy and safety by employing the Bayesian method in a network meta-analysis. We systematically searched PubMed, Embase, CENTRAL, Ichushi web, and PMDA review reports and application materials through October 2020, and found 86 randomized controlled trials. The primary efficacy outcome was the 50% improvement rate according to the American College of Rheumatology criteria (ACR50), and the primary safety outcome was the incidence of serious adverse events. We calculated odds ratios (ORs) and its 95% credible intervals (CrIs) between each treatment, and the surface under the cumulative ranking curve (SUCRA) score for each treatment to rank disease-modifying antirheumatic drug combinations. Individually, most disease-modifying antirheumatic drugs combined with methotrexate are more likely to achieve ACR50 than methotrexate monotherapy, with significant differences (p < 0.05), whereas the incidence of serious adverse events was not significantly different compared with methotrexate monotherapy (p > 0.05). Infliximab combined with methotrexate had the highest efficacy ranking (OR = 10.53, 95% CrI: [3.20, 42.87], SUCRA score: 0.884), and etanercept combined with methotrexate had the highest safety ranking (OR = 0.29, 95% CrI: [0.03, 2.04], SUCRA score: 0.893). Comprehensive cluster analysis revealed that the combination of etanercept, an Fc-fusion protein targeting tumor necrosis factor α, with methotrexate demonstrated higher efficacy and safety. These findings could support the selection of combination therapies for the treatment of RA.

Keywords: disease‐modifying antirheumatic drugs; methotrexate; network meta‐analysis; rheumatoid arthritis.

FIGURE 1

Flow chart of the study selection process. Three researchers independently performed the literature screening, data extraction, and evidence assessment according to the inclusion and exclusion criteria. RA, Rheumatoid arthritis; RCT, Randomized controlled trials.

FIGURE 2

Network of primary efficacy outcomes. White, black, and gray circles represent bDMARDs combination therapy, tsDMARDs combination therapy, and methotrexate monotherapy. The line between two treatments indicates the existence of comparative studies, and the line width represents the number of studies. N: Number of studies; n: Number of patients.

FIGURE 3

Network of primary safety outcomes. White, black, and gray circles represent bDMARDs combination therapy, tsDMARDs combination therapy, and methotrexate monotherapy. The line between two treatments indicates the existence of comparative studies, and the line width represents the number of studies. N: Number of studies; n: Number of patients.

FIGURE 4

Cluster plot of ACR50 (12 ± 4 weeks) with SAE (final). The x‐axis represents the SUCRA score for ACR50 (12 ± 4 weeks), the y‐axis represents the SUCRA score for SAE (final), and solid circles represent each combination therapy. Therapies represented in the upper right corner had a high overall ranking for both ACR50 (12 ± 4 weeks) and SAE (final). Therapies represented in the lower left corner had low combined rankings for ACR50 (12 ± 4 weeks) and SAE (final). Therapies represented in the lower right corner had high ACR50 (12 ± 4 weeks) ranking but low SAE (final) ranking, whereas therapies represented in the upper left corner had low ACR50 (12 ± 4 weeks) ranking but high SAE (final) ranking. ACR50: Comprehensive evaluation indexes put forward by the American College of Rheumatology, indicating that the patient has improved by at least 50% in specified indicators; SAE, Serious adverse event; SUCRA, Surface under the cumulative ranking curves. All treatments except methotrexate monotherapy, were administered in combination with methotrexate.