Exploring the Benefits and Prescribing Informations of Combining East Asian Herbal Medicine with Conventional Medicine in the Treatment of Rheumatoid Arthritis: A Systematic Review and Multifaceted Analysis of 415 Randomized Controlled Trials

Notwithstanding progress in conventional medicine (CM), the management of rheumatoid arthritis (RA) continues to be problematic due to factors such as limited patient response to treatment and restricted medication access. This study aimed to evaluate the extent to which East Asian herbal medicine with CM combination therapy (EACM) provides additional benefits in effectiveness and safety. We conducted a comprehensive search across 11 databases in English, Chinese, Korean, and Japanese for randomized controlled trials. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the American College of Rheumatology (ACR) 20/50/70 Response Criteria and the incidence of adverse events (AEI) as primary outcomes. This meta-analysis was performed using a random-effects model. The quality of each study was assessed according to the RoB 2. Of the 1,036 full-text articles screened, 415 were included in the review. This review included data from 37,839 participants. EACM was associated with higher ACR responses: ACR 20 (RR: 1.2332; 95% CI: 1.1852 to 1.2831, p < 0.0001), ACR 50 (RR: 1.3782; 95% CI: 1.2936 to 1.4684, p < 0.0001), and ACR 70 (RR: 1.7084; 95% CI: 1.5555 to 1.8762, p < 0.0001), as well as a favorable AEI (OR: 0.3977; 95% CI: 0.3476 to 0.4551, p < 0.0001), indicating both better efficacy and safety compared to CM alone. These patterns were consistent across eight secondary outcomes measuring pain, inflammation, and disease activity in RA. Subgroup analyses showed that EACM's effects were independent of the control CM type. Through a comprehensive analysis of a polyherbal prescription dataset, we identified 18 key herbs and 16 significant combination rules, further supported by relevant preclinical evidence. These herbs and synergistic herbal combinations were anticipated to be the most pharmacologically influential in contributing to the meta-analysis outcomes, as substantiated by analytical metrics including network topology and intricate association pattern evaluations. The findings suggest that EACM may serve as a valuable complementary strategy for RA patients insufficiently managed by CM alone. In particular, given that the ACR index integrates multiple aspects of RA patients, the results are expected to provide valuable complementary decision support for the management of RA patients who do not respond well to CM therapy, both for medical and economic reasons. Additionally, the key herbs derived through the multifaceted analysis, which actively reflect clinicians' implicit preferences for prescribing EACMs, may serve as important hypotheses for further research and clinical application. However, additional qualitative and quantitative improvements in research are needed for more definitive conclusions. Further analysis of the herbal prescriptions presented in this study will provide valuable direction for future research.