Objective: The aim of this systematic review was to identify and critically evaluate all published cost-effectiveness analyses of second-line disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with incomplete response to methotrexate (MTX).

Methods: In November 2021, we conducted a systematic search of three databases (Embase, MEDLINE, and EconLit) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Inclusion criteria were: (1) original publications, which (2) evaluated the cost-effectiveness (3) of DMARDs (4) in MTX-refractory populations. No date restrictions were applied, and all reference databases were searched from inception. All included articles underwent a standardized data extraction process. Two reviewers independently extracted data on interventions, patient populations, model inputs and characteristics, and cost-effectiveness outcomes.

Results: A total of 5,436 unique citations were retrieved and screened for eligibility. 237 full-text citations were assessed for eligibility, and cost-effectiveness data were extracted from 60 included publications. Model approaches included patient-level simulations, decision tree analyses, and Markov models. Cost effectiveness estimates varied widely. The majority of studies were industry-sponsored (44 of 60, 73.3%). Indicated time horizons were often insufficient to capture disease progression. The majority of included studies were conducted from a healthcare payer perspective (40 of 60, 66.6%). Treatment responses were typically assessed using EULAR (European League Against Rheumatism) or American College of Rheumatology (ACR) criteria. Population heterogeneity was seldom considered. Biological and targeted synthetic DMARDs were consistently priced higher than conventional therapies.

Conclusions: This review indicates that variation in cost-effectiveness estimates for DMARDs in post-MTX RA appear to be driven by selection of comparators, consideration of adverse events associated with treatment, and underlying assumptions regarding disease progression, as well as differences in model structure and study horizon.