A Head-to-Head Comparison of TNF-Inhibitors as the First Biologic Treatment of Rheumatoid Arthritis

Background: Rheumatoid Arthritis (RA) significantly impacts patients' quality of life. Tumor necrosis factor alpha inhibitors (TNFis) are effective biologic drugs for RA, but their comparative efficacy is unclear due to limited direct comparisons. This study employs an instrumental variable (IV) method for an unbiased head-to-head comparison of TNFis.Purpose: To compare the efficacy of infliximab (INX), certolizumab pegol (CZP), etanercept (ETN), golimumab (GOM), and adalimumab (ADM) in achieving remission at three-months in bio-naïve RA patients. Methods: Using data from the NOR-DMARD study of adult RA patients in Norway starting a TNFi as their first biologic treatment, we employed a target trial emulation approach. TNFi selection was mainly determined by drug prices in annual national tenders, allowing us to use this tender system as an instrument. Applying a novel IV method, causal effects were estimated with remission at three months as the endpoint. Results were compared with standard regression analysis adjusted for baseline variables.Results: The IV analyses ranked the treatments in decreasing order of efficacy as INX, ADM, ETN, CZP and GOM. Due to limited instrumental variation, the primary analysis only identified five direct effects with wide confidence intervals. Only INX-CZP and GOM-ETN comparisons excluded zero difference. Regression analysis suggested no substantial differences, underscoring the importance of accounting for bias due to unobserved confounding effects. Conclusion: The identified efficacy differences are likely influenced by dosing regimens and administration frequency. The uncertainty in the estimates highlights the need for a pragmatic randomized controlled trial to confirm these findings. With decreasing costs of TNFis, such studies are increasingly feasible and critical to guide clinical decision-making.