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

Objectives Tumor necrosis factor alpha inhibitors (TNFis) are effective biologic drugs for rheumatoid arthritis (RA), but their comparative efficacy is unclear due to limited direct comparisons. 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 employ a target trial emulation approach. TNFi selection is mainly determined by drug prices in annual national tenders, allowing us to use drug cost as an instrumental variable (IV). Applying a novel IV method, causal effects are estimated with remission at three months as the end point. Results are compared with standard regression analysis adjusted for baseline variables. Results The IV analysis suggests potential differences in efficacy among TNFis, with INX showing higher remission rates compared with CZP, and ETN performing better than GOM. However, confidence intervals are wide, and many comparisons are not statistically significant. Sensitivity analyses confirm the overall direction of results. Regression analysis adjusting for observed confounders shows no substantial differences, underscoring the importance of addressing unobserved confounding effects. Conclusion This hypothesis-generating study provides evidence that TNFis may not be equally effective. The uncertainty in the estimates highlights the need for a pragmatic randomized controlled trial to validate the findings. With decreasing costs of TNFis, such studies are increasingly feasible and critical to guide clinical decision-making.