Biologic Agents Reduce Cardiovascular Events in Rheumatoid Arthritis Not Responsive to Tumour Necrosis Factor Inhibitors: A National Cohort Study

Background: Tumour necrosis factor inhibitors (TNFis) improve joints outcomes and reduce cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). However, 20%-45% of RA patients are TNFi poor responders and have a significantly higher risk of CV events. In these TNFi nonresponders, the use of second-line biologic agents to improve synovial outcomes is supported by clinical trials and real-world experience. However, it remains unknown what kind of immune-mediated agent has the best CV prevention effect in this high-risk population. Methods: A nationwide RA cohort obtained from Taiwan's National Health Insurance claims database was constructed. RA patients first treated with TNFis who then received either rituximab, tocilizumab, or abatacept were enrolled and followed for 2 years. Results: A total of 89,973 RA patients were screened and 1,584 patients ultimately included. The incidences of major adverse cardiac events (MACE) at 2 years in the rituximab, tocilizumab, and abatacept groups were 7.17%, 2.75% and 2.38%, respectively. Multivariate adjusted Cox analysis showed that tocilizumab had significantly lower risk than rituximab in myocardial infarction (hazard ratio [HR] 0.12, 95% confidence interval [CI] 0.02-0.56; P = 0.008), and MACE (HR 0.41, 95% CI 0.23-0.72; P = 0.002). In addition, abatacept also had significant lower adjusted risk than rituximab in stroke (HR 0.18, 95% CI 0.05-0.64; P = 0.008), heart failure (HR 0.20, 95% CI 0.05-0.83; P = 0.027), and MACE (HR 0.25, 95% CI 0.11-0.55; P < 0.001) in multivariate analysis. Conclusions: TNFi-nonresponder patients with RA who received second-line tocilizumab or abatacept had more benefit on CV events prevention compared with those who received rituximab.