Background/Purpose: Interleukin-6 (IL-6) inhibitors, including tocilizumab and sarilumab, are immunomodulatory agents commonly used in the treatment of rheumatoid arthritis and COVID-19. Prior studies have implicated IL-6 signaling in the pathogenesis of various cardiovascular disorders, including atrial fibrillation and other arrhythmias, raising concerns about potential pro-arrhythmic effects of IL-6 inhibition. To further characterize this risk, we conducted a pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) to evaluate the incidence and nature of arrhythmias associated with IL-6 inhibitor use.

Methods: The FAERS database was searched for cardiac arrhythmias (Tachycardia, bradycardia, atrial fibrillation, QRS complex abnormalities, QT interval abnormalities, bundle branch block (BBB), atrioventricular blocks (AV blocks) and supraventricular tachycardia (SVT)) associated with the use of IL-6 inhibitors (tocilizumab, sarilumab, and siltuximab). Data were reported as frequencies and as reporting odds ratios (ROR) with a 95% confidence interval (95% CI).

Results: We analyzed 30,179,725 adverse event reports from the FAERS database. A total of 107,540 reports were associated with the use of the three anti-IL-6 drugs; 78.3% of them were females, with cardiac arrhythmias being reported in 1% of them. Most of the cases were associated with tocilizumab (85.5%), followed by sarilumab (13.8%). Tachycardia was the most common arrhythmia among tocilizumab users, which was reported in 668 cases, followed by bradycardia, which was reported in 134 cases. Among all arrhythmias tested, only tachycardia and BBB were significantly higher among tocilizumab users compared to all other drugs (ROR=1.959; 95% CI: 1.815 – 2.114) and (ROR=3.599; 95% CI: 2.364 – 5.479), respectively. In addition, siltuximab users had significantly higher odds of atrial fibrillation compared to all other drugs users (ROR=1.3.114; 95% CI: 1.163 – 8.339) (Table 1). When the three anti-IL-6 medications were put into a head-to-head comparison, tocilizumab had the highest ROR of causing tachycardia, bradycardia, SVT, and AV block. However, siltuximab users had the highest odds of causing QT prolongation (ROR=18.73; 95% CI: 6.770 – 51.80) (Table 2).

Conclusion: IL-6 inhibitors, particularly tocilizumab and siltuximab, are associated with increased reporting of specific arrhythmias. These findings highlight the need for arrhythmia monitoring in susceptible patients receiving IL-6 inhibitors. Further studies are needed to clarify causality and the mechanisms underlying these associations.

Table 1. ROR of anti-IL 6 drugs

Table 2. Head to head comparison of anti-IL 6 drugs

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-arrhythmias-following-il-6-inhibitor-use-a-pharmacosurvellience-study-of-fda-adverse-event-reporting-system-faers/