Anifrolumab, a monoclonal antibody targeting the type I interferon receptor subunit 1, was approved by regulatory authorities in 2021 for the treatment of moderate-to-severe systemic lupus erythematosus (SLE). This study conducted a retrospective pharmacovigilance assessment using real-world data from the U.S. FDA Adverse Event Reporting System (FAERS) to evaluate the safety profile of anifrolumab and compare it with belimumab, a biologic agent widely used in SLE management. The aim was to inform clinical risk management and support evidence-based therapeutic strategies.

To ensure robust signal detection, we employed a multi-algorithmic approach using ROR, PRR, BCPNN, and EBGM based on 2×2 contingency tables. Signals were identified only if they met the conservative criteria of all four methods: PRR ≥ 2 and ROR ≥ 3 (both with 95% CI lower limit > 1), IC025 > 0, and EBGM05 > 2. We conducted subgroup analyses stratified by age (<18, 18–44, 45–64, ≥65 years) and gender. Serious adverse events (SADEs), including hospitalization, disability, and death, were analyzed separately via forest plots. Furthermore, a year-by-year trend analysis (2014–2024) was performed for high-frequency AEs to evaluate temporal dynamics. Statistical analyses were supported by MySQL 8.0 and GraphPad Prism 10.

A total of 1,282 adverse reactions for anifrolumab and 24,267 for belimumab were analyzed. For anifrolumab, the most frequently observed ADRs included herpes zoster, infusion-related reactions, and immediate hypersensitivity reactions. In contrast, belimumab was commonly associated with administration errors, device-related complications, infections (e.g., renal and dental infections), and progressive multifocal leukoencephalopathy. Notably, anifrolumab demonstrated a robust disproportionality signal for herpes zoster (ROR = 18.06; 95% CI: 14.05–23.23). Belimumab reports highlighted disproportionate signals for herpes zoster-related complications, including disseminated cutaneous herpes zoster (ROR = 29.24; 95% CI: 14.99–57.01), herpes zoster meningitis (ROR = 27.98; 95% CI: 12.36–63.35), and ophthalmic herpes zoster (ROR = 5.16; 95% CI: 2.92–9.11).

This study underscores significant associations between anifrolumab and infection-related adverse outcomes, particularly herpes zoster, based on post-marketing surveillance data. These findings emphasize the importance of proactive infection monitoring in patients receiving anifrolumab. Further validation through prospective studies and multi-methodological approaches is warranted, along with exploration of effective prevention and management strategies.