Dupilumab Use Is Associated with Reduced Reporting of Systemic Lupus Erythematosus: A Pharmacovigilance Disproportionality Analysis of the FDA Adverse Event Reporting System

Background: Dupilumab (Dupixent; Sanofi/Regeneron) is a fully human monoclonal antibody targeting the interleukin-4 receptor alpha subunit (IL-4Rα), blocking downstream signalling of both IL-4 and IL-13. Spontaneous reporting databases offer a scalable opportunity to detect unexpected pharmacological associations at the population level. Objective: To determine whether dupilumab use is associated with disproportionately reduced reporting of systemic lupus erythematosus (SLE) in the FDA Adverse Event Reporting System (FAERS), and to evaluate the robustness of any detected signal across multiple pre-specified sensitivity analyses. Methods: Twenty consecutive quarters of FAERS ASCII data (2020Q1–2024Q4; N = 8,736,254 primary suspect reports) were analysed. Disproportionality was assessed using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Independent Bayesian corroboration was provided by the BCPNN (IC025) and MGPS (EB05). An active comparator framework used eight mechanistically related biologics and JAK inhibitors. Five pre-specified sensitivity analyses evaluated robustness: active comparator including and excluding upadacitinib, broader MedDRA lupus term aggregation, physician-reporter restriction, and quarter-by-quarter temporal analysis. Results: One hundred and twenty-eight co-reports of dupilumab and SLE were identified from 304,788 dupilumab primary suspect reports. The global ROR was 0.151 (95% CI 0.127–0.180), with a PRR of 0.151; BCPNN IC025 = −3.00; MGPS EB05 = 0.137, yielding four-algorithm concordance. No co-reported case cited SLE as the indication for dupilumab. The active comparator analysis (eight agents) yielded ROR 0.130 (95% CI 0.109–0.156); excluding upadacitinib attenuated the signal (ROR 0.437; 95% CI 0.242–0.790) but preserved statistical significance below the null. Broader MedDRA lupus term aggregation (n = 148) produced a PRR of approximately 0.182. Physician-reporter restriction yielded ROR 0.188 (95% CI 0.151–0.235). The ROR remained below 1.0 in 19 of 20 consecutive quarters. Structural reporting asymmetry from the dermatological prescribing context remains the principal unresolved confound. Conclusions: Dupilumab is associated with a multi-algorithm-confirmed, indication-independent reduction in SLE reporting that is robust across five sensitivity analyses in a population carrying elevated baseline SLE risk. Structural reporting asymmetry is the principal residual confound and must be foregrounded in any interpretation of these findings. Subject to this caveat, the most plausible pharmacological hypothesis implicates IL-4-mediated modulation of autoreactive B-cell class switching. These findings constitute a hypothesis-generating pharmacovigilance signal warranting prospective cohort investigation.