Calcineurin Inhibitors and Risk of CNS Infections: A Disproportionality Analysis of the FDA Adverse Event Reporting System (FAERS)

Purpose

Calcineurin inhibitors (CNIs) are widely used to prevent organ rejection and manage autoimmune disorders. Although post-marketing evidence suggests an increased risk of central nervous system (CNS) infections associated with CNIs, this association has not been sufficiently elucidated. To address this gap, we conducted a pharmacovigilance analysis using real-world data to systematically identify and characterize the safety profile of CNI-related CNS infections, thereby providing robust evidence to inform their potential clinical risks.

Methods

A total of 21,838,627 adverse event (AE) reports were extracted from the FDA Adverse Event Reporting System (FAERS), covering the period from Q1 2004 to Q3 2024. We conducted a comprehensive analysis of the clinical characteristics of CNS infection-related AEs associated with CNIs. To identify significant safety signals, disproportionality analyses were performed using the reporting odds ratio (ROR) and information component (IC) methods. Furthermore, sex-specific differences, time-to-onset (TTO) patterns, and distinct infection profiles across different CNIs were thoroughly investigated. Statistical significance for sex-based comparisons was defined as P value < 0.05.

Findings

We identified 687 CNI-related CNS infection cases, comprising 488 linked to tacrolimus and 199 to cyclosporine. Compared with all other drugs in the FAERS database, both agents demonstrated significantly elevated disproportionality signals, with tacrolimus exhibiting a notably stronger association. Sex-specific analyses revealed that brain abscess (ROR=2.21[1.50–3.27], P < 0.01) and encephalitis (ROR = 1.84[1.22–2.78], P < 0.01) were markedly more prevalent in male patients. Among tacrolimus users, male-specific CNS infection AEs with positive signals included cavernous sinus thrombosis, extradural abscess, neurosarcoidosis, spinal cord abscess, and others. In comparison, male patients receiving cyclosporine exhibited distinct signals for myelitis and myelitis transverse in addition to cavernous sinus thrombosis and extradural abscess. Notably, autoimmune encephalitis was reported exclusively in female patients treated with cyclosporine, suggesting potential sex-based immunological susceptibility. TTO analysis revealed median onset times of 181 days for tacrolimus and 83 days for cyclosporine. While most CNS infections emerged within the first month of therapy, a considerable proportion occurred beyond one year of treatment, underscoring the importance of sustained long-term surveillance in CNI-treated populations.

Implications

Our study provides novel real-world evidence on the safety profiles of CNIs in relation to CNS infections, highlighting differences in infection patterns across CNIs and sexes. Given the potential severity of these infections, clinicians should maintain heightened vigilance, particularly during the early phase of treatment and among high-risk populations, to enable timely detection and intervention, reduce serious outcome risks, and optimize the safety management of CNI therapy.