Table 1_Risk of pulmonary fungal infections associated with biologics: a FAERS database disproportionality analysis.docx

Objectivebiologics have significantly advanced the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). However, real-world data regarding the risks of pulmonary fungal infections (PFI) associated with different biologics are limited. Our study aimed to explore PFI incidence among approved biologics, drawing on sources of real-world evidence.
MethodsWe conducted a disproportionality analysis to evaluate the association between biologics and PFI using data from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) (2004–2024). We analyzed clinical features, co-occurring adverse events (AEs), time-to-onset (TTO).
ResultsOur analysis included 3,695 patients who developed PFI following treatment with biologics. The study comprised 28.5% females, 28.6% males, and 42.9% with unspecified gender. The median age was 63 years (interquartile range [IQR] 52–71). Several biologics were associated with elevated PFI risk. Among them, the highest reporting odds ratio (ROR) were observed for infliximab(ROR = 26.02, 95% CI 17.72–38.21), rituximab(ROR = 16.23, 95% CI 13.06–20.18), tocilizumab(ROR = 14.45, 95% CI 12.28–17.00), and baricitinib(ROR = 11.01, 95% CI 7.77–15.59). Other biologics associated with a disproportionality signal in PFI risk included golimumab(ROR = 6.73, 95% CI 2.15-21.13), upadacitinib(ROR = 4.61, 95% CI 2.61–8.14), ustekinumab(ROR = 4.58, 95% CI 1.46–14.36), adalimumab(ROR = 3.45, 95% CI 2.08–5.72), tofacitinib(ROR = 3.18, 95% CI 2.04–4.95), abatacept(ROR = 3.16, 95% CI 1.74–5.73), etanercept(ROR = 2.58, 95% CI 2.06–3.24), certolizumab pegol(ROR = 1.64, 95% CI 1.27–2.10). The signal for secukinumab was not statistically (ROR = 1.70, 95% CI 0.55–5.32). Female was associated with an elevated risk of PFI and fatal outcomes in the logistic regression analysis. Tocilizumab and baricitinib showed a disproportionality signal for fatal outcomes. Our analysis suggested a trend of more pronounced PFI risk signals in elderly patients. TTO analysis demonstrated no significant gender-based differences. However, significant intergroup differences were observed between patients aged 45–64 years and those aged 65–74 years. Notably, TTO profiles varied substantially among biologics, ranging from 30 days (tocilizumab) to 393 days (etanercept).
ConclusionOur findings suggest that concomitant use of biologics is associated with a stronger disproportionality signal for PFI. The inherent limitations and potential reporting biases of the FAERS database necessitate confirmation through large-scale, prospective clinical studies.

研究目的：生物制剂（biologics）已显著推动类风湿关节炎（rheumatoid arthritis, RA）与银屑病关节炎（psoriatic arthritis, PsA）的治疗进展。然而，针对不同生物制剂相关肺部真菌感染（pulmonary fungal infections, PFI）风险的真实世界数据仍较为有限。本研究旨在依托真实世界证据来源，探究获批生物制剂的PFI发病情况。
方法 本研究借助美国食品药品监督管理局（Food and Drug Administration, FDA）不良事件报告系统（Adverse Event Reporting System, FAERS）2004至2024年的数据，采用不成比例分析方法评估生物制剂与PFI之间的关联。我们对临床特征、共发不良事件（adverse events, AEs）以及发病时间（time-to-onset, TTO）进行了分析。
结果 本分析共纳入3695名接受生物制剂治疗后发生PFI的患者。其中女性占比28.5%，男性占比28.6%，性别未明确者占42.9%；患者中位年龄为63岁（四分位间距[IQR] 52~71岁）。多种生物制剂与PFI风险升高相关，其中报告比值比（reporting odds ratio, ROR）最高的依次为英夫利昔单抗（ROR=26.02，95%CI 17.72~38.21）、利妥昔单抗（ROR=16.23，95%CI 13.06~20.18）、托珠单抗（ROR=14.45，95%CI 12.28~17.00）以及巴瑞替尼（ROR=11.01，95%CI 7.77~15.59）。其余与PFI风险呈现不成比例信号的生物制剂包括戈利木单抗（ROR=6.73，95%CI 2.15~21.13）、乌帕替尼（ROR=4.61，95%CI 2.61~8.14）、乌司奴单抗（ROR=4.58，95%CI 1.46~14.36）、阿达木单抗（ROR=3.45，95%CI 2.08~5.72）、托法替布（ROR=3.18，95%CI 2.04~4.95）、阿巴西普（ROR=3.16，95%CI 1.74~5.73）、依那西普（ROR=2.58，95%CI 2.06~3.24）以及赛妥珠单抗（certolizumab pegol，ROR=1.64，95%CI 1.27~2.10）。司库奇尤单抗的信号无统计学意义（ROR=1.70，95%CI 0.55~5.32）。Logistic回归分析显示，女性与PFI风险升高及不良结局风险相关；托珠单抗与巴瑞替尼则与致命结局呈现不成比例信号。本分析提示，老年患者的PFI风险信号更为显著。发病时间分析未观察到显著的性别差异，但45~64岁与65~74岁患者亚组间存在显著组间差异。值得注意的是，不同生物制剂的发病时间曲线差异显著，最短为托珠单抗相关的30天，最长为依那西普相关的393天。
结论 本研究结果表明，生物制剂的联合使用与PFI更强的不成比例风险信号相关。鉴于FAERS数据库固有的局限性及潜在的报告偏倚，本研究结论需通过大规模前瞻性临床研究进一步验证。