BACKGROUND There have been multiple reports of the anti-IL-4Rα agent, dupilumab, being associated with the onset and/or progression of cutaneous T-cell lymphoma (CTCL). OBJECTIVE We sought to evaluate safety signals associated with dupilumab, with a focus on CTCL, and to evaluate the possible underlying mechanism or mechanisms for the potential association. METHODS First, we used the Food and Drug Administration's pharmacovigilance database, FAERS (FDA Adverse Event Reporting System), to evaluate whether dupilumab was associated with CTCL, including both positive outcome controls (conjunctivitis, eosinophilia, and arthralgia) and exposure controls (other medications with similar indications, including JAK inhibitors and the anti-IL-13 agent, tralokinumab) to evaluate confounding bias. Thereafter, we used publicly available bulk and single-cell RNA sequencing datasets to probe possible underlying mechanisms through which dupilumab might be associated with CTCL. RESULTS Between January 2017 and the fourth quarter of 2023, there were 181,575 unique reports of dupilumab-related adverse events (AEs) in FAERS, with 606 of these being for a neoplasm. Dupilumab had 30.0 times the proportional reporting ratio (PRR) (95% confidence interval, 25.0-35.9) for CTCL compared to all other medications in FAERS. The risk was highest in men aged 45 to 65. The PRR for conjunctivitis, eosinophilia, and arthralgia, known adverse effects of dupilumab, were 35.6 (34.4-36.8), 2.15 (2.00-2.31), and 2.14 (2.07-2.18), respectively. Using the log-count normalized PRR (AE score) to account for PRR inflation when reports were small, the top safety signals included conjunctivitis (AE score 8.3) and CTCL (AE score 4.9). Bulk RNA sequencing data showed changes in IL-4RA and IL-13RA1 expression in CTCL and in epidermal layers of atopic dermatitis (AD) biopsy samples. Single-cell transcriptomic studies revealed that this change was similar in AD and CTCL, and that keratinocytes seemed to be the most divergent cell type with regards to IL-4R and IL-13RA1. An effect on keratinocyte-specific gene expression was also independently observed in available bulk RNA sequencing data. CONCLUSION These data suggest that dupilumab might be causing an unmasking or progression of CTCL via the same mechanism through which it improves AD: IL-13 receptor blockade, which leads to increased IL-13 in the local milieu, driving CTCL stimulation and progression. However, these associations need further evaluation given the inherent limitations of the FAERS database and our nonexperimental approach.

中文翻译：

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综合流行病学和免疫转录组学揭示了 dupilumab 治疗暴露皮肤淋巴瘤或进展的风险和潜在机制。


背景 有多篇报道称抗 IL-4Rα 药物 dupilumab 与皮肤 T 细胞淋巴瘤 （CTCL） 的发作和/或进展有关。目的 我们试图评估与 dupilumab 相关的安全信号，重点是 CTCL，并评估潜在关联的可能潜在机制或机制。方法 首先，我们使用美国食品和药物管理局的药物警戒数据库 FAERS （FDA 不良事件报告系统） 来评估 dupilumab 是否与 CTCL 相关，包括阳性结局对照 （结膜炎、嗜酸性粒细胞增多症和关节痛） 和暴露对照 （其他具有相似适应症的药物，包括 JAK 抑制剂和抗 IL-13 药物 tralokinumab） 来评估混杂偏倚。此后，我们使用公开可用的大量和单细胞 RNA 测序数据集来探索 dupilumab 可能与 CTCL 相关的可能潜在机制。结果 从 2017 年 1 月到 2023 年第四季度，FAERS 中有 181,575 例 dupilumab 相关不良事件 （AE） 的独特报告，其中 606 例是肿瘤。与 FAERS 中的所有其他药物相比，Dupilumab 对 CTCL 的比例报告比 （PRR） （95% 置信区间，25.0-35.9） 的 30.0 倍。45 至 65 岁的男性风险最高。度普利尤单抗已知的不良反应——结膜炎、嗜酸性粒细胞增多症和关节痛的 PRR 分别为 35.6 （34.4-36.8）、2.15 （2.00-2.31） 和 2.14 （2.07-2.18）。当报告较少时，使用对数计数归一化 PRR （AE 评分） 来解释 PRR 充气，主要安全性信号包括结膜炎 （AE 评分 8.3） 和 CTCL （AE 评分 4.9）。 大量 RNA 测序数据显示 CTCL 和特应性皮炎 （AD） 活检样本表皮层中 IL-4RA 和 IL-13RA1 表达的变化。单细胞转录组学研究表明，这种变化在 AD 和 CTCL 中相似，并且角质形成细胞似乎是 IL-4R 和 IL-13RA1 方面差异最大的细胞类型。在可用的大量 RNA 测序数据中也独立观察到对角质形成细胞特异性基因表达的影响。结论 这些数据表明，度普利尤单抗可能通过与改善 AD 的相同机制导致 CTCL 的揭露或进展：IL-13 受体阻断，导致局部环境中 IL-13 增加，驱动 CTCL 刺激和进展。然而，鉴于 FAERS 数据库和我们的非实验方法的固有局限性，这些关联需要进一步评估。