BACKGROUND There have been multiple reports of the anti-IL4Rα agent, dupilumab, as 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 possible underlying mechanism(s) for the potential association. METHODS First, we used the FDA pharmacovigilance database, FAERS, to evaluate if dupilumab was associated with CTCL including both positive controls (conjunctivitis, eosinophilia, and arthralgia) and exposure controls (other medications with similar indications including JAK-inhibitors and the anti-IL13, tralokinumab,) to reduce and evaluate confounding bias. Thereafter, we used publicly available bulk and single cell-RNA seq datasets to probe possible underlying mechanisms through which dupilumab might be associated with CTCL. RESULTS Between January 2019 and Q2 of 2023, there were 181,575 unique reports of dupilumab related adverse events (AE) in FAERS with 606 of these being for a neoplasm. Dupilumab had 30.0 times the proportional reporting ratio (PRR) (95% CI: 25.0 - 35.9) for CTCL compared to all other medications in FAERS. The risk was highest in males aged 45-65. The PRR for conjunctivitis, eosinophilia, and arthralgia, known side 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 (AEscore 8.3) and CTCL (AEscore 4.9). Bulk RNA sequencing data showed changes in IL4RA and IL13RA1 expression in CTCL and in epidermal layers of atopic dermatitis (AD) biopsies. 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 IL4R and IL13RA1. 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 atopic dermatitis: IL13 receptor blockade, which leads to increased IL13 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 non-experimental 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 已有多篇报道称抗 IL4Rα 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。方法 首先，我们使用 FDA 药物警戒数据库 FAERS 来评估 dupilumab 是否与 CTCL 相关，包括阳性对照（结膜炎、嗜酸性粒细胞增多和关节痛）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 IL13，tralokinumab），以减少和评估混杂偏倚。此后，我们使用公开可用的大量和单细胞 RNA seq 数据集来探索 dupilumab 可能与 CTCL 相关的可能潜在机制。结果在 2019 年 1 月至 2023 年第二季度期间，FAERS 中有 181,575 例 dupilumab 相关不良事件 （AE） 的独特报告，其中 606 例是针对肿瘤的。与 FAERS 中的所有其他药物相比，度普利尤单抗的 CTCL 比例报告比 （PRR） （95% CI： 25.0 - 35.9） 是 30.0 倍。45-65 岁的男性风险最高。度普利尤单抗已知的副作用结膜炎、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，使用对数计数标准化 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） 活检表皮层中 IL4RA 和 IL13RA1 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，角质形成细胞似乎是 IL4R 和 IL13RA1 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改善特应性皮炎的相同机制导致 CTCL 的揭露或进展：IL13 受体阻断，导致局部环境中 IL13 增加，驱动 CTCL 刺激和进展。然而，鉴于 FAERS 数据库的固有局限性和我们的非实验方法，这些关联需要进一步评估。