综合流行病学和免疫转录组学揭示了皮肤淋巴瘤在接受杜比单抗治疗后出现隐匿或恶化的风险和潜在机制。

IF 11.4 1区 医学 Q1 ALLERGY
Javier S Cabrera-Perez, Vincent J Carey, Oreofe O Odejide, Sonal Singh, Thomas S Kupper, Shiv S Pillai, Scott T Weiss, Ayobami Akenroye
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引用次数: 0

摘要

背景:关于抗IL4Rα药物杜匹单抗与皮肤T细胞淋巴瘤(CTCL)的发病和/或进展有关的报道很多:有多篇报道称抗IL4Rα药物杜匹单抗与皮肤T细胞淋巴瘤(CTCL)的发生和/或进展有关: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内在机制:首先,我们使用 FDA 药物警戒数据库 FAERS 来评估杜匹鲁单抗是否与 CTCL 相关,包括阳性对照(结膜炎、嗜酸性粒细胞增多症和关节痛)和暴露对照(具有类似适应症的其他药物,包括 JAK 抑制剂和抗 IL13 药物曲洛单抗),以减少和评估混杂偏倚。此后,我们利用公开的大样本和单细胞RNA seq数据集来探究dupilumab可能与CTCL相关的潜在机制:结果:2019年1月至2023年第二季度,FAERS共收到181575份与杜匹单抗相关的不良事件(AE)报告,其中606份报告涉及肿瘤。与FAERS中的所有其他药物相比,杜匹单抗的CTCL比例报告比(PRR)为30.0倍(95% CI:25.0 - 35.9)。45-65岁男性的风险最高。Dupilumab的已知副作用结膜炎、嗜酸性粒细胞增多和关节痛的PRR分别为35.6(34.4 - 36.8)、2.15(2.00 - 2.31)和2.14(2.07 - 2.18)。使用对数归一化 PRR(AE 评分)来考虑报告较少时的 PRR 膨胀,最高的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,IL4RA 和 IL13RA1 在 CTCL 和特应性皮炎(AD)活检组织表皮层的表达发生了变化。单细胞转录组研究显示,这种变化在 AD 和 CTCL 中相似,而角质形成细胞似乎是 IL4R 和 IL13RA1 表达差异最大的细胞类型。在现有的大量 RNA 测序数据中,也独立观察到了对角朊细胞特异性基因表达的影响:这些数据表明,dupilumab 可能会通过其改善特应性皮炎的相同机制导致 CTCL 的解蔽或进展:这些数据表明,dupilumab 可能通过其改善特应性皮炎的相同机制导致 CTCL 的解蔽或进展:IL13 受体阻断,导致局部环境中 IL13 增加,从而推动 CTCL 的刺激和进展。不过,鉴于 FAERS 数据库的固有局限性和我们的非实验方法,这些关联还需要进一步评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrative epidemiology and immunotranscriptomics uncover a risk and potential mechanism for cutaneous lymphoma unmasking or progression with dupilumab therapy.

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.

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来源期刊
CiteScore
25.90
自引率
7.70%
发文量
1302
审稿时长
38 days
期刊介绍: The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.
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