Tanaka Hideyuki, Maezawa Mika, Tanaka Mizuki, Umetsu Ryogo, Hirofuji Sakiko, Miyasaka Koumi, Nakao Satoshi, Nokura Yuka, Yamashita Moe, Ichihara Nanaka, Sugishita Kana, Yamazaki Tomofumi, Shiota Kohei, Tamaki Hirofumi, Iguchi Kazuhiro, Nakamura Mitsuhiro
Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu-shi, Japan.
Chubuyakuhin Co., Ltd., Tajimi-shi, Gifu, Japan.
SAGE Open Med. 2025 Jun 24;13:20503121251348420. doi: 10.1177/20503121251348420. eCollection 2025.
Ruxolitinib is used to treat myelofibrosis, polycythemia vera, and steroid-refractory graft-versus-host disease following allogeneic stem cell transplantation. This study aimed to determine the association between ruxolitinib and adverse events by evaluating case reports published between January 2014 and March 2024 in the Japanese Adverse Drug Event Report database.
The signals for the ruxolitinib-adverse event association were identified using propensity score-adjusted reporting odds ratio analysis. Data obtained from the drug-gene interaction, drug signature, search tool for chemical interactions, and interaction reference index databases were used to construct a drug-gene interaction network. Functional and pathway enrichment analyses were performed using the Disease Ontology Semantic and Enrichment and ReactomePA R packages.
The propensity score-adjusted reporting odds ratio for ruxolitinib-associated adverse events was as follows: anemia, 18.49 (95% confidence interval (CI): 16.15-21.16); myelosuppression, 4.70 (95% CI: 3.54-6.24); pancytopenia, 1.97 (95% CI: 1.23-3.16); cardiac failure, 2.29 (95% CI: 1.60-3.28); hepatic function abnormal, 1.60 (95% CI: 1.15-2.23); herpes zoster, 6.40 (95% CI: 4.35-9.41); pneumonia, 2.96 (95% CI: 2.35-3.73); renal impairment, 1.34 (95% CI: 0.94-1.90); sepsis, 5.14 (95% CI: 3.75-7.05); interstitial lung disease, 0.33 (95% CI: 0.21-0.52); deep vein thrombosis, 0.32 (95% CI: 0.07-1.44); hemorrhage, 1.99 (95% CI: 1.05-3.75). We also assessed 3015 human genes that directly or indirectly interact with ruxolitinib. The molecular complex detection plug-in of Cytoscape was used to detect 24 clusters. Several genes were enriched in the biological processes of "anemia" and "bacterial infections," identified as significant ruxolitinib-related disease terms.
This retrospective analysis using the Japanese Adverse Drug Event Report database indicated potential associations between ruxolitinib and adverse events, including anemia and bacterial infections. Future research should explore the underlying pharmacological mechanisms using functional enrichment analysis of ruxolitinib-associated genes related to blood toxicity and bacterial infections.
芦可替尼用于治疗骨髓纤维化、真性红细胞增多症以及异基因干细胞移植后类固醇难治性移植物抗宿主病。本研究旨在通过评估2014年1月至2024年3月期间日本药品不良事件报告数据库中发表的病例报告，确定芦可替尼与不良事件之间的关联。
使用倾向评分调整后的报告比值比分析来识别芦可替尼与不良事件关联的信号。从药物-基因相互作用、药物特征、化学相互作用搜索工具和相互作用参考索引数据库中获取的数据用于构建药物-基因相互作用网络。使用疾病本体语义和富集以及ReactomePA R包进行功能和通路富集分析。
芦可替尼相关不良事件的倾向评分调整后的报告比值比如下：贫血，18.49（95%置信区间（CI）：16.15 - 21.16）；骨髓抑制，4.70（95% CI：3.54 - 6.24）；全血细胞减少，1.97（95% CI：1.23 - 3.16）；心力衰竭，2.29（95% CI：1.60 - 3.28）；肝功能异常，1.60（95% CI：1.15 - 2.23）；带状疱疹，6.40（95% CI：4.35 - 9.41）；肺炎，2.96（95% CI：2.35 - 3.73）；肾功能损害，1.34（95% CI：0.94 - 1.90）；败血症，5.14（95% CI：3.75 - 7.05）；间质性肺病，0.33（95% CI：0.21 - 0.52）；深静脉血栓形成，0.32（95% CI：0.07 - 1.44）；出血，1.99（95% CI：1.05 - 3.75）。我们还评估了3015个与芦可替尼直接或间接相互作用的人类基因。使用Cytoscape的分子复合物检测插件检测到24个簇。几个基因在“贫血”和“细菌感染”的生物学过程中富集，被确定为与芦可替尼相关的重要疾病术语。
这项使用日本药品不良事件报告数据库的回顾性分析表明芦可替尼与不良事件之间存在潜在关联，包括贫血和细菌感染。未来的研究应通过对与血液毒性和细菌感染相关的芦可替尼相关基因进行功能富集分析，探索潜在的药理机制。
