- 學位論文
含Janus kinase(JAK)抑制劑類成分藥品安全性之比較
Safety Comparison of Janus Kinase Inhibitors
摘要
研究目的： JAK抑制劑是一種新型的小分子口服藥物，用於許多免疫介導發炎性疾病中，越來越多疾病發現可以透過抑制JAK-STAT signaling pathway來達到抑制疾病發展的效果，但其安全性在目前仍具爭議性。本研究透過國家資料庫研究在臺灣接受JAK抑制劑治療後，不同JAK抑制劑的感染（帶狀皰疹、肺結核）、重大心血管疾患（major adverse cardiovascular event，MACE）以及死亡風險及其之間的異同，藉以探討其相對安全性差異。 研究方法及資料： 本研究串聯2018-2020年臺灣全民健康保險資料庫、內政部死亡原因檔，收集在此期間接受JAK抑制劑治療的患者進行分析。共納入 4976人（n= 4976）作為研究對象，首先分類疾病觀察在臺灣健保給付適應症下藥物的利用情形，再將患者分成三種藥物組：Tofacitinib（n= 3855）、Baricitinib（n= 429）、Ruxolitinib（n= 692），統計分析病患感染、MACE及死亡的風險高低。 研究結果： 根據本研究結果，發現於感染風險分析中，Ruxolitinib的感染風險高於Tofacitinib（aHR：1.609；95% CI，1.255-2.062；p＝0.0002），於總死亡率風險分析中，使用Ruxolitinib與Tofacitinib相比死亡風險也顯著增加（aHR：4.782；95% CI，2.944-7.767；p < 0.0001），但由於在本研究中，主要使用Ruxolitinib與Tofacitinib患者的適應症不同，Ruxolitinib為被診斷為骨髓纖維化患者佔大多數（55.62%），Tofacitinib則為類風濕性關節炎（96.49%），在判讀本研究結果時須考量到疾病本身之風險。而心血管疾病、中風、深層靜脈栓塞的風險，於三者中皆無觀察到顯著差異。 結論與建議： 隨著越來越多疾病發現可以透過抑制JAK-STAT signaling pathway來達到抑制疾病發展的效果，JAK抑制劑在核准中的適應症越來越多，其安全性議題也越來越需要被注意，於本研究比較結果中，發現三種不同JAK抑制劑於心血管方面有相似的安全性，而在死亡及感染風險中Ruxolitinib顯著高於Tofacitinib，但也須考慮適應症疾病本身即為影響風險之可能相關因子，未來需要更多大型、長期研究來闡明更多不同JAK抑制劑之間之安全性差異，以利醫事人員做為用藥選擇上的判斷參考依據。
並列摘要
Purpose： JAK inhibitors are novel small-molecule oral drugs which can be used for the treatment of immune-mediated inflammatory diseases. There are a lot of diseases have been found to inhibit the progress of deseases by inhibiting the JAK-STAT signal pathway. However, their safty issues are still concerned. This study aimed to investigate the risk of infection (herpes zoster, tuberculo-sis), major adverse cardiovascular event (MACE), and death risk and their relationship with different JAK inhibitors in Taiwan national health insur-ance database, and further discuss their safety profiles. Methods: The data of the patients who received JAK inhibitor therapy was collected from Taiwan national health insurance database and the cause of death files from the Ministry of the Interior during 2018 to 2020, totally 4976 persons were involved（n= 4976）. First of all, the diseases were classified to ob-serve the utilization of these drugs under Taiwan health insurance payment indications. Followed by dividing the patients into three drug groups: Tofa-citinib（n= 3855）, Baricitinib（n= 429）, and Ruxolitinib（n= 692）, and then statistically analyze the risk of infection, MACE, and death of the pa-tients. Results: The results showed that the infection risk of Ruxolitinib was higher than that of Tofacitinib (aHR: 1.609; 95% CI, 1.255-2.062; p=0.0002), the risk of death was also significantly increased in Ruxolitinb when compared to Tofa-citinib (aHR: 4.782; 95% CI, 2.944-7.767; p < 0.0001). However, as the in-dications of Ruxolitinib and Tofacitinib are different, the risk of the disease itself must be considered when interpreting the results of this study. No sig-nificant difference was observed in the risks of cardiovascular disease, stroke, and deep vein thrombosis among the three incestigated JAK inhibitors. Conclusion: In the comparative results of this study, three different JAK inhibitors have similar safety profiles regarding cardiovascular, but the risk of death and in-fection of Ruxolitinib is significantly higher than that of Tofacitinib. The impact of the indication itself should be also considered during evaluating. It’s suggested that the large-scale and long-term studies are needed to clarify the safety differences between different JAK inhibitors, so that the healthcare professional can choose the suitable medication by referring these studies.