比較Janus kinase 激酶抑制劑與腫瘤壞死因子抑制劑對於類風濕性關節炎關聯之間質性肺病的療效：以TriNetX電子病歷資料庫之回溯性世代研究

研究背景：類風溼性關節炎是一種慢性的發炎疾病，有著許多關節外的影響，間質性肺病是其中之一。目前對於類風濕性關節炎關聯的間質性肺病的治療，目前仍沒有專述的治療指引，並在各式藥物的療效上仍有許多待解之處。研究目的：本研究旨在研究新型標靶小分子藥物，Janus kinase激酶抑制劑，對比腫瘤壞死因子抑制劑於類風濕性關節炎關聯的間質性肺病的療效。研究方法及資料： 本研究利用TriNetX電子病歷資料庫進行回溯性世代研究，收錄診斷有類風濕性關節炎及關聯間質性肺病的患者，且這些患者必須有新接受Janus kinase 激酶抑制劑與腫瘤壞死因子抑制劑。研究的收錄期間設定為自2017年1月1日至2021年12月31日。主要研究目標是比較兩組的全死因死亡率，而次要的目標是醫療利用率，包括住院率、重症利用率及呼吸器使用率。統計方式為利用傾向評分匹配將兩組配對，研究組是使用Janus kinase 激酶抑制劑，而對照組則使用腫瘤壞死因子抑制劑。 分析則使用Cox迴歸模型分析，以風險比及95%信賴區間來衡量相對風險。亞群分析則針對可能影響之變數來分析。研究結果：總共收錄23,707位 類風濕性關節炎及關聯間質性肺病的患者，經過傾向評分匹配，兩組(Janus kinase 激酶抑制劑與腫瘤壞死因子抑制劑)各有812位患者。在Janus kinase 激酶抑制劑組別，相較於腫瘤壞死因子抑制劑組別，有較高的全死因死亡率(風險比(HR) 1.458, 95% 信賴區間(CI): 1.136-1.870)。在次要分析，在Janus kinase 激酶抑制劑組別，相較於腫瘤壞死因子抑制劑組別，有較高的住院率(HR 1.167, 95% CI: 1.011-1.348)、重症利用率(HR 1.854, 95% CI: 1.414-2.431)及呼吸器使用率(HR 2.609, 95% CI: 1.718-3.962)。以不同年齡來做亞群分析，65歲的患者，Janus kinase 激酶抑制劑組別有較高的全因死亡率(HR 1.815, 95% CI: 1.316-2.503)；若以心血管疾病風險因子有無來分析，在Janus kinase 激酶抑制劑組別，有心血管疾病風險因子其全因死亡率(HR 1.636, 95% CI: 1.197-2.237)、重症利用率(HR 1.929, 95% CI: 1.378-2.700)及呼吸器使用率(HR 2.539, 95% CI: 1.502-4.293)較高。結論： 針對類風濕性關節炎關聯之間質性肺病的治療，需要個人化的考量選擇，65歲以上或是有心血管疾病的相關風險因子的患者在選用Janus kinase 激酶抑制劑時要特別注意相關的風險。

Background：Rheumatoid arthritis (RA) is a chronic inflammatory disease with several extra-articular manifestations of RA, one of which is interstitial lung disease (ILD). Currently, there are no established specific treatment guidelines for rheumatoid arthritis-associated interstitial lung disease, and there remain many unresolved issues regarding the efficacy of various medications.Objective：The objective of this study is aimed to investigate the effectiveness of Janus kinase inhibitors (JAKi), a novel targeted small molecular drug, and tumor necrosis factor inhibitors (TNFi) on RA-ILD.Methods and Materials：We conducted a retrospective cohort study using TriNetX database. The study enrolled the patients diagnosed with RA-ILD and have new prescription with JAKi or TNFi during the study period, from January 1, 2017, to December 31, 2021. We separate the patients into two groups, one is JAKi cohort, the other is TNFi cohort. Primary outcome was defined as all-cause mortality, and secondary outcome was defined as healthcare utilizations, including hospitalization, critical care services, and mechanical ventilation. We performed the propensity score matching and set JAKi cohort as study group and TNFi cohort as control group. We conducted the Cox regression model to investigate the risk with representation of hazard ratios (HRs) and 95% confidence interval (CI). Subgroup analyses were also conducted with the potential variables.Results：Among the 23,707 patients, 812 patients were included in each group after propensity score matching. A higher risk of all-cause mortality was found in JAKi cohort compared to TNFi cohort in the primary analysis (HR 1.458, 95% CI: 1.136-1.870). A higher risk of healthcare utilizations was also demonstrated, including hospitalization (HR 1.167, 95% CI: 1.011-1.348), critical care services (HR 1.854, 95% CI: 1.414-2.431), and mechanical ventilation (HR 2.609, 95% CI: 1.718-3.962). Subgroup analysis demonstrated a higher risk of all-cause mortality in JAKi cohort compared to TNFi, especially in the patients aged over 65 years (HR 1.815, 95% CI: 1.316-2.503), and with additional cardiovascular risk factors (HR 1·636, 95% CI: 1·197-2·237).Conclusion：This retrospective cohort study demonstrated the results of a higher risk of all-cause mortality and healthcare utilizations among the JAKi cohort, particularly in the elder patients and patients with additional cardiovascular risk factors. Personalized approaches of treatment of RA-ILD should be considered in every patient when selecting appropriate strategies, especially in using JAKi among the risky patients.