魏正宗黃景揚WEI, CHENG-CHUNGHUANG, JING-YANG陳昱潔CHEN, YU-JIEYU-JIECHEN醫學研究所碩士班2026-10-292028-12-3120262026-07-02https://handle.ncl.edu.tw/11296/aut6mphttps://scholars.csmu.edu.tw/handle/123456789/36775研究背景及目的：異位性皮膚炎（Atopic Dermatitis, AD）是一種高度流行的非傳染性疾病，其導致的失能調整生命年（disability-adjusted life-years, DALY）負擔居所有皮膚疾病之冠，嚴重影響全球中重度 AD 患者的生活品質。AD 的核心病理機制涉及皮膚屏障功能缺損與隨之引發的 Th2 型免疫失調。既有文獻已指出，由於皮膚屏障受損、免疫異常及搔抓行為，AD 患者罹患細菌、病毒及真菌等皮膚感染乃至全身性感染（如肺炎、泌尿道感染、敗血症）的風險顯著增高。目前治療 AD 的藥物除了傳統的類固醇、抗組織胺及照光治療等，還有針對中至重度患者的精準治療選項，包含生物製劑和口服標靶小分子新藥，Dupilumab（一種抑制IL-4與IL-13訊號的生物製劑）及 Janus 激酶抑制劑（JAKi，一類口服標靶小分子藥物）已成為重要的治療選項，兩者均透過不同的免疫調節路徑展現療效。然而真實世界環境下，此二類藥物對 AD 患者感染的相對風險差異仍有待闡明。因此，本研究旨在利用大型電子病歷數據庫，比較接受 Dupilumab 與 JAK 抑制劑治療的中重度 AD 患者，其發生各類感染事件的風險差異。材料方法：本研究為一項回溯性世代研究，數據來源為 TriNetX 全球健康研究網絡。研究對象定義為2022年1月1日至2025年12月31日期間，首次接受全身性治療之中重度異位性皮膚炎患者。每位受試者自索引日期（Index Date）起，接受最長達四年的追蹤分析。研究將納入年齡12歲（含）以上，經確診為 AD 並初次接受 Dupilumab、JAK 抑制劑或傳統全身性藥物（如 Cyclosporine 或 Methotrexate）治療之患者，研究依用藥類型分為三組，並採取兩兩相互對照（Head-to-head pairwise comparisons）之方式，進行安全性與療效的評估。為確保比較組間的基線特徵均衡，將採用傾向分數（Propensity Score, PS）以1:1比例，針對年齡、性別、種族、合併症及併用藥物等潛在混淆變項進行配對。主要觀察終點為治療期間發生之特定感染事件的發生率，包括皮膚（細菌、病毒、真菌）感染、肺炎、泌尿道感染及敗血症等。將使用 Kaplan-Meier 法估算累積感染發生率，並以 log-rank 檢定比較組間差異。Cox 比例風險模型將用於計算校正後之風險比（Hazard Ratio, HR）及其95%信賴區間（Confidence Interval, CI）。結果： 在皮膚感染相關結果上，新興標靶藥物相較傳統療法呈現較低或相近的感染風險；惟本研究為觀察性資料分析，應避免直接推論為預防效果。研究結果顯示，Dupilumab 在預防多項皮膚相關併發症中具有顯著優勢，特別是相較於傳統治療，其能顯著降低整體皮膚感染的發生風險達33%（HR = 0.67, 95% CI: 0.55-0.81; p < 0.001），並能顯著減少細菌性感染達34%（HR = 0.66, 95% CI: 0.50-0.87; p = 0.003）；在其他細項方面，其不僅能顯著降低蜂窩性組織炎與急性淋巴管炎風險達34%（HR = 0.66, 95% CI: 0.44-1.00; p = 0.046），對於其他皮膚及皮下組織的局部感染亦能大幅減少51%的發生風險（HR = 0.49, 95% CI: 0.31-0.78; p = 0.002）。此外，在皮膚真菌病防護上，Dupilumab 組同樣表現優異，能顯著降低整體真菌感染風險達44%（HR = 0.56, 95% CI: 0.40-0.79; p = 0.001），其中尤以皮癬菌的防護最為顯著，風險降低達47%（HR = 0.53, 95% CI: 0.36-0.78; p = 0.001）。相較之下，JAK 抑制劑與傳統治療相比，在整體皮膚感染（p = 0.059）、細菌性感染（p = 0.306）及真菌感染（p = 0.050）等各項風險表現上，皆未達統計學上的顯著差異。進一步針對 JAK 抑制劑與 Dupilumab 進行兩兩對照分析發現，兩者在多數感染項目上的風險表現存在部分顯著差異。數據顯示，JAKi 組在整體皮膚感染的發生風險顯著高於 Dupilumab 組（HR = 1.27, 95% CI: 1.02-1.57; p = 0.031）；在其他細項中，特別是細菌性感染項目，JAKi 組的風險明顯增加46%（HR = 1.46, 95% CI: 1.07-2.00; p = 0.015），其中膿疱的發生風險更是 Dupilumab 組的2.46倍（HR = 2.46, 95% CI: 1.25-4.84; p = 0.007）。至於在病毒與真菌感染指標方面，包含單純疱疹（p = 0.966）、病毒疣（p = 0.685）及皮癬菌（p = 0.836），兩種標靶藥物組間均未觀察到統計學上的顯著風險差異。值得注意的是，本研究亦針對器官外感染與全身性嚴重感染進行深度評估。在呼吸道與眼部感染方面，不論是上呼吸道感染、急性鼻竇炎或結膜炎，三種療法之間的風險皆無顯著差異。而在具有高度臨床意義的嚴重或全身性感染事件中，各組間多展現出相近的安全性特徵，例如在敗血症指標上，JAKi 組與 Dupilumab 組相比並無顯著風險增加（p = 0.905）。然而在肺炎項目中，對照數據顯示 Dupilumab 組相較於 JAKi 組能顯著降低 51%的肺炎發生風險（HR = 0.49, 95% CI: 0.26-0.95; p = 0.031），但在標靶藥物與傳統治療的對比中（Dupilumab vs. CONV, p = 0.785; JAKi vs. CONV, p = 0.704），皆未見統計學上的顯著風險增加趨勢。結論：本研究顯示，新興標靶藥物在異位性皮膚炎治療中展現良好安全性。Dupilumab 與較低的皮膚與皮下組織局部感染、蜂窩性組織炎及皮癬菌等真菌感染風險相關，且相較於傳統療法呈現較佳安全性訊號；而 JAK 抑制劑在多數感染指標上與傳統療法相當，但在整體皮膚感染、細菌性感染以及膿疱疹的特定局部風險上顯著高於 Dupilumab。值得注意的是，三組療法在敗血症等嚴重全身性感染風險上均無統計學差異，儘管 Dupilumab 在肺炎防護上相較於 JAK 抑制劑展現出更好的安全性優勢，但整體而言，標靶藥物在提升療效的同時，並未增加嚴重的全身性感染負擔，可作為臨床個人化用藥之重要參考。Background and Objective:Atopic dermatitis (AD) is a highly prevalent non-communicable disease. Its burden, measured in disability-adjusted life-years (DALYs), ranks highest among all skin diseases, severely impacting the quality of life for patients with moderate-to-severe AD worldwide. The core pathogenesis of AD involves skin barrier defects and subsequent Th2-skewed immune dysregulation. Existing literature indicates that due to impaired skin barriers, immune abnormalities, and scratching behaviors, AD patients have a significantly increased risk of cutaneous infections (bacterial, viral, and fungal) as well as systemic infections (e.g., pneumonia, urinary tract infections, and sepsis). Current treatments for AD include traditional corticosteroids, antihistamines, and phototherapy, alongside precision therapeutic options for moderate-to-severe cases, such as biologics and oral targeted small molecules. Dupilumab (a biologic inhibiting IL-4 and IL-13 signaling) and Janus kinase inhibitors (JAKi, a class of oral targeted small molecules) have emerged as crucial therapeutic options, both demonstrating efficacy through different immunomodulatory pathways. However, the comparative risk of infections between these two classes of drugs in real-world settings remains to be elucidated. Therefore, this study aims to utilize a large electronic health record database to compare the risk of various infection events among moderate-to-severe AD patients treated with Dupilumab versus JAK inhibitors.Materials and Methods:This was a retrospective cohort study utilizing data from the TriNetX global health research network. The study population was defined as patients with moderate-to-severe AD who received their first systemic treatment between January 1, 2022, and December 31, 2025. Each subject was followed for up to four years from the index date. The study included patients aged 12 years and older with a confirmed diagnosis of AD who were initially prescribed Dupilumab, JAK inhibitors, or conventional systemic therapies (CONV; e.g., Cyclosporine or Methotrexate). Patients were categorized into three groups based on their treatment modality, and head-to-head pairwise comparisons were conducted to evaluate safety and efficacy. To ensure balanced baseline characteristics between comparator groups, 1:1 propensity score (PS) matching was performed, adjusting for potential confounders including age, sex, race, comorbidities, and concomitant medications. The primary endpoints were the incidence rates of specific infection events during the treatment period, including cutaneous infections (bacterial, viral, fungal), pneumonia, urinary tract infections, and sepsis. The Kaplan-Meier method was used to estimate the cumulative incidence of infections, and the log-rank test was applied to compare differences between groups. Cox proportional hazards models were utilized to calculate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs).Results:Regarding the overall prevention of cutaneous infections, emerging targeted therapies demonstrated better safety profiles compared to conventional therapies. Results showed that Dupilumab had a significant advantage in preventing multiple skin-related complications. Specifically, compared to CONV, Dupilumab significantly reduced the risk of overall cutaneous infections by 33% (HR = 0.67, 95% CI: 0.55-0.81; p < 0.001) and bacterial infections by 34% (HR = 0.66, 95% CI: 0.50-0.87; p = 0.003). In other subcategories, it not only significantly lowered the risk of cellulitis and acute lymphangitis by 34% (HR = 0.66, 95% CI: 0.44-1.00; p = 0.046) but also substantially decreased the risk of other local infections of the skin and subcutaneous tissue by 51% (HR = 0.49, 95% CI: 0.31-0.78; p = 0.002). Furthermore, in the protection against cutaneous fungal diseases, the Dupilumab group also performed exceptionally well, significantly reducing the risk of overall fungal infections by 44% (HR = 0.56, 95% CI: 0.40-0.79; p = 0.001), with the most notable protection against dermatophytosis, showing a risk reduction of 47% (HR = 0.53, 95% CI: 0.36-0.78; p = 0.001). In contrast, when compared to CONV, JAKi did not reach statistical significance in the risks of overall cutaneous infections (p = 0.059), bacterial infections (p = 0.306), and fungal infections (p = 0.050).Further head-to-head pairwise analysis between JAK inhibitors and Dupilumab revealed significant differences in risk profiles across most infection categories. Data indicated that the risk of overall cutaneous infections was significantly higher in the JAKi group compared to the Dupilumab group (HR = 1.27, 95% CI: 1.02-1.57; p = 0.031). Among the subcategories, particularly in bacterial infections, the JAKi group showed a notably increased risk of 46% (HR = 1.46, 95% CI: 1.07-2.00; p = 0.015), and the risk of impetigo was 2.46 times higher than that of the Dupilumab group (HR = 2.46, 95% CI: 1.25-4.84; p = 0.007). Regarding viral and fungal infection indicators, including herpes simplex (p = 0.966), viral warts (p = 0.685), and dermatophytosis (p = 0.836), no statistically significant risk differences were observed between the two targeted therapy groups.Notably, this study also conducted an in-depth evaluation of extracutaneous and severe systemic infections. In terms of respiratory and ocular infections, including upper respiratory tract infections, acute sinusitis, and conjunctivitis, no significant risk differences were found among the three therapies. For highly clinically significant outcomes of severe or systemic infections, the groups generally exhibited similar safety profiles; for instance, regarding sepsis, the JAKi group showed no significant risk increase compared to the Dupilumab group (p = 0.905). However, for pneumonia, the comparative data showed that the Dupilumab group had a significantly reduced risk of 51% compared to the JAKi group (HR = 0.49, 95% CI: 0.26-0.95; p = 0.031). Nevertheless, in comparisons between targeted therapies and conventional treatments (Dupilumab vs. CONV, p = 0.785; JAKi vs. CONV, p = 0.704), no statistically significant upward trend in risk was observed.Conclusion:This study demonstrates that emerging targeted therapies exhibit favorable safety profiles in the treatment of atopic dermatitis. Dupilumab is significantly superior to conventional therapies in preventing local infections of the skin and subcutaneous tissue, cellulitis, and fungal infections such as dermatophytosis. Meanwhile, JAK inhibitors are comparable to conventional therapies across most infection indicators but carry a significantly higher risk than Dupilumab for overall cutaneous infections, bacterial infections, and specific local risks such as impetigo. Notably, there were no statistical differences among the three treatment groups regarding the risk of severe systemic infections like sepsis. Although Dupilumab demonstrated a better safety advantage over JAK inhibitors in pneumonia protection, overall, targeted therapies do not increase the burden of severe systemic infections while enhancing therapeutic efficacy. These findings can serve as a crucial reference for personalized clinical prescribing.異位性皮膚炎DupilumabJanus Kinase Inhibitors感染風險TriNetX真實世界數據Atopic DermatitisInfection RiskReal-World Datathesis