比較upadacitinib與新機轉藥物在乾癬性關節炎患者之療效及安全性：系統性文獻回顧及網絡統合分析

Abstract

背景： Upadacitinib是近年通過核准治療活動性乾癬性關節炎 (psoriatic arthritis, PsA) 患者之口服標靶免疫調節藥物，本研究以系統性回顧方式整理相關臨床試驗實證並進行網絡統合分析 (network meta-analysis, NMA) ，以了解upadacitinib相較於其他新機轉藥物之療效及安全性差異。 研究方法：搜尋PubMed/Medline及Embase資料庫，截至2022年4月30日發表有關以JAK(Janus activated kinase)抑制劑(upadacitinib和tofacitinib)、新機轉生物製劑(介白素(interleukin, IL)-12/23抑制劑、IL23抑制劑及IL17抑制劑)及活性對照組腫瘤壞死因子(tumor necrosis factor, TNF)抑制劑adalimumab為試驗藥物之隨機對照試驗，進行頻率學派NMA。分析之療效項目包括ACR (American College of Rheumatology Responses) 20/50/70、PASI (Psoriasis Area Severity Index) 75/90/100、指(趾)炎消退、接骨點炎消退、健康評估量表-失能指數 (Health Assessment Questionnaire-Disability Index, HAQ-DI)及最低疾病活動度，安全性項目為不良反應、嚴重藥物不良反應、感染、惡性腫瘤及主要心血管事件，並以P 分數(P-score)進行最佳效果排序。 研究結果： 共收錄22個隨機分派試驗進行網絡統合分析。Upadacitinib 15 mg相較於新機轉藥物，在ACR反應之療效與大多藥物相當，其中與新機轉生物製劑之核准劑量及tofacitinib相比有療效較優之傾向；而PASI療效雖與adalimumab相當，但卻顯著差於其餘新機轉之生物製劑；在指(趾)炎、接骨點炎消退、HAQ-DI及MDA，與生物製劑並無明顯優劣情形；另安全性結果項目中，upadacitinib 30 mg發生不良反應(P分數=0.05) 、嚴重藥物不良反應(P分數=0.06)及感染(P分數=0.06)之風險都較高。不論是療效或是安全性結果項目，其短期和長期治療大致呈現一致的結果。 結論： 在此NMA結果中，upadacitinib在改善周邊關節炎之療效，與其他藥物相當或有略優的趨勢，但在皮膚緩解效果則較差，故建議upadacitinib較適用於周邊關節療效較嚴重之患者，但用藥時需審慎評估藥物所產生之副作用風險。

Background: Upadacitinib is an oral targeted immunomodulatory drug approved in recent years for the treatment of patients with active psoriatic arthritis (PsA). This study systematically reviewed relevant clinical trials and conducted a network meta-analysis (NMA) to understand the differences in efficacy and safety of upadacitinib compared with other novel drugs. Methods: A systematic review was conducted by searching Pubmed/Medline and Embase databases for randomized controlled trials (RCTs) of JAK inhibitors (upadacitinib and tofacitinib) or novel biologics (interleukin (IL)-12/23 inhibitors, IL-23 inhibitors, and IL-17 inhibitors) and tumor necrosis factor(TNF) inhibitor adalimumab in patients with psoriatic arthritis, up to April 30th, 2022. Frequentist random-effect NMA were performed to compare upadacitinib with other included treatments on the efficacy outcomes, including American College of Rheumatology (ACR) 20/50/70 response, Psoriasis Area Severity Index (PASI) 75/90/100, resolution of dactylitis, resolution of enthesitis, Health Assessment Questionnaire-Disability Index(HAQ-DI) and minimal disease activity(MDA); and safety outcomes include adverse events (AEs), serious adverse events (SAEs), infection, malignancy and major cardiovascular events (MACE). The ranking for each treatment was calculated by the p-score. Results: A total of 22 randomized controlled trials were included for NMA. The result showed that upadacitinib 15 mg is comparable to most of the drugs in ACR response, and is superior to the licensed dose of novel biologics. Though, this superiority is not statistically significant. Despite the efficacy of upadacitinib in PASI response is comparable to adalimumab, it is significantly inferior to novel biologics. Regarding the resolution of dactylitis, resolution of enthesitis, HAQ-DI, and MDA outcomes, there’re no significant differences among the treatments. In safety outcomes, upadacitinib 30 mg ranked a higher risk of adverse events (P-score = 0.05), serious adverse events (P-score = 0.06), and infections (P-score = 0.06). The results in short-term trials were roughly consistent with long-term trials in either efficacy or safety outcomes. Conclusions: In this NMA, the efficacy of upadacitinib is comparable or tendency toward superior to other treatments in articular response, but the efficacy on the skin is poor. Therefore, upadacitinib seems to be a favorable treatment option for patients with severe articular manifestation. However, the risk of adverse events for upadacitinib should take into concern.