分析結締組織疾病併發肺動脈高壓的最佳治療：系統性文獻回顧、統合分析以及臨床試驗計畫書

Abstract

背景： 肺動脈高壓（PAH）是結締組織疾病相關的主要併發症之一 (CTD-PAH)，約佔20-30%原發性肺動脈高壓。雖然已有核准PAH治療藥物，但針對CTD-PAH的疾病複雜性與較PAH高的死亡率，目前針對CTD-PAH的治療策略仍不理想，現有的治療指引主要基於專家共識，例如: 2023 TSOC/TCR Guideline，顯示針對該疾病族群之治療方法仍需優化及進一步驗證。本研究藉由分析PAH中次族群之結締組織疾病併發肺動脈高壓 (CTD-PAH)，以實證醫學的角度針對相關療效指標進行統合分析，以其結果規劃於CTD-PAH最佳的治療策略，並擬定相應臨床試驗計畫書以進行驗證。 方法： 本研究根據PRISMA指引對MEDLINE和EMBASE數據庫進行系統性文獻搜索，篩選2000年至2023間發表的隨機分派、安慰劑對照臨床試驗。篩選標準包括需含有CTD-PAH次族群受試者、使用核准的PAH治療藥物、並評估以6分鐘步行距離（6-MWD）、肺血管阻力（PVR）、氮端原生B型利鈉蛋白鏈（NT-proBNP）、平均肺動脈壓（mPAP）、臨床惡化事件（Clinical worsening events）等為主要或次要療效指標。 結果： 經過系統性文獻搜索共有10個隨機對照臨床試驗納入統合分析，其中7篇含CTD-PAH族群之基線數據;含4,372個肺動脈高壓個案，其中1,260名為結締組織疾病併發肺動脈高壓，約占比26%，但並非所有試驗都報告了這一次族群的數據。統合分析結果顯示，在CTD-PAH次族群中，Sildenafil治療在6分鐘步行距離改善了平均55公尺（95% CI: [16.01, 93.99]）; 肺血管阻力、NT-proBNP及臨床惡化事件的分析結果也顯示CTD-PAH治療後有正向改善，但平均肺動脈壓的反應則存在變異。 結論： 研究結果顯示，Sildenafil在CTD-PAH次族群中具顯著的6-MWD改善，成為進一步研究的強力候選藥物。此外，Sotatercept作為新型BMPR2調節劑，在PAH患者中顯示出顯著的6-MWD改善，暨評估，亦表明其對CTD-PAH可能潛在益處。 基於這些結果，提出一項臨床試驗計畫，旨在驗證Sotatercept和Sildenafil在CTD-PAH患者中的療效與安全性。該試驗將是一項第二期、雙盲、隨機對照之臨床研究，評估Sotatercept和Sildenafil在成年CTD-PAH患者中的療效與安全性。Sildenafil作為標準療法已被2023 TSOC/TCR指引推薦，本試驗將設計為非劣效性試驗，證明Sotatercept在療效上不劣於Sildenafil。該試驗將以6分鐘步行距離(6-MWD)為主要終點，同時評估肺血管阻力(PVR)、氨基末端B 型排鈉利尿胜肽前體(NT-proBNP)、平均動脈壓(mPAP)、臨床惡化事件與結締組織疾病自體抗體的變化作為次要終點。受試者將按1:1隨機分配，並根據系統性紅斑狼瘡（SLE）、系統性硬化症（SSc）和其他結締組織疾病進行分層。該設計旨在評估每種治療的療效和安全性，從而改善CTD-PAH患者的預後。通過這些特定療法，試驗旨在優化治療方案，提升患有此類挑戰性疾病患者的生活質量。

Background: Pulmonary arterial hypertension (PAH) is one of the major complications associated with connective tissue diseases (CTD-PAH), representing a substantial subset of the PAH population (20-30%). Despite the availability of approved medications for PAH, the treatment strategies for CTD-PAH remain suboptimal due to the complexity of the disease and its higher mortality rate compared to PAH. Current treatment guidelines are mainly based on expert consensus, i.e., 2023 TSOC/TCR Guideline, indicate the need for further optimization and validation of therapeutic approaches. This meta-analysis aims to assess the optimal treatment strategies for CTD-PAH, offering insights that could guide future clinical trials. Methods: A systematic review and meta-analysis following PRISMA guidelines, searching MEDLINE and PUBMED databases for randomized controlled trials (RCTs) published from 2000 to 2023. Trials included evaluated approved pharmacotherapies in PAH with specific focus on CTD-PAH subgroups, assessing outcomes related to 6-minute walking distance (6-MWD), clinical worsening, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), and N-terminal pro–B-type natriuretic peptide level (NT-proBNP). Results: A total of 10 RCTs were included, encompassing a total of 4,372 participants, of which 1,260 were identified with CTD-PAH, representing approximately 26% of the total. Notably, not all 10 included RCTs reported data specifically for the CTD-PAH subgroup, despite enrolling these patients. The meta-analysis, Sildenafil showed an improvement of 55.00 meters (95% CI: [16.01, 93.99]) in the CTD-PAH subgroup. Analysis of PVR, NT-proBNP, and clinical worsening indicate positive changes post-treatment for CTD-PAH, though the response in mPAP was variable. Conclusion: This meta-analysis shows the need to identify optimal therapies for CTD-PAH. The findings suggest that Sildenafil and Sotatercept, based on their performance in PAH, hold promise for CTD-PAH. Sildenafil showed significant improvement in 6-MWD in CTD-PAH population, making it a strong candidate for further investigation. Additionally, Sotatercept, a novel BMPR2 pathway modulator, demonstrated substantial improvement in 6-MWD in PAH patients, suggesting potential benefits for CTD-PAH as well. Given these results, a proposed clinical trial will validate the efficacy of Sotatercept and Sildenafil in CTD-PAH patients. This phase 3, double-blinded, randomized controlled clinical study will evaluate the efficacy and safety of Sotatercept and Sildenafil in adult participants with CTD-PAH. The 6-MWD as the primary endpoint and PVR, NT-proBNP, mPAP, clinical worsening and changes in autoantibody titer of CTD as secondary endpoints. Participants will be 1:1 randomized and stratified by systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and other connective tissue diseases. The trial design aims to evaluate not only the individual efficacy and safety of each therapy but also to confirm that Sotatercept is non-inferior to Sildenafil, which is recommended as standard care based on guidelines. This study aims to refine treatment protocols and enhance the quality of life for patients with this challenging condition.