狼瘡性腎炎不同治療方案的療效與安全性之評估：系統性回顧與網路統合分析

Abstract

研究簡介 狼瘡腎炎（Lupus Nephritis, LN）為系統性紅斑性狼瘡（Systemic Lupus Erythematosus, SLE）的嚴重併發症，治療目標為達成完全腎臟反應（Complete Renal Response, CRR）並預防進展至末期腎病。近年治療從傳統免疫抑制劑轉向鈣調磷酸酶抑制劑（Calcineurin Inhibitors, CNIs；如Tacrolimus、Voclosporin）與生物製劑（如 Belimumab、Rituximab、Obinutuzumab、Anifrolumab）。目前缺乏直接比較這些新興療法的隨機對照試驗，本研究旨在透過系統性回顧與網路統合分析，評估六種新興療法合併標準治療的相對療效與安全性。 研究方法 本研究採用頻率學派隨機效應模型進行網路統合分析。系統性檢索 PubMed、Embase 與 Cochrane Library 資料庫自2000年至2025年發表的隨機對照試驗（Randomized Controlled Trials, RCTs）。納入標準為16歲以上、經腎臟切片確診為活動性狼瘡腎炎（ISN/RPS Class III, IV, V, III+V 或 IV+V）的患者。試驗組為上述六種藥物合併標準治療（Standard of Care, SoC；如 MMF, CYC, AZA），對照組為安慰劑或單獨使用SoC。主要療效結局為完全腎臟反應（CRR），次要結局包含整體腎臟反應（Overall Renal Response, ORR）、部分腎臟反應 (Partial Renal Response, PRR）及安全性指標。 研究結果 本研究納入16個RCTs，共2987名狼瘡腎炎患者。主分析顯示，與單用MMF相比，低劑量Voclosporin合併MMF (VCS_LD+MMF, OR=2.26; 95%CI: 1.54–3.32)、Belimumab合併MMF (BEL+MMF, OR=1.89; 95%CI: 1.17–3.03) 及Obinutuzumab合併MMF (OBI+MMF, OR=1.79; 95%CI: 1.18–2.72) 均能顯著提升CRR，其中VCS_LD+MMF的P-score排名最高。安全性分析顯示，OBI+MMF顯著增加感染相關不良事件風險 (OR=1.68; 95%CI: 1.10–2.57)。在多數安全性指標中，各組之間無統計學顯著差異，但趨勢上，Rituximab (RTX) 與Tacrolimus (TAC) 風險較低，而VCS_LD+MMF與OBI+MMF風險較高。 研究結論 本網路統合分析顯示，在MMF的基礎上合併低劑量Voclosporin、Belimumab或Obinutuzumab，能顯著改善狼瘡腎炎患者的CRR，其中以低劑量Voclosporin的療效表現最為突出。然而，Obinutuzumab與Voclosporin分別伴隨著較高的感染及治療相關不良事件風險。臨床決策時應權衡其療效與藥物特有的安全性，以制定個人化治療方案。未來或許可透過高品質的頭對頭試驗，進一步比較這些高效療法，以確立更佳的治療策略。

Introduction Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), with the main treatment goals being to achieve complete renal response (CRR) and prevent end-stage kidney disease (ESKD). Recent therapeutic trends have shifted from traditional immunosuppressants to emerging agents such as calcineurin inhibitors (CNIs; e.g., Tacrolimus, Voclosporin) and biologics (e.g., Belimumab, Rituximab, Obinutuzumab, Anifrolumab). However, there is a lack of high-quality, head-to-head randomized controlled trials (RCTs) directly comparing these therapies. This study aims to evaluate the relative efficacy and safety of these six emerging agents combined with standard of care through a systematic review and network meta-analysis. Methods This study employed a frequentist random-effects network meta-analysis to compare the relative efficacy and safety of the six aforementioned agents. A systematic literature search was conducted for RCTs published from 2000 to 2025. Inclusion criteria were patients aged 16 years or older with active LN confirmed by kidney biopsy (ISN/RPS Class III, IV, V, III+V, or IV+V). Interventions included the specified drugs as add-on therapy with standard of care (SoC; e.g., MMF, CYC, AZA) as background treatment. Comparator groups consisted of placebo or SoC alone. The primary outcome was CRR, and secondary outcomes included overall renal response (ORR), partial renal response (PRR), and relevant safety outcomes. Results This study included 16 RCTs, involving a total of 2987 patients with LN. Results showed that, compared to MMF monotherapy, low-dose Voclosporin with MMF (VCS_LD+MMF, OR=2.26; 95%CI: 1.54–3.32), Belimumab with MMF (BEL+MMF, OR=1.89; 95%CI: 1.17–3.03), and Obinutuzumab with MMF (OBI+MMF, OR=1.79; 95%CI: 1.18–2.72) were all significantly superior in improving CRR, with VCS_LD+MMF ranking highest by P-score. The safety analysis revealed that OBI+MMF was associated with a significantly increased risk of infection-related adverse events (OR=1.68; 95%CI: 1.10–2.57). For most safety outcomes, no statistically significant differences were observed among groups; however, Rituximab (RTX) and Tacrolimus (TAC) generally trended towards a lower risk, while VCS_LD+MMF and OBI+MMF showed a trend towards higher safety risks. Conclusion This network meta-analysis indicates that adding low-dose Voclosporin, Belimumab, or Obinutuzumab to a background of MMF significantly improves CRR in patients with LN. In terms of efficacy, the combination of low-dose Voclosporin and MMF was the most prominent. However, Obinutuzumab and Voclosporin are associated with higher risks of infection-related and treatment-related adverse events, respectively, and their use requires close clinical attention. Clinical decisions should balance efficacy against drug-specific safety profiles. Further investigation through high-quality, head-to-head trials is necessary to clarify the comparative effectiveness of these therapies and to define optimal treatment strategies.