Table4_Efficacy and safety of 12 immunosuppressive agents for idiopathic membranous nephropathy in adults: A pairwise and network meta-analysis.doc

Background: Immunosuppressants have been applied in the remedy of idiopathic membranous nephropathy (IMN) extensively. Nevertheless, the efficacy and safety of immunosuppressants do not have final conclusion. Thus, a pairwise and network meta-analysis (NMA) was carried out to seek the most recommended therapeutic schedule for patients with IMN.
Methods: Randomized controlled trials (RCTs) including cyclophosphamide (CTX), mycophenolate mofetil (MMF), tacrolimus-combined mycophenolate mofetil (TAC + MMF), cyclosporine (CsA), tacrolimus (TAC), leflunomide (LEF), chlorambucil (CH), azathioprine (AZA), adrenocorticotropic hormone (ACTH), non-immunosuppressive therapies (CON), steroids (STE), mizoribine (MZB), and rituximab (RIT) for patients with IMN were checked. Risk ratios (RRs) and standard mean difference (SMD) were reckoned to assess dichotomous variable quantities and continuous variable quantities, respectively. Total remission (TR) and 24-h urine total protein (24-h UTP) were compared using pairwise and NMA. Then interventions were ranked on the basis of the surface under the cumulative ranking curve (SUCRA).
Results: Our study finally included 51 RCTs and 12 different immunosuppressants. Compared with the CON group, most regimens demonstrated better therapeutic effect in TR, with RR of 2.1 (95% CI) (1.5–2.9) for TAC, 1.9 (1.3–2.8) for RIT, 2.5 (1.2–5.2) for TAC + MMF, 1.9 (1.4–2.7) for CH, 1.8 (1.4–2.4) for CTX, 2.2 (1.0–4.7) for ACTH, 1.6 (1.2–2.1) for CsA, 1.6 (1.0–2.5) for LEF, and 1.6 (1.1–2.2) for MMF. In terms of 24-h UTP, TAC (SMD, −2.3 (95% CI −3.5 to −1.1)), CTX (SMD, −1.7 (95% CI −2.8 to −0.59)), RIT (SMD, −1.8 (95% CI −3.5 to −0.11)), CH (SMD, −2.4 (95% CI −4.3 to −0.49)), AZA (SMD, −−4.2 (95% CI −7.7 to −0.68)), and CsA (SMD, −1.7 (95% CI −3 to −0.49)) were significantly superior than the CON group. As for adverse effects (AEs), infections, nausea, emesia, myelosuppression, and glucose intolerance were the collective adverse events for most immunosuppressants.
Conclusion: This study indicates that TAC + MMF performed the best in terms of TR, and TAC shows the best effectiveness on 24-h UTP compared with other regimens. On the contrary, there seems to be little advantage on STE alone, LEF, AZA, and MZB in treating patients with IMN compared with CON.
Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021287013]

背景：免疫抑制剂已被广泛应用于特发性膜性肾病（idiopathic membranous nephropathy, IMN）的治疗。然而，免疫抑制剂的疗效与安全性尚未有明确定论。为此，本研究开展配对Meta分析与网络Meta分析（network meta-analysis, NMA），旨在为IMN患者筛选最优推荐治疗方案。
方法：纳入涵盖环磷酰胺（cyclophosphamide, CTX）、吗替麦考酚酯（mycophenolate mofetil, MMF）、他克莫司联合吗替麦考酚酯（tacrolimus-combined mycophenolate mofetil, TAC+MMF）、环孢素（cyclosporine, CsA）、他克莫司（tacrolimus, TAC）、来氟米特（leflunomide, LEF）、苯丁酸氮芥（chlorambucil, CH）、硫唑嘌呤（azathioprine, AZA）、促肾上腺皮质激素（adrenocorticotropic hormone, ACTH）、非免疫抑制治疗（non-immunosuppressive therapies, CON）、糖皮质激素（steroids, STE）、咪唑立宾（mizoribine, MZB）以及利妥昔单抗（rituximab, RIT）的随机对照试验（randomized controlled trials, RCTs）。分别采用风险比（risk ratios, RRs）与标准化均数差（standard mean difference, SMD）对二分类变量与连续变量的效应量进行估算。采用配对Meta分析与网络Meta分析比较完全缓解（total remission, TR）与24小时尿总蛋白（24-hour urine total protein, 24-h UTP）两项结局指标，随后基于累积排序曲线下面积（surface under the cumulative ranking curve, SUCRA）对各干预措施进行疗效排序。
结果：本研究最终纳入51项随机对照试验与12种不同免疫抑制剂。与非免疫抑制治疗组（CON）相比，多数治疗方案在完全缓解率上展现出更优疗效：他克莫司（TAC）的风险比为2.1（95%置信区间：1.5~2.9），利妥昔单抗（RIT）为1.9（1.3~2.8），他克莫司联合吗替麦考酚酯（TAC+MMF）为2.5（1.2~5.2），苯丁酸氮芥（CH）为1.9（1.4~2.7），环磷酰胺（CTX）为1.8（1.4~2.4），促肾上腺皮质激素（ACTH）为2.2（1.0~4.7），环孢素（CsA）为1.6（1.2~2.1），来氟米特（LEF）为1.6（1.0~2.5），吗替麦考酚酯（MMF）为1.6（1.1~2.2）。在24小时尿总蛋白（24-h UTP）方面，他克莫司（标准化均数差：-2.3，95%置信区间：-3.5~-1.1）、环磷酰胺（-1.7，95%置信区间：-2.8~-0.59）、利妥昔单抗（-1.8，95%置信区间：-3.5~-0.11）、苯丁酸氮芥（-2.4，95%置信区间：-4.3~-0.49）、硫唑嘌呤（AZA，-4.2，95%置信区间：-7.7~-0.68）以及环孢素（-1.7，95%置信区间：-3.0~-0.49）均显著优于非免疫抑制治疗组。不良反应（adverse effects, AEs）方面，感染、恶心、呕吐、骨髓抑制与葡萄糖不耐受是多数免疫抑制剂共有的不良事件。
结论：本研究结果显示，他克莫司联合吗替麦考酚酯（TAC+MMF）在完全缓解率方面表现最优，而他克莫司（TAC）在改善24小时尿总蛋白方面的疗效优于其余所有治疗方案。与之相反，单独使用糖皮质激素（STE）、来氟米特（LEF）、硫唑嘌呤（AZA）与咪唑立宾（MZB）相较于非免疫抑制治疗组，治疗IMN患者几乎无优势。
系统评价注册：[https://www.crd.york.ac.uk/prospero/]，注册号：[CRD42021287013]