Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Cochrane Database Syst Rev. 2022 Oct 31;10(10):CD014831. doi: 10.1002/14651858.CD014831.pub2.
Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated in the posterior structures of the eye. Because NIIPPU is typically a chronic condition, people with NIIPPU frequently require treatment with steroid-sparing immunosuppressive therapy. Methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus are non-biologic, disease-modifying antirheumatic drugs (DMARDs) which have been used to treat people with NIIPPU.
To compare the effectiveness and safety of selected DMARDs (methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and azathioprine) in the treatment of NIIPPU in adults.
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE, Embase, the Latin American and Caribbean Health Sciences database, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, most recently on 16 April 2021.
We included randomized controlled trials (RCTs) comparing selected DMARDs (methotrexate, mycophenolate, tacrolimus, cyclosporine, and azathioprine) with placebo, standard of care (topical steroids, with or without oral steroids), or with each other.
We used standard methodological procedures expected by Cochrane.
We included 11 RCTs with a total of 601 participants in this review. DMARDs versus control Two studies compared an experimental DMARD (cyclosporine A or enteric-coated mycophenolate [EC-MPS]) plus oral steroid with steroid monotherapy. We did not pool these results into a meta-analysis because the dose of cyclosporine used was much higher than that used in current clinical practice. The evidence is very uncertain about whether EC-MPS plus low-dose oral steroid results in a higher proportion of participants achieving control of inflammation over steroid monotherapy (risk ratio [RR] 2.81, 95% confidence interval [CI] 1.10 to 7.17; 1 study, 41 participants; very low-certainty evidence). The change in best-corrected visual acuity (BCVA) was reported separately for right and left eyes. The evidence for improvement (lower logarithm of the minimum angle of resolution (logMAR) indicates better vision) between the groups is very uncertain (mean difference [MD] -0.03 and -0.10, 95% CI -0.96 to 0.90 and -0.27 to 0.07 for right and left, respectively; 1 study, 82 eyes; very low-certainty evidence). No data were available for the following outcomes: proportion of participants achieving a 2-line improvement in visual acuity, with confirmed macular edema, or achieving steroid-sparing control. The evidence for the proportion of participants requiring cessation of medication in the DMARD versus control group is very uncertain (RR 2.61, 95% CI 0.11 to 60.51; 1 study, 41 participants; very low-certainty evidence). Methotrexate versus mycophenolate We were able to combine two studies into a meta-analysis comparing methotrexate versus mycophenolate mofetil. Methotrexate probably results in a slight increase in the proportion of participants achieving control of inflammation, including steroid-sparing control, compared to mycophenolate at six months (RR 1.23, 95% CI 1.01 to 1.50; 2 studies, 261 participants; moderate-certainty evidence). Change in BCVA was reported per eye and the treatments likely result in little to no difference in change in vision (MD 0.01 logMAR higher [worse] for methotrexate versus mycophenolate; 2 studies, 490 eyes; moderate-certainty evidence). No data were available for the proportion of participants achieving a 2-line improvement in visual acuity. The evidence is very uncertain regarding the proportion of participants with confirmed macular edema between methotrexate versus mycophenolate (RR 0.49, 95% CI 0.19 to 1.30; 2 studies, 35 eyes; very low-certainty). Methotrexate versus mycophenolate may result in little to no difference in the proportion of participants requiring cessation of medication (RR 0.99, 95% CI 0.43 to 2.27; 2 studies, 296 participants; low-certainty evidence). Steroids with or without azathioprine versus cyclosporine A Four studies compared steroids with or without azathioprine (oral steroids, intravenous [IV] steroids, or azathioprine) to cyclosporine A. We excluded two studies from the meta-analysis because the participants were treated with 8 mg to 15 mg/kg/day of cyclosporine A, a significantly higher dose than is utilized today because of concerns for nephrotoxicity. The remaining two studies were conducted in all Vogt-Koyanagi-Harada disease (VKH) populations and compared cyclosporine A to azathioprine or IV pulse-dose steroids. The evidence is very uncertain for whether the steroids with or without azathioprine or cyclosporine A influenced the proportion of participants achieving control of inflammation (RR 0.84, 95% CI 0.70 to 1.02; 2 studies, 112 participants; very low-certainty evidence), achieving steroid-sparing control (RR 0.64, 95% CI 0.33 to 1.25; 1 study, 21 participants; very low-certainty evidence), or requiring cessation of medication (RR 0.85, 95% 0.21 to 3.45; 2 studies, 91 participants; very low-certainty evidence). The evidence is uncertain for improvement in BCVA (MD 0.04 logMAR lower [better] with the steroids with or without azathioprine versus cyclosporine A; 2 studies, 91 eyes; very low-certainty evidence). There were no data available (with current cyclosporine A dosing) for the proportion of participants achieving a 2-line improvement in visual acuity or with confirmed macular edema. Studies not included in synthesis We were unable to include three studies in any of the comparisons (in addition to the aforementioned studies excluded based on historic doses of cyclosporine A). One was a dose-response study comparing cyclosporine A to cyclosporine G, a formulation which was never licensed and is not clinically available. We excluded another study from meta-analysis because it compared cyclosporine A and tacrolimus, considered to be of the same class (calcineurin inhibitors). We were unable to combine the third study, which examined tacrolimus monotherapy versus tacrolimus plus oral steroid, with any group.
AUTHORS' CONCLUSIONS: There is a paucity of data regarding which DMARD is most effective or safe in NIIPPU. Studies in general were small, heterogenous in terms of their design and outcome measures, and often did not compare different classes of DMARD with each other. Methotrexate is probably slightly more efficacious than mycophenolate in achieving control of inflammation, including steroid-sparing control (moderate-certainty evidence), although there was insufficient evidence to prefer one medication over the other in the VKH subgroup (very low-certainty evidence). Methotrexate may result in little to no difference in safety outcomes compared to mycophenolate.
非传染性中间、后部和全葡萄膜炎（NIIPPU）代表一组自身免疫和炎症性疾病，这些疾病局限于或集中在眼部的后部结构中。由于 NIIPPU 通常是一种慢性疾病，因此 NIIPPU 患者通常需要使用类固醇保留免疫抑制疗法进行治疗。甲氨蝶呤、霉酚酸酯、环孢素、硫唑嘌呤和他克莫司是用于治疗 NIIPPU 患者的非生物、疾病修正抗风湿药物（DMARDs）。
比较选定的 DMARDs（甲氨蝶呤、霉酚酸酯、他克莫司、环孢素和硫唑嘌呤）在治疗成人 NIIPPU 中的有效性和安全性。
我们检索了 CENTRAL（包含 Cochrane 眼与视觉试验注册中心）、MEDLINE、Embase、拉丁美洲和加勒比健康科学数据库、ClinicalTrials.gov 和世界卫生组织国际临床试验注册平台，最近一次检索时间为 2021 年 4 月 16 日。
我们纳入了比较选定的 DMARDs（甲氨蝶呤、霉酚酸酯、他克莫司、环孢素和硫唑嘌呤）与安慰剂、标准治疗（局部类固醇，伴或不伴口服类固醇）或彼此之间的随机对照试验（RCTs）。
我们使用了 Cochrane 预期的标准方法学程序。
我们在本次综述中纳入了 11 项 RCTs，共有 601 名参与者。DMARDs 与对照：两项研究比较了实验性 DMARD（环孢素 A 或肠内给药霉酚酸酯[EC-MPS]）加口服类固醇与类固醇单药治疗。由于所用环孢素 A 的剂量远高于目前临床实践中的剂量，因此我们没有将这些结果纳入荟萃分析。证据非常不确定 EC-MPS 加低剂量口服类固醇是否会导致更多的参与者实现类固醇单药治疗的炎症控制（风险比[RR]2.81，95%置信区间[CI]1.10 至 7.17；1 项研究，41 名参与者；极低确定性证据）。最佳矫正视力（BCVA）的变化分别报告了右眼和左眼。关于组间改善（较低的对数最小角度分辨率（logMAR）表示更好的视力）的证据是非常不确定的（MD-0.03 和-0.10，95%CI-0.96 至 0.90 和-0.27 至 0.07，右眼和左眼；1 项研究，82 只眼；极低确定性证据）。没有数据可用于以下结局：参与者中达到视力提高 2 行、伴有确认的黄斑水肿或达到类固醇保留控制的比例。DMARD 与对照相比，药物停药比例的证据是非常不确定的（RR2.61，95%CI0.11 至 60.51；1 项研究，41 名参与者；极低确定性证据）。甲氨蝶呤与霉酚酸酯：我们能够将两项研究合并进行荟萃分析，比较甲氨蝶呤与霉酚酸酯。与霉酚酸酯相比，甲氨蝶呤可能会略微增加达到炎症控制（包括类固醇保留控制）的参与者比例，在六个月时（RR1.23，95%CI1.01 至 1.50；2 项研究，261 名参与者；中等确定性证据）。每只眼的 BCVA 均有报道，治疗可能导致视力变化的差异很小或没有（MD0.01 logMAR 更高[更差]，甲氨蝶呤优于霉酚酸酯；2 项研究，490 只眼；中等确定性证据）。没有数据可用于参与者中达到视力提高 2 行的比例。关于甲氨蝶呤与霉酚酸酯之间黄斑水肿确认比例的证据是非常不确定的（RR0.49，95%CI0.19 至 1.30；2 项研究，35 只眼；极低确定性证据）。甲氨蝶呤与霉酚酸酯可能导致参与者停药的比例差异很小或没有（RR0.99，95%CI0.43 至 2.27；2 项研究，296 名参与者；低确定性证据）。类固醇加或不加硫唑嘌呤与环孢素 A：四项研究比较了类固醇加或不加硫唑嘌呤（口服类固醇、静脉内[IV]类固醇或硫唑嘌呤）与环孢素 A。我们从荟萃分析中排除了两项研究，因为参与者接受了 8 毫克至 15 毫克/千克/天的环孢素 A，这一剂量明显高于目前因担心肾毒性而使用的剂量。其余两项研究均在所有 Vogt-Koyanagi-Harada 病（VKH）人群中进行，比较了环孢素 A 与硫唑嘌呤或 IV 脉冲剂量类固醇。类固醇加或不加硫唑嘌呤或环孢素 A 是否影响炎症控制（RR0.84，95%CI0.70 至 1.02；2 项研究，112 名参与者；极低确定性证据）、实现类固醇保留控制（RR0.64，95%CI0.33 至 1.25；1 项研究，21 名参与者；极低确定性证据）或需要停药（RR0.85，95%CI0.21 至 3.45；2 项研究，91 名参与者；极低确定性证据）的证据是非常不确定的。关于 BCVA 改善（RR0.04 logMAR 更低[更好]，类固醇加或不加硫唑嘌呤优于环孢素 A；2 项研究，91 只眼；极低确定性证据）的证据是不确定的。目前环孢素 A 剂量下，没有数据可用于参与者中达到视力提高 2 行或伴有黄斑水肿确认的比例。未纳入综合分析的研究：我们无法将三项研究纳入任何比较（除了由于环孢素 A 剂量而从荟萃分析中排除的上述研究之外）。一项是比较环孢素 A 与环孢素 G 的剂量反应研究，环孢素 G 从未获得许可，临床不可用。我们从荟萃分析中排除了另一项研究，因为它比较了环孢素 A 和他克莫司，被认为属于同一类（钙调神经磷酸酶抑制剂）。我们无法将第三项研究（他克莫司单药治疗与他克莫司加口服类固醇）与任何一组进行合并。
关于哪种 DMARD 在 NIIPPU 中最有效或最安全，数据很少。研究总体上规模较小，在设计和结局测量方面存在异质性，而且往往没有比较不同类别的 DMARD 彼此之间的差异。与霉酚酸酯相比，甲氨蝶呤可能在实现炎症控制（包括类固醇保留控制）方面稍显有效，包括在 VKH 亚组中（中等确定性证据），但目前的证据不足以在药物之间进行偏好（极低确定性证据）。与霉酚酸酯相比，甲氨蝶呤在安全性结局方面可能没有差异。
