利妥昔单抗或环孢素治疗膜性肾病。
Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.
机构信息
From the Mayo Clinic, Rochester, MN (F.C.F., S.S., J.C.L., S.B.E., N.L.); Columbia University (G.B.A., P.A.C., J.R.) and the New York University Medical Center (L.B.-L.) - both in New York; the University of British Columbia, Division of Nephrology, Vancouver (S.J.B.), the University Health Network, Toronto General Hospital (C.A.-C., H.N.R., D.C.C.), the Faculty of Community Services, Ryerson University (H.B.), and the Sunnybrook Health Science Centre (M.H.), the Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital (D.K.L., B.R.C., P.J.), and the Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto (B.R.C., P.J.), Toronto, and Centre Hospitalier Universitaire de Québec, Quebec, QC (D.P.) - all in Canada; Ohio State University, Columbus (B.H.R., L.A.H., S.V.P.); Stanford University, Stanford, CA (R.A.L.); the Mayo Clinic, Jacksonville (N.A.), and Florida International University, Miami (D.F.G.) - both in Florida; the University of Washington Medical Center, Seattle (J.A.J.); the University of Michigan Medical Center, Ann Arbor (P.E.G., D.S.G.); the University of Alabama at Birmingham, Birmingham (D.V.R.); Case Western Reserve University (J.R.S.) and the Cleveland Clinic (J.F.S.) - both in Cleveland; Kansas University Medical Center, Kansas City (E.T.M.); Manchester University, Manchester, United Kingdom (P.B.); Washington University School of Medicine, St. Louis (T.L.); the Mayo Clinic, Scottsdale (L.F.T.), and the University of Arizona, Tucson (A.N.S.) - both in Arizona; the University of Mississippi Medical Center, Jackson (L.A.J.); and the Medical College of Wisconsin, Froedtert Hospital, Milwaukee (S.S.B.).
出版信息
N Engl J Med. 2019 Jul 4;381(1):36-46. doi: 10.1056/NEJMoa1814427.
BACKGROUND
B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.
METHODS
We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.
RESULTS
A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06).
CONCLUSIONS
Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).
背景
B 细胞异常在膜性肾病的发病机制中起作用。因此，用利妥昔单抗清除 B 细胞可能并不逊于环孢素治疗，以诱导和维持患有这种疾病的患者蛋白尿完全或部分缓解。
方法
我们将患有膜性肾病、蛋白尿至少 5 g/24 小时、定量肌酐清除率至少 40 ml/分钟/1.73 m 体表面积且已接受血管紧张素系统阻断治疗至少 3 个月的患者随机分为两组，分别接受静脉注射利妥昔单抗（两次输注，每次 1000 mg，间隔 14 天；如果部分缓解则在 6 个月时重复）或口服环孢素（起始剂量为 3.5 mg/千克体重/天，持续 12 个月）。患者随访 24 个月。主要结局为 24 个月时蛋白尿完全或部分缓解的复合结局。还评估了实验室变量和安全性。
结果
共有 130 名患者接受了随机分组。在 12 个月时，利妥昔单抗组 65 名患者中有 39 名（60%）和环孢素组 65 名患者中有 34 名（52%）达到完全或部分缓解（风险差异为 8 个百分点；95%置信区间[CI]，-9 至 25；非劣效性检验 P=0.004）。在 24 个月时，利妥昔单抗组 39 名患者（60%）和环孢素组 13 名患者（20%）达到完全或部分缓解（风险差异为 40 个百分点；95%CI，25 至 55；非劣效性和优效性检验 P 值均<0.001）。在抗磷脂酶 A2 受体（PLA2R）抗体检测为阳性的缓解患者中，利妥昔单抗组自身抗体对 PLA2R 的下降速度更快、幅度更大、持续时间更长。利妥昔单抗组有 11 名患者（17%）和环孢素组有 20 名患者（31%）发生严重不良事件（P=0.06）。
结论
在 12 个月时，利妥昔单抗在诱导蛋白尿完全或部分缓解方面不劣于环孢素，在维持蛋白尿缓解方面在 24 个月时优于环孢素。（由罗氏和富尔克家族基金会资助；MENTOR 临床试验.gov 编号，NCT01180036）。
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