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N Engl J Med. 2019 Jul 4;381(1):36-46. doi: 10.1056/NEJMoa1814427.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

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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.).



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.


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 m2 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.


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 A2 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).


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 number, NCT01180036.).


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