Table 3.
Summary of Included Studies of Membranous Nephropathy (Listed in Chronological Order and According to Type of Study—All Are Induction Regimens).
| Study | Type | Intervention/aim | Number of participants | RTX regimen | Concomitant immunosuppression | B-cell depletion reported | Study duration | Primary findings | Adverse events |
|---|---|---|---|---|---|---|---|---|---|
| Dahan et al18
France |
RCT | Evaluate the efficacy of RTX added to supportive therapy compared with supportive therapy alone | 77 | 2 doses of RTX (375 mg/m2/wk) | None | Yes | 6 months | 6 months CR: NIAT-RTX group: 13/37 (35.1%); 95% CI, 19.7-50.5 NIAT group: 8/38 (21.1%) [8.1-34.0, 19.7-50.5] (P = .21) Observational phase follow-up: Remission rates before change of assigned treatment were NIAT-RTX: 24/37 (64.9%) NIAT: 13/38 (34.2%) (P = .01) |
AE: not mentioned SAE: RTX: 6 NIAT: 5 |
| Fervenza et al19
USA |
RCT | Investigate whether RTX is non-inferior to cyclosporine in inducing & maintaining remission | 130 | 1000 mg on days 0, 14 followed by single 1000 mg in case of PR | None | Yes | 24 months | CR or PR: RTX group: 39 (60%) Cyclosporine group: 13 (20%) Risk difference, 40%; 95% CI, 25%-55%; P < .001 for both noninferiority and superiority |
AE: RTX: 179 Cyclosporine: 218 SAE: RTX: 13 Cyclosporine: 22 |
| Scolari et al20
Italy & Switzerland |
RCT | Obtain estimates of RTX efficacy relative to cyclical CYC/GC and assess RCT recruitment potential using a multisite design | 74 | 1000 mg on days 0, 14 | None | No | 24 months | Probability of CR or PR: RTX group: 0.83 (95% CI, 0.65-0.95) CYC/GC group: 0.82 (95% CI, 0.68-0.93) |
AE: RTX: 2 CYC: 30 SAE: RTX: 7 CYC: 5 |
| Fernández-Juárez21
Spain & Netherlands |
RCT | Investigate if sequential therapy with TAC & RTX is superior to cyclical alternating treatment with GC and CYC in inducing persistent remission in MN | 86 | 1000 mg, 6 months after starting TAC | TAC | No | 24 months | The composite outcome: GC-CYC group: 36
(83.7%) TAC-RTX group: 25 (58.1%) (RR: 1.44; 95% CI, 1.08-1.92) CR: GC-CYC group: 26 (60%) TAC-RTX group: 11 (26%) (RR: 2.36; 95% CI, 1.34-4.16) |
AE: RTX: 170 CYC/GC: 239 SAE: RTX: 7 CYC/GC: 10 |
| Cravedi et al22
Italy |
PCS | Whether titrating RTX to circulating CD20 B-cell counts improves safety and reduces costs | 36 | 4 doses of 375
mg/m2/wk vs targeted B-cell approach: single 375 mg/m2 with monthly evaluation |
None | Yes | 12 months | Only one patient needed a second dose to achieve full
CD20 cell depletion At 1 year, disease remission was identical in both groups (25%) Persistent CD20 cell depletion was achieved in all patients |
AE: 8 SAE: 0 |
| Fervenza et al23
USA & Canada |
PCS | A pilot trial of RTX treatment in severe NS refractory to ACEi and/or ARB but with adequately controlled blood pressure | 15 | 1000 mg on days 0, 14 and 1000 mg after 6 months based on B-cell count | None | Yes | 12 months | 14 completed follow-up: CR: 2/14 (14%) PR: 6/14 (42%) CR or PR: 8/14 (56%) |
AE: 14 SAE: 2 |
| Fervenza et al24
USA & Canada |
PCS | To investigate the efficacy and safety of 4 weekly RTX regimen, with re-treatment at 6 months | 20 | 4 doses of 375 mg/m2/wk and repeated after 6 months | None | Yes | 24 months | 18 completed 24-month follow-up: CR: 4/18 (22%) PR: 12/18 (66%) 1 had a limited response 1 relapse |
AE: 12 SAE: 1 |
| Cravedi et al25
Italy |
PCS | Evaluate whether RTX is equally effective in patients who failed to respond to previous immunosuppressive treatment | 22 | Pre-October 2005, 4 doses of 375
mg/m2/wk. Thereafter, 375 mg/m2 once with redosing based on circulating B cells |
None | Yes | 24 months | CR: RTX: 3/11 Reference: 2/11 PR: RTX: 5/11 Reference: 5/11 |
AE: RTX: 1 Control: 1 SAE: 0 |
| Ruggenenti et al26
Italy |
PCS | Describe the experience of using RTX in persistent NS | 100 | Pre-October 2005, 4 doses of 375
mg/m2/wk. Thereafter, 375 mg/m2 once with redosing based on circulating B cells |
None | Yes | Median: 29 months |
CR or PR: 65/100 (65%) Median time to remission was 7.1 months All 24 patients who had at least 4 years of follow-up achieved CR or PR |
AE: 28 SAE: 0 |
| Lionaki et al27
Greece |
PCS | Assess the long-term benefit of RTX & search for potential predictors of response | 12 | 4 doses of 375 mg/m2/wk (maximum 700 mg) |
None | Yes | Median: 48 months |
CR: 7/12 (58.3%) PR: 4/12 (33.3%) CR or PR: 11/12 (91.6%) |
AE: 0 SAE: 0 |
| Busch et al28
Germany |
PCS | Evaluate the effect of 4 monthly RTX doses on relapse rates | 14 | 375 mg/m2 (maximum 750 mg) monthly for 4 months (4-doses) | None | No | Median: 3 years |
After 1 year: CR: 3/14 (21.4%) PR: 7/14 (50.0%) 2 relapses |
AE: 3 SAE: 2 |
| Waldman et al29
USA |
PCS | Investigate induction treatment with RTX plus a 6-month course of CYC followed by a maintenance course of RTX vs either agent alone | 13 | 1000 mg on days 0, 14 repeated after 6 months | Cyclosporine tapered after 6 months over 9-21 weeks | Yes | 24 months | CR: 54% at 12 months CR or PR: 92% by 9 months 2 relapses |
AE: 45 SAE: 5 |
| Fiorentino et al30
Italy |
PCS | Describe the efficacy and safety of RTX | 38 | 4 doses of 375 mg/m2/wk | None | Yes | Median: 15 months |
CR: 15/38 (39.5%) PR: 14/38 (36.8%) CR or PR: 29/38 (76.3%) |
AE: 2 SAE: 1 |
| Moroni et al3
Italy |
PCS | Evaluate the efficacy and safety of low-dose RTX | 34 | 1-2 doses of RTX (375 mg/m2) | None | Yes | 12 months | CR: 5/34 (14.7%) PR: 10/34 (29.4%) No response: 19/34 (55.8%) |
AE: 5 SAE: 2 |
| Wang et al32
China |
PCS | Examine the efficacy and safety of RTX in non-responsive MN and monitor anti-PLA2R antibodies | 36 | 4 doses of 375 mg/m2/wk or B-cell-based frequency dosing: at discretion of the treating physicians | None | Yes | Median: 12 months |
CR: 2/36 (5%) PR: 13/36 (36%) CR or PR: 15/36 (41.7%) |
AE: 1 SAE: 0 |
| Boyer-Suavet et al33
France |
PCS | Monitor development of anti-RTX Ab in primary MN and assess whether resistance/relapse of MN after RTX is associated with development of anti-RTX Ab | 44 | 1000 mg on days 0, 14 Course was repeated in case of resistance or relapse at 6 months |
None | Yes | Median: 30 months |
CR or PR: 35/44 (79%) after a median of 3 months (range,
3-9) 9 patients were resistant to a first RTX course Remission did not differ by anti-RTX Ab status (8/10 [80%] vs 27/34 [79%] P > .99) but relapses were associated with anti-RTX Ab presence (5/10 [50%] vs 3/34 [9%] P = .009). |
AE: 2 SAE: 0 |
| Ramachandran et al34
India |
PCS | Report clinical outcomes using CYC or RTX in PMN with renal dysfunction | 64 | 4 doses of 375 mg/m2/wk, 1000 mg on days 0, 14, or CD19 targeted treatment | None | No | Median:24 months | 28/64 (44%) and 30/64 (47%) were in remission at 12 months and end of the study, respectively. | AE: 22 SAE: 8 |
RTX = rituximab; RCT = randomized controlled trial; wk = week; CR = complete remission; NIAT = non-immunosuppressive anti-proteinuric treatment; CI = confidence interval; AE = adverse events; SAE = severe adverse events; ACEi = angiotensin-converting-enzyme inhibitors; PR = partial remission; CYC = cyclophosphamide; GC = glucocorticoids; MN = membranous nephropathy; TAC = tacrolimus; PCS = prospective cohort study; NS = nephrotic syndrome; ARB = angiotensin II receptor blockers; RR = relative risk.