Table 4.
Summary of Included Studies of Lupus Nephritis (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 |
|---|---|---|---|---|---|---|---|---|---|
| Li et al35
Hong Kong |
RCT | Assess whether combination RTX & CYC is more effective than RTX monotherapy for induction therapy for proliferative LN | 19 | 1000 mg (single dose) | GC | Yes | 48 weeks | CR: 4/19 (21%) PR: 11/19 (58%) 2/19 (11%) remained the same or stable and 2/19 (11%) worsened No statistical differences in CR or PR between the 2 groups |
AE: RTX: 18 CYC/RTX: 27 SAE: 3 |
| Rovin et al36
US & Latin America |
RCT | Evaluate the efficacy and safety of RTX in patients with LN treated concomitantly with MMF & GC | 144 | 1000 mg on days 1, 15, 168, and 182 | MMF for 52 weeks and GC until week 16 | Yes | 54 weeks | The overall (CR and PR) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving RTX (P = .18); partial responses accounted for most of the difference. Primary end point (RTX superiority) not achieved. | AE: RTX: 72 placebo: 68 SAE: RTX: 29 placebo: 31 |
| Zhang et al37
China |
RCT | Compare the effects of RTX & CYC on serum levels of anti-C1q antibodies and ANCA in assessing the prognosis of severe and refractory LN | 84 | 4 doses of 375 mg/m2/wk | GC and 2 doses of 800 mg of IV CYC with oral GC at weeks 1 and 3 | Yes | 12 months | RTX+CYC group: CR: 27/42 (64.3%) PR: 8/42 (19.0%) CR or PR: 35/42 (83.3%) CYC group: CR: 9/42 (21.4%) PR: 15/42 (35.7%) CR or PR: 24/42 (57.1%) Anti-C1q antibodies and ANCA were decreased to 12 and 26% in the RTX-treated group, which was significantly lower than in CYC-treated patients (21 and 69 % respectively, P < .05). |
Not mentioned |
| Atisha-Fregoso et al38
USA |
RCT | Assess the safety, mechanism of action, and preliminary efficacy of RTX followed by belimumab in the treatment of refractory LN | 43 | 1000 mg Single dose |
RTX in both groups: Belimumab weekly, CYC, and GC CYC, and GC only |
Yes | 48 weeks | Belimumab group: CR or PR: 11/21 (52%) Control: CR or PR: 9/22 (41%) (P = .452) |
AE: RC: 287 RCB: 202 SAE: RC: 40 RCB: 7 |
| Sfikakis et al39
Greece |
PCS | Evaluate the efficacy of RTX in the treatment of LN | 10 | 4 doses of 375 mg/m2/wk | GC – CYC was given to 1 patient with relapse | Yes | 12 months | CR: 5/10 (median 3 months) PR: 3/10 (median 2 months) Sustained remission: 4/5 at 12 months |
AE: 5 SAE: 1 |
| Vigna-Perez et al40
Mexico |
PCS | Evaluate the clinical and immunological effects of RTX in refractory LN | 22 | 500 mg – 1000 mg on days 0, 14 | Immunosuppression was allowed: GC, CYC, AZA, MMF, MTX | Yes | 90 days | CR: 5/22 (22%) PR: 7/22 (31%) CR or PR: 12/22 (53%) |
AE: 2 SAE: 2 |
| Pepper et al41
UK |
PCS | Assess the use of RTX added to MMF in LN | 18 | 1000 mg on days 0, 14 | MMF and GC | Yes | 1 year | CR or PR: 14/18 (78%) Sustained response at 1 year: 12/18 (67%) Relapse: 2/18 with proteinuria |
AE: 6 SAE: 4 |
| Boletis et al42
Greece |
PCS | Assess the use of RTX added to MMF in relapsing proliferative LN | 10 | 4 doses of 375 mg/m2/wk | MMF and GC | Yes | Mean: 38 months |
CR: 6/10 (sustained by 38 months) PR: 8/10 (median of 3.5 months) |
AE: 0 SAE: 0 |
| Pinto et al43
2011 Columbia |
PCS | Report the results of severe and refractory SLE treated with RTX in Colombian patients | 42 (LN: 32) | 1000 mg on days 0, 14 | Immunosuppression was allowed: GC, CYC, AZA, MMF, HCQ | No | 12 months (min. 3 months) | After 3 months (LN results) CR: 28% PR: 36% persisted at 12 months |
AE: 28 SAE: 5 |
| Davies et al44
UK |
PCS | Report the clinical outcome of RTX in refractory LN | 18 | 1000 mg on days 0, 14 | IV CYC and 500 mg IV methylprednisolone, 2 weeks apart. Along with HCQ and oral steroids. | Yes | 6 months | CR: 11/18 (61%) PR: 2/18 (11%) CR or PR: 13/18 (72%) |
AE: 4 SAE: 3 |
| Condon et al45
UK |
PCS | Evaluate the effectiveness of treating LN with RTX and MMF but no oral GC | 50 | 1000 mg on days 0, 14 | Methylprednisolone 500 mg with RTX
infusion MMF |
Yes | 12 months | CR: 26/50 (52%) PR: 17/50 (34%) 12 relapses occurred in 11 patients, at a median time of 65 weeks (20-112) from remission |
AE: 11 SAE: 11 |
| Moroni et al46
Italy |
PCS | Compare RTX and either MMF or CYC pulses in the treatment of active LN | 54 | 1000 mg on days 3, 18 | HCQ and GC AZA, MMF, or cyclosporine from the beginning of the fourth month as maintenance therapy |
No | 12 months | CR: RTX group: 71% MMF group: 53% CYC group: 65% PR: RTX group: 29% MMF group: 41% CYC group: 25% |
AE: RTX: 6 MMF: 6 CYC: 11 SAE: RTX: 1 MMF: 2 CYC: 3 |
| Tanaka et al47
Japan |
PCS | Evaluate the efficacy and safety of RTX in Japanese patients with refractory SLE & LN | 34 (LN: 17) | 1000 mg on days 1, 15, 169, and 183 | Continued to receive pre-study enrolment immunosuppressants at the same dose (cyclosporine/MMF/AZA) | Yes | 53 weeks | Decrease in disease activity was achieved in 16/34 (76.5%). In 17 patients with LN, response rates of 58.8% and 52.9% by ACR and LUNAR criteria, respectively. Successful GC tapering was achieved in association with disease remission. | AE: 154 SAE: 10 |
| Kotagiri et al48
Australia |
PCS | Investigate the response to single-dose RTX, added to standard GC plus additional immunosuppressive agent, in refractory LN | 14 | 375 mg/m2
Single dose |
CYC, MMF, AZA, and GC were all allowed and tapered at the physician’s discretion according to clinical response | Yes | Median 18 months (IQR: 9-24) | CR: 2/14 (14%) PR: 9/14 (64%) CR or PR: 11/14 (79%) Median time to response 5 months 6-month probability of renal response of 43% Five patients (45%) relapsed at a median time of 17 months |
AE: 3 SAE: 3 |
| Kraaij et al49
Netherland |
PCS | Investigate the immunological effects and feasibility of combining RTX and belimumab | 15 (LN: 12) | 1000 mg on days 0, 14 | Induction and maintenance: Belimumab and steroids (MMF was started but quickly tapered to avoid cumulative over-immunosuppression) | Yes | 24 months | 10/15 (67%) achieved a lupus low disease activity state,
of which 8 (53%) continued treatment (BLM + ≤7.5 mg
prednisolone) for the complete 2 years of
follow-up Of 12 patients with LN: Renal response: 9 (75%) CR: 8 (67%) |
AE: 15 SAE: 4 |
| Roccatello et al50
Italy |
PCS | Investigate the safety and efficacy of an intensified B-cell depletion induction therapy without immunosuppressive maintenance regimen compared with standard of care in LN | 60 | 4 doses of 375 mg/m2/wk and 2 more doses 1 and 2 months from last dose | CYC: 2 infusions of 10 mg/kg at days 4 and
17 Pulse GC followed by oral regimen tapered to 5 mg/d by 3 months |
Yes | 12 months Mean post Rx, months: IBCDT 44.5 MMF 48.6 CYC 45.3 |
CR at 12 months: IBCDT group: 93% MMF group: 62.7% CYC group: 75% (P = .03) The dose of oral GC was lower in the IBCDT group (mean ± SD, 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P < .01) or CYC group (7.5 ± 9.0 mg/d, P < .01) At their last follow-up visit, there was no significant differences in proteinuria and serum creatinine, nor in new flares frequency |
AE: IBCDT: 3 MMF: 5 CYC: 4 SAE: 0 |
Note. RTX = rituximab; RCT = randomized controlled trial; CYC = cyclophosphamide; wk = week; LN = lupus nephritis; GC = glucocorticoids; CR = complete remission; PR = partial remission; AE = adverse events; SAE = severe adverse events; MMF = mycophenolate mofetil; ANCA = antineutrophil cytoplasm antibody; PCS = prospective cohort study; AZA = azathioprine; SLE = systemic lupus erythematosus; HCQ = hydroxychloroquine; IQR = interquartile range; IBCDT = intensified B-cell depletion induction therapy; SD = steroid dependent; RC = rituximab and cyclophosphamide; RCB = rituximab, cyclophosphamide, and belimumab; ACR = American college of rheumatology; LUNAR = lupus nephritis assessment with rituximab study; MTX = methotrexate; BLM = belimumab.