Table 3.
Trials of induction therapies for lupus nephritis
| Class of nephritis5 | Study design | Intervention 1 | Intervention 2 | Number of LN patients (intervention 1 vs 2) | Duration of follow-up | Outcome | Reference |
|---|---|---|---|---|---|---|---|
| Trials of various cyclophosphamide regimens | |||||||
| IV | RCT | Prednisone (av 40 mg/d). Maintenance prednisone |
Prednisone (av 29 mg/day) plus PO CYC (average 107 mg/day) for 6 months. Maintenance prednisone | 26 vs 24 | 4 years | Lower relapse rate in PO CYC group (48% vs 14%) with steroid sparing effect of PO CYC | Donadio et al77 |
| WHO III, IV, Vc, Vd | RCT | IV CYC 0.5 g/m2 monthly (increased acc to nadir WBC to max 1.5 g) for 6 months followed by 2 quarterly pulses. AZA 2 weeks after last CYC | Low dose IV CYC: 500 mg fortnightly × 6 doses. AZA 2 weeks after last CYC | 46 vs 44 | 10 years | Similar outcomes for renal remissions, renal flares, death, doubling of creatinine (12%), ESRD (7%) | Houssiau et al (Euro-Lupus Nephritis Trial)78,79 |
| Not classified | RCT | Monthly IV CYC 750 mg/m2 for 6 months followed by quarterly IV CYC for 2 years | High dose (50 mg/kg) IV CYC for 4 days | 26 vs 21 | 30 months | 64% vs 20% complete renal response (P = 0.08) | Petri et al80 |
| Proliferative | RCT | IV CYC 10 mg/kg every 3 weeks for 4 doses. Then PO CYC 5 mg/kg for 2 days every 4 weeks for 9 months; then every 6 weeks for 12 months | PO CYC 2 mg/kg/day for 3 months then AZA 1.5 mg/kg/day | 16 vs 16 | 3.3 years | No difference in efficacy | Yee et al81 |
| Proliferative | Phase I/II pilot study | PO CYC 0.5 g/m2 BSA monthly with SC fludarabine 30 mg/m2 on days 1–3 for 3–6 cycles | – | 13 | 2.6 to 6.7 years | Severe myelosuppression – study terminated | Illei et al82 |
| Trials of mycophenolate vs IV cyclophosphamide | |||||||
| V | Pooled analysis of pure class V nephritis from two studies83,84 | MMF 2.5–3.0 g/day | IV CYC as per NIH protocol | 42 vs 42 | 6 months | Similar outcomes for urine protein, change in urine protein, complete and partial remission rates | Radhakrishnan et al85 |
| III, IV or V | RCT | MMF target dose 3 g/d | IV CYC NIH protocol; median dose received 0.75 g/m2 | 185 vs 185 | 24 weeks, maintenance phase reported below | Similar response rate (56% vs 53%) | Appel et al (ALMS group)84 |
| III, IV or V | Meta-analysis of Ginzler 200583 and Ong 200586 | MMF 1 g bid for 6 months86. MMF pushed up to 3 g daily if tolerated83 | IV CYC 0.75–1.0 g/m2 monthly for 6 months.86 NIH IV CYC83 | 90 vs 94 | 6 months86 | Complete remission rate after induction therapy higher in MMF group | Zhu et al87 |
| Miscellaneous trials of conventional immunosuppressant agents | |||||||
| Various | Retrospective review of Hopkins Lupus Cohort | Addition of tacrolimus to MMF in those failing MMF | – | 7 | 2–54 months | Frequent toxicity, infrequent success (1 patient achieved complete renal remission) | Lanata et al88 |
| WHO III, IV, Vc, Vd | RCT | AZA 2 mg/kg/day and pulse MP (3 × 3 pulses of 1 g over 2 years) | IV CYC 750 mg/m2 (13 doses over 2 years) | 37 vs 50 | 5.7 years | Relapses more frequent in AZA group (RR8.8). Higher chronicity and activity indices on repeat biopsy in AZA group | Grootscholten (Dutch Working Party on SLE)89,90; Chan91 |
| III or IV | RCT | CSA 4–5 mg/kg/d for 9 months, gradually decreasing (3.75–1.25 mg/kg/d) over next 9 months | IV CYC 8 doses of 10 mg/kg IV over 9 months, then 4–5 × PO at same dose ever 6–8 weeks | 19 vs 21 | 18 months | CSA as effective as CYC | Zavada et al (Cyclofa-Lune study)92 |
| Trials of rituximab | |||||||
| III, IV, V | Systematic review including 9 uncontrolled studies and 26 case reports (not including other papers listed in this table) | Various regimens of RTX. 52% had concomitant IV CYC | – | 103 with lupus nephritis (188 SLE in total) | 17 months | Renal response 91%. CRR 67%, PRR 33%. Higher response rate in those having concomitant CYC than those who did not. Lymphoma regimen (375 mg/m2 × 4 doses) appeared more effective | Ramos-Casals et al93 |
| III or IV | RCT | RTX monotherapy. 1000 mg IV 2 doses 2 weeks apart | RTX + IV CYC. As for group1 but with IV CYC 750 mg following the first dose of RTX | 9 vs 10 | 48 weeks | No difference in CRR (21%) or PRR (58%). Rituximab effective as induction therapy |
Li et al94 |
| WHO IV or V | Retrospective study of refractory LN | RTX 375 mg/m2 2 doses 2 weeks apart accompanied by IV CYC 500 mg each time | – | 7 with refractory LN | 18 months | 3/7 had CRR, 4/7 had PRR. Most had disease flares 6–12 months after B cell repopulation | Lateef et al95 |
| WHO III or IV (not all biopsied) | Observational | RTX 1000 mg days 1 and 15. Added to current immunosuppressive treatment | – | 13 Hispanic with active lupus nephritis | 6 months | 38% CRR, 38% PRR | Garcia-Carrasco et al96 |
| WHO III–V | Retrospective | RTX 275 mg/m2 weekly for 4 doses; IV CYC 500–100 mg 3 weeks apart for 2 doses | – | 28 (WHO III and IV) and 15 (WHO V) | 12 months | Membranous and proliferative LN respond similarly to rituximab | Jonsdottir et al97 |
| ISN III or IV | RDBPCT | RTX 1000 mg on days 1 and 15; repeated at 6 months. Background MMF target dose 3 g/day | Placebo + MMF target dose 3 g/day | 72 vs 72 | – | No difference in renal response despite better serological response in rituximab group | Furie et al (LUNAR)33; Looney34 |
| ISN III-V | Prospective observational registry | RTX, various protocols | – | 42 | >3 months | CRR in 45%, PRR in 29% (total renal response rate 74%) | Terrier et al (French AutoImmunity and Rituximab Registry)36 |
Note: All studies are with corticosteroids in both arms, unless specified.
Abbreviations: AZA, azathioprine; bid, twice daily; CRF, chronic renal failure; CRR, complete renal response; CSA, cyclosporine A; CYC, cyclophosphamide; ESRD, end stage renal disease; IV, intravenous; LN, lupus nephritis; MMF, mycophenolate mofetil; PO, per oral; PRR, partial renal response; RCT, randomized controlled trial; RDBPCT, randomized double-blinded placebo-controlled trial; RTX, rituximab.