Suetonia C Palmer1, David J Tunnicliffe2, Davinder Singh-Grewal3, Dimitris Mavridis4, Marcello Tonelli5, David W Johnson6, Jonathan C Craig2, Allison Tong2, Giovanni F M Strippoli7. 1. Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand. 2. Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia. 3. School of Paediatrics and Child Health, The University of Sydney, Sydney, NSW, Australia; Department of Rheumatology, The Sydney Children's Hospitals Network Westmead and Randwick, NSW, Australia. 4. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Primary Education, University of Ioannina, Ioannina, Greece. 5. Cumming School of Medicine, University of Calgary, Calgary, Canada. 6. Division of Medicine, Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia; Translational Research Institute, Brisbane, QLD, Australia. 7. Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia; Diaverum Medical Scientific Office and Diaverum Academy, Lund, Sweden; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. Electronic address: gfmstrippoli@gmail.com.
Abstract
BACKGROUND: Intravenous (IV) cyclophosphamide has been first-line treatment for inducing disease remission in lupus nephritis. The comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors are uncertain. STUDY DESIGN: Network meta-analysis. SETTING & POPULATION: Patients with proliferative lupus nephritis. SELECTION CRITERIA FOR STUDIES: Randomized trials of immunosuppression to induce or maintain disease remission. INTERVENTIONS: IV cyclophosphamide, oral cyclophosphamide, MMF, calcineurin inhibitor, plasma exchange, rituximab, or azathioprine, alone or in combination. OUTCOMES: Complete remission, end-stage kidney disease, all-cause mortality, doubling of serum creatinine level, relapse, and adverse events. RESULTS: 53 studies involving 4,222 participants were eligible. Induction and maintenance treatments were administered for 12 (IQR, 6-84) and 25 (IQR, 12-48) months, respectively. There was no evidence of different effects between therapies on all-cause mortality, doubling of serum creatinine level, or end-stage kidney disease. Compared to IV cyclophosphamide, the most effective treatments to induce remission in moderate- to high-quality evidence were combined MMF and calcineurin inhibitor therapy, calcineurin inhibitors, and MMF (ORs were 2.69 [95% CI, 1.74-4.16], 1.86 [95% CI, 1.05-3.30], and 1.54 [95% CI, 1.04-2.30], respectively). MMF was significantly less likely than IV cyclophosphamide to cause alopecia (OR, 0.21; 95% CI, 0.12-0.36), and MMF combined with calcineurin inhibitor therapy was less likely to cause ovarian failure (OR, 0.25; 95% CI, 0.07-0.93). Regimens generally had similar odds of major infection. MMF was the most effective strategy to maintain remission. LIMITATIONS: Outcome definitions not standardized, short duration of follow-up, and possible confounding by previous or subsequent therapy. CONCLUSIONS: Evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. MMF, calcineurin inhibitors, or their combination were most effective for inducing remission compared to IV cyclophosphamide, while conferring similar or lower treatment toxicity. MMF was the most effective maintenance therapy.
BACKGROUND: Intravenous (IV) cyclophosphamide has been first-line treatment for inducing disease remission in lupus nephritis. The comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors are uncertain. STUDY DESIGN: Network meta-analysis. SETTING & POPULATION: Patients with proliferative lupus nephritis. SELECTION CRITERIA FOR STUDIES: Randomized trials of immunosuppression to induce or maintain disease remission. INTERVENTIONS: IV cyclophosphamide, oral cyclophosphamide, MMF, calcineurin inhibitor, plasma exchange, rituximab, or azathioprine, alone or in combination. OUTCOMES: Complete remission, end-stage kidney disease, all-cause mortality, doubling of serum creatinine level, relapse, and adverse events. RESULTS: 53 studies involving 4,222 participants were eligible. Induction and maintenance treatments were administered for 12 (IQR, 6-84) and 25 (IQR, 12-48) months, respectively. There was no evidence of different effects between therapies on all-cause mortality, doubling of serum creatinine level, or end-stage kidney disease. Compared to IV cyclophosphamide, the most effective treatments to induce remission in moderate- to high-quality evidence were combined MMF and calcineurin inhibitor therapy, calcineurin inhibitors, and MMF (ORs were 2.69 [95% CI, 1.74-4.16], 1.86 [95% CI, 1.05-3.30], and 1.54 [95% CI, 1.04-2.30], respectively). MMF was significantly less likely than IV cyclophosphamide to cause alopecia (OR, 0.21; 95% CI, 0.12-0.36), and MMF combined with calcineurin inhibitor therapy was less likely to cause ovarian failure (OR, 0.25; 95% CI, 0.07-0.93). Regimens generally had similar odds of major infection. MMF was the most effective strategy to maintain remission. LIMITATIONS: Outcome definitions not standardized, short duration of follow-up, and possible confounding by previous or subsequent therapy. CONCLUSIONS: Evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. MMF, calcineurin inhibitors, or their combination were most effective for inducing remission compared to IV cyclophosphamide, while conferring similar or lower treatment toxicity. MMF was the most effective maintenance therapy.
Authors: David J Tunnicliffe; Suetonia C Palmer; Lorna Henderson; Philip Masson; Jonathan C Craig; Allison Tong; Davinder Singh-Grewal; Robert S Flanc; Matthew A Roberts; Angela C Webster; Giovanni Fm Strippoli Journal: Cochrane Database Syst Rev Date: 2018-06-29