Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of Randomized Trials

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.

Keywords: Lupus nephritis; adverse events; calcineurin inhibitor; dialysis; end-stage kidney disease (ESKD); immunosuppression; induction therapy; intravenous cyclophosphamide; maintenance therapy; meta-analysis; mycophenolate mofetil (MMF); remission; renal failure; toxicity.