MMF Effective in Maintaining Remission from Proliferative Lupus Nephritis

In the 10 years following a diagnosis of systematic lupus erythematosus, 20% to 75% of patients experience kidney involvement. In the 1950s, 5-year survival for patients with lupus erythematosus was <50%; due to improved immunosuppression and other medical therapies, the 5-year survival rate is now >90%. Lupus nephritis is now considered a chronic illness, giving the efficacy and safety of longer-term treatments more importance in medical decision-making in this patient population.

The first-line therapy to induce remission from lupus nephritis is intravenous (IV) cyclophosphamide in combination with corticosteroids; however, considerable toxicity is associated with that regimen. There are few data available on the comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors.

Suetonia C. Palmer, MBChB, PhD, and colleagues conducted a network meta-analysis of randomized trials of immunosuppression to induce or maintain disease remission in patients with proliferative lupus nephritis. The primary outcomes of interest were complete remission, end-stage kidney disease, all-cause mortality, doubling of serum creatinine level, relapse, and adverse events. The researchers reported results in the American Journal of Kidney Diseases [2017;70(3):324-336].

A Cochrane review yielded 38 trials and electronic database searching identified 15 additional trials. Of that total, 53 trials met inclusion criteria, representing 4222 participants ≥10 years of age.

In 45 trials, participants with active nephritis were randomly assigned to therapy to induce remission (n=3623); in eight trials, patients who had previously achieved disease remission were randomly assigned to therapeutic strategies to maintain remission. Two trials reported outcomes in participants randomly assigned to induction and then subsequently to maintenance therapy in separate trials within a single cohort.

The median number of participants in the trials was 47; mean age was 30.2 years. Induction treatment was continued for a median follow-up of 12 months; median duration of follow-up of maintenance therapy was 24 months.

In trials conducted between 1972 and 1984, interventions studied were oral azathioprine, oral cyclophosphamide, prednisone alone, or plasma exchange. Researchers reported results from the first trial of intravenous (IV) cyclophosphamide; results of trials examining calcineurin inhibitors were reported beginning in 1992.

The earliest results from a trial of MMF were reported in 2005; rituximab has been evaluated since 2009. Beginning in 2012, other immunomodulatory drugs have been studied as induction therapies, including atacicept, abatacept, laquinimod, sirukumab, and mizoribine.

Induction and maintenance treatments were administered for 12 or 25 months, respectively. All therapies demonstrated similar results in terms of all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. Compared with IV cyclophosphamide, the therapies that were most effective in inducing remission in moderate- to high-quality evidence were combined MMF and calcineurin inhibitor therapy (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.74-4.16), calcineurin inhibitors (OR, 1.86; 95% CI, 1.05-3.30), and MMF (OR, 1.54; 95% CI, 1.04-2.30).

There was a significantly less likely chance that MMF would cause alopecia, compared with IV cyclophosphamide (OR, 0.21; 95% CI, 0.12-0.36). MMF combined with calcineurin inhibitor therapy was less likely to cause ovarian failure (OR, 0.25; 95% CI, 0.07-0.93). Odds of major infection were similar across all regimens. The most effective strategy to achieve remission was MMF.

Limitations to the review cited by the authors included the outcome definitions not being standardized across trials, the short duration of follow-up, and possible confounding by previous or subsequent therapy.

“In conclusion, evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine levels, and end-stage kidney disease. Compared to cyclophosphamide, the most effective therapies for inducing remission were MMF, calcineurin inhibitors, or their combination while conferring similar or lower treatment toxicity. The most effective maintenance therapy was MMF,” the researchers said.

Takeaway Points

  1. Twenty to 75% of patients with systemic lupus erythematosus experience kidney involvement within the first 10 years after diagnosis. Therapies developed over past years have changed lupus nephritis from an acute to a chronic illness; however, there are few data on the efficacy and safety of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors.
  2. Researchers conducted a network meta-analysis of randomized clinical trials of immunosuppression to induce or maintain disease remission.
  3. Compared with IV cyclophosphamide, the most effective treatments were MMF in combination with calcineurin inhibitor therapy, calcineurin inhibitors, and MMF. The most effective strategy to maintain remission was MMF.