Landmark Trials in Lupus Nephritis: Look How Far We’ve Come!

First Posted on RFN: January 9, 2019

Reviewed: November 2020

Lupus nephritis occurs in up to 80% of patients with SLE and is associated with significantly reduced survival.  Interestingly, one of the first studies to describe lupus nephritis was written approximately 50 years ago and was the first to utilize kidney biopsies to classify lupus nephritis based on histologic findings. In this study they also compared high vs low dose corticosteroids for the most active (diffuse proliferative) cases and showed that, although survival was poor in both groups (less than 2 to 5 years in most cases), patients who received corticosteroids survived longer, and that high dose steroids showed a survival advantage over low dose.

Corticoteroids alone, not a good idea…

Twenty years later, the 1986 NIH study evaluated corticosteroids plus azathioprine (AZA), oral or intravenous (IV) cyclophosphamide (CYC), or a combination, for patients with active lupus nephritis.  In all cases, patients also received steroids.  It was evident that high dose prednisone alone was inferior to any cytotoxic regimen.

This was confirmed in a 1992, when Boupas et al compared IV methylprednisolone to short versus long courses of IV CYC and found that again, patients who received only corticosteroids had a higher risk of kidney failure.  Interestingly, a short versus long course of CYC had a similar effect on doubling of serum creatinine, but the short course was associated with a higher probability of exacerbation. A 1996 study found that that the combination of methylprednisolone and CYC was superior for remission compared to either treatment alone.

Cyclophosphamide or MMF?

As a consequence of the above trials, cyclophosphamide became a routine treatment for lupus nephritis, but, given its significant side effect profile – especially in light of a meta-analysis showing a high risk of ovarian failure with this drug- the need to find alternative therapies and possibly reduced dosage was pivotal.

Chan et al with a small cohort group of 42 patients in 2000 did demonstrated that induction therapy with mycophenolate mofetil (MMF) plus prednisolone was as effective a regimen as CYC and prednisolone, each followed by maintenance with AZA and prednisolone (Fig. 3). 

The most robust data regarding MMF use, however, comes from the ALMS trial in 2009. This was an international multicenter open label trial which compared MMF vs IV CYC(NIH regimen) for induction treatment in patient with lupus nephritis class III-IV. The results showed no difference in rates of remission at 24 weeks. Nonetheless, it is possible that the absence of difference was attributable to the short term follow up of the patients. In studies of corticosteroids alone compared to immunosuppression, for example, clinical differences were only detected after a couple of years of follow up. A post hoc analysis of these data later showed that MMF was superior to IV CYC in Hispanic and Black patients and is the preferred induction therapy in these subgroups.

In 2002 the EuroLupus trial, investigators compared low or high dose CYC (NIH regimen), in combination with corticosteroids (AZA for maintenance) in a cohort of 90 patients. Low and high dose CYC were associated with comparable outcomes as far as inducing remission and long-term preservation of kidney function. The low dose group had fewer adverse events, but this was not statistically significant. One of the main weaknesses of this trial is that 76% of the population was White, raising concerns about the external validity of this trial to other population groups.

Now, a word on maintenance…

MMF is overall preferred to AZA for maintenance therapy mainly due to the data on the ALMS maintenance trial and MAINTAIN.

ALMS maintenance looked at the patients that achieved remission with either MMF or IV CYC and divided them to receive either AZA or MMF for maintenance. MMF was superior to AZA in maintaining remission regardless of the induction regimen. The AZA group also had a higher rate of adverse events leading to drug discontinuation.

Employing only CYC with corticosteroids as induction therapy, and with a less diverse population (83% White) and fewer patients, MAINTAIN did not to find that AZA and MMF differed in terms of maintaining remission. Here MMF and AZA were not different as far as maintaining remission. The AZA group, however, developed higher rates of anemia and leukopenia.

To address this issue further, a meta-analysis reviewed these two and an additional 4 trials and showed that maintenance with MMF leads to fewer relapses. Currently MMF is the preferred choice for maintenance treatment in lupus nephritis.

What the future holds

Other therapies have been studied for LN and should be mentioned.

To evaluate the potential role of calcineurin inhibitors (CNIs), a multicenter trial in China recruited approximately 300 patients and compared induction outcomes for MMF plus tacrolimus compared to CYC (NIH dosing). At 6 months, the MMF plus tacrolimus group appeared superior to CYC, however, this was not sustained at 18 months follow up.

The Aura-LV phase 3 trial is currently under way. The phase 2 trial that preceded it compared MMF and corticosteroids + voclosporin (a CNI) vs MMF and steroids + placebo. The steroid taper was rapid. Results showed that at 48 weeks the voclosporin group acheived higher remission rates. This result, however, was associated with a higher rate of mortality and serious adverse events in low dose voclosporin groups. With a phase 3 trial investigators envision gathering further data on the safety profile of voclosporin.

A word of caution about both of the CNI studies mentioned above is that this drug class can decrease proteinuria via a non-immunologic pathway, hence proteinuria as an outcome might not be as meaningful as in other drug studies. To further clarify this, next stages of Aura-LV will include kidney biopsies.

LUNAR trial investigated rituximab as a possible treatment option. Patients received eitherMMF plus corticosteroids plus rituximab or MMF plus corticosteroids plus placebo. The difference in remissions for the two treatment groups was not statically significant.

The most recent trial of B-cell targeted therapies is BLISS-LN. It studied belimumab, a monoclonal antibody that inhibits B-cell activating factor. It showed that in addition to standard of care (MMFplus corticosteroids or CYC+corticosteroids) the group that received belimumab had an improved renal response and lower risk of a renal event or death (HR, 0.51; 95% CI, 0.34 to 0.77; P=0.001).These results are mainly influenced by the finding of increased proteinuria in the placebo group. The trial results raise some other concerns because the study outcomes were changed after 5 years into the trial. If the initially stated outcomes had been maintained, there would be no significant difference between the groups when analyzed. Additionally, there was a low recruitment of Black patients, which tend to have a worse prognosis.

While much has been achieved, in truth, some of the progress for lupus nephritis treatment has been very gradual and much remains to be done to achieve more remissions than occur with current therapies. In addition, we really don’t have data on how long to use maintenance therapy—a big question for clinicians who treat these patients. We look forward to see more advancement in the field.

Find the Spanish version of this post here.

Post by: Diana Mina, MD
Larissa Kruger, MD

Reviewed By: Robert Cohen, MD.