Rituximab Emerging as New Option for Membranous Nephropathy

Pam Harrison

November 16, 2015

SAN DIEGO — For patients with idiopathic membranous nephropathy, the addition of rituximab to nonimmunosuppressive antiproteinuric therapy leads to significant improvements in immunologic and clinical outcomes at 6 months, and over time, according to the first randomized controlled trial of its kind, which was presented here at Kidney Week 2015.

"The treatment of idiopathic membranous nephropathy remains controversial because of the high rate of spontaneous remission and side effects from both the alkylating agents and renal toxicity related to calcineurin inhibitors," said Pierre Ronco, MD, PhD, from Sorbonne Universités in Paris.

The rituximab combination induced "a higher rate of immunologic remission at month 3 and at month 6, whereas during the 24-month observational period, the same combination induced a higher rate of clinical remission than nonimmunosuppressive antiproteinuric therapy alone," he explained. In addition, "rates of serious adverse events were comparable in both groups."

The study involved 80 patients with idiopathic membranous nephropathy and persistent nephrotic syndrome that lasted 6 months.

All patients received nonimmunosuppressive antiproteinuric therapy for 6 months. Half were randomized to also receive rituximab 375 mg/m² on day 1 and day 8; the other half served as the control group.

In the final analysis, 37 patients in the rituximab group and 32 in the control group were evaluated.

At baseline, estimated glomerular filtration rates were comparable in the rituximab and control groups (64 vs 73 mL/min per 1.73 m²), 73% of each group was positive for PLA2R antibodies, and PLA2R antibody titers were similar in the rituximab and control groups (40.5 vs 43.3 RU/mL).

Remission at 6 months, assessed using Kidney Disease: Improving Global Outcomes (KDIGO) criteria, was the primary end point of the study. The composite end point was a reduction in proteinuria of at least 50% and an increase in serum albumin of at least 30%.

Secondary end points were proteinuria, serum albumin, serum creatinine, and PLA2R-Ab.

"There was a significant decrease in proteinuria at both month 3 and month 6 in both groups, although there was no significant difference between the two groups," Dr Ronco reported.

However, there were significant differences between the two groups in serum albumin and PLA2R antibody levels at 3 and 6 months.

Increases in serum albumin reached significance at month 3 in the rituximab group and remained significant at month 6, whereas increases only reached significance at month 6 in the control group. The difference between the two groups was significant at month 3 (P = .01) and at month 6 (P = .003).

PLA2R antibody levels dropped dramatically by month 3 in the rituximab group and stabilized after that, whereas levels decreased progressively in the control group and only reached significance at month 6. Differences between the two groups were significant both at month 3 (P < .001) and at month 6 (P < .001).

Immunologic and clinical outcomes — except remission, the primary end point — were significantly different at month 6.

Table. 6-Month Outcomes

Outcome Rituximab Group, % Control Group, % P Value
Remission assessed with KDIGO criteria 35 21 not significant
Immunologic remission defined by antibody depletion 50 12 <.01
Composite end point of decreased proteinuria and increased serum albumin 41 13 <.01

 

Patients were followed for up to 24 months after the discontinuation of the study regimens. After discontinuation, physicians were free to modify treatment regimens as they saw fit, Dr Ronco reported.

During the observation phase of the trial, rates of remission were significantly higher in the rituximab group than in the control group (64.9% vs 37.5%; P = .02), and more patients in the rituximab group achieved a complete response (7 vs 1).

Time to remission was similar in the rituximab and control groups (7.0 vs 6.5 months).

"KDIGO remission was associated with an absence of detectable PLA2R antibodies by month 3" (odds ratio, 8.1; P = .002), said Dr Ronco.

In contrast, KDIGO remission was not associated with CD19 count at either month 3 or month 6.

"Results of this short, 6-month trial show a dramatic effect of rituximab on anti-PLA2R antibodies, which are specific biomarkers for this disease and are most likely responsible for the occurrence of proteinuria," Dr Ronco told Medscape Medical News.

The primary end point of remission, defined by the presence of proteinuria, did not reach significance in the rituximab group because of the short duration of the trial and the relatively high rate of spontaneous remission — at 21% — in the control group, he explained.

"The trial was, however, positive for the composite end point, while the difference in long-term remission over the 24-month observational period was again statistically significant," he said.

"And while the 6-month randomized controlled trial was negative for the primary end point, the dramatic effect of rituximab on antibody depletion and results from the follow-up study suggest that rituximab will represent a major advance in the management of this disease," he said. In addition, there was a "high safety profile" with rituximab.

Dr Ronco reported that next steps will be to tailor the dose of rituximab to antibody levels during follow-up. The aim of this is to eradicate the antibody-producing clone, which predates by several months proteinuria-defined clinical remission.

Nephrotic Syndrome

Membranous nephropathy is one of the most common causes of the nephrotic syndrome, said session cochair Jean Francis, MD, from the Boston University Medical Center.

"Many patients with persistent severe proteinuria are at risk of worsening kidney function and progression to end-stage renal disease," he told Medscape Medical News.

"The treatment of membranous nephropathy has been challenging and relies on lengthy and complicated regimens, which, while effective, have a high risk of side effects," he added.

Dr Francis said he thinks that this study "came at the right time," in that it shows that rituximab can induce partial and complete remissions in almost 70% of patients, compared with supportive management alone.

"These findings also support data from other groups on the role of anti-PLA2R antibodies in monitoring patients' responses to therapy and in predicting clinical remission after an intervention," he explained.

"These study findings should be welcomed by all clinicians caring for patients with symptomatic membranous nephropathy who are at high risk from lengthy immunosuppressive therapy," Dr Francis concluded.

"The regimen used in this study is easy, short, and produces good responses," he added. "Armed with close serologic monitoring of anti-PLA2R antibodies, data from previously published observational studies, along with the current study, indicate that rituximab should be among the first-line regimens used for the treatment of this disease."

The study was funded by Hoffmann-La Roche and by both private foundation and non-US government support. Dr Francis has disclosed no relevant financial relationships.

Kidney Week 2015: American Society of Nephrology Annual Meeting. Abstract SA-OR011. Presented November 7, 2015.

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