Study Finds Rituximab Noninferior to Cyclosporine for Membranous Nephropathy

A study published in The New England Journal of Medicine examining rituximab in membranous nephropathy found that it is noninferior to cyclosporine in inducing proteinuria remission at 12 months and is superior to maintaining long-term remission up to 24 months in patients at high risk for progressive disease.¹

Membranous nephropathy, an incurable kidney disease sometimes associated with autoimmune diseases or diabetes, is the leading cause of nephrotic syndrome in adults, where an excess of protein is deposited in urine as capillaries in the kidney become damaged.

In an accompanying editorial, the authors noted that the discovery of rituximab for this condition was first made about 20 years ago, but despite what they called “one of the most important findings” of this trial—a large difference between the rituximab group and the cyclosporine group regarding the percentage of patients with complete remission (35% vs none)—they said it is not likely that rituximab will become a top treatment for all patients with this disease.² Rituximab may fail in 25% to 30% of patients with nephrotic syndrome, because of ineffective or transient depletion of nephritogenic antibodies or sensitization syndrome, leading to treatment resistance.

The Membranous Nephropathy Trial of Rituximab (MENTOR) was a prospective, randomized, open-label, noninferiority trial conducted at 22 sites in North America with 130 patients. Since B-cell irregularities play a role in membranous nephropathy, researchers theorized that B-cell depletion with rituximab may be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria.

Patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 mL per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months were randomized to receive rituximab (2 infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months).

The primary outcome for patients, who were followed for 24 months, was a composite of complete or partial remission of proteinuria at 24 months.

At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% CI, —9 to 25; P = .004 for noninferiority).

At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P <.001 for both noninferiority and superiority). Among patients in remission who tested positive for antiphospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group.

In addition, serious adverse events were fewer with rituximab: 11 patients (17%) , compared with 20 patients (31%) in the cyclosporine group (P = .06).

References

1. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med .2019;(381):36-46. doi: 10.1056/NEJMoa1814427.
2. Ruggenenti P, Remuzzi G. A first step toward a new approach to treating membranous nephropathy. N Engl J Med. 2019;(381):86-88: doi 10.1056/NEJMe1906666.