Rituximab Is Preferable to Cyclophosphamide for Treatment of Membranous Nephropathy: PRO

Primary membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. This histologic pattern is related to circulating autoantibodies against the M-type antigen phospholipase A2 receptor (PLA2R) in over 70% of patients with primary MN. Patients with non–PLA2R-associated and primary MN may be positive for other target antigens, such as thrombospondin type-1 domain-containing 7A, neural epidermal growth factor-like 1, or semaphorin 3B (¹). Spontaneous remission of proteinuria can occur in one of every three patients, and is associated with excellent long-term outcomes; in contrast, ESKD may occur in approximately 35% of patients untreated that remain nephrotic at 10-year follow-up (¹). Some factors, such as high levels of anti-PLA2R antibody at the time of diagnosis (≥150 RU/ml by ELISA), nondeclining or increasing titers, protein excretion that exceeds 8–10 g per day, or a decrease in kidney function are related with lower risk of spontaneous remission and progression of disease, in which case immunosuppressive therapy is recommended. Anti-PLA2R measurements have come to play a crucial role informing patients and their nephrologists of the immunologic status of disease to guide treatment decisions (²).

Cytotoxic agents combined with corticosteroids have been considered a gold standard therapy in primary MN for many years, despite their significant adverse event profile (²), possibly under-reported in classic studies. The use of alkylating agents has been associated with increased risk of malignancy, bladder, and gonadal toxicity, infertility, bone-marrow toxicity, dermatologic side effects, and opportunistic infections, among others, prompting a continued search for equally effective, but less toxic, therapeutic options (²). This profile of side effects requires close monitoring for leukopenia and admissions because of complications, increasing costs not usually mentioned. Rituximab (RTX) is a monoclonal antibody directed against CD20 that depletes B cells. Early patient reports demonstrated that 4-weekly infusions of RTX (375 mg/m²) were capable of reducing proteinuria in idiopathic MN with treatment-refractory nephrotic syndrome (³), and as first-line therapy in patients who did not achieve spontaneous remission with supportive treatment (⁴). These early reports, with follow-up periods ranging from 20 weeks to 1 year, were incomplete, because long-term studies in MN have demonstrated that effectiveness in therapy should be evaluated over a longer duration follow-up, with proteinuria nadir not being reached until more than 2 years after the start of therapy (⁵).

Fervenza et al. (⁶) subsequently studied different dose administrations of RTX and outcomes at 24 months in patients with primary MN. The 4-weekly infusions of 375 mg/m² RTX with retreatment at 6 months were compared with 1 g RTX at days 0 and 15, with retreatment at month 6. The 4-weekly dose regimen resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks at 24 months follow-up (⁶). Beck et al. (⁷) evaluated the immunologic response to RTX with anti-PLA2R measurements before and after treatment in 35 patients with primary MN. Nadir levels of anti-PLA2R antibodies were achieved in 68% of patients within 12 months of treatment and preceded decline in proteinuria by 24 months in most patients (⁷). Dahan et al. compared immunologic remissions at month 6 between RTX and alkylating agents; this initially nonfavorable study for RTX at month 6 was re-evaluated after 19.5 months of follow-up, and after a redose of RTX, most patients had achieved immunologic remission (80%), and all had achieved some form of clinical remission (⁸). These early series suggested a clear and effective role of utilizing RTX for treating MN, guided by the immunologic status of disease, but data from large-scale randomized controlled trials (RCTs) were still required to definitively position RTX as the optimal first line immunosuppressive agent for MN.

The RCTs of RTX in primary MN, by order of reporting, have been the Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy trial (⁹), the Membranous Nephropathy Trial of Rituximab (¹⁰), the Sequential Therapy with Tacrolimus and RTX in Primary MN (STARMEN) trial (¹¹), and the Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) trial (¹²). The Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy trial (⁹) included 75 patients with biopsy-proven MN and persistent proteinuria >3.5 g/day after 6 months of supportive care who were randomly assigned to RTX (two infusions of 375 mg/m² administered 1 week apart) or placebo. At 6 months, there was no significant difference in the primary composite endpoint of complete or partial remission of proteinuria between patients treated with or without RTX. Anti-PLA2R antibodies, which were present in 73% of patients at baseline, disappeared in a greater proportion receiving RTX (50% versus 12%), demonstrating a marked improvement in immunologic remission for those treated with RTX. As mentioned above, a 6-month evaluation may be too early to assess proteinuria-based outcomes in MN. Indeed, at the last follow-up reported in this study (median 17 months), RTX demonstrated almost twice the rate of complete or partial remission (65%) compared with placebo (34%) (P<0.01 for comparison).

The Membranous Nephropathy Trial of Rituximab (¹⁰) included 130 patients with proteinuria ≥5 g/day and 24-hour creatinine clearance ≥40 ml/min per 1.73 m² after ≥3 months of supportive care, who were randomly assigned to RTX (1 g administered 14 days apart, repeated at 6 months in the case of partial response) or oral cyclosporine (3.5 mg/kg per day for 6 months, or 12 months in the case of partial response at 6 months, with dose adjustment to maintain a 12-hour trough concentration of 125–175 ng/ml). The primary endpoint was a composite of complete (proteinuria <0.3 g/day and serum albumin ≥3.5 g/dl) or partial (reduction in proteinuria ≥50% and final proteinuria between 0.3 and 3.5 g/day) remission at 24 months. At 24 months, patients receiving RTX had a higher rate of complete or partial remission than those receiving cyclosporine (60% versus 20%, respectively); only patients receiving RTX achieved complete remission (35% versus 0% in the cyclosporine group). In addition, the eGFR was higher in the RTX group at the end of the study (100 versus 87 ml/min per 1.73 m² at 24 months). Anti-PLA2R antibody levels fell more rapidly with sustained clearance in the RTX group, explaining a very low rate of relapses (5%).

The STARMEN trial (¹¹) was a randomized, open-label controlled trial of 86 patients with primary MN. After 6 months of supportive care, the study assigned 43 patients to receive 6 months of cyclical treatment with corticosteroid and cyclophosphamide, and 43 patients to receive 6 months with tacrolimus, followed by one dose of RTX (1 g). The primary endpoint—complete or partial remission of nephrotic syndrome at 24 months—was significantly higher in the cyclophosphamide group (84% versus 58%). Complete remission at month 24 occurred in 60% of patients with cyclophosphamide/steroids versus 26% of patients in the tacrolimus-RTX group. Notably, baseline median levels of anti-PLA2R antibodies in the tacrolimus-RTX group were higher (113 RU/ml versus 59 RU/ml in the cyclophosphamide arm), and rates of immunologic response at 24 months were similar between the groups (83% in the patients on tacrolimus-RTX vs 88% in the patients on cyclophosphamide/steroids). Serious adverse events were similar in both groups. Although the STARMEN trial has been interpreted as a “negative” study for RTX, the similar rates of immunologic remission suggest that over a longer period of follow-up, results between the two groups may be comparable. In addition, the role of RTX monotherapy cannot be evaluated in this study because the drug was dosed after 6 months of tacrolimus and at a lower dose than typically used for MN therapy.

The RI-CYCLO trial (¹²) was an open-label controlled trial of 74 patients randomized to RTX (1 g, 2 weeks apart) or corticosteroid-cyclophosphamide regimen after a run in of ≥3 months. Complete remission was defined as proteinuria ≤0.3 g/day, partial remission as a reduction of proteinuria >50%, and an absolute value of 0.3–3.5 g/day. The primary endpoint of the study, complete remission at 12 months, was achieved in 16% in the RTX group versus 32% in the cyclophosphamide arm. Interestingly, at month 24 outcomes were similar: 62% in the RTX arm had achieved complete or partial remission versus 73% in the cyclophosphamide arm. The probability of complete remission alone at 24 months was also similar in both groups, with no differences in side effects. According to data before the RI-CYCLO trial, from comparable RCTs at month 24, RTX compared with cyclophosphamide/steroids could have superior rates of percentage of complete remission (35% versus 20%) with lower relapse rates of 5% versus 25% (¹³).

Taken together, the data from the RCTs of RTX in MN further support the findings from earlier patient studies. For patients with primary MN who did not achieve spontaneous remission, RTX is able to induce an immunologic remission at 6–12 months: earlier in patients with lower PLA2R antibodies and milder disease, later in patients with higher PLA2R antibodies, who will typically require redosing of RTX. These immunologic remissions anticipate clinical remissions that will occur 3–12 months later. In viewing the disease course of MN as a marathon rather than a sprint, RTX emerges as an ideal first-line agent, given its ability to achieve response in <80% of patients over sufficient periods of follow-up. Although this efficacy is similar to cyclophosphamide-based regimens, the results come via a steroid-free regimen with an overall better side-effect profile and, as an intravenous agent dosed every 6 months, no concerns over treatment adherence. For these reasons, we are firmly in the era of RTX as the preferred immunosuppressive therapy for MN. And this era is expected to last until something even better—perhaps in the form of even more effective B cell depletion with obinutuzumab—comes along.

Disclosures

A.S. Bomback reports having consultancy agreements with Chemocentryx and Novartis; reports receiving research funding from Achillion and Chemocentryx; and reports receiving honoraria from Alexion, Aurinia, Calladitas, Kidney & Urology Foundation of America, the National Kidney Foundation, Novartis, Otsuka, Principio, Retrophin, and UpToDate. The remaining author has nothing to disclose.

Funding

None.