Optimizing Rituximab Dosing in Membranous Nephropathy: A Continuing Debate

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in non-diabetic adults. While characterized as an autoimmune kidney disease, MN is heterogeneous in terms of immunology (presence, type, and titer of autoantibodies) and clinical manifestation (severity of proteinuria and kidney function). The KDIGO Guidelines recommend immunosuppressive therapy, primarily for those with a high risk of progression, guided by clinical features or disease activity biomarkers.¹ Rituximab (RTX) is the preferred first-line treatment, primarily due to its favorable risk-benefit profile compared to the alternatives. At least four randomized controlled trials evaluating RTX have reported efficacy in 60% of cases, a relatively modest figure for a first-line therapy. Compounding this is the lack of consensus on the appropriate dosing regimen, with the KDIGO 2021 guidelines on glomerular disease emphasizing identifying the most appropriate regimen in MN.

In this issue of the Journal, Suresh et al.² have compared remission (partial or complete) rates between low-dose RTX and cyclical cyclophosphamide/corticosteroids at 6 months. Remission rates were similar in the two arms at 6 and 12 months. The authors are to be lauded for tackling this important question. This is especially relevant when considering patients’ out-of-pocket expenditure on biologics. The study’s strengths include its randomized design and the comparison of two first-line therapies. The use of a low RTX dose is a novel aspect.

Among all glomerular diseases, MN currently offers the best evidence-based framework for clinical decision-making.¹ However, the therapeutic landscape is rapidly evolving. In designing future randomized clinical trials in MN, in addition to the appropriate selection of comparators, the following factors warrant careful consideration;

Both cyclical cyclophosphamide/corticosteroids and RTX are recommended as first-line therapies for the management of MN. Short- and medium-term outcomes are inferior with calcineurin inhibitors as compared to cyclical cyclophosphamide/corticosteroids or RTX. In terms of study design, there is at least one pilot study (RI-CYCLO)³ and one superiority trial (STARMEN)⁴ that compares RTX (alone or in combination with tacrolimus) with cyclical cyclophosphamide/corticosteroids. The aim of a pilot study is to provide estimates of the feasibility of conducting a larger clinical trial rather than a robust efficacy comparison. The pilot study by Suresh et al.² shows similar efficacy between the lower-dose RTX and cyclical cyclophosphamide/corticosteroids groups. Notably, although the study concludes that RTX is associated with better safety than modified Ponticelli regimen, the incidence of serious infections, such as pneumonia and sepsis, was similar between the two arms. Similarly, the RICYCLO trial,³ comparing a higher RTX dose (1 g on days 0 and 15) against cyclical cyclophosphamide/corticosteroids, showed no signal towards better safety or efficacy of RTX over cyclical cyclophosphamide/corticosteroids, and highlighted the need for a larger non-inferiority trial. A non-inferiority trial depends on large sample sizes, making recruitment arduous in rare diseases like MN; therefore, future trials must ensure multicenter collaboration to overcome this limitation. With the emergence of newer therapies, such as anti-B-cell agents (e.g., obinutuzumab and ofatumumab), anti-complement therapies, and CD38 inhibitors, it is unlikely that any new clinical trials comparing RTX and cyclical cyclophosphamide/corticosteroids will be conducted in the foreseeable future.

Serum anti-M-type phospholipase A2 receptor (PLA2R) has diagnostic value in MN,⁵ with a strong association with clinical outcomes.^6,7 Anti-PLA2R levels at 3 months can predict clinical response.⁸ There is ongoing debate regarding the optimal assay for antibody measurement; the ELISA technique allows for serial assessment, but uncertainty remains about what constitutes a clinically meaningful reduction. Although the FDA-approved manufacturer defines a titer of <14 RU/mL as negative, some experts argue for a lower threshold or advocate the use of indirect immunofluorescence to confirm successful antibody depletion. We believe that anti-PLA2R can be effectively used for patient stratification and inclusion in clinical trials, for longitudinal monitoring, and as an efficacy endpoint in therapeutic studies. The other podocyte antibodies are not commercially available, and Western blotting for these antigens is neither standardized nor logistically feasible.

While >3/4 patients with MN present with nephrotic syndrome, additional variables influence therapeutic decision-making and long-term prognosis. For example, in those with high anti-PLA2R antibody titers (>150 RU/mL) and/or complications of severe nephrotic syndrome, clinicians may not solely rely on a single RTX course administered initially.⁹ Evidence suggests that such patients may derive greater benefit from supplemental doses during follow-up¹⁰ or may respond more favorably to cyclophosphamide-based therapy.⁹ Additionally, the efficacy of RTX has been inadequately studied in patients with progressive loss of kidney function, although observational studies suggest a potential therapeutic role for this subgroup.¹¹ The study by Suresh et al.² demonstrated a trend toward a greater decline in anti-PLA2R titers and improved clinical remission rates in patients with anti-PLA2R titers >150 RU/mL in the cyclical cyclophosphamide/corticosteroids arm, an effect that could potentially be amplified with a larger sample size. Various strategies have been explored to augment the efficacy of RTX, including administering a higher dose (1 g on days 0 and 15),³ an additional dose¹⁰ at 3-6 months, combination with low-dose corticosteroids or cyclophosphamide,¹² or the addition of calcineurin inhibitors for 6 months to RTX administered at 0 and 6 months.¹³ Future randomized studies in MN should consider stratifying patients based on these additional clinical variables and serological parameters to provide a more nuanced assessment of treatment outcomes.

Outcome assessment is best performed at 24 months, 12 to evaluate the initial response rate, and 12 more to monitor for relapses. MN pathogenesis is such that clearance of immune deposits and proteinuria occurs over a longer term than in inflammatory diseases; therefore, clinical outcome assessment at 6 months would be incomplete, as in the trial by Suresh et al.² At best, 6 months may be sufficient to assess immunological remission. Future trials should incorporate extended follow-up beyond 24 months, as outcome assessment during this period is crucial for evaluating relapse rates, the need for additional therapies, and long-term clinical outcomes such as progressive decline in kidney function or dialysis initiation.

The road ahead for clinical trials in MN involves evaluating novel biologics, repurposing treatments used in other autoimmune diseases, and combination regimens. The latter approach is particularly relevant for the Global South, where newer, expensive therapies may not be accessible or commercially viable in low- and middle-income countries. Emerging therapies under investigation include obinutuzumab,¹⁴ a type II anti-CD20 monoclonal antibody with improved B-cell depletion than RTX (Phase III MAJESTY trial-NCT04629248 has completed enrollment, and results are expected soon). Belimumab, a B cell activating factor inhibitor, is being evaluated in the REBOOT Part B trial (NCT03949855, belimumab + RTX vs. RTX alone). Felzartamab, an anti-CD38 monoclonal antibody targeting plasma cells, is being compared with tacrolimus in the PROMINENT study, a Phase III trial. Additionally, combination regimens, such as RTX with low-dose corticosteroids or cyclophosphamide, have shown promise and warrant further study.

In summary, the therapeutic landscape in MN is evolving rapidly, with biologic agents emerging as dominant players. However, for patients with severe symptoms or rapidly declining kidney function, cyclical therapy has a well-established track record of inducing clinical remission and preserving long-term kidney outcomes.