Obinutuzumab

Glucocorticoids (GCs) remain central to the management of many glomerular diseases, providing rapid and potent antiinflammatory effects. However, their well-recognized toxicities have driven growing efforts to reduce cumulative exposure. This review synthesizes evidence from randomized and key noncontrolled studies evaluating GC-sparing strategies across diseases where these agents have historically played a central therapeutic role. In antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), large trials such as the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial and the Effect of Reduced-Dose versus High-Dose Glucocorticoids Added to Rituximab (LoVAS) trial demonstrate that reduced-dose regimens preserve efficacy while lowering infection risk. In lupus nephritis (LN), lower-dose strategies and early use of multipronged regimens incorporating targeted agents such as belimumab, calcineurin inhibitors, or obinutuzumab support faster tapering. In minimal change disease (MCD), combination approaches with calcineurin inhibitors or mycophenolate achieve remission with less steroid exposure. In IgA nephropathy (IgAN), practice is increasingly shifting away from GC use altogether, as novel immunomodulatory agents targeting disease-specific pathways are integrated into care. Although GCs will likely remain essential for induction in select inflammatory glomerulopathies, their role can increasingly be narrowed to early, time-limited use. Future studies should address key uncertainties, particularly the optimal use of i.v. methylprednisolone in rapidly progressive presentations and evaluate the safety and efficacy of even lower-dose regimens.

Approximately 30% of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) fail rituximab therapy through mechanisms that could be overcome by obinutuzumab.

In this prospective, single-arm, single-center, open-label trial, 20 consenting adults with MN and rituximab-resistant NS received three 1000 mg obinutuzumab infusions at the Bergamo Nephrology Unit (Italy) between March 2022 and February 2024 and were monitored for ≤ 12 months. The primary outcome was a composite end point of normo-albuminemia and complete (proteinuria < 0.3 g/d) or partial (proteinuria < 3.5 g/d with ≥ 50% reduction from baseline) NS remission at 12-month follow-up. Twenty-four-hour proteinuria and glomerular filtration rate (GFR) were evaluated at baseline and at 3, 6, 9, 12, 18, and 24 months posttreatment.

At 12 months, 16 patients met the combined end point, 4 with complete remission. No patient relapsed after remission. Median (interquartile range) 24-h proteinuria decreased from 5.7 (4.7-8.1) to 1.3 (0.5-2.7) g/24 h. Albumin and IgG fractional clearances also decreased, whereas serum albumin increased from 2.9 ± 0.6 g/dl to 3.9 ± 0.3 g/dl (P < 0.0001 for all changes). Dyslipidemia, hypocalcemia, and hypo-gammaglobulinemia improved significantly and GFR stabilized. At 12 months, total B cells and circulating anti-phospholipase A₂ receptor (PLA₂R) antibodies were depleted. Similar findings were observed in the cohort of 10 patients who completed 24 months of follow-up. However, total B cells reemerged in the circulation without an increase in anti-PLA₂R antibodies and proteinuria, or relapses. Treatment was safe and well-tolerated.

Obinutuzumab treatment is extremely effective and safe in patients with MN and rituximab-resistant NS and can achieve persistent remission in this population.