Accelerating the Depletion of Circulating Anti-Phospholipase A&lt;sub&gt;2&lt;/sub&gt; Receptor Antibodies in Patients with Severe Membranous Nephropathy: Preliminary Findings with Double Filtration Plasmapheresis and Ofatumumab

Podestà, Manuel Alfredo; Gennarini, Alessia; Portalupi, Valentina; Rota, Stefano; Alessio, Maria Grazia; Remuzzi, Giuseppe; Ruggenenti, Piero

doi:10.1159/000501858

Cited by 26 publications

(20 citation statements)

References 15 publications

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“…The Membranous Nephropathy Trial of Rituximab (MENTOR trial) confirmed substantial uncontrolled data showing that B-cell depletion with rituximab is a However, there is an unmet need for additional treatment strategies in patients who do not tolerate these therapies, do not achieve immunologic remission with these therapies, and/or develop anti-rituximab antibodies. Case reports have shown that the "next-generation" anti-CD20 antibodies obinutuzumab [6] and ofatumumab [7][8][9] may be promising agents in such cases. Successful treatment of rituximab-resistant patients with obinutuzumab and ofatumumab could imply that additional or more complete B-cell depletion is required in such cases to achieve immunologic remission, but also that the producing anti-PLA2R antibody-producing cell is a CD20positive B cell.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

2021

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Introduction: B-cell depletion has been shown to be an effective strategy for the majority of patients with membranous nephropathy (MN), and in PLA2R-positive MN, immunologic remission (improvement or elimination of measurable serum anti-PLA2R antibodies) precedes renal remission. Yet, cases exist of patients who do not achieve immunologic remission despite achieving peripheral B-cell depletion. This has led to the hypothesis that some patients have plasma cells that are responsible for producing anti-PLA2R antibodies. Case Presentation: A 66-year-old man with a past medical history of hypertension, hyperlipidemia, and cerebrovascular disease presented with nephrotic syndrome and was diagnosed with PLA2R-positive MN on kidney biopsy. He was refractory to multiple therapies including tacrolimus, and was resistant to rituximab despite having achieved B-cell depletion. He also did not enter into remission with plasmapharesis and cyclophosphamide. He then achieved immediate immunologic remission after treatment with the proteasome inhibitor bortezomib, which is used as first-line therapy for multiple myeloma. Discussion/Conclusion: This case suggests that considering the source of PLA2R antibody production could lead to individualized and targeted therapies for MN.

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Section: Discussionmentioning

confidence: 99%

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

2021

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“…Immunoadsorption and plasmapheresis have been used by several groups to accelerate the depletion of circulating THSD7A-and PLA2R-Ab in patients with severe MN [31,32]. Only small series or cases have been reported.…”

Section: Improving the Use Of Anti-cd20 Antibodiesmentioning

confidence: 99%

Advances in Membranous Nephropathy

Ronco

Plaisier

Dębiec

2021

JCM

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Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leapcombining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four “new antigens” were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine.

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“…After more than 2 years from the first ofatumumab infusion, serum anti-PLA 2 R levels increased (67.9 RU/mL) and NS relapsed. In order to limit drug exposure and owing to evidence of efficacy with reduced ofatumumab doses in other cases,26 we treated this patient with 100 mg of ofatumumab. This regimen determined a complete depletion of peripheral CD19 + B cells and reduced circulating autoantibodies below the positivity threshold.…”

Section: Outcome and Follow-upmentioning

confidence: 99%

Ofatumumab for multirelapsing membranous nephropathy complicated by rituximab-induced serum-sickness

et al. 2020

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Rituximab (375 mg/m2) achieved remission of the first episode and six relapses of nephrotic syndrome (NS) in a young male patient with podocyte phospholipase A2 receptor (PLA2R)-related membranous nephropathy (MN) refractory to steroids and cyclosporine. Between-treatments interval averaged 17.4±4.2 months. The seventh infusion was complicated by delayed serum-sickness, which resolved with steroids. On subsequent relapse, the fully human anti-CD20 monoclonal antibody ofatumumab (300 mg) achieved remission of the NS, without significant side effects. Circulating CD19+ B cells were depleted, proteinuria decreased from 10.9 to 1.3 g/day, and serum albumin, immunoglobulin levels and glomerular filtration rate normalised. Twenty-eight months later, despite transient anti-PLA2R depletion, ofatumumab (100 mg) failed to induce remission of the eighth relapse. Remission was safely achieved 5 months later with repeated ofatumumab infusion (300 mg). This treatment (€723) was less expensive than rituximab (€1801). Ofatumumab could be a safe and cost/effective rescue therapy for patients with MN sensitised against rituximab.

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Accelerating the Depletion of Circulating Anti-Phospholipase A<sub>2</sub> Receptor Antibodies in Patients with Severe Membranous Nephropathy: Preliminary Findings with Double Filtration Plasmapheresis and Ofatumumab

Cited by 26 publications

References 15 publications

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

Advances in Membranous Nephropathy

Ofatumumab for multirelapsing membranous nephropathy complicated by rituximab-induced serum-sickness

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