Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody

Dahan, Karine; Johannet, C.; Estève, Emmanuel; Plaisier, Emmanuelle; Dębiec, Hanna; Ronco, Pierre

doi:10.1016/j.kint.2018.08.045

Cited by 34 publications

(29 citation statements)

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“…These findings make a case for the use of the NICE regimen, which was also used in the Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR), instead of the GEMRITUX regimen. They also suggest that the dose of rituximab might be insufficient in patients with heavy proteinuria in whom we have recently shown that reinfusion of rituximab could induce remission in patients that were considered "refractory" to rituximab (35).…”

Section: Discussionmentioning

confidence: 99%

High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

Seitz-Polski

Dahan

Dębiec

et al. 2019

CJASN

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Background and objectivesDifferent rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy.Design, setting, participants, & measurementsTwenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses.ResultsRemissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3–9] and 9 [IQR, 6–12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0–10.8] versus 0.0 [IQR, 0.0–0.0] P<0.001 and 0.0 [IQR, 0.0–2.0] versus 16.5 [IQR, 2.5–31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0–8.0] versus 8.3 [IQR, 0.0–73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0–10.9] versus 0.0 µg/ml [IQR, 0.0–0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses.ConclusionsOur work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.

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Section: Discussionmentioning

confidence: 99%

High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

Seitz-Polski

Dahan

Dębiec

et al. 2019

CJASN

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“…28 In addition, we previously reported that a second course of RTX had a dramatic effect on PLA2R Abs titers, with all but 1 patient reaching complete immunological remission and all retreated patients showing clinical remission. 29 The retreatment regimen was stimulated by the GEMRITUX trial where PLA2R Abs levels were markedly decreased as early as 3 months after RTX but not followed by further decrease at 6 months, suggesting an early loss of efficacy of the monoclonal Ab. A previous study showed that RTX blood levels were lower and the B-cell depletion significantly shorter in patients with MN than in patients with rheumatoid arthritis or antineutrophil cytoplasmic antibody vasculitis.…”

Section: Clinical and Immunological Outcomesmentioning

confidence: 99%

Rituximab in Patients With Phospholipase A2 Receptor–Associated Membranous Nephropathy and Severe CKD

Hanset

Estève

Plaisier

et al. 2020

Kidney International Reports

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Introduction: Patients with phospholipase A2 receptor (PLA2R)-associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m 2 has not been investigated. Methods: We retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m 2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission. Results: The mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 AE 7 ml/min per 1.73 m 2 , 25.2 AE 5.4 g/l, and 13.2 AE 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8-46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events. Conclusion: RTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.

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“…"Spreader" patients achieve spontaneous remission less often and tend to have worse clinical outcomes. Initial data suggested that cyclophosphamide might be more effective in patients with high titers of PLA2R-Ab (9); however, retreatment with additional rituximab was able to alleviate this apparent resistance (10).…”

mentioning

confidence: 99%

Management of Membranous Nephropathy after MENTOR

Trivin-Avillach

Beck

2019

CJASN

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Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody

Cited by 34 publications

References 4 publications

High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

Rituximab in Patients With Phospholipase A2 Receptor–Associated Membranous Nephropathy and Severe CKD

Management of Membranous Nephropathy after MENTOR

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