Rituximab in the treatment of membranous glomerulonephritis. GEMRITUX Trial.

What are anti–phospholipase A2 receptor antibody (PLA2RAb)? To better understand the pathogenesis of of non-diabetic membranous nephropathy it is necessary to understand these antibodies and the role they play in causing this disease. The reporting of anti–phospholipase A2 receptor antibody (PLA2RAb) positivity in 70% of patients with primary MN (PMN) in 2009 was a significant advance in the understanding of the disease pathogenicity. The M-type phospholipase A2 receptor (PLA2R) on the cell surface of podocytes is the target antigen for PLA2RAb. As you can see 70% of PMN is linked to PLA2R. The remaining 30% are linked to drugs, cancer, hepatitis B or are idiopathic. Secondary MN is not included in this discussion. In PMN linked to PLA2R prognosis and response depends on the level of the antibody. It is also to be remembered that the levels of the antibodies fall 2-3 months before the proteinuria starts reducing. I am putting down 2 trials that I have downloaded so that you can make yourself current. Most of this information I got from Dr Irfan Ali Agha who is a brilliant nephrologist working in Texas. He is giving a series of lectures and if you send him an email he will send you an invitation to his lectures. He is a very lucid speaker. He can contacted at this address< iagha@libertynorthtx.com

Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up.

JASN 2017 Jan;28(1):348-358. doi: 10.1681/ASN.2016040449. Epub 2016 Jun 27

Dahan K¹, Debiec H^2,3, Plaisier E^4,2,3, Cachanado M⁵, Rousseau A⁵, Wakselman L⁵, Michel PA⁴, Mihout F⁴, Dussol B⁶, Matignon M⁷, Mousson C⁸, Simon T⁵, Ronco P^1,2,3; GEMRITUX Study Group.

Abstract. Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of non immunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m² intravenous rituximab on days 1 and 8 (n=37) or NIAT alone (n=38). Median times to last follow-up were 17.0 (interquartile range, 12.5-24.0) months and 17.0 (interquartile range, 13.0-23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission (P=0.21). Rates of antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 (P<0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 (P=0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively (P<0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

Copyright © 2016 by the American Society of Nephrology.

KEYWORDS:

anti-PLA2R antibody; anti-THSD7A antibody; idiopathic membranous nephropathy; randomized controlled trial; rituximab; severe adverse eventPMID: 27352623 PMCID: PMC5198292 DOI: 10.1681/ASN.2016040449[Indexed for MEDLINE] Free PMC Article

JASN; 2015 Oct;26(10):2545-58. doi: 10.1681/ASN.2014070640. Epub 2015 Mar 24.

Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy.

Ruggenenti P¹, Debiec H², Ruggiero B³, Chianca A³, Pellé T², Gaspari F³, Suardi F³, Gagliardini E³, Orisio S³, Benigni A³, Ronco P⁴, Remuzzi G⁵

Abstract. Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.

Copyright © 2015 by the American Society of Nephrology.

KEYWORDS:

glomerulonephritis; membranous nephropathy; nephrotic syndrome; polymorphisms; primary; proteinuria

Comment in

• Anti-phospholipase A2 Receptor Antibody and Immunosuppression in Membranous Nephropathy: More Evidence for Pathogenicity of Anti-phospholipase A2 Receptor Autoantibodies. [J Am Soc Nephrol. 2015]

PMID: 25804280 PMCID: PMC4587688 DOI: 10.1681/ASN.2014070640[Indexed for MEDLINE] Free PMC Article