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

Dahan, Karine; Dębiec, Hanna; Plaisier, Emmanuelle; Cachanado, Marine; Rousseau, Alexandra; Wakselman, Laura; Michel, P.; Mihout, Fabrice; Dussol, B.; Matignon, Marie; Mousson, Christiane; Simon, Tabassome; Ronco, Pierre

doi:10.1681/asn.2016040449

Cited by 297 publications

(312 citation statements)

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“…6 This may partly explain the limited rate of complete remission (which does not exceed 20% in all treated patients) and the rates of relapse, partial response, or no response (nearly 80% of all patients) observed in most studies using the anti-CD20 MAb rituximab, as rescue or a firstline therapy in native iMGN. This was recently shown in the French GEMRITUX trial 8 and in a large observational study involving 132 patients. 9 Interestingly, GEMRITUX, the first multicenter randomized controlled trial comparing nonimmunosuppressive antiproteinuric therapy with combined antiproteinuric therapy using rituximab in patients with iMGN, failed to reach its primary endpoint.…”

Section: Introductionmentioning

confidence: 54%

“…The non-proliferating LLMPCs are known to provide the basis for humoral memory and refractory autoimmune diseases. [5][6][7][8][9] Recent evidence has suggested the existence of 2 independent plasma cell (CD19+/CD20+ and CD38+/CD138+) compartments that contribute to autoantibody and alloantibody production. 5,6 As expected, LLMPCs that lack CD20 markers [5][6][7] would be refractory to a CD20+-targeting immunosuppressive therapy (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…8,10 In contrast to regenerating activated CD20+ B cells, SLMPCs and mainly LLMPCs (nonproliferating B cells niched in the bone marrow and inflamed organs), which produce considerable amounts of IgG autoantibodies and alloantibodies, lack both CD20 and CD19 markers. [5][6][7] Consequently, these cells would be resistant to in vivo B-cell depletion by anti-CD20 MAb therapies, as recently reported in patients with rheumatoid arthritis 6 and in patients with iMGN.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Consequently, these cells would be resistant to in vivo B-cell depletion by anti-CD20 MAb therapies, as recently reported in patients with rheumatoid arthritis 6 and in patients with iMGN. 8 This may explain the frequently observed relapses or primary resistance of patients with iMGN to anti-CD20 therapy despite ongoing B-cell depletion defined by eradication of CD19+ and CD20+ cells. 8,10 Proteasome inhibitors (PIs), known plasma celldepleting agents, 11 may offer a novel therapeutic alternative, at least in patients with persistent recurrent nephrotic syndrome following anti-CD20 MAb discontinuation or in patients primarily refractory or partially responsive to combined conventional or conservative rituximab therapy despite total CD20+ cell ablation.…”

Section: Introductionmentioning

confidence: 99%

“…8 This may explain the frequently observed relapses or primary resistance of patients with iMGN to anti-CD20 therapy despite ongoing B-cell depletion defined by eradication of CD19+ and CD20+ cells. 8,10 Proteasome inhibitors (PIs), known plasma celldepleting agents, 11 may offer a novel therapeutic alternative, at least in patients with persistent recurrent nephrotic syndrome following anti-CD20 MAb discontinuation or in patients primarily refractory or partially responsive to combined conventional or conservative rituximab therapy despite total CD20+ cell ablation. For these patients, rituximab fails to induce complete remission despite achieving the same depleting effect on circulating B cells that is observed in rituximab-sensitive patients.…”

Section: Introductionmentioning

confidence: 99%

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Barbari

2017

Exp Clin Transplant

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Idiopathic membranous nephropathy has been recently recognized as an autoimmune disease that may recur or develop de novo posttransplant, whereby specific auto-or alloantibodies are directed against recently recognized podocyte structures such as the phospholipase receptor PLAR2 and the throm bospondin receptor THSD7A. The observed inconsistencies in therapeutic responses with all presently recognized therapies irrespective of immuno suppressive regimen used and the superiority of complete and sustained remission rates in recurrent disease after kidney transplant compared with native disease imply the existence of different immunopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of membranous nephropathy. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help component and distinct auto-and alloantibody-secreting mechanisms involving different B cells. These pathways are present in separate compartments such as in CD20+-activated B cells found in spleen and lymph nodes, CD19+/CD20-plasmablasts and shortlived plasma cells in the blood, and CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney. These latter nonproliferating plasma cells lacking CD19 and CD20 markers would be resistant to in vivo B-cell depletion by anti-CD20 monoclonal therapies. They produce considerable amounts of immunoglobulin G (IgG) autoantibodies and alloantibodies and provide the basis for humoral memory and refractory autoimmune diseases. This may explain the limited rate of sustained complete remission, which, as observed in most studies, does not exceed a rate of 20% in all rituximabtreated patients despite total B-cell eradication. There is an important need for the development of new biomarkers to help identify and predict therapeutic responses. Potential new therapeutic targets against plasma cells such as proteasome inhibitors, anti-CD38 monoclonal antibodies, and autoreactive pathogenic B-cell-specific depleting regimens, as well as new anti-CD20 monoclonal antibodies, may help tailor therapy to the individual need for optimal outcome. Key words: Autoimmune disease, Plasma cell, Proteasome inhibitors IntroductionIn patients with idiopathic membranous glomerulonephritis (iMGN), therapeutic responses to conventional therapies such as alkylating agents and steroids, T-cell-targeted therapies such as calcineurin inhibitors, and B-cell-directed therapies such as mycop henolate mofetil and the recently introduced anti-CD20 monoclonal antibody (MAb) as rescue therapy in cases of primary resistance or partial disease remission or as first-line treatment, irres pective of immunosuppressive regimen used, have been inconsistent. 1 These inconsistencies coupled with the superior complete and sustained remission rates in recurrent disease after kidney transplant versus rates of complete and partial remission, relapse, and resistance in the native kidney with iMGN2...

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Section: Introductionmentioning

confidence: 54%