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American Journal of Kidney Diseases

Multitarget Combination Immunosuppressive Therapy for Primary Membranous Nephropathy

  • Najia Idrees
    Affiliations
    Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
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  • Laurence H. Beck Jr.
    Correspondence
    Address for Correspondence: Laurence H. Beck Jr, MD, PhD, Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, 650 Albany St, EBRC Rm 536, Boston, MA 02118.
    Affiliations
    Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
    Search for articles by this author
Published:August 28, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.06.012
      Related Article, p. 793
      Primary membranous nephropathy (PMN) is an autoimmune process in which podocyte antigens, most commonly the phospholipase A2 receptor (PLA2R), are targeted by circulating autoantibodies that cause complement-mediated injury and failure of the glomerular filtration barrier. While spontaneous remission can occur in one-third of patients, risk factors such as sustained high-level proteinuria, declining kidney function, or thrombotic complications often lead to consideration of immunosuppression. Therapeutic regimens have evolved over the decades, beginning with corticosteroid monotherapy (now known to be ineffective) and followed by the successful combination of alkylating agents alternating with corticosteroids over a 6-month course (the Ponticelli regimen).
      • Ponticelli C.
      • Altieri P.
      • Scolari F.
      • et al.
      A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.
      Next came the popularization of the calcineurin inhibitors cyclosporine and tacrolimus and, most recently, the anti-CD20 B-cell–depleting agent rituximab. Observational trials with rituximab,
      • Ruggenenti P.
      • Cravedi P.
      • Chianca A.
      • et al.
      Rituximab in idiopathic membranous nephropathy.
      coupled with our knowledge of circulating autoantibodies against PLA2R to rationalize and monitor the use of this agent,
      • Beck Jr., L.H.
      • Fervenza F.C.
      • Beck D.M.
      • et al.
      Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.
      ,
      • Ruggenenti P.
      • Debiec H.
      • Ruggiero B.
      • et al.
      Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy.
      led to the MENTOR trial, which effectively established rituximab as a first-line therapeutic choice for achieving clinical remission in PMN.
      • Fervenza F.C.
      • Appel G.B.
      • Barbour S.J.
      • et al.
      Rituximab or cyclosporine in the treatment of membranous nephropathy.
      For reference, the rituximab monotherapy arm of the pivotal MENTOR trial demonstrated a 60% rate of reaching the composite 24-month outcome of partial remission (PR) or complete remission (CR), with 35% achieving CR (vs 0% in the cyclosporine arm). In this issue of AJKD, Zonozi et al
      • Zonozi R.
      • Laliberte K.
      • Huizenga N.R.
      • et al.
      Combination of rituximab, low-dose cyclophosphamide, and prednisone for primary membranous nephropathy: a case series with extended follow-up.
      engage us in questioning whether rituximab monotherapy suffices for treatment of PMN or if a multitarget combination therapy might offer even greater efficacy. These authors describe their single-center observational cohort of 60 patients with PMN—all of whom were treated with rituximab, low-dose cyclophosphamide, and rapid prednisone taper—confirming and extending the report of their first 15 patients.
      • Cortazar F.B.
      • Leaf D.E.
      • Owens C.T.
      • Laliberte K.
      • Pendergraft 3rd, W.F.
      • Niles J.L.
      Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series.
      The authors should be congratulated for standardizing and adhering to this unconventional 3-drug regimen over a decade that saw major changes in treatment preferences for PMN.
      The aggregate results are impressive in terms of primary outcome: all patients achieved a PR (defined as a >50% fall from baseline to a urinary protein-creatinine ratio [UPCR] < 3.0 g/g) in a median time of 3.4 months, while 83% and 87% achieved CR (UPCR < 0.3 g/g) at 24 and 36 months, respectively. Even the 11 participants who only achieved PR showed good response to the protocol; residual proteinuria was due to chronic parenchymal damage that would not be expected to respond to further immunosuppression. The authors also investigated immunological remission—a decline and ultimate disappearance of circulating autoantibodies—which typically precedes clinical remission.
      • Beck Jr., L.H.
      • Fervenza F.C.
      • Beck D.M.
      • et al.
      Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.
      ,
      • Lerner G.B.
      • Virmani S.
      • Henderson J.M.
      • Francis J.M.
      • Beck Jr., L.H.
      A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy.
      At baseline, 29 patients were seropositive for autoantibodies to PLA2R, and the rates of immunologic remission (anti-PLA2R antibody level < 14 RU/mL) in this subgroup were 86% and 100% at 3 and 6 months, respectively. Despite the combined use of 3 potent immunosuppressive agents, the authors report an acceptable rate of serious side effects during treatment and follow-up, the most common of which was late-onset neutropenia. Moreover, the relapse rate was low, only occurring in 4 patients well after the end of treatment and following the reconstitution of B cells.
      Although a regimen combining 3 immunosuppressive agents and extending the duration of rituximab to 2 years may seem extreme, it was designed to act quickly, limit exposure to the more toxic elements of the regimen, and deplete B cells for 2 years to minimize the re-emergence of autoreactive B-cell clones. Corticosteroids are quickly tapered to 20 mg/d by week 4 and then more slowly through month 6, delivering less than 20% of the total steroid dose of the Ponticelli protocol, per the authors’ calculations. Cyclophosphamide, dosed by weight and kidney function, is given for only 8 weeks at less than 40% of the Ponticelli dose. Two 1 g doses of rituximab are provided at the start of the triple-drug regimen, followed by 1 g doses every 4 months for 2 years.
      This observational study follows closely on the heels of 3 randomized controlled trials in PMN: MENTOR,
      • Fervenza F.C.
      • Appel G.B.
      • Barbour S.J.
      • et al.
      Rituximab or cyclosporine in the treatment of membranous nephropathy.
      STARMEN,
      • Fernandez-Juarez G.
      • Rojas-Rivera J.
      • Logt A.V.
      • et al.
      The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.
      and RI-CYCLO.
      • Scolari F.
      • Delbarba E.
      • Santoro D.
      • et al.
      RI-CYCLO Investigators. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: the RI-CYCLO randomized trial.
      How do the results of Zonozi et al compare? The MENTOR trial, a head-to-head comparison of rituximab to cyclosporine, demonstrated a 60% rate of PR/CR at both 12 and 24 months, with CR increasing from 14% to 35% at these 2 time points. While this is markedly lower than the remission rates described by Zonozi et al, MENTOR employed only an initial 2 × 1 g cycle of rituximab, with a second dosing cycle at 6 months for most participants. The STARMEN trial compared a standard 6-month Ponticelli regimen to 6 months of tacrolimus monotherapy with 1 g rituximab administered prior to the tacrolimus taper. There were markedly better outcomes at 24 months in the Ponticelli arm: 84% achieved any remission and 60% had CR; in the tacrolimus-rituximab arm, 58% achieved remission and only 26% achieved CR. While this trial was not a fair test of rituximab owing to the single 1 g dose, it shows that even with the more efficacious Ponticelli regimen, only 60% reached CR at 24 months, in comparison to the 83% rate of CR reported in the current article. Most recently, the RI-CYCLO trial matched a single (2 × 1 g) cycle of rituximab versus the Ponticelli regimen but found no differences in overall remission rate or short-term safety profile, with over 40% CR in each arm at 24 months.
      Is this aggressive protocol described by Zonozi et al, leading to very high rates of CR with few relapses, indicated for all patients or just the select few at the highest risk of progression? A durable remission is associated with preservation of glomerular filtration rate in the long run,
      • Cattran D.C.
      • Kim E.D.
      • Reich H.
      • Hladunewich M.
      • Kim S.J.
      Toronto Glomerulonephritis Registry group. Membranous nephropathy: quantifying remission duration on outcome.
      and the authors of the current study argue that the rapid disappearance of the nephrotic state may also help to reduce infection risk. Yet deciding which patients deserve immunosuppression, and when, is a major challenge in PMN owing to a 30% rate of spontaneous remission and a delayed response to prior therapy.
      • Lerner G.B.
      • Virmani S.
      • Henderson J.M.
      • Francis J.M.
      • Beck Jr., L.H.
      A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy.
      It is not clear that all participants in the Zonozi series had sufficient risk to justify the use of immunosuppression, as some might have benefited from further watchful waiting. The authors do not report patient-level data about indications for treatment with their regimen, but they note that 15% of participants had <4 g/g proteinuria at baseline, while 42% had poorly described debilitating symptoms of the nephrotic syndrome as a treatment indication.
      Another question is whether there were participants with immunologically quiescent disease at the start of treatment. The major subgroup (n = 44) of this cohort comprised participants with PLA2R-associated PMN, defined either by baseline seropositivity for anti-PLA2R antibodies (n = 29) or by the presence of PLA2R within immune deposits on the biopsy specimen. There are insufficient data presented to determine how many of the 15 patients defined by biopsy were tested for circulating anti-PLA2R antibodies at baseline. Seronegative, tissue PLA2R–positive patients are likely to have already achieved immunological remission
      • Lerner G.B.
      • Virmani S.
      • Henderson J.M.
      • Francis J.M.
      • Beck Jr., L.H.
      A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy.
      ,
      • Qin H.Z.
      • Zhang M.C.
      • Le W.B.
      • et al.
      Combined assessment of phospholipase A2 receptor autoantibodies and glomerular deposits in membranous nephropathy.
      and would be expected to more rapidly enter clinical remission even in the absence of immunosuppression. While there were no major differences in outcome comparing PLA2R-associated, PLA2R-nonassociated, or uncharacterized forms of PMN, it should be noted that participants who were seropositive for anti-PLA2R antibodies at baseline had lower rates of CR at 12, 24, and 36 months when compared to the cohort as a whole.
      The comparative short- and long-term adverse effects of the triple regimen are still not fully known. Rituximab is certainly not without risk of infection
      • Trivin C.
      • Tran A.
      • Moulin B.
      • et al.
      Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease.
      and the risk of late-onset neutropenia noted here is not uncommon with extended-dose rituximab.
      • Zonozi R.
      • Wallace Z.S.
      • Laliberte K.
      • et al.
      Incidence, clinical features, and outcomes of late-onset neutropenia from rituximab for autoimmune disease.
      As noted by the authors, future studies are needed to see if the duration of rituximab could be individually tailored and shortened based on achievement of immunological remission to achieve a similar clinical outcome with less risk and lower cost.
      The optimal use and dosing of anti–B-cell therapies as monotherapy or in combination regimens for PMN may be further confounded as more-potent anti-CD20 agents come online. Depletion of noncirculating autoreactive B-cell clones with newer agents or extended treatment may turn out to be equally or more important than depletion of circulating B cells to fully control the underlying autoimmune process and to prevent relapse. Nevertheless, it seems that upfront use of cyclophosphamide and corticosteroids as in the triple-agent protocol can immediately target autoantibody-secreting plasma cells and plasmablasts that would not be expected to respond to anti-CD20 therapy. This likely explains the faster kinetics of anti-PLA2R antibody elimination in response to alkylating agents, as has been previously noted.
      • Hoxha E.
      • Thiele I.
      • Zahner G.
      • Panzer U.
      • Harendza S.
      • Stahl R.A.
      Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy.
      It is reasonable to expect that an effective combination of drugs can be found for PMN that maximizes efficacy while limiting adverse effects. The addition of complement inhibitors may add another adjunctive therapy to quickly reduce glomerular damage and proteinuria while immunosuppression kicks in.
      In summary, the report by Zonozi et al is a provocative challenge that raises the bar of exactly how high a rate of CR one can achieve in PMN, and how quickly. We eagerly await further follow-up of this cohort and would welcome clinical trials pitting this potent regimen against up-and-coming treatments for PMN.

      Article Information

      Authors’ Full Names and Academic Degrees

      Najia Idrees, MD, and Laurence H. Beck Jr, MD, PhD.

      Support

      None.

      Financial Disclosure

      Dr Beck reports royalty income through Boston University related to the patent “Diagnostics for Membranous Nephropathy” and consulting fees for Visterra, Ionis, Alexion, and Genentech about therapeutics for membranous nephropathy. Dr Idrees declares that she has no relevant financial interests.

      Peer Review

      Received June 23, 2021 in response to an invitation from the journal. Accepted June 27, 2021 after editorial review by an Associate Editor and a Deputy Editor.

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