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      Rituximab, Cyclophosphamide, and Corticosteroids for ANCA Vasculitis: The Good, the Bad, and the Ugly

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          Abstract

          Backgrounds: ANCA-associated vasculitis (AAV) frequently present with a chronic relapsing course. Relapse leads to an increased need for therapeutic agents and consequent toxicity. Summary: When referring to the available options for the management of AAV, the efficacy of glucocorticoids (GCs) is unquestionable. However, similarly unquestionable are their side effects. It has been more than 40 years since the efficacy of cyclophosphamide (CYC) as an add-on therapy to GCs in the management of necrotizing vasculitis has been proven. At the same time, concerns about the devastating side effects related to a prolonged exposure to this agent were raised. Despite the well-known side effects, the management of AAV remained centred on CYC until the early 2000s, when the pilot data first supporting the anecdotal efficacy of rituximab (RTX) were reported. However, it was not until 2010 that the non-inferiority of RTX to CYC for remission-induction in AAVs was demonstrated in 2 randomized controlled trials. Key Messages: Treatment of AAV has improved over the last decade, and currently available strategies are able to induce remission in the majority of the cases. Herewith, we aim to critically review available evidence and to critically address the following question: How can we reduce the GCs use the management of patients with AAV? Novel strategies that avoid the toxicity associated with currently used agents should be the goal. Ideally, these approaches should be GC-free.

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          Most cited references 18

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          Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.

          Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.
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            Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

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              Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center.

              This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegener's) (GPA). We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. Fifty-three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long-term remission merits further formal investigation. Copyright © 2012 by the American College of Rheumatology.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2020
                December 2020
                12 October 2020
                : 45
                : 6
                : 784-791
                Affiliations
                Nephrology and Dialysis Unit & CMID (Center of Research of Immunopathology and Rare Diseases), Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital of Turin and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
                Author notes
                *Dario Roccatello, Center of Research of Immunopathology and Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, San Giovanni Hospitall, Piazza del Donatore di Sangue 3, IT–10154 Torino (Italy), dario.roccatello@unito.it
                Article
                509608 Kidney Blood Press Res 2020;45:784–791
                10.1159/000509608
                33045710
                © 2020 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 1, Pages: 8
                Categories
                Review Article

                Cardiovascular Medicine, Nephrology

                Corticosteroids, Rituximab, ANCA vasculitis, Cyclophosphamide

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