Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study

David Jayne; Daniel Blockmans; Raashid Luqmani; Sergey Moiseev; Beulah Ji; Yulia Green; Leanne Hall; David Roth; Robert B. Henderson; Peter A. Merkel; BREVAS Study Collaborators

doi:10.1002/art.40802

Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study

David Jayne
, Daniel Blockmans
, Raashid Luqmani
, Sergey Moiseev
, Beulah Ji
, Yulia Green
, Leanne Hall
, David Roth
, Robert B. Henderson
, Peter A. Merkel
, BREVAS Study Collaborators

Applied Medicine

KU Leuven
Sechenov First Moscow State Medical University
GlaxoSmithKline
University of Pennsylvania
University of Cambridge
University of Oxford

Research output: Contribution to journal › Article › peer-review

120 Citations (Scopus)

12 Downloads (Pure)

Abstract

Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results: The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA–associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

Original language	English
Pages (from-to)	952-963
Number of pages	12
Journal	Arthritis and Rheumatology
Volume	71
Issue number	6
Early online date	16 Apr 2019
DOIs	https://doi.org/10.1002/art.40802
Publication status	Published - Jun 2019

Bibliographical note

Funding Information: GlaxoSmithKline

Funding

The authors would like to acknowledge the advice received from Dr. Rachel Jones (Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, UK). GlaxoSmithKline designed, conducted, and funded this study, contributed to collection, analysis, and interpretation of the data, and supported the authors in development of the manuscript. All authors, including those employed by GlaxoSmithKline, approved the content of the submitted manuscript. GlaxoSmithKline is committed to publicly disclosing the results of its sponsored clinical research that evaluates GlaxoSmithKline medicines, and as such was involved in the decision to submit the manuscript for publication. Anonymized individual participant data and study documents can be requested for further research (at http://www.clinical-studydatarequest.com). Sam Halliwell, PhD and Jennie McLean, PhD (Fishawack Indicia Ltd., UK) provided medical writing support, which was funded by GlaxoSmithKline, but did not contribute to the study design or the acquisition, analysis, or interpretation of the data. Publication of this article was contingent upon approval by GlaxoSmithKline. Collaborators in the multicenter BREVAS study are as follows: Jose Alfaro Lozano (Centro Especializado de Rehabilitación Física y del Dolor, Lima, Peru), Heidemarie Becker (Universitaetsklinikum Muenster, Muenster, Germany), Armando Calvo Quiroz (Hospital Nacional Caye-tano Heredia, Lima, Peru), Simon Carette (Mount Sinai Hospital, Toronto, Ontario, Canada), Sandra Carrillo-Vazquez (Hospital Angeles Lindavista, Mexico), María C. Cid (Hospital Clínic i Provincial de Barcelona, Barcelona, Spain), David D’Cruz (Guy’s and St. Thomas’ NHS Foundation Trust, London, UK), Atul Deodhar (Oregon Health Sciences University, Portland, Oregon), Oliver Flossman (Royal Berkshire Hospital, Berkshire, Reading, UK), Giacomo Garibotto (Università degli Studi di Genova, Genoa, Italy), Loreto Gesualdo (Azienda Ospedaliero-Universitaria Consorziale Poli-clinico di Bari, Bari, Italy), Stephen Hall (Emeritus Research, Malvern, Victoria, Australia), Thomas Hauser (Immunologie-Zentrum, Zurich, Switzerland), Bernhard Hellmich (Kreiskliniken Esslingen Klinik Kirch-heim, Kirchheim unter Teck, Germany), Dana Kidder (Aberdeen Royal Infirmary, Aberdeen, UK), Martin Kimmel (Robert Bosch Krankenhaus, Baden-Wuerttemberg, Germany), Mark Little (Beaumont Hospital, Dublin, Ireland), Maria Majdan (Independent Public Hospital, Lublin, Poland), Kathleen Maksimowicz-McKinnon (Henry Ford Hospital, Detroit, Michigan), Galina Marder (North Shore/Long Island Jewish Medical Center, Great Neck, Long Island, New York), Galina Matsievskaia (City Rheumatology Center, Saint-Petersburg, Russian Federation), Ariel Salinas Meneses (Hospital Nacional Alberto Sabogal Sologuren, Callao, Peru), Eamonn Molloy (Vincent’s University Hospital, Dublin, Ireland), Ruediger Mueller (Kantonsspital St. Gallen, St. Gallen, Switzerland), Clark Neu-welt (East Bay Rheumatology Medical Group, San Leandro, California), Jorge Ravelo Hernandez (Clinica San Juan Bautista, Lima, Peru), Ulrich Specks (Mayo Clinic, Rochester, Minnesota), Vladimir Tesar (Charles University, Prague, Czech Republic), and Michael Walsh (St. Joseph’s Healthcare, Hamilton, Ontario, Canada).

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© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. https://creativecommons.org/licenses/by-nc-nd/4.0/
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Jayne, D., Blockmans, D., Luqmani, R., Moiseev, S., Ji, B., Green, Y., Hall, L., Roth, D., Henderson, R. B., Merkel, P. A., & BREVAS Study Collaborators (2019). Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study. Arthritis and Rheumatology, 71(6), 952-963. https://doi.org/10.1002/art.40802

Jayne, D, Blockmans, D, Luqmani, R, Moiseev, S, Ji, B, Green, Y, Hall, L, Roth, D, Henderson, RB, Merkel, PA & BREVAS Study Collaborators 2019, 'Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study', Arthritis and Rheumatology, vol. 71, no. 6, pp. 952-963. https://doi.org/10.1002/art.40802

@article{04462522da734d44a8e877ad50073106,

title = "Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody{\textendash}Associated Vasculitis: A Randomized Controlled Study",

abstract = "Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA){\textendash}associated vasculitis (AAV). Methods: In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from \textasciitilde{}300 patients to \textasciitilde{}100 patients. Results: The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95\% confidence interval [95\% CI] 0.44{\textendash}2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95\% CI 0.29{\textendash}2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2\%] of 52 patients receiving placebo, 10 [18.9\%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA{\textendash}associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5\%) of 53 patients receiving belimumab and 43 (82.7\%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.",

author = "David Jayne and Daniel Blockmans and Raashid Luqmani and Sergey Moiseev and Beulah Ji and Yulia Green and Leanne Hall and David Roth and Henderson, \{Robert B.\} and Merkel, \{Peter A.\} and \{BREVAS Study Collaborators\} and Dana Kidder",

note = "Funding Information: GlaxoSmithKline",

year = "2019",

month = jun,

doi = "10.1002/art.40802",

language = "English",

volume = "71",

pages = "952--963",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "6",

}

TY - JOUR

T1 - Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

T2 - A Randomized Controlled Study

AU - Jayne, David

AU - Blockmans, Daniel

AU - Luqmani, Raashid

AU - Moiseev, Sergey

AU - Ji, Beulah

AU - Green, Yulia

AU - Hall, Leanne

AU - Roth, David

AU - Henderson, Robert B.

AU - Merkel, Peter A.

AU - BREVAS Study Collaborators

A2 - Kidder, Dana

N1 - Funding Information: GlaxoSmithKline

PY - 2019/6

Y1 - 2019/6

N2 - Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results: The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA–associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

AB - Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results: The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA–associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

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Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study

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