Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

Glen S. Hazlewood; Claudia Metzler; George A. Tomlinson; Wolfgang L. Gross; Brian M. Feldman; Loic Guillevin; Christian Pagnoux

doi:10.1016/j.jbspin.2013.11.006

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

Glen S. Hazlewood^*, Claudia Metzler, George A. Tomlinson, Wolfgang L. Gross, Brian M. Feldman, Loic Guillevin, Christian Pagnoux

^*Corresponding author for this work

Clinic of Rheumatology

25 Citations (Scopus)

Abstract

Objective: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. Methods: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. Results: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. Conclusion: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.

Original language	English
Journal	Joint Bone Spine
Volume	81
Issue number	4
Pages (from-to)	337-341
Number of pages	5
ISSN	1297-319X
DOIs	https://doi.org/10.1016/j.jbspin.2013.11.006
Publication status	Published - 07.2014

Funding

G.H. has received grant support from UCB and honoraria from Abbott and UCB. C.M. has received travel fees from Aventis, Hoffmann–La Roche Ltd, and Glaxo-Smith-Kline and speaking fees from Hoffmann–La Roche Ltd. B.F. has received grant support from Baxter and Bayer and has served on a drug monitoring committee for BMS, Novartis and Pfizer. C.P. has received consulting fees and/or speaking fees from Hoffmann–La Roche Ltd. Several study authors were authors of the original trials reviewed (C.M., W.G., L.G., C.P.). The authors of the LEF-MTX trial who were involved with this study (C.M., W.G.) were not involved with the study concept, design or data analysis, but provided original data key to the study, reviewed, edited and approved the final manuscript. G.H. is supported by an Alberta Innovates Health Solutions Clinical Fellowship. C.P. received fellowship grants from the Vasculitis Clinical Research Consortium and the Toronto General Hospital/Toronto Western Hospital Foundation/University Health Network, Toronto, ON, Canada. Appendix A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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@article{582a0416e9dd45f58ca15842cdea8a92,

title = "Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis",

abstract = "Objective: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. Methods: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. Results: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95\% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95\% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95\% CrI: 0.18-1.2]), although the 95\% CrI also crossed 1. There was a 90\% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55\% probability leflunomide was best. Conclusion: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.",

author = "Hazlewood, \{Glen S.\} and Claudia Metzler and Tomlinson, \{George A.\} and Gross, \{Wolfgang L.\} and Feldman, \{Brian M.\} and Loic Guillevin and Christian Pagnoux",

note = "Funding Information: G.H. has received grant support from UCB and honoraria from Abbott and UCB. C.M. has received travel fees from Aventis, Hoffmann–La Roche Ltd, and Glaxo-Smith-Kline and speaking fees from Hoffmann–La Roche Ltd. B.F. has received grant support from Baxter and Bayer and has served on a drug monitoring committee for BMS, Novartis and Pfizer. C.P. has received consulting fees and/or speaking fees from Hoffmann–La Roche Ltd. Several study authors were authors of the original trials reviewed (C.M., W.G., L.G., C.P.). The authors of the LEF-MTX trial who were involved with this study (C.M., W.G.) were not involved with the study concept, design or data analysis, but provided original data key to the study, reviewed, edited and approved the final manuscript. Funding Information: G.H. is supported by an Alberta Innovates Health Solutions Clinical Fellowship. C.P. received fellowship grants from the Vasculitis Clinical Research Consortium and the Toronto General Hospital/Toronto Western Hospital Foundation/University Health Network, Toronto, ON, Canada. Appendix A Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

year = "2014",

month = jul,

doi = "10.1016/j.jbspin.2013.11.006",

language = "English",

volume = "81",

pages = "337--341",

journal = "Joint Bone Spine",

issn = "1297-319X",

publisher = "Elsevier Masson s.r.l.",

number = "4",

}

TY - JOUR

T1 - Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

AU - Hazlewood, Glen S.

AU - Metzler, Claudia

AU - Tomlinson, George A.

AU - Gross, Wolfgang L.

AU - Feldman, Brian M.

AU - Guillevin, Loic

AU - Pagnoux, Christian

N1 - Funding Information: G.H. has received grant support from UCB and honoraria from Abbott and UCB. C.M. has received travel fees from Aventis, Hoffmann–La Roche Ltd, and Glaxo-Smith-Kline and speaking fees from Hoffmann–La Roche Ltd. B.F. has received grant support from Baxter and Bayer and has served on a drug monitoring committee for BMS, Novartis and Pfizer. C.P. has received consulting fees and/or speaking fees from Hoffmann–La Roche Ltd. Several study authors were authors of the original trials reviewed (C.M., W.G., L.G., C.P.). The authors of the LEF-MTX trial who were involved with this study (C.M., W.G.) were not involved with the study concept, design or data analysis, but provided original data key to the study, reviewed, edited and approved the final manuscript. Funding Information: G.H. is supported by an Alberta Innovates Health Solutions Clinical Fellowship. C.P. received fellowship grants from the Vasculitis Clinical Research Consortium and the Toronto General Hospital/Toronto Western Hospital Foundation/University Health Network, Toronto, ON, Canada. Appendix A Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 2014/7

Y1 - 2014/7

N2 - Objective: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. Methods: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. Results: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. Conclusion: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.

AB - Objective: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. Methods: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. Results: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. Conclusion: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.

UR - https://www.scopus.com/pages/publications/84904116116

U2 - 10.1016/j.jbspin.2013.11.006

DO - 10.1016/j.jbspin.2013.11.006

M3 - Journal articles

C2 - 24387970

AN - SCOPUS:84904116116

SN - 1297-319X

VL - 81

SP - 337

EP - 341

JO - Joint Bone Spine

JF - Joint Bone Spine

IS - 4

ER -

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

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