Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis

M. Walsh; P. A. Merkel; C. A. Peh; W. M. Szpirt; X. Puechal; S. Fujimoto; C. M. Hawley; N. Khalidi; O. Flosmann; R. Wald; L. P. Girard; A. Levin; G. Gregorini; L. Harper; W. F. Clark; C. Pagnoux; U. Specks; L. Smyth; V. Tesar; T. Ito-Ihara; J. R. De Zoysa; W. Szczeklik; L. F. Flores-Suarez; S. Carette; L. Guillevin; C. D. Pusey; A. L. Casian; B. Brezina; A. Mazzetti; C. A. McAlear; E. Broadhurst; D. Reidlinger; S. Mehta; N. Ives; D. R.W. Jayne; PEXIVAS Investigators

doi:10.1056/NEJMoa1803537

Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis

M. Walsh^*, P. A. Merkel, C. A. Peh, W. M. Szpirt, X. Puechal, S. Fujimoto, C. M. Hawley, N. Khalidi, O. Flosmann, R. Wald, L. P. Girard, A. Levin, G. Gregorini, L. Harper, W. F. Clark, C. Pagnoux, U. Specks, L. Smyth, V. Tesar, T. Ito-IharaJ. R. De Zoysa, W. Szczeklik, L. F. Flores-Suarez, S. Carette, L. Guillevin, C. D. Pusey, A. L. Casian, B. Brezina, A. Mazzetti, C. A. McAlear, E. Broadhurst, D. Reidlinger, S. Mehta, N. Ives, D. R.W. Jayne, PEXIVAS Investigators

^*Corresponding author for this work

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

428 Citations (Scopus)

Abstract

BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasmaexchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard- dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K.

Original language	English
Pages (from-to)	622-631
Number of pages	10
Journal	New England Journal of Medicine
Volume	382
Issue number	7
DOIs	https://doi.org/10.1056/NEJMoa1803537
Publication status	Published - 13 Feb 2020

Bibliographical note

Funding Information:
Supported by grants from the National Institute for Health Research, United Kingdom (HTA 08/56/04); the Food and Drug Administration (FDA R01 FD003516); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR0573319); the National Institutes of Health of the U.S. Department of Health and Human Services; the National Health and Medical Research Council, Australia (626939, APP1086192, 631731, and APP1092957); the Canadian Institutes of Health Research (211079 and 159662); the French Ministry of Health, Programme Hospi-talier de Recherche Clinique (AOM11142); the Research Committee on Intractable Vasculitides of the Ministry of Health, Labor, and Welfare of Japan; and the Japan Agency for Medical Research and Development (AMED): the Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline. Terumo BCT, Terumo BCT Mexico, Fresenius Medical Care Australia, Baxter Healthcare (Australia), and Asahi Kasei Medical provided in-kind plasma-exchange disposables. Dr. Walsh was supported by a New Investigator Award from the Canadian Institutes of Health Research.

Keywords

Administration, Oral
Adult
Aged
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications
Combined Modality Therapy
Cyclophosphamide/therapeutic use
Dose-Response Relationship, Drug
Female
Glucocorticoids/administration & dosage
Humans
Immunosuppressive Agents/therapeutic use
Incidence
Induction Chemotherapy
Kidney Diseases/complications
Kidney Failure, Chronic/epidemiology
Male
Middle Aged
Plasma Exchange/adverse effects
Rituximab/therapeutic use
GLOMERULONEPHRITIS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
INDUCTION
MAINTENANCE THERAPY
RITUXIMAB
ALVEOLAR HEMORRHAGE
RANDOMIZED-TRIAL
REMISSION

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Walsh, M., Merkel, P. A., Peh, C. A., Szpirt, W. M., Puechal, X., Fujimoto, S., Hawley, C. M., Khalidi, N., Flosmann, O., Wald, R., Girard, L. P., Levin, A., Gregorini, G., Harper, L., Clark, W. F., Pagnoux, C., Specks, U., Smyth, L., Tesar, V., ... PEXIVAS Investigators (2020). Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. New England Journal of Medicine, 382(7), 622-631. https://doi.org/10.1056/NEJMoa1803537

Walsh, M, Merkel, PA, Peh, CA, Szpirt, WM, Puechal, X, Fujimoto, S, Hawley, CM, Khalidi, N, Flosmann, O, Wald, R, Girard, LP, Levin, A, Gregorini, G, Harper, L, Clark, WF, Pagnoux, C, Specks, U, Smyth, L, Tesar, V, Ito-Ihara, T, De Zoysa, JR, Szczeklik, W, Flores-Suarez, LF, Carette, S, Guillevin, L, Pusey, CD, Casian, AL, Brezina, B, Mazzetti, A, McAlear, CA, Broadhurst, E, Reidlinger, D, Mehta, S, Ives, N, Jayne, DRW & PEXIVAS Investigators 2020, 'Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis', New England Journal of Medicine, vol. 382, no. 7, pp. 622-631. https://doi.org/10.1056/NEJMoa1803537

@article{d0009d2186ad4a3fa309af09a0ad3364,

title = "Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis",

abstract = "BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasmaexchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard- dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K.",

keywords = "Administration, Oral, Adult, Aged, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications, Combined Modality Therapy, Cyclophosphamide/therapeutic use, Dose-Response Relationship, Drug, Female, Glucocorticoids/administration & dosage, Humans, Immunosuppressive Agents/therapeutic use, Incidence, Induction Chemotherapy, Kidney Diseases/complications, Kidney Failure, Chronic/epidemiology, Male, Middle Aged, Plasma Exchange/adverse effects, Rituximab/therapeutic use, GLOMERULONEPHRITIS, CYCLOPHOSPHAMIDE, AZATHIOPRINE, INDUCTION, MAINTENANCE THERAPY, RITUXIMAB, ALVEOLAR HEMORRHAGE, RANDOMIZED-TRIAL, REMISSION",

author = "M. Walsh and Merkel, {P. A.} and Peh, {C. A.} and Szpirt, {W. M.} and X. Puechal and S. Fujimoto and Hawley, {C. M.} and N. Khalidi and O. Flosmann and R. Wald and Girard, {L. P.} and A. Levin and G. Gregorini and L. Harper and Clark, {W. F.} and C. Pagnoux and U. Specks and L. Smyth and V. Tesar and T. Ito-Ihara and {De Zoysa}, {J. R.} and W. Szczeklik and Flores-Suarez, {L. F.} and S. Carette and L. Guillevin and Pusey, {C. D.} and Casian, {A. L.} and B. Brezina and A. Mazzetti and McAlear, {C. A.} and E. Broadhurst and D. Reidlinger and S. Mehta and N. Ives and Jayne, {D. R.W.} and {PEXIVAS Investigators} and Dana Kidder and Neil Basu and Nick Fluck",

note = "Funding Information: Supported by grants from the National Institute for Health Research, United Kingdom (HTA 08/56/04); the Food and Drug Administration (FDA R01 FD003516); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR0573319); the National Institutes of Health of the U.S. Department of Health and Human Services; the National Health and Medical Research Council, Australia (626939, APP1086192, 631731, and APP1092957); the Canadian Institutes of Health Research (211079 and 159662); the French Ministry of Health, Programme Hospi-talier de Recherche Clinique (AOM11142); the Research Committee on Intractable Vasculitides of the Ministry of Health, Labor, and Welfare of Japan; and the Japan Agency for Medical Research and Development (AMED): the Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline. Terumo BCT, Terumo BCT Mexico, Fresenius Medical Care Australia, Baxter Healthcare (Australia), and Asahi Kasei Medical provided in-kind plasma-exchange disposables. Dr. Walsh was supported by a New Investigator Award from the Canadian Institutes of Health Research. ",

year = "2020",

month = feb,

day = "13",

doi = "10.1056/NEJMoa1803537",

language = "English",

volume = "382",

pages = "622--631",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "7",

}

TY - JOUR

T1 - Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis

AU - Walsh, M.

AU - Merkel, P. A.

AU - Peh, C. A.

AU - Szpirt, W. M.

AU - Puechal, X.

AU - Fujimoto, S.

AU - Hawley, C. M.

AU - Khalidi, N.

AU - Flosmann, O.

AU - Wald, R.

AU - Girard, L. P.

AU - Levin, A.

AU - Gregorini, G.

AU - Harper, L.

AU - Clark, W. F.

AU - Pagnoux, C.

AU - Specks, U.

AU - Smyth, L.

AU - Tesar, V.

AU - Ito-Ihara, T.

AU - De Zoysa, J. R.

AU - Szczeklik, W.

AU - Flores-Suarez, L. F.

AU - Carette, S.

AU - Guillevin, L.

AU - Pusey, C. D.

AU - Casian, A. L.

AU - Brezina, B.

AU - Mazzetti, A.

AU - McAlear, C. A.

AU - Broadhurst, E.

AU - Reidlinger, D.

AU - Mehta, S.

AU - Ives, N.

AU - Jayne, D. R.W.

AU - PEXIVAS Investigators

A2 - Kidder, Dana

A2 - Basu, Neil

A2 - Fluck, Nick

N1 - Funding Information: Supported by grants from the National Institute for Health Research, United Kingdom (HTA 08/56/04); the Food and Drug Administration (FDA R01 FD003516); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR0573319); the National Institutes of Health of the U.S. Department of Health and Human Services; the National Health and Medical Research Council, Australia (626939, APP1086192, 631731, and APP1092957); the Canadian Institutes of Health Research (211079 and 159662); the French Ministry of Health, Programme Hospi-talier de Recherche Clinique (AOM11142); the Research Committee on Intractable Vasculitides of the Ministry of Health, Labor, and Welfare of Japan; and the Japan Agency for Medical Research and Development (AMED): the Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline. Terumo BCT, Terumo BCT Mexico, Fresenius Medical Care Australia, Baxter Healthcare (Australia), and Asahi Kasei Medical provided in-kind plasma-exchange disposables. Dr. Walsh was supported by a New Investigator Award from the Canadian Institutes of Health Research.

PY - 2020/2/13

Y1 - 2020/2/13

N2 - BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasmaexchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard- dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K.

AB - BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasmaexchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard- dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K.

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications

KW - Combined Modality Therapy

KW - Cyclophosphamide/therapeutic use

KW - Dose-Response Relationship, Drug

KW - Female

KW - Glucocorticoids/administration & dosage

KW - Humans

KW - Immunosuppressive Agents/therapeutic use

KW - Incidence

KW - Induction Chemotherapy

KW - Kidney Diseases/complications

KW - Kidney Failure, Chronic/epidemiology

KW - Male

KW - Middle Aged

KW - Plasma Exchange/adverse effects

KW - Rituximab/therapeutic use

KW - GLOMERULONEPHRITIS

KW - CYCLOPHOSPHAMIDE

KW - AZATHIOPRINE

KW - INDUCTION

KW - MAINTENANCE THERAPY

KW - RITUXIMAB

KW - ALVEOLAR HEMORRHAGE

KW - RANDOMIZED-TRIAL

KW - REMISSION

UR - http://www.scopus.com/inward/record.url?scp=85079334130&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1803537

DO - 10.1056/NEJMoa1803537

M3 - Article

C2 - 32053298

AN - SCOPUS:85079334130

SN - 0028-4793

VL - 382

SP - 622

EP - 631

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 7

ER -

Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis

Abstract

Bibliographical note

Keywords

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