Efficacy of remission-induction regimens for ANCA-associated vasculitis

Ulrich Specks, Peter A. Merkel, Philip Seo, Robert Spiera, Carol A. Langford, Gary S. Hoffman, Cees G M Kallenberg, E. William St. Clair, Barri J. Fessler, Linna Ding, Lisa Viviano, Nadia K. Tchao, Deborah J. Phippard, Adam L. Asare, Noha Lim, David Ikle, Brett Jepson, Paul Brunetta, Nancy B. Allen, Fernando Custodio FervenzaDuvuru Geetha, Karina Keogh, Eugene Y. Kissin, Paul A. Monach, Tobias D Peikert, Coen Stegeman, Steven R Ytterberg, Mark Mueller, Lourdes P. Sejismundo, Kathleen Mieras, John H. Stone

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is unknown. METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

Original languageEnglish (US)
Pages (from-to)417-427
Number of pages11
JournalNew England Journal of Medicine
Volume369
Issue number5
DOIs
StatePublished - 2013

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Remission Induction
Antineutrophil Cytoplasmic Antibodies
Vasculitis
Azathioprine
Cyclophosphamide
Immunosuppression
National Institute of Allergy and Infectious Diseases (U.S.)
Rituximab
Body Surface Area
Immunosuppressive Agents
B-Lymphocytes
Placebos
Maintenance
Outcome Assessment (Health Care)
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

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Specks, U., Merkel, P. A., Seo, P., Spiera, R., Langford, C. A., Hoffman, G. S., ... Stone, J. H. (2013). Efficacy of remission-induction regimens for ANCA-associated vasculitis. New England Journal of Medicine, 369(5), 417-427. https://doi.org/10.1056/NEJMoa1213277

Efficacy of remission-induction regimens for ANCA-associated vasculitis. / Specks, Ulrich; Merkel, Peter A.; Seo, Philip; Spiera, Robert; Langford, Carol A.; Hoffman, Gary S.; Kallenberg, Cees G M; St. Clair, E. William; Fessler, Barri J.; Ding, Linna; Viviano, Lisa; Tchao, Nadia K.; Phippard, Deborah J.; Asare, Adam L.; Lim, Noha; Ikle, David; Jepson, Brett; Brunetta, Paul; Allen, Nancy B.; Fervenza, Fernando Custodio; Geetha, Duvuru; Keogh, Karina; Kissin, Eugene Y.; Monach, Paul A.; Peikert, Tobias D; Stegeman, Coen; Ytterberg, Steven R; Mueller, Mark; Sejismundo, Lourdes P.; Mieras, Kathleen; Stone, John H.

In: New England Journal of Medicine, Vol. 369, No. 5, 2013, p. 417-427.

Research output: Contribution to journalArticle

Specks, U, Merkel, PA, Seo, P, Spiera, R, Langford, CA, Hoffman, GS, Kallenberg, CGM, St. Clair, EW, Fessler, BJ, Ding, L, Viviano, L, Tchao, NK, Phippard, DJ, Asare, AL, Lim, N, Ikle, D, Jepson, B, Brunetta, P, Allen, NB, Fervenza, FC, Geetha, D, Keogh, K, Kissin, EY, Monach, PA, Peikert, TD, Stegeman, C, Ytterberg, SR, Mueller, M, Sejismundo, LP, Mieras, K & Stone, JH 2013, 'Efficacy of remission-induction regimens for ANCA-associated vasculitis', New England Journal of Medicine, vol. 369, no. 5, pp. 417-427. https://doi.org/10.1056/NEJMoa1213277
Specks, Ulrich ; Merkel, Peter A. ; Seo, Philip ; Spiera, Robert ; Langford, Carol A. ; Hoffman, Gary S. ; Kallenberg, Cees G M ; St. Clair, E. William ; Fessler, Barri J. ; Ding, Linna ; Viviano, Lisa ; Tchao, Nadia K. ; Phippard, Deborah J. ; Asare, Adam L. ; Lim, Noha ; Ikle, David ; Jepson, Brett ; Brunetta, Paul ; Allen, Nancy B. ; Fervenza, Fernando Custodio ; Geetha, Duvuru ; Keogh, Karina ; Kissin, Eugene Y. ; Monach, Paul A. ; Peikert, Tobias D ; Stegeman, Coen ; Ytterberg, Steven R ; Mueller, Mark ; Sejismundo, Lourdes P. ; Mieras, Kathleen ; Stone, John H. / Efficacy of remission-induction regimens for ANCA-associated vasculitis. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 5. pp. 417-427.
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abstract = "BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is unknown. METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS: A total of 197 patients were enrolled. As reported previously, 64{\%} of the patients in the rituximab group, as compared with 53{\%} of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48{\%} and 39{\%}, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39{\%} and 33{\%}, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20{\%}). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)",
author = "Ulrich Specks and Merkel, {Peter A.} and Philip Seo and Robert Spiera and Langford, {Carol A.} and Hoffman, {Gary S.} and Kallenberg, {Cees G M} and {St. Clair}, {E. William} and Fessler, {Barri J.} and Linna Ding and Lisa Viviano and Tchao, {Nadia K.} and Phippard, {Deborah J.} and Asare, {Adam L.} and Noha Lim and David Ikle and Brett Jepson and Paul Brunetta and Allen, {Nancy B.} and Fervenza, {Fernando Custodio} and Duvuru Geetha and Karina Keogh and Kissin, {Eugene Y.} and Monach, {Paul A.} and Peikert, {Tobias D} and Coen Stegeman and Ytterberg, {Steven R} and Mark Mueller and Sejismundo, {Lourdes P.} and Kathleen Mieras and Stone, {John H.}",
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TY - JOUR

T1 - Efficacy of remission-induction regimens for ANCA-associated vasculitis

AU - Specks, Ulrich

AU - Merkel, Peter A.

AU - Seo, Philip

AU - Spiera, Robert

AU - Langford, Carol A.

AU - Hoffman, Gary S.

AU - Kallenberg, Cees G M

AU - St. Clair, E. William

AU - Fessler, Barri J.

AU - Ding, Linna

AU - Viviano, Lisa

AU - Tchao, Nadia K.

AU - Phippard, Deborah J.

AU - Asare, Adam L.

AU - Lim, Noha

AU - Ikle, David

AU - Jepson, Brett

AU - Brunetta, Paul

AU - Allen, Nancy B.

AU - Fervenza, Fernando Custodio

AU - Geetha, Duvuru

AU - Keogh, Karina

AU - Kissin, Eugene Y.

AU - Monach, Paul A.

AU - Peikert, Tobias D

AU - Stegeman, Coen

AU - Ytterberg, Steven R

AU - Mueller, Mark

AU - Sejismundo, Lourdes P.

AU - Mieras, Kathleen

AU - Stone, John H.

PY - 2013

Y1 - 2013

N2 - BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is unknown. METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

AB - BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is unknown. METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

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