Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis

E. M. Miloslavsky, Ulrich Specks, P. A. Merkel, P. Seo, R. Spiera, C. A. Langford, G. S. Hoffman, C. G M Kallenberg, E. W. St.clair, N. K. Tchao, L. Viviano, L. Ding, L. P. Sejismundo, K. Mieras, D. Iklé, B. Jepson, M. Mueller, P. Brunetta, N. B. Allen, Fernando Custodio FervenzaD. Geetha, K. Keogh, E. Y. Kissin, P. A. Monach, Tobias D Peikert, C. Stegeman, Steven R Ytterberg, J. H. Stone

Research output: Contribution to journalArticle

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Abstract

Objective To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Original languageEnglish (US)
Pages (from-to)2441-2449
Number of pages9
JournalArthritis and Rheumatism
Volume65
Issue number9
DOIs
StatePublished - Aug 2013

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Remission Induction
Antineutrophil Cytoplasmic Antibodies
Vasculitis
Myeloblastin
Therapeutics
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Azathioprine
Cyclophosphamide
Glucocorticoids
B-Lymphocytes
Outcome Assessment (Health Care)
Recurrence
Granulomatosis with Polyangiitis
Prednisone

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. / Miloslavsky, E. M.; Specks, Ulrich; Merkel, P. A.; Seo, P.; Spiera, R.; Langford, C. A.; Hoffman, G. S.; Kallenberg, C. G M; St.clair, E. W.; Tchao, N. K.; Viviano, L.; Ding, L.; Sejismundo, L. P.; Mieras, K.; Iklé, D.; Jepson, B.; Mueller, M.; Brunetta, P.; Allen, N. B.; Fervenza, Fernando Custodio; Geetha, D.; Keogh, K.; Kissin, E. Y.; Monach, P. A.; Peikert, Tobias D; Stegeman, C.; Ytterberg, Steven R; Stone, J. H.

In: Arthritis and Rheumatism, Vol. 65, No. 9, 08.2013, p. 2441-2449.

Research output: Contribution to journalArticle

Miloslavsky, EM, Specks, U, Merkel, PA, Seo, P, Spiera, R, Langford, CA, Hoffman, GS, Kallenberg, CGM, St.clair, EW, Tchao, NK, Viviano, L, Ding, L, Sejismundo, LP, Mieras, K, Iklé, D, Jepson, B, Mueller, M, Brunetta, P, Allen, NB, Fervenza, FC, Geetha, D, Keogh, K, Kissin, EY, Monach, PA, Peikert, TD, Stegeman, C, Ytterberg, SR & Stone, JH 2013, 'Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis', Arthritis and Rheumatism, vol. 65, no. 9, pp. 2441-2449. https://doi.org/10.1002/art.38044
Miloslavsky, E. M. ; Specks, Ulrich ; Merkel, P. A. ; Seo, P. ; Spiera, R. ; Langford, C. A. ; Hoffman, G. S. ; Kallenberg, C. G M ; St.clair, E. W. ; Tchao, N. K. ; Viviano, L. ; Ding, L. ; Sejismundo, L. P. ; Mieras, K. ; Iklé, D. ; Jepson, B. ; Mueller, M. ; Brunetta, P. ; Allen, N. B. ; Fervenza, Fernando Custodio ; Geetha, D. ; Keogh, K. ; Kissin, E. Y. ; Monach, P. A. ; Peikert, Tobias D ; Stegeman, C. ; Ytterberg, Steven R ; Stone, J. H. / Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 9. pp. 2441-2449.
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abstract = "Objective To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86{\%}) in the first 6 months, the primary outcome measure was not achieved in 42{\%}. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5{\%}) experienced uncontrolled disease in the first month and 37 (19{\%}) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14{\%}] versus 20 of 62 [32{\%}]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.",
author = "Miloslavsky, {E. M.} and Ulrich Specks and Merkel, {P. A.} and P. Seo and R. Spiera and Langford, {C. A.} and Hoffman, {G. S.} and Kallenberg, {C. G M} and St.clair, {E. W.} and Tchao, {N. K.} and L. Viviano and L. Ding and Sejismundo, {L. P.} and K. Mieras and D. Ikl{\'e} and B. Jepson and M. Mueller and P. Brunetta and Allen, {N. B.} and Fervenza, {Fernando Custodio} and D. Geetha and K. Keogh and Kissin, {E. Y.} and Monach, {P. A.} and Peikert, {Tobias D} and C. Stegeman and Ytterberg, {Steven R} and Stone, {J. H.}",
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TY - JOUR

T1 - Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis

AU - Miloslavsky, E. M.

AU - Specks, Ulrich

AU - Merkel, P. A.

AU - Seo, P.

AU - Spiera, R.

AU - Langford, C. A.

AU - Hoffman, G. S.

AU - Kallenberg, C. G M

AU - St.clair, E. W.

AU - Tchao, N. K.

AU - Viviano, L.

AU - Ding, L.

AU - Sejismundo, L. P.

AU - Mieras, K.

AU - Iklé, D.

AU - Jepson, B.

AU - Mueller, M.

AU - Brunetta, P.

AU - Allen, N. B.

AU - Fervenza, Fernando Custodio

AU - Geetha, D.

AU - Keogh, K.

AU - Kissin, E. Y.

AU - Monach, P. A.

AU - Peikert, Tobias D

AU - Stegeman, C.

AU - Ytterberg, Steven R

AU - Stone, J. H.

PY - 2013/8

Y1 - 2013/8

N2 - Objective To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

AB - Objective To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

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