Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis

A. John Petkau, Richard A. White, George C. Ebers, Anthony T. Reder, William A. Sibley, Fred D. Lublin, Donald W. Paty, Pierre Duquette, Marc Girard, Liette Despault, Renee DuBois, Robert L. Knobler, Leith Kelley, Gordon S. Francis, Y. Lapierre, Jack Antel, Mark Freedman, Stanley Hum, Jeffrey I. Greenstein, Bibhuti Mishra & 32 others Joanne Muldoon, John N. Whitaker, Bradley K. Evans, Beverly Layton, Joan Laguna, John Krikawa, Joel J. Oger, Lorne F. Kastrukoff, G. R Wayne Moore, Stanley A. Hashimoto, Wendy Morrison, Jill Nelson, Douglas S. Goodin, Stephen M. Massa, Elena Gutteridge, Barry G W Arnason, Avertano Noronha, Roberta Martia, George P A Rice, Jane Lesaux, Kenneth P. Johnson, Hillel S. Panitch, Christopher T. Bever, Kathleen Conway, Joy Constine Wallenberg, Lisa Bedell, Stanley van den Noort, Brian G Weinshenker, William Weiss, Stephen Reingold, Andrew Pachner, Wayne Taylor

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

We have analysed data on exacerbation rates, Expanded Disability Status Scale (EDSS) scores, and lesion burdens using the results of two neutralizing antibody (NAB) assays (CPE and MxA) from the pivotal relapsing-remitting multiple sclerosis (MS) trial of interferon beta-1b (IFNB) with a longitudinal approach, where the influence of NABs in individual patients is assessed by comparing responses during NAB-positive and NAB-negative periods. There are apparent influences on exacerbation rate related to dose of IFNB, titer level, and duration of positivity. With the MxA assay, exacerbation rates after switching to NAB-positive status are estimated to be 28% higher [95% confidence interval (CI): (-15%, 92%)] and -2% higher [95% CI: (-21%, 21%)] on the low- and high-dose IFNB arms, respectively. When compared with all NAB-negative periods, exacerbation rates during NAB-positive periods are estimated to be 29% higher [95% CI: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFNB arms, respectively. When NAB-positive patients again become NAB-negative, no evidence of increased exacerbation rates could then be demonstrated. More detailed exploratory analyses indicate that the effects are most evident in the approximately 20% of patients developing high titers. In these patients, the influence of NABs may be self-limited, as titers often diminish or NABs become undetectable with time.

Original languageEnglish (US)
Pages (from-to)126-138
Number of pages13
JournalMultiple Sclerosis
Volume10
Issue number2
DOIs
StatePublished - Apr 2004

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Relapsing-Remitting Multiple Sclerosis
Neutralizing Antibodies
Confidence Intervals
Interferon beta-1b

Keywords

  • EDSS scores
  • Exacerbation rates
  • Generalized estimating equations
  • Longitudinal data
  • T2 lesion burdens

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Petkau, A. J., White, R. A., Ebers, G. C., Reder, A. T., Sibley, W. A., Lublin, F. D., ... Taylor, W. (2004). Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Multiple Sclerosis, 10(2), 126-138. https://doi.org/10.1191/1352458504ms1004oa

Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. / Petkau, A. John; White, Richard A.; Ebers, George C.; Reder, Anthony T.; Sibley, William A.; Lublin, Fred D.; Paty, Donald W.; Duquette, Pierre; Girard, Marc; Despault, Liette; DuBois, Renee; Knobler, Robert L.; Kelley, Leith; Francis, Gordon S.; Lapierre, Y.; Antel, Jack; Freedman, Mark; Hum, Stanley; Greenstein, Jeffrey I.; Mishra, Bibhuti; Muldoon, Joanne; Whitaker, John N.; Evans, Bradley K.; Layton, Beverly; Laguna, Joan; Krikawa, John; Oger, Joel J.; Kastrukoff, Lorne F.; Moore, G. R Wayne; Hashimoto, Stanley A.; Morrison, Wendy; Nelson, Jill; Goodin, Douglas S.; Massa, Stephen M.; Gutteridge, Elena; Arnason, Barry G W; Noronha, Avertano; Martia, Roberta; Rice, George P A; Lesaux, Jane; Johnson, Kenneth P.; Panitch, Hillel S.; Bever, Christopher T.; Conway, Kathleen; Wallenberg, Joy Constine; Bedell, Lisa; van den Noort, Stanley; Weinshenker, Brian G; Weiss, William; Reingold, Stephen; Pachner, Andrew; Taylor, Wayne.

In: Multiple Sclerosis, Vol. 10, No. 2, 04.2004, p. 126-138.

Research output: Contribution to journalArticle

Petkau, AJ, White, RA, Ebers, GC, Reder, AT, Sibley, WA, Lublin, FD, Paty, DW, Duquette, P, Girard, M, Despault, L, DuBois, R, Knobler, RL, Kelley, L, Francis, GS, Lapierre, Y, Antel, J, Freedman, M, Hum, S, Greenstein, JI, Mishra, B, Muldoon, J, Whitaker, JN, Evans, BK, Layton, B, Laguna, J, Krikawa, J, Oger, JJ, Kastrukoff, LF, Moore, GRW, Hashimoto, SA, Morrison, W, Nelson, J, Goodin, DS, Massa, SM, Gutteridge, E, Arnason, BGW, Noronha, A, Martia, R, Rice, GPA, Lesaux, J, Johnson, KP, Panitch, HS, Bever, CT, Conway, K, Wallenberg, JC, Bedell, L, van den Noort, S, Weinshenker, BG, Weiss, W, Reingold, S, Pachner, A & Taylor, W 2004, 'Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis', Multiple Sclerosis, vol. 10, no. 2, pp. 126-138. https://doi.org/10.1191/1352458504ms1004oa
Petkau, A. John ; White, Richard A. ; Ebers, George C. ; Reder, Anthony T. ; Sibley, William A. ; Lublin, Fred D. ; Paty, Donald W. ; Duquette, Pierre ; Girard, Marc ; Despault, Liette ; DuBois, Renee ; Knobler, Robert L. ; Kelley, Leith ; Francis, Gordon S. ; Lapierre, Y. ; Antel, Jack ; Freedman, Mark ; Hum, Stanley ; Greenstein, Jeffrey I. ; Mishra, Bibhuti ; Muldoon, Joanne ; Whitaker, John N. ; Evans, Bradley K. ; Layton, Beverly ; Laguna, Joan ; Krikawa, John ; Oger, Joel J. ; Kastrukoff, Lorne F. ; Moore, G. R Wayne ; Hashimoto, Stanley A. ; Morrison, Wendy ; Nelson, Jill ; Goodin, Douglas S. ; Massa, Stephen M. ; Gutteridge, Elena ; Arnason, Barry G W ; Noronha, Avertano ; Martia, Roberta ; Rice, George P A ; Lesaux, Jane ; Johnson, Kenneth P. ; Panitch, Hillel S. ; Bever, Christopher T. ; Conway, Kathleen ; Wallenberg, Joy Constine ; Bedell, Lisa ; van den Noort, Stanley ; Weinshenker, Brian G ; Weiss, William ; Reingold, Stephen ; Pachner, Andrew ; Taylor, Wayne. / Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. In: Multiple Sclerosis. 2004 ; Vol. 10, No. 2. pp. 126-138.
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AU - Petkau, A. John

AU - White, Richard A.

AU - Ebers, George C.

AU - Reder, Anthony T.

AU - Sibley, William A.

AU - Lublin, Fred D.

AU - Paty, Donald W.

AU - Duquette, Pierre

AU - Girard, Marc

AU - Despault, Liette

AU - DuBois, Renee

AU - Knobler, Robert L.

AU - Kelley, Leith

AU - Francis, Gordon S.

AU - Lapierre, Y.

AU - Antel, Jack

AU - Freedman, Mark

AU - Hum, Stanley

AU - Greenstein, Jeffrey I.

AU - Mishra, Bibhuti

AU - Muldoon, Joanne

AU - Whitaker, John N.

AU - Evans, Bradley K.

AU - Layton, Beverly

AU - Laguna, Joan

AU - Krikawa, John

AU - Oger, Joel J.

AU - Kastrukoff, Lorne F.

AU - Moore, G. R Wayne

AU - Hashimoto, Stanley A.

AU - Morrison, Wendy

AU - Nelson, Jill

AU - Goodin, Douglas S.

AU - Massa, Stephen M.

AU - Gutteridge, Elena

AU - Arnason, Barry G W

AU - Noronha, Avertano

AU - Martia, Roberta

AU - Rice, George P A

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AU - Johnson, Kenneth P.

AU - Panitch, Hillel S.

AU - Bever, Christopher T.

AU - Conway, Kathleen

AU - Wallenberg, Joy Constine

AU - Bedell, Lisa

AU - van den Noort, Stanley

AU - Weinshenker, Brian G

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AU - Reingold, Stephen

AU - Pachner, Andrew

AU - Taylor, Wayne

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N2 - We have analysed data on exacerbation rates, Expanded Disability Status Scale (EDSS) scores, and lesion burdens using the results of two neutralizing antibody (NAB) assays (CPE and MxA) from the pivotal relapsing-remitting multiple sclerosis (MS) trial of interferon beta-1b (IFNB) with a longitudinal approach, where the influence of NABs in individual patients is assessed by comparing responses during NAB-positive and NAB-negative periods. There are apparent influences on exacerbation rate related to dose of IFNB, titer level, and duration of positivity. With the MxA assay, exacerbation rates after switching to NAB-positive status are estimated to be 28% higher [95% confidence interval (CI): (-15%, 92%)] and -2% higher [95% CI: (-21%, 21%)] on the low- and high-dose IFNB arms, respectively. When compared with all NAB-negative periods, exacerbation rates during NAB-positive periods are estimated to be 29% higher [95% CI: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFNB arms, respectively. When NAB-positive patients again become NAB-negative, no evidence of increased exacerbation rates could then be demonstrated. More detailed exploratory analyses indicate that the effects are most evident in the approximately 20% of patients developing high titers. In these patients, the influence of NABs may be self-limited, as titers often diminish or NABs become undetectable with time.

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KW - Exacerbation rates

KW - Generalized estimating equations

KW - Longitudinal data

KW - T2 lesion burdens

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