Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

Richard A. Rudick, Diane L. Cookfair, Nancy A. Simonian, Richard M. Ransohoff, John R. Richert, Lawrence D. Jacobs, Robert M. Herndon, Andres M. Salazar, Jill S. Fischer, Carl V. Granger, Donald E. Goodkin, Jack H. Simon, David M. Bartoszak, Dennis Bourdette, Jonathan Braiman, Carol M. Brownscheidle, Michael E. Coats, Stanley L. Cohan, David S. Dougherty, Revere P. Kinkel & 9 others Michele Mass, Frederick E. Munchsauer, Kathy O'Reilly, Roger L. Priore, Patrick M. Pullicino, Barbara J. Scherokman, Karl Wende, Bianca Weinstock-Guttman, Ruth Whitham

Research output: Contribution to journalArticle

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Abstract

Background and objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827), a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1 a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd- enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Original languageEnglish (US)
Pages (from-to)8-14
Number of pages7
JournalJournal of Neuroimmunology
Volume93
Issue number1-2
DOIs
StatePublished - Jan 1 1999

Fingerprint

Oligoclonal Bands
Multiple Sclerosis
Cerebrospinal Fluid
Light
Immunoglobulin G
Placebos
Therapeutics
Clinical Trials
Recurrence
Phase III Clinical Trials
Organized Financing
Gadolinium
Interferon beta-1a
Cell Count
Magnetic Resonance Imaging
Demography
Brain

Keywords

  • Cerebrospinal fluid
  • Controlled clinical trials
  • CSF free kappa light chains
  • CSF IgG index
  • Interferon
  • Interferon beta
  • Multiple sclerosis
  • Oligoclonal bands

ASJC Scopus subject areas

  • Immunology
  • Clinical Neurology
  • Immunology and Allergy
  • Neurology

Cite this

Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis. / Rudick, Richard A.; Cookfair, Diane L.; Simonian, Nancy A.; Ransohoff, Richard M.; Richert, John R.; Jacobs, Lawrence D.; Herndon, Robert M.; Salazar, Andres M.; Fischer, Jill S.; Granger, Carl V.; Goodkin, Donald E.; Simon, Jack H.; Bartoszak, David M.; Bourdette, Dennis; Braiman, Jonathan; Brownscheidle, Carol M.; Coats, Michael E.; Cohan, Stanley L.; Dougherty, David S.; Kinkel, Revere P.; Mass, Michele; Munchsauer, Frederick E.; O'Reilly, Kathy; Priore, Roger L.; Pullicino, Patrick M.; Scherokman, Barbara J.; Wende, Karl; Weinstock-Guttman, Bianca; Whitham, Ruth.

In: Journal of Neuroimmunology, Vol. 93, No. 1-2, 01.01.1999, p. 8-14.

Research output: Contribution to journalArticle

Rudick, RA, Cookfair, DL, Simonian, NA, Ransohoff, RM, Richert, JR, Jacobs, LD, Herndon, RM, Salazar, AM, Fischer, JS, Granger, CV, Goodkin, DE, Simon, JH, Bartoszak, DM, Bourdette, D, Braiman, J, Brownscheidle, CM, Coats, ME, Cohan, SL, Dougherty, DS, Kinkel, RP, Mass, M, Munchsauer, FE, O'Reilly, K, Priore, RL, Pullicino, PM, Scherokman, BJ, Wende, K, Weinstock-Guttman, B & Whitham, R 1999, 'Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis', Journal of Neuroimmunology, vol. 93, no. 1-2, pp. 8-14. https://doi.org/10.1016/S0165-5728(98)00174-X
Rudick, Richard A. ; Cookfair, Diane L. ; Simonian, Nancy A. ; Ransohoff, Richard M. ; Richert, John R. ; Jacobs, Lawrence D. ; Herndon, Robert M. ; Salazar, Andres M. ; Fischer, Jill S. ; Granger, Carl V. ; Goodkin, Donald E. ; Simon, Jack H. ; Bartoszak, David M. ; Bourdette, Dennis ; Braiman, Jonathan ; Brownscheidle, Carol M. ; Coats, Michael E. ; Cohan, Stanley L. ; Dougherty, David S. ; Kinkel, Revere P. ; Mass, Michele ; Munchsauer, Frederick E. ; O'Reilly, Kathy ; Priore, Roger L. ; Pullicino, Patrick M. ; Scherokman, Barbara J. ; Wende, Karl ; Weinstock-Guttman, Bianca ; Whitham, Ruth. / Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis. In: Journal of Neuroimmunology. 1999 ; Vol. 93, No. 1-2. pp. 8-14.
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title = "Cerebrospinal fluid abnormalities in a phase III trial of Avonex{\circledR} (IFNβ-1a) for relapsing multiple sclerosis",
abstract = "Background and objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827), a (Avonex{\circledR}, Biogen). The clinical trial demonstrated that IFNβ-1 a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods: CSF was analyzed from 262 (87{\%}) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results: (1) At study baseline, 37{\%} of the subjects had abnormal CSF WBC counts, 61{\%} had abnormal levels of CSF free kappa light chains, 84{\%} had abnormal IgG index values, and 90{\%} were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd- enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.",
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TY - JOUR

T1 - Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

AU - Rudick, Richard A.

AU - Cookfair, Diane L.

AU - Simonian, Nancy A.

AU - Ransohoff, Richard M.

AU - Richert, John R.

AU - Jacobs, Lawrence D.

AU - Herndon, Robert M.

AU - Salazar, Andres M.

AU - Fischer, Jill S.

AU - Granger, Carl V.

AU - Goodkin, Donald E.

AU - Simon, Jack H.

AU - Bartoszak, David M.

AU - Bourdette, Dennis

AU - Braiman, Jonathan

AU - Brownscheidle, Carol M.

AU - Coats, Michael E.

AU - Cohan, Stanley L.

AU - Dougherty, David S.

AU - Kinkel, Revere P.

AU - Mass, Michele

AU - Munchsauer, Frederick E.

AU - O'Reilly, Kathy

AU - Priore, Roger L.

AU - Pullicino, Patrick M.

AU - Scherokman, Barbara J.

AU - Wende, Karl

AU - Weinstock-Guttman, Bianca

AU - Whitham, Ruth

PY - 1999/1/1

Y1 - 1999/1/1

N2 - Background and objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827), a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1 a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd- enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

AB - Background and objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827), a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1 a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd- enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

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KW - Controlled clinical trials

KW - CSF free kappa light chains

KW - CSF IgG index

KW - Interferon

KW - Interferon beta

KW - Multiple sclerosis

KW - Oligoclonal bands

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