Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis

R. A. Grove, S. Shackelford, S. Sopper, Samuel Jay Pirruccello, J. Horrigan, E. Havrdova, M. Gold, O. Graff

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background and purpose: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. Methods: Forty-six subjects with relapsing forms of MS were treated for up to 24weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. Results: Median (n, range) CSF lymphocyte counts (cells/μl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4:CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4:CD8 ratios. Conclusions: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

Original languageEnglish (US)
Pages (from-to)1032-1042
Number of pages11
JournalEuropean Journal of Neurology
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2013

Fingerprint

Lymphocyte Count
Leukocyte Count
Multiple Sclerosis
Cerebrospinal Fluid
CD4-CD8 Ratio
Central Nervous System
Integrin alpha4
Lymphocytes
Subarachnoid Space
Blood Cell Count
Natural Killer Cells
Firategrast
Flow Cytometry
B-Lymphocytes

Keywords

  • Firategrast
  • Integrin antagonists
  • Lymphocytes
  • Multiple sclerosis
  • Progressive multifocal leukoencephalopathy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. / Grove, R. A.; Shackelford, S.; Sopper, S.; Pirruccello, Samuel Jay; Horrigan, J.; Havrdova, E.; Gold, M.; Graff, O.

In: European Journal of Neurology, Vol. 20, No. 7, 01.07.2013, p. 1032-1042.

Research output: Contribution to journalArticle

Grove, R. A. ; Shackelford, S. ; Sopper, S. ; Pirruccello, Samuel Jay ; Horrigan, J. ; Havrdova, E. ; Gold, M. ; Graff, O. / Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. In: European Journal of Neurology. 2013 ; Vol. 20, No. 7. pp. 1032-1042.
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AU - Grove, R. A.

AU - Shackelford, S.

AU - Sopper, S.

AU - Pirruccello, Samuel Jay

AU - Horrigan, J.

AU - Havrdova, E.

AU - Gold, M.

AU - Graff, O.

PY - 2013/7/1

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N2 - Background and purpose: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. Methods: Forty-six subjects with relapsing forms of MS were treated for up to 24weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. Results: Median (n, range) CSF lymphocyte counts (cells/μl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4:CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4:CD8 ratios. Conclusions: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

AB - Background and purpose: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. Methods: Forty-six subjects with relapsing forms of MS were treated for up to 24weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. Results: Median (n, range) CSF lymphocyte counts (cells/μl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4:CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4:CD8 ratios. Conclusions: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

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