Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy

Marinos C. Dalakas, Goran Rakocevic, Mohammad Salajegheh, James M. Dambrosia, Angelika F. Hahn, Raghavan Pillai Raju, Beverly McElroy

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

Objective: Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP). Methods: Twenty-six patients were randomized to four weekly infusions of 375mg/m 2 rituximab or placebo. Sample size was calculated to detect changes of ≤1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months. Results: Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by ≤1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34% and anti-MAG titers by 50%. CD25 + CD4 + Foxp3 + regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline. Interpretation: Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.

Original languageEnglish (US)
Pages (from-to)286-293
Number of pages8
JournalAnnals of Neurology
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

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Myelin-Associated Glycoprotein
Placebos
Antibodies
Polyneuropathies
B-Lymphocytes
T-Lymphocytes
anti-IgM
Rituximab
Electrophysiology
Antigen-Presenting Cells
Random Allocation
Sample Size
Walking
Immunoglobulin M
Leg
Therapeutics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Dalakas, M. C., Rakocevic, G., Salajegheh, M., Dambrosia, J. M., Hahn, A. F., Raju, R. P., & McElroy, B. (2009). Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Annals of Neurology, 65(3), 286-293. https://doi.org/10.1002/ana.21577

Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. / Dalakas, Marinos C.; Rakocevic, Goran; Salajegheh, Mohammad; Dambrosia, James M.; Hahn, Angelika F.; Raju, Raghavan Pillai; McElroy, Beverly.

In: Annals of Neurology, Vol. 65, No. 3, 01.03.2009, p. 286-293.

Research output: Contribution to journalArticle

Dalakas, MC, Rakocevic, G, Salajegheh, M, Dambrosia, JM, Hahn, AF, Raju, RP & McElroy, B 2009, 'Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy', Annals of Neurology, vol. 65, no. 3, pp. 286-293. https://doi.org/10.1002/ana.21577
Dalakas, Marinos C. ; Rakocevic, Goran ; Salajegheh, Mohammad ; Dambrosia, James M. ; Hahn, Angelika F. ; Raju, Raghavan Pillai ; McElroy, Beverly. / Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. In: Annals of Neurology. 2009 ; Vol. 65, No. 3. pp. 286-293.
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abstract = "Objective: Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP). Methods: Twenty-six patients were randomized to four weekly infusions of 375mg/m 2 rituximab or placebo. Sample size was calculated to detect changes of ≤1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months. Results: Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by ≤1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34{\%} and anti-MAG titers by 50{\%}. CD25 + CD4 + Foxp3 + regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline. Interpretation: Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.",
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