- •Lymphocyte counts decrease during first year of dimethyl fumarate treatment.
- •Older age and lower lymphocyte counts increase the risk of lymphopenia.
- •Precipitous drop in lymphocyte counts at three months of treatment associates with lymphopenia.
- •Lymphopenic patients experience a specific decrease in NKT cells.
Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy.
To identify factors associated with lymphopenia in DMF-treated patients and explore changes in blood lymphocyte subsets associated with DMF-induced lymphopenia.
Prospective longitudinal study including 106 patients initiating DMF treatment followed for a median time of 24.67 months. Blood lymphocyte subsets were studied in 64 patients by flow cytometry at baseline and 6 months after.
Mean absolute lymphocyte counts (ALCs) decreased by 29% during the first year of DMF-treatment. Patients developing lymphopenia showed a faster decline within the three first months. A reduction of ALCs higher than 38% at this time was associated to subsequent development of grade 2–3 lymphopenia (OR = 5.93, 95% CI: 1.9–18.6, p = 0.002). All patients showed a significant decrease in different T and B lymphocyte subsets upon DMF therapy. In addition, lymphopenic patients experienced a selective decrease in natural killer T (NKT) cell percentages (p = 0.01), and a high drop in NKT total counts (p < 0.0001).
Patients who experience a drop in ALCs by >38% at three months of DMF-treatment are about 6-times more likely to develop significant lymphopenia. This decrease is clearly associated with a considerable loss of NKT cells.
Abbreviations:DMF (dimethyl-fumarate), ALC (absolute lymmphocyte count)
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- Effects of dimethyl fumarate on neuroprotection and immunomodulation.J. Neuroinflammation. 2012; 9: 163
- Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.Brain. 2011; 134: 678-692
- Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.N. Engl. J. Med. 2012; 367: 1098-1107
- Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.N. Engl. J. Med. 2012; 367: 1087-1097
- Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate.Neurol. Neuroimmunol. Neuroinflamm. 2016; 3: e274
- PML in a patient with lymphocytopenia treated with dimethyl fumarate.N. Engl. J. Med. 2015; 372: 1476-1478
- PML in a patient without severe lymphocytopenia receiving dimethyl fumarate.N. Engl. J. Med. 2015; 372: 1474-1476
- Dimethyl fumarate-associated lymphopenia: risk factors and clinical significance.Mult. Scler. J. Exp. Transl. Clin. 2015; 1
- Dimethyl fumarate associated lymphopenia in clinical practice.Mult. Scler. 2015; 21: 796-797
- Common Terminology Criteria for Adverse Events v4.0, NCI, NIH, HHS.NIH publication, Bethesda, MD2009: #09-7473
- Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile.Mult. Scler. 2017; https://doi.org/10.1177/1352458517717088
- Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis.Neurol. Neuroimmunol. Neuroinflamm. 2015; 3e183
- Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients.Mult. Scler. 2016; 22: 1061-1070
- Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets.Neurol. Neuroimmunol. Neuroinflamm. 2016; 3: e211
- Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS.Mult. Scler. 2017; https://doi.org/10.1177/1352458517703799
- Sustained effect of delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting multiple sclerosis: 6-year interim results from an extension of the DEFINE and CONFIRM studies.Neurol. Ther. 2016; 5: 45-57
- Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study.Mult. Scler. 2017; 23: 253-265
- Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis.Neurol. Neuroimmunol. Neuroinflamm. 2017; 4: e340
- Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate.Neurol. Neuroimmunol. Neuroinflamm. 2015; 2: e76
- The effect of dimethyl fumarate (Tecfidera) on lymphocyte counts: a potential contributor to progressive multifocal leukoencephalopathy risk.Mult. Scler. Relat. Disord. 2015; 4: 377-379
- Effects of dimethyl fumarate on lymphocyte subsets.Mult. Scler. Relat. Disord. 2015; 4: 339-341
- Lymphocyte subtypes in relapsing–remitting multiple sclerosis patients treated with dimethyl fumarate.Mult. Scler. J. Exp. Transl. Clin. 2017; 3 (2055217317702933)
- Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining.J. Exp. Med. 2002; 195: 625-636
- The in vivo response of invariant natural killer T cells to glycolipid antigens.Int. Rev. Immunol. 2007; 26: 31-48
Published online: January 09, 2019
Accepted: January 7, 2019
Received in revised form: December 16, 2018
Received: March 28, 2018
© 2019 Elsevier B.V. All rights reserved.