Dimethyl Fumarate Effects on Lymphocyte Phenotype

Background: Lymphopenia developed in ~5% of patients treated with dimethyl fumarate (DMF) in phase III clinical trials; subsequent data suggests that lymphopenia may be even more common in clinical practice. A case of progressive multifocal leukoencephalopathy (PML) was recently identified in a lymphopenic DMF-treated patient. Several additional cases of PML had previously been reported in lymphopenic patients treated with older fumarate compounds. Lymphopenia was the clearest risk factor for PML in all these patients. Surprisingly, little is known about DMF-induced lymphopenia, and with the growing concern about opportunistic infections in patients chronically treated with this medication, it will be important to characterize the cellular populations most affected by this drug. 

Objectives: To phenotypically characterize circulating lymphocytes in DMF treated patients.

Methods: Cross-sectional analysis of patient samples. Patients who had been stably treated with DMF for >6 months were classified as lymphopenic based on absolute lymphocyte counts <800 (Grade 2 lymphopenia or worse). Samples were collected from lymphopenic and non-lymphopenic DMF-treated patients, untreated MS patients, and healthy controls then phenotypically characterized using flow cytometry.

Results: Multiple lymphocyte populations were reduced in lymphopenic patients. These included CD4+ T cells and T-regulatory cells. However, the strongest effect was on CD8+ lymphocytes, which were almost entirely lost. In non-lymphopenic DMF-treated patients, CD4+ cells were not noticeably affected, although CD8+ lymphocytes remained decreased compared to controls. 

Conclusions: DMF can affect many lymphocyte populations, but the drug’s strongest effect appears to be on CD8+ lymphocytes. As CD8+ cells are important for cell medicated immunity and viral clearance, it will be important to determine whether the function of CD8+ lymphocytes is also impaired in DMF-treated patients.