The effect of dimethyl fumarate (Tecfidera™) on lymphocyte counts: A potential contributor to progressive multifocal leukoencephalopathy risk

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Highlights

  • CD4 and CD8 from 256 Tecfidera patients.

  • Major decline both counts.

  • F/U advised.

Abstract

Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug.

Introduction

The mechanism Tecfidera™ exerts its therapeutic effect in MS is unknown, but may have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in both animals and humans. The Nrf2 pathway promotes expression of products that protect against oxidative stress that can inhibit proliferation of lymphocytes and hematopoeietic stem cells (Spencer et al., 2015). However, due to a unknown mechanism, Tecfidera™ may reduce blood lymphocyte counts. In controlled clinical trials (Spencer et al., 2015, Gold et al., 2012), Tecfidera™ reduced the mean lymphocyte counts by 30% during the first year; which then remained stable. Four weeks after stopping the medication, lymphocyte counts increased but did not return to the baseline level. About 6% of patients on Tecfidera™ had an absolute lymphocyte count less than 500/µL (0.5×109/L) less than 1% had lymphocyte counts less than 200/µL (0.2×109/L) cells/mm3. Although no increase in serious infections was seen in the people with low lymphocyte counts, one patient developed progressive multifocal leukoencephalopathy (PML) after the completion of the extension Tecfidera™ trial. This patient was on Tecfidera™ for 54 consecutive months and for approximately 3 1/2 years, the lymphocyte counts were very low, in the 200–500/µL (0.2–0.5×109/L) (Fox et al., 2012).

PML had previously been observed with dimethyl fumarate in patients being treated for psoriasis (Mrowietz and Reich, 2013) (〈http://www.fda.gov/Drugs/DrugSafety/ucm424625.htm〉) and with the related drug, fumaric acid (Fumaderm™) (van Oosten et al., 2013).

Little is known about changes in CD4 and CD8 counts in MS patients taking Tecfidera™. This brief report examines the absolute lymphocyte count, CD4 and CD8 counts in our MS patients before and after initiating Tecfidera™ treatment.

Section snippets

Methods

All patients receiving Tecfidera™ at The Center for Neurological Disorders at Wheaton Franciscan, Milwaukee, WI, had a baseline complete blood count with differential, CD4 and CD8 counts, that was repeated at three month intervals. In this retrospective study, we evaluated changes in lymphocyte, CD4 and CD8 counts and the CD4/CD8 ratio. A paired Student t-test or a Wilcoxon Signed-Rank test was used to determine if there were significant changes from baseline to those noted at follow-up visits.

Results

Data from 256 patients (192 female and 64 male, age range 23–82, mean age 49) were analyzed and displayed in Table 1 and Fig. 1. The total lymphocyte, CD4, and CD8 counts at three, nine and twelve months after treatment initiation were significantly reduced (p<0.0004). This reduction, which stabilized after nine months suppression, was greater for CD8 cells than CD4 cells. Sustained lymphocyte counts less than 500/µL (0.5×109/L) were observed in 6.6% of patients three months after initiating

Discussion

The absolute lymphocyte count, CD4 and CD8 cell counts and CD4/CD8 ratio are a reflection of immune system health. A low CD4 T lymphocyte counts is associated with a variety of conditions, including viral, bacterial, and parasitic infections (Ermis et al., 2013).

We observed significant lymphopenia and a decrease in CD4 and CD8 cell counts in our patients taking Tecfidera™. Similar reduction of CD4+ and CD8+ T lymphocytes were recently reported in 35 patients with relapsing forms of MS by

Conclusion

Our report suggests that Tecfidera™ may also have immunosuppressive properties. Future studies looking at the effect of this drug on central and effector memory cells, premature B (CD34) cells and JCV expression would be vital in an effort to understand the mechanism by which Tecfidera™ may contribute to the development of PML. In the meantime, clinicians should consider discontinuing Tecfidera in patients who are JCV seropositive and or who have leukocyte counts below 3000/µL (3×109/L) or

Conflict of interest

There is no conflict of interest.

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