Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate

Abstract

Objective: To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets.

Methods: Peripheral blood leukocyte and lymphocyte subsets, including CD3(+), CD4(+), and CD8(+) T cells; CD19(+) B cells; and CD56(+) natural killer (NK) cells, were obtained at baseline and monitored at 3 months, 6 months, and 12 months after initiation of DMF treatment.

Results: Total leukocyte and lymphocyte counts diminished after 6 months of DMF therapy. At 12 months, lymphocyte counts had decreased by 50.1% (p < 0.0001) and were below the lower limit of normal (LLN) in one-half of patients. CD3(+) T lymphocyte counts fell by 44.2% (p < 0.0001). Among subsets, CD8(+) T cell counts declined by 54.6% (p < 0.0001), whereas CD4(+) T cell counts decreased by 39.2% (p = 0.0006). This disproportionate reduction of CD8(+) T cells relative to CD4(+) T cells was significant (p = 0.007) and was reflected by a 35.5% increase in the CD4/CD8 ratio (p = 0.007). A majority of CD8(+) T cell counts, but not CD4(+) T cell counts, were below the LLN even when total lymphocyte counts were greater than 500 cells/μL. CD19(+) B cell counts were reduced by 37.5% (p = 0.035). Eosinophil levels decreased by 54.1% (p = 0.006), whereas levels of neutrophils, monocytes, basophils, and NK cells were not significantly altered.

Conclusion: Subsets of peripheral blood leukocytes and lymphocytes are differentially affected by DMF treatment of MS. Reduction of CD8(+) T cells is more pronounced than that of CD4(+) T cells. These findings may have implications for cell-mediated antiviral immunity during DMF treatment.

Figure 1. Peripheral blood leukocyte subset counts during dimethyl fumarate treatment

Complete blood cell counts were obtained at baseline (n = 34) and at month 3 (n = 21), month 6 (n = 15), and month 12 (n = 17) of treatment. Red lines represent lower limit of normal for each subset. Statistical significance was computed using Mann-Whitney U test. p Values less than 0.05 were considered statistically significant. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 2. Peripheral blood lymphocyte subset counts during dimethyl fumarate treatment

(A) Lymphocyte subsets were obtained at baseline (n = 21) and at month 3 (n = 13), month 6 (n = 13), and month 12 (n = 14) of treatment. Red lines represent lower limit of normal for each subset. Statistical significance was computed using Mann-Whitney U test. (B) Paired longitudinal analysis (n = 11) of CD4 counts, CD8 counts, and CD4/CD8 ratio between baseline and month 12. Percent reduction of CD4 and CD8 counts from baseline to month 12 was calculated for each individual. The mean reduction of CD8⁺ T cells (55.5%) was significantly greater than the reduction in CD4⁺ T cells (43.4%) (p = 0.007). The CD4/CD8 ratio increased by 38.3% at month 12. p Values less than 0.05 were considered statistically significant. *p < 0.05; **p < 0.01; ***p < 0.001.