Saturday, 7 March 2015

ClinicSpeak: DMF, lymphocytes and PML

DMF has a differential effect on lymphocyte subtypes that fight viral infections. #ClinicSpeak #MSBlog #MSResearch

"If this blog rated studies the study below would be get my vote for study of the week. It shows that  dimethyl fumarate or DMF (Tecfidera) has a disproportional effect on the so called CD8+ T cells in the peripheral blood; CD8+ T cells numbers declined by over 50% compared to the CD4+ T cells. Is this important? Yes, within the CD8+ T cell population the so called cytotoxic (cell toxic) T cells (CTLs) reside; these are a very important group of T cells that fight virally infected cells. Why is this important? In patients with HIV and AIDs a reduction in the CTLs is what correlates with the development of opportunistic viral infections such as PML. In view of the risk of PML with DMF we may need to start monitoring lymphocyte subsets as well as total lymphocyte numbers. As you are aware the FDA have ruled on a 500 lymphocyte per mm3 cut-off  before interrupting DMF treatment. At BARTS-MS we have set the limit at 800 per mm3 and are waiting for the EMA ruling to whether or not we should adopt a different cut-off. Despite these guidelines we may have to rethink and set some limits based on the CD8+ counts. At the moment we don't have data on this in the MS population, but we could extrapolate from other diseases." 

CTL  or CD8+ T cell killing a virus infected cell

What does Wikipedia have to say about CTLs?  ..... A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cells or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways.Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen. An antigen is a molecule capable of stimulating an immune response, and is often produced by cancer cells or viruses. Antigens inside a cell are bound to class I MHC molecules, and brought to the surface of the cell by the class I MHC molecule, where they can be recognized by the T cell. If the TCR is specific for that antigen, it binds to the complex of the class I MHC molecule and the antigen and the T cell destroys the cell. In order for the TCR to bind to the class I MHC molecule, the former must be accompanied by a glycoprotein called CD8, which binds to the constant portion of the class I MHC molecule. Therefore, these T cells are called CD8+ T cells.The affinity between CD8 and the MHC molecule keeps the TC cell and the target cell bound closely together during antigen-specific activation. CD8+ T cells are recognized as TC cells once they become activated and are generally classified as having a pre-defined cytotoxic role within the immune system. However, CD8+ T cells also have the ability to make some cytokines.....

Spencer et al. Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015 Feb 12;2(3):e76.

OBJECTIVE: To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of 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.

CoI: multiple


  1. thank you, am having a bit of problems posting but assume the moderator will sort out the multiple attempts.
    I find this info a bit worrying but useful. Does it mean there may also be an increased cancer risk? I guess you can't have an effective drug (well, not that effective) without causing knock on problems.
    At present we only have a relatively small cohort of people who have been on this continuously for several years and new problems may start to emerge.
    I do hope that we are closely monitored. I feel that neurologists are seeing this as a rather benign drug and may be too relaxed about it. They are certainly underplaying the side effects (bit of flushing and tummy upsets), really??
    There needs to be meticulous reporting of any concerns so emerging trends of problems and secondary illnesses can be picked up.

  2. I have 2 questions:
    Doesn't Lemtrada treatment affect the CD8 cell population?
    What about Gilenya?

  3. so I should not be concerned if I have a 2950 per L after a year of Gilneya ? , is it considered mild lymphopenia ?


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