DOI: 10.1097/01.NT.0000469136.38193.7a
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Issn Print: 1533-7006
Publication Date: 2015/06/18
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Excerpt
INDIANAPOLIS—Peripheral blood samples of multiple sclerosis (MS) patients who develop lymphopenia while stably treated with dimethyl fumarate (DMF) show a marked and disproportionate drop in their CD8+ lymphocytes, according to a study that was presented here on May 29 at the annual meeting of the Consortium of MS Centers.
Although lymphopenia was previously observed in about 5 percent of patients in the phase 3 trials on which Food and Drug Administration approval was based, subsequent data has suggested that the disorder may be even more common in clinical practice.
Earlier this year, one case of progressive multifocal leukoencephalopathy (PML) was reported. Investigators from Washington University in St. Louis set out to characterize the cellular populations most affected by the drug, about which little had previously been known.
They conducted a cross-sectional analysis of patient samples. Patients who had been stably treated with DMF for more than six months were classified as lymphopenic based on absolute lymphocyte counts of less than 800 (grade 2 lymphopenia or worse). Samples were collected from lymphopenic and non-lymphopenic patients treated with the drug, treatment-naive MS patients, and healthy controls. All samples were then phenotypically characterized using ?ow cytometry.
The researchers reported that multiple lymphocyte populations were reduced in lymphopenic patients, including CD4+ T cells and T-regulatory cells. However, the strongest effect was on CD8+ lymphocytes, which were almost entirely lost. In non-lymphopenic patients treated with dimethyl fumarate, CD4+ cells were not noticeably affected.
Because CD8+ cells are important for cell-mediated immunity and viral clearance, the researchers concluded that more studies are needed to determine whether the function of CD8+ lymphocytes is also impaired in patients treated with DMF.
Erin Longbrake, MD, a fellow in multiple sclerosis and neuroimmunology at Washington University, who presented the study, said that one reason that lymphopenia is being seen more often in practice than it was in the phase 3 trials is that it's now being used in older patients who were not included in those trials. At Washington University, the older patients appeared to be at increased risk of developing the disorder.
“Almost all doctors who treat MS now have a handful of patients who became lymphopenic and are struggling to understand what the best recommendations are for managing these people,” she said.
While the drug's profile of risks and benefits was favorable in the published clinical trials, Dr. Longbrake said, “We don't know what will happen when patients take these drugs for five to 10 years. One has to be vigilant to be sure you're not taken by surprise by any untoward complications of the medication. DMF is a valuable tool, but I don't think we can take lightly that we're modulating the immune system in ways we don't fully understand yet. Ongoing monitoring of these patients is necessary.
