Risk Factors for Lymphopenia in Patients with Relapsing Remitting Multiple Sclerosis Treated with Dimethyl Fumarate

Background: Dimethyl fumarate (DMF) can cause lymphopenia in relapsing remitting multiple sclerosis (RRMS) patients, affecting primarily CD8+ T-lymphocytes. These lymphocytes play a crucial role in the containment of JC virus, the etiologic agent of progressive multifocal leukoencephalopathy (PML). Identifying patients who are at risk for lymphopenia may allow better selection of MS patients to treat with DMF and appropriate early discontinuation of DMF for prevention of PML.

Objectives: To identify risk factors for (DMF-induced lymphopenia and characterize its impact on T lymphocyte subsets in MS patients.

Methods: We performed a retrospective analysis of 93 MS patients treated with DMF at BIDMC since 2013. We reviewed demographics, ethnic background, prior medication history, complete blood counts and T lymphocyte subsets. Possible lymphopenia risk factors examined include age, prior natalizumab exposure, vitamin D levels, and concomitant exposure to carbamazepine, opiates, tobacco, or steroids. Lymphopenia was define as grade 1: absolute lymphocytes count (ALC) 800-999/ul; grade 2: ALC 500–799/ul; grade 3: ALC 200-499/ul and grade 4: ALC <200/ul.

Results: MS patients were on DMF monotherapy for a median of 12 months (range 5-35). These included 84% Caucasians and 16% African Americans. Of 93 DMF-treated patients, 38 (40.8%) developed any grade of lymphopenia and reached an ALC nadir after a median of 486 days (range 82-889). Lymphopenic patients included 17 (18.2%) grade 1, 15 (16.1%) grade 2, and 6 (6.4%) grade 3 individuals. Compared to baseline levels, CD8+ T-cells were more reduced than CD4+ T-cells (84% versus 58% in patients with lymphopenia, p< 0.0004) and CD4/CD8 ratio increased from 2.0 to 4.0. In Caucasian patients, lymphopenia occurred in 44.8%, which is significantly elevated compared to 9% African-Americans (p<0.05).  Risk of developing lymphopenia increased with concomitant steroid exposure (p<0.02). We observed a trend for increased incidence of lymphopenia in smokers, patients treated with carbamazepine, and those with normal vitamin D level (>30 ng/ml) at the time of lymphopenia.  Prior exposure to natalizumab, age, BMI<25, or opiate use were not associated with the incidence of lymphopenia.

Conclusions: Lymphopenia occurs frequently in DMF-treated MS patients and affects CD8+ more than CD4+ T-cells. Caucasians and patients exposed to steroids had a higher incidence of lymphopenia. Further data analysis is in progress.