Vol.:(0123456789) 1 3 Journal of Neurology https://doi.org/10.1007/s00415-019-09557-w ORIGINAL COMMUNICATION Risk factors for lymphopenia in patients with relapsing–remitting multiple sclerosis treated with dimethyl fumarate Fabian Sierra Morales 1,3  · Igor J. Koralnik 1,3  · Shiva Gautam 2  · Soleil Samaan 1  · Jacob A. Sloane 1 Received: 21 April 2019 / Revised: 22 September 2019 / Accepted: 24 September 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract 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 194 RRMS patients treated with DMF at the Beth Israel Deaconess Medical Center (BIDMC) over a median of 17 months. We reviewed demographics, ethnic background, prior medication history, complete blood counts and T lymphocyte subsets. Possible lymphopenia risk factors examined included age, prior natalizumab exposure, vitamin D levels, and concomitant exposure to carbamazepine, opiates, tobacco, or steroids. Lym- phopenia was defned as grade 1: absolute lymphocytes count (ALC) 800–999/μl; grade 2: ALC 500–799/μl; grade 3: ALC 200–499/μl; and grade 4: ALC < 200/μl. Results Of 194 DMF-treated patients, 73 (38%) developed lymphopenia and reached an ALC nadir after a median of 504 days (range 82–932). Risk of developing DMF-induced lymphopenia increased with BMI 25–30, older age, white ethnicity, non-smoking status, and lowest quartile baseline ALC. Prior exposure to natalizumab or concomitant steroid, opiates or carbamazepine/oxcarbamazepine use was not associated with lymphopenia. Compared to baseline levels, CD8 T cells were signifcantly more reduced than CD4 cells. CD8 counts were more commonly reduced with age or white ethnicity. Subjects with BMI 25–30 was associated with a higher risk of abnormal CD4 cell count reductions. In contrast, non-smokers were more likely to experience reductions in both CD4 and CD8 counts while on DMF. Conclusions Patients with low baseline lymphocyte counts, with intermediate BMI, with white ethnicity, with advanced age, or with no tobacco use, had a signifcantly higher incidence of lymphopenia on DMF. Intermediate BMI or lowest quartile baseline ALC predicted low CD4 levels, while advanced age or white ethnicity predicted low CD8 levels from DMF exposure. Keywords Multiple sclerosis · Dimethyl fumarate · Lymphopenia Abbreviations DMF Dimethyl fumarate ALC Absolute lymphocyte count RRMS Relapsing–remitting multiple sclerosis PML Progressive multifocal leukoencephalopathy BMI Body mass index Introduction Dimethyl fumarate (DMF) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) but has an associated risk of lymphopenia [1, 2]. DMF appears to pref- erentially deplete CD8 T cells [3, 4], which may play an important role in the containment of JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopa- thy (PML) [5]. To date, six MS patients on DMF developed lymphopenia with subsequent PML [6–9]. Several additional patients on DMF for psoriasis also developed PML in the setting of prolonged lymphopenia [7]. Careful monitoring of lymphocytes is now standard while on DMF. In addition, * Jacob A. Sloane jsloane@bidmc.harvard.edu 1 Division of Neuro-Immunology, Department of Neurology, Beth Israel Deaconess Medical Center, Multiple Sclerosis Center, Harvard Medical School, 330 Brookline Ave, Ks212, Boston, MA 02115, USA 2 Division of Biostatistics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 3 Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA