Assessing the Incidence of Elevation in Eosinophils with the Use of Dimethyl Fumarate in Multiple Sclerosis

Background: Dimethyl fumarate (DMF) is an oral medication approved for the treatment of relapsing multiple sclerosis (MS). In the pivotal MS studies involving DMF, a transient increase in mean eosinophils was seen during the first 2 months of therapy. However, the incidence of this is not well reported.

Objectives: Our aim with this study is to assess incidence of elevation in eosinophils with the use of DMF in MS, and to begin to glean insight into its clinical relevance by assessing side effects and adverse events occurring among these patients.

Methods: A retrospective chart review was conducted on all patients seen in our MS clinic who were prescribed DMF between March 2013 and March 2015 under routine clinical care.  Those who began treatment and had available pre- and post-dosing complete blood counts (CBC) that included levels of esosinophils were included in analysis. Patients were excluded if their pre-CBCs occurred more than 6 months prior to starting DMF. Elevation in eosinophils in our chart review was defined as elevation above 7% of all leukocytes on differential.

Results: A total of 311 patients were prescribed DMF. Of these, 202 met criteria for inclusion. The incidence of elevation in eosinophils was 9.4% (19 patients). Elevated levels ranged from 7% to 19.5% of all leukocytes on differential. Elevations were sustained for approximately 1 year in only 2 patients and were otherwise transient. Of those with elevation in eosinophils, 47.4% (9 patients) experienced gastrointestinal symptoms, 26.3% (5 patients) experienced flushing, and 15.8% (3 patients) experienced no side effects. Adverse events among patients with elevated eosinophils included cholecystectomy (2 patients), shingles outbreak (2 patients), other infections (2 patients), gastrocnemius rupture (1 patient), and myocardial infarction (1 patient). Thirteen patients (68.4%) discontinued DMF. 

Conclusions: To our knowledge, ours is among the first studies assessing incidence of elevation in eosinophils with the use of DMF in MS. There are several potential clinical implications for this data. First, it has been postulated that DMF-related gastrointestinal symptoms could be due to an eosinophilic gastroenteritis-like syndrome. Second, a transient increase in eosinophils has been observed with fumaric-acid esters, a similar compound to DMF which is used in psoriasis. This has been attributed to elevations in IL-4, which stimulates eotaxin, an eosinophil-activating cytokine. IL-4 also decreases Th1 cells and increases Th2 cells. Given that Th2 activation would be beneficial in MS, this increase in eosinophils might imply a positive treatment response and thus could be considered a biomarker. Further studies are indicated to investigate this.