Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.
To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.
Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.
476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.
A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.