Patient outcomes influenced by reduced lymphocyte counts after dimethyl fumarate initiation

Abstract

Objective:To examine the temporal profile of absolute and lymphocyte subset data from dimethyl fumarate (DMF) start and relationships to disease behavior.Methods:A retrospective study performed on patients with an existing diagnosis of MS and a history of DMF exposure from a single MS center. Demographic, laboratory, and corresponding clinical relapse and MRI data were recorded from baseline and in 3–4-month intervals after treatment initiation extending to 3 years. The Spearman rank coefficient and mixed-effects models were used to assess longitudinal correlations between cell counts and measures of disease activity.Results:A total of 292 patients with MS (228 women; median age at DMF initiation: 40.6 years, range: 16.1–66.7 years) were identified. An increased risk of disease activity was associated with higher absolute lymphocyte count (ALC) values at 3 months (p = 0.001, OR: 1.82) and at 6 months (p = 0.032, hazard ratio: 1.73). A reduced risk of disease evolution in patients with lower ALC values < 1,200 cells/μL compared with midtier (1,210–1,800 cells/μL) and the highest tertile (>1,810 cells/μL) was observed (p = 0.01).Conclusions:Reductions in ALC values at months 3 and 6 after treatment initiation appear to be associated with improved clinical and radiologic outcomes. These data alone may help to provide a better understanding of both the safety and efficacy of DMF.

Lymphocyte Count and Body Mass Index as Biomarkers of Early Treatment Response in a Multiple Sclerosis Dimethyl Fumarate-Treated Cohort

“…However, in DEFINE and CONFIRM, the reduction in ARR at 2 years in patients treated with DMF 240 mg bid vs. placebo was not substantially different in patients with lymphopenia (≥1LC < lower limit of normal) compared to those without lymphopenia (all LCs ≥lower limit of normal) (7). However, real-life data are sometimes discordant on this point; for example, data from a Dallas Multiple Sclerosis Center (33) have shown a greater risk of relapses in patients with higher LC at 3 months [ p < 0.001, hazard ratio [HR]: 1.82], just as we found in our cohort. Moreover, the Dallas examiners stratified LC by tertile, and found a reduced risk in patients with lower LC values: 1,200 cells/mL compared with mid-tier (1,210–1,800 cells/mL) and the highest tertile (>1,810 cells/mL) ( p < 0.01).…”

Dimethyl fumarate‐induced lymphocyte count drop is related to clinical effectiveness in relapsing–remitting multiple sclerosis

“…Since a higher lymphocyte decrease may theoretically reflect a stronger degree of immunosuppression, several studies have explored a possible association between ALC during treatment and disease outcomes, drawing conflicting conclusions. Wright and colleagues [9] showed an increased risk of disease activity in patients with higher ALC values at 3 and 6 months. A recent Italian study, performed on 338 patients, found that lower lymphocyte counts, measured 3 and 6 months after DMF start, were associated with a lower risk of MRI activity at 1‐year follow‐up [10].…”

“…A reduction of absolute lymphocyte count (ALC) of the order of 30% within the first year of treatment has also been observed [5], but its correlation with DMF effectiveness is still uncertain. In fact, several studies have investigated this aspect with heterogeneous methods, obtaining contradictory results [6][7][8][9][10]. Since T and B cells play a key role in MS pathogenesis, it is plausible that DMF therapeutic action might at least partly be attributed to its effects on lymphocyte count.…”

Comparative Efficacy and Safety of Ozanimod and Dimethyl Fumarate for Relapsing-Remitting Multiple Sclerosis Using Matching-Adjusted Indirect Comparison

“…Dimethyl fumarate (DMF; Tecfidera, Biogen Inc., Cambridge, MA, USA) exerts anti-inflammatory and cytoprotective effects arising, at least in part, from the activation of the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway; DMF may also play a part in modulating immune cell responses [10,11]. Clinical studies have demonstrated that DMF treatment results in reduced absolute lymphocyte counts (ALCs) [12]; however, the reductions are not uniform, with the greatest decrease seen in T-cell lymphocytes and, to a lesser extent, in B cells and natural killer (NK) cells [13][14][15]. DMF reduces circulating T cells but also shifts cell polarity from proinflammatory T-helper type 1 (Th 1 ) and Th 17 phenotypes toward antiinflammatory Th 2 cells [16] and shifts B cells toward tolerogenic phenotypes [17].…”