Background

The association between treatment-related lymphopenia in multiple sclerosis, drug efficacy and the risk of infections is not yet fully understood.

Objective

The objective of this study was to assess whether lymphopenia is associated with short-term treatment response and infection rate in a real-life multiple sclerosis population treated with fingolimod and dimethyl-fumarate. We assessed the associations between baseline absolute lymphocyte count and the lymphocyte mean percentage decrease at 6 and 12 months with treatment response and the occurrence of adverse events over 12 months in the entire cohort of patients and in the two treatment groups separately.

Methods

This is a retrospective observational real-world study of patients with multiple sclerosis treated with fingolimod and dimethyl-fumarate at the MS Center of the University of Genoa between 2011 and 2018. Patients with at least 12 months of follow-up were eligible if [1] they had an Expanded Disability Status Scale assessment at baseline and 12 months after treatment onset, [2] they had undergone brain magnetic resonance imaging at baseline and after 12 months, and [3] absolute lymphocyte counts were available at baseline, 6 and 12 months. Patients shifting from dimethyl-fumarate to fingolimod or vice versa were excluded from the analysis.

Results

In total, 137 and 75 patients treated with fingolimod and dimethyl-fumarate, respectively, were included in the analysis. At 12 months, fingolimod-treated patients were more likely to experience grade II and grade III lymphopenia compared with dimethyl-fumarate patients (p < 0.001, χ2 = 94) and had a higher lymphocyte mean percentage decrease (p < 0.001, U = 540). A higher number of previous therapies and a lower baseline absolute lymphocyte count were predictors of lymphopenia at 6 months (p = 0.047, odds ratio = 1.60 and p = 0.014, odds ratio = 1.1) and 12 months (p = 0.003, odds ratio = 1.97 and p = 0.023, odds ratio = 1.1). In fingolimod-treated patients only, female sex and a higher Expanded Disability Status Scale score were predictors of lymphopenia at 12 months (p = 0.006, odds ratio = 7.58 and p = 0.03, odds ratio = 1.56). Neither absolute lymphocyte count at 6 and 12 months nor the mean percentage decrease at 6 and 12 months predicted No Evidence of Disease Activity (NEDA-3) status at 1 year, the occurrence of relapses, disease activity on MRI or disability progression.

Conclusions

Our findings suggest that peripheral blood lymphocyte changes are not associated with short-term treatment response and with the rate of infections during fingolimod and dimethyl-fumarate treatment in real-world patients. Higher treatment exposure and a lower baseline absolute lymphocyte count are risk factors for lymphopenia development during fingolimod and dimethyl-fumarate therapy.

中文翻译：

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芬戈莫德和富马酸二甲酯衍生的淋巴细胞减少症与现实生活中的MS人群的短期治疗反应和感染风险无关。

背景

尚未完全了解多发性硬化症中与治疗有关的淋巴细胞减少，药物疗效和感染风险之间的关系。

目的

这项研究的目的是评估在芬戈莫德和富马酸二甲酯治疗的现实生活中的多发性硬化症人群中，淋巴细胞减少是否与短期治疗反应和感染率相关。我们评估了整个患者队列和两个治疗组在6个月和12个月时的基线绝对淋巴细胞计数和淋巴细胞平均百分比降低与治疗反应和12个月内不良事件发生之间的关联。

方法

这是对2011年至2018年间在热那亚大学MS中心接受芬戈莫德和富马酸二甲酯治疗的多发性硬化症患者的回顾性观察性现实世界研究。如果[1，则至少随访12个月的患者符合条件[1 ]他们在基线和开始治疗后12个月进行了扩展的残疾状态量表评估，[2]在基线和12个月后接受了脑磁共振成像，[3]在基线，6和12时可获得绝对淋巴细胞计数几个月。从富马酸二甲酯转变为芬戈莫德的患者，反之亦然。

结果

总共有137位和75位接受芬戈莫德和富马酸二甲酯治疗的患者被纳入分析。与富马酸二甲酯相比，芬戈莫德组治疗的患者在12个月时更容易出现II级和III级淋巴细胞减少（p  <0.001，χ2= 94），并且淋巴细胞平均百分比降低更高（p  <0.001，U  = 540） ）。在6个月（p  = 0.047，比值比= 1.60和p  = 0.014，比值比= 1.1）和12个月（p  = 0.003，比值比= ）时，较多的既往疗法和较低的基线绝对淋巴细胞计数是淋巴细胞减少的预测指标。1.97和p = 0.023，优势比= 1.1）。仅在芬戈莫德治疗的患者中，女性和较高的“扩展残疾状态量表”评分是12个月时淋巴细胞减少的预测指标（p  = 0.006，优势比= 7.58和p  = 0.03，优势比= 1.56）。6和12个月时的绝对淋巴细胞计数或6和12个月时的平均减少百分比均未预测1年时无疾病活动证据（NEDA-3）状态，复发的发生，MRI上的疾病活动或残疾进展。

结论

我们的研究结果表明，在现实世界中，芬戈莫德和富马酸二甲酯治疗期间外周血淋巴细胞的变化与短期治疗反应以及感染率无关。在芬戈莫德和富马酸二甲酯治疗期间，较高的治疗暴露量和较低的基线绝对淋巴细胞计数是形成淋巴细胞减少症的危险因素。