Objective: The field of multiple sclerosis (MS) has seen a tremendous expansion of treatments in the past decade. However, treatment response in individual patients can currently be determined only by waiting for breakthrough disease activity to occur. This highlights a critical need for biomarkers that can predict treatment response and stratify the risk of impeding disease activity before damage is inflicted to the CNS. Here we show that CCR6+CD3+ T-cell surveillance in peripheral blood can be used to discriminate responders and non-responders to dimethyl-fumarate. Methods: A cohort of 101 treatment-naive, dimethyl-fumarate (DMF) treated MS patients and healthy controls was immunophenotyped and then responders and non-responders were determined retrospectively after clinical and radiographic follow up. Receiver operating characteristic (ROC) curve, linear and logistic regression, mixed effects models, and cox proportional hazards were used for the analysis. Results: Among various clinical and immunophenotypic metrics, the percentage of CCR6+CD3+ T-cells was the most significant predictor of impending disease activity. This immunophenotypic metric was able to discriminate responders and non-responders to DMF with an area under the ROC of 0.85 (95% CI: 0.71-0.99), which was higher than that achieved using surrogate metrics for T-helper-1-like T-helper-17 or T-cytotoxic-17 cells. DMF-treated patients with the highest percentage of CCR6+CD3+ T-cells had a significantly higher risk of impending disease activity compared to patients with a low percentage. Interpretation: Changes in CCR6+CD3+ T-cells in the periphery could precede disease activity by many months and potentially serve as an early biomarker of treatment response, at least for DMF. These results have implications for novel personalized treatment strategies in MS.

中文翻译：

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CCR6 + T细胞的免疫监测可预测对富马酸二甲酯的治疗反应：对多发性硬化症个性化治疗策略的影响

目的：在过去的十年中，多发性硬化症（MS）的领域得到了巨大的发展。但是，目前只能通过等待突破性疾病活动的发生来确定单个患者的治疗反应。这突出表明了对生物标记物的迫切需求，这些标记物可以在中枢神经系统受到损害之前预测治疗反应并分层阻止疾病活动的风险。在这里，我们显示，外周血中的CCR6 + CD3 + T细胞监视可用于区分对富马酸二甲酯的反应者和非反应者。方法：对101名未接受过治疗的富马酸二甲酯（DMF）治疗的MS患者和健康对照者进行免疫表型分析，然后在临床和影像学随访中回顾性确定反应者和非反应者。接收者工作特征（ROC）曲线，线性和逻辑回归，混合效应模型和Cox比例风险用于分析。结果：在各种临床和免疫表型指标中，CCR6 + CD3 + T细胞的百分比是即将发生疾病活动的最重要预测因子。该免疫表型指标能够区分ROC下面积为0.85（95％CI：0.71-0.99）的DMF的反应者和非反应者，这比使用T-helper-1-like T的替代指标所获得的要高。 -helper-17或T-cytotoxic-17细胞。与CCR6 + CD3 + T细胞百分比最高的DMF治疗患者相比，低百分比患者具有更高的即将发生疾病活动的风险。解释：外周CCR6 + CD3 + T细胞的变化可能在疾病活动之前提前数月，并且可能至少对于DMF而言可作为治疗反应的早期生物标记。这些结果对MS中新颖的个性化治疗策略具有影响。